Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([N+:18]([O-])=O)[CH:17]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)=[O:7]>CC(O)=O.CCO.[Fe]>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([CH:15]=[C:5]([C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[O:7])[CH:4]=1)[NH2:18]
Reactant: COc1cc(C(=O)N2CCN(C)CC2)cc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(N)cc(C(=O)N2CCN(C)CC2)c1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
1-(3-Methoxy-5-nitrobenzoyl)-4-methylpiperazine (900 mg; 3.22 mmol; 1 eq) and iron powder (719.82 mg; 12.89 mmol; 4 eq) are heated for 1 h at 100° C. in a mixture of AcOH (10 mL) and EtOH (10 mL). The reaction mixture is cooled down to room temperature, concentrated under vacuum and basified with aqueous Na2CO3. The product is extracted with EtOAc. The organic phase is dried over MgSO4 and the solvent evaporated under reduced pressure to afford 500 mg (62%) of the title compound as an orange oil. 1H NMR (DMSO-d6) δ 6.20-6.17 (m, 1H), 6.11-6.10 (m, 1H), 6.01-5.99 (m, 1H), 5.35-5.27 (m, 2H), 3.66 (s, 3H), 3.55-3.53 (m, 4H), 2.30-2.28 (m, 4H), 2.18 (s, 3H). LC/MS: (ES+): 250.4.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:11][C@@H:10]([C:12]([OH:14])=[O:13])[C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:15][C:9]1([CH3:16])[C@@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:11][C@H:10]1[C:12]([O:14][CH2:23][C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)O)C1(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)OCc2ccccc2)C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To a stirred solution of (1R,3S)-3-(tert-butoxycarbonyl)-2,2-dimethylcyclobutanecarboxylic acid (step 2, 0.200 g) in DMF (5 ml) Cs2CO3 (0.371 g) was added at about 0° C. under nitrogen atmosphere. After 30 minutes, BnBr (0.11 ml) was added by drop wise to the reaction mixture and stirred for about 2 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure to give crude product which upon column chromatography afforded the title compound (150 mg, 53.9% Yield). 1H NMR (300 MHz, CDCl3): δ 7.37-7.34 (5H, m), 5.12 (2H, d, J=3.9 Hz), 2.80 (1H, t, J=8.1 Hz), 2.768-2.52 (2H, m), 2.0 (1H, m), 1.44 (9H, m), 1.32 (3H, s), 0.953 (3H, s); Mass: [M+Na]+ 341.2 (100%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:3])[CH3:2].[C:22]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)#[CH:23]>CCCCCCC.CCOC(C)=O>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]#[C:23][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])=[CH:25][CH:26]=1
Reactant: C#Cc1ccc(N)cc1
Reactant: CC(=O)Nc1ccccc1OS(=O)(=O)c1ccc(C)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccccc1C#Cc1ccc(N)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-acetylamino-phenyl ester and 4-ethynyl-phenylamine following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 9:1; yield (47 mg, 50%); 1H NMR δ (CDCl3): 8.39 (d, J=8.52 Hz, 1H), 7.9 (br s, 1H), 7.59-7.67 (m, 2H), 7.58-7.52 (m, 2H), 7.41-7.35 (m, 2H), 7.02 (t, J=7.21 Hz, 1H), 3.82 (b, 2H), 2.21 (s, 3H); LCMS m/z: 250.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[N:11]([C:17]2[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][C:25]5([CH2:31][CH2:30][NH:29][CH2:28]5)[CH2:24]4)=[C:19]([F:32])[CH:18]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.Br[CH2:34][CH2:35][F:36]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[N:11]([C:17]2[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][C:25]5([CH2:31][CH2:30][N:29]([CH2:34][CH2:35][F:36])[CH2:28]5)[CH2:24]4)=[C:19]([F:32])[CH:18]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1
Reactant: FCCBr
Reactant: O=c1c2ccc(OCC3CC3)cc2ccn1-c1ccc(N2CCC3(CCNC3)C2)c(F)c1
Product: O=c1c2ccc(OCC3CC3)cc2ccn1-c1ccc(N2CCC3(CCN(CCF)C3)C2)c(F)c1

Procedure:
According to Method X, 6-cyclopropylmethoxy-2-[4-(2,7-diaza-spiro[4.4]non-2-yl)-3-fluorophenyl]-2H-isoquinolin-1-one was reacted with 1-bromo-2-fluoro-ethane. In this way the product was obtained with molecular weight 479.57 (C28H31F2N3O2); MS (ESI): 480 (M+H+).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:10]([O-])([O-:12])=[O:11].[K+].[K+].C(=O)=O.Cl>O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]([OH:12])=[O:11]
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: O=C(O)c1nc2ccccc2[nH]1
Temperature: 250 °C
Reaction time: 10 h
Yield: 72.8 %

Procedure:
A mixture of 118 g (1 mol) of benzimidazole, g (2 mol) of K2CO3 and 400 ml of liquid carbon dioxide was stirred in an autoclave at 250° C. under autogenous pressure for 10 hours. The solid output was pulverized, suspended in 2.5 L of water and brought to pH 3-4 with concentrated hydrochloric acid while being cooled with ice. The resulting precipitate was filtered off and recrystallized from water to give 118 g (73%) of benzimidazole-2-carboxylic acid (Compound No. 4); mp. 170° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][CH:9]2O)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:14])([CH3:13])[CH:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)Cc2ccc(Br)cc2C(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)C=Cc2cc(Br)ccc2C1
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
A solution of 7-bromo-3,3-dimethyl-1,2,3,4-tetrahydro-1-naphthol (7.0 g) and p-toluene sulphonic acid (0.5 g) in benzene (100 ml) was heated under reflux, using a Dean-Stark water separator, for 1.5 hours. After cooling, solvent was removed in vacuo, and the residue partitioned between ether and water. The combined ether extracts were washed with sodium bicarbonate solution, water, brine, then dried over sodium sulphate. Removal of drying agent and solvent gave the title compound as an oil (6.2 g) having:
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[N:5][C:6]([Cl:19])=[CH:7][CH:8]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:19][C:6]1[N:5]=[C:4]2[CH:3]=[C:2]([C:32]3[CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH:28]=3)[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:9]2=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)C1
Reactant: Clc1cccc(Cn2c(Br)cc3nc(Cl)ccc32)c1
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: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3nc(Cl)ccc3n2Cc2cccc(Cl)c2)C1
Temperature: 106 °C
Reaction time: 2 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol, Strem) was added to a degassed mixture of 2-bromo-5-chloro-1-(3-chlorobenzyl)-1H-pyrrolo[3,2-b]pyridine (0.50 g, 1.1 mmol, prepared as in Example 103, Step 2), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (0.414 g, 1.40 mmol, Combi-Blocks) and Na2CO3 (0.60 g, 5.6 mmol) in 1,2-dimethoxyethane (10 mL) and water (2 mL), and the sealed reaction mixture was heated at 106° C. for two hours. Additional tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (0.33 g, 1.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol) were added, and heating was continued for additional two hours. Upon cooling to room temperature, the reaction mixture was diluted with water, and the aqueous layer was extracted with three portions of EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-30% EtOAc in hexanes. Yield: (0.12 g, 24%).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.[CH3:16][C:17]1[C:21]([C:22]2[CH:23]=[C:24]([C:41](=[O:49])[C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)[C:25]3[N:29]=[C:28]([O:30]CC)[N:27](C(OC(C)(C)C)=O)[C:26]=3[CH:40]=2)=[C:20]([CH3:50])[O:19][N:18]=1.Cl>C(OCC)C.C(O)C>[CH3:16][C:17]1[C:21]([C:22]2[CH:23]=[C:24]([C:41]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)([OH:49])[C:2]3[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=3[F:10])[C:25]3[NH:29][C:28](=[O:30])[NH:27][C:26]=3[CH:40]=2)=[C:20]([CH3:50])[O:19][N:18]=1
Reactant: CCOc1nc2c(C(=O)c3ccc(F)cn3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Reactant: Fc1cc(F)c(Br)c(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCO
Product: Cc1noc(C)c1-c1cc(C(O)(c2ccc(F)cn2)c2c(F)cc(F)cc2F)c2[nH]c(=O)[nH]c2c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To 1-bromo-2,4,6-trifluorobenzene (0.02 ml, 0.16 mmol) in diethyl ether (0.52 mL) at −78° C. was added n-butyllithium (0.12 mL, 0.18 mmol, 1.6 M in hexanes). After 30 minutes, tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(5-fluoropicolinoyl)-1H-benzo[d]imidazole-1-carboxylate (50 mg, 0.10 mmol) in diethyl ether (1 mL) was added drop-wise to the reaction. After 60 minutes, the reaction was warmed, quenched with saturated NH4Cl(aq) (10 mL), extracted with ethyl acetate (3×10 mL), dried over Na2SO4, and concentrated in vacuo. To the crude residue in ethanol (3.5 mL) was added hydrochloric acid (0.35 mL, 1.4 mmol, 4 M in 1,4-dioxane) and the mixture was heated to 70° C. in a microwave reactor for 45 minutes. Purification by reverse-phase HPLC (40-50% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ) afforded 6-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(2,4,6-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-one as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]([N:13]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:14][CH:15]([O:18][CH3:19])[O:16][CH3:17])=[O:12])#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:36][OH:37].C(O)C>O>[CH:20]1([N:13]([CH2:14][CH:15]([O:18][CH3:19])[O:16][CH3:17])[C:11](=[O:12])[CH2:10][CH2:9][O:8][CH2:7][CH2:6][C:5]2[CH:26]=[CH:27][CH:28]=[C:3]([C:1](=[NH:2])[NH:36][OH:37])[CH:4]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NO
Reactant: COC(CN(C(=O)CCOCCc1cccc(C#N)c1)C1CCCCC1)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COC(CN(C(=O)CCOCCc1cccc(C(=N)NO)c1)C1CCCCC1)OC
Temperature: 90 °C
Reaction time: 72 h

Procedure:
To 3-(3-cyanophenethoxy)-N-cyclohexyl-N-(2,2-dimethoxyethyl)propanamide [Example 10, Step i)] (1.5 g) within a 35 mL microwave vial was added potassium carbonate (0.80 g), hydroxylamine hydrochloride (0.402 g), water (2.5 mL) and ethanol (10 mL). The vial was sealed and stirred for 3 days before being heated at 90° C. for a total of 3 h. The reaction was diluted with water, extracted twice with ethyl acetate, which was pooled and washed twice with water, twice with brine, dried over sodium sulphate, filtered and the solvent removed to afford a colourless gum (1.7 g). This material was used in the next step directly.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:8]=[C:9]([N:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]=[N:12]2)[CH:10]=1)=[O:4].O[Li].O>C1COCC1.O>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([C:7]2[CH:8]=[C:9]([N:11]3[C:15]([C:16]([F:18])([F:19])[F:17])=[N:14][N:13]=[N:12]3)[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(-n2nnnc2C(F)(F)F)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3nnnc3C(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a stirred solution of 4′-methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid methyl ester (3.7 mmol, 1.34 g) in 50 ml of THF was added a solution of LiOH.H2O (18.5 mmol, 776.3 mg) in 12 mL of water. The reaction mixture was heated to reflux for 3.5 hours, then cooled to room temperature. Solvent was removed under reduced pressure, and the pH of the liquid residue was adjusted to 2.0 by addition of 2N aqueous HCl solution. The mixture was extracted with ethyl acetate and the combined ethyl acetate layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give 4′-methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid as light yellow solid (1.25 g, 97% yield).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Br[CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(#N)C>[CH:1]1([NH:4][CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: NC1CC1
Solvent: CC#N
Product: CCOC(=O)C(NC1CC1)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
Cyclopropylamine (0.30 mL) was added to an acetonitrile (10 mL) solution of diethyl bromopropanedioate (1.0 g), and the mixture was stirred for 16 hours at room temperature. The precipitated solid was filtered out, and the filtrate was concentrated under reduced pressure. Then, the resulting residue was purified by OH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=90/10→70/30) to obtain diethyl (cyclopropylamino)propanedioate (colorless oil) (0.57 g, 63%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][NH2:27].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:27][CH2:26][CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Reactant: NCCc1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cnc(Oc2ccc(CNCCc3cccs3)cc2F)cn1
Reaction time: 8 h
Yield: 17.6 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), 2-(2-thienyl)ethylamine (0.217 g, 1.68 mmol) and 3 Å molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 15% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes). Concentrate the fractions containing the product. Take the solid up in dichloromethane (100 mL) and wash with 1.0 N NaOH (2×25 mL) to give the title compound (0.100 g, 18%): TOF MS ES+ 373.1 (M+H)+, HRMS calcd for C15H11N4O2FS 373.1135 (M+H)+, found 373.1150, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min. 20-95% over 18], tR=10.3 min. 100% purity.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([Br:12])=[CH:4][N:3]=1.[CH:13]1([CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:12][C:5]1[C:6]([N:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH:13]3[CH2:15][CH2:14]3)[CH2:18][CH2:19]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: C1CN(CC2CC2)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Br)c(N2CCN(CC3CC3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 20 h

Procedure:
To a mixture of 2-amino-5-bromo-4-chloro-3-nitropyridine (0.126 g, 0.50 mmol) and isopropanol (6 ml) was added 1-cyclopropylmethylpiperazine (0.078 g, 0.55 mmol) with the aid of isopropanol (3 ml), followed by diisopropylethylamine (0.10 ml, 0.57 mmol). The reaction mixture was stirred at 45° C. for 20 h, then allowed to cool to room temperature and diluted with isopropanol (4 ml). The resulting yellow precipitate was collected by filtration, washed with isopropanol (2×4 ml), diethyl ether (3×4 ml), and dried. The title compound was obtained as a yellow solid (0.096 g). The filtrate was concentrated in vacuo, and purification of the resulting residue by chromatography (10 g isolute column) eluting with a gradient of methanol (2 to 4%) in dichloromethane/ethyl acetate (v/v; 1:1) afforded an additional 0.038 g of the product (overall yield: 76%). 1H-NMR (500 MHz, DMSO-d6) 0.08 (m, 2H) and 0.46 (m, 2H), (cyclopropyl CH2), 0.86 (m, 1H, cyclopropyl CH), 2.22 (d, J=6.6 Hz, 2H, N—CH2cyclopropyl), 2.57 (br s, 4H, piperazine N(CH2)2), 3.06 (br s, 4H, piperazine N(CH2)2), 6.96 (s, 2H, NH2), 8.15 (s, 1H, pyridine 6-H);
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:17]([NH:19][O:20][CH3:21])=[O:18].CCN(C(C)C)C(C)C>C1COCC1>[Cl:10][C:6]1[N:5]=[C:4]([S:11][CH3:12])[N:3]=[C:2]([NH:13][C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=2[CH3:25])[C:17]([NH:19][O:20][CH3:21])=[O:18])[C:7]=1[C:8]#[N:9]
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Reactant: CONC(=O)c1ccc(C)c(N)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)c1ccc(C)c(Nc2nc(SC)nc(Cl)c2C#N)c1
Yield: 91.5 %

Procedure:
4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (2.19 g, 10 mmol), 3-amino-N-methoxy-4-methyl-benzamide (1.80 g, 10 mmol) and DIEA (1.9 mL) in THF (80 mL) were stirred at room temperature for overnight. The solvent was removed in vacuo and the product (3.33 g, 92%) was obtained after purification by silica gel column chromatography.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:18]
Reactant: CNCCC#Cc1ccccn1
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: CN(CCC#Cc1ccccn1)C(=O)c1cccc(Cl)c1
Yield: 60.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (100 mg, 0.62 mmol) and 3-chlorobenzoyl chloride (109 mg, 0.62 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: 98/2 as eluent) to afford 112 mg of 3-chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 60%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[O:30]1C[CH:31]1[CH2:33][N:34]1[C:42]2[CH2:41][CH2:40][N:39]([C:43](=[O:45])[CH3:44])[CH2:38][C:37]=2[C:36]([C:46]2[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=2)=[N:35]1>C(Cl)Cl>[Cl:21][C:20]1[CH:19]=[N:18][CH:17]=[C:16]([Cl:22])[C:15]=1[O:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:6][CH:31]([OH:30])[CH2:33][N:34]2[C:42]3[CH2:41][CH2:40][N:39]([C:43](=[O:45])[CH3:44])[CH2:38][C:37]=3[C:36]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=3)=[N:35]2)[CH2:13][CH2:12]1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cncc2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(Oc3c(Cl)cncc3Cl)CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A solution of 103 mg (0.30 mmol) of 4-(3,5-dichloro-pyridin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2 (2 mL) was treated with trifluoroacetic acid (0.5 mL) at room temperature overnight. The solvent was then removed and the crude product dissolved in MeOH and stirred over 100 mg of sodium bicarbonate for 1 h. The solid was filtered off and the filtrate concentrated. The crude piperidine was then dissolved in 4 mL EtOH and treated with 100 mg (0.27 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 90 mg (54%) of a white solid. MS (electrospray): exact mass calculated for C28H30Cl2F3N5O3, 611.17; m/z found, 612.2 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 8.44 (s, 2H), 7.77 (d, J=8.41 Hz, 1H), 7.72 and 7.68 (A and B of AB quartet, J=8.41 Hz, 2H), 7.65 (d, J=8.41 Hz, 1H), 4.88 and 4.76 (A and B of AB quartet, J=15.65 Hz, 1H), 4.66 (br s, 1H), 4.55 (br s, 1H), 4.26-4.08 (m, 2H), 4.08-3.98 (m, 2H), 3.91-3.69 (m, 2H), 3.03-2.92 (m, 1.6H), 2.91-2.85 (m, 0.8H), 2.85-2.75 (m, 1.6H), 2.52-2.40 (m, 3H), 2.35-2.24 (br m, 1H), 2.22 (s, 1.5H), 2.17 (s, 1.5H), 2.03-1.90 (m, 4H).
Reaction SMILES: [NH4+:1].[OH-].[NH2:3][C:4]1[N:12]=[C:11]2[C:7](=[N:8][CH:9]=[N:10]2)[C:6](=[S:13])[N:5]=1>[OH-].[K+]>[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([S:13][NH2:1])[N:5]=1
Reactant: NC1=NC(=S)C2=NC=NC2=N1
Reactant: [NH4+]
Agent: [K+]
Agent: [OH-]
Product: NSc1nc(N)nc2nc[nH]c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
To an ice-cold 5.25% sodium hypochlorite solution (33.8 mL) was added 7N NH4OH (17.8 mL) and stirred for 10 minutes. A solution of 2-aminopurine-6-thione 1, see A. G. Beaman and R. K. Robins, J. Am. Chem. Soc., 83, 4038, (1961), (1.67 g, 22 mmol) in 2N KOH (11 mL) was added and continued stirring for 25 min at 0.C. The mixture was allowed to stand at 0° C. without stirring for 1.5 h. The precipitate was collected by filtration and washed with small amount of water and EtOH to obtain 1.45 g (36%) of the title compound, mp>250° C.: UV: λmax (pH 1) 325 nm (ε 6,400), 240 nm (sh): λmax (pH 7) 310 nm (ε 5,900), 237 nm (ε 6,800): λmax (pH 11) 312 nm (ε 5,900): 1H NMR (DMSO-d6): δ 5.78 (br s, 2, NH2, exchangeable in D2O), 7.73 (s, 1, C8H): Anal. Calcd for C5H6N6S.1/2 H2O (191.1): C, 31.41: H, 3.27: N, 43.98: S, 16.79. Found: C, 1.89: H, 3.27: N, 43.38: S, 17.19.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:15][N:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][NH2:26])=[CH:24][C:19]=2[N:18]=[N:17]1>>[CH3:15][N:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][NH:26][S:2]([C:5]3[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: Cn1nnc2cc(CN)ccc21
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(c2)nnn3C)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and (1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanamine.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH:20]([CH3:25])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([OH:24])([C:2]2[C:7]3[CH:8]=[CH:9][O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:20]([CH3:25])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Brc1cccc2occc12
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Product: CC1CN(Cc2ccccc2)CCC1(O)c1cccc2occc12
Yield: 68.3 %

Procedure:
Beginning with 2.0 gm (10.2 mMol) 4-bromobenzofuran and 2.06 gm (10.2 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 2.24 gm (69%) of the desired compound were prepared essentially as described in EXAMPLE 19.