Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([OH:28])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:35][CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:35][CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)=[O:28])#[N:2]
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: NCc1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)NCc3ccncc3)n([C@H]3CCCc4ccccc43)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 4-aminomethylpyridine (175 mg, 1.62 mmol), triethylamine (0.451 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the objective product as a solid material.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:9][NH:10][CH:11]([CH3:13])[CH3:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1([CH2:9][N:10]([C:23]2[C:24]([N+:28]([O-:30])=[O:29])=[CH:25][N:26]=[C:21]([Cl:20])[N:22]=2)[CH:11]([CH3:12])[CH3:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C1(CNC(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])C(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl1-[(propan-2-ylamino)methyl]cyclopropane-1-carboxylate (Intermediate 211; 9.55 g, 50 mmol) in acetone (300 mL) was added potassium carbonate (7.05 g, 51 mmol) followed by 2,4-dichloro-5-nitropyrimidine (Aldrich; 10.675 g, 55 mmol). The mixture was stirred overnight at room temperature, concentrated in vacuo and partitioned between EtOAc and water. The EtOAc layer was separated, dried over sodium sulfate, then purified by column chromatography (EtOAc/isohexane 10:90), to yield the title compound as a yellow oil. (11 g, 64%)
Reaction SMILES: C1(P(Cl)(Cl)(Cl)[Cl:8])C=CC=CC=1.[F:12][C:13]([F:40])([C:36]([F:39])([F:38])[F:37])[C:14]([F:35])([F:34])[C:15]([P:18]([C:21]([F:33])([F:32])[C:22]([F:31])([F:30])[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])(=O)[OH:19])([F:17])[F:16].Cl>>[F:12][C:13]([F:40])([C:36]([F:39])([F:38])[F:37])[C:14]([F:35])([F:34])[C:15]([P:18]([Cl:8])([C:21]([F:33])([F:32])[C:22]([F:31])([F:30])[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])=[O:19])([F:17])[F:16]
Reactant: O=P(O)(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: ClP(Cl)(Cl)(Cl)c1ccccc1
Agent: Cl
Product: O=P(Cl)(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 75.9 %

Procedure:
Variant b) The mixture of 4.6 g (18.4 mmol) of phenyltetrachlorophosphorane and 7.3 g (14.5 mmol) of bis(nonafluorobutyl)phosphinic acid is stirred at room temperature for four hours When the evolution of gas (HCl) is complete, the nonafluorobutylphosphonyl dichloride is separated off by distillation at atmospheric pressure, giving 5.73 g of bis(nonafluorobutyl)phosphinyl chloride as colourless liquid substance. This corresponds to a yield of 76%, based on the phosphinic acid employed.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]2[C:11]([NH:16][C:17]3[CH:18]=[C:19]([NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)[CH:20]=[CH:21][C:22]=3[CH3:23])=[N:12][N:13]([CH3:15])[CH:14]=2)[CH:5]=1)=O.[N:37]1([CH2:43][CH2:44][NH2:45])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.CS(C)=O>CC(O)C>[CH3:23][C:22]1[CH:21]=[CH:20][C:19]([NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[CH:18][C:17]=1[NH:16][C:11]1[C:10]([C:6]2[CH:5]=[C:4]([NH:45][CH2:44][CH2:43][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:9]=[CH:8][N:7]=2)=[CH:14][N:13]([CH3:15])[N:12]=1
Reactant: NCCN1CCOCC1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1nn(C)cc1-c1cc(S(C)=O)ncn1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1nn(C)cc1-c1cc(NCCN2CCOCC2)ncn1
Temperature: 80 °C

Procedure:
The mixture of N-{3-[4-(6-Methanesulfinyl-pyrimidin-4-yl)-1-methyl-1H-pyrazol-3-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide (30 mg, 0.058 mmol) and 2-Morpholin-4-yl-ethylamine (100 uL) in 2-propanol is heated to 80° C. for 3 hours. The reaction mixture is cooled to room temperature and condensed. The crude product is then treated with 1 mL DMSO and purified by LC/MS to afford N-(4-Methyl-3-{1-methyl-4-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-pyrazol-3-ylamino}-phenyl)-3-trifluoromethyl-benzamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([C@H:8]([OH:22])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:7]=1.[H-].[Na+].Br[CH2:27][C:28]#[N:29]>CC#N>[C:28]([CH2:27][O:22][C@@H:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:23])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:10]1)#[N:29]
Reactant: N#CCBr
Reactant: Cc1ccc(F)cc1[C@H](O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(F)cc1[C@H](OCC#N)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -40 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(5-fluoro-2-methylphenyl)(hydroxy)methyl)piperidine-1-carboxylate (1.2 g, 0.0037 mol) in MeCN (20 mL), NaH (0.27 g, 0.011 mol) was added at 0° C. The mixture was stirred for 1 hr followed by cooling to −40° C. and adding bromoacetonitrile (1.3 g, 0.011 mol) in portions. The mixture was stirred for 0.5 hour at −20° C. The reaction was quenched with H2O. The mixture was extracted with CH2Cl2. The organic layer was dried by Na2SO4, concentrate to get the target molecule (R)-tert-butyl 3-((R)-(cyanomethoxy)(5-fluoro-2-methylphenyl)methyl)piperidine-1-carboxylate (1.2 g, 90%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:15][CH:16]=1>>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:12]=[C:13]([CH2:17][CH2:18][C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH:22]=[CH:23][CH:24]=3)[CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCc2cccc(N)c2)c1
Reactant: Clc1ncc(Br)c(Cl)n1
Product: CC(C)(C)OC(=O)Nc1cccc(CCc2cccc(Nc3nc(Cl)ncc3Br)c2)c1
Yield: 70 %

Procedure:
This compound was prepared according to the procedure of Example B5, step G using 5-bromo-2,4-dichloropyrimidine and tert-butyl {3-[2-(3-aminophenyl)ethyl]phenyl}carbamate as the starting materials in 70% yield. LCMS calculated for C23H25BrClN4O2 (M+H)+: m/z=503.1, 505.1.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:18].[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][Cl:24])[CH3:20].C(=O)([O-])O.[Na+]>C(O)C>[ClH:24].[ClH:18].[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][S:15][C:13]1[NH:14][C:10]2[CH:9]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=[CH:16][C:11]=2[N:12]=1)[CH3:20]
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)CCSc1nc2ccc(Cc3ccccc3)cc2[nH]1

Procedure:
6 g (25 mmoles) of 5-benzyl-benzimidazoline-2-thione, 5.16 g (30 mmoles) of 2-(diethylamino)-ethylchloride hydrochloride and 2.55 g of sodium hydrogen-carbonate are reacted in 40 ml of ethanol. After filtering off the inorganic salt and concentration of the solution, the title product is precipitated by hydrochloric ethanol.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.[C:23]([OH:27])(=[O:26])[CH2:24][OH:25]>CC(C)=O>[CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[C:4]=2[CH:3]=1.[C:23]([O-:27])(=[O:26])[CH2:24][OH:25]
Reactant: O=C(O)CO
Agent: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Solvent: CC(C)=O
Product: O=C([O-])CO
Temperature: 4 °C
Reaction time: 8 h

Procedure:
To a solution of 5.0 g of olanzapine in 150 ml of acetone was added 1.22 g of glycolic acid in 25 ml acetone slowly at room temperature. The mixture was stirred overnight at 4° C. The crystals were isolated by filtration, washed with 15 ml of acetone and 20 ml of ether and dried overnight at 40° C. in vacuo. Yield: 5.76 g
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:8]2=[NH:27])=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH2:42][CH2:41][C:40]([CH3:44])([CH3:43])[CH2:39][C:38]=2[CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH2:42][CH2:41][C:40]([CH3:43])([CH3:44])[CH2:39][C:38]=2[CH2:45][N:46]2[CH2:47][CH2:48][N:49]([C:2]3[CH:29]=[CH:28][C:5]([CH2:6][N:7]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[N:9]([CH2:16][CH2:17][CH2:18][O:19][C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=5)[C:8]4=[NH:27])=[CH:4][CH:3]=3)[CH2:50][CH2:51]2)=[CH:33][CH:32]=1
Reactant: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccc(Br)cc1
Reactant: CC1(C)CCC(c2ccc(Cl)cc2)=C(CN2CCNCC2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(CN2CCN(c3ccc(Cn4c(=N)n(CCCOc5ccc(F)cc5)c5ccccc54)cc3)CC2)C1
Temperature: 95 °C
Reaction time: 0.03 h
Yield: 11.1 %

Procedure:
To a degassed solution of 1-(4-bromo-benzyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (60 mg, 0.13 mmol) in anhydrous toluene (2 ml) was added Pd(OAc)2 (0.3 mg, 0.7 □mol). Nitrogen was bubbled through the suspension for 10 min before BINAP (8 mg, 11 □mol) was added. After a further 2 min 1-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazine (48 mg, 0.14 mmol) in degassed toluene (2 ml) was introduced and then after a additional 2 min Cs2CO3 (0.86 g, 2.6 mmol) was added and the reaction was stirred for 2 min. Throughout all of the additions nitrogen was continuously bubbled through the reaction mixture. The reaction was then sealed and heated to 95° C. where it was maintained for 2 h. After this time, the reaction was cooled to rt and additional Pd(OAc)2 and BINAP were introduced. The reaction was then sealed and heated to 95° C. where it was maintained for a further 22 h. The mixture was cooled to rt and filtered through Celite®. The collected solids were washed with additional toluene and dichloromethane and then the combined filtrate and washings were concentrated under reduced pressure to give the crude product. After purification by preparative HPLC, the product was redissolved in dichloromethane and washed with saturated NaHCO3 and H2O. The organic phase was separated, dried (Na2SO4) and filtered to provide 1-(4-{4-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (10 mg, 11%). HPLC-MS 692 [M+1]+, 347 (100%).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][C:9]1[C:10]([CH3:24])=[C:11]([CH3:23])[C:12]2[O:16][CH:15]([CH2:17][CH2:18][CH2:19][OH:20])[S:14][C:13]=2[C:21]=1[CH3:22].[CH3:25][O:26][CH2:27]Cl>C1C=CC=CC=1.O>[CH3:25][O:26][CH2:27][O:8][C:9]1[C:10]([CH3:24])=[C:11]([CH3:23])[C:12]2[O:16][CH:15]([CH2:17][CH2:18][CH2:19][OH:20])[S:14][C:13]=2[C:21]=1[CH3:22]
Reactant: COCCl
Reactant: Cc1c(C)c2c(c(C)c1O)SC(CCCO)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccccc1
Product: COCOc1c(C)c(C)c2c(c1C)SC(CCCO)O2

Procedure:
340 mg of a 55% w/w oily suspension of sodium hydride was added to 20 ml of dimethylformamide, followed by 2.0 g of crystals of 3-(5-hydroxy-4,6,7-trimethyl-1,3-benzoxathiole-2-yl)propanol (prepared as described in Example 71), with ice cooling and under a stream of nitrogen. The reaction mixture was then cooled with ice for 30 minutes, after which it was allowed to react for 1 hour at room temperature; it then was again cooled with ice. A solution of 630 mg of chloromethyl methyl ether in 2 ml of benzene was then added dropwise, after which the temperature of the reaction mixture was gradually raised and the reaction mixture was allowed to react further for 20 hours at room temperature. The reaction mixture was then poured into water and extracted with benzene. The extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel Lobar column chromatography. The title compound was obtained from the fraction eluted with a 9:1 by volume mixture of benzene and ethyl acetate.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH:24][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1ccccc1F
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Fc1ccccc1CNc1nccc(-n2cnc3ccccc32)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2-fluorobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 320.1 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.62 (s, 1H); 8.43 (br s, 1H); 8.09 (br s, 1H); 7.86 (m, 1H); 7.13 (m, 2H); 6.85 (d, J=5.3 Hz, 1H; 5.87 (br s, 1H); 4.81 (d, J=6.1 Hz, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:12]=[C:11]([NH:13][NH2:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH3:15][C:16]([CH3:23])([CH3:22])[C:17](=O)[CH2:18][C:19]#[N:20].Cl.[OH-].[Na+]>C(O)C>[NH2:20][C:19]1[N:13]([C:11]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:3][CH3:2])[CH:12]=2)[N:14]=[C:17]([C:16]([CH3:23])([CH3:22])[CH3:15])[CH:18]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: COc1cc(NN)ccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(-n2nc(C(C)(C)C)cc2N)ccc1C(=O)O
Temperature: 25 °C
Yield: 71.7 %

Procedure:
A suspension of 2-methoxy-4-hydrazinylbenzoic acid hydrochloride (1.05 g, 90% purity, 4.34 mmol) and 4,4-dimethyl-3-oxopentanenitrile (664 mg, 5.31 mmol) in ethanol (20 mL) containing conc hydrochloric acid (12 M, 0.44 mL, 5.0 mmol) was heated at reflux for 28 hr and then cooled to RT. The reaction mixture was treated with aq NaOH (2.0 M, 8.6 mL, 17 mmol) and was maintained at RT for 20 hr and then concentrated to half its original volume in vacuo. Then residue was washed with DCM (2×15 mL) and the aq layer was acidified to pH 5 with conc hydrochloric acid (12 M, 1.0 mL) and re-extracted with DCM (5×30 mL). The combined organic extracts were washed with brine (10 mL) and then dried and evaporated in vacuo to afford 4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)-2-methoxybenzoic acid as a brown solid (900 mg, 61%); Rt 1.47 min (Method 2); m/z 290 (M+H)+, (ES+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1.C(N1C=C(B2OC(C)(C)C(C)(C)O2)C=N1)C.C([O-])([O-])=O.[K+].[K+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:3]1[CH:2]=[CH:7][N:6]=[C:5]2[NH:8][CH:9]=[C:10]([CH:11]=[O:12])[C:4]=12
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Solvent: O
Product: O=Cc1c[nH]c2nccnc12
Temperature: 100 °C

Procedure:
To a solution of 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (1.33 g, 3.73 mmol) and 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (995 mg, 4.48 mmol) in 1,2-DME (20 mL) were added Pd(Ph3P)4 (0.22 g, 0.19 mmol) and 2.0 M aqueous K2CO3 (5.6 ml, 11.2 mmol). The reaction mixture was degassed by bubbling N2 for 15 min then heated at 100° C. overnight. The resultant maroon reaction mixture was cooled and diluted with H2O then extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated. The crude residue was purified by SiO2 chromatography (30% to 80% EtOAc/hexanes) to afford 1.12 g (81%) of 2-(1-ethyl-1H-pyrazol-4-yl)-5-(2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a light orange-brown solid.
Reaction SMILES: [NH:1]1[CH2:5][C@H:4]([CH2:6][OH:7])[C@H:3]([CH2:8][OH:9])[CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>CO.O>[OH:9][CH2:8][C@H:3]1[C@@H:4]([CH2:6][OH:7])[CH2:5][N:1]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:2]1
Reactant: OC[C@@H]1CNC[C@@H]1CO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(OCc1ccccc1)N1C[C@@H](CO)[C@@H](CO)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
(cis)-3,4-Pyrrolidinediyldimethanol (970 mg, 7.4 mmol) was dissolved in a mixture of MeOH (20 mL) and water (7 mL) and cooled to 0° C. Na2CO3 (1.96 g, 19 mmol) was added followed by benzyl chloroformate (1.15 mL, 8.1 mmol) and the resulting solution was stirred for 4 hours, maintaining the temperature at 0° C. The reaction was concentrated under reduced pressure to remove most of the methanol, and the remaining aqueous solution was extracted twice with EtOAc. The combined organics were washed with brine and dried over sodium sulfate before being concentrated in vacuo. RP-HPLC yielded phenylmethyl (cis)-3,4-bis(hydroxymethyl)-1-pyrrolidinecarboxylate (450 mg, 22%, 1.7 mmol). LCMS: (M+H)+: 266.1.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]=[C:8]2[NH:18][CH3:19])=[CH:4][CH:3]=1.[CH3:22]C(C)([O-])C.[K+].CI>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]=[C:8]2[N:18]([CH3:22])[CH3:19])=[CH:20][CH:21]=1
Reactant: CC(C)(C)[O-]
Reactant: CNc1nc(=O)c2cccnc2n1Cc1ccc(F)cc1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(C)c1nc(=O)c2cccnc2n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 10.0 g. of powdered 1-(4'-fluorobenzyl)-2-methylamino-pyrido[2,3-d]pyrimidin-4(1H)-one in 300 ml. of tetrahydrofuran is added portionwise over the course of 5 minutes 4.8 g. of potassium t-butoxide and the resulting mixture is stirred at room temperature for 45 minutes. There is then added 6.5 g. of methyl iodide followed by stirring at room temperature for two days. The resulting mixture is filtered through celite and the filtrate evaporated to dryness. The residue is dissolved in 100 ml. of methylene chloride, washed twice with water, dried, filtered and evaporated to dryness. The residue is dissolved in a small amount of chloroform and filtered through a 650 ml. filter column using silica and chloroform. The combined product containing fractions are evaporated to dryness, the residue dissolved in 50 ml. of methylene chloride and ether added while warming on a steam bath to obtain 1-(4'-fluorobenzyl)-2-dimethylamino-pyrido[2,3-d]pyrimidin-4(1H)-one, m.p. 167°-170°C.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH2:7][N:8]=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1)(=O)[CH3:2]>C1(C)C(C)=CC=CC=1>[Cl:16][C:14]1[S:13][C:11]2[N:12]3[C:1]([CH3:2])=[N:4][N:5]=[C:6]3[CH2:7][N:8]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:10]=2[CH:15]=1
Reactant: CC(=O)NNC1=Nc2sc(Cl)cc2C(c2ccccn2)=NC1
Solvent: Cc1ccccc1C
Product: Cc1nnc2n1-c1sc(Cl)cc1C(c1ccccn1)=NC2

Procedure:
2.2 g of 2-(2-acetylhydrazino)-7-chloro-5-(2-pyridyl)-3H-thieno[2,3-e]-1,4-diazepine are refluxed for 2 hours in 120 ml of absolute xylene. The solution is then cooled and the precipitated impurities are filtered off. The solvent is evaporated under reduced pressure and there is obtained 2-chloro-9-methyl-4-(2-pyridyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine in the form of a crystalline product which, after recrystallization from ethyl acetate, melts at 174°-176° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][NH:48][C@@H:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH3:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:48]([CH3:47])[C@@H:49]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH3:50])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CN[C@H](C)c1ccccc1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)[C@H](C)c2ccccc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with methyl-((R)-1-phenyl-ethyl)-amine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C45H54Cl2N5O3 [(M+H)+] 782.3598, observed 782.3594.
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([C:12](=O)[CH3:13])=[CH:7][C:6]=1[F:15].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([CH:12]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:13])=[CH:7][C:6]=1[F:15]
Reactant: CC(=O)c1cc(F)c(OCC(F)F)c(F)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1cc(F)c(OCC(F)F)c(F)c1
Yield: 88 %

Procedure:
The title compound is prepared in 88% yield (750 mg, a white solid) from 1-(4-(2,2-difluoroethoxy)-3,5-difluorophenyl)ethanone (590 mg, 2.5 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.