Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:26][CH2:27][C:28](Cl)=[O:29]>>[Cl:26][CH2:27][C:28]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:24][CH:25]=1)=[O:29]
Reactant: O=C(Cl)CCl
Reactant: NCc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Product: O=C(CCl)NCc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Yield: 62.1 %

Procedure:
1-[1-(4-Aminomethylphenethyl)piperidin-4-yl]indoline (0.1 g) and chloroacetyl chloride (0.026 ml) were treated as in Example 36 to give the title compound (0.074 g) as a pale yellow oil (yield: 62.1%).
Reaction SMILES: C1(OC([N:10]2[CH:15]=[C:14]([CH:16]=[O:17])[CH:13]=[C:12]([Cl:18])[CH2:11]2)=O)C=CC=CC=1.[S].C1C2C(=CC=CC=2)C=CC=1>C(OCC)C>[Cl:18][C:12]1[CH:13]=[C:14]([CH:16]=[O:17])[CH:15]=[N:10][CH:11]=1
Reactant: O=CC1=CN(C(=O)Oc2ccccc2)CC(Cl)=C1
Agent: [S]
Solvent: c1ccc2ccccc2c1
Solvent: CCOCC
Product: O=Cc1cncc(Cl)c1
Temperature: 25 °C

Procedure:
The mixture of 3-chloro-5-formyl-2H-pyridine-1-carboxylic acid phenyl ester (2.3 g, 8.8 mmol), sublimed sulfur (0.29 g, 9 mmol) and naphthalene (6 g) was refluxed under an argon atmosphere for 2 h. After the reaction was complete, the mixture was cooled to r.t., dissolved in ethyl ether (30 mL), and extracted with aqueous 10% HCl. The combined acid extracts were washed with ethyl ether (20 mL) and cooled to 0° C. Dichloromethane (30 mL) was added and “pH” of the mixture was adjusted to be basic with 25% aqueous NaOH, and the mixture was extracted with dichloromethane (20 mL). The combined organic phase was washed with brine, dried over K2CO3, filtered, and concentrated to give a brown solid. (0.8 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:13][CH2:14][CH2:15][CH2:16][C@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:24]=[CH:25][C:26]3[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=3[CH:33]=2)[CH2:18]1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH:13][CH2:14][CH2:15][CH2:16][C@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:24]=[CH:25][C:26]3[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=3[CH:33]=2)[CH2:18]1)=[O:6]
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Reactant: COc1ccc(N)c(C(=O)O)c1
Product: COc1ccc(N)c(C(=O)NCCC[C@@H]2CN(c3ccc4c(c3)NC(=O)CS4)C(=O)O2)c1
Yield: 82 %

Procedure:
Starting from 2-amino-5-methoxybenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (180 mg; 82% yield).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.P(Cl)(Cl)Cl.[NH2:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=2[N:24]=1>O>[Cl:29][C:27]1[CH:26]=[CH:25][C:23]2[N:24]=[C:20]([NH:19][C:12]([C:3]3[C:2]([OH:1])=[C:11]4[C:6]([CH:7]=[CH:8][CH:9]=[N:10]4)=[CH:5][CH:4]=3)=[O:14])[S:21][C:22]=2[CH:28]=1
Reactant: Nc1nc2ccc(Cl)cc2s1
Reactant: O=C(O)c1ccc2cccnc2c1O
Solvent: O
Solvent: ClP(Cl)Cl
Product: O=C(Nc1nc2ccc(Cl)cc2s1)c1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
A solution of 8-hydroxyquinoline-7-carboxylic acid (0.30 g) of Preparation 1 in 75 mL xylenes is heated to reflux. PCl3 (0.07 mL) is added dropwise and the mixture stirred for 15 minutes. 2-Amino-6-chlorobenzothiazole (0.31 g) is added in one portion and the reaction refluxed overnight. The reaction is cooled to room temperature and H2O is added to quench excess PCl3. After stirring the solution for 30 minutes, a yellow solid is filtered, dried, and recrystallized from DMSO to give the title product (0.31 g).
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][C:40]([C:43]([O:45]C)=[O:44])=[CH:39][C:38]=4[CH3:47])[CH:33]=[CH:34][C:35]=3[Cl:36])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[K+]>C(O)C>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][C:40]([C:43]([OH:45])=[O:44])=[CH:39][C:38]=4[CH3:47])[CH:33]=[CH:34][C:35]=3[Cl:36])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(Cl)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1-c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1

Procedure:
methyl 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-chloro-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (25 mg, 0.034 mmol), aqueous potassium hydroxide (300 μL, 3M, 0.90 mmol) and ethanol (2 mL) were stirred at 20° C. overnight. Volatiles were removed under reduced pressure. The resulting residue was treated with brine followed by extraction with ethyl acetate. The combined extracts were dried over Na2SO4 followed by filtration and concentration in vacuo to afford an oil. This oil was purified by preparative TLC on SiO2 (eluted with 50% EtOAc in hexanes) to afford a clear glass. The glass was further purified by reverse phase preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting by a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture affording 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-chloro-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS calc.=715.12; found=716.12 (M+1)+. 1H NMR signals are doubled because of atropisomerism 1H NMR (CDCl3, 500 MHz) δ 7.99 (d, J=8.0 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.85 (d, J=5 Hz, 1H), 7.72-7.68 (m, 1.5H), 7.67-7.60 (m, 2.5H), 7.47-7.36 (m, 2H), 7.32 (d, J=8.0 Hz, 0.5H), 7.28 (d, J=8.0 Hz, 0.5H), 7.15 (s, 1H), 7.08 (dd, J=8.5, 7.0 Hz, 1H), 5.58 (d, J=8.0 Hz, 0.5H), 5.29 (d, J=6.5 Hz, 0.5H), 4.97 (d, J=15.5 Hz, 0.5H), 4.94 (d, J=14 Hz, 0.5H), 4.16 (d, J=16 Hz, 0.5H), 3.96 (d, J=15.5 Hz, 0.5H), 3.87 (s, 3H), 3.83-3.74 (m, 1H), 2.38, 2.33 (s, 3H), 0.55 (d, J=6.5 Hz, 1.5H), 0.42 (d, J=7 Hz, 1.5H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9]Cl)=[CH:4][CH:3]=1.[C-:17]#[N:18].[Na+]>CS(C)=O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: Fc1ccc(Oc2ccccc2CCl)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccccc1Oc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 26 h

Procedure:
12.0 g of 2-(4-fluorophenoxy)benzyl chloride are added portionwise over a 30 minute span to a mixture of 2.9 g of sodium cyanide in 120 ml of dimethylsulfoxide. After total addition, the reaction mixture is stirred for 26 hours before being poured onto 150-200 ml of crushed ice. The mixture is extracted four times with 70 ml portions of ether and the combined ether extracts are successively washed four times with 50 ml portions of water, washed once with 25 ml of saturated sodium chloride solution and dried, providing a clear oil. The oil is distilled at 128.5°-130° C. and 0.1 mm to provide 2-(4-fluorophenoxy)benzyl cyanide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Clc1cc(Cl)nc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,4,6-trichloropyrimidine (5.5 g, 30 mmol) in tetrahydrofuran (15 mL) was added dropwise to a solution of aniline (2.8 mL, 1 equivalent) in tetrahydrofuran (25 mL). N,N-diisopropylethylamine (5.2 mL) was added and the solution was stirred at room temperature overnight. The solvent was removed and the crude material was purified by flash chromatography on silica gel. The column was eluted with 3% ethyl acetate in hexane, followed by 15% ethyl acetate in hexane. The eluent was removed, giving 4,6-dichloro-N-phenyl-2-pyrimidinamine (1.11 g, 4.6 mmol, 15%, Rf=0.4 in 3% ethyl acetate in hexane).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][CH:8]=2)[C:3]1=O.[BH4-].[Na+].Cl>O1CCCC1.CO>[CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=2
Reactant: CC1Cc2ccc(C(C)(C)C)cc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1=Cc2ccc(C(C)(C)C)cc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
5.3 g (26 mmol) of 8 were dissolved in 50 ml of tetrahydrofuran/methanol (2:1), 1.5 g of sodium borohydride were added at 0° C. with magnetic stirring, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured onto ice, conc. HCl was added to pH 1, and the mixture was extracted a number of times with diethyl ether. The combined organic phases were washed with saturated aqueous NaHCO3 solution and NaCl solution and dried (MgSO4). The solvent was removed in vacuo, and the crude product, without further purification, was taken up in 300 ml of toluene, 0.1 g of p-TsOH was added, and the mixture was refluxed for 1 hour. The reaction mixture was washed with 100 ml of saturated aqueous NaHCO3 solution, and the solvent was removed in vacuo. The crude product was purified by filtration through 200 g of silica gel (hexane), giving 4.8 g (99%) of 9 as a colorless oil.
Reaction SMILES: Cl.C[N:3](C)[CH2:4][CH2:5][CH2:6][N:7]=C=NCC.C(CC(O)=[O:17])#N.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])N.O>C1COCC1>[Cl:19][C:20]1[CH:21]=[C:22]([CH:5]([C:4]#[N:3])[C:6]([NH2:7])=[O:17])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: N#CCC(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: N#CC(C(N)=O)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
A 500-mL round bottomed flask under N2 equipped with overhead stirrer, a condenser, thermocouple and 100 mL dropping funnel was charged with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (21.17 g, 0.11 ml) and THF (140 mL). A solution of cyanoacetic acid (10.03 g, 0.118 mol) and 3-chloro-4-fluoroaniline (15.44 g, 0.106 mol) in THF (60 mL) was added to the dropping funnel and added to the reaction flask at 25-45° C. At the end of the addition the reaction became a clear solution. The solution was stirred at ambient temperature for 1.5 hours then poured slowly into water (500 mL) forming a white suspension. The suspension was stirred at room temperature overnight then filtered and the filter cake washed with water and dried under vacuum (50 mm Hg) at 45° C. to provide (3-chloro-4-fluorophenyl)-2-cyanoacetamide as a white solid (21.27 g, 94% yield, 97.5% by HPLC). 1H NMR (300 MHz, DMSO-d6): 10.4 (s, 1H), 7.80 (d, J=8 Hz, 1H), 7.5-7.3 (m, 2H), 3.92 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([N:26]3[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28][CH2:27]3)=[N:9]2)=[CH:5][CH:4]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]2[C:54](=[O:55])[C:53]([C:56](O)=[O:57])=[CH:52][CH:51]=[N:50]2)=[CH:45][CH:44]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CS(C)=O>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:56]([C:53]2[C:54](=[O:55])[N:49]([C:46]3[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=3)[N:50]=[CH:51][CH:52]=2)=[O:57])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:41][CH:40]=3)[N:9]=[C:10]([N:26]3[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:28][CH2:27]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(N3CCCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(N3CCCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
A 100 mL round-bottomed flask was charged with tert-butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-1,4-diazepane-1-carboxylate (110.4 mg, 0.1962 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (137.9 mg, 0.5887 mmol, prepared according to Example 19, step C), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (188.1 mg, 0.9811 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (132.6 mg, 0.9811 mmol), N-ethyl-N-isopropylpropan-2-amine (253.6 mg, 1.962 mmol) and DMSO (25 mL). The reaction mixture was stirred at room temperature overnight. The reaction was partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (118.3 mg, 77.4%). LRMS (APCI pos): m/e 679 (M−99).
Reaction SMILES: C[C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:10](NC(C)C)(C)C.[Li].[CH3:18][O:19][C:20](Cl)=[O:21]>C1COCC1>[C:2]1([C:7]([O:9][CH3:10])=[O:8])([C:20]([O:19][CH3:18])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)NC(C)C
Reactant: COC(=O)Cl
Reactant: CC1(C(=O)O)CCCC1
Agent: [Li]
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)OC)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A solution of methyl cyclopentanecarboxylic acid (7.1 g, 38.16 mmol) in THF (14 mL) was added dropwise to a solution of lithium diisopropylamine (6.62 g, 61.2 mmol) in THF (55 mL) at −78° C. After stirring for 1 h at the same temperature, a solution of methylchloroformate (5.78 g, 61.2 mmol) in THF (14 mL) was added slowly and the mixture was allowed to warm to room temperature. After 18 h the reaction mixture was quenched with saturated aqueous NH4Cl solution (100 mL). THF was removed in vacuo and the aqueous residue was extracted with dichloromethane (100 mL×3). The combined organic layers were dried (MgSO4). After removal of the solvent under reduced pressure, purification by flash column chromatography using an eluting system of hexane/EtOAc (95:5) yielded the title compound as a clear colorless liquid (7.1 g, 93%). MH+187.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N+:15]([O-])=O)[CH:7]=2)[CH2:3][CH2:2]1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]3[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=3)=[O:32])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]3[N:12]=[C:37]([C:36]4[CH:35]=[CH:34][C:33]([C:31]([NH:30][C:27]5[CH:26]=[CH:25][C:24]([N:21]6[CH2:20][CH2:19][O:18][CH2:23][CH2:22]6)=[CH:29][CH:28]=5)=[O:32])=[CH:40][CH:39]=4)[NH:15][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(OCC2CC2)cc1[N+](=O)[O-]
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3ccc(OCC4CC4)cc3[nH]2)cc1

Procedure:
Compound 640 was prepared according to the procedure similar to that described in Scheme III from 1-cyclopropylmethoxy-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C28H28N4O3: 469.22; found: 469.03.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]=[C:10](B3OC(C)(C)C(C)(C)O3)[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:31].[Na+].[Na+].CCO.[C:39]1([CH3:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]=[C:10]([C:41]3[CH2:40][C@H:39]([CH3:45])[O:31][C@@H:43]([CH3:44])[CH:42]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1
Reactant: COc1ccccc1-n1nc(B2OC(C)(C)C(C)(C)O2)cc1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccccc1-n1nc(C2=C[C@H](C)O[C@@H](C)C2)cc1-c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 66 %

Procedure:
A flask is charged with 5-(4-chlorophenyl)-1-(2-methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.10 g, 3.70 mmol), trans-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate (1.06 g, 4.07 mmol), Pd(PPh3)4 (0.24 g, 5 mol %), 2 M Na2CO3 (16 mL), EtOH (16 mL) and toluene (32 mL) and heated at 80° C. for 6 h. The reaction was diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (2×100 mL) and brine (100 mL), and the organic layer dried over Na2SO4 and evaporated. The crude product was purified by silica gel chromatography (Thomson Scientific 25-g cartridge, 10-100% EtOAc/heptane in 10 column volumes) to give 0.68 g (66%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[C:11]1[C:20]2[C:15](=CC=CC=2)[CH:14]=[CH:13][C:12]=1C=O>>[C:2]1([C:11]2[CH:20]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: O=Cc1ccc2ccccc2c1Br
Reactant: O=Cc1cccc(Br)c1
Product: O=Cc1cccc(-c2ccccc2)c1

Procedure:
The title compound was synthesized using the same procedure employed for Example 370 (1), but with 3-bromobenzaldehyde as the starting material instead of 1-bromo-2-naphthaldehyde. The product was obtained as a colorless oil (320 mg, 82%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH2:12][N:13]1[CH2:18][CH2:17][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)([OH:19])[CH2:15][CH2:14]1)[CH2:6]2.B(Br)(Br)Br.C(Cl)Cl.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:19][C:16]1([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[CH2:15][CH2:14][N:13]([CH2:12][CH:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[C:3]([OH:2])[CH:4]=3)[NH:8]2)[CH2:18][CH2:17]1
Reactant: COc1ccc2c(c1)CC(CN1CCC(O)(Cc3ccc(C)cc3)CC1)N2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(CC2(O)CCN(CC3Cc4cc(O)ccc4N3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
To (RS)-1-(5-methoxy-2,3-dihydro-1H-indol-2-ylmethyl)-4-(4-methyl-benzyl)-piperidin-4-ol (131 mg, 0.357 mol) in CH2Cl2 (10 ml) was added 1M BBr3—CH2Cl2 (2.14 ml, 2.74 mmol, 6 eq.) at −78° C. over 5 min. The reaction was stirred at RT for 48 hr., then MeOH (20 ml) was added followed by 10% NaHCO3 (20 ml), and the aqueous phase extracted with CH2Cl2 (2×50 ml) and the combined extracts washed with satd. NaCl solution (50 ml), dried over (Na2SO4) filtered and evaporated. Purification of the crude product over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2-MeOH (9:1) afforded (RS)-2-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-ylmethyl]-2,3-dihydro-1H-indol-5-ol as a brown solid (64.6 mg, 0.183 mmol, 51%), Mp. 90-94° C., MS: m/e=353.3 (M+H+).
Reaction SMILES: C([C@H]1COC(=O)N1[C:14]([C@@H:16]1[CH2:20][C:19](=[O:21])[CH2:18][C@H:17]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[O:15])C1C=CC=CC=1.[OH2:29].[OH-].[Li+].OO>O1CCCC1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C@@H:17]2[CH2:18][C:19](=[O:21])[CH2:20][C@H:16]2[C:14]([OH:15])=[O:29])=[CH:23][CH:24]=1
Reactant: O=C1C[C@@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@H](c2ccc(Cl)cc2)C1
Reactant: O
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Temperature: 0 °C

Procedure:
A 100 mL round bottom flask equipped with a magnetic stir bar was charged with a solution of 1.002 g (2.52 mmol) of the product of Step C dissolved in 41 mL of tetrahydrofuran followed by the addition of 9 mL of water. The reaction mixture was stirred and cooled to 0° C. with an external ice-water bath and a fine suspension was observed. Lithium hydroxide (0.120 g, 5.02 mmol) was added followed by 1.71 mL (15.1 mmol) of 30% aqueous hydrogen peroxide. The reaction mixture was stirred for 1 h at room temperature during which time it developed a yellow color. The reaction mixture was then quenched by addition of excess saturated aqueous sodium sulfite and the tetrahydrofuran was removed in vacuo. The residue was extracted three times with methylene chloride to remove the oxazolidinone, then the aqueous layer was adjusted to pH=1-2 with 1 N hydrochloric acid. The aqueous layer was then extracted three times with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and evaporated in vacuo. The residual amorphous yellow solid (0.412 g) was used directly in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])=[O:5].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O.O>[F:13][C:8]1[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[C:12]2[C:7]=1[NH:6][C:4](=[O:5])[CH2:3][CH2:2]2
Reactant: O=[N+]([O-])O
Reactant: O=C(CCCl)Nc1ccccc1F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCc2cc([N+](=O)[O-])cc(F)c2N1
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
To a stirred solution of 8-fluoro-3,4-dihydroquinolin-2(1H)-one (see Example 41 for details), (5 g, 30.3 mmol) in sulfuric acid, cooled to −5° C. was added nitric acid, fuming (1.413 ml, 30.3 mmol) as a 1:1 mixture in water. The resulting mixture was stirred at −5° C. for 20 min. After 20 min the reaction was quenched via addition of ice, precipitating the product which was collected by filtration. The filter cake was dissolved in dichloromethane and a minimal amount of methanol, dried, filtered and concentrated onto silica gel then chromatographed using 0-10% ethyl acetate in dichloromethane to give the desired 8-fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one (5.9 g, 28.1 mmol, 93% yield). 1H NMR (DMSO-d6) δ 10.73 (brs, 1H), 8.03 (m, 1H), 8.02 (m, 1H), 3.08 (t, J=7.5 Hz, 2H), 2.57 (t, J=7.5 Hz, 1H).