Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1C.Cl[S:9]([OH:12])(=[O:11])=[O:10].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)=[CH:16][C:15]=1I.C(=O)([O-])[O-].[Na+:34].[Na+]>>[S:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:9](=[O:11])(=[O:10])[O-:12])=[CH:15][CH:16]=1.[Na+:34]
Reactant: O=S(=O)(O)Cl
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccn1
Product: O=S(=O)([O-])Nc1ccc(-c2nc3ccccc3s2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To anhydrous 2-picoline (1.05 g, 11 mmol) was slowly added dropwise chlorsulphonic acid (0.26 g, 2.21 mmol) below 10° C. then 2-(4'-amino-3'-iodophenyl)benzothiazole (0.5 g, 2.21 mmol). The mixture was heated to 50° C. with stirring for 1 hour. After leaving to stand for 2 hours at room temperature, 6 ml of 10% aqueous sodium carbonate was added. The resulting mixture was stirred for 40 minutes at room temperature and concentrated under reduced pressure. The precipitate was filtered off, washed carefully with cold water and treated with hot chlorform. Golden crystals were afforded (0.62 g, 85.5%), m.p. 288-290° C.
Reaction SMILES: Cl[C:2]1[O:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[CH2:22][O:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:8])[N:6]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[O:33]1[CH2:34][CH2:35][N:30]([C:2]2[O:3][CH:4]=[C:5]([C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]3[CH2:22][O:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:8])[N:6]=2)[CH2:31][CH2:32]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(Cl)n2)C(COc2cccnc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(N3CCOCC3)n2)C(COc2cccnc2)C1
Temperature: 25 °C
Yield: 125.8 %

Procedure:
A solution of tert-butyl 4-(2-chlorooxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (117 mg, 0.277 mmol), morpholine (48 mg, 0.554 mmol) and potassium carbonate (76 mg, 0.554 mmol) in THF (2 mL) was heated to 70° C. overnight. Upon cooling to rt, the reaction mixture was filtered and concentrated under reduced pressure. The material was purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient), yielding 165 mg (100%) of the title compound as the TFA salt. LC-MS: RT=6.60 min. [M+H]+=474.1.
Reaction SMILES: CO.[NH2:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:44])[C@@H:16]([CH2:30][CH2:31][CH2:32][NH:33]C(OCC2C=CC=CC=2)=O)[NH:17][C:18]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[O:19])=[CH:9][CH:8]=1)=[O:5]>C(O)(=O)C.CO.[Pd]>[NH2:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:44])[C@@H:16]([CH2:30][CH2:31][CH2:32][NH2:33])[NH:17][C:18]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[O:19])=[CH:9][CH:8]=1)=[O:5]
Reactant: NC(=O)Cc1ccc(CNC(=O)[C@@H](CCCNC(=O)OCc2ccccc2)NC(=O)c2ccc3ccccc3c2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: NCCC[C@@H](NC(=O)c1ccc2ccccc2c1)C(=O)NCc1ccc(CC(N)=O)cc1
Yield: 86 %

Procedure:
Prepared analogously to Example 1d) but using glacial acetic acid/methanol=1/1 (v/v) as solvent instead of methanol, from (R)-N-[[4-(aminocarbonylmethyl)phenyl]methyl]-N2 -[(2-naphthyl)carbonyl]-N5 -(phenylmethoxycarbonyl)-ornithinamide by catalytic hydrogenation in the presence of palladium on activated charcoal in a yield of 86% of theory. Colourless, highly viscous oil which was used without any further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][CH2:8][CH2:7][C:6]=2[C:5]([C:13]([O:15]C)=[O:14])=[CH:4][C:3]=1[O:17][CH:18]([CH3:20])[CH3:19].[CH2:21]([O:28][C:29]1[C:34]([CH2:35]Cl)=[C:33]([CH3:37])[CH:32]=[C:31]([CH3:38])[N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCOCC1>[CH2:21]([O:28][C:29]1[C:34]([CH2:35][N:9]2[CH2:8][CH2:7][C:6]3[C:5]([C:13]([OH:15])=[O:14])=[CH:4][C:3]([O:17][CH:18]([CH3:20])[CH3:19])=[C:2]([Cl:1])[C:11]=3[C:10]2=[O:12])=[C:33]([CH3:37])[CH:32]=[C:31]([CH3:38])[N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Reactant: COC(=O)c1cc(OC(C)C)c(Cl)c2c1CCNC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CN2CCc3c(C(=O)O)cc(OC(C)C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Temperature: 100 °C
Yield: 33 %

Procedure:
To a mixture of methyl 8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (Cpd F, 92.0 mg, 0.310 mmol) and 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 97.1 mg, 0.371 mmol) in 1,4-dioxane (3 mL) was added KHMDS (308 mg, 1.54 mmol). The reaction mixture was heated at 100° C. for 1 hour. The solvent was removed under vacuum and the residue diluted with EtOAc (10 mL) and water (10 mL). The pH of the aqueous layer was adjusted to 3-4 using 1N HCl. The aqueous layer was extracted with EtOAc (25 mL) and the organic layer concentrated under vacuum. The residue was purified by column chromatography (silica gel, heptanes/EtOAc) to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (90a, 52 mg, 33% yield) as an oil.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([C:12]2[N:13]=[N:14][C:15]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:20][CH:19]=3)[CH:17]=2)=[O:11])[CH2:5][CH2:4]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:38][N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([C:12]2[N:13]=[N:14][C:15]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:20][CH:19]=3)[CH:17]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: CCCCc1nnc(C(=O)NC2CCNCC2)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nnc(C(=O)NC2CCN(C)CC2)cc1-c1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 5-(4-benzyloxy-phenyl)-6-butyl-pyridazine-3-carboxylic acid piperidin-4-ylamide dihydrochloride salt (0.096 mmol, 50 mg) and paraformaldehyde (0.96 mmol, 87 mg) in DCM was stirred for 20 min, and then sodium triacetoxyborohydride (0.96 mmol, 204 mg) was added, and stirring continued over night. The solvent was evaporated and to the residue was added saturated NaHCO3 solution, and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The resultant product was purified by column chromatography using 5% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to provide 5-(4-benzyloxy-phenyl)-6-butyl-pyridazine-3-carboxylic acid (1-methyl-piperidin-4-yl)-amide LCMS: m/z 460.3 [M+2].
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19].C(Cl)Cl.[Cl:29][C:30]1[CH:31]=[C:32]([C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=2)=[CH:37]C(O)=O)[CH:33]=[CH:34][CH:35]=1>C(N(CC)CC)C>[Cl:29][C:30]1[CH:31]=[C:32]([C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=2)=[CH:37][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)C=C(c1cccc(Cl)c1)c1cccc(Cl)c1
Reactant: O=CN1CCNCC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=C(c1cccc(Cl)c1)c1cccc(Cl)c1)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5.51 ml of diphenylphosphoryl azide and 1.93 ml of N-formylpiperazine were added, in that order, to 100 ml of a methylene chloride solution containing 5.00 g of 3,3-bis(3-chlorophenyl)acrylic acid (prepared as described in Preparation 110) and 4.75 ml of triethylamine. The reaction mixture was then stirred at room temperature for 18 hours, after which it was washed with a saturated aqueous solution of sodium bicarbonate and then with water. It was then dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was dissolved in a mixture of 100 ml of ethanol and 50 ml of tetrahydrofuran, and 50 ml of a 10% w/v aqueous solution of sodium hydroxide were added. The resulting mixture was stirred for 8 hours at room temperature, after which it was poured into water. The solution was extracted twice, each time with methylene chloride, and the combined extracts were washed with water and dried over anhydrous sodium sulfate: the solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 150 g of silica gel, using mixtures of methylene chloride and methanol ranging from 49:1 to 9:1 by volume as eluent, to give 5.23 g of the title compound as a viscous oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH:11]([NH2:14])([CH3:13])[CH3:12].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:14][CH:11]([CH3:13])[CH3:12])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CC(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CC(C)NC(=O)c1cccc(Br)n1

Procedure:
By the reaction in the same manner as in Example 55-(i) using 6-bromopicolinic acid (3.04 g), isopropylamine (5 ml), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.44 g) and 1-hydroxybenzotriazole (2.70 g), the title compound (3.10 g) was obtained as a colorless oil.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[S:21][CH3:22])[O:11][CH3:12])=[O:9])[C:4](=[O:23])O1.C=O.[N:27]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.Cl[C:37]1C=C(C=CC=1Cl)CN(C)C(C1CN(CCO)C(=O)C=1O)=O>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8]([C:7]2[CH2:37][N:35]([CH2:34][CH2:33][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:4](=[O:23])[C:5]=2[OH:6])=[O:9])=[C:15]([S:21][CH3:22])[CH:16]=1
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCO)C1
Reactant: NCCN1CCOCC1
Reactant: CON(Cc1ccc(F)cc1SC)C(=O)C=C1OC(C)(C)OC1=O
Agent: C=O
Product: CON(Cc1ccc(F)cc1SC)C(=O)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Yield: 18 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methylsulfanyl-benzyl)-N-methoxy-acetamide was reacted with paraformaldehyde and 2-morpholin-4-yl-ethylamine using the method described for the preparation of Compound 767 to give the title compound as a white solid (0.012 g, 18% yield). 1HNMR (300 MHz, CDCl3) δ: 7.27–7.22 (1H, m), 6.94 (1H, dd, J=9.51, 2.56 Hz), 6.83 (1H, td, J=8.42, 2.56 Hz), 4.95 (2H, s), 4.28 (2H, s), 3.97–3.75 (8H, m), 3.68 (3H, s), 3.40 (2H, t, J=5.85 Hz), 2.95 (2H, bs), 2.49 (3H, s).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C@@H:8]([C:10]1[N:11]([CH3:22])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=2)[N:14]=1)[CH3:9])=[O:6].C1COCC1.CC(C)([O-])C.[K+].CCOC(C)=O>O>[I:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:14]=[C:10]([C@H:8]([N:7]3[CH2:2][CH2:3][CH2:4][C:5]3=[O:6])[CH3:9])[N:11]([CH3:22])[CH:12]=2)=[CH:16][CH:17]=1
Reactant: C[C@@H](NC(=O)CCCCl)c1nc(-c2ccc(I)cc2)cn1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](c1nc(-c2ccc(I)cc2)cn1C)N1CCCC1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To a 20-dram vial was added (R)-4-chloro-N-(1-(4-(4-iodophenyl)-1-methyl-1H-imidazol-2-yl)ethyl)butanamide and THF (10 mL). The vial was then cooled to 0° C. under a nitrogen atmosphere and potassium t-butoxide (214 mg, 1.91 mmol) was added. The reaction was stirred for 1.5 h. To the reaction mixture was added EtOAc (50 mL) and water (10 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The residue was then dissolved in DCM and purified by silica gel chromatography (5-50% CH3CN/CH2Cl2) to afford 593 mg (86%) of (R)-1-(1-(4-(4-iodophenyl)-1-methyl-1H-imidazol-2-yl)ethyl)pyrrolidin-2-one as a white solid (M+H (m/z)=396).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][N:3]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)[Cl:15]>>[Cl:15][CH2:14][CH:16]([OH:18])[CH2:17][N:3]1[C:2](=[O:1])[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:4]1
Reactant: Cc1c(O)noc1-c1ccccc1
Reactant: ClCC1CO1
Product: Cc1c(-c2ccccc2)on(CC(O)CCl)c1=O
Temperature: 75 °C
Yield: 71.1 %

Procedure:
A mixture of 6.00 g (34.2 mmoles) of 3-hydroxy-4-methyl-5-phenylisoxazole and 6.33 g (68.4 mmoles) of epichlorohydrin was stirred, whilst heating at 75° C., for 5 hours. At the end of this time, the excess epichlorohydrin was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of cyclohexane and ethyl acetate as eluent, to give 6.51 g (yield 71.1%) of the title compound as a colorless powder, melting at 82°-83° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:23](OC)=[O:24])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.[NH3:27].CO>>[Br:1][C:2]1[CH:3]=[C:4]([C:23]([NH2:27])=[O:24])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[O:16])[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1
Reactant: N
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Solvent: CO
Product: NC(=O)c1cc(Br)nc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 105 °C
Yield: 75.8 %

Procedure:
Methyl 2-bromo-7-(morpholine-4-carbonyl)-5H-pyrido[3,2-b]indole-4-carboxylate (1.008 g, 2.410 mmol, Example 212D) was suspended in NH3/MeOH (7M) (18 mL, 126 mmol) in a sealed microwave vial. The mixture was heated at 105° C. for 8 hours in a microwave reactor. Product crystallized from reaction mixture upon cooling and was collected by filtration, washed with MeOH and dried in nitrogen stream to give 736.4 mg 2-bromo-7-(morpholine-4-carbonyl)-5H-pyrido[3,2-b]indole-4-carboxamide. 1H NMR (DMSO-d6) δ ppm 11.4 (b, 1H), 8.56 (s, 1H), 8.22 (d, 1H, J=8.6), 7.81 (s, 1H), 7.31 (dd, 1H, J=7.9, 1.2), 3.75-3.35 (b, 10H). MS (ESI) m/e−=401/403, m/e+=403/405 (1 Br isotope pattern) consistent with [M−H]− and [M+H]+. HPLC retention time 6.74 min. (Sunfire C18 3.5 μm, 4.6×150 mm column, 15 min gradient, 10-100% B, 1 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([NH:24][C:25]([C:27]3[N:28]=[C:29]([CH3:32])[S:30][CH:31]=3)=[O:26])[C:12]3[C:16]([CH:17]=2)=[N:15][N:14](C2CCCCO2)[CH:13]=3)[CH:5]=[N:6][C:7]=1[Cl:8].[CH:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1.Cl.C(Cl)Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Cl:8][C:7]1[N:6]=[CH:5][C:4]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[C:11]([NH:24][C:25]([C:27]3[N:28]=[C:29]([CH3:32])[S:30][CH:31]=3)=[O:26])[CH:10]=2)=[CH:3][C:2]=1[NH:1][S:36]([CH:33]1[CH2:35][CH2:34]1)(=[O:38])=[O:37]
Reactant: Cc1nc(C(=O)Nc2cc(-c3cnc(Cl)c(N)c3)cc3nn(C4CCCCO4)cc23)cs1
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(C(=O)Nc2cc(-c3cnc(Cl)c(NS(=O)(=O)C4CC4)c3)cc3[nH]ncc23)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
N-[6-(5-Amino-6-chloro-3-pyridinyl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl]-2-methyl-1,3-thiazole-4-carboxamide (40 mg) was dissolved in pyridine (1 ml) and cyclopropanesulfonyl chloride (24 mg) was added. The reaction was stirred at RT for 1 h. DMAP (3 mg) and cyclopropanesulfonyl chloride (24 mg) were added and the reaction was stirred for 1 h. Further cyclopropanesulfonyl chloride (48 mg) was added and the reaction stirred overnight. Further cyclopropanesulfonyl chloride (48 mg) was added and the reaction was stirred for 2 h. 2M HCl (aq) and DCM were added and the DCM was separated, passed through a hydrophobic frit and evaporated to dryness. The residue was dissolved in DMSO:methanol (1 ml, 7:3, v/v) and purified by MDAP (method E). The product fraction was evaporated to dryness and methanol (3 ml) and a few drops of 2M HCl (aq) were added and the reaction stirred for 2 h. The reaction was evaporated to dryness to give title compound (12 mg).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)OC)#[N:2].[N+]([O-])(O)=O.[O:16]([CH2:20][CH2:21][NH2:22])[N+:17]([O-:19])=[O:18].C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=[N:22][CH2:21][CH2:20][O:16][N+:17]([O-:19])=[O:18])#[N:2]
Reactant: COC(=NC#N)c1cccs1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CCN(CC)CC
Solvent: CO
Product: N#CNC(=NCCO[N+](=O)[O-])c1cccs1
Temperature: 25 °C
Reaction time: 17 h
Yield: 40.5 %

Procedure:
Methyl N-cyano-2-thiophenecarboximidate (0.32 g, 1.9 mmol) was dissolved in methanol (3 ml), and 2-nitroxyethylamine nitrate (0.34 g, 2.0 mmol) and triethylamine (0.20 g, 2.0 mmol) were added. The mixture was stirred at room temperature for 17 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 25 g) eluting with ethyl acetate. The eluted fractions were concentrated under reduced pressure and crystallized from ethyl acetate-hexane to give the title compound (0.18 g, 0.77 mmol, yield: 40%) as colorless crystals.
Reaction SMILES: Br[C:2](=[CH:5]OC(C)C)[CH:3]=[O:4].[S:10]1[CH2:14][C:13](=[NH:15])[NH:12][CH2:11]1.C(N(CC)CC)C>C(#N)C>[N:15]1[C:2]([CH:3]=[O:4])=[CH:5][N:12]2[C:13]=1[CH2:14][S:10][CH2:11]2
Reactant: N=C1CSCN1
Reactant: CC(C)OC=C(Br)C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=Cc1cn2c(n1)CSC2
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 36.9 %

Procedure:
The solution of 2-bromo-3-isopropoxypropenal (6.9 g) in dry acetonitrile (326 mL) was added to the solution of crude thiazolidin-4-ylideneamine (3.3 g) in dry acetonitrile (326 mL) at room temperature. The reaction mixture was stirred at room temperature for 19.5 h, added triethylamine (4.9 mL) and then refluxed for 2 h. The reaction mixture was cooled to room temperature and then evaporated under reduce pressure. The residue was dissolved in dichloromethane (300 mL) and washed with 50% potassium carbonate aqueous solution (20 g). After filtration and separation, the aqueous layer was extracted with dichloromethane (50 mL×4). The organic layers were combined, dried (MgSO4) and filtered. The filtrate was evaporated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with CHCl3-MeOH (100:3) to obtain crude 7H-Imidazo[1,2-c]thiazole-2-carbaldehyde as a brown solid. The crude product was re-crystallized twice from CHCl3-n-hexane (1St: 30:5, 2nd: 30:60) at 0° C. to give the required aldehyde as pale brown crystals (Yield: 1.84 g, 15%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].Br[CH2:27][C:28]1[CH:32]=[C:31]([C:33]2[S:34][C:35]([Cl:38])=[CH:36][CH:37]=2)[O:30][N:29]=1.CC#N.O>C(O)=O>[Cl:38][C:35]1[S:34][C:33]([C:31]2[O:30][N:29]=[C:28]([CH2:27][N:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:2])=[O:4])[C:13]=4[N:12]=[C:11]3[C:14](=[O:25])[NH:15][CH:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:23][CH2:24]4)[CH2:20][CH2:21]3)[CH:32]=2)=[CH:37][CH:36]=1.[Cl:38][C:35]1[S:34][C:33]([C:31]2[O:30][N:29]=[C:28]([CH2:27][N:12]3[C:13]4[C:5]([C:3]([OH:2])=[O:4])=[CH:6][CH:7]=[CH:8][C:9]=4[N:10]=[C:11]3[C:14](=[O:25])[NH:15][CH:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:23][CH2:24]4)[CH2:20][CH2:21]3)[CH:32]=2)=[CH:37][CH:36]=1
Reactant: COC(=O)c1cccc2[nH]c(C(=O)NC3CCN(C4CC4)CC3)nc12
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Solvent: CC#N
Solvent: O=CO
Solvent: O
Product: O=C(O)c1cccc2c1nc(C(=O)NC1CCN(C3CC3)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1
Product: O=C(O)c1cccc2nc(C(=O)NC3CCN(C4CC4)CC3)n(Cc3cc(-c4ccc(Cl)s4)on3)c12

Procedure:
1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-4-carboxylic acid were prepared by a procedure according to example 81 starting from 248.0 mg (0.72 mmol) 2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester and 221.9 mg (0.79 mmol) 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole. Hydrolysis of the resulting esters and purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave the title compounds as their formiates in form of white amorphous solids. The corresponding hydrochlorides were obtained by treatment of both products with a 0.1 M HCl-solution and following lyophilization. Yield of 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid: 119 mg MS (ES+): m/e=526, chloro pattern.
Reaction SMILES: C(OC(N[C@H]1CC[C@H](C(O)=O)CC1)=O)C1C=CC=CC=1.[Br:21][C:22]1[N:23]=[C:24]([C@H:32]2[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34][CH2:33]2)[N:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[C:26]=12.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][CH:47]([F:49])[F:48]>CN(C)C=O>[Br:21][C:22]1[N:23]=[C:24]([C@H:32]2[CH2:37][CH2:36][C@H:35]([NH:38][CH2:46][CH:47]([F:49])[F:48])[CH2:34][CH2:33]2)[N:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[C:26]=12
Reactant: FC(F)CBr
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N)CC1
Agent: O=C(N[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](NCC(F)F)CC1
Temperature: 60 °C

Procedure:
Using the procedures described in example 17 (trans)-4-(benzyloxycarbonylamino)cyclohexanecarboxylic acid was used to prepare (trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexanamine. The latter compound (0.217 mmol, 67.1 mg) was dissolved in N,N-dimethylformamide, potassium carbonate (0.651 mmol, 90 mg) was added followed by 2-bromo-1,1-difluoroethane (0.217 mmol, 17.47 μl, 31.5 mg) and the reaction mixture was stirred in the micro wave at 60° C. After one hour another amount of 2-bromo-1,1-difluoroethane (0.217 mmol, 17.47 μl, 31.5 mg) was added and the reaction mixture was stirred in the micro wave at 60° C. for another hour. The reaction mixture was filtered, the filter was rinsed with acetonitrile and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, gradient dichloromethane/methanol 10/0 to 9/1) to give (trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)-N-(2,2-difluoroethyl)cyclohexanamine (39.8 mg).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:14])=O>>[CH3:11][C:12](=[N:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:14]
Reactant: CC(C)=O
Reactant: NNC(=O)c1ccccc1
Product: CC(C)=NNC(=O)c1ccccc1
Temperature: 5 °C

Procedure:
A four neck flask (1 liter) equipped with a thermometer, a reflux condenser and a stirrer was charged with 136 g (1.0 mol) of benzohydrazide and 600 ml of acetone and then heated under reflux for 12 hours. The reaction liquid was cooled down to 5° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby white crystal was obtained.
Reaction SMILES: [C:1]1(O)C=CC=C[CH:2]=1.[OH:8][C:9]([C:17]1[CH:18]=[C:19]([O:23][Si](C(C)(C)C)(C)C)[CH:20]=[CH:21][CH:22]=1)([C:12]1S[CH:14]=[CH:15][N:16]=1)[CH2:10][CH3:11]>>[OH:8][C:9]([C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)([C:12]1[CH:2]=[CH:1][CH:14]=[CH:15][N:16]=1)[CH2:10][CH3:11]
Reactant: CCC(O)(c1cccc(O[Si](C)(C)C(C)(C)C)c1)c1nccs1
Reactant: Oc1ccccc1
Product: CCC(O)(c1cccc(O)c1)c1ccccn1

Procedure:
Following the procedure described for Phenol 6, Step 3 but substituting 3-[1-hydroxy-1-(pyridin-2-yl)propyl](O-tert-butyldiphenylsilyl)phenol from Step 4 for 3-[1-hydroxy-1-(thiazol-2-yl)propyl](O-tert-butyldimethylsilyl)phenol, the title compound was obtained.