Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[CH:15]([CH3:17])[CH3:16])[NH2:11].[CH3:18][C:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>C(N(CC)CC)C>[Cl:7][C:8]1[CH:9]=[C:10]([NH:11][C:22]([C:19]2([CH3:18])[CH2:21][CH2:20]2)=[O:23])[CH:12]=[CH:13][C:14]=1[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)c1ccc(N)cc1Cl
Reactant: CC1(C(=O)Cl)CC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)c1ccc(NC(=O)C2(C)CC2)cc1Cl
Reaction time: 1 h
Yield: 0 %

Procedure:
To 90 ml of benzene were added 1.0 g (5.9/1000 mole) of 3-chloro-4-isopropylaniline, 0.7 g of triethylamine, and 0.8 g (6.8/1000 mole) of 1-methylcyclopropanecarboxylic acid chloride. The mixture was stirred for 1 hour at 5° to 10° C. The precipitated crystals were separated by filtration, and the filtrate was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The resulting dried filtrate was concentrated by an evaporator. The resulting oily product was isolated and purified by silica gel column chromatography [eluent: benzene/ethyl acetate=40/1 (v/v)] to give 1.3 g of N-(3-chloro-4-isopropylphenyl)-1-methylcyclopropanecarboxamide as an oil in a yield of 87.6 % based on 3-chloro-4-isopropylaniline. On standing for a long period of time, the oil crystallized.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C@@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][N:13]2[C:17]3=[N:18][C:19]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:28]=4)=[N:20][CH:21]=[C:16]3[CH:15]=[N:14]2)[CH2:8][CH2:7]1>C1COCC1>[CH3:33][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:19]2[N:18]=[C:17]3[N:13]([CH2:12][C@@H:9]4[CH2:8][CH2:7][C@H:6]([NH:5][C:1](=[O:3])[CH3:2])[CH2:11][CH2:10]4)[N:14]=[CH:15][C:16]3=[CH:21][N:20]=2)=[CH:28][C:27]=1[S:29](=[O:31])(=[O:30])[NH2:32]
Reactant: Cc1ccc(Nc2ncc3cnn(C[C@H]4CC[C@@H](N)CC4)c3n2)cc1S(N)(=O)=O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)N[C@H]1CC[C@@H](Cn2ncc3cnc(Nc4ccc(C)c(S(N)(=O)=O)c4)nc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetyl chloride (0.027 mL, 0.38 mmol) was added to a 10 mL vial charged with 5-(1-((cis-4-aminocyclohexyl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-methylbenzenesulfonamide (0.15 g, 0.36 mmol, Example #C.1.1) and TEA (1 mL) in THF (4 mL). The reaction mixture was stirred at ambient temperature for about 2 h, then concentrated under reduced pressure. The crude product was purified by RP-HPLC (Table 2, Method b) to give N-(cis-4-((6-(4-methyl-3-sulfamoylphenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexyl)acetamide (0.021 g, 13%) as a white solid. LC/MS (Table 2, Method a) Rt=1.71 min; MS m/z: 458 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].S(Cl)(Cl)=O.[CH3:14]O>>[NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([O:9][CH3:14])=[O:8])=[O:4]
Reactant: CO
Reactant: NCC(=O)NCC(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)CNC(=O)CN
Reaction time: 8 h

Procedure:
2.5 g (19 mmoles) of Gly-Gly-OH was suspended in 25 mL of dry methanol. Two equivalents of thionyl chloride were added, and the suspension stirred to dissolution. The mixture was allowed to sit at room temperature overnight. The solvent was removed under vacuum, the residue taken up in a minimum of methanol, and anhydrous ether added to effect crystallization. Yield 3.2 g (92%). M.P. 146°-146° C. 1H-NMR (DMSO) 3.6 (s, 3H OMe), 3.8 and 3.9 (d, 2H, Gly α-H's).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)#[N:27]>CN(C=O)C>[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)#[N:27]
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Reactant: N#Cc1ccccc1B(O)O
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1C#N

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide and 2-cyanophenylboronic acid (CAS RN 138642-62-3) and using DMF as solvent for the reaction. Off-white solid (21%). MS (ESI): m/z=450.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(c2cccc(Cl)c2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCN(c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
158 mg (0.59 mmol) of ethyl 1-(3-chlorophenyl)-piperidine-4-carboxylate were dissolved in 2.30 ml of methanol and 0.3 ml of water, and 99 mg (1.77 mmol) of powdered potassium hydroxide were added. The mixture was stirred at room temperature overnight After evaporation of the solvent, water was added and the mixture was acidified to pH 2-3 with 2N hydrochloric acid. The aqueous phase was extracted with ethyl acetate three times, the combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to give 127 mg (90% yield) of 1-(3-chlorophenyl)-piperidine-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([OH:25])=O)=[CH:21][CH:22]=3)=[C:18]([CH3:26])[CH:17]=[C:16]4[CH3:27])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>>[F:32][C:33]([F:37])([F:36])[CH2:34][NH:35][C:23]([C:20]1[C:19]2[N:15]([C:16]([CH3:27])=[CH:17][C:18]=2[CH3:26])[C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:28]([F:29])([F:31])[F:30])[O:13][N:12]=2)=[CH:22][CH:21]=1)=[O:25]
Reactant: Cc1cc(C)n2c(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc(C(=O)O)c12
Reactant: NCC(F)(F)F
Product: Cc1cc(C)n2c(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc(C(=O)NCC(F)(F)F)c12

Procedure:
Using a procedure similar to that described in Example 1, except using 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-1,3-dimethylindolizine-8-carboxylic acid (90 mg) and 2,2,2-trifluoroethylamine (38 mg), the title compound was isolated as a solid (85 mg, 81%). Rf=0.35 (3:7 EA/heptane). MS (ES): M/Z [M+H]=552. 1H NMR (400 MHz, DMSO-d6): 2.18 (s, 3H), 2.19 (s, 3H), 4.11 (qd, J=9.7, 6.6 Hz, 2H), 4.48 (d, J=18.7 Hz, 1H), 4.56 (d, J=18.6 Hz, 1H), 6.57 (s, 1H), 6.62 (d, J=7.0 Hz, 1H), 7.04 (d, J=7.0 Hz, 1H), 7.67 (d, J=1.7 Hz, 2H), 7.84 (t, J=1.9 Hz, 1H), 9.21 (t, J=6.3 Hz, 1H). 19F NMR (376 MHz, DMSO-d6): −78.8 (s, 3F) and −70.6 (t, J=9.9 Hz, 3F)
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[OH-].[Na+:10]>O>[Na+:10].[NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH-:8])=[O:7])=[N:2]1
Reactant: NC(=O)c1nc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: [NH-]C(=O)c1nc[nH]n1

Procedure:
A solution consisting of 1,2,4-triazole-3-carboxamide (1.12 g, 10.0 mmol), sodium hydroxide (0.40 g, 10.0 mmol) and water (10.0 ml) was frozen and the sample was lyophilized. The product was obtained as the semihydrate of 1,2,4-triazole-3-carboxamide sodium salt with a melting point of >320°.
Reaction SMILES: [CH2:1]([N:4]([CH3:20])[CH2:5][CH:6]=[CH:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14][CH2:13]2)[CH:2]=[CH2:3].[CH2:21]([O:23][C:24](Cl)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([N:16]1[C:17]2[C:12](=[CH:11][C:10]([O:9][CH2:8][CH:7]=[CH:6][CH2:5][N:4]([CH2:1][CH:2]=[CH2:3])[CH3:20])=[CH:19][CH:18]=2)[CH2:13][CH2:14][CH2:15]1)=[O:25])[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: C=CCN(C)CC=CCOc1ccc2c(c1)CCCN2
Product: C=CCN(C)CC=CCOc1ccc2c(c1)CCCN2C(=O)OCC

Procedure:
In analogy to example 3.9, Allyl-methyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-but-2-enyl]-amine and ethylchloroformate were converted to yield 6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester as brown oil, MS: 345 (MH+).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[O:19][C:20](=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.Cl>O.CS(C)=O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]([OH:32])=[O:19])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: COC(=O)CCCCCCCCCCBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CCCCCCCCCCOc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a 250 mL Erlenmeyer flask was added freshly ground potassium hydroxide (4.2 g, 74.91 mmol) and 100 mL dimethyl sulfoxide. 2-benzyloxy-phenol (5 g, 24.97 mmol) and 11-bromoundecanoic acid methyl ester (7 g, 25.07 mmol) was added and the mixture was allowed to stir at room temperature overnight. Water (75 mL) was added and the solution was heated to 85° C., with stirring, for 3 hours. The reaction was cooled to room temperature and acidified with concentrated hydrochloric acid to pH 2. The acidified solution was cooled to 4° C. for 2 hours, and the precipitate then collect by suction filtration. The product was recrystallized form ethanol/water. The product (8.88 g, 93%) was isolated as a light brown solid, mp 62-63° C. Combustion analysis: Found: C, 74.71; H, 8.08%; C24H32O4 requires C, 74.97; H, 8.39%;
Reaction SMILES: [O:1]=[C:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:17]([OH:19])=[O:18])[CH2:3]1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:20]([O:18][C:17](=[O:19])[C@@H:4]1[CH2:3][C:2](=[O:1])[CH2:6][N:5]1[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=C1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1
Reaction time: 1 h
Yield: 49 %

Procedure:
5 g (0.02 mmol) of 4-keto-1-[(phenylmethoxy)carbonyl]-L-proline was dissolved in 50 ml dimethylformamide, 2.62 ml (0.022 mmol) of benzyl bromide and 3.59 g (0.026 mmol) of potassium carbonate were added. The reaction mixture was stirred for 1 hour followed by normal extractive work to give the title compound, 3.5 gm (49% yield), m.p. 55°-56° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:12][C@H:11](/[CH:13]=[N:14]/[S:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:21][Mg]Br>C(Cl)Cl>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][C@@H:9]1[CH2:12][C@H:11]([CH:13]([NH:14][S:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:21])[CH2:10]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: C[Mg]Br
Reactant: CC(C)(C)S(=O)/N=C/[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Solvent: ClCCl
Product: CC(NS(=O)C(C)(C)C)[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid 1-[cis-3-(tert-butyldimethylsilanyloxy)-cyclobutyl]-meth-(E)-ylideneamide (640 mg, 2.02 mmol) in CH2Cl2 (10 mL) at 0° C. was slowly added methylmagnesium bromide (3.0 M in Et20, 1.14 mL, 3.43 mmol). The reaction mixture was stirred at 0° C. for 1 h then quenched with saturated aqueous NH4Cl, diluted with water and extracted with EtOAc (3×). The combined organics were dried over MgSO4 and concentrated to provide 685 mg of 2-methyl-propane-2-sulfinic acid {1-[cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-ethyl}-amide as an off-white waxy solid which was used without further purification. 1H NMR (CDCl3, 300 MHz): δ (ppm) 4.05-4.18 (m, 1H), 3.16-3.31 (m, 1H), 2.85 (d, J=7.2 Hz, 1H), 2.21-2.44 (m, 2H), 1.59-1.76 (m, 3H), 1.20 (s, 9H), 1.18 (d, J=6.0 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][C:6]=1[CH3:7].[Br:13]N1C(=O)CCC1=O.[OH-].[Na+]>ClCCl>[Br:13][C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[NH:5][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(Cl)c(C)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c(C)c(Cl)c1Br
Temperature: 25 °C

Procedure:
Ethyl 4-chloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 7, 300 mg, 1.6 mmol) was dissolved in dry dichloromethane (10 ml), N-bromosuccinimide (285 mg, 1.6 mmol) was added at 0° C. and resulting mixture was stirred at room temperature over night. The mixture was poured into cold sodium hydroxide aqueous solution (2M) (20 ml), extracted with diethyl ether (2×20 ml). The organic phase was then washed with water (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (hexanes/ethyl acetate, gradient) to give the desired product as a yellowish solid. (424 mg).
Reaction SMILES: [CH3:1][N:2]([C@@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([F:13])([F:12])[F:11].Cl[C:21]1[C:22]2[CH:29]=[CH:28][NH:27][C:23]=2[N:24]=[CH:25][N:26]=1.CCN(C(C)C)C(C)C>CCO>[N:24]1[C:23]2[NH:27][CH:28]=[CH:29][C:22]=2[C:21]([N:17]2[CH2:18][CH2:19][C@@H:15]([N:2]([CH3:1])[C:3](=[O:14])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:10]([F:13])([F:11])[F:12])[CH2:16]2)=[N:26][CH:25]=1
Reactant: CN(C(=O)c1ccccc1C(F)(F)F)[C@@H]1CCNC1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN(C(=O)c1ccccc1C(F)(F)F)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 25 °C

Procedure:
To a solution of (R)—N-methyl-N-(pyrrolidin-3-yl)-2-(trifluoromethyl)benzamide (1 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.8 mmol) in the EtOH (3 mL) was added DIPEA (2 mmol) with stirring at room temperature. The reaction mixture was refluxed overnight. The mixture was then concentrated, and purified by flash chromatography to give the title compound. MS (m/z): 390 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[CH:17]1([C:7]2([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:11]3[CH2:12][N:13]([C:32]([NH:31][C:25]4[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=4[F:23])=[O:33])[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C1OC(C2CCCCC2)(C2CCCCC2)C2CNCCN12
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(F)cc1F)N1CCN2C(=O)OC(C3CCCCC3)(C3CCCCC3)C2C1
Temperature: 60 °C
Reaction time: 14 h
Yield: 61.9 %

Procedure:
1,1-Dicyclohexyl-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one (0.13 g, 0.42 mmol) was dissolved in toluene (1.5 mL). 2,4-Difluorophenyl isocyanate (0.10 g, 0.64 mmol) was added thereto, and the mixture was stirred at 60° C. for 14 hours. The reaction solution was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:2) and crystallized from hexane to obtain the title compound (0.12 g, yield 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6].[H-].[Na+].Cl[C:15]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=[C:17]([S:26][CH3:27])[N:16]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][O:6][C:19]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][N:16]=[C:17]([S:26][CH3:27])[N:18]=1
Reactant: COc1ccc(CO)cc1Cl
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(SC)nc1OCc1ccc(OC)c(Cl)c1
Yield: 11.7 %

Procedure:
3-Chloro-4-methoxybenzyl alcohol (20 g, 116 mmol) was dissolved in 200 mL of DMF, NaH (7.0 g, 174 mmol) was added under ice-water-bath. After 1 h of reaction, ethyl 4-chloro-2-(methylmercapto)pyrimidine-5-carboxylate (27 g, 116 mmol) was added in portions for continuing the reaction for 3 h. 300 mL of water was added, extraction was performed with ethyl acetate, the organic layer was dried, concentrated and separated with silica gel column (petroleum ether: ethyl acetate=10:1) to obtain ethyl 4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxylate as white solid (5.0 g, 12%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:15]=[C:14]([I:16])[CH:13]=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O>[I:16][C:14]1[CH:13]=[N:12][N:11]([CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)[CH:15]=1
Reactant: Ic1cnn(C2CCC3(CC2)OCCO3)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(n2cc(I)cn2)CC1
Temperature: 65 °C
Yield: 98.6 %

Procedure:
The mixture of 1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-iodo-1H-pyrazole (20.0 g, 59.8 mmol), pyridinium p-toluenesulfonate (30.1 g, 120 mmol) in acetone (300 mL) and H2O (300 mL) was heated at 65° C. for 16 h. The reaction mixture was partitioned between EtOAc (200 mL) and H2O (100 mL), and the layers were separated. The aqueous layer was re-extracted with EtOAc (3×100 mL), and the combined organic fractions were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo resulting in 17.1 g (98% yield) of the title compound as a white solid. The material was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ=7.54 (s, 1H), 7.52 (s, 1H), 4.62 (tt, J=4.0, 10.1 Hz, 1H), 2.64-2.38 (m, 6H), 2.36-2.24 (m, 2H). MS (ES+): m/z=291.00 [MH+]. HPLC: tR=3.37 min (polar—5 min, ZQ3).
Reaction SMILES: [C:1]([C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[H][H]>CO.[Ni]>[NH2:2][CH2:1][C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: N#Cc1cccc2nnsc12
Agent: [Ni]
Solvent: CO
Product: NCc1cccc2nnsc12

Procedure:
In a hydrogenation vessel, a solution of 14.5 g of 7-cyanobenzo-1,2,3-thiadiazole in 150 ml of methanol is treated with 4.4 g of Raney nickel and with 15 g of liquid nitrogen. Hydrogen is subsequently injected, the vessel is heated, and the mixture is hydrogenated at 60° C. and constant hydrogen pressure of 107Pa until hydrogen is no longer taken up. The mixture is then cooled, the catalyst is removed by filtration, the filtrate is evaporated and chromatographed on silica gel (hexane/ethyl acetate 2:1), resulting in the title compound of m.p. 136°-139° C.).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1)([O-:3])=[O:2].C(N1C=CN=C1)([N:14]1C=CN=C1)=O.N>CN(C=O)C.CO>[N+:1]([C:4]1[CH:5]=[C:6]([C:9]([NH2:14])=[O:11])[NH:7][N:8]=1)([O-:3])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Agent: N
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1cc([N+](=O)[O-])n[nH]1
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of 5-nitro-3-pyrazolecarboxylic acid (6.28 mg, 40 mmol) in DMF (30 mL) was added carbonyldiimidazole (12.96 mg, 80 mmol) The mixture was allowed to stir for 30 min, and ammonia in MeOH (2M, 60 mL) was added. The reaction mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure to afford the crude product which was then washed with ether to afford 3-nitro-1H-pyrazole-5-carboxamide (3.0 g, 48%), which was used directly in the next step without further purification. LC-MS (ESI) m/z 155 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[C:3]=1[CH3:26].[CH3:27][O:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([O:28][CH3:27])=[C:34]([CH3:35])[CH:33]=5)[C:3]([CH3:26])=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1C
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc(C)c2C)cc1C
Temperature: 80 °C
Yield: 59.4 %

Procedure:
To N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (70 mg, 0.18 mmol), 2-methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (69 mg, 0.27 mmol) and tetrakis(triphenylphosphine)palladium (0) (21 mg, 0.018 mmol) in 1,2-dimethoxyethane (2.0 mL), 2 M Na2CO3 (276 μL, 0.55 mmol) was added. The reaction mixture was stirred and heated at 80° C. for 20 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,4,5′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (50 mg, 58%). ESI-MS m/z calc. 467.4. found 468.7 (M+1)+. Retention time 1.96 minutes.
Reaction SMILES: [C:1]([N:8]1C=CN=C1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].O1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[N:3]1[C:1](=[O:2])[N:8]=[C:14]2[CH:15]=[CH:16][CH:17]=[CH:6][C:7]=12
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: O=C1N=c2ccccc2=N1

Procedure:
In Scheme I, 2-fluoro-nitrobenzene is reacted with a primary amine, intermediate (h), wherein R1 is as described herein, to provide intermediate (i), which is reduced to a diaminophenyl, intermediate (j). The diaminophenyl is reacted with carbonyldiimidazole in the presence of an inert diluent, such as tetrahydrofuran, at a temperature range of from about 20° C. to about 40° C. for between about 12 and about 30 hours, to provide a benzoimidazolone compound of intermediate (d). A representative synthesis of a compound of intermediate (d) is described herein in Example 1, steps (a)-(c).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>ClCCCl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:3]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Brc1cncc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-3-pyridinecarboxaldehyde in 20 mL of 1,2-dichloroethane are successively added, under argon, 4.55 g of sodium triacetoxyborohydride and 0.94 mL of pyrrolidine. The reaction mixture is stirred at room temperature for 3 hours and then washed with saturated sodium hydrogen carbonate solution, with water and with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of ethyl acetate and cyclohexane (80/20 by volume) to give 1.4 g of 3-Bromo-5-pyrrolidin-1-ylmethylpyridine in the form of a pale yellow oil.