Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C2C(=CC([C:11]3[S:12][C:13]4[C:19]([C:20]5[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=5)=[C:18]([C@H:27]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]([CH3:38])=[CH:16][C:14]=4[N:15]=3)=CC=2)N(C)N=1.Br[C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[N:46]([CH3:50])[N:45]=[C:44]2[NH2:51]>>[NH2:51][C:44]1[C:43]2[C:47](=[CH:48][CH:49]=[C:41]([C:11]3[S:12][C:13]4[C:19]([C:20]5[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=5)=[C:18]([C@H:27]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]([CH3:38])=[CH:16][C:14]=4[N:15]=3)[CH:42]=2)[N:46]([CH3:50])[N:45]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(N)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Reactant: Cn1nc(N)c2cc(Br)ccc21
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(N)nn4C)sc2c1-c1ccc(Cl)cc1

Procedure:
Prepared in a manner similar to (S)-ethyl 2-(2-(3-amino-1-methyl-1H-indazol-6-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate except using 5-bromo-1-methyl-1H-indazol-3-amine instead of 6-bromo-1-methyl-1H-indazol-3-amine. LCMS-ESI+: calc'd for C30H31ClN4O3S: 563.2, 565.2 (M+H+); Found: 563.3, 565.2 (M+H+).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=O)[C:5]1=[O:29])[CH:2]=[CH2:3].[C@@H:31]12[CH2:37][C@@H:34]([NH:35][CH2:36]1)[CH2:33][O:32]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C@@H:31]12[CH2:37][C@@H:34]([N:35]([CH2:25][C@@H:24]([N:6]3[C@H:7]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[C@@H:8]([C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=4)[CH2:9][C@@:4]([CH2:1][CH:2]=[CH2:3])([CH3:30])[C:5]3=[O:29])[CH2:27][CH3:28])[CH2:36]1)[CH2:33][O:32]2
Reactant: C1O[C@H]2CN[C@@H]1C2
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2C[C@H]3C[C@@H]2CO3)C1=O
Reaction time: 8 h

Procedure:
To a solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (100 mg, 0.224 mmol; Example 91, Step C) in DCE (2 mL) was added (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane (Butora, G.; Goble, S.; Pastemak, A.; Yang, L.; Zhou, C.; Moyes, C. U.S. Patent Publication No. 2008/0081803 (50 mg, 0.504 mmol) followed by sodium triacetoxyborohydride (95 mg, 0.448 mmol) and acetic acid (1.2 μL, 0.022 mmol). After stirring overnight, the mixture was quenched with sat. aq. NaHCO3 solution. The mixture was extracted with ethyl acetate (2×). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 1 to 5% methanol/dichloromethane) to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[S:3]([CH2:6][C:7](OC)=[O:8])(=[O:5])=[O:4].[NH2:25][OH:26]>>[OH:26][NH:25][C:7](=[O:8])[CH2:6][S:3]([N:2]([CH3:1])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)(=[O:5])=[O:4]
Reactant: NO
Reactant: COC(=O)CS(=O)(=O)N(C)CCc1ccc(-c2ccccc2)cc1
Product: CN(CCc1ccc(-c2ccccc2)cc1)S(=O)(=O)CC(=O)NO

Procedure:
In a manner similar to Example 1 (b), methyl 2-({methyl-[2-(biphen-4-yl)ethyl]amino}sulfonyl)acetate was reacted with hydroxylamine to give the title compound as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([OH:28])[CH:22]=3)=[N:19][N:20]=2)[C@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>N1C=CC=CC=1.C(Cl)Cl>[C:32]([O:28][C:23]1[CH:22]=[C:21]([C:18]2[O:17][C:16]([C@H:12]([NH:11][C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@H:13]([O:15][C:16](=[O:17])[CH2:12][CH2:13][CH3:14])[CH3:14])=[N:20][N:19]=2)[CH:26]=[CH:25][C:24]=1[F:27])(=[O:33])[CH2:31][CH2:30][CH3:29]
Reactant: CCCC(=O)Cl
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(F)c(O)c3)o2)[C@@H](C)O)ccc(C#N)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)Oc1cc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@@H](C)OC(=O)CCC)o2)ccc1F
Reaction time: 23 h

Procedure:
To a solution of 2-chloro-4-((1R,2R)-1-(5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (Example 41) (135.5 mg, 0.34 mmol) in pyridine (0.6 mL) and CH2Cl2 (4 mL) was added n-butyryl chloride (0.17 mL, 1.68 mmol). Upon complete addition the reaction mixture was stirred for 23 h, then quenched with 10% aqueous HCl (6 mL). The mixture was partitioned between H2O (40 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (40 mL). The combined organic extracts were washed with NaHCO3 (45 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (20-25% EtOAc in hexanes) to provide the title compound as an off white solid (137.3 mg, 74%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 7.94 (ddd, J=2.2, 4.5, 8.6 Hz, 1H), 7.86 (dd, J=2.0, 7.0 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.52 (dd, J=8.8, 10.0 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 6.13 (d, J=8.8 Hz, 1H), 5.68 (pentet, J=6.5 Hz, 1H), 5.36 (dd, J=6.5, 8.4 Hz, 1H), 2.67 (t, J=7.2 Hz, 2H), 2.28-2.22 (m, 2H), 2.07-2.03 (m, 2H), 1.82-1.71 (m, 2H), 1.53 (d, J=6.5 Hz, 3H), 1.03 (t, J=7.2 Hz, 3H), 0.82 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(O)(=O)C.[N+:14]([O-])([OH:16])=[O:15]>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[OH:9]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(F)cc1Cl
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)cc(Cl)c1O
Temperature: 0 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
2-Chloro-4-fluorophenol (5.64 g, 38.5 mmol) was added to a solution of acetic acid (16.5 mL), nitric acid (8.66 mL) and water (7.5 mL) at 0° C. The reaction mixture was stirred vigorously for 5 hours at 0° C. The resulting precipitate was, filtered, washed with water and dried under vacuum to yield 2-chloro-4-fluoro-6-nitrophenol (6.12 g, 32.0 mmol, 83%) as a yellow powder.
Reaction SMILES: [N+]([O-])(O)=O.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH:15][C:16]([NH2:18])=[NH:17].CN(C)[CH:21]=[CH:22][C:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=O.[OH-].[Na+]>C(O)(C)C>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH:15][C:16]1[N:18]=[C:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][N:17]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Reactant: CN(C)C=CC(=O)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Temperature: 0 °C

Procedure:
To a mixture of 2-methyl-5-nitrophenylguanidine nitrate (25 g, 96 mmol) and 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (17 g, 96 mmol) in isopropanol (200 ml) was added sodium hydroxide (4.5 g). The reaction was refluxed for 12 hours and cooled to 0° C. The precipitate was filtered and washed with isopropanol to give N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25](N(CC)CC)[CH3:26]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1[C:25]#[CH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(I)c(OCc2ccccc2)ccn1Cc1cccc(F)c1
Reactant: CCN(CC)CC
Solvent: CC#N
Product: C#Cc1c(OCc2ccccc2)ccn(Cc2cccc(F)c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Degassed a solution of 4-(benzyloxy)-1-(3-fluorobenzyl)-3-iodopyridin-2(1H)-one (2.01 g, 4.62 mmol) in anhydrous acetonitrile (25 mL) under argon atmosphere. Triethylamine (1.11 g, 11 mmol) was added and quickly degassed. The reaction mixture was chilled in an ice bath for 15 minutes before adding bistriphenylphosphine-palladium chloride (0.34 g, 0.48 mmol) and cuprous iodide (0.2 g). The reaction was stirred at room temperature for 30 minutes before heating at 60° C. under an atmosphere of argon for 2 hours. The reaction mixture was filtered through a bed of celite and the filtrate was concentrated under reduced pressure. The dark brown residue was diluted with CH2Cl2 (100 mL) and washed with water. The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The dark brown residue was purified by flash chromatography using 30% ethyl acetate in hexane. The appropriate fractions were combined and concentrated under reduced pressure to afford the desired product (1.34 g, 72%) as a light yellow solid. 1H-NMR (CD3OD, 400 MHz) δ 7.74 (d, 1H, J=7.6 Hz), 7.47 (d, 2H, J=7.6 Hz), 7.35 (m, 4H), 7.09 (m, 3H), 6.46 (d, 1H, J=7.6 Hz), 5.26 (s, 2H), 5.13 (s, 2H), 0.18 (s, 9H); ES-HRMS m/z 406.1638 (M+H calculated for C24H25NO2FSi requires 406.1610). Step 3. Preparation of 4-(benzyloxy)-3-ethynyl-1-(3-fluorobenzyl)pyridin-2(1H)-one
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]1([C@H:17]([CH2:19][OH:20])[NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:18][C@H:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:19][OH:20])=[O:6]
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: ClCCl
Product: O=C(N[C@@H](CO)c1ccccc1)c1cccc(Br)c1
Reaction time: 3 h

Procedure:
To a vigorously stirred solution of 3-bromobenzoyl chloride (13 g, 58 mmol) in dichloromethane (500 ml) was rapidly added a solution of (R)-(-)-2-phenyl-glycinol (10.5 g, 76 mmol) in dichloromethane (50 ml). The reaction mixture was stirred for 3 h and insolubles removed by filtration. Concentration of the filtrate gave 2-(3-bromobenzamido)-2(R)-phenylethan-1-ol as colorless solids (18.5 g, quant).
Reaction SMILES: [OH:1][CH:2]([CH2:19][OH:20])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[K+].[OH:23][CH:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:25]([O:27]C)=O>>[OH:1][CH:2]([CH2:19][OH:20])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:25](=[O:27])[CH:24]([OH:23])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCCCCCC(O)C(=O)OC
Reactant: CCCCCCCCCCCCCCNCC(O)CO
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCC(O)C(=O)N(CCCCCCCCCCCCCC)CC(O)CO

Procedure:
N-(2,3-dihydroxypropyl)-N-tetradecylamine (1.00 g, 0.0035 mole) and potassium hydroxide (0.01 g, 0.18 mmole) were heated to 85° C. under vacuum and methyl 2-hydroxyhexadecanoate (0.94 g, 0.0035 mole) was heated and added dropwise to the reaction. The reaction was heated under vacuum for 6 hours. A waxy off-white solid was obtained (crude yield=1.8 g). The waxy solid was recrystalized from hot hexane (yield=1.09 g)
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].CCN(CC)CC.CC(C)(C)C(Cl)=O.[CH3:22][C@H:23]1[C@@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:26][C:25](=[O:34])[NH:24]1.[Li+].[Cl-]>C1COCC1>[CH3:22][C@H:23]1[C@@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:26][C:25](=[O:34])[N:24]1[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)O
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. stirred solution of valeric acid (3.83 mL, 35.2 mmol) and Et3N (14.7 mL, 106 mmol) in dry THF (175 mL) was added trimethylacetyl chloride (5.29 mL, 42.3 mmol) dropwise. The mixture was stirred at 0° C. for 1 hour and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone (7.50 g, 42.3 mmol) was added followed by LiCl (1.79 g, 42.3 mmol). The reaction was warmed to room temperature overnight with good stirring. The mixture was filtered and the filtrate was concentrated under reduced pressure. Et2O (75 mL) was added to the residue, which was washed with sat. NaHCO3 (3×40 mL), 1N HCl (3×40 mL), and brine (2×40 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give a quantitative yield of crude product.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]([C:22]#[N:23])=[N:11][N:12]([CH2:19][CH2:20][CH3:21])[C:13]=1[CH2:14][CH2:15][CH2:16][CH2:17][Cl:18]>C(O)C>[Cl:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]1[N:12]([CH2:19][CH2:20][CH3:21])[N:11]=[C:10]2[C:9]=1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:2]=[C:22]2[NH2:23]
Reactant: CCCn1nc(C#N)c(-c2ccccc2N)c1CCCCCl
Agent: Cl
Solvent: CCO
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Yield: 63.7 %

Procedure:
Hydrochloric acid (18 mL, 71.0 mmol) in ethanol was added dropwise to a solution of 4-(2-aminophenyl)-5-(4-chlorobutyl)-1-propyl-1H-pyrazole-3-carbonitrile (7.50 g, 23.7 mmol) in 150 mL of ethanol. The resultant solution was heated to reflux overnight, concentrated under reduced pressure, and diluted with water. The pH of the mixture was adjusted to 9-10 by slow addition of solid sodium carbonate. The aqueous layer was extracted with several portions of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford a reddish solid. The material was purified via flash column chromatography on silica gel (eluting with a 96:4 mixture of dichloromethane/methanol) to afford 4.78 g of 1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](O)=[N:13][C:12]([C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:31])=O.C(N(CC)C1C=CC=CC=1)C>>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:31])=[N:13][C:12]([C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccc(C(F)(F)F)nc2)nc2c1CCN(Cc1ccccc1)C2
Solvent: CCN(CC)c1ccccc1
Product: FC(F)(F)c1ccc(-c2nc(Cl)c3c(n2)CN(Cc2ccccc2)CC3)cn1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of 232 mg (0.6 mmol) of 7-benzyl-2-[6-(trifluoromethyl)pyridin-3-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol from Step A and 1.0 mL of phosphorous oxychloride in a 25-mL round bottom flask was treated with 90 mg (0.095 mL, 0.6 mmol) of N,N-diethylaniline. The mixture was warmed to 110° C. After 4 h, it was cooled to ambient temperature and concentrated in vacuo. Water (15–20 mL) was added. The mixture was neutralized by the addition of solid sodium bicarbonate and extracted with 2 portions of ethyl acetate. The combined organic phases were washed with brine, dried, and concentrated. Purification by flash chromatography (silica gel, 0 to 20% ethyl acetate/hexane step gradient) gave 220 mg of a light yellow oil. LC-MS 405.2 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:32])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=1)[C:11]([CH3:31])([CH3:30])[CH2:10]2)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:32][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([N:27]([CH3:29])[CH3:28])=[CH:25][CH:26]=3)[CH:18]=[CH:19][CH:20]=1)[C:11]([CH3:31])([CH3:30])[CH2:10]2
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(-c3ccc(N(C)C)cc3)c1)C(C)(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(C)c1ccc(-c2cccc(C3Nc4c(cc(Cl)cc4C(=O)O)CC3(C)C)c2)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a stirred mixture solution of 6-chloro-2-(4′-dimethylamino-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (400 mg, 0.9 mmol) in methanol (5.0 mL) and tetrahydrofuran (6.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 6-chloro-2-(4′-dimethylamino-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (351 mg, 90%) as a white solid: LC/MS m/e calcd for C26H27ClN2O2 (M+H)+: 435.98, observed: 435.0.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21]O)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:15][CH:14]=3)=[O:9])=[CH:23][CH:24]=1
Reactant: C1COCCN1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CO)cc2c1O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CN3CCOCC3)cc2c1O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide from Example No. 166 (1.0 g), collidine (0.45 mL), and DMAP (60.0 mg) in 50 mL anhydrous DMF is cooled to 0° C. Methanesulfonyl chloride (0.25 mL) is added dropwise. The reaction is stirred at room temperature for approx. 2-3 h. Morpholine (0.34 mL) is added. The product is precipitated by addition of H2O. The crude product is adsorbed onto silica and chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC were combined and condensed to afford 352 mg of the title compound as a white solid.
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH3:38][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[CH2:5][CH2:4]1
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.1 %

Procedure:
Formaldehyde (37% in H2O; 15.6 μL, 0.210 mmol) was added to a suspension of 2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (I1) (25 mg, 0.053 mmol) in anhydrous methanol (5 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (0.111 g, 0.525 mmol) was then added in one portion to the reaction mixture. The reaction was stirred at room temperature for 1.5 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (25 mL) and saturated aq. NaHCO3 (25 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL), the combined organic layers were washed with water (25 mL), brine (25 mL) and dried over Na2SO4. The solvent was removed under reduced pressure yield a white solid. The solid was suspended in DCM (2 mL) and cyclohexane (10 mL) then filtered to afford the title compound (16) (19 mg, 73%) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.14 (s, 1H), 8.65 (s, 1H), 7.70-7.61 (m, 2H), 7.44 (s, 1H), 7.27-7.12 (m, 6H), 6.93 (s, 1H), 3.50 (s, 2H), 3.14-2.97 (m, 4H), 2.88 (d, J=10.6 Hz, 2H), 2.46-2.36 (m, 1H), 2.22 (s, 3H), 2.07-1.93 (m, 2H), 1.78-1.58 (m, 4H). LCMS Method C: rt 4.86 min; m/z 498 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]([N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22]3[CH:27]=[C:26]([N:28]4[C:36]5[C:31](=[CH:32][C:33]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:34][CH:35]=5)[CH2:30][CH2:29]4)[N:25]=[CH:24][N:23]=3)[CH2:17][CH2:16]2)=[O:14])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([O:12][C:13]([N:15]2[CH2:16][CH2:17][CH:18]([O:21][C:22]3[CH:27]=[C:26]([N:28]4[C:36]5[C:31](=[CH:32][C:33]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:34][CH:35]=5)[CH2:30][CH2:29]4)[N:25]=[CH:24][N:23]=3)[CH2:19][CH2:20]2)=[O:14])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(OC(=O)N2CCC(Oc3cc(N4CCc5cc(S(C)(=O)=O)ccc54)ncn3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OC3CNC3)CC2)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Half of 22a was dissolved in 2.5 mL of DCM and 2.5 mL of TFA was added. The mixture was stirred at room temperature for 2 h then evaporated. The crude material was purified by preparative HPLC to afford 22-1, LCMS 474.1 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:17]2[C:12](=[N:13][C:14]([C@@H:24]([NH2:26])[CH3:25])=[C:15]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][CH:19]=3)[CH:16]=2)[CH:11]=[CH:10]1.[Cl:27][C:28]1[C:33]([C:34]#[N:35])=[C:32](Cl)[N:31]=[C:30]([S:37][CH3:38])[N:29]=1.CCN(CC)CC>C1COCC1>[Cl:27][C:28]1[C:33]([C:34]#[N:35])=[C:32]([NH:26][C@H:24]([C:14]2[N:13]=[C:12]3[CH:11]=[CH:10][N:9]([CH3:8])[C:17]3=[CH:16][C:15]=2[C:18]2[N:22]([CH3:23])[N:21]=[CH:20][CH:19]=2)[CH3:25])[N:31]=[C:30]([S:37][CH3:38])[N:29]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc(Cl)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2-c2ccnn2C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine 2,2,2-trifluoroacetate (1562 mg, 4.23 mmol) in THF (27.5 mL) along with 4,6-dichloro-2-(methylthio)pyrimidine-5-carbonitrile (931 mg, 4.23 mmol) and Et3N (1297 μL, 9.31 mmol) were added to a pear-shaped flask. The resulting mixture was stirred at room temperature for 2 hours and then concentrated to give the title compound, which was used in next step without further purification. ESI-MS m/z [M+H]+ calc'd for C20H19ClN8S, 439.11. found 439.4.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:23])[C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[N:18][CH:17]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C1CCCCC=1>CCO.[OH-].[OH-].[Pd+2]>[CH3:22][C:20]1[CH:19]=[N:18][CH:17]=[C:16]([CH:21]=1)[C:15]([NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:23]
Reactant: Cc1cncc(C(=O)NC2CCN(Cc3ccccc3)CC2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Cc1cncc(C(=O)NC2CCNCC2)c1
Yield: 102.6 %

Procedure:
N-(1-Benzyl-piperidin-4-yl)-5-methyl-nicotinamide (1.3 g, 4 mmol), Pd(OH)2/C (0.1 g) and cyclohexene (2 ml) were heated at reflux in EtOH (15 mL) for 2 h, after which time the reaction was filtered hot through a pad of Hyflo. The filtrate was concentrated to afford the title compound as a white powder (0.9 g, 98%).