Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([CH2:25][S:26][CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)([CH2:25][S:26]([CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:39])[F:40])[CH:29]=2)=[O:6])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CSCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CS(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
m-Chloroperoxybenzoic acid (80-90%, 0.4 g) was added to a solution of Example 3 (1 g) in dichloromethane (20 ml) containing potassium carbonate (0.5 g), at 0° C. The solution was stirred for 30 min, diluted with dichloromethane (20 ml), washed with water, dried (Na2SO4) and removal of the solvent in vacuo gave an off white solid. The solid was recrystallised from diethyl ether/petrol giving 1-t-butoxycarbonyl-4-phenyl-4-[3,5-bis(trifluoromethyl)benzylsulphinylmethyl]piperidine as a white solid, m.p. 123°-134° C., m/z (CI+) 567 (M+ +NH4+). Found: C, 57.00; H, 5.18; N, 2.36. C26H29NO3SF6 requires C, 56.82; H, 5.32; N, 2.55.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:16]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
To a solution of 4-amino benzoic acid (20.0 g, 0.14 mol) in methanol (400 mL) was added conc. sulphuric acid (40 mL). The reaction mass was stirred at RT for 6-7 h. The reaction mass was quenched with water and basified with NaHCO3 and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 15.0 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.72 (s, 3H), 5.96 (br s, 2H), 6.55 (d, J=8.1 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H) MS (m/z): 152.21 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[OH-].[K+]>CS(C)=O>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)=[CH:8][C:6]=1[NH2:7])([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: c1cc[nH]c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cc(-n2cccc2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 5-chloro-2nitroaniline (1.73 g, 10 mmol), pyrrole (2.8 mL, 40 mmol) and KOH (85%, 990 mg, 15 mmol) in DMSO (8.6 mL) at 80° C. for 24 h according to the general procedure E (method a). Obtained as a brown solid (1.52 g).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([N+:19]([O-:21])=[O:20])[CH:6]=1)=[O:4].COC1C=CC(CC(C)NCC2C=CC=CC=2)=CC=1.B.O1CCBN1.N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O>>[Br:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([N+:19]([O-:21])=[O:20])[CH:6]=1)[OH:4]
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: B
Agent: B1CCON1
Agent: COc1ccc(CC(C)NCc2ccccc2)cc1
Product: O=[N+]([O-])c1cc(C(O)CBr)ccc1OCc1ccccc1

Procedure:
from 2-bromo-4′-benzyloxy-3′-nitroacetophenone and 4-methoxy-α-methyl-N-(phenylmethyl)benzeneethanamine comprising the sequential steps of: (a) reducing 2-bromo-4′-benzyloxy-3′-nitroacetophenone with about one equivalent of a borane reagent in the presence of a catalytic amount of a single enantiomer of an oxazaborolidine derived from cis 1-amino-2-indanol to produce substantially enantiomerically pure α-(bromomethyl)-4-phenylmethoxy-3-nitrobenzenemethanol (FBH); (b) reducing the α-(bromomethyl)-4-phenylmethoxy-3-nitrobenzenemethanol with hydrogen in the presence of a noble metal catalyst to produce an aniline FBH2; (c) formylating the aniline with formic acid and acetic anhydride to produce a compound of formula FBH3:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([F:10])[CH:4]=1)#[N:2].CC(N=NC(C#N)(C)C)(C#N)C.[Br:23]N1C(=O)CCC1=O>ClCCCl>[Br:23][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[F:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: N#Cc1ccc(CBr)c(F)c1
Temperature: 72 °C

Procedure:
1,2-Dichloroethane (151 kg) was charged to a suitable vessel along with 4-cyano-2-fluorotoluene (24 kg) and AIBN (2 kg). The mixture was heated to 70-74° C. Once the batch temperature reached 70° C., N-bromosuccinimide (47.4 kg) was added in portions at the rate of 12 kg/h, maintaining the temperature at 70˜74° C. (it is important to control addition rate to avoid exothermic reaction). The mixture was sampled via GC detection after 24 kg of N-bromosuccinimide was added, and the reaction was heated at 70-74° C. until complete reaction was observed. The mixture was cooled to 0-5° C. and allowed to stand for 2 additional hours. The mixture was filtered, and the cake was washed with MTBE (24 kg). The filtrate was washed with water (3×65 kg). The organic layer was dried with sodium sulfate (10.3 kg) for 6 hours, filtered and the cake was washed with MTBE (24 kg). The solution was evaporated under reduced pressure, ethanol (12 kg) was added and the mixture was heated to 40-45° C., then cooled slowly to 0-5° C. while stirring to crystallize. The mixture was filtered and the cake was washed with cold ethanol (5 kg). The crude solid was recrystallized from petroleum ether, filtered and washed with petroleum ether (10 kg), giving the title compound 4-(bromomethyl)-3-fluorobenzonitrile as an off white solid (21 kg, 55% yield). 1H NMR (300 MHz, CDCl3) δ ppm 4.46-4.50 (m, 2H) 7.36 (dd, J=8.85, 1.32 Hz, 1H) 7.44 (dd, J=7.91, 1.32 Hz, 1H) 7.52 (dd, J=7.91, 7.16 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ ppm 23.65 (d, J=4.60 Hz, 1C) 113.76 (d, J=9.77 Hz, 1C) 117.09 (d, J=2.87 Hz, 1C) 119.44 (d, J=24.71 Hz, 1C) 128.44 (d, J=4.02 Hz, 1C) 130.66-130.81 (s, 1C) 130.81-131.06 (s, 1C) 132.18 (d, J=3.45 Hz, 1C) 159.86 (d, J=254.03 Hz, 1C). IR: (KBr) 3088, 3077, 3040, 2982, 2250, 1571, 1508, 1439, 1248 cm−1.
Reaction SMILES: [CH:1]([C:3]([CH2:5][CH3:6])=[O:4])=[CH2:2].[N+:7]([CH3:10])([O-:9])=[O:8].C[O-].[Na+]>CO>[N+:7]([CH2:10][CH2:2][CH2:1][C:3](=[O:4])[CH2:5][CH3:6])([O-:9])=[O:8]
Reactant: C=CC(=O)CC
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)CCC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To ethyl vinyl ketone (90.1 g, 1285 mmol) in 550 mL of methanol and 556 mL (10282 mmol) of nitromethane at −40° C. was added as a steady stream 84 mL (ca. 386 mmol) of 25% methanolic NaOMe. The resultant pale yellow slurry was allowed to warm to rt over 5 h, and was stirred overnight. The mixture was quenched with 300 mL of saturated NH4Cl followed by 250 mL water and 250 mL brine. The mixture was then extracted with CH2Cl2 (250 mL×4). The extracts were treated with MgSO4 and decolorizing carbon, filtered and concentrated to yield 154 g (92%) pale yelow liquid: 1H NMR: δ 4.43 (t, J=6.6 Hz, 2H), 2.56 (t, J=6.6 Hz, 2H), 2.44 (t, J=7.5 Hz, 2H), 2.25 (m, 2H), 1.06 (t, J=7.5 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([NH:15]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[C:9]([OH:13])=[C:8]([Br:14])[CH:7]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([I:32])[CH:27]=1>>[NH2:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]([Br:14])[C:9]([O:13][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([I:32])[CH:27]=2)=[C:10]([Br:12])[CH:11]=1)[C:3]([OH:2])=[O:23]
Reactant: COC(=O)C(Cc1cc(Br)c(O)c(Br)c1)NC(=O)OC(C)(C)C
Reactant: BrCc1cccc(I)c1
Product: NC(Cc1cc(Br)c(OCc2cccc(I)c2)c(Br)c1)C(=O)O
Yield: 38 %

Procedure:
Methyl-2-tert-butoxycarbonylamino-3-(3,5-dibromo-4-hydroxyphenyl)propionate (0.035 mmol) was coupled with 1-bromomethyl-3-iodobenzene and hydrolyzed using the method described in “General procedure for the preparation of Examples 8-22”. This gave 38% yield of 2-amino-3-[3,5-dibromo-4-(3-iodobenzyloxy)phenyl]propionic acid. LC/MS (electrospray): m/z 554 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([S:29](Cl)(=[O:31])=[O:30])[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26]>O1CCOCC1.CN(C=O)C.C(OCC)(=O)C>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([S:29]([O:1][C:2]2[CH:7]=[CH:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=2)(=[O:30])=[O:31])[CH:20]=[C:19]([O:18][CH3:17])[C:24]=1[O:25][CH3:26]
Reactant: COc1cc(S(=O)(=O)Cl)cc(OC)c1OC
Reactant: Cn1ccc(O)cc1=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(S(=O)(=O)Oc2ccn(C)c(=O)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.9 %

Procedure:
A solution of 4-hydroxy-1-methyl-1H-pyridin-2-one ([40357-87-7], 44.9 mg, 0.358 mmol) in dioxane (2 mL) and DMF (1 mL) was treated with triethylamine (0.15 mL) and 3,4,5-trimethoxybenzenesulfonylchloride (97.1 mg, 0.358 mmol), stirred for 48 hours at room temperature, diluted with ethyl acetate, washed with 1.1M NaHSO4, dried (MgSO4), filtered and concentrated. Chromatography of the concentrate on silica gel with 40% ethyl acetate/hexane provided 47 mg of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[CH3:26][C:27]([CH3:29])=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:27]([CH3:29])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:6][CH:5]=1
Reactant: CC(C)=O
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3N)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Temperature: 10 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
4-[1-(3-Amino-2-pyridyl)piperazin4-yl-carbonyl]benzoic acid methyl ester (4 g) was dissolved in methanol (90 ml) and then, acetone (2 ml), acetic acid (5 ml) and sodium cyanoborohydride (2.4 g) were added at 10° C. in order. The reaction mixture was stirred at 10° C. for 4 hours and heated to 20~25° C. and stirred for 1 hour. The solution was neutralized (pH=~8) by addition of aqueous 3N-sodium hydroxide, and excess of water was added gradually for precipitation. The mixture was stirred for 1 hour, filtered, washed with water, methanol and ether in order and dried to give 3.5 g (yield: 78%) of the desired compound as white crystal.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:18]=[C:17]([C:19]4[N:23]([CH:24]([CH3:26])[CH3:25])[C:22]([CH3:27])=[N:21][CH:20]=4)[C:16]([F:28])=[CH:15][N:14]=3)=[CH:8][CH:7]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[F:28][C:16]1[C:17]([C:19]2[N:23]([CH:24]([CH3:25])[CH3:26])[C:22]([CH3:27])=[N:21][CH:20]=2)=[N:18][C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([N:4]3[CH2:3][CH:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:5]3)=[CH:11][CH:10]=2)=[N:14][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC(N)C4)cc3)ncc2F)n1C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC(NS(C)(=O)=O)C4)cc3)ncc2F)n1C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of N-[4-(3-aminoazetidin-1-yl)phenyl]-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (Example 140; 110 mg, 0.29 mM) and triethylamine (44 μl, 0.317 mM) in dry DCM (4.0 ml), methanesulphonyl chloride (25 μl, 0.317 mM) was added. The reaction was stirred at room temperature under nitrogen for 24 hours. The reaction was filtered and the filtered solid washed with DCM. This solid which was pure product was retained. The filtrate was taken and more DCM added. The solution was washed in turn with water (twice), saturated sodium chloride and then dried with anhydrous sodium sulphate, filtered and evaporated. The product so obtained was combined with the 1st batch of product and both were triturated with ether, filtered, washed with ether and dried to give the title compound as a yellow solid. NMR 1.4 (d, 6H), 2.6 (s, 3H), 2.9 (s, 3H), 3.55 (t, 2H), 4.13 (t, 2H), 4.25 (m, 1H), 5.37 (m, 1H), 6.4 (d, 2H), 7.33 (d, 2H), 7.58 (d, 1H), 7.75 (d, 1H), 8.5 (d, 1H), 9.22 (s, 1H); m/z 460.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].CC(O)=O.[Br:18]Br.C([O-])([O-])=O.[Na+].[Na+]>O>[Br:18][C:10]1[C:11]([CH3:13])=[CH:12][C:3]([O:2][CH3:1])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C)cc1OC
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c(C)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A 250 ml 3-neck RBF fitted with a magnetic stirring bar, a thermometer and a dropping funnel was charged with methyl 2-methoxy-4-methylbenzoate 10b (10 g, 0.056 mol) and AcOH (70 mL). To this solution bromine (3 mL, 0.06 mol) was added drop-wise while maintaining the reaction temperature below 25° C. When bromine addition was complete, the reaction mixture was stirred at RT for 2 hours, then poured into 600 mL of cold water and the pH was adjusted to 8-9 with Na2CO3. The crude product was extracted with Et2O (3×300 mL), the combined extracts washed with brine, dried over sodium sulfate and the solvent was removed under vacuum to give methyl 5-bromo-2-methoxy-4-methylbenzoate as an orange oil, which solidified on standing (14.3 g, 99% yield, >90% purity by 1H NMR).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[N:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:11]([CH2:24][CH2:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[N:46]1([CH2:52][CH2:53][CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][NH:55]2)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C)C=O>[N:46]1([CH2:52][CH2:53][CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][N:55]2[CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:14]3[N:13]=[C:12]([CH2:15][O:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[N:11]([CH2:24][CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]4)[C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCCCBr)cccc32)CC1
Reactant: C1CCN(CCC2CCCCN2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCCCN4CCCCC4CCN4CCCCC4)cccc32)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 4-[3-bromopropoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (77 mg, 0.124 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (51.3 mg, 0.37 mmol, 2 eq) and 2-[2-(piperidin-1-yl)ethyl]piperidine (0.19 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to yield an oily crude product which was purified by flash chromatography to provide the title product.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([N:13]([CH2:21][CH3:22])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH3:12]>>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:20][C:17]1[CH:16]=[CH:15][C:14]([N:13]([CH2:21][CH3:22])[CH2:11][CH3:12])=[CH:19][CH:18]=1
Reactant: Clc1nc2ccccc2s1
Reactant: CCN(CC)c1ccc(N)cc1
Product: CCN(CC)c1ccc(Nc2nc3ccccc3s2)cc1

Procedure:
The title compound was synthesised from 2-Chloro-benzothiazole (commercially available) and N,N-Diethyl-p-phenylenediamine (commercially available) according to the procedure described for Example 1a) above. MS (m/e): 298.2 (MH+, 100%).
Reaction SMILES: [N+:1]([C:4]([CH3:16])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)([O-])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OC(=O)C)C>C1COCC1.CCCCCC>[CH3:16][CH:4]([NH2:1])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:10][CH:11]=1
Reactant: CC(=Cc1ccc(C(F)(F)F)cc1)[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(N)Cc1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 99.8 %

Procedure:
1-(2-Nitro-propenyl)-4-trifluoromethyl-benzene (I-43a: 2.85 g, 12.33 mmol) was reacted with LiAlH4 (1.87 g, 49.31 mmol) in dry THF (40 mL). The resulting mixture was refluxed for 5 hours at 70° C. The reaction was monitored by TLC (20% ethylacetate in hexane). The reaction mass was cooled to 0° C., quenched with 10% NaOH solution (2 mL) and stirred for 20 minutes. The precipitated solid was filtered, washed with DCM and concentrated under reduced pressure to afford 2.5 g of the crude product which was used for the next step without further purification. LCMS: m/z=204.1 (M+1)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=O)[NH:14][CH2:15][C:16]1([OH:23])[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=[O:5])[CH3:2].Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][C:16]1([OH:23])[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCC1(O)CCN(C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)c[nH]c1CCNCC1(O)CCN(C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 104.1 %

Procedure:
A stirred solution of 2-{[(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-carbamoyl]-methyl}-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (5.937 g, 17.62 mmol) in tetrahydrofuran (50 ml) was added slowly with another portion of 1M borane-tetrahydrofuran complex in tetrahydrofuran (52.1 ml, 52.1 mmol) under an argon atmosphere. Upon completion of the addition, the mixture was stirred for 1.5 hours at room temperature, heated to reflux for 1.5 hours and stirred at room temperature overnight. The resulting mixture was added with 1M borane-tetrahydrofuran complex in tetrahydrofuran (36 ml, 36 mmol) and stirred at room temperature for 0.5 hour, heated to reflux for another 5 hours. The mixture was added dropwise with 2 N hydrochloric acid in an ice-water bath. The resulting mixture was adjusted to pH 8 with 2N aqueous sodium hydroxide solution and distilled under reduced pressure. The residue was extracted with ethyl acetate (80 ml×8). The combined extracts were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-{2-[(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-amino]-ethyl}-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (5.931 g) as an orange solid which was used as such.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41](O)=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:56]([S:59]([NH2:62])(=[O:61])=[O:60])([CH3:58])[CH3:57].C1CCN2C(=NCCC2)CC1>C1COCC1.CO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41]([NH:62][S:59]([CH:56]([CH3:58])[CH3:57])(=[O:61])=[O:60])=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)S(N)(=O)=O
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)S(=O)(=O)NC(=O)C12CC1C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(Oc3nccc4ccccc34)CC1C(=O)N2
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.6 %

Procedure:
14-tert-butoxycarbonylamino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid (67 mg, 0.10 mmol) was dissolved in 5 mL of THF and treated with CDI (21 mg, 0.13 mmol). (Care was taken to avoid moisture by using oven dried glassware and maintaining a dry N2 atmosphere.) After refluxing the reaction mixture for one hour, it was cooled to rt and treated sequentially with isopropylsulfonamide (16 mg, 0.13 mmol) and DBU (20 mg, 0.13 mmol). After stirring for 24 h at rt, the THF was removed by rotary evaporation. The residue was partitioned between ethyl acetate and pH 4 buffer. The organic phase was dried (MgSO4) and concentrated in vacuo to give the crude product. Flash chromatography (1–5% MeOH/methylene chloride) gave 50 mg (71%) of the desired product. Further purification by preparative HPLC (YMC ODS-A, S5, 20×100 mm, gradient: 60% to 100% B) gave 30 mg (43%) of [18-(isoquinolin-1-yloxy)-2,15-dioxo-4-(propane-2-sulfonylaminocarbonyl)-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white powder: 1H NMR (300 MHz, CD3Cl3) δ 1.22 (S, 9H), 1.31 (d. J=6.6 Hz, 3H), 1.41 (d, J=6.9 Hz, 3H), 1.20–1.96 (m, 11H), 2.30 (q, J=8.4 Hz, 1H), 2.56 (m, 1H), 2.69 (m, 2H), 3.69 (m, 1H), 4.03 (m, 1H), 4.29 (m, 1H), 4.62 (m, 2H), 4.97–5.06 (m, 2H), 5.68 (q, J=9.5 Hz, 1H), 5.91 (s, 1H), 6.76 (s, 1H), 7.23 (m, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.63 (t, J=8.1 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.97 (d, J=5.9 Hz, 1H), 8.17 (d, J=8.1 Hz, 1H), 9.89 (s, 1H). LC-MS (Method A, retention time: 3.79 min), MS m/z 670 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CCC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(CCC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To 20 ml of the solution of 0.14 g of methyl 4-[3-(4-chlorobenzenesulfonamido)-3-(3-pyridyl)propyl}benzoate in methanol-1,4 dioxane (1:1) was added 5 ml of aqueous 2N sodium hydroxide solution, and stirred at room temperature overnight. After completion of the reaction followed by neutralization with 5 ml of 2N hydrogen chloride, the crystalline deposited was filtered to obtain 72 mg of 4-[3-(4-chlorobenzenesulfonamido)-3-(3-pyridyl)propyl]benzoic acid. The spectrometric data supports the structure of [37] as follows.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[C@@H:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:6]1)=[N+]=[N-]>CO>[OH:9][CH:5]1[CH2:4][NH:1][C:8](=[O:10])[CH:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CN=[N+]=[N-])OC1=O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CC(O)CNC1=O
Reaction time: 4 h
Yield: 93.8 %

Procedure:
To a stirred, argon-purged solution of compound 1B, (7.20 g, 28.1 mmol) in 150 mL of methanol at room temperature was added 10% Pd-on-carbon (1.0 g). The reaction mixture was purged, evacuated twice with argon and stirred under a hydrogen balloon near atmospheric pressure for 4 h. The slurry was purged with argon, filtered through a 0.45μ nylon filter and the filtrate evaporated to give the title compound (6.07 gm, 94%) as a gray solid, 95:5 diastereomeric mixture by HPLC. MS [M+Na]+: found 253.