Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.CC([O-])(C)C.[Na+].[C:17]([CH2:19][C:20](OC(C)(C)C)=O)#[N:18]>O1CCOCC1.ClCCl>[Cl:8][C:5]1[N:4]=[C:3]([O:9][CH3:10])[C:2]([CH:19]([CH3:20])[C:17]#[N:18])=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: COc1nc(Cl)ccc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1nc(Cl)ccc1C(C)C#N
Temperature: 75 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a suspension of 3-bromo-6-chloro-2-methoxypyridine (99.9 g, 449 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (2.76 g, 3.38 mmol), and NaOtBu (105 g, 1090 mmol) in dioxane (805 mL) was added tert-butyl cyanoacetate (64.8 mL, 454 mmol) under nitrogen. The reaction mixture was heated for 235 min while maintaining the internal reaction temperature at 75° C. under nitrogen. After being cooled to 20° C., to the reaction mixture was added Mel (55.9 mL, 898 mmol) in one portion, and the resulting mixture was stirred overnight at r.t. Celite® (24 g) was added to the reaction mixture, and the resulting mixture was filtered through a 370 g silica plug. The plug was eluted with EtOAc/heptanes (1/3, 2.0 L), and the combined filtrate was concentrated. A solution of the crude residue (133.9 g) in DMSO (330 mL) and water (67 mL) was heated at 130° C. for 15.8 h. The reaction mixture was filtered through a plug of Celite®, and the filter cake was rinsed with MTBE and water. The filtrate was filtered again through a plug of Celite® and the filter cake was washed with MTBE and water. The filtrate was partitioned between MTBE (total volume=2.0 L), water (total volume=1.0 L) and brine (100 mL). The layers were separated and the organic layer was washed with water (1.0 L) and brine (750 mL), dried over Na2SO4, and concentrated to afford the crude 2-(6-Chloro-2-methoxypyridin-3-yl)propanenitrile (87.6 g, 99%) as a dark brown oil, which was used for the next step without any further purification. 1H NMR (600 MHz, CDCl3) δ 1.58 (d, 3H), 4.01 (s, 3H), 4.11 (q, 1H), 6.97 (d, 1H), 7.66 (d, 1H). MS (ES+)(M+H) 197.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[S:12]1[C:16]2[CH:17]=[C:18]([NH2:21])[CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1>N1C=CC=CC=1>[S:12]1[C:16]2[CH:17]=[C:18]([NH:21][S:8]([C:7]3[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:9])[CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: Nc1ccc2ncsc2c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2ncsc2c1)c1cccnc1Cl
Yield: 50.8 %

Procedure:
The title compound (1.1 g, 3.38 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (1.56 g, 7.36 mmol), 1,3-benzothiazol-6-amine (1.0 g, 6.66 mmol) and pyridine (10 mL) at rt using the methods of (IntC1).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH:25](Cl)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19]1>CN(C=O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH:25]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19]1
Reactant: Oc1ccccc1
Reactant: COc1ccccc1N1CCN(C(=O)C(Cl)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(C(=O)C(Oc2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride 80% dispersion in oil (1.7 g) was added to dry DMF (100 ml) under argon. Phenol (3.76 g; 0.04 m) was added over 20 mins and the resulting grey mixture was stirred a further 20 mins and cooled to 0° C. A solution of 1-(2-methoxyphenyl)-4-(1-oxo-2-chloro-2-phenylethyl)piperazine (13.8 g; 0.04 m) in dry DMF (60 ml) was added over 20 mins. The mixture was heated to 60° C. over a period of about 3 hrs and then maintained at 60° C. for 21/2 hrs and then stirred at ambient temperature overnight. The mix was cooled to 0° C., treated with 10 ml crushed ice and the DMF was vacuumed off. The residue, in methylene chloride, was washed well with water and dried over magnesium sulphate. The oil resulting on evaporation, solidified on standing for a few days to give 1-(2-methoxyphenyl)-4 -(1-oxo-2-phenoxy-2-phenylethyl)piperazine.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:7]>CO.O1CCCC1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][N:2]([CH3:3])[CH3:1])=[CH:9][CH:10]=1
Reactant: CNC
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
A 2.0 M solution of dimethylamine (0.5 mmol) in methanol was added to a solution of 2-bromo-1-(4-bromophenyl)ethanone (114.5 mg, 0.41 mmol) in tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 15 min. The solvent was removed by distillation, and the residue was then purified by column chromatography on silica gel (hexane:ethyl acetate=10:1 to 0:100) to give 84.7 mg (yield 86%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.CCN(C(C)C)C(C)C.[CH:21]1([NH2:25])[CH2:24][CH2:23][CH2:22]1.[Cl-].[Na+]>CN(C=O)C>[CH:21]1([NH:25][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: NC1CCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(NC2CCC2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a stirring solution of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (2 g, 10.8 mmol) in DMF (10 mL) was added DIEA (4.2 g, 32.4 mmol) and cyclobutanamine (2.3 g, 32.4 mmol) at 0° C. The resulting mixture was stirred at 60° C. for 2 h. The reaction mixture was poured into saturated sodium chloride, and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude product. The crude product was purified via silica gel column chromatography (10% ethyl acetate in petroleum ether) to get the desired product as a white solid (1.7 g, 7.7 mmol, 71% yield). MS (ESI) m/z=221.2[M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[N+:34]([O-])([OH:36])=[O:35]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([O:31][CH3:32])=[CH:25][CH:26]=[C:27]([N+:34]([O-:36])=[O:35])[C:28]=2[O:29][CH3:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)ccc([N+](=O)[O-])c2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 50 °C
Reaction time: 8 h

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (1.59 g) was dissolved in THF (4 mL) under N2 then 70% HNO3 (4 mL) was added and the mixture was stirred at 50° C. overnight. The mixture was diluted with AcOEt (150 mL) and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated. The residue was dissolved in anhydrous MeOH (100 mL) and dry HCl gas was bubbled through the mixture at 0° C. for a few minutes. The mixture was stirred at room temperature overnight, concentrated, taken up with AcOEt and washed with 1N HCl, satd. NaHCO3 and brine. The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash column chromatography (silica gel; eluent: hexanes and AcOEt) to give N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxy-3-nitrophenyl)-L-phenylalanine methyl ester (1.1 g).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)C.[H][H]>[Pd]>[NH2:15][C:11]1[CH:10]=[C:9]([C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[CH:14]=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)N1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C(=O)N2CCOCC2)c1

Procedure:
Morpholin-4-yl-(3-nitro-phenyl)-methanone (2.74 g, 11.6 mmol) was dissolved in Ethanol (30.0 mL, 514 mmol) and the solution was carefully added to a Parr vessel containing 10% Palladium on Carbon (0.750 g, 56.2 mmol) under nitrogen. The mixture was then placed on a Parr hydrogenation apparatus and was allowed to shake at 55 psi until uptake of hydrogen ceased. The catalyst was then filtered to afford (3-Amino-phenyl)-morpholin-4-yl-methanone without further purification. (M+H)=207.6.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)[NH:7][C:8](=[O:10])[CH3:9])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:28]([N:35]1[C:39](=[O:40])[C:38](=[C:41]2[N:45]([CH3:46])[C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[S:42]2)[S:37][CH2+:36]1SC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]1[C:39](=[O:40])[C:38](=[C:41]2[N:45]([CH3:46])[C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[S:42]2)[S:37][C:36]1=[N:14][C:13]1[CH:12]=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[NH:3][CH2:1][CH3:2])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCNc1cc(NC(C)=O)ccc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1cc(NC(C)=O)ccc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 3′-ethylamino-4′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.45–7.53 (3H, m), 7.27–7.37 (4H, m), 7.17 (1H, m), 7.03–7.09 (2H, m), 6.91 (1H, d), 6.83 (1H, br d), 6.75 (1H, brs), 5.18 (2H, s), 3.78 (3H, s), 2.99 (2H, m), 2.15 (3H, s), 1.03 (3H, t); MS(ESI): 530 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=1[O:40][CH3:41].CN(C)CCN(C)C.C([Li])CCC.[CH3:55][S:56]C>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:41][O:40][C:25]1[C:26]([O:36][CH2:37][O:38][CH3:39])=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:30][CH2:31][O:32][CH3:33])[C:24]=1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:4]1[C:5]([O:15][CH2:16][O:17][CH3:18])=[C:6]([O:13][CH3:14])[C:7]([S:56][CH3:55])=[C:8]([O:9][CH2:10][O:11][CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Reactant: CSC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OCOC)c(OC)c(SC)c(OCOC)c2OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.51 Grams of 2,2'-pentamethylenebis[1,4-dimethoxy- 3,6-bis(methoxymethoxy)benzene] was dissolved in a mixed solvent of 40 ml of tetrahydrofuran with 4 ml of hexamethylphosphoric triamide, to this solution was added 0.55 ml of N,N,N',N'-tetramethylethylenediamine and the whole mixture was cooled to -78° C., on a dry ice-acetone bath. Then, 2.41 ml of n-butyllithium (1.6 M, n-hexane solution) was added dropwise to the reaction mixture and stirred for 30 minutes. Next, 0.25 ml of dimethyl sulfide was added to the reaction mixture and stirred overnight. The solvent was removed by evaporation under reduced pressure, then the residue obtained was extracted twice with 100 ml of ethyl acetate, then the ethyl acetate layer was washed twice with 100 ml of water, and twice with a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue obtained was purified by means of a preparative thin layer chromatography (thickness: 2 mm, adsorbent: Merck Art 5717 silica gel, developing solvent: 20% ethyl acetate-n-hexane). There were obtained 572 mg of 1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-(methylthio)phenyl]pentane, as well as 522 mg of 2,2'-pentamethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)-5-(methylthio)benzene].
Reaction SMILES: Cl.[CH2:2]([C:9]1[CH2:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][NH2:20])=[CH:15][C:14]([O:21][CH3:22])=[CH:13][CH:12]=2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23](Cl)(=[O:25])[CH3:24]>>[CH2:2]([C:9]1[CH2:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][NH:20][C:23](=[O:25])[CH3:24])=[CH:15][C:14]([O:21][CH3:22])=[CH:13][CH:12]=2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(CCN)=C(Cc1ccccc1)C2
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1ccc2c(c1)C(CCNC(C)=O)=C(Cc1ccccc1)C2

Procedure:
Starting with 2-(2-benzyl-5-methoxy-1H-inden-3-yl) ethylamine hydrochloride and acetyl chloride, the title compound was synthesized in otherwise the same manner as Example 8 (yield 94%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4]I.[Cl:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[CH:17]=2)[CH:12]=[N:11]1.[S:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:37]=[C:36]3[C:32]([CH:33]=[N:34][NH:35]3)=[CH:31][CH:30]=2)=[CH:25]1.[H-].[Na+]>CN(C=O)C>[Cl:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[CH:17]=2)[CH:12]=[N:11]1.[Cl:1][CH2:2][CH2:3][CH2:4][N:34]1[CH:33]=[C:32]2[C:36]([CH:37]=[C:29]([C:26]3[CH:27]=[CH:28][S:24][CH:25]=3)[CH:30]=[CH:31]2)=[N:35]1
Reactant: ClCCCI
Reactant: c1cc(-c2ccc3cn[nH]c3c2)cs1
Agent: ClCCCn1ncc2ccc(-c3ccsc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCCCn1cc2ccc(-c3ccsc3)cc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28 %

Procedure:
1-(3-chloropropyl)-6-(3-thienyl)-1H-indazole 1-chloro-3-iodopropane (0.14 mL, 1.3 mmol) was added to a DMF (3 mL) solution of 6-(3-thienyl)-1H-indazole (88.4 mg, 0.44 mmol) and sodium hydride (60%, 72 mg, 1.8 mmol) that had been allowed to stir for 5 min at room temperature under argon. The reaction mixture was allowed to stir at room temperature overnight before quenching with brine (20 mL) and partitioning into ethyl acetate (100 mL), and drying over anhydrous sodium sulfate. The solvent was removed in vacuo and flash chromatography (silica gel, 10-20% ethyl acetate in hexane) yielded 1-(3-chloropropyl)-6-(3-thienyl)-1H-indazole (76.6 mg, 63%) as well as the side product 2-(3-chloropropyl)-6-(3-thienyl)-2H-indazole (33.9 mg, 28%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[CH:31]1([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32]1>CN(C=O)C>[CH:31]1([N:36]2[CH2:37][CH2:38][N:39]([C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)=[O:16])[CH2:40][CH2:41]2)[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: C1CCC(N2CCNCC2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(C3CCCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57 %

Procedure:
1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (2.2 g) in dry DMF (40 ml) was treated with EDC (3.71 g) followed by HOAT (0.1 g). After 5 min, N-cyclopentylpiperazine (1.5 g) in dry DMF (5 ml) was added and the reaction mixture was stirred at rt for 18 h. Excess DMF was removed by evaporation and the resulting residue was re-dissolved in DCM, adsorbed onto silica gel (10 g) and purified by chromatography [silica gel 0-10% MeOH (containing 10% 0.88 ammonia solution/DCM)]. The pure fractions were combined and the solvent removed by evaporation to give the subtitled compound (2 g). LCMS electrospray(+ve) 366(MH+).
Reaction SMILES: [CH2:1]([NH:5][C:6]([CH:8]=[C:9]1[C:17]2[CH:16]=[C:15]([C:18]([OH:20])=[O:19])[S:14][C:13]=2[CH2:12][CH2:11][CH2:10]1)=[O:7])[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.CO.[CH3:28]COC(C)=O>O>[CH2:1]([NH:5][C:6]([CH:8]=[C:9]1[C:17]2[CH:16]=[C:15]([C:18]([O:20][CH3:28])=[O:19])[S:14][C:13]=2[CH2:12][CH2:11][CH2:10]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(C)=O
Reactant: CCCCNC(=O)C=C1CCCc2sc(C(=O)O)cc21
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CCCCNC(=O)C=C1CCCc2sc(C(=O)OC)cc21

Procedure:
A mixture of 4-(N-butylcarbamoyl)methylidene-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid (0.57 g), conc. sulfuric acid (H2SO4) (3 ml), and methanol (MeOH) (15 ml) was stirred at reflux for 1.5 hours. The reaction mixture was poured into a mixture of AcOEt and water. The organic layer was washed with saturated aqueous solution of NaHCO3, water and brine, and dried over MgSO4, and evaporated in vacuo. After evaporation, the resulting oil was purified by chromatography on silica gel (AcOEt-n-hexane as an eluent). The fractions including the object compound were collected and evaporated to give 4-(N-butylcarbamoyl)methylidene-2-methoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (115.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=O)[CH:13]([CH2:16][C:17]([OH:19])=O)[C:12]3=[N:20][N:21]=[C:22]([CH3:23])[N:11]3[C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]2=3)=[CH:4][CH:3]=1.[CH2:28]([NH2:30])[CH3:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH:13]([CH2:16][C:17]([NH:30][CH2:28][CH3:29])=[O:19])[C:12]3=[N:20][N:21]=[C:22]([CH3:23])[N:11]3[C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]2=3)=[CH:6][CH:7]=1
Reactant: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2CC(=O)O
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)CC1CN(c2ccc(Cl)cc2)c2ccccc2-n2c(C)nnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
A mixture of 2-(6-(4-chlorophenyl)-1-methyl-5-oxo-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-4-yl)acetic acid (15 mg, 0.04 mmol), ethanamine (4 mg, 1.12 mmol), HATU (19 mg, 0.05 mmol), DIEA (8 mg, 0.06 mmol) in DCM (5 mL) was stirred overnight at room temperature. The mixture was concentrated and purified by prep-HPLC to give 2-(6-(4-chlorophenyl)-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-4-yl)-N-ethylacetamide as a white solid (4 mg).
Reaction SMILES: OC[C@@H](NC(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)CC(C)C.[CH3:26][O:27][CH2:28][CH2:29][O:30][C:31]1[N:36]=[C:35]([C:37]([OH:39])=O)[CH:34]=[N:33][C:32]=1[N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.[CH3:46][O:47][C:48](=[O:55])[C@H:49]([CH2:51][CH:52]([CH3:54])[CH3:53])[NH2:50]>>[CH3:46][O:47][C:48](=[O:55])[C@@H:49]([NH:50][C:37]([C:35]1[CH:34]=[N:33][C:32]([N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[C:31]([O:30][CH2:29][CH2:28][O:27][CH3:26])[N:36]=1)=[O:39])[CH2:51][CH:52]([CH3:54])[CH3:53]
Reactant: COCCOc1nc(C(=O)O)cnc1N1CCCCC1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Product: COCCOc1nc(C(=O)N[C@@H](CC(C)C)C(=O)OC)cnc1N1CCCCC1

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 6-(2-methoxy-ethoxy)-5-piperidin-1-yl-pyrazine-2-carboxylic acid and (S)-leucine methyl ester (commercially available). m/z (ES+): 409.3 (M+H).
Reaction SMILES: Cl[SiH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.[CH2:24]([Mg]Cl)[CH2:25][CH3:26]>O1CCCC1>[F:23][C:18]1[CH:17]=[C:16]([C@H:13]2[CH2:14][CH2:15][C@H:10]([CH2:9][CH2:8][C@H:5]3[CH2:6][CH2:7][Si@H:2]([CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4]3)[CH2:11][CH2:12]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: Fc1ccc([C@H]2CC[C@H](CCC3CC[SiH](Cl)CC3)CC2)cc1F
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)CC1

Procedure:
A mixed solution of 3.7 g (10 mmol) of 1-chloro-4-(2-(trans-4-(3,4-difluorophenyl)cyclohexyl)ethyl)-1-silacyclohexane and 30 ml of tetrahydrofuran (hereafter abbreviated as "THF") was prepared, and a 5 ml THF solution of 2.5M n-propylmagnesium chloride (12.5 mmol) was dripped into this solution. The silacyclohexane rings of the target product thus obtained were a mixture of trans isomers and cis isomers. Following a conventional after treatment, they were separated by means of chromatography to obtain 2.9 g of the trans isomers of the target product (yield 80%). The results of its analysis are shown below.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[C:25]#[C:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[C:25]#[C:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc2[nH]nc(C#Cc3ccccc3)c2c1
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(C#Cc3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 17 %

Procedure:
2-Methylsulfonyl-N-(3-phenylethynyl-1H-indazol-5-yl)benzenesulfonamide can be obtained in the following way: 0.23 g of 2-methylsulfonylbenzenesulfonyl chloride is added to a solution, at a temperature in the region of 0° C. and under argon, of 0.2 g of 5-amino-3-phenylethynyl-1H-indazole in 3.5 ml of pyridine. The reaction mixture is then stirred for 1.5 hours at 0° C. and then 2 hours at a temperature in the region of 20° C., and is then diluted with 10 ml of water. After settling out, the aqueous phase is washed with 3 times 15 ml of ethyl acetate. The organic extracts are pooled, washed with 3 times 5 ml of water, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20° C. The residue thus obtained is purified by chromatography under argon pressure (50 kPa), on a cartridge of 25 g of silica (particle size 20-40 μm), eluting with pure dichloromethane then successively with dichloromethane/methanol (99.5/0.5; 99/1 by volume) mixtures. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20° C. The residue is recrystallized from 5 ml of isopropanol in the presence of 3S black. The crystals are filtered through sintered glass, washed with diisopropyl ether, partially dried, and then dried under reduced pressure (3 kPa) at a temperature in the region of 50° C. for 2 hours. 66 mg of 2-methylsulfonyl-N-(3-phenylethynyl-1H-indazol-5-yl)benzenesulfonamide are obtained in the form of an off-white powder melting at 198° C. (analysis C22H17N3O4S2 % calculated C, 58.52; H, 3.79; N, 9.31; O, 14.17; S, 14.20. % found C, 58.37; H, 3.88; N, 9.11; S, 13.73).