Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH3:12])[N:3]=1.CCO.[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19]>C(Cl)Cl.O>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([NH:16][CH2:17][CH:18]([OH:20])[CH3:19])[N:4]([CH2:11][CH3:12])[N:3]=1
Reactant: CCn1nc(Br)c([N+](=O)[O-])c1Br
Reactant: CC(O)CN
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCn1nc(Br)c([N+](=O)[O-])c1NCC(C)O

Procedure:
A mixture of 3,5-dibromo-1-ethyl-4-nitro-1H-pyrazole (3) (20.0 g; 66.9 mmol), EtOH (100 ml) and 1-amino-2-propanol (25.1 g, 334.2 mmol) was refluxed for 15 hours. The reaction medium was concentrated to the maximum under reduced pressure and the excess 1-amino-2-propanol was then distilled off under vacuum. The oil obtained was suspended in DCM (100 ml) and water (100 ml). The aqueous phase was washed with DCM (100 ml). The combined organic phases were washed with water (50 ml) and were then dried over NaSO4. After evaporating off the solvent under reduced pressure, a brown solid was obtained (19.1 g), which was purified by chromatography on silica gel (eluent: EtOAc/hexane). After recrystallization of the solid from an EtOAc/hexane mixture (13 ml/20 ml), the 1-(5-bromo-2-ethyl-4-nitro-2H-pyrazol-3-ylamino)propan-2-ol was obtained in the form of a yellow solid (7.1 g, 36%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[CH:24]=[C:23]([C:34]([F:37])([F:36])[F:35])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH:24]=[C:23]([C:34]([F:36])([F:35])[F:37])[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[N:26]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.5 %

Procedure:
To a cooled and stirred solution of 3′-[4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.47 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an white solid (0.31 g, 63%). MS (ISN) 488.1 [(M−H)−]; mp 165° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Cl[C:16]1[C:25]2[C:20](=[C:21]([C:27]([O:29][CH3:30])=[O:28])[CH:22]=[C:23]([I:26])[CH:24]=2)[N:19]=[CH:18][N:17]=1.O.[OH-].[Na+]>CC#N>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][C:16]2[C:25]3[C:20](=[C:21]([C:27]([O:29][CH3:30])=[O:28])[CH:22]=[C:23]([I:26])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH2:3]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: COC(=O)c1cc(I)cc2c(Cl)ncnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(I)cc2c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)ncnc12
Yield: 14.3 %

Procedure:
Dissolved tert-butyl (35)-3-aminopiperidine-1-carboxylate (632.11 mg; 3.16 mmol; 1.10 eq.) in MeCN (18.00 ml) and TEA (1.00 ml). Added this mixture to methyl 4-chloro-6-iodoquinazoline-8-carboxylate (1000.00 mg; 2.87 mmol; 1.00 eq.). Stirred reaction at room temperature for 45 hours. LCMS indicated M+1=513 present. Diluted reaction with water and 1N NaOH. Filtered the resulting precipitate. Washed with water and dried to give a yellowish solid (210 mg). Carried material on without further purification. LCMS: M+1=513
Reaction SMILES: S([O:7][CH2:8][CH3:9])(OCC)(=O)=O.[CH3:10][N:11]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]1[CH2:17][C:18](O)=[O:19].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:10][N:11]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]1[CH2:17][C:18]([O:7][CH2:8][CH3:9])=[O:19]
Reactant: Cc1cc(CC(=O)O)n(C)c1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1cc(C)cn1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 5.48 ml (0.042 mol) sample of diethyl sulfate was added to a suspension of 6.12 g (0.040) of 1,4-dimethylpyrrole-2-acetic acid and 16.6 g (0.12 mol) of potassium carbonate in 50 ml of DMSO. The mixture was stirred for 6 hours at room temperature. It was poured into water and extracted with ether. The ether extract was washed with brine, dried (MgSO4) and the solvent was evaporated in vacuo. The oily residue was distilled to give 6.0 g of ethyl 1,4-dimethylpyrrole-2-acetate, bp 68° at 0.005 Torr as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8](CC1C=CC(OC)=CC=1)[C:7](=[O:21])[NH:6][C:5]2([CH:24]1[CH2:26][CH2:25]1)[C:22]#[CH:23].FC(F)(F)C(O)=O.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:21])[NH:6][C:5]2([CH:24]1[CH2:26][CH2:25]1)[C:22]#[CH:23]
Reactant: C#CC1(C2CC2)NC(=O)N(Cc2ccc(OC)cc2)c2ccc(Cl)cc21
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CC1(C2CC2)NC(=O)Nc2ccc(Cl)cc21
Yield: 71 %

Procedure:
A solution of 1.4 g (4.11 mmol) of 6-chloro-4-cyclopropyl-4-ethynyl-3,4-dihydro-1-(p-methoxybenzyl)quinazolin-2(1H)-one in 5 mL of CH2Cl2 was treated with 10 mL of trifluoroacetic acid (Aldrich) under N2 overnight at r.t. The reaction was concentrated by rotovap under reduced pressure and the residue partitioned between ethyl acetate and 10% citric acid. The organic layer was washed with water, brine, dried over MgSO4 and the solvents removed to give an oil which was flash chromatographed on SiO2 using 95:5 CHCl3 --CH3OH to give a foam. Trituration of this material with ether gave 720 mg (80%) of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:11]=1.[C:16](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][N:7]([CH3:16])[C:6]=2[CH:11]=1
Reactant: COC(=O)c1cc(Cl)cc2c1OCCN2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc2c1OCCN2C
Temperature: 70 °C
Yield: 72.7 %

Procedure:
To a solution of 9.2 g of methyl 6-chloro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate and 6.7 g of potassium carbonate in 100 ml of dimethylformamide was added 6.4 g of methyl iodide with cooling and stirring. The resulting mixture was heated at 70° C. for 2 hours with stirring. The liquid reaction mixture was added to 200 ml of water, and the resulting insoluble substance was filtered off, washed with water, and dried, thereby obtaining 7.1 g of methyl 6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate. Melting point: 91°-92° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([C@H:29]([NH2:33])[C:30]([OH:32])=[O:31])[CH2:15][C:16]([NH:18][C@H:19]([C:22]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23])[CH2:20][SH:21])=[O:17]>>[N+:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[S:21][CH2:20][C@@H:19]([C:22]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23])[NH:18][C:16](=[O:17])[CH2:15][CH2:14][C@@H:29]([C:30]([OH:32])=[O:31])[NH2:33])([O-:13])=[O:12]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Product: N[C@@H](CCC(=O)N[C@@H](CSc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)NCC(=O)O)C(=O)O

Procedure:
DNP-GS was synthesized from 1-chloro-2,4-dinitrobenzene and GSH by a modification of the enzymatic procedure of Kunst et al., (1989, Biochim. Biophys. Acta 983:123; Li et al., 1995, supra).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]2([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:5]=[C:6]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[C:7]=1I.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[F-].[Cs+].CCOC(C)=O>COCCOC.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.O>[CH2:23]([O:22][C:20]([C:15]1([C:4]2[CH:5]=[C:6]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[C:7]([C:30]3[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=3)=[C:2]([Cl:1])[CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:21])[CH3:24]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C1(c2cc(Cl)c(I)c(OCC(F)(F)F)c2)CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C1(c2cc(Cl)c(-c3ccc(C(F)(F)F)cc3)c(OCC(F)(F)F)c2)CCCC1
Yield: 80.8 %

Procedure:
A mixture of ethyl 1-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (0.58, 1.2 mmol), 4-trifluoromethylphenylboronic acid (0.56 g, 2.4 mmol), CsF (0.46 g, 3.0 mmol) and Pd (PPh3)4 (0.14 g, 0.12 mmol) in 20 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 25 mL of EtOAc and 25 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylate (0.480 g) as a color less oil.
Reaction SMILES: [Si]([O:8][C@H:9]([C:11]1[N:15]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C@@H:23]3[CH2:25][C@H:24]3[C:26]3[N:30]([CH3:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=3)[CH:17]=2)[N:14]=[C:13]([CH3:36])[N:12]=1)[CH3:10])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:36][C:13]1[N:12]=[C:11]([C@@H:9]([OH:8])[CH3:10])[N:15]([C:16]2[CH:17]=[C:18]([C@@H:23]3[CH2:25][C@H:24]3[C:26]3[N:30]([CH3:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=3)[N:19]=[C:20]([CH3:22])[N:21]=2)[N:14]=1
Reactant: Cc1nc([C@@H]2C[C@H]2c2nc3ccccc3n2C)cc(-n2nc(C)nc2[C@H](C)O[Si](C)(C)C(C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1nc([C@@H]2C[C@H]2c2nc3ccccc3n2C)cc(-n2nc(C)nc2[C@H](C)O)n1
Reaction time: 16 h

Procedure:
A solution of 13-1 (2.8 g, 5.6 mmol), acetic acid (0.41 ml, 7.2 mmol) and 1 N tetrabutylammonium fluoride (7.8 mL, 7.8 mmol) in THF (15.6 ml) was stirred at 23° C. for 16 h. Additional 1 N tetrabutylammonium fluoride in THF (4 mL, 4 mmol) was added and stirring was continued for 16 h. The white precipitate that formed was collected by filtration, washed with THF (2×50 mL) followed by ether (2×50 mL). The white solid was dissolved in DCM (100 mL) and washed with saturated aqueous sodium bicarbonate solution (2×100 mL), brine (2×100 mL) and water (2×100 mL) successively. The organic layer was dried over sodium sulfate, filtered, and concentrated to afford a clear oil. The oil was triturated from 5:1 ether/EtOAc and the resulting white solid was collected by filtration and air dried to provide Example 13. 1H NMR (500 MHz, CDCl3) δ 7.77 (s, 1H), 7.71-7.69 (m, 1H), 7.32-7.24 (m, 3H), 6.12 (d, 1H, J=5.4 Hz), 5.19-5.17 (m, 1H), 3.83 (s, 3H), 2.89-2.86 (m, 2H), 2.73 (s, 3H), 2.44 (s, 3H), 2.09-2.00 (m, 2H), 1.73 (d, 3H, J=6.6 Hz); MS: m/z=390.3 (M+H).
Reaction SMILES: C[C@H]1O[C@H]2O[C@H:10]3[C@H:15](O[C@@]2(O)C(=O)C1)[C@@H:14]([NH:17]C)[C@@H:13]([OH:19])[C@@H:12]([NH:20]C)[C@@H:11]3O.[OH:24]C1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O.OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].[O-]S([O-])(=O)=O.[Mg+2].OC(CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1)=O.C([O-])([O-])=O.[Ca+2].N[C@H](C(O)=O)CCO.N[C@H](C(O)=O)[C@@H](C)O.N[C@H](C(O)=O)[C@H](CC)C.N[C@H](C(O)=O)C(C)C>[O-]S([O-])(=O)=O.[Mn+2]>[NH2:17][C@H:14]([C:13]([OH:24])=[O:19])[CH2:15][CH2:10][CH2:11][CH2:12][NH2:20]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Reactant: CN[C@@H]1[C@H](O)[C@H](NC)[C@H]2O[C@@]3(O)C(=O)C[C@@H](C)O[C@H]3O[C@@H]2[C@H]1O
Agent: [Mn+2]
Agent: CC(C)[C@H](N)C(=O)O
Agent: CC[C@H](C)[C@H](N)C(=O)O
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 16 h

Procedure:
Each strain was cultured in NB medium at 30° C. for 16 hours. For the culture of the transformants, spectinomycin was added to NB medium at a concentration of 100 μg/ml. Then, 0.5 ml of the seed culture was inoculated into 5 ml of a production medium (pH 7.2) comprising 100 g/l lactose, 30 g/l (NH4)2SO4, 0.5 g/l KH2PO4, 0.5 g/l K2HPO4, 1 g/l MgSO4 ·7H2O, 10 mg/l FeSO4 ·7H2O, 10 mg/l MnSO4 ·7H2O, 100 μg/l biotin and 30 g/l CaCO3 in a test tube. Homoserine (100 μg/ml) was further added to the production medium for RH6 strain and its transformant, and 100 μg/ml each of threonine, isoleucine and valine were added to the production medium for ATCC 21086 strain and its transformant. Shaking culture was carried out at 30° C. for 72 hours. After the culturing was finished, the amount of L-lysine formed was colorimetrically determined by the acidic copper ninhydrin method [Chinard, J. Biol. Chem., 199, 91 (1952)]. The results are shown in Table 7.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:13]2[C:18]([NH:19][C:20]([CH:22]3[CH2:24][CH2:23]3)=O)=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(O)(=O)C>[CH:22]1([C:20]2[N:12]([C@H:10]3[CH2:11][C@H:8]([NH2:7])[CH2:9]3)[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:18]3[N:19]=2)[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2ncccc2NC(=O)C2CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: N[C@H]1C[C@H](n2c(C3CC3)nc3cccnc32)C1
Temperature: 105 °C
Yield: 53.9 %

Procedure:
Tert-butyl(trans-3-((3-(cyclopropanecarboxamido)pyridin-2-yl)amino)cyclobutyl)carbamate (1.27 g, 3.67 mmol, was dissolved in acetic acid (300 mL) and heated at 105° C. After 4½ hours, trifluoroacetic acid (1 mL) was added and the reaction stirred at 105° C. After heating for an additional 5 hours, the reaction was evaporated to dryness under reduced pressure. The crude product was free based by partitioning between dichloromethane and saturated aqueous sodium bicarbonate. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude was purified using silica chromatography (0-10% methanol in dichloromethane gradient) to give trans-3-(2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)cyclobutanamine (0.579 g, 2.54 mmol, 53.9% yield).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:46])[C@H:14]([CH3:45])[NH:15][C:16](=[O:44])[C@H:17]([CH3:43])[NH:18][C:19](=[O:42])[C@H:20]([CH3:41])[NH:21][C:22](=[O:40])[C@@H:23]([NH:32]C(=O)OC(C)(C)C)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[N:5][CH:4]=1)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:32][C@@H:23]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1)[C:22]([NH:21][C@@H:20]([CH3:41])[C:19]([NH:18][C@@H:17]([CH3:43])[C:16]([NH:15][C@@H:14]([CH3:45])[C:13]([NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1)=[O:46])=[O:44])=[O:42])=[O:40]
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCCCNc1ncc(C=O)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCCCNc1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Following the procedure as described in Example 3, except using material from Example 75 (100.2 mg, 0.129 mmol), CH2Cl2 (2 mL), TFA (2 mL, 26 mmol) and stirring at room temp for 2 h, the title compound (quantitative yield) is isolated as an off white solid, as a TFA salt, that is used directly “as is” in the next coupling step. LC/MS (Condition A): ret. T=1.88 min, (M+H)+ 562.37.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[Cl:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>>[Cl:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: COc1cccc(CN)c1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Product: COc1cccc(CNC(=O)c2ccc(CCl)cc2)c1
Yield: 83.9 %

Procedure:
Using 3-methoxybenzylamine (754 mg, 5.39 mmol) and 4-chloromethylbenzoyl chloride (1.17 g, 6.0 mmol), the procedure of Reference Example 13 was repeated to obtain 1.31 g (83.9%) of the title compound in the form of colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[N:9]([S:12]([C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[C:10]=[O:11]>C(Cl)Cl>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([NH:1][C:10]([NH:9][S:12]([C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[O:11])=[N:7][CH:6]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Nc1ncc(Cl)cn1
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1ncc(Cl)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Amino-5-chloropyrimidine (1.3 g) was suspended in 20 ml of methylene chloride and to this was added with stirring 2.4 g of methyl 2-(isocyanatosulfonyl)-benzoate. After stirring for three hours at ambient temperature, the desired product, 2-{[(5-chloropyrimidin-2-yl)aminocarbonyl]aminosulfonyl}benzoic acid, methyl ester, which had precipitated as a white solid, was filtered off. It melted at 217°-221° and showed peaks in the nuclear magnetic resonance spectrum (trifluoroacetic acid solvent) at 4.0δ (singlet) for OCH3, 9.0δ for H at the 4- and 6-position of the hetero ring and at 7.9δ and 8.2-8.4δ for aromatic H, consistent for the above-named product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([S:15]([CH2:18]CO)(=[O:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].Cl.C(O[C:25](=N)[CH2:26][Br:27])C>C(O)C>[Br:27][CH2:26][C:25]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH3:18])(=[O:16])=[O:17])=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccc(-c2ccccc2S(=O)(=O)CCO)cc1N
Reactant: CCOC(=N)CBr
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1-c1ccc2[nH]c(CBr)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.7 %

Procedure:
A mixture of 2-(3′,4′-diamino-biphenyl-2-sulfonyl)-ethanol (0.140 g, 0.479 mmol) and 2-bromoacetimidic acid ethyl ester hydrochloride salt (0.116 g, 0.575 mmol) in anhydrous ethanol (100%, 6 mL) was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate and brine. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to provide 2-bromomethyl-5-(2-methanesulfonyl-phenyl)-1H-benzoimidazole as yellow oil (0.178 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[C:24]1([CH3:33])[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:33])=[CH:17][CH:16]=1
Reactant: Cc1ccccc1B(O)O
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
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: [I-]
Solvent: COCCOC
Solvent: O
Product: Cc1ccccc1Cc1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 59.4 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(2-methylbenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.075 g; 0.209 mmol), o-tolylboronic acid (0.031 g; 0.215 mmol), tetrakis(triphenylphosphine)palladium(0) (0.013 g; 0.011 mmol), sodium carbonate (0.046 g; 0.432 mmol), sodium iodide (0.065 g; 0.432 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.050 g (57%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14][CH2:13]3)[C:8]2=[O:19])=[C:4]([Cl:22])[CH:3]=1.[H-].[Na+].[CH2:25]1COCC1>>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([C@H:12]3[CH2:13][CH2:14][C@@H:15]([O:18][CH3:25])[CH2:16][CH2:17]3)[C:8]2=[O:19])=[C:4]([Cl:22])[CH:3]=1
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCN1[C@H]1CC[C@@H](O)CC1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CO[C@H]1CC[C@@H](N2CCC(Cc3ccc(Br)cc3Cl)C2=O)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
Dissolve 3-(4-bromo-2-chloro-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one (Example 134) (0.20 g, 0.52 mmol) in THF (10 mL) and cool to 0° C. Add NaH (0.062 g, 1.55 mmol, 60% wt.) and stir the reaction mixture for 1 hour at 0° C. Then add Mel (0.11 g, 0.78 mmol) and continue to stir the reaction mixture overnight until LC-MS shows the starting material has gone. Add water (10 mL) and extract the aqueous layer with EtOAc (3×50 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 20-50% of EtOAc/Hexane) to give 0.17 g (83%) of the title compound as colorless oil: MS (APCI-pos mode) m/z (rel intensity) 400.0 (70), 402.0 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=3)[CH:13]([CH3:23])[CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[NH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1>>[CH2:34]([O:33][C:31](=[O:32])[C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH:13]([CH3:23])[CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:24][CH3:25])(=[O:9])=[O:10])=[CH:15][CH:16]=2)=[O:21])=[CH:37][CH:36]=1)[CH3:35]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CC(C)c2ccc(C(=O)O)cc21
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3C)cc1

Procedure:
1-(5-Chloro-2-methoxy-benzenesulfonyl)-3-methyl-2,3-dihydro-1H-indole-6-carboxylic acid was reacted with ethyl 4-aminobenzoate in analogy to example 62, step 4, yielding 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-3-methyl-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester. White foam, MS (ISP) 529.1 (M+H).