Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][NH2:8])=[C:5]([N+:9]([O-])=O)[C:4]([CH3:12])=[N:3]1.[ClH:13].O>C(O)C.[Pd]>[ClH:13].[ClH:13].[NH2:9][C:5]1[C:4]([CH3:12])=[N:3][N:2]([CH3:1])[C:6]=1[NH:7][NH2:8]
Reactant: Cc1nn(C)c(NN)c1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1nn(C)c(NN)c1N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension of 8.6 g (0.05 mol) of 1,3-dimethyl-5-hydrazino-4-nitropyrazole and 1.5 g of 5% by weight palladium-on-charcoal containing 50% water in 200 cm3 of ethanol was placed in a hydrogenator. After stirring under a hydrogen pressure of 10 bar, at a temperature of 75° C. for 3 hours, the reaction medium was poured into a solution of 60 cm3 of ethanol and 20 cm3 of 12 N hydrochloric acid cooled to 0° C. The solution was clarified by filtration on a sinter funnel and then evaporated to dryness under reduced pressure. The brown solid obtained was taken up, at reflux, in 50 cm3 of 5 N hydrochloric ethanol and 14 cm3 of water and was then cooled to room temperature. The white precipitate obtained was filtered off on a sinter funnel and then dried under vacuum at room temperature. 9.5 g of 4-amino-1,3-dimethyl-5-hydrazinopyrazole dihydrochloride were obtained in the form of white crystals, the melting point of which was from 202 to 204° C. The elemental analysis calculated for C5H11N5.2HCl was:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC.C(OCC)(=O)C>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([O:12][C:4]2[CH:3]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(Br)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 85.2 %

Procedure:
To a solution of methyl 4-bromo-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-benzoate (0.207 g, 0.5 mmol) in 1,2-dimethoxyethane (3 mL) was added 4-chlorophenyl-boronic acid (0.094 g, 0.6 mmol), tetrakis(triphenylphospine)palladium(0) (0.010 g), and 1 M aq potassium phosphate (0.8 mL). The reaction mixture was heated at 80° C. overnight under a nitrogen atmosphere. The reaction was then cooled to room temperature and water (10 mL) and ethyl acetate (50 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by RPHPLC (ethyl acetate/hexane 1:4) to give 0.190 g (85%) of product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:15]=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]Br.O.[OH-].[Na+]>CCO>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([Br:18])=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cccn3ccnc23)cc1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Brc1cnc2c(OCc3ccccc3)cccn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of crude 8-(benzyloxy)imidazo[1,2-a]pyridine (8.73 g, 38.9 mmol) in 100 mL of EtOH was added, dropwise, 4.8 mL (46.7 mmol) of a solution of 1:1 Br2/H2O at ambient temperature under an atmosphere of N2. The resulting dark orange suspension was stirred at ambient temperature for 30 min, added 60 mL 1N NaOH, and the reaction mixture extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 30% EtOAc/hexanes) to provide 7.04 g of product.
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH2:24][C@H:25]2[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[O:26]2)=[CH:21][C:5]2[C:6]([CH3:20])([CH3:19])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([Cl:18])[CH:10]=4.[O:32]1CCOCC1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[OH-].[K+]>O>[OH:32][C:2]1[C:22]([O:23][CH2:24][C@H:25]2[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[O:26]2)=[CH:21][C:5]2[C:6]([CH3:20])([CH3:19])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([Cl:18])[CH:10]=4
Reactant: C1COCCO1
Reactant: CC1(C)OC[C@H](COc2cc3c(cc2Br)C(=O)c2c([nH]c4cc(Cl)ccc24)C3(C)C)O1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1(C)OC[C@H](COc2cc3c(cc2O)C(=O)c2c([nH]c4cc(Cl)ccc24)C3(C)C)O1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
9-Bromo-3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S7-1, 30 mg, 0.06 mmol) was dissolved in the mixture solvent of water.dioxane (1:1) (0.5 mL), added with tris(benzylidenacetone dipalladium)chloroform complex (3.1 mg, 0.05 eq.), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (2.5 mg, 0.1 eq.) and KOH (0.5 N aqueous solution 180 μL, 1.5 eq.), and stirred at 60° C. for 12 hr. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residues were purified by HPLC to obtain the title compound (white solid, 4.6 mg).
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18]CC(O)=O)(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(NC2CCCCC2)CCCCC1.C([O:45][C:46](=[O:59])[CH2:47][CH2:48]NS(C1SC(N)=NC=1)(=O)=O)C>>[CH:1]1([N:7]([CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:48][CH2:47][C:46]([OH:59])=[O:45])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNS(=O)(=O)c1cnc(N)s1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: C1CCC(NC2CCCCC2)CC1
Product: O=C(O)CCNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via dicyclohexylamine and 3-(2-amino-thiazole-5-sulfonylamino)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])[CH3:2].[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)#[CH:19].C(N(CC)CC)C>CN(C)C=O.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:19]#[C:18][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Br)cc1[N+](=O)[O-]
Reactant: C#Cc1cccc(F)c1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(C#Cc2cccc(F)c2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 51.6 %

Procedure:
To a solution of (4-bromo-2-nitro-phenoxy)-acetic acid ethyl ester (2.95 g, 9.70 mmol, 1 equiv) and 1-ethynyl-3-fluorobenzene (1.34 mL, 11.6 mmol, 1.2 equiv) in dimethylformamide (15 mL) in a microwave reactor vessel was added triethylamine (4.05 mL, 29.1 mmol, 3 equiv), copper iodide (55 mg, 0.29 mmol, 0.03 equiv) and trans-dichlorobis(tri-o-tolylphosphine) palladium(II) (152 mg, 0.19 mmol, 0.02 equiv). The reaction was placed under an argon atmosphere then heated to 80° C. in a microwave reactor for 30 min. The reaction mixture was then partitioned between ethyl acetate:heptane (1:1) and 1.0 N aqueous hydrochloric acid (100 mL each). The organic layer was separated and washed successively with saturated aqueous sodium bicarbonate, 1:1 saturated aqueous sodium bicarbonate:saturated aqueous ammonium chloride, saturated brine solution (100 mL each) then dried (MgSO4), filtered and concentrated. The product was purified using an Isco CombiFlash automated chromatography system. The residue was loaded onto a 120 g silica gel column as a solution in dichloromethane (5 mL) then eluted with ethyl acetate in heptane (0-40% ethyl acetate linear gradient over 16 column volumes at a flow rate of 85 mL/min) to give 1.72 g (5.01 mmol, 52%) of the title compound as a brown oil.
Reaction SMILES: [I-].C([N+]1C2C(=CC=CC=2)C=CC=1I)C.[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:23]1([CH2:29][C:30](O)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[C:23]1([CH2:29][C:30]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: OCc1ccccc1
Agent: CC[n+]1c(I)ccc2ccccc21
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)OCc1ccccc1
Yield: 95 %

Procedure:
To a suspended CH2Cl2 (2 ml) solution of 1-ethyl-2-iodoquinolinium iodide (493 mg, 1.2 mmol) was added a mixture of benzyl alcohol (108 mg, 1.0 mmol), phenylacetic acid (136 mg, 1.0 mmol) and tri-n-butylamine (444 mg, 2.4 mmol) in CH2Cl2 (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl phenylacetate was isolated in 95% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([N:19]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[F:8]>CN>[NH2:19][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC(c1ccc(F)c(F)c1)N1C(=O)c2ccccc2C1=O
Agent: CN
Product: CC(C)(C)OC(=O)NCC(N)c1ccc(F)c(F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
6.13 g of rac-tert-butyl [2-(3,4-difluorophenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]carbamate (Example 39A, purity about 60%, about 9.14 mmol) were initially charged in 13.1 ml of 40% aqueous methylamine solution, and the mixture was stirred in a closed vessel at 60° C. overnight. The reaction mixture was concentrated and the residue was purified by means of silica gel chromatography (eluent:dichloromethane:methanol:diethylamine 30:1:0.1; 20:1:0.1). 1.83 g of the title compound were obtained (74% of theory).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)(=[O:7])=[O:6].[F:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:28]=1[C:42]1[N:43]=[CH:44][C:45]([NH2:48])=[N:46][CH:47]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:48][C:45]1[N:46]=[CH:47][C:42]([C:28]2[C:27]([F:26])=[CH:32][C:31]([C:2]3[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=3[CH2:4][S:5]([N:8]3[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]3)(=[O:7])=[O:6])=[CH:30][CH:29]=2)=[N:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)Cc2ccccc2Br)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)Cc2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CC1
Reaction time: 5 h
Yield: 76.3 %

Procedure:
A mixture of tert-butyl (1-((2-bromobenzyl)sulfonyl)piperidin-4-yl)carbamate (200 mg, 0.46 mmol), 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine (175 mg, 0.55 mmol), Pd(dppf)Cl2.CH2Cl2 (34 mg, 0.046 mmol) and Na2CO3 (150 mg, 1.36 mmol) in dry DMF (15 mL) was stirred at 130° Celsius under N2. After 5 hours, the solvent was removed under vacuum and the residue was subjected to FCC purification to give tert-butyl 1-((4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yl)methylsulfonyl)piperidin-4-ylcarbamate (190 mg, 76%). MS (ESI): mass calcd. for C27H32FN5O2S, 541.22; m/z found, 542.1 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.78-7.29 (m, 7H), 6.87 (d, J=5.2, 1H), 6.73 (s, 2H), 4.34 (s, 2H), 3.45-3.33 (m, 3H), 2.85-2.75 (m, 2H), 1.72 (d, J=12.4, 2H), 1.45-1.30 (m, 11H).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]([NH2:41])(=[NH:40])[CH3:39]>>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([NH:41][C:38](=[NH:40])[CH3:39])=[O:16])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(=N)N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=N)NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2

Procedure:
9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid 28, triphenylphosphine, and acetamidine were reacted to give 29.
Reaction SMILES: CC(C)=O.[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:27]=[CH:26][C:25]3[C:24](=[N:28]O)[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]=2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.[OH-].[K+]>O>[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:27]=[CH:26][C:25]3[C:24](=[N:28][S:36]([C:33]4[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=4)(=[O:38])=[O:37])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]=2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ON=C1CCCc2nc(N3CCN(Cc4ccccc4)CC3)ncc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=C2CCCc3nc(N4CCN(Cc5ccccc5)CC4)ncc32)cc1

Procedure:
Added to a mixture of 30 ml of acetone, 2 g (5.35 mmol, Referential Example 49) of 2-(4-benzylpiperazino)-5,6,7,8-tetrahydro-5-hydroxyiminoquinazoline, and 1.6 g (8.4 mmol) of p-toluenesulfonyl chloride was a solution of 0.7 g (11 mmol) of KOH in 10 ml of water. The resultant mixture was stirred at 20° C. for 4 hours.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O.[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH2:23][CH:22]2[CH2:31][C:32]([O:34]CC)=[O:33]>>[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:25][CH2:26][N:27]([C:11](=[O:13])[CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][C:2]([F:1])([F:15])[F:14])[CH2:28][CH2:29]1)[CH2:23][CH:22]2[CH2:31][C:32]([OH:34])=[O:33]
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Reactant: O=C(O)Cc1ccccc1OC(F)(F)F
Product: O=C(O)CC1CC2(CCN(C(=O)Cc3ccccc3OC(F)(F)F)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 2-(2-(trifluoromethoxy)phenyl)acetic acid and ethyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate. LC-MS Method 1 tR=1.88, min, m/z=484, 482
Reaction SMILES: F[C:2](F)([O:12]C)[CH:3]([C:8]([F:11])(F)F)[C:4]([F:7])([F:6])[F:5].CN(C)C.[F:19][C:20]1[CH:39]=[CH:38][CH:37]=[CH:36][C:21]=1[CH2:22][N:23]1[C:27]([C:28]2[CH:32]=[CH:31][O:30][N:29]=2)=[CH:26][C:25]([C:33](=[NH:35])[NH2:34])=[N:24]1>CN(C=O)C.C(OCC)(=O)C.CO>[F:11][C:8]1[N:34]=[C:33]([C:25]2[CH:26]=[C:27]([C:28]3[CH:32]=[CH:31][O:30][N:29]=3)[N:23]([CH2:22][C:21]3[CH:36]=[CH:37][CH:38]=[CH:39][C:20]=3[F:19])[N:24]=2)[NH:35][C:2](=[O:12])[C:3]=1[C:4]([F:5])([F:6])[F:7]
Reactant: COC(F)(F)C(C(F)(F)F)C(F)(F)F
Reactant: N=C(N)c1cc(-c2ccon2)n(Cc2ccccc2F)n1
Agent: CN(C)C
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: O=c1[nH]c(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)nc(F)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
To a cold solution of 2-(difluoro(methoxy)methyl)-1,1,1,3,3,3-hexafluoropropane (81 mg, 1 equiv.) in DMF (876 μl) at 0° C., was added, slowly, trimethylamine (98 μl, 2 equiv.). The mixture was stirred at 0° C. for 1 h. To this mixture, was added a solution of 1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamide (Intermediate 8C, 100 mg, 1 equiv.) in DMF (876 μl). The mixture was stirred at room temperature for 1 h and heated to 70° C. for an additional 1 h. The mixture was cooled to room temperature. It was diluted in ethyl acetate (100 ml) and washed with water (50 ml×3). The organic layer was dried, filtered and evaporated to give solid. The resulting solid was dissolved in methanol and absorbed onto silica gel. Purification by column chromatography (0 to 100% ethyl acetate in hexanes) gave 6-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4(3H)-one (35 mg, 24% yield) as a yellow solid.
Reaction SMILES: [OH-].[Na+].C(O)C.[F:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][C:8]=1[NH:20]C(=O)OC>O>[F:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][C:8]=1[NH2:20]
Reactant: COC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 25 °C
Yield: 99.6 %

Procedure:
2N sodium hydroxide aqueous solution (3.5 ml) was added to an ethanol solution (1.5 ml) of methyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate (1.507 g, 5.24 mmol), and the mixture was heated under reflux for 2 hours. After reaction, the reaction liquid was cooled to room temperature, water was added thereto, and this was extracted with ethyl acetate (20 ml ×2). The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The drying agent was taken out by filtration, and the solvent was removed by distillation under reduced pressure, to obtain 2-fluoro-4-chloro-5-cyclopentyloxyaniline (1.20 g, 5.22 mmol). Yield: ~100 %.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[N:21]1[C:30]2[C:25](=[CH:26][C:27]([C:31](O)=[O:32])=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]([OH:20])[CH2:2][NH:1][C:31]([C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:21]=[CH:22][CH:23]=[CH:24]3)=[O:32])[CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Product: O=C(NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1ccc2ncccc2c1

Procedure:
Prepared as described in Example from (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) and quinoline-6-carboxylic acid (0.054 g). Title compound obtained as white solid (0.032 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[N:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[S:29][C:28]3[C:23](=[N:24][CH:25]=[CH:26][C:27]=3Cl)[CH:22]=2)=[O:20])=[CH:14][CH:13]=1>>[N:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[S:29][C:28]3[C:23](=[N:24][CH:25]=[CH:26][C:27]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:22]=2)=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(Nc1ccncc1)c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)Nc5ccncc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid pyridin-4-ylamide by a procedure analogous to Example 1C. MS: 400 (MH+); HPLC Rf: 4.24 min.; HPLC purity: 99%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[CH:6][N:7]=1.C([O-])([O-])=O.[Na+].[Na+].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](B(O)O)[CH:18]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:2]2[CH:3]=[C:4]3[CH:10]=[N:9][NH:8][C:5]3=[CH:6][N:7]=2)[CH:18]=1
Reactant: Brc1cc2cn[nH]c2cn1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: c1cncc(-c2cc3cn[nH]c3cn2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 60.1 %

Procedure:
To a solution of 5-bromo-1H-pyrazolo[3,4-c]pyridine from Example 6 (100 mg, 0.5 mmol) in DMF (5 mL) was added Pd(dppf)Cl2 (20 mg), saturated solution of Na2CO3 (1 mL) and pyridin-3-ylboronic acid (74 mg, 0.6 mmol). The mixture was stirred under argon for 16 h at 80° C. After cooling down, the solvent was removed under reduced pressure and the residue was purified by silica-gel column chromatography (mobile phase: EA:PE=1:1) to afford 5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine (59 mg, 60%). 1H NMR (500 MHz, MeOD) δ 9.17 (s, 1H), 9.09 (s, 1H), 8.52 (d, J=3.5, 1H), 8.44 (q, J=7, 2, 1H), 8.29 (d, J=5, 1H), 8.23 (s, 1H), 7.53 (q, J=9.5, 5.5, 1H). ESI MS m/z=197.1 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(=O)(O)[O-].[Na+]>CCCCCC>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:12][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Product: COC(=O)CNc1ccc(Oc2ccccc2)cc1
Reaction time: 24 h
Yield: 32.6 %

Procedure:
A mixture of 4-phenoxyaniline (30 g, 0.162 mol), methyl chloroacetate (21.3 ml, 0.243 mol) and sodium bicarbonate (27.2 g, 0.324 mol) was heated at 100°-120° C. with magnetic stirring for 24 hours. The resulting semi-solid was partitioned between dichloromethane (300 ml) and water (300 ml) then separated. The aqueous layer was extracted with dichloromethane (200 ml) and the organic extracts were combined. The extracts were washed with 2N hydrochloric acid (2×200 ml) and water (2×200 ml), dried (MgSO4) and evaporated to give a brown oil. This was heated with hexane (300 ml) to give an oil suspension. The hexane was decanted off and residual oil crystallised on cooling. The solid was triturated with ether/hexane 1:1 and filtered to give a brown solid (13.6 g, 33%) m.p. 80°-82° C. A second crop of a pale yellow solid was also given (10.5 g, 25%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:5][N:4]=1)[NH2:2].[CH:17]([O-])([O-])OCC>>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]3[N:4]([CH:17]=[N:2][N:1]=3)[CH:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC([O-])[O-]
Reactant: COc1cccc(-c2ccc(NN)nc2)c1
Product: COc1cccc(-c2ccc3nncn3c2)c1

Procedure:
In a manner similar to Example 8, 2-hydrazino-5-(3-methoxyphenyl)pyridine is treated with ethyl orthoformate to give 6-(3-methoxyphenyl)-1,2,4-triazolo[4,3-a]pyridine. Hydrogenation of this product affords the product of the Example.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18](SC)=[N:17][C:16]3=[O:22])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[N:31]1([CH2:37][CH2:38][OH:39])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18]([N:34]4[CH2:35][CH2:36][N:31]([CH2:37][CH2:38][OH:39])[CH2:32][CH2:33]4)=[N:17][C:16]3=[O:22])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(S(C)(=O)=O)cc3Cl)c2)S1
Reactant: OCCN1CCNCC1
Product: CS(=O)(=O)c1ccc(Cn2ncc3cc(C=C4SC(N5CCN(CCO)CC5)=NC4=O)ccc32)c(Cl)c1

Procedure:
5-[1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(2-chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 2-piperazin-1-yl-ethanol following General Procedure C.