Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:9][C:10]=1[C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)=[O:12])=[O:4]>CO.O1CCOCC1>[NH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[CH:9][C:10]=1[C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1)=[O:12])=[O:4]
Reactant: COc1ccc(-c2cc(C(=O)N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c(NC(N)=O)s2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(-c2cc(C(=O)N[C@H]3CCCNC3)c(NC(N)=O)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
hydrochloride. To a stirred solution of tert-butyl(3S)-3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylate (0.70 g, 1.47 mmol) in anhydrous MeOH (5.0 mL) was added 4.0N HCl in 1,4-dioxane (10 mL). A small amount of precipitate forms shortly and the reaction is stirred for an additional 4 h at room temperature. The solvent was removed under vacuum. The residue was redissolved in methanol and concentrated under vacuum (2×) to yield 0.51 g (85%) of a light yellow solid. 1H NMR (d6-DMSO δ 10.9, s, 1H; δ 9.39, br s, 1H; δ 9.20, br s, 1H; δ 8.37, d, 1H; δ 7.88, s, 1H; δ 7.49, d, 2H; δ 6.96, d, 2H; δ 6.97, br s, 2H; δ 4.24, m, 1H; δ 3.77, s, 3H; δ 3.29, m, 1H; δ 3.11, m, 1H; δ 2.93, m, 2H; δ 1.91, m, 2H; δ 1.68, m, 2H), LC/MS (APCI, ES, M+H=6875).
Reaction SMILES: Cl.C(OCC)(=O)C.[CH2:8]([O:11][C:12](=[O:47])[NH:13][C@@H:14]([C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29](=[O:46])[NH:30][CH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([NH:38]C(OC(C)(C)C)=O)[CH2:34][CH2:33]1)=[O:23])[C:15]([S:18][CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH2:9][CH3:10]>>[CH2:8]([O:11][C:12](=[O:47])[NH:13][C@@H:14]([C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29](=[O:46])[NH:30][CH2:31][C@H:32]1[CH2:33][CH2:34][C@H:35]([NH2:38])[CH2:36][CH2:37]1)=[O:23])[C:15]([S:18][CH:19]([CH3:20])[CH3:21])([CH3:16])[CH3:17])[CH2:9][CH3:10]
Reactant: CCCOC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NC[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)C(C)(C)SC(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCOC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NC[C@H]1CC[C@H](N)CC1)C(C)(C)SC(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,200 ml of a 4N hydrogenchloride-ethyl acetate solution was added to 200 g of [(S)-1-[(S)-2-[(trans-4-t-butoxycarbonylaminocyclohexylmethyl) carbamoyl]-pyrrolidine-1-carbonyl]-2-isopropylthio-2-methylpropyl]carbamic acid propyl ester prepared by the method as disclosed in Example 1 of WO97/05108, followed by stirring at 0° C. for 1 hour. This solution was concentrated by a rotary evaporator, and to the obtained residue, 1,800 ml of diethyl ether was added, followed by stirring at room temperature. Twenty-four hours later, the solid was collected by filtration and dissolved in 1,000 ml of dichloromethane, and a solution having 25 g of potassium hydroxide dissolved in 400 ml of water, was added thereto. The organic layer was separated, and the aqueous layer was extracted twice with dichloromethane. Then, the organic layer was dried over anhydrous magnesium sulfate. A solution obtained by filtration was concentrated by a rotary evaporator and then dried under reduced pressure of about 5 mmHg at room temperature to obtain 164 g of [(S)-1-[(S)-2-[(trans-4-aminocyclohexylmethyl)carbamoyl]pyrrolidine-1-carbonyl]-2-isopropylthio-2-methylpropyl]carbamic acid propyl ester.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=1)#[N:2].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:26]=[C:25]([C:27]#[N:28])[N:24]([C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=3)[N:23]=2)[CH:17]=1>>[C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:35][C:32]2[CH:31]=[CH:30][C:29]([N:24]3[C:25]([C:27]#[N:28])=[CH:26][C:22]([C:18]4[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=4)=[N:23]3)=[CH:34][CH:33]=2)=[O:13])=[CH:9][N:8]=1)#[N:2]
Reactant: N#Cc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Reactant: N#CCCCOc1ccc(C(=O)O)cn1
Product: N#CCCCOc1ccc(C(=O)Nc2ccc(-n3nc(-c4cccnc4)cc3C#N)cc2)cn1
Yield: 63.2 %

Procedure:
6-(3-cyanopropyloxy)nicotinic acid (0.6 mmol) was coupled with 3-(3-pyridyl)-5-cyano-1-(4′-aminophenyl)-pyrazole (0.5 mmol) under standard EDC mediated conditions (Method A). Standard work-up gave the title compound (142 mg, 62%), m.p. 190-191° C. 1H NMR(CDCl3): δ 2.04-2.11 (m, 2H), 2.67-2.70 (7, J=7.1 Hz, 2H), 4.42-4.5 (t, J=6.2 Hz, 2H), 6.98-7.00 (d, J=8.7 Hz, 1H), 7.53-7.56 (m, 1H), 7.82-7.84 (d, J=8.9 Hz, 2H), 8.02-8.04 (d, J=8.9 Hz, 2H), 8.1 (s, 1H), 8.28-8.32 (m, 2H), 8.63-8.64 (m, 1H), 8.82-8.83 (m, 1H), 9.15-9.16 (m, 1H), 10.6 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:7][CH:6]=[C:5]([C:18]#[N:19])[N:4]=1)#[N:2].[C:20](OC)(=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[SH:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:8]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])=[CH:7][CH:6]=[C:5]([C:18]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20](=[O:28])[N:19]=2)[N:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CCc1ccc(C#N)nc1C#N
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCc1ccc(-c2nc(=O)c3ccccc3s2)nc1C#N
Yield: 25.4 %

Procedure:
tert-Butyl 3-(2,6-dicyano-3-pyridyl)propanoate (0.31 g, 1.20 mmol) and methyl thiosalicylate (0.40 g, 2.40 mmol) were dissolved in toluene (30 ml), and triethylamine (0.75 ml, 5.41 mmol) was added thereto. The mixture was refluxed for 18 hrs, and the solvent was evaporated. The residue was washed with hexane-ethyl acetate to give the titled compound (0.12 g, 25%) as white amorphous solid.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[F:6][S:7]([C:10]([F:15])([F:14])[C:11]([OH:13])=[O:12])(=[O:9])=[O:8]>>[F:6][S:7]([C:10]([F:15])([F:14])[C:11]([O:13][Si:2]([CH3:4])([CH3:3])[CH3:1])=[O:12])(=[O:9])=[O:8]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Product: C[Si](C)(C)OC(=O)C(F)(F)S(=O)(=O)F
Temperature: 25 °C
Yield: 75.6 %

Procedure:
Under argon protection and at 0° C., trimethylsilyl chloride (11.5 g, 106 mmol) was added dropwise slowly into 2-(fluorosulphonyl)difluoroacetic acid (5 g, 28 mmol). Then the mixture was stirred over weekend at r.t. Then the solvent was removed to give 5.3 g crude product as a liquid.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([S:1][C:2]2[NH:3][CH:4]=[CH:5][N:6]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Sc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Sc2ncc[nH]2)cc1
Temperature: 0 °C
Yield: 86 %

Procedure:
Acetonitrile (100 ml) suspension of 2-mercaptoimidazole (5.0 g) and 4-chloronitrobenzene (8.7 g), potassium carbonate (8.3 g) was stirred under refluxing for 1 day. The reaction mixture was poured into ice-water. The deposited solid matters were collected by filtration, washed with water and diethyl ether. The thus obtained solids were dried, there was obtained 2-(4-nitrophenylthio)imidazole (9.5 g, yield: 86%) as yellow powdery product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:13]([CH3:22])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].[NH2:23][OH:24]>C(O)C>[OH:24][N:23]=[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:13]([CH3:22])[CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:10][O:11][CH3:12])=[CH:5][CH:4]=1)[NH2:2]
Reactant: NO
Reactant: COCC(c1ccc(C#N)cc1)N(C)CC(=O)OC(C)(C)C
Solvent: CCO
Product: COCC(c1ccc(C(N)=NO)cc1)N(C)CC(=O)OC(C)(C)C
Yield: 92.9 %

Procedure:
A solution of tert-butyl 2-((1-(4-cyanophenyl)-2-methoxyethyl)(methyl)amino)acetate (0.136 g; 0.45 mmol) and 50% aqueous hydroxylamine (0.137 mL; 2.24 mmol) in ethanol (2 mL) was heated at 80° C. for 18 hours. The solvent was evaporated in vacuo. The residue was partitioned between DCM and water. The organic phase was poured through a hydrophobic frit and evaporated in vacuo to afford the title compound (0.141 g, 93%). 1H NMR (CDCl3, 400 MHz) δ 7.78 (d, J=8.4 Hz, 2H), 7.59-7.57 (m, 2H), 6.70 (br s, 1H), 4.84 (br s, 2H), 4.05-4.02 (m, 1H), 3.71-3.67 (m, 1H), 3.63-3.60 (m, 1H), 3.40-3.35 (m, 1H), 3.34 (s, 3H), 3.21-3.16 (m, 1H), 2.40 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:5](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[N:6][CH:7]=[CH:8][C:9]=1[Cl:10].C(N(CC)CC)C>O1CCOCC1>[Cl:10][C:9]1[C:4]2[CH2:3][CH2:2][NH:1][CH:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:5]=2[N:6]=[CH:7][CH:8]=1
Reactant: COC(=O)/C=C/c1nccc(Cl)c1CCN
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)CC1NCCc2c(Cl)ccnc21
Yield: 85.9 %

Procedure:
94-5. A yellow solution of (E)-methyl 3-(3-(2-aminoethyl)-4-chloropyridin-2-yl)acrylate (530 mg, 1.49 mmol) and triethylamine (1.04 mL, 7.47 mmol) in dioxane (10 mL) was stirred at 50° C. for 1 h. The solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera One, eluent: gradient from 2% MeOH in DCM to 20% MeOH in DCM in 14 min) to yield the title compound as a clear oil (308 mg). UPLC-MS: MS 241.1 (M+H+); UPLC rt 0.43 min.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C>[N:3]1[CH:8]=[CH:7][C:6]([N:9]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:21][CH:22]=2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N(c1ccncc1)c1ccc(O)cc1
Reactant: CCOC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCOc1ccc(N(C(=O)OC(C)(C)C)c2ccncc2)cc1
Reaction time: 0.08 h

Procedure:
Sodium hydride (50% w/w dispersion in mineral oil, 55 mg) was added under argon to a stirred solution of the product from step (iii) above (300 mg) in dry DMF (5 ml). After five minutes, ethyl 6-bromohexanoate (0.20 ml) was added and the mixture stirred for 16 hours. The DMF was evaporated in vacuo and the residue partitioned between dichloromethane and water. The aqueous phase was extracted with further dichloromethane. The combined organic extracts were washed with water then dried, and evaporated. The residue was purified by chromatography on alumina, eluting with dichloromethane and then 1% v/v methanol/dichloromethane. Evaporation of the appropriate fractions gave ethyl 6-[4-[N-(4-pyridyl)-N-tertiarybutyloxycarbonylamino]phenoxy]hexanoate, 260 mg, as a yellow gum: NMR (CDCl3) δ8.40 (2H, dd), 7.16 (2H, dd), 7.07 (2H, m), 6.90 (2H, m), 4.13 (2H, q), 3.98 (2H, t), 2.34 (2H, t), 1.78 (4H, m), 1.57 (2H, m), 1.44 (9H, s), 1.26 (3H, t); m/e 429 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
Di-t-butyl dicarbonate (595.14 g, 2.73 mol, 1.05 eq) was slowly added to a solution of piperidin-3-ylmethanol (300.0 g, 2.60 mol, 1 eq), sodium hydroxide (124.8 g, 3.12 mol, 1.2 eq), DCM (1.5 L) and water (800 mL) while maintaining the internal temperature below 10° C. with an ice-water bath. The reaction was warmed to room temperature and stirred for 24 h. The mixture was filtered and sodium bisulfate was added until the solution was acidic (pH 3). The phases were separated, and the organic phase was washed with water (600 mL) and brine (600 mL). The solution was dried over sodium sulfate, and the solvent removed under vacuum to afford t-butyl 3-(hydroxymethyl)piperidine-1-carboxylate as a colorless oil. Crude t-butyl 3-(hydroxymethyl)piperidine-1-carboxylate was dissolved in DCM (1.5 L), Et3N (315.71 g, 3.12 mol, 1.2 eq) was added, and the reaction vessel was flushed with nitrogen. The reaction mixture was cooled to below 0° C. in a dry ice/isopropyl alcohol bath and methanesulfonyl chloride (357.4 g, 3.12 mol, 1.2 eq) was slowly added. After the addition was complete, the reaction was warmed to ambient temperature and stirred for 24 h. The reaction mixture was filtered, washed with water (500 mL) and saturated sodium bicarbonate (500 mL), and dried over sodium sulfate. The solvent was removed under vacuum, and the yellow oil was added to hexane (2.5 L) and stirred for 3 h. The precipitate was filtered and washed with hexane (700 mL) to afford title compound as a white solid (609.11 g, 2.08 mol, 80%).
Reaction SMILES: [O:1]=[C:2]1[CH:9]2[CH2:10][C:5]3([C:12](O)=[O:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][NH2:26])[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:24][O:23][C:21]1[CH:20]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[CH:22]=1)[CH2:25][NH:26][C:12]([C:5]12[CH2:4][CH:3]3[CH2:11][CH:7]([CH2:8][CH:9]([C:2]3=[O:1])[CH2:10]1)[CH2:6]2)=[O:13]
Reactant: COc1cc(CN)cc(OC)c1
Reactant: O=C1C2CC3CC1CC(C(=O)O)(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CNC(=O)C23CC4CC(C2)C(=O)C(C4)C3)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
4-oxoadamantane-1-carboxylic acid (200 mg, 1.03 mol), (3,5-dimethoxyphenyl)methanamine (172 mg, 1.03 mmol), EDCI (410 mg, 2.06 mmol), and HOBt (280 mg, 2.06 mmol) were dissolved in dry CH2Cl2. DIEA (1.3 g, 10 mmol) was added under nitrogen at 0° C. and the mixture was stirred overnight at rt. The mixture was washed with water and brine. The organic layer was dried and concentrated to give crude product which was purified by preparative TLC to give N-(3,5-dimethoxybenzyl)-4-oxoadamantane-1-carboxamide (231 mg, 65%). 1H NMR: (400 MHz, CDCl3): δ=1.62 (s, 4H) 1.95-2.25 (m, 13H), 2.59 (s, 2H), 3.78 (s, 3H), 3.83 (s, 3H), 4.35 (d, 2H), 6.05 (s, 1H), 6.44 (m, 2H), 7.15 (d, 1H).
Reaction SMILES: [Na+].[Cl:2][C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][C:6]([NH:11][CH2:12][C:13]([O-])=[O:14])=[C:5]([N+:16]([O-])=O)[CH:4]=1.O.O.[Sn](Cl)Cl>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:11][CH2:12][C:13](=[O:14])[NH:16]2)=[CH:7][C:8]=1[CH2:9][CH3:10]
Reactant: CCc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1cc2c(cc1Cl)NC(=O)CN2
Temperature: 25 °C

Procedure:
A suspension of N-(4'-Chloro-5'-ethyl-2'-nitrophenyl)glycine sodium salt (0.082 g, 0.31 mmol) and tin (II) chloride dihydrate (0.215 g, 0.953 mmol) in ethanol (1.0 mL) was refluxed for 45 min. It was then cooled to room temperature and the precipitated solid was filtered, washed with ethanol (1.0 mL), and dried under vacuum to yield 0.048 g (72%) pure (1H NMR) title compound as a light yellow powder; 1H NMR (DMSO-d6) δ 1.05 (t, 3H, J=7.2 Hz), 2.52 (d, 2, J=7.2), 3.67 (s, 2H), 6.04 (s, 1H), 6.54 (s, 1H), 6.67 (s, 1H), 10.25 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:11]([NH:18][C:8]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[CH3:7])=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: NCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
A solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid (3.00 g, 13.51 mmol) in methylene chloride (20 mL) was added benzyl amine (1.60 mL, 14.86 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (6.57 g, 14.86 mmol) and N,N-diisopropylethylamine (4.71 mL, 27.02 mmol) and the mixture was stirred under nitrogen at room temperature for 16 hr. The reaction mixture was diluted with methylene chloride (100 mL), and washed with water (100 mL) and brine (2×100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash-chromatography (eluent hexanes-ethyl acetate, 1:1) to provide 2-bromo-4-methyl-thiazole-5-carboxylic acid benzyl amide as a yellow solid (3.50 g, 83% yield). MS (M+H)+=312; Rt=1.31 min.
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][CH:16]=O)[CH:13]=2)[N:8]([CH3:18])[CH:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][N:25]=C(S(C)(=O)=O)[N:23]=1.[OH-].[Na+]>C1COCC1.CN(C=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][N:25]=[C:16]([NH:15][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH3:18])[CH:7]=[C:6]3[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[N:23]=1
Reactant: CC(C)C(=O)c1cn(C)c2ccc(NC=O)cc12
Reactant: CS(=O)(=O)c1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)C(=O)c1cn(C)c2ccc(Nc3nccc(Cl)n3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a solution of N-(3-isobutyryl-1-methyl-1H-indol-5-yl)formamide (450 mg, 1.84 mmol) in anhydrous THF (3 mL) and anhydrous DMF (3 mL) was added 60% NaH (228 mg, 5.52 mmol) at 0° C. After being stirred for 30 min at room temperature, it was cooled to 0° C. To this, was added 4-chloro-2-(methylsulfonyl)pyrimidine (466 mg, 2.43 mmol) and then stirred for 2 hours. Quenching the reaction by addition of ice and 2N solution of sodium hydroxide (2 mL) resulted precipitation of brown solids. Additional 20 mL of water was added to complete of solid formation. The resulted solids were collected by filtration, rinsed with water and the dried in vacuo to provide the desired intermediate 5 as a brown solid (542 mg, 89%); MS (ESI) m/z 329 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].Cl[C:18]1[C:23]([Cl:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1>CC#N>[Cl:24][C:23]1[C:18]([O:10][C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[NH:1][CH:2]=[CH:3][C:4]=23)=[N:19][CH:20]=[C:21]([N+:25]([O-:27])=[O:26])[CH:22]=1
Reactant: Oc1ccnc2[nH]ccc12
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(Oc2ccnc3[nH]ccc23)c(Cl)c1
Reaction time: 0.17 h
Yield: 54.1 %

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridin-4-ol (210 mg, 1.56 mmol, see: Thibault, C. et al. Org. Lett. 2003, 5, 5023) in 3 mL of MeCN was added K2CO3 (240 mg, 1.74 mmol). The suspension was stirred for 10 min and treated with 2,3-dichloro-5-nitropyridine (270 mg, 1.40 mmol, see: Koch, V. and Schnatterer, S. Synthesis, 1990, 499). The reaction mixture was stirred for 12 h and quenched with 20 mL of H2O. The solution was extracted with EtOAc and the organic layer was washed with brine, and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash column chromatography (ISCO RediSep® silica gel cartridge) to give the title compound (220 mg, 54%). MS (ESI) m/z 291.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26]([OH:28])=O)[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:29]1([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)[CH2:31][CH2:30]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:25][C:26]([N:32]([CH:29]2[CH2:31][CH2:30]2)[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)=[O:28])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cccc(CNC2CC2)c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Product: COc1cccc(CN(C(=O)CN(c2ccc3ncccc3c2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with cyclopropyl-(3-methoxy-benzyl)-amine
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH2:8]([O:15][C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCC(=O)O1
Solvent: Cc1ccccc1
Product: O=C(O)CCC(=O)OCc1ccccc1

Procedure:
A solution of succinic anhydride (16.0 g, 160 mmol) and benzyl alcohol (17.1 g, 158 mmol) in toluene (200 mL) was heated at reflux for 3.5 hr. At this time, the solvent was removed in vacuo to leave 3-(benzyloxycarbonyl)propanoic acid as a white solid.
Reaction SMILES: C(C([NH:7][C@H:8]([C:15]([NH:17][C@@H:18]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C@@H:19]([OH:33])[CH2:20][C@@H:21]([C:29]([OH:32])([CH3:31])[CH3:30])[C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])=[O:16])[CH2:9][C:10]1[N:11]=[CH:12][S:13][CH:14]=1)=O)(C)(C)C.Cl.[CH2:42]([C@H:49]([CH2:53][C:54]([N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1)=[O:55])[C:50]([OH:52])=O)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1>[CH2:42]([C@H:49]([CH2:53][C:54]([N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1)=[O:55])[C:50]([NH:7][C@H:8]([C:15]([NH:17][C@@H:18]([CH2:34][CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[C@@H:19]([OH:33])[CH2:20][C@@H:21]([C:29]([OH:32])([CH3:30])[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])=[O:16])[CH2:9][C:10]1[N:11]=[CH:12][S:13][CH:14]=1)=[O:52])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)C(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A mixture of 200.7 mg (0.336 mmole) of (2S, 4S, 5S)-5-[N-(t-butylcarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-butylhexanamide in 6 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes under an atmosphere of nitrogen. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and then benzene was added to the residue. The solvent was removed by distillation under reduced pressure from the resulting solution. The same operation was repeated, in total, three times, and the residue was then dried by evaporation under reduced pressure for 8 hours. The dried material was then suspended in 10 ml of anhydrous tetrahydrofuran, and 98.2 mg (0.354 mmole) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid were added to the suspension. 0.06 ml (0.396 mmole) of 95% diethyl cyanophosphate and 0.2 ml (0.143 mmole) of triethylamine were then added to the resulting mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 8 hours, after which the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), followed by recrystallization from a mixture of ethyl acetate and diisopropyl ether, to give 229.8 mg of the title compound as white crystals, melting at 92°-95° C.