Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:17])[O:6][C:7]2[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]([OH:16])[C:8]=2[C:9]=1[CH3:10].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[OH:16][C:11]1[C:8]2[C:9]([CH3:10])=[C:4]([CH2:3][CH2:2][N:29]3[CH2:28][CH2:27][N:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][CH3:18])[CH2:31][CH2:30]3)[C:5](=[O:17])[O:6][C:7]=2[CH:14]=[C:13]([OH:15])[CH:12]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1c(CCCl)c(=O)oc2cc(O)cc(O)c12
Product: COc1ccccc1N1CCN(CCc2c(C)c3c(O)cc(O)cc3oc2=O)CC1
Yield: 23 %

Procedure:
Process B; starting materials: 3-(2-chloroethyl)-5,7-dihydroxy-4-methyl-2H-1-benzopyran-2-one (Example 36) and 1-(2-methoxyphenyl)piperazine; yield 23% of crude crystalline product.
Reaction SMILES: Cl.[CH3:2][NH:3]C.C[Al](C)C.C[O:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[C:14]([C:23]2[N:27]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]3[CH:32]=[CH:33][C:34]([C:36]4[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=4)=[CH:35][C:25]=3[N:24]=2)[CH:13]=1.O>C1(C)C=CC=CC=1>[NH2:42][C:39]1[N:38]=[CH:37][C:36]([C:34]2[CH:33]=[CH:32][C:26]3[N:27]([C:28]([CH3:29])([CH3:30])[CH3:31])[C:23]([C:14]4[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=4[N:18]4[CH:22]=[N:21][CH:20]=[N:19]4)[C:11]([NH:3][CH3:2])=[O:10])=[N:24][C:25]=3[CH:35]=2)=[CH:41][N:40]=1
Reactant: COC(=O)c1ccc(-n2cncn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Reactant: CNC
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CNC(=O)c1ccc(-n2cncn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 24.2 %

Procedure:
To a solution of dimethlyamine hydrochloride (20 mg, 0.3 mmol) in dry toluene (8 mL) is added AlMe3 (0.22 mL, 0.45 mmol) at room temperature. The solution is stirred at the same temperature for 15 minutes. 3-[5-(2-Amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzoimidazol-2-yl]-4-[1,2,4]triazol-1-yl-benzoic acid methyl ester (example 7) (70 mg, 0.15 mmol) is added to the solution and it is heated to 90° C. for 12 hours. The mixture is cooled down to room temperature and water (10 mL) is added. The mixture is extracted with EtOAc (3×10 mL) and the combined organic layer is dried by Mg2SO4 (300 mg) and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (17 mg, 25%). LCMS (ESMS): m/z 468.20 (M++1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[N:10](CC=C)[CH2:9]1.B(F)(F)F.CCOCC>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:14])(=[O:15])[NH:10][CH2:9]1
Reactant: C=CCN1CC(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CCS1(=O)=O
Agent: [Pd]
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)NC3)c(F)c2)C(=O)O1
Yield: 58.9 %

Procedure:
N-[[(5S)-3-[3-Fluoro-4-[tetrahydro-1,1-dioxido-2-(2-propenyl)-2H-1,2-thiazin-4-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (350 mg, 0.82 mmol), 10% palladium on carbon (500 mg), boron trifluoride etherate (179 mg, 1.26 mmol) and absolute ethanol (8 ml) are heated under reflux for 5 hr. Upon cooling the suspension is filtered and evaporated. Chromatography over silica gel (55 g) eluting with 2-6% methanol-chloroform affords the title compound as a foam (186 mg, 59%). HRMS(FAB): calcd for m+H=386.1186; Found: 386.1194.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7].CCN(C(C)C)C(C)C.Cl[C:26]([O:28][C@@H:29]1[CH2:34][C@H:33]([CH3:35])[CH2:32][CH2:31][C@H:30]1[CH:36]([CH3:38])[CH3:37])=[O:27].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:11]([O:10][C:9]([NH:8][C:3]1([CH3:7])[CH2:4][CH2:5][CH2:6][CH:2]1[NH:1][C:26](=[O:27])[O:28][C@@H:29]1[CH2:34][C@H:33]([CH3:35])[CH2:32][CH2:31][C@H:30]1[CH:36]([CH3:38])[CH3:37])=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1(C)CCCC1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl N-(2-amino-1-methylcyclopentyl)carbamate (Intermediate 24; 5.49 ml, 26.1 mmol) in DCM (87 ml) at 0° C. was added DIPEA (4.56 ml, 26.1 mmol) followed by (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl chloroformate (CAS number 14602-86-9; 17.15 g, 78 mmol) drop wise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was diluted with DCM (150 ml) and a saturated solution of sodium bicarbonate solution (200 ml). The aqueous layer was re-extracted with DCM (100 ml) and the combined organics were washed further with a saturated solution of sodium bicarbonate (100 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)Cl.[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])([CH3:15])([CH3:14])[CH3:13]>C(OCC)(=O)C>[C:12]([C:16]1[CH:21]=[C:20]([C:1](=[O:3])[CH3:2])[CH:19]=[CH:18][C:17]=1[OH:22])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccccc1O
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(O)c(C(C)(C)C)c1
Temperature: 0 °C
Yield: 55 %

Procedure:
Acetyl chloride (287 g) was added to a mixture of aluminum chloride (488 g) and methylene chloride (1.8 l) at −60° C. while stirring. 2-tert-Butylphenol (500 g) was added at −70° C. to −50° C. over a period of 1.5 hours, and the temperature was then raised to 0° C. The reaction mixture was poured into ice and extraction was performed with ethyl acetate. The organic layer was washed with brine, the solvent was distilled off under reduced pressure, methanol (1 l) and potassium carbonate (300 g) were added to the residue and the mixture was stirred at room temperature for 2 hours. After adding water to the reaction mixture and neutralizing it with concentrated hydrochloric acid, extraction was performed with ethyl acetate and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane was added to the residue and the resulting crystals were filtered off to yield the title compound (352 g) as white crystals.
Reaction SMILES: C[O:2][CH:3]=[CH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1>O1CCCC1>[C:15]([C:14]1[CH:17]=[CH:18][C:11]([C@H:8]2[CH2:9][CH2:10][C@H:5]([CH2:4][CH:3]=[O:2])[CH2:6][CH2:7]2)=[CH:12][CH:13]=1)#[N:16]
Reactant: COC=C[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2CC[C@H](CC=O)CC2)cc1

Procedure:
A solution of 10.1 g of p-[trans-4-(2-methoxyvinyl)cyclohexyl]benzonitrile in 200 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) was heated to reflux for 1 hour while stirring. The mixture was subsequently partitioned three times in diethyl ether/water. The organic extracts were washed twice with water, dried over magnesium sulphate, filtered and evaporated, there being obtained 9.8 g of 2-[trans-4-(p-cyanophenyl)cyclohexyl]acetaldehyde as a light yellowish, crystalline residue.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9](O)=O)=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[N:62]1[CH:67]=[CH:66][C:65]([NH2:68])=[C:64]([NH2:69])[CH:63]=1>CN(C=O)C.CCOC(C)=O>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]2[NH:69][C:64]3[CH:63]=[N:62][CH:67]=[CH:66][C:65]=3[N:68]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccncc1N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)c1nc2ccncc2[nH]1
Reaction time: 0.17 h

Procedure:
To a solution of (S)-3-(biphenyl-4-yl)-2-(tert-butoxycarbonylamino)propanoic acid (400 mg, 1.172 mmol) in DMF (5 mL) were added BOP (580 mg, 1.289 mmol) and DIPEA (0.246 mL, 1.406 mmol) at room temperature. After being stirred for 10 minutes, pyridine-3,4-diamine (130 mg, 1.230 mmol) was added and stirred for 1 hour. The reaction mixture was diluted with EtOAc and washed with H2O and brine. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel flash column chromatography (10% MeOH in DCM/DCM). The obtained residue was stirred in acetic acid (5 mL) for 4 hours. The reaction mixture was concentrated and purified by silica gel flash column chromatography to give (S)-tert-butyl 2-(biphenyl-4-yl)-1-(3H-imidazo[4,5-c]pyridin-2-yl)ethylcarbamate; 1H NMR (400 MHz, CDCl3) δ 1.41 (s, 9H), 3.33-3.56 (m, 2H), 5.18-5.27 (m, 1H), 5.37-5.48 (m, 1H), 7.22-7.29 (m, 2H), 7.30-7.36 (m, 1H), 7.42 (t, J=7.83 Hz, 2H), 7.48-7.58 (m, 4H), 7.60-7.66 (m, 1H), 8.32 (d, J=5.81 Hz, 1H), 8.94 (s, 1H); MS: m/z (MH+) 415.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.O.[NH2:11][NH2:12].C(O)CC>ClC>[NH:11]([C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1)[NH2:12]
Reactant: NN
Reactant: Fc1cnc(F)c(F)c1
Agent: CCl
Solvent: CCCO
Solvent: O
Product: NNc1ncc(F)cc1F
Yield: 85.6 %

Procedure:
6.65 g of the compound obtained in Step 3 and 4.6 ml of hydrazine monohydrate were added to 100 ml of n-propanol. The resulting mixture was refluxed for 6 hours, and distilled under a reduced pressure to remove the solvent. The residue thus obtained was dissolved in 80 ml of chloromethane, washed with water, and dried over anhydrous magnesium sulfate. The resulting organic layer was concentrated under a reduced pressure to obtain 6.20 g (yield: 85.6%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[Cl:11]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)ccc1Cl
Temperature: 25 °C

Procedure:
To a stirred solution of 5-amino-2-chloro-benzoic acid (50 g, 291 mmol) in methanol (300 mL) was added thionyl chloride (45 mL, 605 mmol) dropewise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 5-amino-2-chloro-benzoic acid methyl ester (54 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8ClNO2 (M+H)+: 186.61, observed: 185.9.
Reaction SMILES: [Na+].[CH3:2][CH:3]([CH3:9])[C:4](=O)[C:5]([O-:7])=[O:6].[NH2:10][C@H:11]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[CH3:12].C([BH3-])#N.[Na+]>>[C:5]([CH:4]([NH:10][C@H:11]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[CH3:12])[CH:3]([CH3:9])[CH3:2])([OH:7])=[O:6]
Reactant: CC(C)C(=O)C(=O)[O-]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)C(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)O
Yield: 73.2 %

Procedure:
A mixture of 3-methyl-2-oxobutyric acid sodium salt (1.46 g) and L-alanyl-L-proline (0.40 g) was treated with sodium cyanoborohydride (0.41 g) as described above. Crude N-(1-carboxy-2-methylpropyl)L-alanyl-L-proline (0.45 g) was obtained by elution from ion-exchange resin. The product melted at 131°-142°. The nmr spectrum shows complex absorption in the 4.6 to 3.3 region, a broad multiplet centered at 2.2 and doublets at 1.65 and 1.1 ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:9](=[O:11])[CH3:10])=[CH:3][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(N)cc1
Product: CC(=O)Nc1ccc(C)cc1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
Into three neck round bottom flask (5 L) equipped with a mechanical stirrer, a condenser, and an addition funnel, were added p-toluidine (995 g, 9.3 mol) and hexanes (1.6 L). Acetic anhydride (960 mL, 10.2 mol) was added dropwise for 2 h enough to reflux, then refluxed for 1 h and cooled to room temperature to give a brown solid. This was collected by suction filtration, transferred into a beaker, and washed with water (2 L) for 30 min. The filtration and washing procedures were repeated. The wet white crystals were air dried for 7 days to provide N-(4-methylphenyl)acetamide (1,343 g, 97% yield). Melting point: 150-152° C. (lit. 153° C., Merck index. 11, 67;).
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6]2.[C:24]1([CH2:30][S:31](Cl)(=[O:33])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH2:35].ClCCl>N1C=CC=CC=1>[C:21]([OH:32])(=[O:35])[CH3:22].[CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:31]([CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:33])=[O:32])[CH:20]=[CH:21][CH:22]=2)[CH:3]2[CH:7]1[CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4]2
Reactant: O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC1(c2cccc(N)c2)C2CN(CCCc3ccccc3)CC21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O
Product: CC1(c2cccc(NS(=O)(=O)Cc3ccccc3)c2)C2CN(CCCc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 16 h
Yield: 1 %

Procedure:
To a solution of 3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 8, 200 mg, 0.65 mmol) in pyridine (2 ml) under nitrogen at 0□ C. was added α-toluenesulfonyl chloride (186 mg, 0.98 mmol), then the mixture was stirred at room temperature for 16 hours. Water (5 ml) and dichloromethane (5 ml) were added and the mixture was stirred for 10 minutes. The organic phase was washed further with water (5 ml), separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica (10 g) column chromatography eluting with ethyl acetate:hexane:ammonia solution (0.880) (20:80:1 then 60:40:1). Product-containing fractions were combined and concentrated in vacuo. The residue was further purified by preparative HPLC (condition 4). Combination and evaporation of appropriate fractions gave the title compound as a pale brown solid (3 mg, 1%).
Reaction SMILES: C([O:3][C:4](=[O:30])/[CH:5]=[C:6](\[CH3:29])/[CH:7]=[CH:8]/[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)C.[OH-].[K+].C(Cl)Cl.Cl>CO>[CH3:29]/[C:6](/[CH:7]=[CH:8]/[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)=[CH:5]\[C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C1=C(c2ccc3c(c2)C(C)(C)CCC3(C)C)CCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(/C=C/C1=C(c2ccc3c(c2)C(C)(C)CCC3(C)C)CCCC1)=C\C(=O)O
Temperature: 25 °C

Procedure:
The mixed (15:2) ester product from Example 1 is combined with 5 ml of 2N aqueous potassium hydroxide in 10 ml of methyl alcohol and stirred at reflux temperature for 3 hours. The reaction mixture is cooled to room temperature, poured into a mixture of ice and methylene chloride, and acidified to pH 3 with 3N hydrochloric acid. The organic layers are combined, dried over sodium sulfate and evaporated to give a light yellow solid. The solid is recrystallized form absolute ethyl alcohol to give 0.5 g of the desired compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[CH2:5]2.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[BH4-].[Na+].O.[CH2:25](O)C>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][CH2:25][C:14]1[CH:21]=[CH:20][C:17]([CH3:18])=[CH:16][CH:15]=1)[NH:7][C:6](=[O:12])[CH2:5]2
Reactant: CCO
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(CNc2cc3c(cc2F)CC(=O)N3)cc1
Temperature: 25 °C
Yield: 45 %

Procedure:
5-Fluoro-6-Amino-1,3-dihydro-indol-2-one 9d(2.26 g, 13.6 mmol) was dissolved in 40 mL of ethanol under stirring at room temperature. The solution was cooled down to 0° C. in an ice-water bath, and 4-fluoro-benzaldehyde (1.5 mL, 13.6 mmol) was then added to the solution. Upon completion of the addition, the reaction mixture was stirred at room temperature for 1 hour, and sodium borohydride (1.08 g, 28.5 mmol) was then added to the mixture. The reaction mixture was refluxed for 18 hours. The reaction mixture was naturally cooled down to room temperature, and iced water was added to precipitate solids. The resulting solids were filtered. The filter cake was washed with water (50 mL ×3), and purified by silica gel column chromatography to give the title compound 5-fluoro-6-(4-methyl-benzylamino)-1,3-dihydro-indol-2-one 10a (1.67 g, 45%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[CH2:12]=O.[CH3:14][C:15]1([CH3:23])[O:22][C:20](=[O:21])[CH2:19][C:17](=[O:18])[O:16]1.O>C(#N)C.CC(C)=O.N1CCC[C@H]1C(O)=O>[CH3:14][C:15]1([CH3:23])[O:22][C:20](=[O:21])[CH:19]([CH2:12][C:7]2[NH:8][C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:17](=[O:18])[O:16]1
Reactant: COc1ccc2[nH]ccc2c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: O
Solvent: CC#N
Solvent: CC(C)=O
Product: COc1ccc2[nH]c(CC3C(=O)OC(C)(C)OC3=O)cc2c1

Procedure:
A solution of 5-methoxyindole (10.0 g, 67.9 mmol), 5.5 ml formaldehyde (37% aqueous solution), Meldrum's acid (10 g, 69 mmol), and proline (0.4 g) in 40 ml of acetonitrile was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to provide a brown foam. The product was taken up in about 50 ml of acetone, and about 50 ml of water was added to the cloud point. The mixture was allowed to stand in the freezer and, after crystallization began, additional water was added with swirling again to the cloud point Vacuum-assisted filtration provided 16.2 g of 2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)methyl-5-methoxyindole as sand-colored crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[Li][CH2:12][CH2:13][CH2:14]C.C(I)CC>O1CCCC1.CCCCCC>[CH2:12]([C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[O:9][CH3:10])[CH2:13][CH3:14]
Reactant: [Li]CCCC
Reactant: COc1cccc(OC)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCCI
Product: CCCc1c(OC)cccc1OC
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
1,3-Dimethoxybenzene (20 g, 145 mmol) in 200 mL of dry tetrahydrofuran was cooled to -10° C. To this solution at -10° C. added nBuLi (100 mL of a 1.6M solution in Hexane, 160 mmol ) over 20 min. The reaction was then stirred for 2.5 hours at 0° C. At 0° C., propyliodide (24.65 g, 145 mmol ) was added slowly over 15 min. When the addition was complete, the reaction was allowed to warm to room temperature and stirred overnight. After stirring overnight, the reaction was refluxed for 1.5 hour then cooled to room temperature and quenched with ice. The THF was remove under vacuum, and the resulting aqueous layer was extracted several times with Et2O. The organic extract was dried over MgSO4 and filtered to give a clear oil after solvent removal (26.11 g). The oil was purified by vacuum distillation (24.0 g, 92%).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:29][C@@H:30]([C@H:32]4[CH2:36][NH:35][C:34](=[O:37])[CH2:33]4)[CH3:31])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][N:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[CH:38]1(N2C3C(O[C@@H]([C@H]4CNC(=O)C4)C)=NC(C4C=CC(N5CCNCC5)=CC=4)=CC=3N=C2)C[CH2:39]1.C1(S(Cl)(=O)=O)CC1>>[CH:1]1([N:4]2[C:8]3[C:9]([O:29][C@@H:30]([C@H:32]4[CH2:36][NH:35][C:34](=[O:37])[CH2:33]4)[CH3:31])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][N:22]([S:25]([CH:28]6[CH2:39][CH2:38]6)(=[O:26])=[O:27])[CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCN(S(C)(=O)=O)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: O=S(=O)(Cl)C1CC1
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(S(=O)(=O)C4CC4)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1

Procedure:
Following the procedure described for intermediate 3.45, starting from (R)-4-((R)-1-((3-cyclopropyl-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (180 mg, 0.4 mmol) and cyclopropanesulfonyl chloride (0.05 ml, 0.44 mmol), to provide 25.3 mg of (R)-4-((R)-1-((3-cyclopropyl-6-(4-(4-(cyclopropylsulfonyl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one.
Reaction SMILES: [CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.S(=O)(=O)(O)O.O.[Cl-].[Na+].[CH3:24]O>>[CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:5][C:6]([O:8][CH3:24])=[O:7])[CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)CC(c1cccc(O)c1)C1CC1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CC(c1cccc(O)c1)C1CC1
Temperature: 64 °C
Reaction time: 2 h

Procedure:
To a solution of 3-cyclopropyl-3-(3-hydroxyphenyl)propanoic acid (99.0 g) in methanol (990 mL) was added conc. sulfuric acid (4.71 g), and the mixture was stirred at 64° C. for 2 hr. Water and sodium chloride were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (84.0 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:29])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([NH:27][CH3:28])[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:30]([F:33])([F:32])[F:31])=[N:10]2)=[CH:5][CH:4]=1.[C:34]([O-])([O-])=O.[K+].[K+].ClC[C:42]([NH2:44])=[O:43].CCOC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:29])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([N:27]([CH3:34])[CH2:28][C:42]([NH2:44])=[O:43])[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:30]([F:32])([F:33])[F:31])=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: CNC1(c2ccc(N3CCc4c(C(F)(F)F)nn(-c5ccc(OC)cc5)c4C3=O)cc2)CC1
Reactant: NC(=O)CCl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(N(C)CC(N)=O)CC4)cc2)CC3)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
The product of Example 130 (50 mg, 0.11 mmol) was stirred in DMF (0.3 mL). K2CO3 (45 mg, mmol, 0.33 mmol, 3 eq) and chloroacetamide (20 mg, 0.21 mmol, 2 eq) were added. The mixture was stirred at 70° C. for 2 h. EtOAc was added, washed with H2O and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by Silica gel purification to yield the title compound. LC/MS (ESI+) 514.8 (M+H)+, tR=2.00 min (10–90% CH3CN/H2O in a 4-min run). 1H NMR (CDCl3) δ 87.46 (d, J=9.2 Hz, 2H), 7.27 (m, 4H), 6.91 (d, J=8.8 Hz, 2H), 4.12 (t, J=6.6 Hz, 2H), 3.81 (s, 3H), 3.15 (m, 4H), 2.29 (m, 3H), 0.97 (m, 2H), 0.87 (m, 2H) ppm.