Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([S:20]([CH:23]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]4)(=[O:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:35])=[N:6][CH:7]=1.[ClH:36].CCO>C(Cl)Cl>[ClH:36].[F:35][C:9]1[CH:10]=[C:11]([C:14]2[C:15]([S:20]([CH:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)(=[O:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:12]=[CH:13][C:8]=1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ncccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: Nc1cnc(-c2ccc(-c3cccnc3S(=O)(=O)C3CCNC3)cc2F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution consisting of tert-butyl 3-(3-(4-(5-aminopyrazin-2-yl)-3-fluorophenyl)pyridin-2-ylsulfonyl)pyrrolidine-1-carboxylate (150 mg, 0.300 mmol) and DCM (10 mL) was added HCl/EtOH (5 N, 10 mL). The mixture was stirred at rt for 2 h, concentrated to dryness, and the resultant residue subjected to HPLC purification to give the title compound (67 mg, 52%). MS (ESI): mass calcd. For C19H18FN5O2S.HCl 399.12; m/z found, 400.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 9.79 (br s, 1H), 9.42 (br s, 1H), 8.79 (d, J=4.6, 1H), 8.51-8.30 (m, 1H), 8.20-7.78 (m, 3H), 7.51-7.02 (m, 3H), 4.81 (dd, J=14.1, 7.6, 1H), 3.72 (s, 1H), 3.49-3.14 (m, 3H), 2.44-2.20 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[C:15]([N+:22]([O-])=O)[CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl-].[NH4+]>C(O)(C)C.O.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[C:15]([NH2:22])[CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cccc2ccc(-c3cc(F)cc(C(F)(F)F)c3)nc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: Nc1cccc2ccc(-c3cc(F)cc(C(F)(F)F)c3)nc12
Temperature: 90 °C
Yield: 49.3 %

Procedure:
Crude 2-(3-fluoro-5-(trifluoromethyl)phenyl)-8-nitroquinoline (2.78 mmol) was taken up in isopropyl alcohol (120 mL) and ammonium chloride (150 mg, 2.8 mmol) in water (20 mL) was added. The mixture was heated to 90° C., iron powder (550 mg, 9.85 mmol) was added and the reaction was continued stirring at 90° C. 18 hours. The reaction mixture was filtered over celite and the celite cake was washed with ethyl acetate (150 mL). The filtrate was concentrated and the residue was taken up in 1N aqueous NaOH (80 mL) and extracted with ethyl acetate (3×25 mL). The organic layers were combined, washed with brine, dried (MgSO4), and concentrated. The crude material was purified by flash chromatography (a gradient of 0 to 100% ethyl acetate in pentane) to obtain 2-(3-fluoro-5-(trifluoromethyl)phenyl)quinolin-8-amine (0.42 g, 1.37 mmol, 49% yield over two steps).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].[Br:19]Br>ClCCCl>[Br:19][C:12]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:18])[C:6]3([CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH2:17][CH2:16][CH2:15][C:13]=1[C:14]=23
Reactant: BrBr
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Solvent: ClCCCl
Product: O=C1Nc2ccc(Br)c3c2C1(CCCCBr)CCC3
Temperature: -20 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A 20 ml portion of 1,2-dichloroethane solution containing 0.50 g (1.62 mmol) of 2a-(4-bromobutyl)-2a,3,4,5-tetrahydrobenz[cd]-indole-2(1H)-one was cooled to −20° C. and mixed with 0.10 ml (1.94 mmol) of bromine. The reaction solution was stirred at −20° C. for 1 hour, extracted with chloroform and then washed with saturated sodium thiosulfate aqueous solution and saturated sodium bicarbonate aqueous solution in that order. After drying (Na2SO4), the solvent was evaporated under a reduced pressure, and the thus obtained residue was re-precipitated from ethyl acetate-hexane to obtain 0.54 g of the title compound (86% in yield).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][OH:14])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]=2C)[N:6]=1)(=O)=O.[C-:26]#[N:27].[Na+].C(OCC)(=O)C>CS(C)=O>[C:21]([C:17]1[CH:16]=[C:15]([C:7]2[CH:8]=[C:9]([CH2:11][CH2:12][CH2:13][OH:14])[N:10]=[C:5]([C:26]#[N:27])[N:6]=2)[CH:20]=[CH:19][CH:18]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: [C-]#N
Reactant: Cc1c(-c2cc(CCCO)nc(S(C)(=O)=O)n2)cccc1C(C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(-c2cc(CCCO)nc(C#N)n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.7 %

Procedure:
To a stirring solution of 2-methylsulphonyl-4-(3-hydroxypropyl)-6-(3-tert-butyl-methyl-phenyl)-pyrimidine (4.6 g) in DMSO (120 ml) at room temperature was added sodium cyanide (647 mg). The resulting suspension was stirred at room temperature for 3 hours. After adding ethyl acetate (200 ml), the mixture was then washed with water (100 ml×3). Organic layer was dried over MgSO4 and concentrated in vacuo, the residue was columned on silica gel using Petrol and EtOAc as eluent to give 4-(3-tert-butyl-phenyl)-6-(3-hydroxy-propyl)-pyrimidine-2-carbonitrile (4.0 g) as an oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[N:23]=[C:22]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[N:21]=[C:20]([NH:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([O:41][CH2:42][CH2:43][CH2:44][Cl:45])[CH:32]=2)[N:19]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[N:23]=[C:22]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[N:21]=[C:20]([NH:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([O:41][CH2:42][CH2:43][CH2:44][Cl:45])[CH:32]=2)[N:19]=1
Reactant: COC(=O)c1ccc(Nc2nc(NCCCCCCCCNC(=O)OC(C)(C)C)nc(OCC(F)(F)F)n2)cc1OCCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(Nc2nc(NCCCCCCCCN)nc(OCC(F)(F)F)n2)cc1OCCCCl
Reaction time: 1 h
Yield: 120.4 %

Procedure:
methyl 4-((4-((8-((tert-butoxycarbonyl)amino)octyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-2-(3-chloropropoxy)benzoate (280 mg, 0.422 mmol) was dissolved in TFA (1 mL, 12.98 mmol) and DCM (2 mL). The reaction was stirred for 1 h. The solvent was removed under vacuum to give 286 mg (100%) methyl 4-(4-(8-aminooctylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-2-(3-chloropropoxy)benzoate, TFA which was used in the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:19])([F:20])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[N:35][CH:34]=[CH:33][N:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cnccn3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M82) (0.36 g, 0.66 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (163 mg, 58%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(O)C.[CH3:14][S-:15].[Na+]>O>[CH3:14][S:15][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: C[S-]
Reactant: O=C(CBr)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of 21.4 g of bromoacetophenone is added to 90 ml of ethanol at 0° C., followed by slow addition of a solution of 5 g of sodium thiomethoxide in 25 ml of water. The reaction medium is stirred for one hour at 0° C. and then for 2 hours at room temperature, and is subsequently poured on to 500 ml of ice-water and extracted with twice 200 ml of ethyl ether. The ether phases are combined and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulphate and then evaporated to dryness. The residue is distilled to give 2-(methylthio)acetophenone.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:29])[CH:3]=1.[C:30]1([CH2:36][C:37]([N:39]=[C:40]=[O:41])=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.CCCCCC>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:19]1[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:27]=[CH:28][C:2]([NH:1][C:40]([NH:39][C:37](=[O:38])[CH2:36][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:41])=[CH:3][C:4]=3[F:29])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:17][CH2:18]1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(2-dimethylaminoethyl)piperazin-1-yl]carbonylamino}pyridine (87.4 mg) in tetrahydrofuran (4.5 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 2.2 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the titled compound (82 mg, 67%) as white powder.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:28]([CH:29]3[CH2:31][CH2:30]3)=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([F:32])[CH:21]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([S:35]([NH2:38])(=[O:37])=[O:36])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCCl>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:28]([CH:29]3[CH2:30][CH2:31]3)=[CH:27][C:23]([C:24]([NH:38][S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])=[O:26])=[C:22]([F:32])[CH:21]=2)[CH2:15]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Reactant: CCS(N)(=O)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Temperature: 35 °C
Reaction time: 1 h

Procedure:
A mixture of 4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid (35.6 mg), ethanesulfonamide (22.5 mg), HBTU (41.9 mg), and DIPEA (0.073 mL) in DCE (0.83 mL) was heated at 35° C. for 16 hr then at 55° C. for 1 hr. More ethyanesulfonamide (9 mg) was added. Heating continued for 1 hr. Added with 1M NaH2PO4, the contents were extracted with DCM (2×). The combined extracts were dried (Na2SO4). The crude was purified with HPLC (23 mg). LCMS (Method D): RT=5.08 min, m/z: 523.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 7.49-7.36 (m, 4H), 7.28 (dd, J=8.3, 6.8 Hz, 4H), 7.22-7.09 (m, 3H), 6.95 (d, J=12.8 Hz, 1H), 4.49 (s, 1H), 4.21 (d, J=6.2 Hz, 2H), 3.47-3.36 (m, 2H), 3.02 (s, 2H), 2.93-2.81 (m, 1H), 2.10-1.99 (m, 1H), 1.22 (t, J=7.5 Hz, 3H), 0.95-0.82 (m, 2H), 0.71-0.61 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:40]=[CH:39][C:7]([O:8][CH2:9][CH:10]([OH:38])[CH2:11][O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22]([C:24]3[N:28](CC4C=CC(OC)=CC=4)[N:27]=[N:26][N:25]=3)=[O:23])[C:16]([CH3:20])=[CH:17][C:18]=2[Br:19])=[C:6]([CH2:41][CH2:42][C:43]([F:46])([F:45])[F:44])[C:5]=1[OH:47])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:1]([C:4]1[CH:40]=[CH:39][C:7]([O:8][CH2:9][CH:10]([OH:38])[CH2:11][O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22]([C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[O:23])[C:16]([CH3:20])=[CH:17][C:18]=2[Br:19])=[C:6]([CH2:41][CH2:42][C:43]([F:45])([F:46])[F:44])[C:5]=1[OH:47])(=[O:3])[CH3:2]
Reactant: COc1ccc(Cn2nnnc2C(=O)Nc2cc(OCC(O)COc3ccc(C(C)=O)c(O)c3CCC(F)(F)F)c(Br)cc2C)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc(OCC(O)COc2cc(NC(=O)c3nnn[nH]3)c(C)cc2Br)c(CCC(F)(F)F)c1O

Procedure:
A solution of 6.2 g of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propoxy}-4-bromo-6-methyl-phenyl}}-1-(4-methoxybenzyl)-tetrazole-5-carboxamide in 130 ml of trifluoroacetic acid and 14 ml of anisole is refluxed for 30 minutes. The reaction mixture is concentrated under reduced pressure, about 200 ml of ether and 300 ml of petroleum ether are added and the crystals are filtered off. N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propoxy}-4-bromo-6-methyl-phenyl}}-1H-tetrazole-5-carboxamide is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH:36][C@H:37]([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34]>>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[C:28]([S:33]([NH:36][C@H:37]([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: C[C@H](CO)NS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)OC1(C)C
Product: C[C@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3[nH]ccc3c2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine and (R)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide. MS (ESI): mass calcd. for C22H20FN3O3S, 425.12; m/z found, 426.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.65 (s, 1H), 8.30-8.19 (m, 2H), 7.93-7.84 (m, 1H), 7.69-7.61 (m, 1H), 7.61-7.53 (m, 1H), 7.44-7.31 (m, 4H), 7.27 (d, J=7.8, 1H), 6.56-7.47 (m, 1H), 6.07 (d, J=6.5, 1H), 3.57 (t, J=7.0, 1H), 3.49-3.32 (m, 2H), 2.41 (s, 1H), 1.04 (d, J=6.4, 3H).
Reaction SMILES: Cl.CS([O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:31])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:18][CH:17]=3)=[C:13]([C:32]3[CH:37]=[CH:36][C:35]([O:38]S(C)(=O)=O)=[CH:34][CH:33]=3)[S:12][C:11]=2[CH:43]=1)(=O)=O.[OH-].[Na+]>CC(C)=O>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:31])[C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:20][CH:21]=3)=[C:13]([C:32]3[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=3)[S:12][C:11]=2[CH:43]=1
Reactant: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12

Procedure:
A 4 g. portion of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl) -3-[4-(2-piperidinoethoxy)-benzoyl]benzo[b]thiophene, hydrochloride, was combined with 100 ml. of denatured alcohol and 10 ml. of 5 N sodium hydroxide, and stirred under reflux for 1.5 hours under a nitrogen atmosphere. The reaction mixture was then evaporated to dryness under vacuum, and the residue was dissolved in 200 ml. of water and washed with 300 ml. of diethyl ether. The water layer was degassed under vacuum, and then nitrogen was bubbled through it to remove all traces of ether. The mixture Was then acidified with 1 N hydrochloric acid, and then made basic with excess sodium bicarbonate. The precipitate Was collected by filtration and washed with cold water to obtain 2.4 g. of crude product. It was purified on a 2×30 cm. column of silica gel, eluting first with 700 ml. of 55 methanol in chloroform, followed by 1 liter of 10% methanol in chloroform. The impurities came off first, and the product-containing fractions were combined and evaporated under vacuum to obtain 1.78 g. of yellow oil. The oil was dissolved in 6 m. of acetone, seeded and chilled in a freezer to obtain 1.2 g. of purified product, m.p. 143°-147° C. The identity of the product was confirmed as follows:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C1C(=O)N([Br:23])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC1C=CC=CC=1.CC(=O)OCC>[Br:23][CH2:15][C:12]1[CH:13]=[CH:14][C:3]2[C:2]([Cl:1])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[S:5][C:4]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sc2cc(C)ccc2c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: COC(=O)c1sc2cc(CBr)ccc2c1Cl
Yield: 68.6 %

Procedure:
2.5 g (10.4 mmol) of 3-chloro-2-methoxycarbonyl-6-methylbenzo[b]thiophene (prepared according to J. Org. Chem. 41, 3399 (1976)) are boiled under reflux in 150 ml of chlorobenzene with 1.87 g of NBS and 420 mg of dibenzoyl peroxide for 5 h. After distilling off the chlorobenzene in a rotary evaporator, the residue obtained is taken up in EA, and the EA solution is washed with satd. NaHCO3 solution, 10% strength Na2SO3 solution and satd. NaCl solution, dried over Na2SO4 and concentrated. Chromatography on SiO2 using EA/Hep 1:20 yields 2.28 g of the title compound.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].[F:13][C:14]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:15]=1[CH2:16]Br>C(O)C>[F:13][C:14]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:15]=1[CH2:16][S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Sc1nc2ccccc2s1
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Fc1c(F)c(F)c(CSc2nc3ccccc3s2)c(F)c1F
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
To a slurry of 1.67 g of the 2-mercaptobenzothiazole in 18 ml of hot 95% ethanol was added 0.4 g of sodium hydroxide. After all materials had dissolved, the mixture was added to 2.79 g of 2,3,4,5,6-pentafluorobenzyl bromide. The mixture was stirred at 30°-32° C. for 1 minute, then poured into 75 ml ice-water. The product precipitated, was filtered and dried to yield 3.21 g, mp 58°-59.5° C. Recrystallization from aqueous ethanol yielded 2.19 g, mp 51°-53° C.
Reaction SMILES: [N:1]1([C:6]2[CH:39]=[CH:38][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[OH:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:40][O-:41].[Na+]>C1(C)C=CC=CC=1>[N:1]1([C:6]2[CH:39]=[CH:38][C:9]([CH2:10][C:11]3[C:12]([O:41][CH3:40])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[OH:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C[O-]
Reactant: OC(c1ccc(Cl)cc1)(c1cccnc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cccnc3)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 105 °C

Procedure:
(3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloroquinolin-6-yl)(4-chlorophenyl)(pyridin-3-yl)methanol (61.9 mg, 0.108 mmol, Intermediate 37) and sodium methoxide (0.0313 g, 0.579 mmol) were charged to a microwave vial with dry toluene (0.57 mL) and heated to 105° C. for 4 hours. The mixture was allowed to cool to room temperature, then filtered through Celite® and rinsed with dichloromethane. The filtrate was concentrated to dryness and purified by reverse-phase chromatography (acetonitrile/H2O+0.05% TFA). The isolated product fractions were basified with saturated aqueous sodium bicarbonate, extracted with DCM, dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.46 (d, J=4.0 Hz, 1H), 8.02 (d, J=1.9 Hz, 1H), 7.84 (dd, J=2.5, 0.5 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.68-7.63 (m, 2H), 7.56-7.52 (m, 2H), 7.49 (dd, J=8.8, 2.2 Hz, 1H), 7.33 (dd, J=6.5, 4.6 Hz, 2H), 7.31-7.27 (m, 2H), 7.25-7.20 (m, 3H), 6.42 (dd, J=2.4, 1.8 Hz, 1H), 4.29 (s, 2H), 4.08 (s, 3H); MS m/e 567.2 [M+H]+.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].C(O[C:8](=[O:18])[CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C>>[CH2:11]([N:10]1[CH2:9][C:8](=[O:18])[NH:3][C:2]1=[S:1])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: N#C[S-]
Agent: [NH4+]
Product: O=C1CN(Cc2ccccc2)C(=S)N1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
Ammonium thiocyanate (47.27 g) and N-benzylglycine ethyl ester (40.0 g) were fused together at 140° C. for 4 hours. The deep red solution was allowed to cool to room temperature and the solid residue washed with ethanol/water (1:1) (200 ml). The solid was collected by filtration, washed with ethanol/water (1:1) (5×200 ml) and with diethyl ether (3×100 ml) to afford 1-benzyl-2-thiohydantoin (24.72 g), m.p. 150°-152° C.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C1C=CC=CC=1>[Cl-].[Zn+2].[Cl-].O>[C:1]1(=[N:7][CH:13]2[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: NC1C=CCCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: c1ccccc1
Product: C1=CC(N=C2CCCCC2)CCC1
Yield: 69.9 %

Procedure:
A mixture of 2-cyclohexenylamine (9.7 g, 0.1 mole), cyclohexanone (9.8 g, 0.1 mole), zinc chloride (0.16 g) and benzene (50 ml) was heated under reflux, and resulting water was removed by azeotropic distillation. The mixture was concentrated and distilled to obtain 12.4 g of N-cyclohexylidene-2-cyclohexenylamine [Compound (344)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@H:17]([C:19](=[O:26])[CH2:20][C:21](OCC)=[O:22])[CH2:16][CH2:15][N:14]2[C:27]([O:29][CH3:30])=[O:28])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@H:17]([C:19]3[O:26][NH:33][C:21](=[O:22])[CH:20]=3)[CH2:16][CH2:15][N:14]2[C:27]([O:29][CH3:30])=[O:28])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:10])([F:9])[F:11]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2cc(F)c(C(F)(F)F)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(C(F)(F)F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 6.9 %

Procedure:
Trans-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylate (110 mg, 0.25 mmol) (from example 70, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. Sodium hydroxide (0.066 mL, 0.25 mmol) dissolved in water (0.500 mL) was added. After 20 min at −40° C., hydroxylamine (50% by weight in water, 7.71 μL, 0.25 mmol) was added and stirring continued for 4 h. The reaction mixture was then added to a prewarmed 80° C. solution of 6 M hydrogen chloride (1.299 mL, 7.80 mmol) and stirred for 1 h. The solvent was evaporated in vacuo. DCM (50 mL) and water (50 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 20-65% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer, over 30 minutes with a flow of 19 mL/min. Trans-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (7.00 mg, 6.85%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.61-1.73 (m, 1H), 1.90-2.01 (m, 1H), 2.06 (dt, 1H), 2.56 (d, 1H), 2.76 (t, 1H), 2.89 (t, 1H), 3.78 (s, 3H), 4.13-4.47 (m, 1H), 5.46-5.74 (m, 1H), 5.68 (s, 1H), 6.89 (d, 2H). MS m/z 407 (M+H)+