Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C1COCC1.O>[C:17]([C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)[N:9]([CH2:21][CH3:22])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:30](=[O:32])[CH3:31])=[CH:7][CH:6]=1)#[N:18]
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCn1c(-c2ccc(NC(C)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 0 °C
Yield: 71.2 %

Procedure:
A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in Example 1Ga, step B in THF (3 mL) is cooled to 0° C. and treated with triethylamine (0.04 mL, 0.31 mmol) and acetyl chloride (0.02 mL, 0.29 mmol) and stirred, warming to room temperature overnight. The reaction mixture is then diluted with H2O and extracted with ethyl acetate (3×). The organic phase is washed with H2O and saturated NaCl, dried and concentrated and purified by flash chromatography using EtOAc/hexanes (30-50%) to afford 57 mg (71%) of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]acetamide as a tan solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:8]O)[CH2:2][CH3:3].P(Br)(Br)[Br:16]>C(OCC)C>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:8][Br:16])[CH2:2][CH3:3]
Reactant: BrP(Br)Br
Reactant: CCCOc1cc(CO)ccc1OC
Solvent: CCOCC
Product: CCCOc1cc(CBr)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 193.9 %

Procedure:
To a solution of 3-(propyloxy)-4-methoxybenzyl alcohol (2.28 g, 11.62 mmol) in anhydrous diethyl ether (30 mL) was slowly added PBr3 (0.55 mL, 5.81 mmol) via syringe, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with diethyl ether (150 mL) and washed with saturated aqueous NaHCO3 (2×75 mL) and brine (2×75 mL). The organic layer was dried over anhydrous MgSO4, and the solvent was removed under reduced pressure to afford 3-(propyloxy)-4-methoxybenzyl bromide (2.92 g, 97%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2>>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[C:25]2=[CH:16][C:13]1[NH:12][C:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:3]3[CH2:19][CH2:20][CH2:2][CH2:1]3)[C:7](=[O:18])[C:8]=2[C:14]=1[CH3:15]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: Cc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 94.2 %

Procedure:
The title Compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-bromo-1,3-dihydro-indol-2-one as starting materials to give 2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (1.33 g, 94.2%) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Cl:12][C:13]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([F:24])[C:14]=1[C:15](Cl)=[O:16]>CN(C=O)C>[Cl:12][C:13]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([F:24])[C:14]=1[C:15]([N:9]([C:15](=[O:16])[C:14]1[C:18]([F:24])=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:13]=1[Cl:12])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])=[O:16]
Reactant: Nc1ccnc(Cl)c1F
Reactant: N#Cc1cc(F)c(C(=O)Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(C(=O)N(C(=O)c2c(F)cc(C#N)cc2Cl)c2ccnc(Cl)c2F)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.7 %

Procedure:
To a solution of 2-chloro-3-fluoropyridin-4-ylamine (1.05 g, 7.1 mmol) in DMF (25 mL) at 0° C. was added sodium hydride (0.343 g, 14.3 mmol). The resulting violet mixture stirred for 20 minutes before a solution of 2-chloro-4-cyano-6-fluoro-benzoyl chloride (1.87 g, 8.6 mmol) in DMF (10 mL) was added. The mixture was warmed to room temperature stirred for 16 hours, then quenched with water and 1M HCl. The mixture was filtered through Celite®, washing with EtOAc. The organic filtrate was dried over Na2SO4 and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography eluting with DCM to give the desired compound as an off-white foam (0.869 g, 25% yield). 1H NMR (300 MHz, CDCl3): δ 8.24 (d, J=5.1 Hz, 1H), 7.55 (s, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.32-7.23 (m, 1H).
Reaction SMILES: [N+]([N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10]2)=[N:5]1)([O-])=O.[N:16]1([CH2:22][CH2:23][NH2:24])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C1COCC1.C(OCC)(=O)C>[N:16]1([CH2:22][CH2:23][NH:24][C:12]2[C:11]3[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=3)[NH:5][N:4]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1ccc2cn([N+](=O)[O-])nc2c1
Reactant: NCCN1CCOCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2c(NCCN3CCOCC3)n[nH]c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2,6-dinitro-2H-indazole (1 mmol) (prepared by nitration of 6-nitroindazole; Wrzeciono, et al., E. Pharmazie, 1980, 35, 593-596) in dry THF (4 mL) at 0° C., 2-morpholin-4-yl-ethylamine (2 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The contents were diluted with ethyl acetate (20 mL), washed with water (2×10 mL), and brine (10 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to yield 3-(2-morpholin-4-yl-ethylamino)-6-nitro-1H-indazole as a brown solid, which was reduced to 3-(2-morpholin-4-yl-ethylamino)-1H-indazol-6-ylamine by hydrogenation following general procedure F.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[C:27]#[N:28]>>[C:27]([C:26]([NH:25][C:22]([C:21]1[CH:20]=[N:19][N:16]2[CH:17]=[CH:18][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[C:4]3[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:14][C:15]=12)=[O:23])([CH3:30])[CH3:29])#[N:28]
Reactant: CC(C)(N)C#N
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Product: CC(C)(C#N)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Yield: 57 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I) and 2-amino-2-methylpropanenitrile to yield the title compound as a white solid (21 mg, 57% yield). MS (apci) m/z=394.1 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH:22]=[CH:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)=[CH:6]1.[H][H]>C(O)C.[Pd]>[CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:11][CH:12]=2)[C:7]([CH2:22][CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)=[CH:6]1
Reactant: [H][H]
Reactant: CN(CCc1ccccc1)C(=O)Cn1cc(C=Cc2nnn[nH]2)c2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCO
Product: CN(CCc1ccccc1)C(=O)Cn1cc(CCc2nnn[nH]2)c2cc(OCc3ccccc3)ccc21

Procedure:
To a solution 0.2 g (0.42 mmoles) of N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-tetrazol-5-ylvinyl)indol-1-yl]acetamide in 30 ml of ethanol is added 0.08 g of 10% palladium on carbon and the mixture is shaken under 30 psi of hydrogen for 4 hours. The mixture is filtered and the filtrate concentrated in vacuo. The residue is crystallized from methylene chloride to give N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-tetrazol-5-yl)ethylindol-1-yl]acetamide.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:16]=[CH:15][C:10](C(OC)=O)=[CH:9][C:8]=1[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].NC1C(C)=CC=CC=1.C(Cl)(=O)CCC>>[C:1]([NH:6][C:7]1[CH:16]=[CH:15][CH:10]=[CH:9][C:8]=1[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Nc1ccc(C(=O)OC)cc1C
Agent: CCCC(=O)Cl
Solvent: Cc1ccccc1N
Product: CCCC(=O)Nc1ccccc1C

Procedure:
A process for preparing methyl N-butyryl-4-amino-3-methyl-benzoate, comprising a first step of reacting o-toluidine with butyryl chloride to give N-butyryl-2-methylaniline, a second step of brominating the N-butyryl-2-methylaniline to give N-(4-bromo-2-methylphenyl)butanamide and a third step of converting the N-(4-bromo-2-methylphenyl)butanamide by reaction with carbon monoxide and methanol in the presence of a palladium catalyst to give methyl N-butyryl-4-amino-3-methylbenzoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C)[C@@H:9](C)C(N[C@@H](C(C)C)C(N1C2C(=CC=CC=2)C[C@H]1C(O)=O)=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)O
Agent: On1nnc2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 221.9 %

Procedure:
(S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-indole-2-carboxylic acid (60 mg, 134 μmol, Eq: 1) and EDC (77.1 mg, 402 μmol, Eq: 3) and HOAT (54.7 mg, 402 μmol, Eq: 3) were stirred in DMF (6 mL) for 10 min to give a light yellow solution. To this solution was added ammonium chloride (71.7 mg, 1.34 mmol, Eq: 10) and diisopropylethylamine (0.47 μL, 2.68 mmol, Eq: 20) in 2 mL of DMF. The mixture was stirred at rt overnight, and then concentrated in vacuo. The reaction mixture was poured into saturated aqueous NaHCO3 (30 mL) and extracted with DCM (2×20 mL). The organic layer was washed with 0.5 M aqueous citric acid and brine, and then concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 90% EtOAc in hexanes) to afford {(S)-1-[(S)-1-((S)-2-carbamoyl-2,3-dihydro-indole-1-carbonyl)-2-methyl-propylcarbamoyl]-ethyl})-methyl-carbamic acid tert-butyl ester as an off-white powder (39 mg), m/z=447 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:13](=[O:14])[CH:12]3[CH2:15][CH2:16][CH:17]=[CH:18][CH:11]3[C:10]2=[O:19])=[CH:4][C:3]=1[OH:20].[N+:21]([O-])([OH:23])=[O:22]>>[Cl:1][C:2]1[C:3]([OH:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:5]([N:9]2[C:10](=[O:19])[CH:11]3[CH2:18][CH2:17][CH:16]=[CH:15][CH:12]3[C:13]2=[O:14])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=C1C2C=CCCC2C(=O)N1c1cc(O)c(Cl)cc1F
Product: O=C1C2C=CCCC2C(=O)N1c1c(F)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
2-Chloro-4-fluoro-5-(tetrahydrophthalimido)phenol (5.0 g) was added into nitric acid (50 ml) at 0° C., warmed up to room temperature in 30 minutes. Crushed ice was added and the solution extracted with methylene chloride. The organic phase was washed with water, dried over anhydrous sodium sulfate, and purified by a silica gel column, eluted with methylene chloride-ethyl acetate (19:1) to give 3.67 g of the desired product.
Reaction SMILES: Br[CH:2]([CH2:4]CCCCCC)[CH3:3].C[CH:12]([CH2:24][CH2:25][CH3:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].C=O.[CH2:29](Br)CC>>[CH2:3]([CH:20]([CH2:19][CH2:18][CH2:17][CH:16]([CH3:29])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:24][CH2:25][CH3:26])[C:21]([OH:23])=[O:22])[CH2:2][CH3:4]
Reactant: CCCBr
Reactant: CCCC(C)CCCCCCCCC(=O)O
Reactant: CCCCCCCC(C)Br
Agent: C=O
Product: CCCCCCCC(C)CCCC(CCC)C(=O)O

Procedure:
The procedure used is that of GENERAL PROCEDURE III except that 2-bromononane is used as compound (1) in step (a), formaldehyde is used in place of ethylene oxide in step (b), y=1, and propyl bromide is used in place of methyl iodide in step (h).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:23](=[O:24])[C@H:22]([NH:25]C(=O)OCC3C=CC=CC=3)[CH2:21][C:20]3[CH:19]=[CH:18][C:17]4[NH:16][N:15]=[CH:14][C:13]=4[C:12]=3[CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.[CH3:44][S:45]([OH:48])(=[O:47])=[O:46]>ClCCl.C(OCC)C>[CH3:44][S:45]([OH:48])(=[O:47])=[O:46].[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:23](=[O:24])[C@H:22]([NH2:25])[CH2:21][C:20]3[CH:19]=[CH:18][C:17]4[NH:16][N:15]=[CH:14][C:13]=4[C:12]=3[CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N2Cc3c(ccc4[nH]ncc34)C[C@@H](NC(=O)OCc3ccccc3)C2=O)CC1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCOCC
Solvent: COc1ccccc1
Product: CC(=O)N1CCC(N2Cc3c(ccc4[nH]ncc34)C[C@@H](N)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-benzyl 9-(1-acetylpiperidin-4-yl)-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylcarbamate (38 mg, 0.08 mmol) was dissolved in dichloromethane (1 mL). Anisole (30 μL, 0.27 mmol) was added to the mixture followed by methanesulfonic acid (250 μL). Reaction stirred at room temperature for 2 hours. Mixture was diluted with diethyl ether. Mixture sat at room temperature for 30 minutes. Solvents were decanted off. Remaining residue was dried in vacuo. Title compound was obtained as dark oil in quantitative yield. MS m/e (M+H)+=342.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH2:21]>>[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: Cc1ccc(C)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Product: Cc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)c1

Procedure:
The title compound was prepared similar to 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (30 mg, 0.115 mmol) and 2,5-dimethylaniline (21 mg, 0.172 mmol) similar to Example 180 and was isolated as an off white solid (35 mg, 80% yield). 1H NMR (CDCl3): 9.74 (d, J=1.5 Hz, 1H), 8.76 (dd, J=1.5, 2.4 Hz, 1H), 8.71 (d, J=2.4 Hz, 1H), 7.48 (brs, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.12 (m, 2H), 6.65 (s, 1H), 2.36 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:10]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C[Si]([C:21]#[N:22])(C)C>C(O)(=O)C>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:10]2([C:21]#[N:22])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCCCC1
Reactant: COc1ccc(N)cn1
Solvent: CC(=O)O
Product: COc1ccc(NC2(C#N)CCCCC2)cn1
Reaction time: 0.25 h

Procedure:
5 g (40.3 mmol, 1 eq.) of 5-amino-2-methoxypyridine (starting material 1) are added to a solution of 4.2 ml (40.5 mmol, 1 eq.) of cyclohexanone (starting material 2) in 20 ml of acetic acid at 0° C. The solution is stirred for 15 minutes, and 5.4 ml (40.5 mmol, 1 eq.) of trimethylsilyl cyanide are added. The reaction medium is stirred for 2 hours at room temperature. It is then poured gently into ice-cold ammonium hydroxide solution and extracted with ethyl acetate. The organic phases are combined and washed with water. They are dried over sodium sulfate. The residue is precipitated from dichloromethane and heptane. 1-(6-Methoxypyridin-3-ylamino)-cyclohexanecarbonitrile is obtained in the form of a pink-coloured solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[I:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].C(N(CC)CC)C>ClCCl>[I:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH:9][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccccc1I
Reaction time: 1.5 h
Yield: 75.4 %

Procedure:
Methanesulfonyl chloride (4.4 mL, 57 mmol) was added to a 0° C. dichloromethane (200 mL) solution containing 2-iodoaniline (5.0 g, 23 mmol) and triethylamine (9.6 mL, 69 mmol). The resulting mixture was stirred for 90 minutes, washed with HCl (0.5 M). The organics were separated then dried over sodium sulfate and concentrated in vacuo. The residue was then treated with potassium hydroxide (2.0 M in 1:1 methanol:water, 75 mL) for 30 min. This material was then diluted with dichloromethane and washed with HCl (1.0 N, 300 mL). The organics were separated then dried over sodium sulfate and concentrated to provide the title compound (5.15 g) as a tan solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25](I)=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[CH2:41]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:42]#[CH:43].C(N(CC)CC)C>O1CCCC1.C(OCC)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([C:43]#[C:42][CH2:41][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: C#CCc1ccccc1
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1I
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1C#CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 15B (1.69 g) in tetrahydrofuran (30 mL) was added bis(triphenylphosphine)palladium (II) dichloride (88 mg), CuI (4.8 mg), prop-2-ynylbenzene (584 mg) and triethylamine (1.5 mL). The mixture was stirred at room temperature for 3 hours, diluted with diethyl ether and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography, eluting with 10% ethyl acetate in hexanes, to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[N:34]=[CH:33][C:32](Br)=[CH:31][C:28]=1[C:29]#[N:30]>>[NH2:26][C:27]1[N:34]=[CH:33][C:32]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: N#Cc1cc(Br)cnc1N
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: N#Cc1cc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cnc1N

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and 2-amino-5-bromo-nicotinonitrile (example C.23 step 1) (200 mg, 1.0 mmol) according to general procedure II. Obtained as a red solid (280 mg, 59%). MS (ISP) 473.2 [(M+H)+]; mp 264° C.
Reaction SMILES: C(C1C=CC(C2C=C(F)SC=2CO)=CC=1)C.OC1C=CC(CCC(OCC)=O)=C(C)C=1C.[F:33][C:34]1[S:38][C:37]([CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][C:49]([O:51]CC)=[O:50])=[C:43]([CH3:54])[C:42]=2[CH3:55])=[C:36]([C:56]2[CH:61]=[CH:60][C:59]([CH2:62][CH3:63])=[CH:58][CH:57]=2)[CH:35]=1>>[CH2:62]([C:59]1[CH:58]=[CH:57][C:56]([C:36]2[CH:35]=[C:34]([F:33])[S:38][C:37]=2[CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][C:49]([OH:51])=[O:50])=[C:43]([CH3:54])[C:42]=2[CH3:55])=[CH:61][CH:60]=1)[CH3:63]
Reactant: CCOC(=O)CCc1ccc(OCc2sc(F)cc2-c2ccc(CC)cc2)c(C)c1C
Agent: CCOC(=O)CCc1ccc(O)c(C)c1C
Agent: CCc1ccc(-c2cc(F)sc2CO)cc1
Product: CCc1ccc(-c2cc(F)sc2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 196 by coupling of [3-(4-ethylphenyl)-5-fluorothiophen-2-yl]methanol and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((5-fluoro-3-(4-ehtylphenyl)thiophen-2-yl)methoxy)-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H-NMR (300 MHz, CD3OD) δ 7.34 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.62-6.64 (m, 2H), 5.05 (s, 2H), 2.89 (t, J=8.1 Hz, 2H), 2.65-2.72 (m, 2H), 2.49 (d, J=8.1 Hz, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 1.29 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C24H25FO3S, 411.2 (M−H). found 411.2.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:28](O)=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[NH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[CH:16]1[C:17]2[CH:5]([CH2:4][O:3][C:1]([NH:18][C@@H:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[C:28]([NH:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])=[O:2])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)CN
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
Following the procedure as described in Example 24, except using Fmoc-Tyrosine (4.97 g, 12.32 mmol), tert-butyl 2-aminoacetate, 1.00HCl (2.168 g, 12.94 mmol), 1-hydroxy-7-azabenzotriazole (0.503 g, 3.70 mmol), CH2Cl2 (125 mL), N-methylmorpholine (1.490 mL, 13.55 mmol), EDC (2.61 g, 13.61 mmol) and stirring at room temp for 18 h, 6.76 g (quantitative yield) of the title compound is isolated as a white, sticky solid. Purification is done by BIOTAGE® Silica gel chromatography on a 90 g Thompson Single Step silica cartridge using a linear gradient from 100% CH2Cl2 to 50% EtOAc/CH2Cl2 over 10 column volumes. LC/MS (Condition A): ret. T=3.98 min, (M+H)+ 517.27. 1H NMR (500 MHz, methanol-d4) δ ppm 7.80 (2 H, d, J=7.63 Hz), 7.58 (2 H, d, J=7.32 Hz), 7.25-7.45 (4 H, m), 7.09 (2 H, d, J=7.93 Hz), 6.71 (2 H, d, J=8.24 Hz), 4.36 (2 H, dd, J=9.92, 6.26 Hz), 4.15-4.25 (2 H, m), 3.84 (2 H, d, J=1.53 Hz), 3.11 (2 H, dd, J=13.89, 4.73 Hz), 2.79 (2 H, dd, J=13.89, 9.92 Hz), 1.48 (9 H, s).
Reaction SMILES: [CH3:1][NH:2][NH2:3].O[CH:5]=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])=O>CO.O>[CH3:1][N:2]1[CH:5]=[CH:6][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[N:3]1
Reactant: CNN
Reactant: O=C(C=CO)c1ccccc1O
Solvent: O
Solvent: CO
Product: Cn1ccc(-c2ccccc2O)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Methyl hydrazine (23.2 mmol, 1.23 ml) is added to a solution of 2-(3-hydroxy-2-propen-1-on-1yl)phenol (J. Am. Chem. Soc., 72:3396, 1950), 15.4 mmol, 2.54 g) in methanol (7 ml) and the mixture is heated at 100° C. for one hour. After cooling, the reaction mixture is diluted with water (100 ml) and stirred for one hour. The precipitate is collected via filtration and purified on silica gel (30% ethyl acetate/hexane) to give 811 mg of 2-(1-methylpyrazol-3-yl)phenol.