Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2.O.[Cl-].[NH4+].ClCCl>C(O)C.[Fe]>[NH2:14][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([F:1])[CH:3]=1)[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: CN1C(=O)CCc2cc([N+](=O)[O-])cc(F)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CN1C(=O)CCc2cc(N)cc(F)c21
Temperature: 90 °C
Yield: 100 %

Procedure:
8-Fluoro-1-methyl-6-nitro-3,4-dihydro-1H-quinolin-2-one (Step 2, 2.28 g, 0.0102 mol) is heated in ethanol (75 ml) until dissolved. Water (25 ml) and ammonium chloride (5.46 g, 0.102 mol) are added and the mixture heated to 90° C. Iron powder (2.27 g, 0.0407 mol) is added portionwise and the mixture stirred and heated for 30 minutes. The reaction is cooled and dichloromethane (200 ml) added. The mixture is filtered and the organic layer separated, washed with saline, dried (MgSO4) and evaporated to give the title compound as a yellow solid (1.98 g, 99%); [M+H]+=195.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CCC)CCC)CC.Cl[C:21]1[N:26]([CH3:27])[S:25](=[O:29])(=[O:28])[N:24]=[C:23]([O:30][CH3:31])[N:22]=1>ClCCCl>[CH3:27][N:26]1[S:25](=[O:29])(=[O:28])[N:24]=[C:23]([O:30][CH3:31])[N:22]=[C:21]1[O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC1=NS(=O)(=O)N(C)C(Cl)=N1
Reactant: OCCc1ccccc1
Agent: CCCN(CCC)CCC
Solvent: ClCCCl
Product: COC1=NS(=O)(=O)N(C)C(OCCc2ccccc2)=N1
Reaction time: 0.25 h

Procedure:
22 parts of 2-phenylethanol and 26.8 parts of tri-n-propylamine were added, in the course of 10 minutes, to 31.7 parts of 5-chloro-6-methyl-3-methoxy-6H-1,2,4,6-thiatriazine-1,1-dioxide in 200 parts of 1,2-dichloroethane at from 0° to 5° C., while stirring. Stirring was continued for 15 minutes at room temperature, after which the reaction solution was washed successively with 1N hydrochloric acid, with 0.5N sodium hydroxide solution and with water, dried over magnesium sulfate and chromatographed over neutral aluminum oxide. After evaporating down under reduced pressure, 36 parts (81% of theory) of 6-methyl-3-methoxy-5-(2-phenylethoxy)-6H-1,2,4,6-thiatriazine-1,1-dioxide of melting point 74°-77° C. were obtained.
Reaction SMILES: CS(C1CCN([C@@H](C[NH:17][S:18]([C:21]2C=CC(OCC3C4C(=CC=CC=4)N=C(C)C=3)=CC=2)(=[O:20])=[O:19])C(OC)=O)CC1)(=O)=O.CS(C1[CH2:49][CH2:48][N:47]([C@@H:50]([CH2:54][NH:55][S:56]([C:59]2[CH:64]=[CH:63][C:62]([O:65][CH2:66][C:67]3[C:76]4[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=4)[N:70]=[C:69]([CH3:77])[CH:68]=3)=[CH:61][CH:60]=2)(=[O:58])=[O:57])[C:51]([OH:53])=[O:52])[CH2:46][CH2:45]1)(=O)=O>>[CH3:21][S:18]([N:17]1[CH2:45][CH2:46][N:47]([C@@H:50]([CH2:54][NH:55][S:56]([C:59]2[CH:64]=[CH:63][C:62]([O:65][CH2:66][C:67]3[C:76]4[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=4)[N:70]=[C:69]([CH3:77])[CH:68]=3)=[CH:61][CH:60]=2)(=[O:58])=[O:57])[C:51]([OH:53])=[O:52])[CH2:48][CH2:49]1)(=[O:20])=[O:19]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)O)N3CCC(S(C)(=O)=O)CC3)cc2)c2ccccc2n1
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1)N1CCC(S(C)(=O)=O)CC1
Product: Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)O)N3CCN(S(C)(=O)=O)CC3)cc2)c2ccccc2n1

Procedure:
In a manner analogous to example 3.7, using 130 mg (0.2 mmol) of methyl (S)-2-(4-methanesulfonyl-piperidin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate, 120 mg (99%) of (S)-2-(4-methanesulfonylpiperidin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-propanoic acid are obtained in the form of a white solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1Oc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1Oc1ccccc1
Yield: 98.5 %

Procedure:
2-Nitrodiphenyl ether (16 g, 74 mmol) in methanol (250 ml) was shaken with palladium on charcoal (1.6 g) under an atmosphere of hydrogen at 20-50° C. for 30 min. There was a rapid uptake of hydrogen and a detectable exotherm 20-50° C. with the temperature rapidly rising before cooling. Shaking was stopped for short periods to control the temperature from rising above 50° C. The reaction was then filtered through celite and concentrated in high vacuum to give 2-aminodiphenyl ether as an oil (13.5 g, 72.9 mmole, 98%) that crystallized on standing to give a buff solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:55]([CH2:63][CH2:64][CH2:65]O)[Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57].CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[C:10]([O:11][CH2:65][CH2:64][CH2:63][O:55][Si:56]([C:59]([CH3:60])([CH3:62])[CH3:61])([CH3:57])[CH3:58])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(O)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCCCO[Si](C)(C)C(C)(C)C)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 64 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-chloro-5-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (65.7 mg, 0.136 mmol) was dissolved in THF (3.5 mL), and the solution was treated with triphenylphosphine (178 mg, 0.680 mmol), 3-(tert-butyldimethylsiloxy)-1-propanol (0.145 mL, 0.680 mmol) and 40% DEAD-toluene solution (0.310 mL, 0.680 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=6/1) to obtain 4-chloro-5-[3-(tert-butyldimethylsiloxy)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (58.2 mg, yield 64%).
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]3[C:14](=[O:17])[O:15][CH2:16][C:12]=3[CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:20][C:21]1[CH:28]=[C:27]([CH2:29][CH:30]=O)[C:26]([F:32])=[CH:25][C:22]=1[C:23]#[N:24]>>[F:20][C:21]1[CH:28]=[C:27]([CH2:29][CH2:30][N:5]2[CH2:6][CH2:7][N:2]([CH2:8][CH2:9][C:10]3[CH:11]=[C:12]4[C:13](=[CH:18][CH:19]=3)[C:14](=[O:17])[O:15][CH2:16]4)[CH2:3][CH2:4]2)[C:26]([F:32])=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Reactant: N#Cc1cc(F)c(CC=O)cc1F
Agent: Cl
Product: N#Cc1cc(F)c(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2)cc1F

Procedure:
2,5-Difluoro-4-[2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2,5-difluoro-4-(2-oxoethyl)benzonitrile. LC-MS (IE, m/z): 412.1 [M+1]+. (0.23 μM)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][CH:11]([CH2:13]O)[N:12]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>N1C=CC=CC=1>[Br:35][CH2:13][CH:11]1[CH2:10][O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:12]1
Reactant: BrC(Br)(Br)Br
Reactant: OCC1COC(c2ccc(F)cc2)=N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: Fc1ccc(C2=NC(CBr)CO2)cc1
Yield: 46.5 %

Procedure:
To a solution of [2-(4-fluorophenyl)-1,3-oxazolin-4-yl]methan-1-ol (500 mg, 2.5 mmol) in pyridine (30 ml) cooled to 0° under inert conditions was added triphenylphosphine (1.3 g, 5.0 mmol). Carbon tetrabromide (817 mg, 2.5 mmol) was added in 4 fractions (˜200 mg each). The reaction mixture was stirred at zero degrees until all starting material was consumed, as shown by TLC (1:1 EtOAc:Hexanes). Methanol (˜5 ml) was added to quench the reaction. The solution was evaporated under reduced pressure, and the residue was purified using column chromatography (1:1 EtOAc:Hexanes) to yield compound 4-(bromomethyl)-2-(4-fluorophenyl)-1,3-oxazoline (300 mg, HNMR).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N=C=NCCCN(C)C)C.Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1.C(N(CC)CC)C.[NH4+].[Cl-]>CN(C)C=O>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:6]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0 %

Procedure:
To a solution of 2,5-dichloronicotinic acid (1.84 g, 7.06 mmol) in dry dimethylformamide (15 ml) 1-Hydroxybenzotriazole hydrate (1.08 g, 7.06 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (2.03 g, 10.58 mmol), a solution of methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (1.67 g, 7.06 mmol) and triethylamine (0.98 ml, 7.06 mmol) in dry dimethylformamide (15 ml) was added and the resulting mixture was stirred 1 h at room temperature. NH4Cl saturated solution (50 ml) was added the mixture was extracted with ethylacetate (3×50 ml). Collected organics, after solvent evaporation, was purified by Biotage column SNAP-Si (50 g) eluting with a mixture dichloromethane/ethylacetate from 100/0 to 95:5. Collected organics after solvent evaporation afforded the title compound (D97) (1.03 mg)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[O:26]([CH2:30][CH2:31][NH2:32])[CH2:27][CH2:28][NH2:29]>>[NH2:29][CH2:28][CH2:27][O:26][CH2:30][CH2:31][NH:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCOCCN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCOCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2,2′-oxydiethanamine. MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 8.08 (dd, J=1.2, 7.6 Hz, 1 H), 7.92 (s, 1 H), 7.83 (d, J=7.2 Hz, 1 H), 7.70-7.67 (m, 2 H), 7.59-7.55 (m, 2 H), 5.96 (s, 1 H), 5.28 (s, 2 H), 4.49 (s, 2 H), 3.81 (t, J=5.2 Hz, 2 H), 3.72-3.68 (m, 6 H), 3.13 (t, J=4.8 Hz, 2 H), 2.45 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[Cl:9].[N+:10]([O-])([OH:12])=[O:11]>>[Br:1][C:2]1[C:3]([Cl:9])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([Cl:8])[CH:7]=1
Reactant: Clc1ccc(Cl)c(Br)c1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(Cl)c(Br)cc1Cl
Temperature: 0 °C
Yield: 95 %

Procedure:
A solution of 2-bromo-1,4-dichlorobenzene (1.000 g, 4.443 mmol, Aldrich, used as received) in fuming HNO3 (7.0 mL) was stirred at 50° C. for 1.5 h and poured into ice (80 g). The yellowish precipitate was filtered, washed with water (10 mL) and dried under vacuum to give 1.14 g (95%) of pure title compound as a yellowish powder; m.p. 50°-53° C.; 1H NMR (CDCl3):7.863 (s, 1H), 8.030 (s, 1H).
Reaction SMILES: Cl.[Si]([O:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[CH:24]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[C:22]3[C:33](=[O:37])[NH:34][C:35](=[O:36])[C:21]=3[C:20]=2[C:19]2[CH:18]=[C:17]([O:38][CH3:39])[CH:16]=[CH:15][C:14]1=2)(C(C)(C)C)(C)C>C1COCC1.CO>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[C:22]2[C:33](=[O:37])[NH:34][C:35](=[O:36])[C:21]=2[C:20]2[C:19]3[CH:18]=[C:17]([O:38][CH3:39])[CH:16]=[CH:15][C:14]=3[N:13]([CH2:12][CH2:11][CH2:10][OH:9])[C:25]=2[CH:24]=1
Reactant: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCCO[Si](C)(C)C(C)(C)C)C(=O)NC3=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCCO)C(=O)NC3=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3N HCl (50 mL) was added to a solution of 6-(3-{[tert-Butyl(dimethyl) silyl]oxy}propyl)-4-(2-chlorophenyl)-9-methoxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (4.87 g, 8.85 mmol) prepared according to example 39 in 1:1 THF/methanol (200 mL). After stirring at room temperature for 2 h most of the solvents were removed in vacuo, the residue was extracted with ethyl acetate, washed well with water and the organic portion was concentrated to a volume of 60 mL. Petroleum ether was added to precipitate the product, which was filtered off and triturated several times with diethyl ether. The solid was crystallised from THF/petroleum ether and gave 4-(2-Chlorophenyl)-6-(3-hydroxypropyl)-9-methoxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (V; Ar=2-chlorophenyl, R10═CH2CH2CH2OH) (31)in a 3.77 g, 88% yield as a yellow powder; mp 228–230° C. 1H NMR δ [(CD3)2SO] 11.12 (br s, 1H), 8.52 (d, J=2.5 Hz, 1H), 7.80 (s, 1H), 7.70 (d, J=8.9 Hz, 1H), 7.58 (dd, J=8.1, 22 Hz, 1H), 7.53–7.42 (m, 3H), 7.31 (dd, J=8.9, 2.5 Hz, 1H), 4.63 (br, 1H), 4.53 (t, J=6.9 Hz, 2H), 3.91 (s, 3H), 3.40 (m, 2H), 1.91 (m, 2H). Found: C, 66.00; H, 4.23; N, 6.55. C24H19ClN2O4 requires C, 66.29; H, 4.40; N, 6.44.
Reaction SMILES: C([C:3]1[C:4](=[O:11])[NH:5][CH:6]=[CH:7][C:8]=1[O:9]C)#N.C(O)(=O)C.[N+:16]([O-])([OH:18])=[O:17]>O>[OH:11][C:4]1[C:3]([N+:16]([O-:18])=[O:17])=[C:8]([OH:9])[CH:7]=[CH:6][N:5]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc[nH]c(=O)c1C#N
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)ccnc1O
Temperature: 177.5 °C
Reaction time: 1 h

Procedure:
86% phosporic acid (90 mL, 151.3 g) and 3-cyano-4-methoxy-2(1H)-pyridinone (Compound X) (30.0 g, 0.20 mole) are combined under argon in a 500 mL flask equipped with a mechanical stirrer, reflux condensor. The mixture is heated in an oil bath at 175-180° C. for 23 hours. The reaction mixture is cooled to 71° C. and glacial acetic acid (90 mL, 94.5 g) added and the mixture heated at 90° C. for about 90 minutes. Fuming nitric acid (density=1.52) (12.6 g, 8.3 ml) is then added carefully over a period of 15 minutes (giving a mild exotherm), and the mixture heated at 90-95° C. for 2 hours. Water (90 mL) is then added to the mixture and heating at 90° C. continued for 1 hour. The mixture is then cooled slowly with stirring to room temperature, filtered through a sintered glass funnel and the residue washed with water to give Compound XII, m.p. 268° C.; NMR (DMSO) δ 7.44 (1H, d); 6.0 (1H, d); 3.5 (2H).
Reaction SMILES: [CH2:1]([C:8]1([CH3:20])[C:12]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:11]=2[O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl>ClCCl.CN(C=O)C>[I:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:17]([C:15]1[CH:14]=[CH:13][C:12]2[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)([CH3:20])[CH2:9][O:10][C:11]=2[CH:16]=1)=[O:19]
Reactant: CC1(Cc2ccccc2)COc2cc(C(=O)O)ccc21
Reactant: Nc1ccccc1I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(Cc2ccccc2)COc2cc(C(=O)Nc3ccccc3I)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of 3-Benzyl-3-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (80 mg, 0.3 mmol) and 2-Iodoaniline (72 mg, 0.33 mmol) in dichloromethane (3 mL) and DMF (2 mL) were added O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (125 mg, 0.33 mmol) and then a solution of N,N-diisopropylethylamine (58 mg, 78 μL, 0.45 mmol, mL) in DMF (1 mL). The reaction mixture was stirred at ambient temperature for 18 h. The reaction medium is acidified by adding a 1.2 M hydrochloric acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried (MgSO4), and concentrated to give the amide which is purified by flash chromatography (AcOEt/heptane: 4/6). The column was chosen too small and a bigger column was chosen (AcOEt/heptane: 4/6) to afford 22 mg of the desired amid as a pale yellow solid (16%).
Reaction SMILES: O1C2C=CC=CC=2OB1.[Br:10][C:11]1[C:12]([N:27]2[CH2:32][CH2:31][C:30]([O:34][CH3:35])([CH3:33])[CH2:29][CH2:28]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1>[Br:10][C:11]1[C:12]([N:27]2[CH2:32][CH2:31][C:30]([O:34][CH3:35])([CH3:33])[CH2:29][CH2:28]2)=[C:13]([C@H:19]([OH:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]
Reactant: COC1(C)CCN(c2c(Br)c(C)nc(C)c2C(=O)C(=O)OC(C)C)CC1
Agent: B1Oc2ccccc2O1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Product: COC1(C)CCN(c2c(Br)c(C)nc(C)c2[C@H](O)C(=O)OC(C)C)CC1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
The 1.55 mL of benzo[d][1,3,2]dioxaborole (870 mg, 7.25 mmol) was added to a nitrogen purged solution of isopropyl 2-(5-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (1.55 g, 3.63 mmol) and 1.45 mL of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (402 mg, 1.45 mmol) in toluene (30 mL) at −60° C. and allowed to warm to −15° C. before being placed in the freezer overnight. The reaction was quenched with 1M Na2CO3, diluted with EtOAc, and stirred for 30 min. The organic layer was washed with sat'd Na2CO3 solution, brine, and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (0-30% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate 1.48 g (95%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 5.89 (br. s, 1H), 4.95-4.92 (m, 1H), 3.78 (t, J=11.0 Hz, 1H), 3.53 (t, J=10.6 Hz, 1H), 3.37-3.35 (m, 1H), 3.25 (br. s, 1H), 3.14 (s, 3H), 2.52 (s, 3H), 2.37 (s, 3H), 1.75-1.69 (m, 2H), 1.64-1.52 (m, 2H), 1.15-1.16 (m, 6H). 1.07 (d, J=6.2 Hz, 3H). UPLC (M+H)=431.3.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>C(OC(=O)C)(=O)C>[CH:14]1[C:10]2[C:11](=[O:13])[O:12][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8][C:9]=2[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1Sc1ccccc1O
Solvent: CC(=O)OC(C)=O
Product: O=C1Oc2ccccc2Sc2ccccc21
Yield: 54.8 %

Procedure:
2-(2-Hydroxy-phenylsulfanyl)-benzoic acid (2 g, 8 mmol) was dissolved in acetic anhydride and the resultant solution was refluxed at 145-148° C. for 8 h. Upon completion, the excess acetic anhydride was removed by rotary evaporation and the residue was poured into ice water. The mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous MgSO4, filtered, evaporated by a rotatory evaporator and purified by column chromatography to obtain the product (1 g, 54%). m.p. 124° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=O)OC(C)(C)C)[CH2:9][CH2:8]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH3:14][NH:13][CH:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:21]=[CH:22][CH:23]=[C:3]([C:2]([F:25])([F:1])[F:24])[CH:4]=2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 1-(3-(trifluoromethyl)benzyl)piperidin-4-ylcarbamate (0.358 g, 1 mmol; Example 41A) in tetrahydrofuran (40 mL) was added LiAlH4 (0.056 g, 1.5 mmol) and the resultant mixture was heated to reflux for 16 hours. Then the reaction mixture was cooled in an ice bath and Na2SO4.10H2O (0.1 g) was added. The mixture was stirred for 1 hour at room temperature, and then the inorganic salts were removed by filtration. The filtrate was evaporated, and the obtained residue was chromatographed on silica gel eluting with 5-10% methanol/dichloromethane to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.58 (s, 1H), 7.51 (m, 2H), 7.42 (m, 1H), 5.36 (Bs, 1H), 3.54 (s, 2H), 2.82 (m, 2H), 2.43 (s, 3H), 2.37 (m, 1H), 2.07 (m, 2H), 1.87 (d, J=12.55 Hz, 2H), 1.38 (m, 2H); MS (DCI+) m/z 273 (M+H)+.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:9]1([S:15]([CH2:18][C:19]2[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23](OS(C(F)(F)F)(=O)=O)[C:22]([C:37]3[CH:41]=[CH:40][O:39][CH:38]=3)=[CH:21][CH:20]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:42]1COC[CH2:43]1>O>[C:9]1([S:15]([CH2:18][C:19]2[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([CH2:42][CH3:43])[C:22]([C:37]3[CH:41]=[CH:40][O:39][CH:38]=3)=[CH:21][CH:20]=2)(=[O:16])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OS(=O)(=O)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)OC
Temperature: 140 °C

Procedure:
A mixture of potassium phosphate tribasic (0.244 g), methyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-(trifluoromethanesulphonyloxy)benzoate (Intermediate 123, 0.2 g) in THF (2 ml) and water (1 ml) was sealed in a microwave vial and degassed with argon. Palladium (II) chloride dppf complexed with DCM (0.02 g) and triethylborane (0.29 ml) were added and the mixture was heated in the microwave at 140° C. for 15 minutes. After cooling, ethyl acetate and water were added and the organic layer was separated, washed with brine, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-18% to give methyl 6-(benzenesulphonylmethyl)-2-ethyl-3-(furan-3-yl)benzoate (0.092 g) as a white solid.
Reaction SMILES: [BH4-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[NH:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)c1ccc2ncccc2c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1ccc2c(c1)CCCN2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
257 mg (1.1 mmol) of nickel chloride hexahydrate and then 770 mg (20.3 mmol) of sodium borohydride were added to a mixture of 1.00 g (5.0 mmol) of ethyl quinoline-6-carboxylate and 15 ml of methanol under cooling with ice, and they were stirred at room temperature for 20 minutes. Methanol was evaporated, and the residue was purified by the silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([Br:17])=[C:14](Br)[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li]CCCC.[F:23][C:24]([F:34])([F:33])[C:25](C(O)C(F)(F)F)=[O:26]>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([Br:17])=[C:14]([C:25](=[O:26])[C:24]([F:34])([F:33])[F:23])[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(C(O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)N1CCc2sc(Br)c(Br)c2CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2sc(C(=O)C(F)(F)F)c(Br)c2CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 35.1 %

Procedure:
The product of Example 1, step (e) (200 mg, 0.52 mmol) was dissolved in 5 mL THF, cooled to −78° C. and treated with BuLi (0.33 mL of 1.6 M). After stirring for 15 minutes at −78° C., trifluoroacetyl 2,2,2-trifluoroethanol (132 uL, 0.68 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was quenched with water (50 uL) and concentrated. The residue was purified by silica gel chromatography to give 73 mg of the sub-title compound.