Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:35][CH:34]=2)[C:19](=[O:31])[C:20]([C:24]2[C:25]([CH3:30])=[N:26][O:27][C:28]=2[CH3:29])=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]>O>[CH2:13]([C:17]1[N:18]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]3[NH:3][C:4](=[O:7])[O:5][N:46]=3)=[CH:37][CH:38]=2)[C:19](=[O:31])[C:20]([C:24]2[C:25]([CH3:30])=[N:26][O:27][C:28]=2[CH3:29])=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)c(-c2c(C)noc2C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(C)c(-c2c(C)noc2C)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.42 g), sodium hydrogen carbonate (0.6 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[2-butyl-5-(3,5-dimethylisoxazol-4-yl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.32 g) was added, and the mixture was stirred at 90° C. for 5 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.12 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.12 g, 19%).
Reaction SMILES: Cl.[C:2]1([NH:8]N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]([C:20](=O)[CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][S:16]([OH:19])(=[O:18])=[O:17].O.[CH2:24](O)[CH3:25]>[Cl-].[Cl-].[Zn+2]>[CH3:10][C:11]1([CH2:12][CH2:13][CH2:14][CH2:15][S:16]([O-:19])(=[O:18])=[O:17])[C:3]2[C:4]3[CH:10]=[CH:11][CH:20]=[CH:21][C:5]=3[CH:6]=[CH:7][C:2]=2[N+:8]([C:25]2[CH:24]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:20]1[CH3:21]
Reactant: CC(=O)C(C)CCCCS(=O)(=O)O
Reactant: NNc1ccccc1
Reactant: CCO
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: CC1=[N+](c2ccccc2)c2ccc3ccccc3c2C1(C)CCCCS(=O)(=O)[O-]

Procedure:
N-(2-Naphtyl), N-phenylhydrazine hydrochloride (19.51 mmol, 5.28 g), 5-methyl-6-oxoheptanesulfonic acid (17.18 mmol, 3.70 g) and anhydrous ZnCl2 (17.18 mmol, 2.34 g) in absolute ethanol (30 ml) were stirred at room temperature for 30 min, then at 80° C. for 2 h. the reaction progress was checked by TLC (10% H2O in CH2CN). After completion the reaction was cooled down and the solvent removed under vacuum. The residue was dissolved in DCM and purified by flash column on silica-gel. Yield: 3.06 g, 42%.
Reaction SMILES: CS[C:3]([C:5]1[NH:6][C:7]([Cl:11])=[C:8]([Cl:10])[N:9]=1)=[O:4].[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C(O)C>[C:12]1([NH:18][NH:19][C:3]([C:5]2[NH:6][C:7]([Cl:11])=[C:8]([Cl:10])[N:9]=2)=[O:4])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNc1ccccc1
Reactant: CSC(=O)c1nc(Cl)c(Cl)[nH]1
Solvent: CCO
Solvent: O
Product: O=C(NNc1ccccc1)c1nc(Cl)c(Cl)[nH]1
Yield: 49.8 %

Procedure:
21.1 g (0.1 mol) of 4,5-dichloro-imidazole-2-thiocarboxylic acid S-methyl ester were boiled with 10.8 g (0.1 mol) of phenylhydrazine in 150 ml of ethanol for 4 hours under reflux. The cooled reaction mixture was mixed with 500 ml of water and the crystals which had separated out were filtered off and dried. 13.5 g (50% of theory) of 4,5-dichloro-imidazole-2-carboxylic acid N'-phenyl-hydrazide with a melting point of 229°-230° C. (from ethyl acetate) were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:9][C:10]1[NH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.Cl>>[ClH:9].[NH:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Cc1ccccc1N
Agent: Cl
Product: Cc1ccccc1Nc1nc2ccccc2[nH]1
Reaction time: 2 h
Yield: 9.1 %

Procedure:
2-Methylaniline (0.5 g) and 2-chlorobenzimidazole (0.71 g) were mixed in a flask and then kept at 250° C. for 2 h. After cooling, the residue was dissolved out of the flask at boiling heat using 1 N HCl, the insoluble material was filtered off with suction, and the filtrate was evaporated. The residue was purified by means of preparative HPLC on RP-18 using acetonitrile/water (0.05% TFA). The clean fractions were combined, the acetonitrile was stripped off, the residue was rendered alkaline using potassium carbonate solution, extracted three times with EA, and the combined phases were then dried, filtered, and concentrated. The residue was taken up using 2 N HCl and the solution was freeze-dried. 110 mg of the title compound were obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[CH2:16]CC#N)[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-:26].[Na+].[CH2:28]([OH:30])[CH3:29]>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:29][C:28]([OH:26])=[O:30])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CCO
Reactant: CC(C)c1ccc(-c2csc(N(CCC#N)Cc3cccs3)n2)cc1
Agent: [Na+]
Product: CC(C)c1ccc(-c2csc(N(CCC(=O)O)Cc3cccs3)n2)cc1

Procedure:
3-{[4-(4-Isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionic acid was prepared following general procedure I using 3-{[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionitrile (368 mg, 1 mmol), 1 N NaOH (aq) solution (4 mL) and ethanol (2 mL). The mixture was refluxed for 15 h. Trituration in hexanes gave 3-{[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionic acid. LCMS m/z: 387 (M+1)+. The sodium salt was prepared following general procedure J using 3-{[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionic acid (93.8 mg, 0.243 mmol), 1 N NaOH (aq) solution (0.243 mL), THF (1 mL) and MeOH (1 mL). Trituration in hexanes gave sodium 3-{[4-(4-isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-amino}-propionate.
Reaction SMILES: CN([CH:4]=[O:5])C.P(Br)(Br)[Br:7].[O:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:7][C:13]1[CH2:14][CH2:15][O:10][CH2:11][C:12]=1[CH:4]=[O:5]
Reactant: CN(C)C=O
Reactant: BrP(Br)Br
Reactant: O=C1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=CC1=C(Br)CCOC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture of DMF (10 mL) and chloroform (200 mL) at 5° C. was treated with PBr3 (10 mL), stirred at 25° C. for 40 minutes, treated with tetrahydropyran-4-one (5 g) in chloroform (50 mL) at 0° C., stirred at 25° C. for 18 hours, poured onto ice, treated with sodium bicarbonate, and extracted with diethyl ether. The extract was washed with saturated sodium bicarbonate and brine and dried (MgSO4), filtered and concentrated. The concentrate was flash chromatographed on silica gel with 10% ethyl acetate/hexanes.
Reaction SMILES: [I:1]I.[I-].[K+].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[NH:14]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]=[C:15]1[SH:21]>O.CO>[IH:1].[NH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][N:14]=[C:15]1[S:21][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:5][CH:6]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: SC1=NCCCCN1
Reactant: II
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: I
Product: c1ccc2c(SC3=NCCCCN3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 12.7 g of iodine and 20 g of potassium iodide in 100 ml of water is added dropwise to a well-stirred mixture of 5.85 g of indole in 20 ml methanol and 6.5 g of 4,5,6,7-tetrahydro-1H-1,3-diazepine-2-thiol in 100 ml methanol. The reaction mixture is stirred at room temperature for 2 hours. The crystalline precipitate formed was filtered off and recrystallized from a mixture of methanol, ethyl acetate and ether to afford 3-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-ylthio)-indole hydriodide which melts at 236° (with decomposition).
Reaction SMILES: Cl[C:2]1[C:7]([O:8]C)=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1.C1N2CC[N:19](CC2)[CH2:18]1.[C-]#N.[K+].Cl>CN(C=O)C.ClCCl.CN1C(=O)CCC1>[OH:8][C:7]1[C:2]([C:18]#[N:19])=[N:3][CH:4]=[N:5][C:6]=1[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1
Reactant: C1CN2CCN1CC2
Reactant: COc1c(Cl)ncnc1-c1ccc(C)cc1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ncnc(C#N)c2O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-chloro-5-methoxy-6-p-tolylpyrimidine P5 (100 mg, 0.43 mmol) in DMF (2 mL) and NMP (0.5 mL) was added triethylenediamine (62 mg, 0.55 mmol) and potassium cyanide (55 mg, 0.85 mmol). The reaction mixture was stirred at room temperature for 18 hours. Dichloromethane and 1 N hydrochloric acid were added. The organic layer was dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to afford the desired 5-hydroxy-6-p-tolylpyrimidine-4-carbonitrile P69 (70 mg, 0.33 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][O:39][CH2:40][CH:41]([NH2:43])[CH3:42]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:43][CH:41]([CH3:42])[CH2:40][O:39][CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: COCC(C)N
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: COCC(C)Nc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-methoxy-1-methylethylamine according to conditions described in general procedure C. Mp: 94-95° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.97 (s, 3 H), 1.56-1.61 (m, 6 H), 3.00-3.32 (m, 9H), 4.10 (s, 1 H), 6.31 (s, 1 H), 6.95-7.03 (m, 2 H), 7.15 (d, J=9.1 Hz, 1 H), 7.38 (d, J=8.0 Hz, 1 H), 7.43 (s, 1 H), 7.50-7.62 (m, 3 H), 7.79-7.82 (m, 1 H), 7.95-7.97 (m, 1 H), 8.20 (s 1 H), 10.40 (s, 1 H).
Reaction SMILES: CS(C)=O.[H-].[Na+].[CH3:7][N:8]1[C:12]2[CH:13]=[C:14]([C:17]([O:19]C)=O)[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1.[CH3:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]([O:33]C)=O)=[CH:30][C:25]=2[N:24]=[CH:23]1>CC#N>[CH3:7][N:8]1[C:12]2[CH:13]=[C:14]([C:17](=[O:19])[CH2:25][C:26]#[N:22])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1.[CH3:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31](=[O:33])[CH2:11][C:12]#[N:8])=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: COC(=O)c1ccc2c(c1)ncn2C
Reactant: COC(=O)c1ccc2ncn(C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC#N
Product: Cn1cnc2cc(C(=O)CC#N)ccc21
Product: Cn1cnc2ccc(C(=O)CC#N)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
A mixture of CH3CN (0.62 mL, 11.84 mmol), DMSO (2 mL) and NaH (410 mg, 10.26 mmol) was stirred for 45 minutes at room temperature before a solution of methyl 1-methyl-1H-benzo[d]imidazole-6-carboxylate and methyl 1-methyl-1H-benzo[d]imidazole-5-carboxylate (1.5 g, 7.89 mmol) in CH3CN (5 mL) was added dropwise. The resulting mixture was stirred at room temperature for 2 h before quenching by the addition of saturated NH4Cl and extraction with DCM (3×30 ml). The combined organic layers were concentrated to give the desired products 3-(1-methyl-1H-benzo[d]imidazol-6-yl)-3-oxopropanenitrile and 3-(1-methyl-1H-benzo[d]imidazol-5-yl)-3-oxopropanenitrile (600 mg, 38%) and used in the next step without further purification. LCMS (m/z): 200.07 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([N:29]1[CH:33]=[C:32]([CH2:34][NH:35][C:36]2[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[CH:38][CH:37]=2)[CH:31]=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:35]([CH2:34][C:32]1[CH:31]=[N:30][N:29]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:33]=1)[C:36]1[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[CH:38][CH:37]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NCc2cnn(Cc3ccccc3)c2)cc1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccccc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 59.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and [(1-benzylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.61 g) as starting materials, 5-benzyloxy-N-[(1-benzylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.67 g) was obtained.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[CH:4][C:3]=1[O:10][CH3:11].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:11][O:10][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH:24]([NH:23][S:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]
Reactant: COc1cncc(OC)c1Br
Reactant: COC(=O)CCCCC=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCCC(NS(=O)C(C)(C)C)c1c(OC)cncc1OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of commercially available 4-bromo-3,5-dimethoxypyridine (4.998 g; 22.92 mmol) in anh. THF (90 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (14.30 ml; 22.88 mmol). The resulting solution was further stirred at −78° C. for 10 min. A solution of methyl 6-((tert-butylsulfinyl)imino)hexanoate (3.780 g; 15.28 mmol) in anh. THF (10 ml) was then added to the cooled reaction mixture, and stirring at −78° C. was continued for 60 min. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (80 ml), Et2O (250 ml) and water (75 ml). The separated organic layer was then washed with brine (75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded methyl 6-(3,5-dimethoxypyridin-4-yl)-6-(1,1-dimethylethylsulfinamido)hexanoate as a yellow oil. LC-MS (conditions A): tR=0.49 min.; [M+H]+: 387.11 g/mol.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:5](Cl)=[O:6])[CH3:3].CC(C)CC(Cl)=[O:19]>>[CH3:1][CH:2]([C@H:4]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:5]([OH:19])=[O:6])[CH3:3]
Reactant: CC(C)[C@H](CC1CCCCC1)C(=O)Cl
Reactant: CC(C)CC(=O)Cl
Product: CC(C)[C@H](CC1CCCCC1)C(=O)O

Procedure:
α(S)-(1-Methylethyl)cyclohexanepropionic acid chloride: By following procedure (a) of this example but replacing propionyl chloride with 3-methylbutanoyl chloride, α(S)-(1-methylethyl)-cyclohexane propionic acid is obtained. 1H NMR (CDCl3) δ 2.27 (ddd, J=10.5, 7, 3.5 Hz, 1H), 1.91-1.80 (m, 2H), 1.73-1.55 (m, 5H), 1.35-1.08 (m, 5H), 0.98-0.77 (m, 2H), 0.97 (d, J=7 Hz, 3H), 0.96 (d, J=7 Hz, 3H). Thereafter, the latter compound was converted to its corresponding acid chloride in the same manner as described in section (a) of this example.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2/[CH:11]=[C:12]1\[O:13][C:14]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:15]=2[C:16]\1=[O:17].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[CH2:36]=O>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2/[CH:11]=[C:12]1\[O:13][C:14]2[C:21]([CH2:36][N:33]3[CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:29])[CH2:31][CH2:32]3)=[C:20]([OH:22])[CH:19]=[CH:18][C:15]=2[C:16]\1=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1/C(=C/c2c[nH]c3ccc(Br)cc23)Oc2cc(O)ccc21
Reactant: C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccc(Br)cc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
A solution of (Z)-2-[(5-bromo-1H-indol-3-yl)methylene]-6-hydroxybenzofuran-3(2H)-one (0.30 g, 0.84 mmol) in ethanol (3.0 mL) was added with 1-tert-butoxycarbonylpiperazine (0.17 g, 0.93 mmol), and 37% aqueous formaldehyde (0.093 g, 1.1 mmol), and the mixture was stirred overnight at 50° C. in a sealed tube. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain tert-butyl (Z)-4-({2-[(5-bromo-1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}-methyl)piperazine-1-carboxylate (0.15 g, 33%).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:9][N:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=12)=O.S(O)(O)(=O)=O.[N:33]1([C:38](=[NH:40])[NH2:39])[CH2:37][CH2:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CN1CCCC1=O.O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:8]2[C:7]([C:5]3[CH:4]=[CH:3][N:39]=[C:38]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[N:40]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:19])[F:18])=[CH:15][N:10]3[N:9]=2)=[CH:25][CH:24]=1
Reactant: N=C(N)N1CCCC1
Reactant: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: Fc1ccc(-c2nn3cc(C(F)(F)F)ccc3c2-c2ccnc(N3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-[2-(4-fluorophenyl)-6-(trifluoromethyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-propen-1-one (100 mg, 0.27 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was added 1-pyrrolidinecarboximidamide sulfate (111 mg, 0.53 mmol), and potassium carbonate (73 mg, 0.53 mmol). The mixture was heated at reflux for 8 hours. Upon cooling to room temperature, ether was added followed by water. The organics were washed with brine, and the aqueous layer was extracted with ether. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica (6:1 hexanes-ethyl acetate) to give 2-(4-fluorophenyl)-3-[2-(1-pyrrolidinyl)-4-pyrimidinyl]-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine (80 mg, 71%) as a foam. 1H NMR (CDCl3): δ 8.86 (s, 1 H), 8.61 (d, 1 H), 8.19 (m, 1 H), 7.67 (m, 2 H), 7.46 (d, 1 H), 7.19 (m, 2 H), 6.31 (m, 1 H), 3.70 (m, 4 H), 2.08 (m, 4 H); 19F NMR (CDCl3) δ −62.68, −112.27.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[CH:15]1([S:18](Cl)(=[O:20])=[O:19])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.O>C1COCC1>[CH3:1][N:2]([C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)[S:18]([CH:15]1[CH2:17][CH2:16]1)(=[O:20])=[O:19]
Reactant: CN[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN([C@@H]1CCN(C(=O)OC(C)(C)C)C1)S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (100 mg, 0.5 mmol) in 2.5 mL THF was added cyclopropanesulfonyl chloride (77 mg, 0.55 mmol) and DIPEA (0.10 mL, 0.60 mmol) at ambient temperature. The mixture was stirred at ambient temperature overnight. Water was added, and then extracted with EtOAc. The organic layers were combined washed with brine, dried over Na2SO4, and evaporated in vacuo to afford the crude title product which was used for the next step without further purification. MS (m/z): 305 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1)[NH2:9]
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)c1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.6 %

Procedure:
Step D (2): 10% Palladium on carbon (250 mg) was added under an atmosphere of nitrogen to a chilled (ice-water bath) solution of 1-(2-methoxy-4-nitrophenyl)-4-methyl-1H-imidazole (2.56 g, 11.0 mmol) dissolved in methanol (150 mL). The flask was repeated evacuated and flushed with hydrogen gas (double balloon). The resulting mixture was allowed to warm to rt and left to stir for 18 h under the hydrogen atmosphere. Purged with nitrogen gas. Filtered the crude reaction mixture through a short diatomaceous earth (Celite®) plug. Rinsed reaction vessel and plug with methanol. Concentrated filtrate in vacuo. Dried residue on high vacuum overnight to afford 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (2.25 g, 100% yield) as a blackish/grey waxy solid. LC-MS (M+H)+ 204.1. 1H NMR (500 MHz, chloroform-d) δ ppm 7.69 (s, 1 H) 7.01 (d, J=8.55 Hz, 1 H) 6.82 (s, 1 H) 6.33 (d, J=2.14 Hz, 1 H) 6.30 (d, J=8.55 Hz, 1 H) 3.78 (s, 3 H) 2.33 (s, 3 H).
Reaction SMILES: N1([C:6]([C:8]2[C:9]([CH3:16])=[C:10]([CH:14]=O)[NH:11][C:12]=2[CH3:13])=[O:7])C=CN=C1.[CH2:17]([N:19]([CH2:23][CH3:24])[CH2:20][CH2:21][NH2:22])[CH3:18].[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH2:29]2.C(N(CC)CC)C>C(#N)C>[CH2:17]([N:19]([CH2:23][CH3:24])[CH2:20][CH2:21][NH:22][C:6]([C:8]1[C:9]([CH3:16])=[C:10](/[CH:14]=[C:29]2\[C:30](=[O:35])[NH:31][C:32]3[C:28]\2=[CH:27][C:26]([F:25])=[CH:34][CH:33]=3)[NH:11][C:12]=1[CH3:13])=[O:7])[CH3:18]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)n1ccnc1
Reactant: CCN(CC)CCN
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Temperature: 60 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (14.0 g), N,N-diethylethylenediamine (15.0 g), 5-fluorooxindole (9.86 g), triethylamine (27 ml), and acetonitrile (250 ml) were mixed and heated to 60° C. The black slurry was stirred for 18 h at 60° C. (needs mechanical stirrer). The resulting yellow slurry was cooled to room temperature, diluted with 100 ml acetonitrile, and filtered. The cake was washed with 3×100 ml acetonitrile and dried overnight at 50° C. under house vacuum. N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (21.7 g) was obtained with 85% yield.