Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:17][C@H:14]([O:15][CH3:16])[C@H:13]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:12]([O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:11]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:40])(=O)=O>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@H:10]1[O:17][C@H:14]([O:15][CH3:16])[C@H:13]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:12]([O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@H:11]1[Cl:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Solvent: c1ccncc1
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](Cl)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of crude methyl 6-O-benzyl-2,3-di-O-benzoyl-α-D-glycopyranoside (compound 66) (from previous step) in 300 mL of pyridine at -40° C. was added sulfuryl chloride (15 mL). After 1 hour, the cooling bath was removed and stirring was continued at room temperature for 3 hours. Dichloromethane was then added and the resulting solution was washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on a silica gel, eluting with dichloromethane, to provide methyl 6-O-benzyl-2,3-di-O-benzoyl-4-chloro-4-deoxy-α-D-galactopyranoside (compound 67) (15.3 g, 90.0% --based on compound 65) as a syrup.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].C(#N)C.Cl[CH:9]([C:15]([C:17]([F:20])([F:19])[F:18])=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(N(CC)CC)C>>[CH3:2][C:1]1[S:3][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([C:17]([F:18])([F:20])[F:19])[N:4]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1sc(C)nc1C(F)(F)F
Temperature: 76 °C

Procedure:
A solution of thioacetamide in acetonitrile (6.66 mol), prepared as in Example 1, is placed in a flask. Ethyl 2-chloro-4,4,4-trifluoroacetoacetate (5.06 mol) is added and an exotherm is observed. Triethylamine (13.64 mol) is added and the mixture is heated to reflux (approx. 76° C.) for one hour. The resulting solution is cooled. Ethyl 2-methyl-4-(trifluoromethyl)-thiazole-5-carboxylate may be isolated by standard means.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][C:32]([CH3:37])([CH3:36])[CH2:31]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH:30]3[CH2:35][CH2:34][O:33][C:32]([CH3:36])([CH3:37])[CH2:31]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: CC1(C)CC(CCCBr)CCO1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCC1CCOC(C)(C)C1

Procedure:
Prepared similarly to Intermediate 223 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(3-bromopropyl)-2,2-dimethyltetrahydro-2H-pyran.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>C(O)(C)C>[O:23]1[CH2:22][CH:21]1[CH2:19][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Reactant: ClCC1CO1
Solvent: CC(C)O
Product: O=c1c(-c2ccccc2)coc2cc(OCC3CO3)ccc12

Procedure:
7-Hydroxy-3-phenylchromone and epichlorohydrin were reacted according to general procedure A, and the product obtained was white prisms, m.p. 151°-152° (83% crude yield) from isopropyl alcohol.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:6]2[CH:20]=1)#[N:2].C(=O)([O-])[O-:22].[K+].[K+].OO>CS(C)=O.O>[C:1]([C:3]1[N:4]=[C:5]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:6]2[CH:20]=1)(=[O:22])[NH2:2]
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(C#N)nc1-2
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)OCCn1cc(C(N)=O)nc1-2
Yield: 75.8 %

Procedure:
Methyl 2-cyano-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (0.46 g, 1.7 mmol) was stirred with potassium carbonate (469 mg, 3.4 mmol), water (1.2 mL) and hydrogen peroxide (408 mg, 6 mmol) in DMSO (7 mL) for 4 hours. The mixture was diluted with 70 mL of water and extracted with ethyl acetate. Ethyl acetate solution was washed with water, 5% Na2S2O3, water, brine, dried over MgSO4 and concentrated under vacuum to give methyl 2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (0.37 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH2:22]O)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>O1CCCC1>[Br:50][CH2:22][C:19]1[N:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[N:17][CH:18]=1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(CO)cn2)cc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(CBr)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.7 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-pyrazin-2-yl)-propionamide (457.1 mg, 1.04 mmol) in tetrahydrofuran (10 mL) was treated with triphenylphosphine (573.5 mg, 2.19 mmol) and carbon tetrabromide (726.2 mg, 2.19 mmol). The reaction solution was stirred at 25° C. for 6 h and then was concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/2 ethyl acetate/hexanes) afforded N-(5-bromomethyl-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (337.2 mg, 65%) as a purple foam: mp 98–103° C. (foam to gel); (ES)+-HRMS m/e calcd for C20H23BrClN3O3S (M+H)+ 500.0405, found 500.0410.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:23])=[C:20]([CH:22]=2)[NH2:21])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:23])=[C:20]([NH:21][S:38]([C:32]3[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=3[F:30])(=[O:40])=[O:39])[CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3ccc(F)cc3F)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 0 °C
Reaction time: 4 h
Yield: 49.8 %

Procedure:
To a solution of 5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline (12 g, 34.4 mmol) in DCM (100 mL) was added pyridine (8.2 g, 103 mmol). The mixture was cooled to 0° C. 2,4-Difluorobenzene-1-sulfonyl chloride (7.32 g, 34.4 mmol) in DCM (30 mL) was added dropwise to the mixture. The reaction was stirred at rt for 4 h. Then the reaction was washed with water (200 mL), and extracted with DCM (2×200 mL). The organic layer was washed with brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:DCM 1:1) to afford the title compound (9.0 g, 49.8% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.63-10.70 (br, 1H), 8.55 (d, J=5.3 Hz, 1H), 7.71-7.82 (m, 1H), 7.50-7.57 (m, 1H), 7.41-7.48 (m, 1H), 7.34-7.40 (m, 1H), 7.24-7.32 m, 1H), 7.15-7.23 (m, 1H), 7.08 (d, J=5.3, 1H), 3.27-3.37 (m, 1H), 1.36 (d, J=6.8 Hz, 6H). MS (ES+): 525 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[C:19]([CH3:27])[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[C:19]([CH3:27])[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COC(=O)c1cc(C)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1

Procedure:
The title compound was prepared in analogous manner as described in example 1e) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and methyl 2-chloro-6-methyl-pyrimidine-4-carboxylate. The reaction was heated to reflux for 16 h. The title compound was obtained as a pale-brown solid in 18% yield.
Reaction SMILES: C(O[CH:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:9]2[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:8]=2[NH:7][C:6]1=[O:24])(=O)C.[I-].[Na+].[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K]>CN(C)C=O>[C:27]1(=[O:37])[N:31]([CH:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:9]3[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:8]=3[NH:7][C:6]2=[O:24])[C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(=O)OC1N=C(c2ccccc2F)c2cccc(Cl)c2NC1=O
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2c(Cl)cccc2C(c2ccccc2F)=NC1N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
A mixture of (3RS)-3-acetoxy-5-(2-fluorophenyl)-9-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one (3.60 g), sodium iodide (15.59 g) and potassium phthalimide (2.89 g) in dimethylformamide (25 ml) was stirred at 100° C. for 1 hour. The reaction mixture was poured into ice-water and the resultant precipitate was collected by filtration. After washing with water several times and dried over phosphorus pentoxide under reduced pressure, the crude powder was subjected to column chromatography on silica gel eluting with a mixture of chloroform and methanol (100:1). The fractions containing the desired product were combined and evaporated in vacuo to give (3RS)-3-phthalimido-5-(2-fluorophenyl)-9-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one (0.82 g, 18.9% yield) as a crystalline powder.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[N:22][C:21]([CH3:24])=[N:20]1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=1>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[N:22][C:21]([CH3:24])=[N:20]2)=[O:11])=[N:27][CH:28]=1
Reactant: Fc1ccc(Br)nc1
Reactant: Cc1ccc(-n2cnc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2cnc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(F)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described in Example A44, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanone and 2-bromo-5-fluoropyridine. ESI-MS (m/z): 423 [M+1]+.
Reaction SMILES: [Na].[C:2]([C:5]1[N:6]=[N:7][NH:8][C:9]=1[SH:10])(=[O:4])[NH2:3].CC(O[CH2:15][C:16]1[CH2:25][S:24][C@@H:19]2[C@H:20]([NH2:23])[C:21](=[O:22])[N:18]2[C:17]=1[C:26]([OH:28])=[O:27])=O>>[NH2:23][CH:20]1[C:21](=[O:22])[N:18]2[C:17]([C:26]([OH:28])=[O:27])=[C:16]([CH2:15][S:10][C:9]3[NH:8][N:7]=[N:6][C:5]=3[C:2](=[O:4])[NH2:3])[CH2:25][S:24][C@H:19]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: NC(=O)c1nn[nH]c1S
Agent: [Na]
Product: NC(=O)c1nn[nH]c1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1

Procedure:
Reaction of 4-carbamoyl-1,2,3-triazole-5-thiol sodium salt and 7-aminocephalosporanic acid as described hereinabove gives the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:11](=[O:13])[CH3:12])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[F:14][CH:15]([F:21])[C:16](OCC)=[O:17].C[O-].[Na+].[O-]CC.[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:11](=[O:13])[CH2:12][C:16](=[O:17])[CH:15]([F:21])[F:14])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C(C)=O)s1
Reactant: CCOC(=O)C(F)F
Agent: CC[O-]
Agent: C[O-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(C(=O)CC(=O)C(F)F)s1
Yield: 85 %

Procedure:
Prepared from 5-Acetyl-thiophene-2-carboxylic acid ethyl ester and ethyl difluoroacetate by the method described in Preparative Example 3. Sodium methoxide was substituted with sodium ethoxide. The product was obtained as a crude oil (5.4 g, 85%). An approx. 5:1 isomer mixture was observed in the NMR spectra of product. 1H NMR (CDCl3) 1.41 (t, J=7.0, 3H), 3.63 (q, J=7.0, 2H), 5.98 (t, minor isomer, J=53.2, 1H), 6.05 (t, major isomer, J=54.0, 1H), 6.45 (s, 1H), 7.74 (d, J=4.0, 1H), 7.80 (d, J=4.0, 1H). 19F NMR −127.8 (minor isomer, J=53.5), −127.1 (major isomer, J=55.5). LC/MS 5.18 min, [M+1]+ 277.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[I-].[K+].[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([OH:42])=[C:28]([CH:41]=1)[CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([O:42][CH2:2][C:3]([N:5]2[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:7][C@H:6]2[CH3:20])=[O:4])=[C:28]([CH:41]=1)[CH2:29][N:30]1[C:31](=[O:40])[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]1=[O:39]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CN1C(=O)c2ccccc2C1=O
Temperature: 70 °C
Yield: 63.3 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.75 g, 2.50 mmol) in dry dimethylformamide (25 mL) was added potassium iodide (0.40 g, 2.39 mmol), 2-(5-chloro-2-hydroxy-benzyl)-isoindole-1,3-dione (0.80 g, 2.76 mmol) and potassium carbonate (0.70 g, 5.10 mmol). The resulting mixture was heated to 70° C. for 23 hours. The reaction was cooled to ambient temperature, diluted with water and extracted with 1:1 diethyl ether/hexanes (3×). The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered and evaporated to give the title compound (0.87 g).
Reaction SMILES: [C:1]([N:11]([CH3:36])[C@H:12]([C:16]([N:18]([CH3:35])[C@H:19]([C:32](O)=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C[N:38]1CCOCC1>C1COCC1.ClC(OCC)=O>[C:1]([N:11]([CH3:36])[C@H:12]([C:16]([N:18]([CH3:35])[C@H:19]([C:32]([NH2:38])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:29])([CH3:31])[CH3:30])[CH:22]=1)=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CN1CCOCC1
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)O)N(C)C(=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of 1.96 g of Z-N-Me-Val-N-Me-Tyr(3-tBu)-OMe in 1,4-dioxane (40 ml), 2 N NaOH (5 ml) was added at room temperature and the mixture was stirred for 2 hours. The reaction mixture was adjusted to pH 3 with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine and the organic layer was dried with sodium sulfate. The solvent was distilled off under reduced pressure to give Z-N-Me-Val-N-Me-Tyr(3-tBu)-OH. To a solution of this Z-N-Me-Val-N-Me-Tyr(3-tBu)-OH in THF (20 ml), ethyl chloroformate (0.40 ml) and NMM (0.46 ml) were added under cooling with ice and the mixture was stirred for 15 minutes. Subsequently, ammonia gas was bubbled into the reaction mixture for 5 minutes. The solvent was distilled off under reduced pressure and the precipitating salt was filtered off and washed with ethyl acetate. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent; n-hexane:ethyl acetate=2:3) to give Z-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 in the amount of 1.17 g (61%).
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([N:23]3[CH2:27][CH2:26][C:25]([NH:29]C(=O)C)([CH3:28])[CH2:24]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:33])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.Cl.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[O:34]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([N:23]3[CH2:27][CH2:26][C:25]([CH3:28])([NH2:29])[CH2:24]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:33])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)NC1(C)CCN(c2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccc(C)cc23)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCC(C)(N)C3)c2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 2.8 %

Procedure:
A mixture of N-{1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-3-methylpyrrolidin-3-yl}acetamide (102 mg, 0.21 mmol) and hydrochloric acid (2 N, 120 mL) was heated with stirring at 100° C. for 16 hours. After being cooled to room temperature, the reaction mixture was adjusted to pH 9 with a saturated aqueous solution of potassium carbonate and exacted with dichloromethane (200 mL×3). The combined organic layers were dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford 2.6 mg of the product (yield was 2.8%). MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.10-8.08 (d, J=7.6 Hz, 1 H), 8.01 (s, 1 H), 7.85-7.83 (d, J=7.6 Hz, 1 H), 7.76-7.71 (m, 2 H), 7.60-7.58 (m, 2 H), 5.92 (s, 1 H), 5.31 (s, 2 H), 4.51 (s, 2 H), 4.22-3.97 (m, 4 H), 3.75-3.73 (d, J=8 Hz, 2 H), 2.47 (s, 3 H), 3.11-3.08 (m, 2 H), 2.47-2.31 (m, 2 H), 1.63 (s, 3 H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([SH:18])[NH: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.Br[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][S:18][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[CH3:28]
Reactant: CCOC(=O)CCCCBr
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 68 %

Procedure:
Part A. To a solution of 4,5-diphenyl-2-imidazolethiol (25.2 g, 0.1 mol) in N,N-dimethylformamide (250 mL) was added, dropwise, a solution of ethyl 5-bromopentanoate (23.73 mL, 31.35 g, 0.15 mol) in N,N-dimethylformamide (80 mL), and the reaction mixture was stirred at reflux under nitrogen for 18 hours. The reaction mixture was cooled, poured into 5% sodium bicarbonate and ice, and then extracted with ethyl acetate. The combined organic extracts were washed sequentially with 5% sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under vacuum. The residue was chromatographed with 7:3 hexane-ethyl acetate, and the resulting solid was recrystallized from acetonitrile and triturated with hexane to give 5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentanoic acid ethyl ester (25.95 g, 0.068 mol) as a white solid, mp 87°-89°. 1H NMR (DMSO-d6) δ 7.55-7.15 (m,11H), 4.0(q,2H,J=8 Hz) , 2.9(t,2H,J= 7 Hz) , 2.3(t,2H,J=7 Hz), 1.9-1.6(m,4H), 1.2(t,3H,J=8 Hz).
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:18]=1[NH:25][NH2:26]>C(O)C.C1(C)C=CC=CC=1>[C:1]([C:3](=[CH:12][NH:26][NH:25][C:18]1[C:17]([Cl:16])=[CH:22][C:21]([Cl:23])=[CH:20][C:19]=1[Cl:24])[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)NC(=O)C(C#N)=CNNc1c(Cl)cc(Cl)cc1Cl

Procedure:
Four grams (18.9 mmol) of α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide is dissolved in hot ethanol/toluene. To this is added, portionwise, 4 g of 2,4,6-trichlorophenylhydrazine. The mixture is heated to reflux for three days. Cooling of the mixture and evaporation of the solvent gives the crude product, which is recrystallized from ethanol (3X) to yield α-cyano-β-(2,4,6-trichlorophenylhydrazino)-N-ethoxycarbonylacrylamide, m.p.=161° (dec.).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:33]=[N:34][C:35]([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([C:47](O)=[O:48])[CH:45]=3)[C:40]([S:50]([CH3:52])=[O:51])=[CH:39]2)=[N:36][CH:37]=1.[CH3:53][C:54]([OH:59])([CH3:58])[CH2:55][NH:56][CH3:57]>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:33]=[N:34][C:35]([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([C:47]([N:56]([CH2:55][C:54]([OH:59])([CH3:58])[CH3:53])[CH3:57])=[O:48])[CH:45]=3)[C:40]([S:50]([CH3:52])=[O:51])=[CH:39]2)=[N:36][CH:37]=1
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Reactant: CNCC(C)(C)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN(CC(C)(C)O)C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4ccccc4F)cn3)c2c1

Procedure:
HATU coupling of 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indole-6-carboxylic acid with 2-methyl-1-(methylamino)propan-2-ol. White solid. Yield: 110 mg
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N+:18]([O-])=O)=[CH:7][CH:6]=1>CO.[Ni]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH2:18])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(Nc2ccncc2[N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CO
Product: COC(=O)Cc1ccc(Nc2ccncc2N)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of 4-chloro-3-nitropyridine (0.500 g, 3.06 mmol) (LANCASTER) and (4-aminophenyl)-acetic acid (0.467 g 3.06 mmol) (Aldrich) in MeOH/dioxane (10 mL, 1/1 v/v) is stirred and refluxed for 6 h. The mixture is allowed to cool to rt and concentrated in vacuo to afford crude [4-(3-nitro-pyridin-4-ylamino)-phenyl]-acetic acid methyl ester. A suspension of the crude ester (0.569 g) and Raney Ni (˜0.140 g) in MeOH (15 mL) is stirred for 21 h at rt, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of Celite and concentrated. Trituration of the residue in CH2Cl2 affords the title compound as a beige solid: ES-MS: 258.0 [M+H]+; single peak at tR=2.54 min (System 1).