Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17]([N:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[N:21]1)[CH2:18][CH3:19]>O1CCOCC1.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>[CH2:17]([N:20]1[C:24]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=2)=[CH:23][CH:22]=[N:21]1)[CH2:18][CH3:19]
Reactant: COC(=O)c1cc(Br)cs1
Reactant: CCCn1nccc1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCCn1nccc1-c1csc(C(=O)OC)c1
Temperature: 70 °C
Yield: 70.3 %

Procedure:
To a solution of methyl 4-bromo-2-thiophenecarboxylate (221 mg, 1.0 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (414 mg, 3.0 mmol), tetrakistriphenylphosphine Pd(0) (60 mg, 0.05 mmol), and 1-propyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (404 mg, 1.5 mmol). The reaction mixture was heated to 70° C. in a sealed tube for 2 h. The reaction mixture was concentrated and purified on silica gel (EtOAc/Hex 10-40%) to give the title compound (176 mg, 70%) as a white solid: LC-MS (ES) m/z 251 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:15][CH2:16][O:17][CH3:18])[C:3]1=[O:19].[OH:20][C@@H:21]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:22]([NH:24][C@H:25]([C:30](O)=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23]>>[OH:20][C@@H:21]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:22]([NH:24][C@H:25]([C:30]([NH:1][C@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:4]([CH2:15][CH2:16][O:17][CH3:18])[C:3]1=[O:19])=[O:31])[CH2:26][CH:27]([CH3:28])[CH3:29])=[O:23]
Reactant: COCCN1C(=O)[C@@H](N)CC=C[C@H]1c1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](O)CC(C)C)C(=O)O
Product: COCCN1C(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](O)CC(C)C)CC=C[C@H]1c1ccccc1

Procedure:
Utilizing (3S,7S)-3-amino-1-(2-methoxyethyl)-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (6d) and N-[(2S)-2-hydroxy-4-methylpentanoyl]-L-leucine (7b), the title compound was synthesized using the same procedure as that described for Example 6.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:27][O:28][CH2:29][CH2:30][O:31][CH2:32]Cl>>[CH3:15][C:14]([C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]=1[O:13][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[CH:8]=[O:9])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Yield: 75.7 %

Procedure:
A mixture of 11.7 g (0.05 mole) of 3,5-di-tert-butyl 4-hydroxybenzaldehyde and 19.4 g (0.15 mole) of diisopropylethylamine in 150 mL of CH1C12 is treated with 18.7 g (0.15 mole) of 2-methoxyethoxymethyl chloride (MEM-Cl) and the resulting solution is heated under reflux for 48 hours and evaporated to dryness. The residue is taken up in CH2Cl2, washed with IN HCl and brine, and dried with MgSO4. The solution is evaporated and the residue is filtered through flash grade silica gel, washing with 1:1 CH2Cl2 /n-hexane. Evaporation gives a tan oil, 12.2 g of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzaldehyde (76%) which is used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:20][C:21]1[C:26]2[C:27]3([CH2:33][O:34][C:25]=2[CH:24]=[CH:23][CH:22]=1)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([N:30]3[CH2:31][CH2:32][C:27]4([C:26]5[C:21]([F:20])=[CH:22][CH:23]=[CH:24][C:25]=5[O:34][CH2:33]4)[CH2:28][CH2:29]3)=[O:18])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Reactant: Fc1cccc2c1C1(CCNCC1)CO2
Agent: Cl
Product: CCOC(=O)c1cnn2c(O)c(C(=O)N3CCC4(CC3)COc3cccc(F)c34)cnc12
Yield: 34.5 %

Procedure:
In the same manner as in Example 1, step 2 and using 3-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.430 g, 1.71 mmol) obtained in Example 19, step 2 and 4-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.500 g, 2.05 mmol) obtained in Reference Example 2, the title compound (0.260 g, 35%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]([C:36](Cl)=[O:37])[CH:27]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:36]([C:28]4[CH:27]=[N:26][C:35]5[C:30]([CH:29]=4)=[CH:31][CH:32]=[CH:33][CH:34]=5)=[O:37])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C(Cl)c1cnc2ccccc2c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cnc5ccccc5c4)cc3)cc2C1=O
Yield: 20 %

Procedure:
The compound of example 650 was prepared analogous to the compound of example 640 by reaction of compound of example 6 with commercially available quinoline-3-carbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH:40]1[CH2:45][OH:46])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:29])([F:31])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:41][C@@H:40]1[CH2:45][OH:46])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCNCC1CO
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C[C@@H]1CO

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure B.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].[C:11](OC(=O)C)(=[O:13])[CH3:12]>CN(C)C1C=CN=CC=1>[C:11]([O:5][CH2:4][C:3]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=1[CH3:1])(=[O:13])[CH3:12]
Reactant: Cc1cccc(C)c1CO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CC(=O)OCc1c(C)cccc1C
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a mixture of 2,6-dimethylbenzyl alcohol (17.1 g) and acetic anhydride (14.2 ml) was added 4-dimethylaminopyridine (17 mg), and the mixture was stirred at 70° C. for 5 hours. After cooling, the mixture was concentrated in vacuo, and ethyl acetate was added to the residue. The solution was washed with water, dried over magnesium sulfate and evaporated in vacuo to give 2,6-dimethylbenzyl acetate (22.5 g) as colorless oil.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[NH:17])OC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[S:18]([NH2:22])([NH2:21])(=[O:20])=[O:19]>CO>[S:18]([NH:22][C:14](=[NH:17])[CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)(=[O:20])(=[O:19])[NH2:21]
Reactant: COC(=N)CCSCc1csc(NC(=N)N)n1
Reactant: NS(N)(=O)=O
Solvent: CO
Product: N=C(N)Nc1nc(CSCCC(=N)NS(N)(=O)=O)cs1
Yield: 64.6 %

Procedure:
In 30 ml of methanol was dissolved 4.09 g of methyl 3-[(2-guanidinothiazol-4-yl)methylthio]propionimidate and then 15 ml of a methanol solution of 2.88 g of sulfamide was added to the solution under refluxing. After refluxing for about 3 hours, the solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography using a mixture of chloroform and methanol (20:1→10:1) as the developing solvent to provide 3,26 g of N-sulfamoyl-3-[(2-guanidinothiazol-4-yl)methylthio]propionamidine. The product shows the following physical chemical properties:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([C:40]([OH:43])([CH3:42])[CH3:41])[CH:37]=[N:38][CH:39]=2)O1>>[OH:43][C:40]([C:36]1[CH:35]=[C:34]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]5[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:21])[CH3:22])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:39]=[N:38][CH:37]=1)([CH3:42])[CH3:41]
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC(C)(O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(C(C)(C)O)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G) and 2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-propan-2-ol (Stage 215.1.1) to give the title compound as a white foam. (HPLC: tR 2.13 min (Method A); M+H=457 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.69-8.66 (m, 1H), 8.46-8.44 (m, 1H), 8.21 (s, 1H), 8.16-8.12 (m, 1H), 7.98-7.91 (m, 2H), 7.58-7.56 (m, 1H), 5.26 (s, 1H), 4.53 (hp, 1H), 3.59 (s, 3H), 1.97 (s, 3H), 1.49 (s, 6H), 1.44 (d, 6H))
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH:5]([OH:9])[C:6]([OH:8])=[O:7].[CH:17]1(O)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[ClH:1].[CH:17]1([O:7][C:6](=[O:8])[CH:5]([OH:9])[C@@H:4]([NH2:3])[CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N[C@@H](CC1CCCCC1)C(O)C(=O)O
Reactant: OC1CCCC1
Agent: Cl
Product: N[C@@H](CC1CCCCC1)C(O)C(=O)OC1CCCC1
Temperature: 90 °C

Procedure:
Hydrogen chloride was passed into a solution of 300 mg of (2RS, 3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid hydrochloride, which was prepared in Reference Example 2, in 5 ml of cyclopentyl alcohol with stirring under ice-cooling, and then the mixture was heated at 90° C. for 5 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=15/1 by volume). The eluate was acidified by adding hydrochloric acid, and then evaporated to dryness under reduced pressure to obtain 380 mg of (2RS, 3S)-3-amino-4-cyclohexyl-2hydroxybutyric acid cyclopentyl ester hydrochloride as a white powder.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1([C:9]([OH:25])([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:10][C:11]([Cl:18])=[C:12]([Cl:17])[C:13](O)([CH3:15])[CH3:14])[CH2:8][CH2:7]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Cl:5][C:6]1([C:9]([OH:25])([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:10][C:11]([Cl:18])=[C:12]([Cl:17])[C:13]([CH3:15])=[CH2:14])[CH2:7][CH2:8]1
Reactant: CC(C)(O)C(Cl)=C(Cl)CC(O)(Cn1cncn1)C1(Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: C=C(C)C(Cl)=C(Cl)CC(O)(Cn1cncn1)C1(Cl)CC1
Yield: 29.7 %

Procedure:
0.71 g (6 mmol) of thionyl chloride are added at room temperature with stirring to a mixture of 1.77 g (5 mmol) of 6-(1-chlorocyclopropyl)-3,4-dichloro-2,6-dihydroxy-2-methyl-7-(1,2,4-triazol-1-yl)-hept-3-ene and 20 ml of methylene chloride, and the mixture is then heated at reflux for 5 hours. Aqueous sodium carbonate solution is subsequently added to the reaction mixture, which is then subjected several times to extraction with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The product which remains is chromatographed over silica gel using ethyl acetate. Concentration of the eluate gives 0.5 g (20% of theory) of 6(1-chlorocyclopropyl)-3,4dichloro-6-hydroxy-2-methyl-7-(1,2,4-triazol-1-yl)hepta-1,3-diene in the form of a colourless oil.
Reaction SMILES: [N:1]1([CH2:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH2:12][N:11](C(=O)C(F)(F)F)[CH2:10][CH2:9]3)[CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[ClH:28].C(OCC)C>CO>[ClH:28].[ClH:28].[N:1]1([CH2:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH2:12][NH:11][CH2:10][CH2:9]3)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N1CCc2cc(CN3CCC3)ccc2C1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: c1cc2c(cc1CN1CCC1)CCNC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[6-(Azetidin-1-yl-methyl)-1,2,3,4-tetrahydro-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone (5.162 mmol, 1 equiv.) was dissolved in methanol (20 ml); K2CO3 (10.32 mmol, 2 equiv.) was added, and the mixture was stirred for 1 hour at 25° C. Methanol was concentrated in vacuo, and the residue was taken up in dichloromethane (30 ml) and washed with distilled water (5 ml). The aqueous phase was extracted with DCM (20 ml), and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. For purification, the crude product was dissolved in diethyl ether (50 ml), and a hydrochloride was precipitated with 2 M HCl in diethyl ether solution (3 equiv.). The hydrochloride was filtered off, washed with diethyl ether and dried in vacuo to yield the desired product. Yield: 1.03 g (73%)
Reaction SMILES: CO[C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7]1.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7]2)[C:3]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: Nc1nccs1
Reactant: COC(=O)C(CC1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Yield: 53.2 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-3-(3-hydroxy-cyclopentyl)-propionic acid methyl ester (25 mg, 0.08 mmol) and 2-aminothiazole (9.4 mg, 0.09 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. %, 0.22 mL, 0.15 mmol) was heated to 110° C. for 18 h. At this time, the reaction mixture was cooled to 25° C. and then filtered through a pad of celite (methylene chloride as eluent). The filtrate was washed with a 1N aqueous hydrochloric acid solution. The organics were dried over sodium sulfate, filtered and then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 ethyl acetate/hexanes) afforded 2-(3,4-dichloro-phenyl)-3-(3-hydroxy-cyclopentyl)-N-thiazol-2-yl-propionamide (16.4 mg, 54%) as light tan oil: EI-HRMS m/e calcd for C17H18Cl2N2O2S (M+H)+ 385.0537, found 385.0542.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([S:14]([C:17]1[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[N:8][NH:9]2.[N-:27]=[N+:28]=[N-:29].[Na+]>CS(C)=O.O>[N:27]([CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([S:14]([C:17]1[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[N:8][NH:9]2)=[N+:28]=[N-:29]
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2cccc(OCCCl)c12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCOc1cccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.2 g, 0.5 mmoles) and sodium azide (0.04 g, 0.62 mmoles) in DMSO (2 mL) was stirred together in a round bottom flask under nitrogen at 90° C. for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. Crude compound was purified by normal phase HPLC using as eluent 40% EtOAc/hexane to afford the title compound as an off white solid (0.17 g, 0.45 mmoles).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.[Na].Cl.[NH2:11][CH2:12][CH2:13][SH:14].Cl>C(O)C>[ClH:1].[NH2:11][CH2:12][CH2:13][S:14][CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: ClCc1cnccn1
Reactant: NCCS
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NCCSCc1cnccn1
Reaction time: 2 h

Procedure:
2-Chloromethylpyrazine (6.4 g.) was added over 20 minutes to a solution freshly prepared from sodium (0.23 g.) in ethanol (50 ml.) to which cysteamine hydrochloride (5.7 g.) had been added gradually at 0° and stirred at this temperature for 2 hours. The suspension finally obtained was stirred at room temperature overnight, acidified with hydrochloric acid (pH 5) and concentrated under reduced pressure. The dry residue was extracted with ethanol and the extracts filtered and concentrated to give the crude product. Extraction with isopropyl alcohol, with the removal of some polymeric material and the addition of ether gave a cream coloured solid (3.5 g.), which was recrystallised from ethanol-ether to furnish 2-[(2-aminoethyl)thiomethyl]pyrazine hydrochloride m.p. 144°-146°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:9][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:12][C:13]=3[O:14][C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([S:29]([O-:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.[Na+]>>[Cl:22][C:23]1[CH:24]=[C:25]([S:29]([C:2]2[CH:7]=[CH:6][C:5]3[C:8]4[CH2:9][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:12][C:13]=4[O:14][C:4]=3[CH:3]=2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3cc(Br)ccc3c2C1
Reactant: O=S([O-])c1cccc(Cl)c1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3cc(S(=O)(=O)c4cccc(Cl)c4)ccc3c2C1
Yield: 52 %

Procedure:
The product of step A was coupled with sodium 3-chlorobenzenesulfinate following the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 100:0 to 30:70 hexanes/ethyl acetate) provided tert-butyl 7-(3-chlorophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (66 mg, 52%) as an oil: 1H NMR (CDCl3, 300 MHz) δ 8.06 (d, J=1.3 Hz, 1H), 7.92 (t, J=1.9 Hz, 1H), 7.83 (td, J=7.9, 1.4 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.50 (m, 1H), 7.42 (t, J=7.9 Hz, 1H), 4.55 (br s, 2H), 3.83 (br s, 2H), 2.89 (br s, 2H), 1.49 (s, 9H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[NH:9][C:10]([Br:14])=[C:11]([CH3:13])[N:12]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[S:25](Cl)(=[O:27])=[O:26].O>C(#N)C>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[S:25]([N:12]1[C:11]([CH3:13])=[C:10]([Br:14])[N:9]=[C:8]1[Br:7])(=[O:27])=[O:26]
Reactant: Cc1nc(Br)[nH]c1Br
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)n1c(Br)nc(Br)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.1 %

Procedure:
1.4 g (10 mmol) of potassium carbonate are added to a solution of 1.7 g (7 mmol) of 2,5-dibromo-4-methyl-1H-imidazole in 40 ml of acetonitrile at room temperature. The mixture is stirred for 10 minutes at room temperature, and 1.7 g (7 mmol) of 2-methyl-5-nitro-benzenesulphonyl chloride are then added. Stirring is carried out for a further 20 hours at room temperature and the reaction mixture is then poured onto 100 ml of water. The mixture formed is extracted twice with 50 ml of diethylether in each case. The combined organic~phases are dried over sodium sulphate and then evaporated down under reduced pressure. The remaining residue is chromatographed on silica gel using methylene chloride as mobile phase. 1.6 g (51% of theory) of 1-(2-methyl-5-nitro-benzenesulphonyl)-2,4-dibromo-5-methyl-1H-imidazole are obtained in this manner in the form of a colorless solid substance of melting point 187 to 189° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH:11]1([C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17])[CH2:13][CH2:12]1>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:15]([C:14]([CH:11]2[CH2:13][CH2:12]2)=[O:19])[C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(=O)CC(=O)C1CC1
Reactant: N#Cc1ccc(C=O)cc1
Product: CC(=O)C(=Cc1ccc(C#N)cc1)C(=O)C1CC1

Procedure:
The procedure described in Example 19 was repeated by using 2.6 g 4-cyanobenzaldehyde and 2.5 g 4-cyclopropyl-2,4-butanedione. The product was purified by column chromatography. Yield 0.37 g, mp 83°-85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:26]CCl>S(Cl)(Cl)=O.CN(C)C=O>[Cl:26][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: ClCCl
Reactant: OCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CCl)cc2)=NO1
Temperature: 0 °C

Procedure:
In a solution of 4.2 g of 5-(3,5-dichlorophenyl)-3-[4-(hydroxymethyl)phenyl]-5-trifluoromethyl-4,5-dihydro-isoxazole in 100 mL of dichloromethane, 1.2 mL of thionyl chloride and a catalytic amount (2 to 3 drops) of N,N-dimethylformamide were added, and stirred under reflux with heating for 3 hours. After the completion of the reaction, the reaction mixture was poured into 30 mL of ice water, the organic phase was collected, washed with water (50 mL×1) and saturated sodium hydrogen carbonate aqueous solution (30 mL×3), and thereafter dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluted with ethyl acetate-hexane (1:5) to obtain 4.1 g of the aimed product as pale yellow crystal.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[OH-].[K+].[C:11](#[N:14])[CH:12]=[CH2:13]>O>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][CH2:13][CH2:12][C:11]#[N:14])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: C=CC#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)CNCCC#N
Yield: 48 %

Procedure:
139.6g (1 mole) of glycine ethyl ester hydrochloride was dissolved in 80 ml of distilled water and to this solution was added 230 ml of an aqueous solution of 67.3 g (1.2 mole eq.) of potassium hydroxide. Then, 106.2 g (2 mole eq.) of acrylonitrile was added to the reaction solution while heating and stirring at 50° to 60° C. The reaction mixture was stirred for 5 hours with heating and then the organic layer was separated. The aqueous layer was extracted with ethyl ether and the extract was combined with the organic layer as separated above. The combined organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The residue was distilled under reduced pressure (100° to 150° C./10.25 torr) to obtain 65.6 g (Yield: 48%) of the title compound.