Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:11]2[CH2:10][CH2:9][N:8]([CH3:6])[CH2:13][CH2:12]2)=[CH:16][CH:17]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCNc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCNc1ccc(OC2CCN(C)CC2)cc1
Yield: 79.5 %

Procedure:
To a solution of the compound of Example 68 (1.5 g) in tetrahydrofuran (20 ml) was added lithium aluminum hydride (0.15 g) and the mixture was heated under reflux for hours. Water was added to the mixture and the precipitate formed was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (developing solvent: methylene chloride/methanol=10/1 (v/v)) to obtain 4-(4-hexylaminophenyloxy)-1-methylpiperidine (0.92 g) as a brown oil. The oil was dissolved in ethanol (20 ml), conc. hydrochloric acid (0.53 ml) was added to the solution and the solvent was distilled off to leave a solid. The solid was recrystallized from ethanol/ethyl ether to obtain 4-(4-hexylaminophenyloxy)-1-methylpiperidine dihydrochloride (0.76 g) as white crystals, m.p. 163°-172° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[N:8]([CH3:16])[CH:7]=[C:6]2[CH3:17].B(Br)(Br)Br>C(Cl)Cl>[CH3:16][N:8]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[C:11]([C:12]([F:13])([F:14])[F:15])[CH:10]=2)[C:6]([CH3:17])=[CH:7]1
Reactant: COc1cc2c(C)cn(C)c2cc1C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cn(C)c2cc(C(F)(F)F)c(O)cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 34.2 %

Procedure:
5-Methoxy-1,3-dimethyl-6-trifluoromethyl-1H-indole (725 mg, 3 mmol) in methylene chloride (15 ml) was cooled to zero degrees C, and BBr3 (14.9 ml of a 1 N solution in methylene chloride) was slowly added via syringe. The reaction mixture was stirred 15 minutes at zero degrees C, then allowed to warm to room temperature with stirring for one hour. The reaction mixture was quenched slowly with 75 mL 1 N NaOH. The mixture was acidified to pH 5 with 1 N HCl, extracted with methylene chloride, and the combined organic layers were washed with water, brine, and dried over magnesium sulfate. Solvent was removed under reduced pressure, and the residue was chromatographed (20% EtOAc/Hexanes) to give 235 mg (75% ) 1,3-Dimethyl-6-trifluoromethyl-1H-indol-5-ol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]2OCC[O:14]2)=[C:8]([CH3:18])[CH:7]=1>CC(C)=O.O>[CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:19])([CH3:20])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[O:14])=[C:8]([CH3:18])[CH:7]=1
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(C2OCCO2)c(C)c1
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C(C)(C)Cc1cc(C)c(C=O)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-(4-[1,3]dioxolan-2-yl-3,5-dimethylphenyl)-2,2-dimethylpropionic acid methyl ester (1.7 g, 5.8 mmol) in acetone (20 mL) and water (0.3 mL) was added Amberlyst-15 (233 mg). The suspension was stirred at ambient temperature overnight and the suspension was filtered and washed with acetone. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (5:1) to give 3-(4-formyl-3,5-dimethylphenyl)-2,2-dimethylpropionic acid methyl ester as a pale-yellow oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:22][NH:23][O:24][CH3:25].C(N(CC)CC)C>ClCCl>[CH3:25][O:24][N:23]([CH3:22])[C:6]([CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:8]
Reactant: CNOC
Reactant: O=C(O)C1CCOC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of tetrahydrofuran-3-carboxylic acid (10 g, 86.1 mmol) in dichloromethane (200 mL). EDC.HCl (18.2 g, 94.9 mmol), N,O-dimethylhydroxylamine hydrochloride (10 g, 103 mmol) and triethylamine (24.0 mL, 172 mmol) were added and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with DCM (50 mL) and washed with aqueous HCl (1 M, 3×10 mL), sodium bicarbonate (sat., 2×30 mL) and brine (3×20 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the title compound as light yellow oil (6.71 g, 49%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: Ic1ccccn1
Reactant: c1ccc2[nH]ccc2c1
Product: c1ccc(-n2ccc3ccccc32)nc1

Procedure:
Prepared by Procedure C and Scheme O using 2-iodopyridine and 1H-indole: ESMS m/e: 195.0 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[CH2:9]Br.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][C:28](=[O:34])[C@H:29]([CH:31]([CH3:33])[CH3:32])[NH2:30].O>C(#N)C>[CH3:32][CH:31]([CH3:33])[CH:29]([N:30]1[CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[C:5]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[CH:4]=2)[CH2:9]1)[C:28]([O:27][CH3:26])=[O:34]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=[N+]([O-])c1ccc(-c2ccc(CBr)c(CBr)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1

Procedure:
The compound of example 671 (3 g, 7.79 mmol) was taken in acetonitrile and to the reaction mixture, potassium carbonate (3.25 g, 23.37 mmol) was added followed by the addition of valine methyl ester (1.56 g, 9.35 mmol). The reaction mixture was refluxed for about 16 h and water was added to quench the reaction. The aqueous mixture was extracted with ethyl acetate to obtain a crude material, which was purified using column chromatography (silicagel, 30% ethyl acetate in petroleum ether).
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([CH2:10][N:11]([C@@H:45]([CH3:53])[CH:46]([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])[C:12](=[O:44])[C@@H:13]([NH:26]C(=O)OCC3C4C=CC=CC=4C4C3=CC=CC=4)[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=3)=[CH:8][CH:7]=[CH:6][C:5]=12.N1CCCCC1>>[NH2:26][C@@H:13]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1)[C:12]([N:11]([CH2:10][C:9]1[C:4]2[C:5](=[N:1][S:2][N:3]=2)[CH:6]=[CH:7][CH:8]=1)[C@@H:45]([CH3:53])[CH:46]([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])=[O:44]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2nsnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2nsnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Yield: 139.7 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (9H-fluoren-9-yl)methyl(S)-1-((benzo[c][1,2,5]thiadiazol-4-ylmethyl)((S)-1,1-diethoxypropan-2-yl)amino)-3-(4-tert-butoxyphenyl)-1-oxopropan-2-ylcarbamate (Compound III-8) (509 mg, 0.69 mmol) was treated with piperidine and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (496 mg, 139%).
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C(=O)(O)[O-].[Na+].[Br:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][C:14]=1[Cl:22]>C(OCC)C.O>[Cl:22][C:14]1[CH:15]=[C:16]([NH:19][C:20]([N:4]([O:3][CH3:2])[CH3:5])=[O:21])[CH:17]=[CH:18][C:13]=1[CH2:12][Br:11]
Reactant: O=C=Nc1ccc(CBr)c(Cl)c1
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CON(C)C(=O)Nc1ccc(CBr)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
A stirred solution of 58.3 grams (0.597 mole) of O,N-dimethylhydroxylamine hydrochloride in 400 ml of diethyl ether was cooled to 0° C. and a slurry of 50.2 grams (0.597 mole) of sodium bicarbonate in 50 ml of water was added. Upon completion of addition the reaction mixture stirred at 0° C. for one hour, then a solution of 147.2 grams (0.597 mole) of 4-bromomethyl-3-chlorophenylisocyanate in 100 ml of diethyl ether was added. During the addition, additional diethyl ether was added to the reaction mixture to promote stirring. Upon completion of addition the reaction mixture was stirred for an additional one hour, then was filtered. The filtrate was dried with magnesium sulfate and refiltered. The filtrate was concentrated under reduced pressure to a solid residue. The solid was triturated with ethanol to remove a yellow color. The solid was collected by filtration to give 51.5 grams of 2-chloro-4-[(N-methoxy-N-methylamino)carbonylamino]phenylmethyl bromide.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>C(#N)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 84.3 %

Procedure:
To a solution of (4-fluorophenyl)(piperidin-4-yl)methanone hydrochloride (51.8 g, 213 mmol) in acetonitrile (400 mL) was added ethyl 2-bromoacetate (38.2 mL, 345 mmol) and triethylamine (70 mL, 506 mmol). The mixture was heated at reflux for 5 h, the solvent was evaporated under reduced pressure and purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0) to provide product (52.7 g, 85% yield). 1H NMR (400 MHz, CDC3) δ 7.98 (dd, J=8.5, 5.5 Hz, 2H), 7.16 (t, J=8.5 Hz, 2H), 4.22 (q, J=7.2 Hz, 2H), 3.16-3.27 (m, 1H), 3.03 (d, J=11.5 Hz, 2H), 2.43 (td, J=11.2, 3.3 Hz, 2H), 1.81-2.09 (m, 4H), 1.51-1.73 (m, 2H), 1.30 (t, J=7.3 Hz, 3H). MS m/z 294.4 (M+1), retention time=1.94 min.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:21](=[O:23])[NH2:22])[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:9][CH:8]=1.[CH:24]([O-])([O-])OCC.CN(C)C=O>C(OCC)(=O)C>[OH:23][C:21]1[N:3]2[N:4]=[CH:5][C:6]([C:7]3[CH:12]=[CH:11][C:10]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=4)=[CH:9][CH:8]=3)=[C:2]2[N:1]=[CH:24][N:22]=1
Reactant: CCOC([O-])[O-]
Reactant: Cc1cccc(Cc2ccc(-c3cnn(C(N)=O)c3N)cc2)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(Cc2ccc(-c3cnn4c(O)ncnc34)cc2)c1
Reaction time: 1 h

Procedure:
A mixture of 3-amino-2-carbamoyl-4- {4-(3-methylphenylmethyl) phenyl} pyrazole (3.0 g), ethyl orthoformate (2 ml) and N,N-dimethylformamide (4 ml) was heated and stirred at 100° C. to 110° C. After 1 hour, to the mixture was added ethyl acetate (50 ml). The precipitate was separated by filtration, washed with etyl acetate, dried to give the title compound (2.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[S:10]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11]1>CC(O)C>[S:10]1[CH:14]=[CH:13][C:12]([CH:15]2[O:5][CH2:4][C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[NH:1]2)=[CH:11]1
Reactant: O=Cc1ccsc1
Reactant: Nc1ccccc1CO
Solvent: CC(C)O
Product: c1ccc2c(c1)COC(c1ccsc1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A mixture of 2-aminobenzyl alcohol (0.1218 mol), 3-thiophenecarboxaldehyde (0.1218 mol) and molecular sieves (3 Å) in 2-propanol (150 ml) was stirred overnight at room temperature. The crude reaction mixture was filtered, the residue was treated with CH2Cl2, and the mixture was filtered again. The solvent was evaporated, yielding 21.53 g (81%) of (±)-1,4-dihydro-2-(3-thienyl)-2H-3,1-benzoxazine (interm. 3).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([O:24][C:25](=[O:55])[C@H:26]([NH:38][C:39](=[O:54])[C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][CH:49]([CH:52]=O)[CH2:48][CH2:47]2)=[CH:42][CH:41]=1)[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:17]([O:24][C:25](=[O:55])[C@H:26]([NH:38][C:39](=[O:54])[C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][CH:49]([CH2:52][NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:48][CH2:47]2)=[CH:42][CH:41]=1)[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=CC1CCN(c2ccc(C(=O)N[C@H](CC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(c3ccc(C(=O)N[C@H](CC(=O)OCc4ccccc4)C(=O)OCc4ccccc4)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
A solution of N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methane-sulfonamide (0.104 g, 0.421 mmol), (2R)-2-{[4-(4-(formyl)piperidin-1-yl)benzoyl]-amino}butanedioic acid dibenzyl ester (0.4 mmol) and glacial acetic acid (0.024 g, 0.421 mmol) in 5 mL methanol was stirred for 1 hour over 4A molecular sieves. In one portion sodium cyanoborohydride (0.028 g, 0.421 mmol) was added and the mixture stirred overnight at ambient temperature. The sieves were filtered and the filtrate was preabsorbed on silica gel. The solids were purified by flash chromatography (CH2Cl2—CH3OH, 19:1). to give the product (0.110 g).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][CH2:4][C@@H:5]([N:12]1C(=O)C2C(=CC=CC=2)C1=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.NN>CCO>[F:1][CH:2]([F:23])[O:3][CH2:4][C@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:12]
Reactant: O=C1c2ccccc2C(=O)N1[C@H](COC(F)F)c1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: N[C@H](COC(F)F)c1ccccc1
Temperature: 85 °C

Procedure:
(S)-2-(2-(difluoromethoxy)-1-phenylethyl)isoindoline-1,3-dione (659 mg, 2.077 mmol) was dissolved in EtOH (7 ml), charged with hydrazine hydrate (1.01 ml, 20.77 mmol) and heated to 85° C. for 90 minutes. The reaction was diluted with 10 mL EtOH, filtered, and the solvents were evaporated in vacuo. The residue was purified on silica gel 2-10% MeOH/DCM to provide (S)-2-(difluoromethoxy)-1-phenylethanamine MS: [M+H]+ m/z 188.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[CH:26]=3)[CH2:23][C:22](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccncc3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
The title compound was prepared from {2′-fluoro-3-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert-butyl ester (Example M18) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (237 mg).
Reaction SMILES: [CH3:1][C:2]([OH:22])([CH3:21])[CH2:3][N:4]([CH3:20])[CH2:5][CH2:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:30][Si:31](Cl)([CH3:33])[CH3:32]>C(Cl)Cl>[CH3:21][C:2]([O:22][Si:31]([CH3:33])([CH3:32])[CH3:30])([CH3:1])[CH2:3][N:4]([CH3:20])[CH2:5][CH2:6][CH:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)Cl
Reactant: CN(CCC(c1ccccc1)c1ccccc1)CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCC(c1ccccc1)c1ccccc1)CC(C)(C)O[Si](C)(C)C
Temperature: 12.5 °C

Procedure:
2,N-Dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propanol (5.0 gm) is dissolved in methylene chloride (25 ml) at 25-30° C., triethylamine (2.5 gm) is added and then the contents are cooled to 10-15° C. under N2 atmosphere. Trimethylsilyl chloride (2.5 gm) is slowly added to the reaction mass while maintaining the temperature 10-15° C., the mass temperature is raised to 25-30° C. and maintained for 2 hours at the same temperature to give the reaction mass of 2,N-dimethyl-2-(trimethylsilyloxy)-N-(3,3-diphenylpropyl)-1-propanamine.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH2:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:22][CH:21]=2)[C:12]2[C:13](=[O:17])[NH:14][CH:15]=[CH:16][C:11]=2[N:10]=1)[CH2:6][CH2:7][CH3:8].CC([O-])(C)C.[K+].Cl>CN(C=O)C>[CH2:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:24][CH:25]=2)[C:12]2[C:13](=[O:17])[N:14]([CH2:2][C:3]#[N:4])[CH:15]=[CH:16][C:11]=2[N:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCc1nc2cc[nH]c(=O)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: N#CCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc2ccn(CC#N)c(=O)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.5 h

Procedure:
A solution of 0.79 g of chloroacetonitrile in 5 ml of DMF is added dropwise at 20°, with stirring, to a solution of 3.82 g of 2-butyl-3-(2'-cyanobiphenyl-4-ylmethyl)-4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine and 1.17 g of potassium tert-butylate in 20 ml of DMF. The mixture is stirred at 20° for a further 30 min and poured on to ice, hydrochloric acid is added to pH 6 and the mixture is worked up in conventional manner to give 2-butyl-3-(2'-cyanobiphenyl-4-ylmethyl)-5-cyanomethyl-4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine , m.p. 64°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[NH:14][C:13]=2[CH:12]=[C:11]([Br:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:23][O:24][CH3:25].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:23][O:24][CH3:25])[C:13]=2[CH:12]=[C:11]([Br:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: Cc1nc2c(OCc3ccccc3)cc(Br)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCn1c(C)nc2c(OCc3ccccc3)cc(Br)cc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 26.4 %

Procedure:
2.0 g (6.3 mmol) 4-Benzyloxy-6-bromo-2-methyl-1H-benzimidazole were solved in dimethylformamide (10 ml) and the solution was cooled to 0° C. 151 mg (6.5 mmol) sodium hydride (60%) were added in portions and the reaction was stirred for 20 min. 435 μl (6.3 mmol) 1-Chloro-1-methoxy-methane were added and the reaction was stirred at 0° C. After 2 h the mixture was poured into water (200 ml) and extracted with ethyl acetate. The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (toluene/dioxane=6:1) to afford 0.6 g (26%) of the title compound as a yellow oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH:21]4[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]4)=[CH:17][NH:18]3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([F:37])[CH:36]=1)[C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([F:37])[CH:36]=1)[C:31]([N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([C:16]2[C:15]3[C:19](=[CH:20][C:12]([C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]4)=[O:11])=[CH:13][CH:14]=3)[NH:18][CH:17]=2)[CH2:22]1)=[O:32]
Reactant: CC(C)N1CCN(C(=O)c2ccc3c(C4CCCNC4)c[nH]c3c2)CC1
Reactant: O=C(O)c1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3c(C4CCCN(C(=O)c5cc(F)cc(F)c5)C4)c[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.9 %

Procedure:
A mixture of 0.02 g (0.56 mmol) (4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanone, 0.01 g (0.06 mmol) 3,5-difluorobenzoic acid, 0.02 g (0.06 mmol) TBTU and 0.044 g (0.3 mmol) DIPEA in 0.8 mL DMF was stirred at room temperature for 16 h. The mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient formed from acetonitrile/water/NEt3. Evaporation of the product fractions yielded 16 mg (57%) of the title compounds as off-white foam. MS (m/e): 495.4 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH:11](O)[CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:16])=O>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH:11]([Cl:16])[CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)c1cc(C(C)(C)C)ccn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(Cl)c1cc(C(C)(C)C)ccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
4-t-Butyl-2-(1-hydroxyethyl)-pyridine (3.6 g, 20.1 mmole) is dissolved in 60 ml dichloromethane in a 200 ml one neck round bottom flask under nitrogen. The solution is cooled to 0° C., is treated with thionyl chloride (2.2 ml, 30 mmole) in 10 ml dichloromethane, and the reaction is stirred 1 h at 0° C. followed by 2 h at room temperature. The reaction is quenched with 1×75 ml saturated sodium bicarbonate, the layers are separated and the aqueous layer is extracted with 3×25 ml dichloromethane. The combined organics are dried over potassium carbonate and are concentrated in vacuo to give 3.9 g (98%) of 4-t-Butyl-2-(1-chloroethyl)-pyridine as a yellow oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[C:8]([F:37])=[C:9]([C:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH3:28])[N:20]=3)=[CH:17][N:16]([CH:34]([CH3:36])[CH3:35])[N:15]=2)[CH:10]=[C:11]([Cl:13])[CH:12]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[Cl:13][C:11]1[CH:12]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:8]([F:37])=[C:9]([C:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH3:28])[N:20]=3)=[CH:17][N:16]([CH:34]([CH3:35])[CH3:36])[N:15]=2)[CH:10]=1
Reactant: COC(=O)N[C@@H](C)CNc1nccc(-c2cn(C(C)C)nc2-c2cc(Cl)cc(N)c2F)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N[C@@H](C)CNc1nccc(-c2cn(C(C)C)nc2-c2cc(Cl)cc(NS(C)(=O)=O)c2F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (0.277 mL, 3.57 mmol) was added to a solution of (S)-methyl 1-(4-(3-(3-amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (550 mg, 1.2 mmol) in DCM (30 mL) and pyridine (10 mL), and the mixture was stirred at rt for 16 h. Aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate and washed with brine. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (60:1 to 40:1 DCM/methanol) to provide the title compound. An alternative synthesis is described in example 6, infra.