Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1F)[O:9][CH2:8][CH2:7][CH:6]2[C:14]([O:16][CH3:17])=[O:15])#[N:2].[OH:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][C:20]=1[CH3:32].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:26]([O:25][C:23]([C:22]1[CH:30]=[CH:31][C:19]([O:18][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]([C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:8][O:9]3)=[CH:4][C:3]=2[C:1]#[N:2])=[C:20]([CH3:32])[CH:21]=1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3C)c(C#N)cc21
Temperature: 150 °C
Yield: 37 %

Procedure:
Methyl 6-cyano-7-fluorochroman-4-carboxylate (0.200 g, 0.850 mmol), tert-butyl 4-hydroxy-3-methylbenzoate (0.195 g, 0.935 mmol) and potassium carbonate (0.141 g, 1.02 mmol) were dissolved in 4 mL of dry DMSO and degassed with argon. The solution was heated in a microwave oven at 150° C. for 15 minutes, then at 170° C. for 15 additional minutes. The reaction was poured into 10% HCl/water (1 L), extracted with ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to a yellow film. The crude product was adsorbed onto silica gel and purified by column using 20-30% ethyl acetate/hexanes to provide the desired product (0.133 g, 37%) as a light yellow foam.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1>CN(C)C=O>[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: NCCCCCO
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCCO)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
A solution of 5-amino-1-pentanol (28.03 g, 271.4 mmol) in N,N-dimethylformamide (200 mL) was added over a period of 45 minutes to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (60.01 g, 271.4 mmol) in N,N-dimethylformamide. The reaction was stirred overnight and then the N,N-dimethylformamide was removed by vacuum distillation. The residue was dissolved in ethyl acetate (500 mL), washed with water (4×75 mL), dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was dissolved in hot ethyl acetate (400 mL). Hexane was added until a clear solution was obtained then the mixture was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration and washed with cold hexane to provide 26.87 g of 5-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]pentan-1-ol as a solid. An additional 4.41 g was isolated from the filtrate.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]([C:24]2[C:28]3[CH:29]=[N:30][CH:31]=[C:32]([F:33])[C:27]=3[N:26]([CH:34]([CH3:37])[CH2:35][OH:36])[CH:25]=2)=[O:23])[CH:19]=[N:20][CH:21]=1>>[F:33][C:32]1[C:27]2[N:26]([CH:34]([CH3:37])[CH2:35][OH:36])[CH:25]=[C:24]([C:22]([C:18]3[CH:17]=[C:16]([NH:15][C:10](=[O:12])[CH2:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:13])=[CH:8][CH:7]=4)[CH:21]=[N:20][CH:19]=3)=[O:23])[C:28]=2[CH:29]=[N:30][CH:31]=1
Reactant: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Product: CC(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(C(F)(F)F)cc3)c2)c2cncc(F)c21

Procedure:
Prepared according to Method M (Example 206) using 4-trifluoromethylphenylacetic acid and (5-aminopyridin-3-yl)[7-fluoro-1-(2-hydroxy-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 1, Preparation 26).
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:31]([O:32]C(=O)C)[C@H:30]([O:36]C(=O)C)[C@@H:29]([CH2:40][O:41]C(=O)C)[O:28][C@H:9]1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]=[CH2:27])=[CH:20][CH:19]=1)(=O)C>CO.O1CCCC1>[O:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]=[CH2:27])=[CH:22][CH:23]=1)[C@@H:9]1[O:28][C@H:29]([CH2:40][OH:41])[C@@H:30]([OH:36])[C@H:31]([OH:32])[C@H:8]1[OH:7]
Reactant: C=CCOc1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCOc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.1 %

Procedure:
Sodium methoxide (28% methanol solution; 0.030 mL) was added to a solution of 2-(4-allyloxybenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.44 g) in methanol (2.5 mL) and tetrahydrofuran (1.5 mL), and the mixture was stirred at room temperature for 4 hours. The solvent of the reaction mixture was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 2-(4-allyloxybenzyl)phenyl β-D-glucopyranoside (0.23 g).
Reaction SMILES: [CH:1]([C@@H:4]1[C@H:9]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:7]2([CH3:8])[C@@H:6]([OH:31])[CH2:5]1)[C@:18]1([CH3:19])[C@H:13]([CH2:14][C@H:15]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH2:16][C@@H:17]1[CH3:23])[CH2:12][CH2:11]3)=[CH:2][CH3:3].[N+](C1C=CC(C(OO)=O)=CC=1)([O-])=[O:33]>C(Cl)CCl>[OH:31][C@H:6]1[CH2:5][C@H:4]([CH:1]2[O:33][CH:2]2[CH3:3])[C@H:9]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:7]12[CH3:8])[C@:18]1([CH3:19])[C@H:13]([CH2:14][C@H:15]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH2:16][C@@H:17]1[CH3:23])[CH2:12][CH2:11]3
Reactant: CC=C[C@H]1C[C@H](O)[C@@]2(C)CC[C@H]3[C@@H](CC[C@H]4C[C@H](OC5CCCCO5)C[C@H](C)[C@@]43C)[C@H]12
Reactant: O=C(OO)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCCl
Product: CC1OC1[C@H]1C[C@H](O)[C@@]2(C)CC[C@H]3[C@@H](CC[C@H]4C[C@H](OC5CCCCO5)C[C@H](C)[C@@]43C)[C@H]12
Reaction time: 1 h
Yield: 74.2 %

Procedure:
36.0 g of 15α-propenyl-17β-hydroxy-1α-methyl-3α-tetrahydropyranyloxy-5α-androstane (German Laid-Open Application 35 39 244, Example 15a) is dissolved in 900 ml of ethylene chloride, combined with 63.0 g of p-nitroperbenzoic acid, and stirred for one hour at 0°-5° C. After dilution with methylene chloride, the mixture is washed with 1-molar sodium hydroxide solution and with water, and evaporated under vacuum. By chromatography on silica gel and crystallization from ether-pentane, 27.7 g of 17β-hydroxy-15α-(1,2-epoxypropyl)-1α-methyl-3α-tetrahydropyranyloxy-5α-androstane is produced, mp 172°-174° C.
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1[C:9]1[C:10](=[O:24])[C:11](=[O:23])[C:12]2[C:21]([CH:22]=1)=[N:20][C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:13]=2.CN1C(=O)N(C)CCC1>C1COCC1>[C:11]1(=[O:23])[C:12]2[C:21](=[N:20][C:19]3[C:14]([CH:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:22]=[CH:9][C:10]1=[O:24]
Reactant: Cc1cc(C)c(C2=Cc3nc4ccccc4cc3C(=O)C2=O)c(C)c1
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: O=C1C=Cc2nc3ccccc3cc2C1=O
Yield: 95 %

Procedure:
Under an atmosphere of argon, 151.4 mg (2.45×10−4 mol) of mesityl-acridine-quinone 43 was dissolved in 30 mL of 0.1M SmI2 in THF. Then, 2.2 mL (18.2 mmol) of DMPU were added dropwise. The reaction mixture was refluxed for 24 hr. Filtration to remove a precipitate and evaporation of solvent yielded an orange oil, which was purified by column chromatography on silica gel with 5% MeOH in CH2Cl2 to afford 48.7 mg (45%) of acridine-quinone 44 as an orange glassy solid: 1H NMR (300 MHz, DMSO-d6, TMS) δ8.54 (d, J=8 Hz, 2H), 7.96 (t, J=7 Hz, 2H), 7.92 (d, J=7 Hz, 1H), 7.79 (d, J=8 Hz, 2H), 7.7-7.6 (m, 3H), 7.51 (t, J=8 Hz, 2H), 6.01 (s, 1H), 4.20 (t, J=6 Hz, 2H), 4.13 (t, J=7 Hz, 2H), 2.1-1.9 (m, 4H), 1.7-1.6 (m, 2H).
Reaction SMILES: [O:1]=[C:2]([CH3:20])[C:3](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[C:4]([O:6][CH3:7])=[O:5].[CH3:21]OC(OC)N(C)C>>[O:1]=[C:2]1[CH:20]=[CH:21][N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[N:8]=[C:3]1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)C(=NNc1cccc(C(F)(F)F)c1)C(C)=O
Product: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of methyl 3-oxo-2-{[3-(trifluoromethyl)phenyl]hydrazono}butanoate (15.20 g, 52.7 mmol) in N,N-dimethylformamide dimethylacetal (150 mL) was heated at reflux for 2 h. After that time, the reaction was cooled to room temperature and then on an ice water bath. The product was collected by filtration to give methyl 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (13.7 g, 87%) as pale yellow crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]([CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:8]2=[O:14].[C:22]1([C:28]2[CH:32]=[C:31]([CH:33]=O)[O:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(N(C(C)C)CC)(C)C>[Cl:2][C:3]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]([CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:33][C:31]3[O:30][N:29]=[C:28]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:32]=3)[CH2:18][CH2:17]1)[C:8]2=[O:14]
Reactant: O=Cc1cc(-c2ccccc2)no1
Reactant: O=c1c2ccc(Cl)c(Cl)c2ccn1CC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c2ccc(Cl)c(Cl)c2ccn1CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
The compound prepared in Example 77 (0.041 g), the compound prepared in Example 7 (0.026 g) and sodium triacetoxyborohydride (0.074 g) were suspended in dichloromethane (5 mL) and diisopropylethylamine (0.10 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=3:1) to obtain the title compound (0.029 g) having the following physical data.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:10]1[C:15]2[C:14](=[CH:14][CH:13]=[CH:12][C:11]=2[NH:10][S:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)(=[O:8])=[O:7])[CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1nccs1
Reactant: c1ccncc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc2cccnc12)c1nccs1
Yield: 15 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoqunoline (250 mg, 1.73 mmol), thiazole-2-sulfonyl chloride (Intermediate 444) (413 mg, 2.25 mmol), pyridine (2 ml), DMAP (cat.) and DCM (2 ml) gave the title compound (110 mg, 15%), after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: C([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([C:32]([O:34]C)=[O:33])=[O:31])=[CH:20][CH:19]=2)[C:7]([C:15]#[N:16])=[C:8]([CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12])[N:9]=1)CCC.[OH-:36].[Na+]>>[CH2:15]([NH:16][C:15]([C:7]1[N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([C:32]([OH:34])=[O:33])=[O:31])=[CH:22][CH:23]=2)[CH:5]=[N:9][C:8]=1[CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12])=[O:36])[CH2:7][CH2:8][CH3:10]
Reactant: CCCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Reactant: [OH-]
Agent: [Na+]
Product: CCCCNC(=O)c1c(C(O)C(C)C)ncn1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1

Procedure:
245 mg of 2-butyl-4-(1-hydroxy-2-methylpropyl)-1-[(2'-methoxalylbiphenyl-4-yl)methyl]imidazole-5-carbonitrile [prepared as described in step (a) above] were subjected to hydrolysis using 6 ml of a 1N aqueous solution of sodium hydroxide in the same manner as described in Example 10(b), to give 187 mg of the title compound as a powder, at softening 144°-146° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:21]([O-:23])=[O:22])=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][N:10](C(=O)C(F)(F)F)[CH2:9][CH2:8][C:7]=2[N:20]=1.C([O-])([O-])=O.[K+].[K+].CO>O>[CH3:1][O:2][C:3]1[C:4]([N+:21]([O-:23])=[O:22])=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[N:20]=1
Reactant: COc1nc2c(cc1[N+](=O)[O-])C(C)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1nc2c(cc1[N+](=O)[O-])C(C)CNCC2
Yield: 98.3 %

Procedure:
Nitric Acid (200 μl) was added dropwise to a stirred solution of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (174 mg, 604 μmol) in H2SO4 (1.5 ml). The reaction mixture was added into cold water after 3 d of stirring at room temperature. K2CO3 was added to neutralize the mixture to pH=8. After extraction with EtOAc, the organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 155 mg (77%) of 2-methoxy-5-methyl-3-nitro-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 334. After treatment of 2-methoxy-5-methyl-3-nitro-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (30.0 mg, 90.0 μmol) with K2CO3 (30 mg), methanol (1 ml) and H2O (0.2 ml) at 60° C. for 10 minutes, the reaction was quenched with sat. aq. NH4Cl and extracted with DCM. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 21 mg (99%) of 2-methoxy-5-methyl-3-nitro-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 8.10 (s, 1H), 4.09 (s, 3H), 3.25 (m, 2H), 3.10 (m, 3H), 2.93 (dd, 1H), 2.72 (dd, 1H), 1.39 (d, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].[Br:17][CH2:18][C:19](Br)=[O:20]>C1C=CC=CC=1>[Br:17][CH2:18][C:19]([NH:1][C:2]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5])=[O:20]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(I)cc1C(=O)c1ccccn1
Solvent: c1ccccc1
Product: O=C(CBr)Nc1ccc(I)cc1C(=O)c1ccccn1
Reaction time: 0.5 h

Procedure:
To a suspension of 18.7 g of 2-(2-amino-5-iodobenzoyl)pyridine (R. I. Fryer, P. Zhang & R. Rios, Synth.Commun. 1993, 23, 985-992) in 760 ml of benzene were added 10.2 ml of bromoacetyl bromide and the mixture was heated to reflux temperature for 20 h. After cooling the crystals are filtered off and these are then stirred for 30 min. in a mixture of 3 l of saturated aqueous sodium hydrogen (sic) carbonate solution and 1 l of dichloromethane. The aqueous phase was separated and extracted again with dichloromethane. The dichloromethane solutions were dried over sodium sulphate and evaporated. The dark brown crystalline residue (25 g) was chromatographed over 400 g of silica gel. With toluene/ethyl acetate 8:1 there were eluted 19.1 g of the desired product which was recrystallized from ethanol/diethyl ether. There were obtained 17.6 g of 2-[2-(bromoacetylamino)-5-iodobenzoyl]-pyridine, which was used without further purification for the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18]([OH:20])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Si]([O:51][CH2:52][C@H:53]([C:55]1[CH:56]=[N:57][C:58]([CH3:61])=[N:59][CH:60]=1)[NH2:54])(C(C)(C)C)(C)C.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:51][CH2:52][C@@H:53]([NH:54][C:18]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:11]=1)=[O:20])[C:55]1[CH:56]=[N:57][C:58]([CH3:61])=[N:59][CH:60]=1
Reactant: Cc1ncc([C@H](N)CO[Si](C)(C)C(C)(C)C)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](CO)c3cnc(C)nc3)cc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-(methylsulfonyl)biphenyl-3-carboxylic acid (35 mg, 0.12 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (46 mg, 0.24 mmol), 1-hydroxybenzotriazole hydrate (18 mg, 0.12 mmol), and CH2Cl2 (3 mL) were added (S)-2-(tert-butyldimethylsilyloxy)-1-(2-methylpyrimidin-5-yl)ethanamine (48 mg, 0.18 mmol) (WO 2008/130481) and N,N-diisopropylethylamine (42 μL, 0.24 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was dissolved in MeOH (5 mL) and concentrated HCl solution (0.5 mL) was added. The mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-80% MeCN-water[10 mM Et2NH]) to afford a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[CH:11]=2)=O)[CH:5]=[CH:6][CH:7]=1.O.[NH2:21][NH2:22].CC1C=CN=C(N)C=1C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:22][N:21]=[C:8]2[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[CH:11]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(Cl)c2F)cc1F
Agent: Cc1ccnc(N)c1C
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1F

Procedure:
Prepared according to Method D, Step A from (3-chloro-2-fluorophenyl)(3-fluoro-4-methoxyphenyl)methanone (0.80 g, 2.83 mmol), hydrazine hydrate (1 mL), dimethyl-aminopyridine (0.390 g) and pyridine (5 mL). The reaction mixture was combined with a previous batch at this stage and the title compound was obtained as a white solid and recrystallized from ethyl acetate/hexane (1.30 g, 4.79 mmol, 83%).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH2:18][CH:19]([OH:24])[C:20]([O:22]C)=[O:21])[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3>CCO>[Br:17][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:18][CH:19]([OH:24])[C:20]([OH:22])=[O:21])[C:7]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][C:4]([Br:3])=[CH:5][CH:6]=3
Reactant: COC(=O)C(O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.5 %

Procedure:
NaOH (0.64 mL, 1M solution in H2O) was added to a suspension of methyl 3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropanoate (0.055 g, 0.129 mmol) in EtOH (2.6 mL) and the reaction was stirred at ambient temperature for 2.5 h. The reaction was concentrated in vacuo and the residue was acidified with 1N aqueous HCl. The mixture was extracted with EtOAc (3×), and the combined organics were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated in vacuo to afford the desired product as a white solid (53 mg, 99%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:6])[CH3:3]>O1CCOCC1>[CH2:2]([O:4][C:5]([C:7]1([CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1(COCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1(COCc2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of hydrochloric acid (12N, 1.5 mL) in dioxane (7.5 mL) is added to 4-benzyloxymethylpiperidine-1,4-dicarboxylic acid-1-tert butyl ester-4-ethyl ester (1.9 g, 0.005 mol) and stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure and the residue is treated with aqueous solution of sodium bicarbonate to adjust the pH to 8-9. It is again concentrated under reduced pressure and the residue is treated with dichloromethane. After drying over sodium sulfate solvent is removed to get 4-benzyloxymethylpiperidine-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Cl)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([NH2:30])[CH2:25]1.CC(C)([O-])C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:30][CH:26]3[CH2:27][CH2:28][CH2:29][N:24]([CH3:23])[CH2:25]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCCC(N)C1
Reactant: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1Cc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc(NC3CCCN(C)C3)c3nnc(C)n32)n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A degassed mixture of 6-benzyl-4-chloro-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (25.0 mg, 0.0804 mmol, Example 228, Step 7), 1-methylpiperidin-3-amine (37 mg, 0.32 mmol, racemic, ChemBridge), Sodium tert-butoxide (15 mg, 0.16 mmol, Aldrich), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (9.3 mg, 0.016 mmol, Aldrich) and tris(dibenzylideneacetone)dipalladium(0) (7.4 mg, 0.0080 mmol, Aldrich) in toluene (1.2 mL) was heated at 100° C. overnight. Additional 1-methylpiperidin-3-amine (37 mg, 0.32 mmol), sodium tert-butoxide (15 mg, 0.16 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (46 mg, 0.080 mmol) and tris(dibenzylideneacetone)dipalladium(0) (44 mg, 0.040 mmol), were added, the mixture was again degassed and heating at 100° C. was continued for 3 hours. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted with two further portions of EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The product was purified via preparative HPLC-MS (Waters SunFire C18, eluting with a gradient of MeOH/H2O containing 0.1% TFA), followed by repurification using HPLC-MS (Waters SunFire C18, eluting with a gradient of MeCN/H2O containing 0.1% TFA), again followed by a final purification using HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product as the free base. Yield: (3 mg, 10%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6](NC(=O)C)=[CH:7][CH:8]=2)[NH:3]1.NC1C=C2C(=CC=1)[NH:21][C:20](=[O:25])[CH2:19]2>>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:21][C:20](=[O:25])[CH3:19])[CH:8]=2)[NH:3]1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Product: CC(=O)Nc1ccc2c(c1)CC(=O)N2

Procedure:
According to procedure for the synthesis of N-(2-oxoindolin-6-yl)acetamide, except substituting 5-aminoindolin-2-one (50 mg, 0.34 mmol), the title compound was prepared as a beige solid (46 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.31 (d, J=7.0 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 3.52 (s, 2H), 2.10 (s, 3H).