Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[C:24]([F:25])=[CH:23][C:12]2[C:13](=O)[CH2:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[S:17][C:11]=2[CH:10]=1>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:8][C:9]1[C:24]([F:25])=[CH:23][C:12]2[C:13]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[S:17][C:11]=2[CH:10]=1
Reactant: O=C1Cc2ccccc2Sc2cc(Cl)c(F)cc21
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN1CCN(C2=Cc3ccccc3Sc3cc(Cl)c(F)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
1-Methylpiperazine (18.2 ml) was added to a solution of 7-chloro-8-fluorodibenzo(b,f)thiepine-10(11H)-one (see Example 24) (10.16 g) in benzene (90 ml). To this mixture a solution of titanium tetrachloride (3.7 g) in benzene (30 ml) was added dropwise during 5 minutes. The mixture was refluxed for 24 hours, cooled and decomposed by addition of ice-cold water (150 ml). After 30 minutes' standing, the precipitated solid was filtered and washed with benzene. The aqueous layer of the filtrate was extracted with the same solvent, the benzene layers combined, washed with water, dried and taken down, leaving 12.1 g (91%) of the oily base which slowly crystallizes from ethanol. When pure, it melts at 158°-160° C. Neutralization with maleic acid in ethanol yielded the crystalline maleate, m.p. 228°-230° C. (aqueous ethanol).
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.[Br:18][CH2:19]C#N>ClCCl>[Br:18][CH2:19][C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Reactant: N#CCBr
Solvent: ClCCl
Product: BrCc1nsc2nc3ccccc3n12
Yield: 76.9 %

Procedure:
A solution of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzi-midazole-3(2H)-one (15 g, 60.65 mmol) and bromoacetonitrile (18.19 g, 151.6 mmol) in dichloromethane (150 mL) was stirred for 48 h. A white precipitate was formed and the insoluble solid was filtered to give 12.50 g (77%) of the title compound: 1H NMR (CDCl3)δ 4.79 (s, 2H, CH2), 7.42 (t, 1H, ArH), 7.51 (t, 1H, ArH), 7.84 (d, 1H, ArH), 7.94 (d, 1H, ArH); mp 242-244° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][S:15]([CH:18]3[CH2:20][CH2:19]3)(=[O:17])=[O:16])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:22]=2)[CH2:3]1.[C:34](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([N:14]([CH3:34])[S:15]([CH:18]3[CH2:20][CH2:19]3)(=[O:17])=[O:16])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[CH:22]=2)[CH2:3]1
Reactant: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(N3CCOCC3)c1)N2)S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.7 %

Procedure:
To a mixture of cyclopropanesulfonic acid [4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (100 mg, 0.21 mmol), and potassium carbonate (89.4 mg, 0.64 mmol) in N,N-dimethylformamide (4 mL) was added idomethane (0.02 mL, 0.32 mmol). The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was extracted with ethyl acetate (2×50 mL), washed with water (2×20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methyl-amide (20 mg, 19%) as a white solid: MS (ESI) M+1=484.3.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:41][CH:42]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]2[CH:56]=[CH:55][C:52]([C:53]#[N:54])=[CH:51][CH:50]=2)[CH2:44][CH2:43]1>O>[Br:1][C:2]1[S:3][C:4]([C:7]([NH:41][CH:42]2[CH2:47][CH2:46][N:45]([CH2:48][C:49]3[CH:56]=[CH:55][C:52]([C:53]#[N:54])=[CH:51][CH:50]=3)[CH2:44][CH2:43]2)=[O:9])=[CH:5][N:6]=1
Reactant: N#Cc1ccc(CN2CCC(N)CC2)cc1
Reactant: O=C(O)c1cnc(Br)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1ccc(CN2CCC(NC(=O)c3cnc(Br)s3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred mixture of 2-bromothiazole-5-carboxylic acid (500 mg, 2.4 mmol) in anhydrous N,N-dimethylormamide (5 mL) was added triethylamine (1.1 mL, 7.92 mmol), HATU (1 g, 2.64 mmol), and 4((4-aminopiperidin-1-yl)methyl)benzonitrile (762 mg, 2.64 mmol). The mixture was stirred at room temperature overnight and then poured into water. The resulting solids were collected by filtration and purified by column chromatography to yield 972 mg (100%) of 2-bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)thiazole-5-carboxamide as a yellow solid. LCMS (m/z): 406 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH:12]([CH3:14])[CH3:13])[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH:12]([CH3:14])[CH3:13])[C:9]([Cl:18])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](C(=O)O)c1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)[C@@H](C(=O)Cl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 32.3 g (0.165 mol) of [R]-(-)-2-(p-fluorophenyl)-3-methylbutyric acid in 250 ml of abs. methylene chloride was treated with 27.3 ml of oxalyl chloride. After stirring at room temperature for 4 hours and evaporation of the solvent under reduced pressure, [R]-(-)-2-(p-fluorophenyl)-3-methylbutyryl chloride was obtained as an oil, b.p. 100°/65 Pa; [α]D20 =-53.2° (c=1, chloroform).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[NH:7][N:6]=[C:5]([NH2:8])[N:4]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[O:11]1[C:15]2([CH2:20][CH2:19][CH:18]([NH:8][C:5]3[N:4]=[C:3]([C:2]([F:10])([F:9])[F:1])[NH:7][N:6]=3)[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Nc1n[nH]c(C(F)(F)F)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1nc(NC2CCC3(CC2)OCCO3)n[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.3 %

Procedure:
To a solution of 5-(trifluoromethyl)-1H-1,2,4-triazol-3-amine (12.19 g) and 1,4-dioxaspiro[4.5]decan-8-one (12.49 g) in acetic acid (180 mL) was added sodium triacetoxyborohydride (25.43 g), and the mixture was stirred at room temperature for 3 days. The solvent was evaporated under reduced pressure, the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=0/100→10/90 (volume ratio)] and crystallized from diisopropyl ether to give the title compound as a colorless solid (9.88 g, 42%).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[S:33])[CH:28]=[CH:29][CH:30]=1.C(N(CC)CC)C>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:33])[CH:28]=[CH:29][CH:30]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: COc1cccc(N=C=S)c1
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4cccc(OC)c4)CC3)nc21

Procedure:
Pipemidic acid (25 mg, 0.0824 mmol), 3-methoxyphenyl isothiocyanate (11.6 μL, 0.0824 mmol) and triethylamine (23 μL, 0.165 mmol) were used. Purification on silica yielded compound 19 in Table 1, below (21.4 mg, 55%). 1H NMR (300 MHz, CDCl3) δ 9.31 (s, 1H), 8.67 (s, 1H), 7.47 (s, 1H), 7.30-7.21 (m, 1H), 6.80-6.68 (m, 3H), 4.32 (q, J=6.90 Hz, 2H), 4.23-3.89 (m, 8H), 3.79 (s, 3H), 1.48 (t, J=7.16 Hz, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1>O1CCCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=1
Reactant: CC(C)(C)Oc1cc(Br)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cc(Br)c2cc(C(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (4-bromo-2-tert-butoxyquinolin-6-yl)(4-chlorophenyl)methanone (4 g, 9.55 mmol, 1.00 equip) in tetrahydrofuran (65 mL). To the resulting mixture was then added (4-chlorophenyl)magnesium bromide (8.2 mL, 1.30 equip, 1 M) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at 0° C. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate (3×150 mL) and the organic layers combined. The resulting mixture was washed with water (2×100 mL) of water and brine (1×100 mL). The resulting mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether (1:4) to yield (4-bromo-2-tert-butoxyquinolin-6-yl)bis(4-chlorophenyl)methanol as white solid. (ES, m/z): [M+H]+ 532
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:22]=1.O>CN(C)C=O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)=[CH:15][CH:14]=3)[N:22]=2)=[CH:32][CH:31]=1
Reactant: ClCc1cccc(-c2ccc(Cl)cc2)n1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-c2cccc(COc3ccc(CCCCn4ccnn4)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
A solution of 89 mg (0.42 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 17 mg (0.42 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 100 mg (0.42 mmol) 2-Chloromethyl-6-(4-chloro-phenyl)-pyridine [ZA 6706809] were added and stirred continued at r.t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water and n-heptane. The residue was dried at 40° C. and purified by LC-MS to give 80.5 mg (47%) of the title compound as white powder.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH3:23][O:24][C:25]1[C:26]([CH3:39])=[C:27]([CH:36]=[CH:37][CH:38]=1)[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C:30]1=O.Cl>C1COCC1>[CH3:23][O:24][C:25]1[C:26]([CH3:39])=[C:27]([CH:36]=[CH:37][CH:38]=1)[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]=[C:30]1[C:9]1[O:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: c1ccc(-c2ncoc2-c2ccccc2)cc1
Reactant: COc1cccc(CC2CCCCC2=O)c1C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1C
Temperature: 5 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a solution of 4,5-diphenyloxazole (990 mg) in THF (15 ml) was added n-BuLi (1.56M solution in hexane, 2.87 ml) at −60° C. and stirred for 1 hour. To the mixture was added a solution of 2-(3-methoxy-2-methylbenzyl)cyclohexanone (945 mg) in THF (4 ml), warmed to 5° C., and stirred for 2 hours. To the reaction mixture was added 1N HCl and extracted with EtOAc. The organic layer was washed with water, saturated sodium hydrogen carbonate, water, and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was dissolved in toluene (45 ml) and p-TsOH.H2O (79 mg) was added. The mixture was refluxed for 48 hours, cooled to room temperature, diluted with EtOAc, washed with saturated sodium hydrogen carbonate, water, and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 15:1 to 10:1) to give 2-[1-(3-methoxy-2-methylbenzyl)-2-cyclohexen-2-yl]-4,5-diphenyloxazole (1.19 g) as an amorphous solid.
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7](=[O:25])[C:8]1[CH:13]=[CH:12][C:11]([O:14]C(OCC2C=CC=CC=2)=O)=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH3:5].[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH3:1][CH:2]([O:6][C:7](=[O:25])[C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCC(C)OC(=O)c1ccc(OC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(C)OC(=O)c1ccc(O)cc1
Yield: 89 %

Procedure:
A solution of 10 m moles of the above 4-carbobenzoxyoxybenzoic acid 1-methylbutyl ester, 0.5 g of palladium carbon (5% catalyst) in 40 ml of ethyl acetate was reacted for four hours in an atmosphere of hydrogen gas. After the reaction, palladium carbon was filtered out using a membrane filter, and the filtrate was concentrated and purified by column chromatography to obtain 1.9 g of 4-hydroxybenzoic acid 1-methylbutyl ester. (yield: 89%)
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[CH2:38]([O:40][C:41](=[O:47])[CH2:42][S:43](Cl)(=[O:45])=[O:44])[CH3:39]>C(Cl)Cl>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C@@H:3]4[NH:2][S:43]([CH2:42][C:41]([O:40][CH2:38][CH3:39])=[O:47])(=[O:45])=[O:44])=[N:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Reactant: CCOC(=O)CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CS(=O)(=O)N[C@H]1CCc2c(-c3nnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Reaction time: 0.75 h
Yield: 30.3 %

Procedure:
Prepared using General Procedure 14: To a stirred solution of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile 4 (177 g, 0.47 mmol) and DIEA (182 mg, 1.4 mmol) in DCM (8 mL) was added freshly prepared ethyl-2-(chlorosulfonyl)acetate (131 mg, 0.7 mmol). After 45 min, the crude reaction was partitioned between DCM and NaHCO3. The organic layer was dried over MgSO4, concentrated, and purified by column chromatography (EA/hexanes) to provide 75 mg (30%) of (S)-ethyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate as light yellow solid. LCMS-ESI (m/z) calculated for C25H26N4O5S2: 526.1; found 527.1 [M+H]+, tR=3.71 min. 1H NMR (400 MHz, CDCl3) δ 8.16 (dd, J=8.9, 2.3 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.03 (d, J=9.0 Hz, 1H), 5.46 (t, J=7.9 Hz, 1H), 4.70 (dt, J=12.2, 6.1 Hz, 1H), 4.26-4.17 (m, 2H), 4.00 (d, J=8.2 Hz, 2H), 3.49 (ddd, J=17.4, 9.5, 3.9 Hz, 1H), 3.26-3.05 (m, 1H), 2.56 (ddd, J=12.9, 9.0, 4.4 Hz, 1H), 2.23-2.08 (m, 1H), 1.41-1.37 (m, 6H), 1.28 (dd, J=11.7, 4.6 Hz, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].C(N(C(C)C)CC)(C)C.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])=[O:20]>O1CCCC1>[C:1]([CH:3]([CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])=[O:20])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: Cc1ccccc1C(=O)CBr
Reactant: COC(=O)CC#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C#N)CC(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
2′-Methylacetophenone (16.0 g) was dissolved in chloroform (50 mL) and diethyl ether (50 mL), and a solution of bromine (16.0 g) in chloroform (15 mL) was added dropwise while maintaining the reaction temperature at not higher than 25° C. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 30 min, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude 2-bromo-1-(2-methylphenyl)ethanone (21.4 g) as an oil. To a solution (700 mL) of methyl cyanoacetate (10.9 g) and diisopropylethylamine (31.0 g) in tetrahydrofuran was added dropwise a solution (100 mL) of crude 2-bromo-1-(2-methylphenyl)ethanone (21.4 g) obtained above in tetrahydrofuran. The reaction mixture was stirred at room temperature for 16 hr, then at 70° C. for 2 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give methyl 2-cyano-4-(2-methylphenyl)-4-oxobutanoate as an oil (yield 16.0 g). This was dissolved in ethyl acetate (16 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (80 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, 6% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give methyl 2-chloro-5-(2-methylphenyl)-1H-pyrrole-3-carboxylate as an oil (yield 2.7 g). This was dissolved in methanol (15 mL), 10% palladium carbon (50% containing water, 1.0 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a colorless solid (yield 0.66 g, 3%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:19](CC)CC)C.C(OC(Cl)=O)C(C)C.N>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH2:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)CCNC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.05 h

Procedure:
111.7 g of benzyloxycarbonyl-β-alanine were dissolved in 1 liter of dimethylformamide, cooled to -20° C, treated with 70 ml of triethylamine and 67 ml of chloroformic acid isobutyl ester and stirred at -20° C for 3 minutes. Dry ammonia gas was led into this mixture until the pH rose to 11, care being taken that the temperature did not, exceed -10° C. The mixture was stirred for a further 30 minutes at room temperature, filtered and the filtrate concentrated in vacuo. The residue was recrystallised from water. Yield: 91 g; melting point 162°-165° C.
Reaction SMILES: CN(CCCN=C=NCC)C.[C:12]([O:16][C:17](=[O:26])[CH2:18][C@@H:19]([CH2:23][CH:24]=[CH2:25])[C:20]([OH:22])=O)([CH3:15])([CH3:14])[CH3:13].ON1C2N=CC=CC=2N=N1.Cl.[NH2:38][C@@H:39]([C:51]([CH3:54])([CH3:53])[CH3:52])[C:40]([NH:42][C@@H:43]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH3:44])=[O:41].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:53][C:51]([CH3:52])([CH3:54])[C@H:39]([NH:38][C:20]([C@H:19]([CH2:23][CH:24]=[CH2:25])[CH2:18][C:17]([O:16][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:26])=[O:22])[C:40]([NH:42][C@@H:43]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH3:44])=[O:41]
Reactant: C[C@@H](NC(=O)[C@@H](N)C(C)(C)C)c1ccccc1
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
N-(Dimethylaminopropyl)-N′-ethylcarbodiimide (4.21 g, 22.0 mmol) was added to a stirred mixture of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]pent-4-enoic acid (A. L. Castelhano, S. L. Bender, J. G. Deal, S. Homer, T. J. Liak, Z. Yuan, World Patent WO96/16027 (1996)) (3.80 g, 17.8 mmol) and 1-hydroxy-7-azabenzotriazole (2.49 g, 18.3 mmol) in anhydrous dimethylformamide (60 mL) under nitrogen at 4° C. After 1 h, (2S)-amino-3,3-dimethyl-N-[(1R)-1-phenylethyl]butanamide hydrochloride (Preparation 1)(5.10 g, 18.8 mmol) was added, followed by diisopropylethylamine (2.42 g, 19.2 mmol). After another 30 min, the mixture was allowed to warm to room temperature. After 17 h at room temperature, the mixture was concentrated under reduced pressure, and partitioned between ethyl acetate (400 mL) and water (400 mL). The aqueous layer was saturated with sodium bicarbonate and extracted with ethyl acetate (2×100 mL). The combined organic solutions were concentrated under reduced pressure, the residue was dissolved in ether (500 mL) and washed with water (3×200 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was triturated with pentane, filtered and dried to give tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)hex-5-enoate (6.70 g, 88%), as a colourless solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:15]2[CH:21]([C:22]([O-:24])=[O:23])[NH:20][CH2:19][CH2:18][CH2:17][S:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:15]2[CH:21]([C:22]([OH:24])=[O:23])[NH:20][CH2:19][CH2:18][CH2:17][S:16]2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2SCCCNC2C(=O)[O-])cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(S(=O)(=O)C2SCCCNC2C(=O)O)cc1

Procedure:
Following the procedure of Step 3 of Example 173, tert-butyl(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-thiazepane-3-carboxylate (800 mg, 1.88 mmol), trifluoroacetic acid (6 mL) in methylene chloride (15 mL) provide 650 mg (94%) of (3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-thiazepane-3-carboxylic acid; 1H NMR (300 MHz, acetone-d6): δ 1.74 (m, 3H), 1.90 (m, 2H), 2.59 (m, 2H), 2.90 (m, 1H), 3.18 (m, 1H), 3.26 (m, 1H), 3.70 (m, 1H), 4.70 (m, 3H), 7.03 (d, 2H, J=8.7 Hz), 7.77 (d, 2H, J=8.7 Hz); HRMS (C16H19NO5S2)(M+H); calcd. 370.0777, found 370.0765.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][C:22]1([CH3:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([N:25]2[CH2:26][CH2:27][C:22]([CH3:28])([CH3:21])[CH2:23][CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CC1(C)CCNCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CC1(C)CCN(C(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (200 mg, 0.56 mmol) and 4,4-dimethyl piperidine (83 mg, 0.65 mmol). The title compound was obtained as a solid (34 mg, 14% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.97 (2H, s), 7.90 (1H, s), 3.57 (4H, m), 1.33 (4H, m), 0.95 (6H, s). MS m/z: 446.21, 448.23 [M+H]+.