Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:3]=1[C:4]#[N:5].CCOC(C)=O.[NH4+:17].[OH-]>C1COCC1>[NH2:17][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:3]=1[C:4]#[N:5]
Reactant: [NH4+]
Reactant: N#Cc1c(Br)ccnc1Br
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1c(Br)ccnc1N
Temperature: 100 °C
Yield: 26.8 %

Procedure:
A mixture of compound D7 (32 g, 122.2 mmol) in NH4OH (200 ml, 30% in water) and THF (200 ml) was heated at 100° C. for 12 h. in a PARR pressure vessel. After cooling, EtOAc was added. The organic layer was separated, washed with brine, dried (Na2SO4) and evaporated in vacuo. The solid residue thus obtained was triturated with DCM and then filtered off. The filtrate was evaporated in vacuo to yield compound D8 (6.5 g, 26.8%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].[C:12](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:12][NH:5][C:4]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(OC)c(N)c1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CNc1cc(OC)ccc1OC
Temperature: 40 °C
Reaction time: 72 h
Yield: 30.5 %

Procedure:
To a 100 ml three neck round bottom flask was added 2,5-dimethoxyaniline (1.53 g), anhydrous potassium carbonate (1.66 g), acetonitrile (25 ml) and iodomethane (1.42 g). The reaction mixture was stirred at 40° C. for 3 days under nitrogen in the dark. The reaction mixture was quenched with ethyl acetate (50 ml) and filtered. The residue was washed with ethyl acetate (3×20 ml) The filtrate and the washings were combined and washed with water (3×30 ml). The organic layer was filtered through MgSO4 and evaporated under reduced pressure. The residue was dissolved in a minimum amount of ethyl acetate/hexane 1:8. The solution was placed on a wet column of silica gel (80 g) and eluted with ethyl acetate/hexane: 300 ml (1:8), 500 ml (1:5) to afford 0.51 g of N-methyl-2,5-dimethoxyaniline. To a 50 ml three neck round bottom flask with compound 117 (0.32 g, 1.61 mmol), N-methyl-2,5-dimethoxyaniline (0.40 g) and anhydrous potassium carbonate (0.27 g) was added anhydrous DMSO (3 ml) and the reaction mixture stirred at 45° C. for 8 h under nitrogen in the dark. Distilled water (10 ml) was added to precipitate the product and the suspension stirred for 2 h and then cooled to 5° C. and filtered. The solid was washed with cold water (2×2 ml) suspended in MeOH (200 ml). Silica gel (1 g) was added and the suspension sonicated and then heated to 50° C. for 15 min. The suspension was then evaporated under reduced pressure and dried in vacuo at room temperature for 10 h. The residue was powdered and poured on top of a wet column of silica gel (40 g) and eluted with 5% of MeOH in CHCl3. Fractions corresponding the product spot (TLC) were pooled and evaporated. The residue was washed with ether and air dried to afford 0.15 g (28%) of compound 434 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[NH2:16][C:17]1[NH:21][N:20]=[CH:19][C:18]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(OCC)(=O)C>CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([OH:12])[N:21]3[N:20]=[CH:19][C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]3[N:16]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn[nH]c1N
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1cnn2c(O)cc(-c3ccc(Cl)cc3)nc12
Temperature: 160 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
A mixture of ethyl 3-(4-chloro-phenyl)-3-oxo-propionate (18.1 g, 0.080 mol) and ethyl 5-amino-1H-pyrazole-4-carboxylate (13.7 g, 0.088 mol) was stirred at for 3 h 160° C. Ethyl acetate (40 mL) and hexane (40 mL) were successively added to the cooled mixture and stirring was continued at 0° C. for 0.5 h. The crystals were isolated by filtration and triturated for 1.2 h with 0.2 N HCl (80 mL). The solid was filtered off, washed with water and dried to give ethyl 5-(4-chloro-phenyl)-7-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylate (13.3 g, 52%). White solid. MS (ISN) 316.3 [(M−H)−]; mp 190-192° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]=[C:5]2[CH:13]1[CH2:15][CH2:14]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1>CN(C=O)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:32][C:31]1[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)[C:7](=[O:12])[N:6]=[C:5]2[CH:13]1[CH2:15][CH2:14]1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1nc(C2CC2)c2cc(Cl)ccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1ccc(Cn2c(=O)nc(C3CC3)c3cc(Cl)ccc32)cc1
Reaction time: 8 h
Yield: 51.3 %

Procedure:
To a 0° C. solution of 9.0 g (0.04 1 mol) of 6-chloro-4-cyclopropylquinazolin-2(1H)-one in 150 mL of dry DMF (Aldrich Sure-Seal) under Ar was added 42.5 mL of a 1.0M solution of lithium bis(trimethylsilyl)amide in hexane dropwise. After the addition, 8.14 mL (0.06 mol) of p-methoxybenzyl chloride (Aldrich) was added in one portion, and the flask immersed in an oil bath maintained at 55°-60° C. The reaction was heated for 12.5 h, then allowed to stand at room temperature overnight. The solvents were removed by rotovap at reduced pressure and the residue partitioned between CHCl3 and cold 1M citric acid. The aqueous layer was extracted with CHCl3 and the combined organic layers washed with 10% Na2CO3, dried over MgSO4. After removal of the solvents by rotovap at reduced pressure, the residue was triturated with ether to give 10.5 g (75%) of the title compound as a light yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].C(O)(=[O:17])C>[O-2].[O-2].[O-2].[Cr+6]>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[C:10](=[O:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc2c(cc1Br)CCC2
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Product: CC(=O)Nc1cc2c(cc1Br)C(=O)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 5-acetylamino-6-bromoindane (43.0 g, 0.17 mol) in glacial acetic acid (400 mL) at 50°-55° C. was added dropwise a solution of chromium trioxide (70.0 g, 0,7 mol) in 50% aqueous acetic acid (400 mL) over a period of 30 min. After further stirring for 15 min, the mixture was cooled to 0° C. and quenched with 2-propanol (100 mL). Solvent was removed in vacuo. The residue was diluted with water (1 L) and extracted with ethyl acetate (2×500 mL). The combined ethyl acetate layer was washed with 0.5M aqueous NaOH (1 L), brine, dried over anhydrous MgSO4 and concentrated to give 36 g (80%) of the title compound as a light brown solid which was contaminated with about 10% of 5-bromo-6-acetylamino- 1-indanone. 1H NMR (CDCl3): δ8.60 (1H, s), 7.98 (1H, s), 7.90 (1H, s), 3.10 (2H, t), 2.70 (2H, t), 2.30 (3H, s).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])[C:16]([CH3:19])([CH3:18])[S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:36]([O:38][CH2:39][C:40]([Cl:43])([Cl:42])[Cl:41])=[O:37]>C(Cl)Cl>[O:1]([CH2:8][C:9]([N:11]([CH:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:21])[C:16]([CH3:18])([CH3:19])[S:17][C@H:13]12)[C:36]([O:38][CH2:39][C:40]([Cl:43])([Cl:42])[Cl:41])=[O:37])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)S[C@@H]2C(N(C(=O)COc3ccccc3)C(=O)OCC(Cl)(Cl)Cl)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 72 %

Procedure:
A mixture of 4.855 gms. (10 mmol.) of p-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate, 16.94 gms. (80 mmol.) of 2,2,2-trichloroethyl chloroformate, 18 ml. of N,O-(bis-trimethylsilyl)trifluoromethylacetamide, and 20ml. of methylene chloride was prepared. The mixture was permitted to stand at room temperature overnight. The mixture then was heated at reflux for 7 hours after which it was again permitted to stand at room temperature overnight. Heating then was continued for an additional 6 hours. The mixture then was evaporated to a residue, and the residue was dissolved in benzene which then was added to a large excess of heptane. The resulting insoluble material was filtered off, dissolved in benzene, and chromatographed over silica gel using a benzene-ethyl acetate elution gradient. p-Nitrobenzyl 6-[N-(phenoxyacetyl)-N-(2,2,2-trichloroethoxycarbonyl)amino]-2,2-dimethylpenam-3-carboxylate (4.76 gms.; 72 percent) was obtained as product.
Reaction SMILES: [NH2:1][C:2]([C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]([OH:22])=[C:9]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:12])[N:10]=1)([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35]>C(Cl)(Cl)Cl>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:11]([C:9]2[N:10]=[C:5]([C:2]([NH:1][C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35])([CH3:4])[CH3:3])[N:6]([CH3:24])[C:7](=[O:23])[C:8]=2[OH:22])=[O:12])=[CH:20][CH:19]=1
Reactant: Cn1c(C(C)(C)N)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Reactant: COC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C(=O)NC(C)(C)c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred mixture of 2-(1-amino-1-methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (4) and triethyl amine (3 eq) in chloroform, methyl chlorooxoacetate (1.5 eq) was added with an external cooling. Finished the addition, the ice bath was removed and the mixture was stirred at room temperature for 3 h. Reaction mixture was then partitioned between chloroform and 1N HCl. Organic layer was separated, washed with brine, dried (Na2SO4), filtered and concentrated to obtain title product.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][S:15]([O-:18])(=O)=[O:16].[K+].P(Cl)(Cl)(Cl)(Cl)[Cl:21]>ClCCl>[Cl:21][S:15]([CH2:14][CH2:13][CH2:12][N:3]1[C:2](=[O:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]1=[O:11])(=[O:18])=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1CCCS(=O)(=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [K+]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCS(=O)(=O)Cl
Reaction time: 8 h
Yield: 34.8 %

Procedure:
Adapting a procedure according to Shue et al., Bioorg. Med. Chem. 1996, 6, 1709-1714, a 250 mL round-bottomed flask equipped with a magnetic stirring bar and a reflux condenser was charged under an atmosphere of nitrogen with 5.4 g (20 mmol) of potassium 3-(1,3-dioxobenzo[c]azolin-2-yl)propanesulfonic acid (10a), 150 mL of anhydrous dichloromethane (DCM), and 4.6 g (22 mmol) of phosphorus pentachloride (PCl5). The reaction mixture was heated to reflux. After reacting overnight, the reaction mixture was quenched with water and the phases were separated. The aqueous phase was extracted with dichloromethane (DCM). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate (MgSO4), filtered, and the solvents removed under reduced pressure using a rotary evaporator. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 2.0 g (35% yield) of the title compound (10) as a off-white to beige solid. 1H NMR (400 MHz, CDCl3): δ=2.42-2.49 (m, 2H), 3.75-3.79 (m, 2H), 3.91 (t, J=6.4 Hz, 2H), 7.75-7.77 (m, 2H), 7.87-7.89 (m, 2H) ppm. MS (ESI) m/z 287.99 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=O)[CH:12]3[CH:10]([CH2:11]3)[C:9]2=O)[CH:5]=[CH:6][CH:7]=1.CO.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH:10]3[CH:12]([CH2:11]3)[CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2CC2C(=O)N1c1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Brc1cccc(N2CC3CC3C2)c1
Temperature: 50 °C
Yield: 95.3 %

Procedure:
3-(3-Bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione (4.25 g, 16.0 mmol) was suspended in 80 mL of THF. Borane dimethyl sulfide complex (14.2 mL of a 10.1 M solution) was added and the reaction was heated at 50° C. for 1 h. The reaction was cooled in an ice bath. Methanol (65 mL) was slowly added, followed by 150 mL of water. This mixture was extracted with EtOAc (2×) and the combined organics were dried over MgSO4 and concentrated. The residue was taken up in dichloromethane and the resulting suspension was filtered. The filtrate was concentrated and the residue was purified by SiO2 chromatography using a gradient of 0% to 20% ethyl acetate/heptane to afford 3.63 g (95%) of 3-(3-bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][CH2:5][CH2:6][CH:7]1[CH2:13][N:12]([CH3:14])[C:11](=[O:15])[C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[O:8]1>C(O)C>[ClH:4].[CH3:1][N:2]([CH3:3])[CH2:5][CH2:6][CH:7]1[CH2:13][N:12]([CH3:14])[C:11](=[O:15])[C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[O:8]1
Reactant: CN1CC(CCCl)Oc2ccccc2C1=O
Reactant: CNC
Solvent: CCO
Product: CN(C)CCC1CN(C)C(=O)c2ccccc2O1
Product: Cl
Temperature: 100 °C

Procedure:
A solution of 9 g (0.2 mole) of dimethylamine in 250 ml of ethanol was added to 24 g (0.1 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)one in a steel bomb. The mixture was heated at 100° C. for 18 hrs. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate and dilute sodium hydroxide. The ethyl acetate layer was concentrated and the residue comprised substantially of the free base of the title compound was dissolved in methyl isobutyl ketoneisopropanol mixture. The solution was acidified with hydrogen chloride gas to give the title compound, m.p. 188°-197° C.
Reaction SMILES: [CH2:1]([CH:8]([CH2:12]C(C)(C)C)[C:9]([OH:11])=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[O:18][S:19]([O-:21])=O.[K+].[OH2:23]>CO>[CH2:1]([CH:8]([CH2:12][S:19]([C:2]([CH3:7])([CH3:3])[CH3:1])(=[O:21])=[O:18])[C:9]([OH:11])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC(Cc1ccccc1)C(O)=S
Reactant: O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: CC(C)(C)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
280 mg of 2-benzyl-3-tert.-butylthio-propionic acid was dissolved in 5 ml of methanol and, while cooling with ice, 1 g of oxone in 4 ml of water was added and the whole was stirred overnight at room temperature. The solution was diluted with water and extracted with methylene chloride, and the extracts were dried and concentrated by evaporation (260 mg, 82% yield) 1H NMR: 300 MHz spectrum consistent with proposed structure. Anal. calcd. for C14H20O4S: C, 59.13; H, 7.09. Found: C, 59.39; H, 7.08.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:20]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[F:12])=[O:21])[CH:10]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C=Nc1ccccc1F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1F)Nc1cc(Cl)ccc1C(=O)O

Procedure:
2-Amino-4-chlorobenzoic acid (0.3 g), 2-fluorophenylisocyanate (0.2 ml) and triethylamine (0.24 ml) were stirred in toluene (20 ml) for a week. More 2-fluorophenylisocyanate (0.1 ml) was added and stirring continued for another week. The mixture was concentrated to almost dry, water was added and the pH was adjusted to 1 with diluted HCl. Water was decanted and the residue was dissolved in warm 96% EtOH. The pH was adjusted to 1 again with 4N HCl resulting in the precipitation of a solid, which was filtered and dried to give 4-chloro-2-[3-(2-fluoro-phenyl)-ureido]-benzoic acid (0.25 mg). Mp.=195-197° C. 4-Chloro-2-[3-(3-trifluromethyl-phenyl)-ureido]-benzenesulfonamide (Compound 10):
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17](OC2CCCCC2)=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[Cl:25])[C:2]1C=CC=CC=1.C(Cl)(=O)C([Cl:29])=O.CN(C=O)C.[NH2:37][C:38]1[CH:50]=[CH:49][C:41]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[C:40]([O:51][CH3:52])[CH:39]=1>C(Cl)Cl>[Cl:29][C:17]1[CH:16]=[C:12]([CH:11]=[C:10]([Cl:25])[C:9]=1[O:8][CH2:1][CH3:2])[C:13]([NH:37][C:38]1[CH:50]=[CH:49][C:41]([C:42]([O:44][C:45]([CH3:47])([CH3:48])[CH3:46])=[O:43])=[C:40]([O:51][CH3:52])[CH:39]=1)=[O:15]
Reactant: O=C(O)c1cc(Cl)c(OCc2ccccc2)c(OC2CCCCC2)c1
Reactant: COc1cc(N)ccc1C(=O)OC(C)(C)C
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1c(Cl)cc(C(=O)Nc2ccc(C(=O)OC(C)(C)C)c(OC)c2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
3,5-Dichloro-4-ethoxybenzoic acid (4) (75 mg, 0.32 mmol) in DCM (5 mL) was treated with oxalyl chloride (56 μL, 0.64 mmol) dropwise, followed by a drop of DMF. The reaction mixture was stirred at RT for 1 h, and then the solvent was removed in vacuo. The residue was dissolved in DCM (5 mL) and TEA (133 μL, 957 μmol) was added. The mixture was added to tert-butyl 4-amino-2-methoxybenzoate (3) (71 mg, 0.32 mmol) and stirred at RT for 16 h. The mixture was sequentially washed with sat. aq. NaHCO3 (5 mL) and 1 M HCl (5 mL), and the organic phase was concentrated in vacuo. The residue was purified by silica gel chromatography (12 g, 0-100% EtOAc in isohexane) to afford tert-butyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-methoxybenzoate (5) (59 mg, 42%) as a white solid: m/z 384 [M−tBu+2H]+ (ES+); 1H-NMR (400 MHz, DMSO-d6) δ: 10.51 (1H, s), 8.09 (2H, s), 7.63 (1H, d), 7.60 (1H, d), 7.43 (1H, dd), 4.15 (2H, q), 3.81 (3H, s), 1.51 (9H, s), 1.41 (3H, t).
Reaction SMILES: C(OC([N:6]=[C:7]=S)=O)C.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=1)=[O:12].Cl.ON.C([N:26](C(C)C)CC)(C)C>C(O)C.CO.O1CCOCC1>[NH2:26][C:7]1[N:19]=[C:15]2[CH:14]=[C:13]([C:11]([O:10][CH3:9])=[O:12])[CH:18]=[CH:17][N:16]2[N:6]=1
Reactant: COC(=O)c1ccnc(N)c1
Reactant: CCOC(=O)N=C=S
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CO
Solvent: C1COCCO1
Solvent: CCO
Product: COC(=O)c1ccn2nc(N)nc2c1
Reaction time: 1.5 h

Procedure:
Ethoxycarbonyl isothiocyanate (9.0 g) was added to a 1,4-dioxane (100 ml) suspension of 2-aminopyridine-4-carboxylic acid methyl ester (10 g) at an internal temperature of 19° C. to 23° C. over 20 minutes. The obtained mixture was stirred for 90 minutes at the same temperature as described above, and was then concentrated under reduced pressure to obtain a crude product. The obtained crude product was added to a mixed suspension of methanol (70 ml) and ethanol (70 ml) containing hydroxyamine hydrochloride (22.8 g) and diisopropylethylamine (34 ml), and thereafter, the reaction solution was stirred at room temperature for 67 hours, at 60° C. for 5 hours, and again, at room temperature for 20 hours. Thereafter, the generated solid was collected, and it was washed with ethanol (30 ml) and was then dried, so as to obtain the title compound (11.3 g) in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:20]([OH:22])=O)[CH3:19])=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[S:23]1[CH2:27][CH2:26][NH:25][CH2:24]1>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:20]([N:25]2[CH2:26][CH2:27][S:23][CH2:24]2)=[O:22])[CH3:19])=[O:16])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C1CSCN1
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](C)C(=O)N1CCSC1

Procedure:
Following General Procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7 above) and thiazolidine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.25 in 9:1 CHCl3/MeOH).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7](O)=[O:8].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:40][CH2:41][NH2:42])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:40][CH2:41][NH:42][C:7]([C:6]2[S:5][C:4]([NH:10][C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:3][C:2]=2[CH3:1])=[O:8])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39]
Reactant: COc1ccc(CCN)cc1OC
Reactant: Cc1nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)sc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)c2sc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc2C)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a mixture of 4-methyl-2-tritylamino-5-thiazolecarboxylic acid (7.2 g) and 2-(3,4-dimethoxyphenyl)ethylamine (3.26 g) in N,N-dimethylformamide (100 ml) were added 1-hydroxybenzotriazole (2.92 g) and dicyclohexylcarbodiimide (4.45 g) and the mixture was stirred at ambient temperature for 1 hour. After filteration, the filtrate was evaporated under reduced pressure. The residue was dissolved in chloroform-methanol (9:1 v/v, 20 ml), removed undissolved materials by filtration, and the filtrate was subjected to column chromatography on silica gel to give N-[2-(3,4-dimethoxyphenyl)ethyl]-4-methyl-2-tritylamino-5-thiazolecarboxamide (8.65 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][OH:8])[NH:4][N:3]=1.[Cl:9][CH:10]([CH:13]=O)[CH:11]=O>C(O)(=O)C>[Cl:9][C:10]1[CH:11]=[N:1][C:2]2[N:3]([N:4]=[C:5]([CH2:7][OH:8])[N:6]=2)[CH:13]=1
Reactant: Nc1n[nH]c(CO)n1
Reactant: O=CC(Cl)C=O
Solvent: CC(=O)O
Product: OCc1nc2ncc(Cl)cn2n1
Temperature: 80 °C

Procedure:
To a slurry of (3-amino-1H-1,2,4-triazol-5-yl)methanol (28.5 g, 150 mmol) in acetic acid was added chloromalonaldehyde (16 g, 150 mmol). The mixture was heated to 80° C. for 4 hours. Upon cooling of the reaction to room temperature, the product crystallized out as a white solid (25.5 g, 92%). 1H NMR (300 MHz, DMSO-D6) δ: 4.67 (s, 2H), 5.62 (s, 1H), 8.94 (d, J=2.45 Hz, 1H), 9.81 (d, J=2.45 Hz, 1H). MS (APCI): 185.0 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:8][N:7]1[C:3]([CH2:2][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([CH2:2][C:3]3[N:7]([CH3:8])[N:6]=[C:5]([C:9]4[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=4)[CH:4]=3)[CH2:23][CH2:22]2)=[CH:4][C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:6]1
Reactant: COc1cc(-c2cc(CCl)n(C)n2)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(-c2cc(CN3CCCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)nn4C)CC3)n(C)n2)cc(OC)c1OC

Procedure:
5-Chloromethyl-1-methyl-3-(3,4,5-trimethoxy-phenyl)pyrazole (119 mg) and homopiperazine (20 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.