Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4](Cl)=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Cl:12])[C:7]=1F.NC(N)=[S:22].N1C=CC=CC=1.CCN(CC)CC>C(O)(C)C>[Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]1[S:22][C:7]2[C:8]([Cl:12])=[N:9][CH:10]=[CH:11][C:6]=2[N:5]=1
Reactant: NC(N)=S
Reactant: Fc1c(N=C(Cl)c2c(Cl)cccc2Br)ccnc1Cl
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Clc1cccc(Br)c1-c1nc2ccnc(Cl)c2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
A stirred solution of 2-bromo-6-chloro-N-(2-chloro-3-fluoropyridin-4-yl)-benzimidoyl chloride (4.2 g, 11.0 mmol), thiourea (2.5 g, 33.0 mmol) and pyridine (3.1 mL, 38.4 mmol) in isopropanol (50 mL) under a nitrogen atmosphere was heated under reflux for 3 hours. Et3N (7.6 mL, 54.6 mmol) was added and the reaction mixture was heated under reflux for 1.5 hours. After cooling to room temperature, the volatiles were removed under reduced pressure. The resultant residue was triturated with water (100 mL) and then boiled in isopropanol (15 mL) for 10 minutes. After cooling to room temperature, the resultant solid was collected by filtration and then purified by column chromatography on silica gel eluting with 25% diethyl ether in pentane to afford the title compound as a colourless solid (2.1 g, 53%). LCMS (Method E): RT=4.16 min, m/z: 361 [M+H+].
Reaction SMILES: C1(O[C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)C=CC=CC=1.CS(O)(=O)=O>O>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[O:16])=[CH:10][CH:11]=1
Reactant: O=C(Oc1ccccc1)c1ccc(O)cc1
Agent: CS(=O)(=O)O
Solvent: O
Product: O=C(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
Phenyl-4-hydroxybenzoate (5.0 g; 0.02 mole) was heated with 98% methane sulphonic acid (10 ml; 15.1 g; 0.16 mole) at 80° C. for 2 hours. The solution was poured into water and the solid product washed with water and dried at 110° C. in a vacuum oven to yield 4,4'-dihydroxy-benzophenone (infra-red spectrum indentical with that of an authentic sample); the yield was 3.4 g (68%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][O:29][C@H:30]([CH3:34])[C:31](O)=[O:32]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[C@H:30]([O:29][CH3:28])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CO[C@H](C)C(=O)O
Agent: Cl
Product: CO[C@H](C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (21 mg, 72%), MS (ISP) m/z=418.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol?) and (R)-2-methoxypropanoic acid
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:34])[CH3:37]
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c(OCC2CC2)c1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A152) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: C([O:4][C@@H:5]([CH3:40])[C:6]([NH:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[C:20]([F:22])[C:19]([NH:23][C:24]([C:26]3([C:29](=[O:38])[NH:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:28][CH2:27]3)=[O:25])=[CH:18][C:17]=2[F:39])[CH:12]=[CH:11][N:10]=1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:22][C:20]1[CH:21]=[C:16]([O:15][C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6](=[O:7])[C@@H:5]([OH:4])[CH3:40])[CH:14]=2)[C:17]([F:39])=[CH:18][C:19]=1[NH:23][C:24]([C:26]1([C:29]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)=[O:38])[CH2:28][CH2:27]1)=[O:25]
Reactant: CC(=O)O[C@@H](C)C(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@H](O)C(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.2 %

Procedure:
To a solution of (S)-1-((4-(2,5-difluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl acetate (180 mg, 0.323 mmol) in a solution of MeOH—H2O (3:1, 20 mL) was added potassium carbonate (111.6 mg, 0.809 mmol), the mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated and purified by prep-TLC to give (S)—N-(2,5-difluoro-4-((2-(2-hydroxypropanamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (100 mg, 60% yield). 1H NMR (400 MHz, Methanol-d4): δ 8.21-8.16 (m. 2H), 7.78 (d, J=2.4 Hz, 1H), 7.54-7.51 (m, 2H), 7.28-7.24 (m, 1H), 7.10-7.05 (m, 2H), 6.76-6.74 (dd, J=6.0, 2.4 Hz, 1H), 4.23 (q, J=6.8 Hz, 1H), 1.75-1.67 (m, 4H), 1.39 (d, J=6.8 Hz, 3H); MS (ESI): m/z 515.2 [M+H]+.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[O:29]1[C:34]2[CH:35]=[C:36](/[CH:39]=[CH:40]/[C:41](O)=[O:42])[CH:37]=[CH:38][C:33]=2[O:32][CH2:31][CH2:30]1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:41](=[O:42])/[CH:40]=[CH:39]/[C:36]4[CH:37]=[CH:38][C:33]5[O:32][CH2:31][CH2:30][O:29][C:34]=5[CH:35]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Reactant: O=C(O)/C=C/c1ccc2c(c1)OCCO2
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccc3c(c2)OCCO3)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-3-(2,3-dihydro-1,4-benzodioxin-7-yl)prop-2-enoic acid, by the method of Example 1, step K, giving a solid that was mostly the more polar cyclohexyl diastereomers by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C32H38N4O4: 543 (M+H). Found: 543
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:10]1[CH2:15][CH:14]=[C:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=3)[N:21]=2)[CH2:12][CH2:11]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:10]1[CH2:11][CH:12]=[C:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=3)[N:21]=2)[CH2:14][CH2:15]1
Reactant: O=Cc1cccc(F)c1
Reactant: FC(F)(F)c1nnc2ccc(C3=CCNCC3)nn12
Product: Fc1cccc(CN2CC=C(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Yield: 46 %

Procedure:
A mixture of 3-fluorobenzaldehyde and 6-(3,6-dihydro-2H-pyridin-4-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 5 to give 6-[1-(3-fluorobenzyl)-1,2,3,6-tetrahydropyridin-4-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in 46% yield.
Reaction SMILES: [CH:1]([O:4][S:5]([CH:8]=[CH2:9])(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH:10]([Si:13]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:14][CH2:15][CH2:16][CH2:17][NH2:18])([CH3:12])[CH3:11]>CO>[CH:1]([O:4][S:5](=[O:7])(=[O:6])[CH2:8][CH2:9][NH:18][CH2:17][CH2:16][CH2:15][O:14][Si:13]([CH:22]([CH3:24])[CH3:23])([CH:10]([CH3:12])[CH3:11])[CH:19]([CH3:21])[CH3:20])([CH3:3])[CH3:2]
Reactant: C=CS(=O)(=O)OC(C)C
Reactant: CC(C)[Si](OCCCN)(C(C)C)C(C)C
Solvent: CO
Product: CC(C)OS(=O)(=O)CCNCCCO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
Vinylsulfonic acid isopropyl ester (0.3 g, 2.00 mmol) obtained in step 1 and 3-triisopropylsilyloxypropylamine (0.9 g, 3.89 mmol) were dissolved in methanol (10 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound (0.65 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+].ClCCl>C1COCC1.CO>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]([C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]3)=[CH:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1cccc(-c2ncc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(-c3cccc(CO)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
862 mg (2.16 mmol) of tert-butyl 4-[2-(3-methoxycarbonylphenyl)pyrimidin-5-yl]piperazine-1-carboxylate are dissolved in 15 ml of THF, and 10.8 ml (10.8 mmol) of 1 M diisobutylaluminium hydride in THF are added at room temperature. The reaction mixture is stirred at room temperature for 1 h. 3 ml of saturated sodium sulfate solution are added to the reaction mixture with ice cooling. 30 ml of dichloromethane and 5 ml of methanol are added to the gelatinous mixture, which is then stirred for 10 min and filtered through kieselguhr with suction. The filtrate is dried over sodium sulfate and evaporated. The residue is dissolved in dichloromethane and filtered, and the filtrate is evaporated. The product is reacted further without further purification;
Reaction SMILES: O.[SH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.C(N(CC)CC)C.[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24].O>CN(C)C=O>[Cl:19][CH2:20][CH2:21][NH:22][C:23]([S:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2)=[O:24]
Reactant: Sc1ncnc2nc[nH]c12
Reactant: O=C=NCCCl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCCl)Sc1ncnc2nc[nH]c12
Temperature: 15 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
A suspension of 6-mercaptopurine monohydrate (17.0 g, 0.1 mole) in dimethylformamide (150 ml) is treated with triethylamine (10.1 g, 0.1 mole) and the solid is dissolved by warming of the mixture to 50°-60° C. The solution is cooled to 15° C. and 2-chloroethylisocyanate (11.6 g, 0.11 mole) is dripped in under cooling with tap water to 15°-20° C. The reaction mixture is stirred at this temperature for 2 hours, and the precipitated product is collected on filter, washed with acetone and dried under reduced pressure at a temperature of approx. 50° C. to give 20.7 g (80%) of the title compound Ia, melting at 221°-223° C. UV absorption spectrum (in dimethylsulfoxide), λ max 326 nm (log ε4.33).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][CH2:10][O:9]2)=[CH:4][C:3]=1[F:14].C([Li])CCC.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[C:24]([N:28]=[C:29]=[S:30])=[CH:23][N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.CN(C=O)C>[O:9]1[CH2:10][CH2:11][CH2:12][O:13][CH:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:29]2[S:30][C:25]3[CH:26]=[C:21]([Cl:20])[N:22]=[CH:23][C:24]=3[N:28]=2)=[C:3]([F:14])[CH:4]=1
Reactant: S=C=Nc1cnc(Cl)cc1Cl
Reactant: Fc1cc(C2OCCCO2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2cnc(Cl)cc2s1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-bromo-3-fluorophenyl)-1,3-dioxane (3.12 g, 11.9 mmol) in 40 mL THF at −78° C. under argon was added butyllithium, 2.5 M solution in hexanes (5.26 mL, 13.1 mmol) slowly dropwise. The resulting solution was allowed to stir 1 h at −78° C., at which point a solution at ambient temp of 2,4-dichloro-5-isothiocyanatopyridine (2.45 g, 11.9 mmol) in 10 mL THF was added slowly via cannula. The dark red reaction mixture was allowed to stir 15 min, and was then removed from the bath and quenched by slow addition of sat'd aq. NH4Cl. The reaction mixture was diluted with 40 mL MTBE, and the organic layer washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting material was treated with sodium carbonate (1.90 g, 17.9 mmol) and 10 mL DMF. The reaction was heated under nitrogen to 80° C. An additional 5 mL DMF was added to give a stirrable slurry. After 30 min additional, the reaction mixture was cooled slightly and treated with 100 mL water. After 10 min stirring, the mixture was filtered, rinsing with water and MeOH. The solid was collected and dried in vacuo overnight to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-chlorothiazolo[4,5-c]pyridine as a tan solid. MS (ESI) m/z: calculated: 350.0; Observed: 351.0 (M++1).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][CH2:17][CH2:18]O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][NH:41][CH2:40][CH2:39][NH:38]1)=[O:36])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][N:41]([CH2:18][CH2:17][CH2:16][N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:40][CH2:39][NH:38]1)=[O:36])[CH3:33]
Reactant: CCOC(=O)C1CNCCN1
Reactant: OCCCN1c2ccccc2CCc2ccccc21
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(CCCN2c3ccccc3CCc3ccccc32)CCN1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a stirred solution of 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propanol (1.17 g, 0.0046 mol, prepared similarly as described in example 2) and triethylamine (1.18 g, 0.012 mol) in toluene (30 ml) at 0° C., methanesulfonyl chloride (0.70 ml, 0.009 mol) was added dropwise over 10 minutes. The resulting mixture was stirred at 0° C. for 1 h. Toluene (50 ml) and water (100 ml) were added, and the phases were separated. The aqueous layer was extracted with toluene (50 ml), and the combined organic phases were washed with brine (2×100 ml), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in acetonitrile (10 ml) and the above 2-piperazine-carboxylic acid ethyl ester (1.40 g, 0.0089 mol), potassium carbonate (0.67 g, 0.0049 mol) and toluene (5 ml) were added. The resulting mixture was heated at reflux temperature for 18 h. Water (50 ml) was added, and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with brine (2×20 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (27 g) using a gradient of methanol and ethyl acetate (5:100→20:100), affording 0.6 g (33%) of 4-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-2-piperazinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][CH:2]1[N:6]([C:7]2[CH:11]=[C:10]([O:12][CH:13]([F:15])[F:14])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]1(C1C=CNN=1)[C:17]([O:19]CC)=[O:18].[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:11]=[C:10]([O:12][CH:13]([F:14])[F:15])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)C1(c2cc[nH]n2)C=NN(c2cc(OC(F)F)n(C)n2)C1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(-n2ncc(C(=O)O)c2N)cc1OC(F)F
Temperature: 80 °C

Procedure:
18.9 g (0.06 mol) Ethyl 5-Amino-1-(5-difluoromethoxy-1-methyl-3-pyrazolyl)-4-pyrazolyl-4-pyrazolecarboxylate was dissolved in 150 ml 50% ethanol and treated with 15 ml 45% caustic soda. The mixture was heated for 2 hours at 80° C., the ethanol distilled, the residue treated with ice-water and acidified with concentrated hydrochloric acid. The residue was removed by suction filtration, washed with water and dried in vacuo at 75° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)(=[O:21])=[O:20])[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:32][NH:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[NH:42])[NH2:41])=[CH:36][CH:35]=1.[C:43](Cl)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)(=[O:21])=[O:20])[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:32][NH:33][C:34]1[CH:35]=[CH:36][C:37]([C:40](=[NH:41])[NH:42][C:43](=[O:50])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:38][CH:39]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCOC(=O)CN(c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Product: CCCOC(=O)CN(c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 31 from 1-methyl-2-[N-(4-amidino-phenyl)-aminomethyl]-5-[N-(n-propyloxycarbonylmethyl)-quinoline-8-sulphonylamino]-benzimidazole and benzoyl chloride.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[N:28]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37](=[O:38])[C:36]5[CH:40]=[CH:41][C:33]([N:28]6[CH:32]=[CH:31][CH:30]=[CH:29]6)=[CH:34][CH:35]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(-n2cccc2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(-n2cccc2)cc1

Procedure:
The title compound, white solid (72 mg, 58%), MS (ISP) m/z=500.4 [(M+H)+], mp 234° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-pyrrol-1-yl-benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:15])=[C:7]([Cl:14])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].[Br:16]Br>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:15])=[C:7]([Cl:14])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[C:10]2[Br:16])=[O:4]
Reactant: COC(=O)c1c(N)c(Cl)cc2cn[nH]c12
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1c(N)c(Cl)cc2c(Br)n[nH]c12
Temperature: 80 °C
Yield: 11 %

Procedure:
To a solution of 9 g (29.92 mmol) of 6-amino-5-chloro-1H-indazole-7-carboxylic acid methyl ester in 68 mL of acetic acid at 80° C., is added dropwise 2 mL (38.89 mmol) of bromine. The mixture is stirred over the night at 80° C. The solvents are evaporated and water is added to the residue. The product is precipitated at pH 5 by addition of 1N aqueous NaOH, filtrated, washed with a minimum of water and dried under high vacuum. 1 g (3.28 mmol, 11%) of pure product is obtained; LC/MS:305/306 (M+H)+.
Reaction SMILES: [C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:8]1[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11](=[O:21])[C:10]=3[CH:9]=1)[CH2:2]2.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:26](C)=O.[Na+]>O>[CH3:26][N:6]1[CH2:7][C@@H:1]2[C@H:5]1[CH2:4][N:3]([C:8]1[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11](=[O:21])[C:10]=3[CH:9]=1)[CH2:2]2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1c2ccccc2-c2ccc(N3C[C@@H]4CN[C@@H]4C3)cc21
Agent: C=O
Agent: [Na+]
Solvent: O
Product: CN1C[C@H]2CN(c3ccc4c(c3)C(=O)c3ccccc3-4)C[C@H]21
Temperature: 25 °C
Reaction time: 60 h
Yield: 80 %

Procedure:
A solution of the product of Example 39B (70 mg, 0.25 mmol) in water (2 mL), was treated with formaldehyde (38% aq., 3 mL) and NaBH(OAc)3 (250 mg, 1.18 mmol; Aldrich). After stirring at room temperature for 60 h, the reaction mixture was concentrated under vacuum and purified by flash chromatography (40 g silica gel, 1:10:89 NH4OH-MeOH-CH2Cl2) to afford the title compound (57 mg, 0.20 mmol; 91% yield): 1H NMR (300 MHz, CD3OD) δ ppm 7.37-7.51 (4H, m), 7.10-7.19 (1H, m), 7.02 (1H, d, J=2 Hz), 6.85 (1H, dd, J=8, 2 Hz), 4.02 (1H, dd, J=6, 5 Hz), 3.72-3.82 (2H, m), 3.15-3.40 (4H, m), 3.03 (1H, dd, J=11, 4 Hz), 2.39 (3H, s); MS (DCl/NH3): m/z 291 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:12]3[NH:13][C:14](=[O:18])[C:15]([CH3:17])=[N:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[N:33]=[C:34]=[O:35]>>[F:21][C:3]1[CH:4]=[C:5]([O:6][C:7]2[C:12]3[NH:13][C:14](=[O:18])[C:15]([CH3:17])=[N:16][C:11]=3[N:10]=[CH:9][CH:8]=2)[CH:19]=[CH:20][C:2]=1[NH:1][C:34]([NH:33][C:24]1[CH:25]=[C:26]([C:29]([F:30])([F:32])[F:31])[CH:27]=[CH:28][C:23]=1[F:22])=[O:35]
Reactant: Cc1nc2nccc(Oc3ccc(N)c(F)c3)c2[nH]c1=O
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: Cc1nc2nccc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c2[nH]c1=O
Yield: 85 %

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)-3-methylpyrido[3,2-b]pyrazin-2(1H)-one and 2-fluoro-5-trifluoromethylphenyl isocyanate to afford the title compound; yield=85%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COC(=O)C1(CCCC(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
To a solution of 4-(1-(tert-butoxycarbonyl)-4-(methoxy-carbonyl)piperidin-4-yl)butanoic acid (23.4 g, 0.071 mol) from Step D in 3:1 dichloromethane/methanol (480 mL) at 0° C. was added a solution of trimethylsilyldiazomethane (53 mL, 0.11 mol, 2.0M in hexane). The reaction mixture was stirred for 15 min and then concentrated to afford 25.5 g. The residue was purified by flash chromatography eluting with 20–30% ethyl acetate in hexanes to give the title compound (20.1 g).
Reaction SMILES: C([BH3-])#N.[Na+].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[CH3:18][C:19]([CH3:21])=O.Cl>CO.O>[CH:19]([N:15]1[CH2:16][CH2:17][N:12]([C:9]2[CH:8]=[CH:7][C:6]([OH:5])=[CH:11][CH:10]=2)[CH2:13][CH2:14]1)([CH3:21])[CH3:18]
Reactant: CC(C)=O
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)N1CCN(c2ccc(O)cc2)CC1

Procedure:
Sodium cyanoborohydride (3.78 g.) was added to a stirred solution of N-(4-hydroxyphenyl)piperazine (5.35 g.) and acetone (8.7 g.) in a mixture of methanol (100 ml) and water (20 ml.). The pH of the resulting solution was adjusted to pH 7.5 by the addition of a few drops of N hydrochloric acid and stirring was continued at room temperature (~20° C.) for a period of 19 hours. Upon completion of this step, further acetone (8.7 g.) and sodium cyanoborohydride (1.89 g.) were added to the mixture and the pH was again adjusted to a value of 7.5. After a further period of stirring at room temperature for eight hours, water (100 ml.) was added to the reaction mixture and the precipitated solid product was subsequently collected by means of suction filtration and thereafter vacuum dried over phosphorous pentoxide to constant weight. Recrystallization of the crude material so obtained from a mixture of ethanol and methanol then gave pure 1-isopropyl-4-(4-hydroxyphenyl)piperazine in the form of a crystalline solid (yield, 4.78 g.), m.p. 244°-246° C. The yield of pure product amounted to 72% of the theoretical value.