Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Cl:2][C:3]1[N:4]=[N:5][C:6](Cl)=[CH:7][CH:8]=1.[CH3:10][OH:11]>>[Cl:2][C:3]1[N:4]=[N:5][C:6]([O:11][CH3:10])=[CH:7][CH:8]=1
Reactant: CO
Reactant: Clc1ccc(Cl)nn1
Agent: [Na]
Product: COc1ccc(Cl)nn1

Procedure:
Sodium (4.8 g, 0.21 mol) is added portion-wise to MeOH (200 ml) with stirring. After a clear solution is formed, it is added slowly to a solution of 3,6-dichloro-pyridazine (29.6 g, 0.2 mol) in MeOH (200 ml). After addition, the mixture is heated at reflux for 3 h, then cooled and concentrated under reduced pressure. EtOAc and water are added. The organic layer is separated, dried and concentrated under reduced pressure to give 26.4 g of 3-chloro-6-methoxy-pyridazine as a white solid.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4](Cl)([O:6][CH2:7][CH:8]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:5]>CC#N.O.CC#N>[C:4]([O:6][CH2:7][CH:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)(=[O:5])[NH:2][NH2:3]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NN
Solvent: CC#N
Solvent: O
Product: NNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a well-stirred solution of hydrazine hydrate (19 g, 386 mmol) in 150 mL of CH3CN/H2O (1/1, v/v), a solution of FmocCl (10 g, 38.65 mmol) in 600 mL CH3CN was added dropwise at 0° C. over 2 h. The reaction mixture was then allowed to warm to room temperature and stirred for an additional 12 hours, concentrated in vacuo to 150 mL and filtered to yield the title compound as a white solid, which was washed with water and hexane and dried to a constant weight in vacuo (9.74 g, 99%): mp 172-173° C.; 1H NMR (DMSO) □ 4.08 (brs, 2H), 4.21 (t, J=7.2 Hz, 1H), 4.28 (d, J=7.2 Hz, 2H), 7.32 (t, J=7.4 Hz, 2H), 7.42 (t, J=7.4 Hz, 2H), 7.69 (d, J=7.4 Hz, 2H), 7.89 (d, J=7.4 Hz, 2H), 8.36 (brs, 1H); 13C NMR (DMSO) □□ 47.7, 66.7, 121.1 (2C), 126.3 (2C), 128.1 (2C), 128.7 (2C), 141.7 (2C), 144.9 (2C), 159.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](Cl)[N:11]=[C:10]([N:15]3[CH2:20][C@@H:19]4[CH2:21][C@H:16]3[CH2:17][N:18]4[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:9]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].Cl.[CH:34]12[CH2:39][CH:37]([CH2:38]1)[CH2:36][NH:35]2.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:35]3[CH2:36][CH:37]4[CH2:39][CH:34]3[CH2:38]4)[N:11]=[C:10]([N:15]3[CH2:20][C@@H:19]4[CH2:21][C@H:16]3[CH2:17][N:18]4[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:9]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]
Reactant: C1NC2CC1C2
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cc(-c2cnc(N)c(C(F)(F)F)c2)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cc(-c2cnc(N)c(C(F)(F)F)c2)nc(N2CC3CC2C3)n1
Temperature: 90 °C
Yield: 53.4 %

Procedure:
To a solution of (1S,4S)-tert-butyl 5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-chloropyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (220 mg, 0.47 mmol) in DMSO (2 mL) was added 2-azabicyclo[2.1.1]hexane hydrochloride (68 mg, 0.56 mmol) and potassium carbonate (130 mg, 0.93 mmol). The mixture was heated at 90° C. for 16 h. After cooling to room temperature, water (50 mL) was added to. The mixture was extracted with ethyl acetate (30 mL (3 times)). The organic layer was dried over sodium sulfate, concentrated and purified by flash column chromatography (50% ethyl acetate in petroleum ether to 100% ethyl acetate) to provide (1S,4S)-tert-butyl 5-(6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-2-(2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (130 mg, 53.7% yield). LCMS (ESI): [MH]+=518.0.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([C:13]1([CH2:17][OH:18])[CH2:16][O:15][CH2:14]1)[CH3:12].N1C=CC=CC=1>CCOCC>[CH2:11]([C:13]1([CH2:17][O:18][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)[CH2:16][O:15][CH2:14]1)[CH3:12]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCC1(CO)COC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCC1(COC(=O)c2ccc(I)cc2)COC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4-iodobenzoyl chloride (11.5 gms) in dry ether (50 ml) was added to a stirred solution of 3-ethyl-3-hydroxymethyloxetane (5 gms) and pyridine (3.5 mls) in ether (100 ml) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 24 hours. After this time the mixture was washed with water and brine. The organic extracts were dried over anhydrous magnesium sulphate and then evaporated in vacuo. The residue was purified by column chromatography on silica (preeluted with 1% triethylamine in hexane) and eluted with 5% ethyl acetate in hexane. 3-Ethyl-3-(4-iodobenzoyloxymethyl) oxetane was obtained as a colourless oil (8.1 gms).
Reaction SMILES: C([BH3-])#N.[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1([C:15]2[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22]([O:25][CH3:26])[CH:23]=3)[CH2:18][CH2:17][N:16]=2)[CH2:14][CH2:13]1.C(O)(=O)C.[OH-].[Na+]>CO>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1([CH:15]2[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22]([O:25][CH3:26])[CH:23]=3)[CH2:18][CH2:17][NH:16]2)[CH2:14][CH2:13]1
Reactant: COc1cc2c(cc1F)CCN=C2C1(c2ccccc2Cl)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc2c(cc1F)CCNC2C1(c2ccccc2Cl)CC1
Temperature: 0 °C
Reaction time: 22 h

Procedure:
Sodium cyanoborohydride (10.7 g) was added at 0° C. to a mixture of 1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-3,4-dihydroisoquinoline (26.7 g, prepared in a similar manner to that described above), acetic acid (185 ml) and methanol (95 ml) under nitrogen. The mixture was allowed to reach ambient temperature and was stirred for 22 hours. The mixture was poured onto water, and solid sodium hydroxide (150 g) in ice-water (500 ml) was added. The product was extracted into ether and the solvent then removed in vacuo to yield 1-[1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-1,2,3,4-tetrahydroisoquinoline as a gum.
Reaction SMILES: [CH:1](=[C:8]1[CH:16]([NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1](=[C:8]1[CH:16]([NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[OH:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(=Cc2ccccc2)C(NC2CCCCC2)c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1C(=Cc2ccccc2)C(NC2CCCCC2)c2ccccc21
Reaction time: 8 h

Procedure:
2-Benzylidene-3-cyclohexylamino-indan-1-one (3, BCI) (317 mg, 1 mmol) was dissolved in dry THF (15 mL) under nitrogen. Solution of LiAlH4 (76 mg, 2 mmol) in dry THF (10 mL) was added dropwise at 0° C. Solution was stirred overnight and quenched with 100 μL of water followed by 100 μL of 15% NaOH followed by 300 μL of water. Precipitate was filtered off and washed with ether (3×30 mL). Combined liquid was evaporated in vacuum, and residue was separated by column chromatography on silica (DCM-MeOH—NH4OH 100:1:0.5).
Reaction SMILES: C([O-])(=O)CCC.[CH3:7][CH:8]([CH3:21])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28]([O:35][C:36](=[O:41])[CH2:37][CH2:38][CH2:39]Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(#N)C.CCOC(C)=O.CCCCCCC>[CH3:7][CH:8]([CH3:21])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:20])[C:17]([O:19][CH2:39][CH2:38][CH2:37][C:36]([O:35][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:41])=[O:18])=[CH:12][CH:11]=1
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: O=C(CCCBr)OCc1ccccc1
Agent: CCCC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)Cc1ccc(C(C)C(=O)OCCCC(=O)OCc2ccccc2)cc1
Temperature: 90 °C

Procedure:
Benzyl 4-({2-[4-(2-methylpropyl)phenyl]propanoyl}oxy)butanoate was synthesized from benzyl-4-bromo)butanoate, 2-[4-(2-methylpropyl)phenyl]propanoic acid and potassium carbonate. To a solution of benzyl-4-bromobutanoate (2.0 g, 7.8 mmol) in acetonitrile (20 ml) at ambient temperature was added potassium carbonate (1.13 g, 8.2 mmol) and 2-[4-(2-methylpropyl)phenyl]propanoic acid (1.6 g, 7.8 mmol). The reaction was heated to 90° C. for 18 hours and monitored by TLC (4:1 heptane:EtOAc) The mixture was allowed to cool to room temperature and concentrated in vacuo. The crude product was partitioned between water and EtOAc and the organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. The title compound was purified by silica column chromatography eluting with heptane:EtOAc (4:1, v:v) and isolated as a clear, colorless oil (2.5 g, 84% yield). 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 7.30-7.46 (5H, m), 7.02-7.23 (4H, m), 5.11 (2H, s), 3.99-4.21 (2H, m), 3.68 (1H, q, 7.2 Hz), 2.43 (2H, d, 7.2 Hz), 2.27-2.39 (2H, m), 1.73-2.04 (3H, m), 1.48 (3H, d, 7.2 Hz) 0.89 (6H, d, 6.6 Hz).
Reaction SMILES: [CH2:1]([N:8]1[CH2:38][CH2:37][C:11]2([N:16]3[N:17]=[C:18]([C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:25][CH:24]=4)[C:19]([C:20]([NH2:22])=[O:21])=[C:15]3[NH:14][C:13](=O)[CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>B.C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([N:16]3[N:17]=[C:18]([C:23]4[CH:24]=[CH:25][C:26]([O:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:27][CH:28]=4)[C:19]([C:20]([NH2:22])=[O:21])=[C:15]3[NH:14][CH2:13][CH2:12]2)[CH2:37][CH2:38]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)CC21CCN(Cc2ccccc2)CC1
Agent: B
Solvent: C1CCOC1
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC21CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
A solution of 1-benzyl-5′-oxo-2′-(4-phenoxyphenyl)-5′,6′-dihydro-4′H-spiro[piperidine-4,7′-pyrazolo[1,5-a]pyrimidine]-3′-carboxamide (180 mg, 0.36 mmol) in BH3/THF (IN, 20 mL) was heated to reflux for 3 hr. The reaction was quenched with MeOH (20 mL) and con. HCl (2 mL). The mixture was stirred at 60° C. for 1 hr, then was basified with NaHCO3 and extracted with EA (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated and purified by chromatography column on silica gel eluting with 5% of MeOH in DCM to give the product (120 mg, 67.6%) as a yellow solid. 1H NMR (400 MHz, CD3OD-d4) δ 7.39-7.22 (m, 9H), 7.09-7.04 (m, 1H), 6.99-6.94 (m, 4H), 3.86 (s, 2H), 3.35 (t, J=5.6 Hz, 2H), 3.19-3.11 (m, 2H), 2.80-2.66 (m, 2H), 2.50-2.40 (m, 2H), 2.10 (t, J=5.6 Hz, 2H), 1.87-1.78 (m, 2H). MS (ESI, m/e) [M+1]+ 493.9.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:38])[C@@H:12]([N:23]2[C:27](=[O:28])[C@@H:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[NH:25][C:24]2=[O:37])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].[Cl-].[NH4+]>CO.O1CCCC1.CN(C)C=O.O.[Zn]>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:38])[C@@H:12]([N:23]2[C:27](=[O:28])[C@@H:26]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[NH:25][C:24]2=[O:37])[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccc([N+](=O)[O-])cc2)N2C(=O)N[C@H](c3ccc(OC)cc3)C2=O)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccc(N)cc2)N2C(=O)N[C@H](c3ccc(OC)cc3)C2=O)n1
Reaction time: 0.25 h
Yield: 22 %

Procedure:
To a stirred solution of 2-[(S)-2-[(R)-4-(4-methoxy-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester (0.32 g, 0.59 mmol) in methanol (125 mL), tetrahydrofuran (25 mL) and N,N-dimethylformamide (3 mL) was added a solution of ammonium chloride (0.63 g, 11.8 mmol) in water (3 mL) followed by zinc dust (<10 μM particle size) (0.388 g, 5.94 mmol). After 15 minutes the reaction mixture was filitered through a pad of Celite® and washed through with methanol. The filtrate was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic solution was washed with saturated aqueous sodium bicarbonate, water, brine, dried over sodium sulfate and concentrated in vacuo to a yellow solid (0.35 g). Purification by chromatography using silica eluted with 90:10:6:5 chloroform/water/acetic acid/methanol followed by drying in vacuo gave 2-{(S)-3-(4-amino-phenyl)-2-[(R)-4-(4-methoxy-phenyl)-2,5-dioxo-imidazolidin-1-yl]-propionylamino}-thiazole-4-carboxylic acid methyl ester as a brown solid (66 mg, 22%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])=[CH:11][N:10]=1)(C)(C)C.Cl>CCOC(C)=O>[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])=[CH:11][N:10]=1
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N3CCc4ccccc4C3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(CN)ncc(C(=O)N3CCc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.9 %

Procedure:
A solution of [4-(3,4-dihydro-1H-isoquinoline-2-carbonyl)-6,8-dimethoxy-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester (79 mg, 0.17 mmol) in 3 mL of EtOAc was stirred at room temperature, and 2 mL of HCl (3.2 M in EtOAc) was added. After stirring at room temperature overnight (deprotection is typically complete after 4-8 hours) the solvent was removed under reduced pressure and the residue was triturated with ether to give 75 mg of product as the HCl salt. H1-NMR (DMSO): δ, 8.42 (br s, 1H), 7.18 (m, 4H), 6.60 (m, 2H), 4.65 (br s, 2H), 4.27 (m, 2H), 3.98 (br s, 3H), 3.80 (s, 3H), 3.39 (m, 3H), 3.86 (m, 2H), [Note: Rotamers observed.] MS: APCI (M+H) calc'd for C22H23N3O3+H 378.4; found 378.2.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH:5]([O:15][CH2:16][CH2:17][Cl:18])[N:6]1[CH2:10][CH2:9][NH:8][C:7]1=[N:11][N+:12]([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Cl)=[CH:28][N:27]=1.CS(C)=O>O>[Cl:1][CH2:2][CH2:3][O:4][CH:5]([O:15][CH2:16][CH2:17][Cl:18])[N:6]1[CH2:10][CH2:9][N:8]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[N:27][CH:28]=2)[C:7]1=[N:11][N+:12]([O-:14])=[O:13]
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=[N+]([O-])N=C1NCCN1C(OCCCl)OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])N=C1N(Cc2ccc(Cl)nc2)CCN1C(OCCCl)OCCCl
Yield: 61.8 %

Procedure:
16.0 g of 1-[bis-(2-chloroethoxy)methyl]-2-nitroiminoimidazolidine, 13.0 g of anhydrous potassium carbonate, 13.0 g of 2-chloro-5-chloromethylpyridine and 70 ml of dimethyl sulfoxide were agitated at 70° C. for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. After washing with water, the extract was dried with anhydrous sodium sulfate, after which the solvent was distilled off under reduced pressure. The resultant oily residue was purified by column chromatography [silica gel, eluant: hexane/ethyl acetate (1:2)] to give 14.0 g of 1-[bis-(2-chloroethoxy)-methyl]-2-nitroimino-3-(2-chloropyridin-5-ylmethyl)imidazolidine.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:13](CC3C=NC=CC=3)[CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28]([C:31]3SC=[CH:34][CH:35]=3)(=[O:30])=[O:29])[CH2:9][C:8]=2[CH:36]=1)#[N:3].C(S(Cl)(=O)=O)CC>>[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28]([CH2:31][CH2:35][CH3:34])(=[O:29])=[O:30])[CH2:9][C:8]=2[CH:36]=1)#[N:3]
Reactant: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1cccnc1
Agent: CCCS(=O)(=O)Cl
Agent: Cl
Product: CCCS(=O)(=O)N1Cc2cc(C#N)ccc2NC[C@H]1Cc1ccccc1

Procedure:
The title compound was prepared by reaction of Compound A of Example 23 with 1-propanesulfonylchloride following the procedure of Compound B of Example 23.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:13]([N+:14]([O-])=O)=[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([Br:12])[N:6]2[N:5]=1.C(O)C.O>[Zn].C(O)(=O)C>[Br:12][C:11]1[N:6]2[N:5]=[C:4]([CH2:3][O:2][CH3:1])[C:13]([NH2:14])=[C:7]2[CH:8]=[CH:9][CH:10]=1
Reactant: COCc1nn2c(Br)cccc2c1[N+](=O)[O-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COCc1nn2c(Br)cccc2c1N
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
To a suspension of (7-bromo-3-nitropyrazolo[1,5-a]pyridin-2-yl)methyl methyl ether (540 mg) in a mixed solution of ethanol (10 mL), water (5 mL) and acetic acid (1 mL) was added zinc powder (540 mg), and the reaction mixture was heated and stirred for 30 minutes at 60° C. After filtering off insoluble residue, water was added to the filtrate, extraction was performed with ethyl acetate and the organic extract was washed with saturated aqueous sodium bicarbonate and brine. The obtained organic extract was dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and 7-bromo-2-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-amine (371 mg) was obtained as a brown oil from the n-hexane:ethyl acetate (2:1) fraction.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)[CH2:2][CH3:3].[C:14]1(B(O)O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:22]2[C:23]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:19]=[CH:20][CH:21]=2)[CH:7]=1)[CH2:2][CH3:3]
Reactant: CCCNC(=O)c1cccc(Br)c1
Reactant: OB(O)c1cccc2ccccc12
Product: CCCNC(=O)c1cccc(-c2cccc3ccccc23)c1
Yield: 75 %

Procedure:
Using Preparation Method 2, N-n-propyl-3-bromobenzamide from Example 1A was reacted with 1-naphthylboronic acid. The resulting reaction mixture was purified using SiO2 with CH2Cl2/Petroleum ether 80:20 to CH2Cl2/AcOH 80:20 to give a thick yellow oil (75%). NMR 1H (ppm, CDCl3): 7.92-7.78 (m, 5H), 7.67-7.40 (m, 6H), 6.16 (br. s., 1H), 3.50-3.36 (m, 2H), 1.64 (sext., J3=7.33 Hz, 2H), 0.97 (t, J3=7.38 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:20][C:19](=O)[C:11]3[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][O:14][C:10]=3[CH2:9]2)=[CH:4][CH:3]=1.[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].[ClH:27].Cl>C(O)C>[ClH:27].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:20]/[C:19](=[N:26]\[NH:25][C:22]([NH2:24])=[NH:23])/[C:11]3[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][O:14][C:10]=3[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccc(F)cc2)Cc2occ(C(F)(F)F)c21
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: N=C(N)N/N=C1\CC(c2ccc(F)cc2)Cc2occ(C(F)(F)F)c21
Temperature: 90 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
To a mixture of 6-(4-fluorophenyl)-3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.25 g) and aminoguanidine hydrochloride (93 mg) were ethanol (20 ml) and 6N hydrochloric acid (0.072 ml), and the mixture was stirred at 90° C. for 4 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(4-fluorophenyl)-4-guanidinoimino-3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 51) (0.20 g).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](O)=[O:24])[CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:6]2=[N:7][CH:8]=[CH:9][C:5]2=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:23]([C:19]3[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=3)=[O:24])[CH2:14][CH2:15]2)[N:3]=[CH:2]1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Reactant: O=C(O)c1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCN(c2nc[nH]c3nccc2-3)CC1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (100 mg), 3-pyridinecarboxylic acid (56.7 mg, 0.460 mmol), HATU (210 mg, 0.552 mmol) and HOAt (37.60 mg, 0.276 mmol) in DMF (2.3 mL) was added DIPEA (386 μL, 2.209 mmol). The reaction mixture was stirred at room temperature for 2 hours then the solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E10 (113 mg), 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 9.0 (1H, s), 8.70 (1H, d), 8.50 (1H, d), 8.17 (2H, m), 7.50 (1H, m), 7.17 (1H, d), 6.62 (1H, d), 4.70 (2H, dt), 4.17 (1H, m), 3.22 (2H, dt), 1.95 (2H, m), 1.55 (2H, m), MS(ES+) 323 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[N:3]=1.[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][N:4]1[CH:5]=[CH:6][C:2]([NH:1][C:19]([NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[S:20])=[N:3]1
Reactant: Nc1ccn(CCCCO)n1
Reactant: S=C=Nc1ccccc1
Solvent: CC#N
Product: OCCCCn1ccc(NC(=S)Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 28.9 %

Procedure:
To a solution of 3-amino-1-(4-hydroxybutyl)pyrazole (1.0 g.) in dry acetonitrile (3 ml.) was slowly added phenylisothiocyanate (0.95 g.) and the mixture was stirred at room temperature for 17 hours. The solvent was evaporated and the residue purified by column chromatography on silica gel using EtOAc as eluant to give 1-(4-hydroxybutyl)-3-(3-phenylthioureido)pyrazole (0.54 g.; 29%), m.p. 112°-117°.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1.Cl.[NH:32]1[CH2:35][CH:34]([OH:36])[CH2:33]1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[S:22][CH:23]=[C:19]([CH2:18][S:17][C:4]3[C:5]([C:15]#[N:16])=[C:6]([C:10]4[S:14][CH:13]=[N:12][CH:11]=4)[C:7]([C:8]#[N:9])=[C:2]([N:32]4[CH2:35][CH:34]([OH:36])[CH2:33]4)[N:3]=3)[N:20]=2)=[CH:25][CH:26]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Reactant: OC1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CC(O)C2)c(C#N)c1-c1cncs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg (0.206 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile, together with 45 mg (0.411 mmol) of azetidin-3-ol hydrochloride and 53 mg (0.411 mmol) of N-ethyl-N-(1-methylethyl)propan-2-amine, were dissolved in 1.5 ml of THF. The mixture was stirred at room temperature for two hours, and the product was then purified by preparative HPLC (acetonitrile/water: 10:90→95:5, 0.1% TFA added). This gave 40 mg (37% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1I.[Cu][C:19]#[N:20].NC1C=CC(C2SC3C=CC=CC=3N=2)=CC=1Cl>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[C:19]#[N:20]
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1I
Reactant: N#C[Cu]
Agent: Nc1ccc(-c2nc3ccccc3s2)cc1Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2nc3ccccc3s2)ccc1N

Procedure:
2-(4'-amino-3'-iodophenyl)benzothiazole (0.123 g, 0.35 mmol) was treated with copper (I) cyanide (63 mg, 0.7 mmol) in DMF according to procedure for preparation of 2-(4'-amino-3'-chlorophenyl) benzothiazole. The crude product was purified by chromatography on silica gel, eluting with ethyl acetate-hexane (2:3) to give a pale yellow powder (0.032 g, 36%%), m.p. 207.3-211.0° C.