Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[CH3:3][O:4][C@@H:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C@H:6]1OS(C)(=O)=O.C[O-].[Na+]>O>[CH3:3][O:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: CO[C@@H]1c2ccccc2C[C@H]1OS(C)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1C=Cc2ccccc21
Temperature: 0 °C
Reaction time: 6 h
Yield: 98.2 %

Procedure:
A stirrer, thermometer and reflux condenser were mounted to a 500-ml four-necked flask which was filled with 200 ml of methanol and 12.1 g (0.05 mol) of trans-1-methoxy-2-methane sulfonyloxy indane, and cooled in an ice-salt bath to 0° C. The cream-colored slurry was stirred while 27 g (0.5 mol) of sodium methoxide was added. The reaction liquid was heated to 70° C., stirred for 6 hours, cooled to 25° C., 200 ml of water was added, and extraction was performed twice with 200 ml of methylene chloride and the methylene chloride layer was dried with anhydrous sodium sulfate and vacuum-concentrated to obtain 7.17 g of a reddish-brown oil of 1-methoxyindene (yield of 98.2%). The purity of this compound according to gas chromatography (GC) was 90.9% (surface area percentage). Its physical properties are given below.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[N:8]=1)(=O)=O.[CH2:27]([NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:23][CH:22]([CH3:24])[CH2:21][NH:20][C:15]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[N:8]=[C:7]([N:34]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC(C)CNc1c2c(nc(OS(=O)(=O)C(F)(F)F)c1[N+](=O)[O-])CCCC2
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)CNc1c2c(nc(N(Cc3ccccc3)Cc3ccccc3)c1[N+](=O)[O-])CCCC2
Yield: 92.2 %

Procedure:
5,7,6,8-tetrahydro-4-[(2-methylpropyl)amino]-3-nitroquinolin-2-yl trifluoromethanesulfonate (4.0 g, 0.01 mole), dibenzylamine (1.9 mL, 0.01 mole), triethylamine (1.4 mL, 0.01 mole) and benzene (100 mL) were combined and heated at reflux for 36 hours. The benzene was evaporated under vacuum and the residue purified by silica gel chromatography eluting with hexane:ethyl acetate 70:30 to provide 4.1 g of the desired product as a viscous orange oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:20])=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:20][Br:1])=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1
Reactant: Cc1ccc(Br)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(Br)ccc1CBr
Yield: 83.1 %

Procedure:
N-Bromosuccinimide (2.6 g) and 2,2′-azobis(isobutyronitrile) (35 mg) were added to a solution of 5-bromo-2-methylbenzotrifluoride (CAS #86845-27-4, 3.5 g) in carbon tetrachloride (35 mL), and the mixture was heated under reflux for five hours. The reaction solution was ice-cooled and then the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Wakogel C-200; elution solvent: heptane) to obtain 3.86 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:33]=[CH:32][N:31]([CH2:34][CH2:35][CH2:36][CH3:37])[C:30](=[O:38])[CH:29]=2)=[CH:22][N:21]=1)([O-])=O.N1C=CC=CC=1>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:33]=[CH:32][N:31]([CH2:34][CH2:35][CH2:36][CH3:37])[C:30](=[O:38])[CH:29]=3)=[CH:22][N:21]=2)[CH:6]=1)[CH3:1]
Reactant: CCCCn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Reactant: CN(C)Cc1ccnc(CSCCN)c1
Solvent: c1ccncc1
Solvent: CCO
Product: CCCCn1ccc(Cc2cnc(NCCSCc3cc(CN(C)C)ccn3)[nH]c2=O)cc1=O

Procedure:
2-[4-(Dimethylaminomethyl)pyrid-2-ylmethylthio]ethylamine (0.90 g) and 2-nitroamino-5-(1-n-butyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (1.12 g) were refluxed in ethanol (15 ml) for 72 hours. As the reaction had not gone to completion, the ethanol was replaced by pyridine (15 ml) and the mixture was refluxed for a further 6 hours.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[NH2:16][C@H:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19]>C(#N)C>[CH3:21][O:20][C:18](=[O:19])[C@H:17]([N:16]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:22]
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@@H](C)N(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Potassium carbonate (49.5 g, 358 mmol) and benzyl bromide (42.5 mL, 358 mmol) were each added to a partial solution of (R)-methyl 2-aminopropanoate hydrochloride (10 g, 71.6 mmol) in acetonitrile (200 mL) and the reaction was allowed to stir at 60° C. overnight. The reaction was filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography using hexane (to elute the excess benzyl bromide) followed by 5:1 hexane:ethyl acetate to elute the product. After concentration and drying of the fractions containing the major product, the title compound (20.13 g, 71.0 mmol, 99% yield) was obtained as a colorless oil. HPLC (condition B): retention time=2.80 min. LCMS (condition B): m/z 284.2. 1H NMR (500 MHz, MeOD) δ ppm 7.38-7.44 (4 H, m), 7.34 (4 H, t, J=7.63 Hz), 7.22-7.30 (2 H, m), 3.84 (2 H, d, J=13.87 Hz), 3.77 (3 H, s), 3.65 (2 H, d, J=13.87 Hz), 3.52 (1 H, q, J=7.12 Hz), 1.35 (3 H, d, J=7.21 Hz).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][CH:13]2[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:15]1[CH2:16][CH:13]([CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC(CNC(=O)OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC1CNC1)OCc1ccccc1
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of 1,1-dimethylethyl 3-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-azetidinecarboxylate (17.2 mmoles, 5.5 g) in DCM (100 mL) at RT was added TFA (50 mL). After 2 h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to give the title compound (3.59 g, 95%) as a light yellow oil: LC-MS (ES) m/e 221 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:19]2[O:25][C@H:24]([CH2:26][O:27]C(=O)C)[C@@H:22]([OH:23])[C@H:20]2[OH:21])[C:4]2[C:9]([C:10]=1[C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]([Cl:17])=[C:6]([Cl:18])[CH:5]=2.C[O-].[Na+]>CO.CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]([C@@H:19]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@H:20]2[OH:21])[C:4]2[C:9]([C:10]=1[C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:8][C:7]([Cl:17])=[C:6]([Cl:18])[CH:5]=2
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)c(C(=O)C(F)(F)F)c3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(c1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.3 %

Procedure:
2,5,6-Trichloro-3-trifluoroacetyl-1-(5-O-acetyl-β-D-ribofuranosyl)indole (4.45, 94 mg, 0.19 mmol) was dissolved in dry MeOH (20 mL) to which was added sodium methoxide (12 mg, 0.22 mmol). The solution was stirred at room temperature for 90 min, then the solvent was removed under vacuum. The residue was suspended in brine (40 mL) and water (5 mL), and the suspension extracted with EtOAc (2×50 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to yield a yellow-orange solid. The solid was dissolved in 10% MeOH/CHCl3 (1 mL) and subjected to column chromatography (40×350 mm) on silica gel with 10% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield a white solid which was recrystallized from MeOH/H2O to yield 48 mg (56%) of 4.48 as a pale yellow powder: mp 179-180 C; Rf 0.3 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.80 (s, 1H), 8.23 (s, 1H), 6.14 (d, 1H), 5.50 (b, 2H, D2O exch.), 5.34 (b, 1H, D2O exch.), 4.44 (t, 1H), 4.19 (dd, 1H), 4.06 (d, 1H), 3.76 (dq, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 173.47 (J=37 Hz), 132.34, 132.65, 127.38, 127.28, 125.47, 121.35, 116.29, 115.88 (J=289 Hz), 106.90, 89.42, 86.88, 71.96, 69.49, 60.86. 19F-NMR (300 MHz, DMSO-d6): δ −72.34. HRMS (EI) m/z calcd. for C15H11Cl3F3NO5 446.9655. found 446.9661. Anal calcd for C15H11Cl3F3NO5: C, 40.16; H, 2.47; N, 3.12. Found: C, 40.18; H, 2.60; N, 2.98.
Reaction SMILES: [NH3:1].CO.[NH2:4][C:5]1[C:6]2[C:31]([CH3:37])([C:32]([O:34]CC)=O)[C:30](=[O:38])[NH:29][C:7]=2[N:8]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[N:12]=2)[N:10]=1>>[NH2:4][C:5]1[C:6]2[C:31]([CH3:37])([C:32]([NH2:1])=[O:34])[C:30](=[O:38])[NH:29][C:7]=2[N:8]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][C:22]([F:27])([F:28])[C:23]([F:26])([F:25])[F:24])[N:12]=2)[N:10]=1
Reactant: N
Reactant: CCOC(=O)C1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Solvent: CO
Product: CC1(C(N)=O)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21

Procedure:
A 2 M solution of ammonia in MeOH (28.6 mL, 57.3 mmol) was added to ethyl 4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate, as prepared by the procedure described in Example 158, (220 mg, 0.441 mmol) and the resultant mixture heated at 50° C. for 16 hours. The reaction mixture was concentrated in vacuo and the residue purified by silica gel column chromatography using a DCM/MeOH (with 0.5% NH4OH) gradient. Chiral separation by SFC using a Chiralpak AD column provided both enantiomers of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 11.27 (1H, s), 9.02 (1H, dd, J=8.06, 1.62 Hz), 8.64 (1H, dd, J=4.50, 1.63 Hz), 7.45 (1H, s), 7.38 (1H, dd, J=8.07, 4.49 Hz), 7.19 (1H, s), 6.82 (2H, s), 4.88 (2H, t, J=6.80 Hz), 3.04-2.90 (2H, m), 1.57 (3H, s). m/z=471.1 (M+H).
Reaction SMILES: [CH3:1][CH:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][CH2:11][CH2:12]O.Br>ClCCl>[BrH:10].[Br:10][CH2:11][CH2:12][NH:9][CH:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCBr
Reactant: CC(N)c1ccccc1
Agent: Br
Solvent: ClCCl
Product: CC(NCCBr)c1ccccc1
Temperature: 51 °C
Reaction time: 50 h
Yield: 109.8 %

Procedure:
76.61 g (630 mmole) of α-methylbenzylamine was dissolved in 77 ml of dichloromethane and 94.8 g (760 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 286.4 ml (2500 mmole) of 48% aqueous hydrobromic acid solution was added thereto and allowed to react at 126° C. for 30 minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 250 ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 350 ml of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10° C. and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50 ml of ethyl acetate and then dried to obtain 128.9 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[CH3:3][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]3)=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[CH3:1]
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: OC1CCN(CCCCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CC1(c2ccc(OCCCN3CCC(O)CC3)cc2)CCOCC1
Yield: 51.2 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), 1-(3-chloro-propyl)-piperidin-4-ol (378 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. The isolated material was dissolved in EtOAc (30 ml), washed with NaOH (2M, 2×20 ml) and water (25 ml), dried over MgSO4 filtered and concentrated in vacuo at 35° C. to give the title compound (411 mg, 51%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.86 (d, 2H), 4.00 (t, 2H), 3.80-3.65 (m, 3H), 3.55 (td, 2H), 2.85-2.73 (m, 2H), 2.52 (t, 2H), 2.40 (s, 2H), 2.22-1.82 (m, 10H), 1.97 (s, 6H), 1.66-1.54 (m, 2H), 1.52 (br s, 1H).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:4]([O:26][CH3:27])=[CH:3][C:2]=1[NH:31][CH2:30][CH2:28][OH:29]
Reactant: NCCO
Reactant: COc1cc(F)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Product: COc1cc(NCCO)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 72 %

Procedure:
As described for example 26, 2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.54 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using ethanolamine instead of thiomorpholine to the title compound (160 mg, 72%) which was obtained as an off-white solid. MS: m/e=411.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:19])([CH3:18])[CH2:15][CH2:16]O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:27]>C1C=CC=CC=1>[Br:27][CH2:16][CH2:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)([OH:19])[CH3:18]
Reactant: CC(O)(CCO)c1ccc(-c2ccc(F)cc2)cc1
Reactant: BrP(Br)Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(O)(CCBr)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A solution of 2.6 g. of 3-(4'-fluoro-4-biphenylyl)-1,3-butanediol in 10 ml. of pyridine is added dropwise, at -5°, while stirring, to a mixture of 1 g. of PBr3, 1 ml. of pyridine and 3 ml. of benzene. The reaction mixture is then stirred for 24 hours at 20° and worked up in the customary manner to give 1-bromo-3-(4'-fluoro-4-biphenylyl)-butan-3-ol, m.p. 72° -74°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].Cl[C:19]1[CH:36]=[CH:35][C:22]([CH2:23][CH2:24][NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[O:33][C:30]1[CH:29]=[CH:28][C:27]([C:26](=[O:34])[NH:25][CH2:24][CH2:23][C:22]2[CH:21]=[CH:20][CH:19]=[CH:36][CH:35]=2)=[CH:32][CH:31]=1)#[N:2]
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccccc3)cc2)c(C#N)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 50.7 %

Procedure:
A mixture of tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (0.122 g), N-(4-chlorophenethyl)-4-hydroxybenzamide (0.150 g), and potassium carbonate (0.086 g) was dissolved in 2 ml of DMSO and stirred at 90° C. After 1 day, the reaction was cooled, loaded onto a silica gel samplet and product eluted with a solvent system gradient of 0.5% methanol/dichloromethane to 5% methanol/dichloromethane to give tert-butyl 2-(3-cyano-4-(4-(phenethylcarbamoyl)phenoxy)phenyl)acetate (0.120 g).
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[C:25]([Cl:26])=[CH:24][N:23]([CH3:27])[N:22]=1>CN(C=O)C>[Cl:26][C:25]1[C:21]([CH2:20][S:1][C:2]2[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[N:3]=2)=[N:22][N:23]([CH3:27])[CH:24]=1
Reactant: Cn1cc(Cl)c(CBr)n1
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(Cl)c(CSc2nc(O)cc(C(F)(F)F)n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.2 %

Procedure:
2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (721 mg, 3.7 mmol) was dissolved in anhydrous DMF (20 mL), and then potassium carbonate (1.53 g, 11.0 mmol) and 3-(bromomethyl)-4-chloro-1-methyl-1H-pyrazole (4.7 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 4-10% DCM/MeOH to afford 2-{[(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (135 mg, 11% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 3.78 (s, 3H), 4.39 (s, 2H), 6.66 (s, 1H), 7.93 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][N:32]2C(OC(C)(C)C)=O)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)N1CCCCC1C(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1C(=O)C1CCCCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-[1-(tert-Butoxycarbonyl)piperidine-2-carbonyl]-piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (32) (1.05 g; 1.78 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 4 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]([N:15]2[CH:19]=[CH:18][N:17]=C2)=[O:14])[CH2:8]1>C(Cl)Cl.C(O)(C)C>[NH2:17][CH2:18][CH2:19][NH:15][C:13]([NH:12][C@H:9]1[CH2:10][CH2:11][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8]1)=[O:14]
Reactant: O=C(N[C@H]1CCN(c2ccccn2)C1)n1ccnc1
Solvent: ClCCl
Solvent: CC(C)O
Product: NCCNC(=O)N[C@H]1CCN(c2ccccn2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of imidazole-1-carboxylic acid ((S)-1-pyridin-2-yl-pyrrolidin-3-yl)-amide (9.9 ml of a 0.1 M solution in DCM, 0.99 mmol) in iso-propanol (1 ml) is added ethyl-1,2-diamine (2 ml, 37 mmol). The reaction mixture is stirred at room temperature for 4 hours and then extracted with DCM using a continuous liquid-liquid extraction system to yield the titled compound as 1:4 mole ratio mixture with imidazole.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12]2[N:18]([CH3:31])[C:19](=[O:30])[C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])=[CH:21][C:11]3=2)[N:7]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[C:20]1[C:19](=[O:30])[N:18]([CH3:31])[C:12]2[N:13]([CH3:17])[C:14]3[C:10]([C:11]=2[CH:21]=1)=[CH:9][C:8]([C:6]1[N:7]=[C:3]([CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[S:4][CH:5]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CN)n4)ccc3n(C)c21
Reactant: CS(=O)(=O)Cl
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CNS(C)(=O)=O)n4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 99 above, with the compound from Example 147, 6-(2-aminomethylthiazol-4-yl)-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, and methanesulphonyl chloride.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1>[C:9]([C:8]1[CH:12]=[CH:13][C:5]([CH2:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1)([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(=O)Cc1ccc(C(=O)Cl)cc1
Reactant: OCc1ccccc1
Solvent: c1ccccc1
Product: CC(=O)Cc1ccc(C(=O)OCc2ccccc2)cc1
Reaction time: 48 h

Procedure:
4-Acetonylbenzoyl chloride (3.92 g) and benzyl alcohol (2.16 g) were refluxed in benzene for 4 hours and then left at room temperature for 48 hours. Removal of the solvent gave the title compound. τ (CDCl3) 7.9 (3H, s), 6.32 (2H, s), 4.69 (2H, s), 2.78 (2H, d, J=8 Hz), 2.70 (5H, m), 1.99 (2H, d, J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([NH:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[C:34]([O:42][C:43]([F:46])([F:45])[F:44])[CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:38]([C:35]1[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][C:34]=1[O:42][C:43]([F:44])([F:45])[F:46])(=[O:40])=[O:39])[C:6](=[O:11])[C:5]2([NH:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1ccccc1C1(NCCC(=O)OC(C)(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(NCCC(=O)OC(C)(C)C)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 88.2 %

Procedure:
With 1.50 g of tert-butyl N-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-β-alaninate, which is the compound described in Preparation 1.29A of the brochure Publication No. WO03/008407, and 1.15 g of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 2.13 g of the title compound (light yellow solid) was obtained by a similar method to Example 2.