Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][CH2:10][C:11]([CH3:15])([OH:14])[CH2:12][OH:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:16]([O:21][CH2:22][CH3:23])(=[O:20])[C:17]([CH3:19])=O.C1C=CC=CC=1>O>[CH2:2]([O:9][CH2:10][C:11]1([CH3:15])[CH2:12][O:13][C:17]([CH3:19])([C:16]([O:21][CH2:22][CH3:23])=[O:20])[O:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)=O
Reactant: CC(O)(CO)COCc1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1(C)OCC(C)(COCc2ccccc2)O1
Temperature: 90 °C

Procedure:
Dry hydrogen chloride gas was passed into a mixture of 3-benzyloxy-2-methylpropane-1,2-diol (14.9 grams) and ethyl pyruvate (9.15 grams) for 1 hour. The mixture was heated at 90° C for a further 1 hour and then cooled to 50° C. Benzene (100 milliliters) was added to the mixture and the water formed in the reaction was removed azeotropically. The cooled solution was washed with potassium carbonate solution and dried. The solvent was removed under reduced pressure and the residue was fractionally distilled to yield the desired product boiling point 124-126° C at 0.3 Torr.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=[O:4].[CH2:10]([K])[CH:11]=[CH2:12].C(Cl)(=O)C([Cl:17])=O.C(OC(=O)[C@H](CC1C=CC(O)=CC=1)N)C1C=CC=CC=1>ClCCl>[Cl-:17].[CH2:12]([O:8][C:7](=[O:9])[CH:6]1[O:1][CH:2]1[C:3]([OH:5])=[O:4])[CH:11]=[CH2:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1OC1C(=O)O
Reactant: C=CC[K]
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: C=CCOC(=O)C1OC1C(=O)O
Product: [Cl-]

Procedure:
When 0.65 g of epoxysuccinic acid monoallylester chloride which was prepared from 1.0 g of allyl potassium epoxysuccinate (i.e. allyl potassium oxirane 2,3-dicarboxylate) by treatment with oxalyl chloride in a manner as described in Example 46 was reacted with L-tyrosine benzyl ester in dichloromethane by the method as described in Example 46, N-(3-allyloxycarbonyloxirane-2-carbonyl)-L-tyrosine benzyl ester(EP-147) was obtained as a colorless oil. Yield 1.0 g (68%). Mass: m/e 425 (M+). IRνfilm (cm-1): 3480 (amine, hydroxy), 1755 (ester), 1685, 1525 (amide), 1625 (C=C), 895 (epoxide). NMR(CDCl3)δ: 2.98 (2H, d, J=6 Hz), 3.19 (0.5H, d, J=2 Hz), 3.43 (0.5H, d, J=2 Hz), 3.58 (0.5H, d, J=2 Hz), 3.61 (0.5H, d, J=2 Hz), 4.5-6.2 (6H, m), 5.08 (2H, d, J=3 Hz), 6.25-7.0 (4H, m), 7.25 (5H, s).
Reaction SMILES: [I-:1].[Na+].[CH3:3][C:4](=O)[CH2:5][CH3:6]>>[CH:3](/[C:4]1[CH:3]=[C:4]([CH2:5][CH2:6][I:1])[CH:3]=[CH:6][CH:5]=1)=[CH:4]\[CH2:5][CH2:6][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [I-]
Reactant: CCC(C)=O
Agent: [Na+]
Product: CCCCCC/C=C/c1cccc(CCI)c1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
Sodium iodide (3.99 g) was added to a solution of the above-mentioned compound (5.51 g) in 2-butanone (60 ml) and the mixture was stirred at 45° C. for 3 hours. The reaction mixture was concentrated, poured into ice water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=100:1) to give 4.75 g of the subject compound as an oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=O>>[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:11][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6]
Reactant: COc1ccc(C=O)cc1O
Reactant: COC(=O)CN
Product: COC(=O)CNCc1ccc(OC)c(O)c1
Yield: 47 %

Procedure:
Prepared as in example 10-10a from glycine methyl ester and 3-hydroxy-4-methoxybenzaldehyde. Yield 47%. MS M+H calculated 226.1. found 226.1.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[ClH:19].[N:20]1([CH2:26][CH2:27][NH:28][S:16]([C:14]2[O:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: NCCN1CCOCC1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)o2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCN3CCOCC3)o2)c(C)[nH]c1=O
Product: Cl
Yield: 51 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)furan-2-sulfonyl chloride is reacted with (2-morpholin-4-yl)ethylamine as described in Step 5, Example 24 to give the title compound as a solid (51% yield). LC/MS: RT 1.93 min; m/e 396 (M+H); 1H NMR (δ, ppm): 11.85 (1H, s), 8.46 (1H, t), 7.52 (1H, s), 7.24 (1H, d); 6.73 (1H, d), 3.85 (4H, m), 3.12 (8H, m), 2.49 (5H), 1.11 (3H, t).
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[Br:9][C:10]1[CH:11]=[C:12]([C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][C:15]=1[F:16]>O1CCCC1.C(OCC)(=O)C>[Br:9][C:10]1[CH:11]=[C:12]([C:17](=[O:19])[CH2:18][C:3]([O:6][CH3:7])=[O:8])[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: CC(=O)c1ccc(F)c(Br)c1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1ccc(F)c(Br)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a suspension of sodium hydride (1.1 g of 60% suspension in mineral oil, hexane-washed, 27.6 mmol) in 50 mL of tetrahydrofuran was added dimethyl carbonate (2.3 mL, 27.6 inmol) and 3'-bromo-4'-fluoroacetophenone (3.0 g, 13.8 mmol). The resulting suspension was stirred at 65° C. for 1 h and then was cooled to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 3:1 hexane/ethyl acetate) to afford 1.0 g (26%) of the title compound. 1H NMR (CDCl3) (data for keto tautomer) δ8.15 (dd, 1H), 7.87 (m, 1H), 7.2 (m, 1H), 3.95 (s, 2H), 3.73 (s, 3H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.Cl[S:14]([C:17]1[N:18]=[CH:19][N:20]2[CH:24]=[CH:23][S:22][C:21]=12)(=[O:16])=[O:15].C(OCC)(=O)C>CN(C=O)C>[CH3:5][O:4][N:3]([CH3:2])[S:14]([C:17]1[N:18]=[CH:19][N:20]2[CH:24]=[CH:23][S:22][C:21]=12)(=[O:15])=[O:16]
Reactant: CNOC
Reactant: O=S(=O)(Cl)c1ncn2ccsc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CON(C)S(=O)(=O)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (0.23 g) and 0.56 ml of triethylamine were added to a solution of 0.44 g of 7-chlorosulfonylimidazo[5,1-b]thiazole in 5 ml of DMF. The mixture was stirred at room temperature for one hr. Ethyl acetate was added thereto, followed by washing with water and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 0.44 g of 7-(N-methoxy-N-methylsulfamoyl)imidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[N:32]=[C:33]=[O:34]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([C:33](=[O:34])[NH:32][C:26]3[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:25]=3[F:24])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Reactant: O=C=Nc1c(F)cccc1F
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3c(F)cccc3F)CC2)c1C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 75.5 mg, 0.239 mmol) in methylene chloride (8.0 mL) was added neat 2,6-difluorophenyl isocyanate (74.1 mg, 0.478 mmol) at room temperature under nitrogen. The resulting light brown solution was stirred overnight. The reaction mixture was diluted with water (˜20 mL) and the resulting mixture was extracted with methylene chloride (2×30 mL). The combined organic layers were washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, filtered, then concentrated to a yellowish film. Silica gel chromatography (33% ethyl acetate in hexanes) provided {4-[1-(2,6-difluoro-phenylcarbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (95.4 mg, 85%) as a colorless film. MS cald. for C26H26F3N2O3 [(M+H)+]: 471, obsd. 471.2.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]2=[N:7][N:8]([C:10]3[CH:11]=[C:12]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=3[OH:21])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:9]=[C:5]2[CH:4]=1.[CH2:30](O)[CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:29][C:2]([C:3]1[C:4]2[C:5](=[N:9][N:8]([C:10]3[CH:11]=[C:12]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=3[OH:21])[CH2:13][CH2:14][C:15]([O:17][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:16])[N:7]=2)[CH:6]=[CH:26][CH:27]=1)([F:28])[F:1]
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(-n2nc3ccc(C(F)(F)F)cc3n2)c1O
Reactant: CC(C)CCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(C)CCCCCOC(=O)CCc1cc(-n2nc3cccc(C(F)(F)F)c3n2)c(O)c(C(C)(C)C)c1
Yield: 99.5 %

Procedure:
The acid prepared in Example 39 (8 g, 0.02 mol), EXXAL® 8 (isooctanol isomers, Exxon, 5 g, 0.038 mol), p-toluenesulfonic acid hydrate (0.5 g, 0.0026 mol) and xylenes (100 mL) are charged to a reactor and refluxed for six hours. TLC shows when the reaction is complete. The solvent is removed and the resulting oil is chromatographed on silical gel. The title compound is obtained in 99.5% yield as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[Br:14]Br.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:14][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[O:9][CH3:10]
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2,4-dimethoxy-nitrobenzene (0.50 g) in chloroform (3 mL) is added dropwise a solution of bromine (0.23 g) in chloroform (1 mL) and the mixture is allowed to stir at room temperature for approximately 15 hours. Additional bromine (0.15 g) in chloroform (1 mL) is added and the reaction is stirred for an additional 4 hours. The mixture is then poured onto 5% aqueous sodium bisulfite and then extracted with chloroform. Pooled organic extracts are then washed successively with 5% aqueous sodium bisulfite then saturated sodium chloride, and then dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure and recrystallization of the residue from toluene provides the desired product as a yellow solid.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14](=[O:45])[NH:15][C@@:16]([C:31]2[CH:36]=[C:35]([O:37][C:38]([F:43])([F:42])[CH:39]([F:41])[F:40])[CH:34]=[C:33]([F:44])[CH:32]=2)([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:14]([NH:15][C@@:16]([C:31]2[CH:36]=[C:35]([O:37][C:38]([F:43])([F:42])[CH:39]([F:41])[F:40])[CH:34]=[C:33]([F:44])[CH:32]=2)([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:45])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)[C@@H]1C[C@@H](F)CN1
Reaction time: 8 h
Yield: 80.2 %

Procedure:
(2S,4R)-tert-butyl 4-fluoro-2-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylcarbamoyl)pyrrolidine-1-carboxylate (18 mg, 0.03 mmol) was dissolved in a solution of CH2Cl2 (1 mL)/TFA (1 mL) at rt. The reaction mixture was stirred overnight and concentrated to dryness under a stream of argon. The resulting residue was dissolved in MeOH and purified by preparative HPLC (Phenoma Luna AXIA 10A, C18, eluting with 10%-90% MeCN/H2O containing 0.1% TFA, monitoring at 220 nm) to provide (2S,4R)-4-fluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)-phenyl)-1-(4-fluorophenyl)-2-phenylethyl)pyrrolidine-2-carboxamide (Example 276) as a white solid (13 mg, 83% yield). 1H NMR (500 MHz, MeOH-d4) 5 ppm 7.22-7.13 (m, 7H), 7.07-6.96 (m, 7H), 6.68 (d, J=5 Hz, 2H), 6.40-6.18 (m, 1H, —CF2H), 5.43 (app d, J=50 Hz, 1H, —CFH), 4.55-4.51 (m, 1H), 4.01 (d, J=10 Hz, 1H), 3.92 (d, J=15 Hz, 1H), 3.65-3.49 (m, 2H), 2.72-2.64 (m, 1H), 2.10-1.96 (m, 1H); LC/MS: RT=3.310 min [M+H] 541.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeCN/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: O=[C:2]1[C:14]2[C:13]3[C:12]([C:15]([O:17]C)=O)=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][N:4]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:3]1.C(O)(=O)C.O.[NH2:34][NH2:35]>CO>[O:17]=[C:15]1[C:12]2=[CH:11][CH:10]=[CH:9][C:8]3[NH:7][C:6]4[CH2:5][N:4]([C:19]([O:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[O:20])[CH2:3][C:2]([C:14]=4[C:13]=32)=[N:35][NH:34]1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(C(=O)OCc1ccccc1)C3
Reactant: NN
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C1NN=C2CN(C(=O)OCc3ccccc3)Cc3[nH]c4cccc1c4c32
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of compound 2-benzyl 5-methyl 4-oxo-3,4-dihydro-1H-pyrido[3,4-b]indole-2,5(9H)-dicarboxylate (70 mg, 0.18 mmol), acetic acid (0.15 mL, 2.6 mmol), and hydrazine hydrate (0.86 mL, 1.5 mmol) in methanol (4 mL) was heated at reflux. After 8 h, the solid was collected by hot filtration and washed with water, EtOAc, and dichloromethane, to give the target compound (61 mg, 94%). 1H NMR DMSO-d6) δ 11.8 (s, 1H), 10.1 (s, 1H), 7.54 (d, 1H, J=8.4 Hz), 7.48 (d, 1H, J=7.2 Hz), 7.38 (m, 4H), 7.32 (m, 1H), 7.18 (dd, 1H, J=8.4, 7.2 Hz), 5.15 (s, 2H), 4.82 (m, 2H), 4.28 (m, 2H). MS (ESI) m/e [M+1]+ 361.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][N:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:7](=[O:9])[N:8]=1.[H-].[Na+].[H][H].C1(C)C=C(C)C=C(C)C=1S([NH:32]O)(=O)=O>CN(C)C=O>[NH2:32][N:4]1[C:3]([S:2][CH3:1])=[N:8][C:7](=[O:9])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:5]1
Reactant: Cc1cc(C)c(S(=O)(=O)NO)c(C)c1
Reactant: [H][H]
Reactant: CSc1nc(=O)c(-c2ccc(F)cc2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(=O)c(-c2ccc(F)cc2)nn1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.3 %

Procedure:
To a solution of 3-methylthio-6-(p-fluorophenyl)-5-oxo-2,5-dihydro-1,2,4-triazine (2.5 g) in anhydrous dimethylformamide (50 ml), sodium hydride (50% dispersion, 0.5 g) was gradually added and stirred until the generation of hydrogen gas was not detected. o-Mesitylenesulfonylhydroxylamine (2.1 g) was added to the mixture, followed by stirring at room temperature for 6 hours. After completion of the reaction, the resultant mixture was poured into ice-water. The precipitated crystals were collected by filtration. Recrystallization of the obtained crystals from methanol gave 2.0 g of 2-amino-3-methylthio-6-(p-fluorophenyl)-5-oxo-2,5-dihydro-1,2,4-triazine in 74% yield. M.P., 192° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]3[CH2:20][CH2:19]3)[N:13]=2)[CH:3]=1.[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN1CCCC1=O>[CH:21]1([NH:27][C:2]2[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]4[CH2:20][CH2:19]4)[N:13]=3)[CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC(=O)c1nnc(Cl)cc1Nc1cccc(C2CC2)n1
Reactant: NC1CCCCC1
Solvent: CN1CCCC1=O
Product: NC(=O)c1nnc(NC2CCCCC2)cc1Nc1cccc(C2CC2)n1
Temperature: 130 °C
Yield: 66.7 %

Procedure:
A suspension of 6-chloro-4-(6-cyclopropylpyridin-2-ylamino)pyridazine-3-carboxamide (100 mg, 345 μmol, prepared as described for example 12) and cyclohexylamine (342 mg, 395 μL, 3.45 mmol) in N-methyl-2-pyrrolidinone (0.5 mL) was heated at 130° C. for 14 h. The mixture was cooled and concentrated under high vacuum at 120° C. to remove all residual solvent and amine starting material. The brown solid obtained was purified by chromatography (silica, 11 g spherical, 0-20% acetone in dichloromethane, 20 min) to give 6-(cyclohexylamino)-4-(6-cyclopropylpyridin-2-ylamino)pyridazine-3-carboxamide (81 mg, 230 μmol, 67% yield) as a white solid. 1H NMR (DMSO-d6) δ: 11.72 (br. s., 1H), 8.37 (br. s., 1H), 7.83 (s, 1H), 7.62 (br. s., 1H), 7.56 (t, J=7.7 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H), 6.88 (d, J=7.3 Hz, 1H), 6.66 (d, J=8.1 Hz, 1H), 3.52-3.69 (m, 1H), 2.04-2.18 (m, 1H), 1.90-2.00 (m, 2H), 1.72-1.82 (m, 2H), 1.63 (d, J=12.6 Hz, 1H), 1.24-1.45 (m, 4H), 1.09-1.23 (m, 1H), 0.95-1.03 (m, 4H); MS (EI/CI) m/z: 353.1 [M+H].
Reaction SMILES: [C@H:1]1([CH2:9][OH:10])[CH2:6][CH2:5][C@H:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.CN1CCOCC1.P(Cl)(Cl)(=O)OCCCCCC>C(Cl)Cl>[CH2:3]1[CH:4]([CH2:7][OH:8])[CH2:5][CH2:6][CH:1]([CH2:9][OH:10])[CH2:2]1
Reactant: OC[C@H]1CC[C@H](CO)CC1
Agent: CCCCCCOP(=O)(Cl)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: OCC1CCC(CO)CC1
Temperature: -40 °C

Procedure:
Under an argon stream, 10 g of trans-1,4-cyclohexane dimethanol (CHDM), 15.25 mL (14.03 g) of N-methyl morpholine (NMM), and 50 mL of methylene chloride were transferred into a 250 mL flash equipped with a funnel. The solution in the flask was cooled down to −40° C. with stirring. A solution of 15.19 g of hexyl phosphoro-dichloridate (HOP) in 20 mL of methylene chloride was added through the funnel, and an additional 10 mL of methylene chloride was used to flush through the funnel. The mixture was then brought up to room temperature gradually and kept stirring for four hours.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:3]1[C:4]2[C:9](=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: O=Cc1ccc2cn[nH]c2c1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1ccc2c(-c3cccs3)n[nH]c2c1
Yield: 70.6 %

Procedure:
A mixture of 1H-indazole-6-carbaldehyde (50 mg, 0.18 mmol), thiophen-2-ylboronic acid (47 mg, 0.37 mmol), Pd(PPh3)4 (21 mg, 0.018 mmol) and 2M Na2CO3 (0.28 mL, 0.55 mmol) in DME/H2O (2 mL/1 mL) was heated under reflux for 16 hours. The crude reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel using EtOAc (10 to 20%) in DCM as the eluent to provide the title compound as a pale yellow solid (29 mg, 70%). 1H NMR (400 MHz, CD3OD) δ ppm 10.09 (s, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.09 (s, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.69 (d, J=3.8 Hz, 1H), 7.48 (d, J=5.0 Hz, 1H), 7.19 (dd, J=4.8, 3.8 Hz, 1H); MS ESI 229.0 (100) [M+H]+, calcd for [C12H8N2OS+H]+ 229.04.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[C:7]1\[C:8](=[O:16])[NH:9][C:10]2[C:15]\1=[CH:14][CH:13]=[CH:12][CH:11]=2.[CH2:17]=O.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CCO>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:17][N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7](=[CH:6][C:2]3[NH:1][CH:5]=[CH:4][CH:3]=3)[C:8]2=[O:16])[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: C=O
Reactant: O=C1Nc2ccccc2/C1=C/c1ccc[nH]1
Solvent: CCO
Product: CN1CCN(CN2C(=O)C(=Cc3ccc[nH]3)c3ccccc32)CC1
Temperature: 0 °C
Reaction time: 23 h
Yield: 20.7 %

Procedure:
A mixture of Z-(1H-Pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one (120 mg, 0.57 mmol), paraformaldehyde (17 mg, 0.57 mmol), and 1-methylpiperazine (63 μL, 0.57 mmol) in 4.0 mL EtOH was heated at reflux for 6.5 h. After standing at room temperature for 23 h, the mixture was concentrated to 3 mL solvent and 1 mL of hexane added. The resulting solution was cooled to 0° C. and the yellow solid which formed was collected by filtration. The solid collected was partitioned between 30 mL dilute HCl and 20 mL Ethyl acetate. The organic layer was removed and the aqueous layer washed with ethyl acetate (15 mL). The aqueous layer was made basic to pH 8 with saturated NaHCO3 and extracted with ethyl acetate. The ethyl acetate layer was washed with H2O, brine and dried with Na2SO4. The organic layer was concentrated and the residue was crystallized from ethyl acetate/hexane to give the title compound (38 mg, 21%) as a bright yellow solid.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([NH2:16])=[O:15])[NH:2]1.C(N(CC)CC)C.[C:24](=[S:26])=[S:25].[CH3:27]I>C(O)C>[CH3:27][S:25][C:24]([N:2]1[CH:3]([C:14]([NH2:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:26]
Reactant: CI
Reactant: NC(=O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Solvent: CCO
Solvent: CCN(CC)CC
Product: CSC(=S)N1Cc2[nH]c3ccccc3c2CC1C(N)=O

Procedure:
In the same manner as described in Example 53, (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxamide (0.71 g), triethylamine (0.46 ml), carbon disulfide (0.22 ml), 70% ethanol (20 ml) and methyl iodide (0.22 ml) are reacted and treated. The product is crystallized from ethyl acetate to give the title compound (0.414 g), m.p. 224°-225° C. (decomp.).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([NH:13][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: ClCC1CO1
Product: OC(CCl)CNCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43 %

Procedure:
Epichlorohydrin (39 ml, 0.5 mol) and benzylamine (54.6 ml, 0.5 mol) were dissolved in petroleum ether (500 ml), stirred at room temperature for 48 hours, and filtered. The resulting solid product was dissolved in toluene (50 ml), and normal hexane (500 ml) was added to the resulting solution to obtain the title compound as a crystalline form in a yield of 43%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5]O.[CH2:11]([O:13][C:14]([CH:16]=[PH3])=[O:15])[CH3:12]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:16][C:14]([O:13][CH2:11][CH3:12])=[O:15])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: OCc1ccc(F)c(Br)c1
Reactant: CCOC(=O)C=[PH3]
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(F)c(Br)c1
Reaction time: 8 h

Procedure:
9.65 g (111 mmol) of manganese dioxide were added to a solution of 6.5 g (31.7 mmol) of 3-bromo-4-fluorobenzyl alcohol and 13.25 g (38 mmol) of ethoxycarbonylmethylenephosphorane in 390 ml of toluene. The reaction mixture was heated at reflux, a further 9.65 g of manganese dioxide were added after 1 h and heating under reflux was continued overnight. After cooling, the mixture was filtered through celite and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (mobile phase cylclohexane/ethyl acetate 5:1). This gave 7.05 g (81% of theory) of the target product in the form of an E/Z isomer mixture.