Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:64]([N:71]1[CH2:76][CH2:75][N:74]([CH:77]2[CH2:82][CH2:81][CH:80]([NH2:83])[CH2:79][CH2:78]2)[CH2:73][CH2:72]1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C=O)C>[CH2:64]([N:71]1[CH2:72][CH2:73][N:74]([C@H:77]2[CH2:82][CH2:81][C@H:80]([NH:83][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([NH:21][C:19]4[N:18]=[CH:17][C:8]5[N:9]([CH3:16])[C:10](=[O:15])[C:11]6([CH2:14][CH2:13]6)[CH2:12][N:6]([CH:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)[C:7]=5[N:20]=4)=[C:23]([O:31][CH3:32])[CH:24]=3)[CH2:79][CH2:78]2)[CH2:75][CH2:76]1)[C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1
Reactant: NC1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(Cc4ccccc4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (66 mg, 0.15 mmol, 1 eq), DIPEA (52 μl, 0.3 mmol, 2 eq) and TBTU (54 mg, 0.17 mmol, 1.1 eq) were added to 1 mL DMF and the resulting solution was stirred at rt for 20 min before the addition of 4-(4-benzylpiperazin-1-yl)cyclohexanamine (Intermediate 18) (35 mg, 0.18 mmol, 1.2 eq) dissolved in DMF (0.5 mL). The RM was then stirred at rt for 2 hours before purifying by preparative RP-HPLC-MS (Preparative—2) to provide N-((trans)-4-(4-benzylpiperazin-1-yl)cyclohexyl)-4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzamide (white solid, 13 mg, 13%).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:24]=[CH:23][C:7]([C:8]([C:10]2[N:14]3[CH:15]=[C:16]([C:19]([O:21]C)=[O:20])[CH:17]=[CH:18][C:13]3=[CH:12][N:11]=2)=[O:9])=[CH:6][C:5]=1[O:25][CH3:26].O1CCOCC1.ClCCl>CO>[NH2:3][C:4]1[CH:24]=[CH:23][C:7]([C:8]([C:10]2[N:14]3[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:13]3=[CH:12][N:11]=2)=[O:9])=[CH:6][C:5]=1[O:25][CH3:26]
Reactant: COC(=O)c1ccc2cnc(C(=O)c3ccc(N)c(OC)c3)n2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(C(=O)c2ncc3ccc(C(=O)O)cn23)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.51 ml (1.51 mmol) of a 1N aqueous sodium hydroxide solution are added to 300 mg (0.92 mmol) of methyl 3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridine-6-carboxylate obtained in example 83 in 15 ml of a mixture (5/5/5) of dioxane, dichloromethane and methanol. The reaction medium is stirred at ambient temperature overnight and then concentrated under reduced pressure. The residue is dissolved in water, washing is carried out with ethyl acetate and then the aqueous phase is acidified with 1.5 ml of 1N hydrochloric acid. The precipitate formed is filtered off, washed with water and then dried. 346 mg of a yellow solid are collected, which solid is salified in the sodium salt.0.7H2O form. Melting point: 306° C.; 1H NMR (d6-DMSO): 3.87 (3H, s), 6.72 (1H, d), 7.70-7.78 (3H, m), 7.96 (1H, s), 8.18 (1H, d), 10.09 (1H, s)
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[S:27][C:26]([CH2:28]O)=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:22][C:23]1[S:27][C:26]([CH2:28][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)=[CH:25][CH:24]=1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1ccc(Cl)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)s4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 32.8 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chloro-2-thienyl)methanol (158 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, and washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (72 mg) as a white solid.
Reaction SMILES: CO/[CH:3]=[C:4]1/[C:5](=[O:20])[NH:6][C:7](=[O:19])[C:8]2[C:13]/1=[CH:12][C:11]([N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1)=[CH:10][CH:9]=2.CN(C)C=O.[NH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31]>CCOCC>[O:19]=[C:7]1[C:8]2[C:13](=[CH:12][C:11]([N:14]3[CH:15]=[CH:16][CH:17]=[CH:18]3)=[CH:10][CH:9]=2)/[C:4](=[CH:3]/[NH:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])/[C:5](=[O:20])[NH:6]1
Reactant: NCCCC(=O)O
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(O)CCCN/C=C1\C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (E)-4-(methoxymethylene)-6-(1H-pyrrol-1-yl)isoquinoline-1,3(2H,4H)-dione (201 mg, 0.75 mmole), dimethylformamide (5 mL), and 4-aminobutanoic acid (78 mg, 0.75 mmole) is stirred at room temperature for 1 hour. The reaction mixture is diluted with ether, filtered, washed with fresh ether and dried to give a beige solid, 215 mg, (84%), mp 230-40° C. dec; MS (ES+): m/z 338.1 (M+H).
Reaction SMILES: [CH:1]1([C:4](=[O:25])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:7])[CH2:3][CH2:2]1.[CH2:26]([O:28][CH:29](OCC)OCC)[CH3:27]>C(OC(=O)C)(=O)C>[CH:1]1([C:4](=[O:25])[C:5](=[CH:29][O:28][CH2:26][CH3:27])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=2[S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(OCC)OCC
Reactant: O=C(CC(=O)C1CC1)c1ccc(C(F)(F)F)cc1Sc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(C(F)(F)F)cc1Sc1ccccc1)C(=O)C1CC1
Yield: 96.8 %

Procedure:
A mixture of 3-cyclopropyl-1-(2-phenylsulphenyl-4-trifluoromethylphenyl)propan-1,3-dione (6.0 g) and triethylorthoformate (4.9 g) in acetic anhydride was stirred and heated at reflux for 3 hours. It was cooled and evaporated. The residue was treated with toluene and re-evaporated to dryness to give 1-cyclopropyl-2-ethoxymethylene-3-(2-phenylsulphenyl-4-trifluoromethylphenyl)propan-1,3-dione (6.7 g) as a red oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:32][C:33]1[C:34]([O:56][CH2:57][C:58](O)=[O:59])=[C:35]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[N:36]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[C:37]=1[C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.[NH4+:70].[Cl-]>C1COCC1>[NH2:70][C:58](=[O:59])[CH2:57][O:56][C:34]1[C:33]([O:32][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]([C:43]2[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=2)[C:35]=1[C:51]([O:53][CH2:54][CH3:55])=[O:52]
Reactant: CCOC(=O)c1c(OCC(=O)O)c(OCc2ccccc2)c(C(=O)OCC)n1-c1ccc(OC)cc1
Reactant: [NH4+]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(OCC(N)=O)c(OCc2ccccc2)c(C(=O)OCC)n1-c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 66.5 %

Procedure:
HATU (153 mg, 0.40 mmol) was added to a stirred solution 2-((4-(benzyloxy)-2,5-bis(ethoxycarbonyl)-1-(4-methoxyphenyl)-1H-pyrrol-3-yl)oxy)acetic acid (24) (100 mg, 0.20 mmol), DIPEA (176 μL, 1.00 mmol), and NH4Cl (53.8 mg, 1.00 mmol) in THF (2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 20 min and then at RT for 2 h volatiles were removed in vacuo, dissolved in EtOAc (30 mL) and washed with 1 M HCl (3×30 mL), sat. NaHCO3 (aq.) (3×30 mL) and brine (30 mL), dried (MgSO4), filtered and solvents removed in vacuo to give a yellow oil. The product was purified by silica gel chromatography (12 g, 0-100% EtOAc in isohexane) to afford diethyl 3-(2-amino-2-oxoethoxy)-4-(benzyloxy)-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (25) (66 mg, 66%) as a white solid: m/z 497 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.58 (br s, 1H), 7.51 (br s, 1H), 7.49-7.44 (m, 2H), 7.43-7.33 (m, 3H), 7.17-7.09 (m, 2H), 6.95-6.86 (m, 2H), 5.10 (s, 2H), 4.46 (s, 2H), 4.00 (q, J=7.1 Hz, 2H), 3.98 (q, J=7.1 Hz, 2H), 3.79 (s, 3H), 0.97 (t, J=7.1 Hz, 3H), 0.96 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7].[C:10](Cl)(Cl)=[S:11]>C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:8][N:5]1[C:6]([CH3:7])=[C:2]([N:1]=[C:10]=[S:11])[C:3]([CH3:9])=[N:4]1
Reactant: Cc1nn(C)c(C)c1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nn(C)c(C)c1N=C=S
Reaction time: 0.33 h
Yield: 101.5 %

Procedure:
A mixture of 4-amino-1,3,5-trimethylpyrazole (1.32 g, 10.6 mmol) in 50 mL each of CHCl3 and saturated aqueous NaHCO3 was treated dropwise with thiophosgene (0.812 mL, 10.6 mmol) and stirred vigorously for 20 minutes. The layers were separated and the organic phase was washed with brine. After drying (Na2SO4), the solvent was evaporated in vacuo to provide the title compound (1.8 g, brown oil) suitable for use directly in the next step.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH:20][NH:21][C:22]([C:24]34[CH2:31][CH2:30][C:27]([NH:32]C(=O)OC(C)(C)C)([CH2:28][CH2:29]3)[CH2:26][CH2:25]4)=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O=S(Cl)Cl>O1CCOCC1>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:22]([C:24]45[CH2:29][CH2:28][C:27]([NH2:32])([CH2:30][CH2:31]4)[CH2:26][CH2:25]5)=[N:21][N:20]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)C45CCC(NC(=O)OC(C)(C)C)(CC4)CC5)cnc32)cc1
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(N)(CC4)CC5)n23)cc1
Temperature: 80 °C
Yield: 24.4 %

Procedure:
To a solution of tert-butyl 4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)-bicyclo[2.2.2]octan-1-ylcarbamate (6.1 g, 11.0 mmol), TEA (6.1 mL, 44.0 mmol) in 1,4-dioxane (110 mL) was added SOCl2 (2.0 mL, 27.5 mmol). The reaction mixture was heated at about 80° C. for about 2 h then cooled to ambient temperature. The reaction mixture was washed with saturated aqueous NaHCO3 (3×50 mL). The aqueous portion was filtered to give 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]-octan-1-amine as a brown solid (1.17 g, 24%): LC/MS (Table 1, Method a) Rt=1.28 min; MS m/z: 437 (M+H)+. The remaining filtrate was extracted with EtOAc (10 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concd under reduced pressure to afford crude tert-butyl 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-ylcarbamate (3.5 g). The crude Boc-protected material was dissolved in 1,4-dioxane (38 mL) and HCl (4 N in 1,4-dioxane, 8 mL) was added. The reaction mixture was heated at about 50° C. for about 3 h. The precipitate formed was filtered, dissolved in DCM (50 mL), and washed with saturated aqueous NaHCO3 (3×20 mL). The layers were separated and the organic portion was dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give additional 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine as a brown solid (2.3 g, 50% over 2 steps): LC/MS (Table 1, Method a) Rt=1.28 min; MS m/z: 437 (M+H)+.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[C:20]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: OB(O)C1=CCCCC1
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2=CCCCC2)C1
Yield: 85.3 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of cyclohexen-1-ylboronic acid (115 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (170 mg, 85.4%) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:12]([O:11][C:9]([CH:8]([O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)Cc1ccccc1Br
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1ccc(CO)cc1)c1ccccc1

Procedure:
41.8 g (0.172 mol) of ethyl 2-bromo-phenylacetate and 21.3 g (0.172 mol) of 4-hydroxybenzyl alcohol are dissolved in 850 ml of acetone and 24.8 g (0.18 mol) of potassium carbonate and 5.0 g (0.03 mol) of potassium iodide are added thereto. The reaction mixture is refluxed for 60 hours with stirring. Then the inorganic salts are filtered off and the residue is washed with hot acetone. The filtrate is evaporated down and the residue is purified over a silica gel column (particle size: 0.063-0.02 mm), initially using petroleum ether as eluant and then using mixtures of petroleum ether and ethyl acetate of increasing polarity (9:1, 8:2 and 7:3). The unified fractions are evaporated down in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]([F:10])([F:9])[F:8])=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:7]([F:10])([F:9])[F:8])=[N:4][N:5]([CH2:18][C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:25][CH2:26]2)=[O:20])[CH:6]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: FC(F)(F)c1n[nH]cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(Cn1cc(Cl)c(C(F)(F)F)n1)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 4-Chloro-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as colorless oil. 1H NMR (400 MHz, CDCl3): 7.64–7.68 (d, 1H), 6.98–7.4 (m, 2H), 6.86–6.92 (m, 2H), 6.98–7.2 (m, 1H), 5.4 (s, 2H), 3.78–3.84 (m, 2H), 3.68–3.92 (m, 2H), 3–3.1 (m, 4H). 13C NMR (400 MHz, CDCl3): 164.4, 158, 152.2, 144, 132, 118.2, 116, 54, 50.2, 50.0, 46.0, 42.2.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C@@H:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:23][C@@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cc(CN[C@H]2CCCc3ccccc32)ccc1Cl

Procedure:
4-Chloro-3-nitrobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]1=[S:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccn(Cc2ccccc2)c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1cccn(Cc2ccccc2)c1=S
Temperature: 25 °C
Yield: 134.8 %

Procedure:
A suspension of 141b (0.060 g, 0.28 mmol) and Lawesson's reagent (0.067 g, 0.17 mmol) in toluene (10 mL) was heated to reflux overnight. Reaction mixture was then cooled to room temperature. Toluene was evaporated in vacuo and resulting crude solid was directly loaded on prep-TLC. Elution with CH2Cl2:Acetone:MeOH (5:1:0.2) gave 143b 53 mg (82%) of yellow solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[F:5][C:6]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[C:25]([F:28])([F:27])[F:26])[N:17]=[C:16]([NH:29][CH3:30])[N:15]=2)[CH:11]=[C:10](F)[C:7]=1[C:8]#[N:9]>CO>[F:5][C:6]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[C:25]([F:28])([F:27])[F:26])[N:17]=[C:16]([NH:29][CH3:30])[N:15]=2)[CH:11]=[C:10]([O:2][CH3:1])[C:7]=1[C:8]#[N:9]
Reactant: CNc1nc(-c2cc(F)c(C#N)c(F)c2)cc(N2CCC[C@H]2C(F)(F)F)n1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CNc1nc(-c2cc(F)c(C#N)c(OC)c2)cc(N2CCC[C@H]2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of sodium methoxide was made from 65 mg of sodium dissolved in 2.8 mL of CH3OH. From that solution 0.4 mL was added to a predissolved solution of 2,6-difluoro-4-{2-(methylamino)-6-[(2S)-2-(trifluoromethyl)-1-pyrrolidinyl]-4-pyrimidinyl}benzonitrile (127 mg, 0.331 mmol) in CH3OH (3 mL). The reaction was stirred at room temperature overnight. The reaction was concentrated, then diluted with water (15 mL) and extracted with EtOAc (3×15 mL). The organic was combined, dried over MgSO4, filtered and concentrated to afford the crude title compound (131 mg). LC-MS (ES) m/z=396 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:5]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:6]=2[S:7][CH:8]=1)(=[O:3])[CH3:2].[ClH:14].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.Cl.[CH2:30]=O>CCO.C(OCC)C>[ClH:14].[ClH:14].[CH3:13][C:11]1[CH:10]=[CH:9][C:6]2[S:7][CH:8]=[C:4]([C:1](=[O:3])[CH2:2][CH2:30][N:26]3[CH2:27][CH2:28][N:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][CH3:15])[CH2:24][CH2:25]3)[C:5]=2[CH:12]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: C=O
Reactant: CC(=O)c1csc2ccc(C)cc12
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: COc1ccccc1N1CCN(CCC(=O)c2csc3ccc(C)cc23)CC1
Reaction time: 24 h
Yield: 10 %

Procedure:
650 mg of 3-acetyl-5-methylbenzo[b]thiophene (3.42×10−3 moles) and 860 mg of 2-methoxyphenylpiperazine hydrochloride (3.76×10−3 moles) were dissolved in 15 ml of EtOH and HCl to pH=2-3. When the mixture was under reflux, 310 mg of paraformaldehyde (10×10−3 moles) were added. After 24 hours stirring under reflux the reaction mixture was poured over ice and was extracted with AcOEt. It was washed with H2O and dried with Na2SO4, the solvent being removed to dryness. It was purified in silica column using AcOEt/hexane (1:1) as mobile phase. The oil obtained was dissolved in ethyl ether (20 ml) and EtOH (4 ml) and precipitates as hydrochloride on adding HCl(c). Yield: 10%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:17](O)=O>>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]2[N:8]=[CH:17][NH:1][C:2]=2[CH:3]=1)#[N:12]
Reactant: N#Cc1ccccc1-c1ccc(N)c(N)c1
Reactant: O=CO
Product: N#Cc1ccccc1-c1ccc2nc[nH]c2c1

Procedure:
2-(3,4-Diaminophenyl)benzonitrile (0.04 moles, 8.3 g) was refluxed in 100 ml formic acid for 3 hours. The solution was concentrated in vacuo, triturated with toluene, and dissolved in water. The DH of the solution was adjusted to 7.5 with 2N sodium hydroxide. The intermediate was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The solid was triturated with 25% ethyl acetate/75% hexane, filtered and purified by HPLC on silica gel eluted with a gradient of 50-75% ethyl acetate in hexane. The reaction yielded 7.3 g of 5-(2-Cyanophenyl)benzimidazole. (MS)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[NH:7][N:6]=1.[O-:22][C:23]#[N:24].[K+].C(O)C.C(O)(=O)C>O>[Cl:21][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:23]([NH2:24])=[O:22])[C:13]=23)[CH:20]=[CH:19][CH:18]=1
Reactant: NCCNc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: NC(=O)NCCNc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 200 mg (0.655 mmol) of 3-(2-amino-ethylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (water content: 0.48%), 72 mg (0.887 mmol) of potassium cyanate, 1.2 ml of ethanol, 1.2 ml of water and 46.8 ml (0.819 mmol) of acetic acid is stirred at RT for 15 hours. 2 ml of water are added to the resulting suspension and the mixture is filtered. Washing the filter residue with water and a small amount of ethanol and drying in vacuo (about 100 mbar, 8 hours, 1 00C) yield the title compound having a water content of 5.54%; m.p. 212-214° C.; ESI-MS: (M+H)+=347