Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][Ge:6]([Cl:19])([Cl:18])[CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9](O)=[O:10]>>[Cl:5][Ge:6]([Cl:19])([Cl:18])[CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9]([Cl:3])=[O:10]
Reactant: O=C(O)CC(c1ccccc1)[Ge](Cl)(Cl)Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CC(c1ccccc1)[Ge](Cl)(Cl)Cl
Yield: 69.1 %

Procedure:
Sixty grams of thionyl chloride was added to 16.4 g (0.05 mol) of β-(trichlorogermyl)hydrocinnamic acid (7), and the mixture was heated under reflux for 2 hours. Then excess thionyl chloride was distilled away in the usual manner. The residue, upon vacuum distillation, gave 12.9 g of a fraction, bp 148°-149° C./4 mmHg. The yield was 69.1%.
Reaction SMILES: C([Li])CCC.C(N[CH:10]([CH3:12])[CH3:11])(C)C.[I:13][C:14]1C(C)=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18].IC.Cl>O1CCCC1>[I:13][C:14]1[C:12]([CH2:10][CH3:11])=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18]
Reactant: CC(C)NC(C)C
Reactant: Cc1c(I)cccc1C(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCc1c(I)cccc1C(=O)O
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 103.9 %

Procedure:
A n-butyllithium-1.58M n-hexane solution (36.2 ml, 57.2 mmol) was added dropwise to a solution of diisopropylamine (8.02 ml, 57.2 mmol) in tetrahydrofuran (114 ml) under ice-cooling, and the mixture was further stirred for 30 minutes. After the reaction mixture was cooled to −50° C., a solution of 3-iodo-2-methylbenzoic acid (5.00 g, 19.1 mmol) in tetrahydrofuran (38 ml) was added thereto. After the mixture was stirred for 1 hour, iodomethane (9.51 ml, 153 mmol) was added thereto and the temperature of the mixture was raised from −50° C. to −20° C. over 1 hour. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid, water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3-iodo-2-ethylbenzoic acid (5.48 g, yield: 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:30])[C:5]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)([CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1cccc(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(F)c1
Reaction time: 20 h

Procedure:
2-(3-Fluorophenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) and treated with 5% palladium on carbon (300 mg), and stirred under an atmosphere of hydrogen for 20 h. The suspension was filtered rough celite and concentrated in vacuo to an oil.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C1(C)C(C)=CC=CC=1>C1(C)C=CC=CC=1>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:22]=[CH:21][C:20]([C:23](=[O:25])/[CH:24]=[CH:1]/[N:5]([CH3:11])[CH3:6])=[CH:19][CH:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: CN(C)/C=C/C(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1

Procedure:
A mixture of 1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}ethanone (E214) (186 mg, 0.55 mmol), dimethylformamide dimethyl acetyl (0.25 ml) and xylene (4 ml) was heated at reflux for 8 hours. The residue was diluted with toluene and concentrated in vacuo to afford the title compound (D53); MS (ES+) m/e 392 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: CNCCC#Cc1ccccn1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CN(CCC#Cc1ccccn1)C(=O)c1ccc(F)cc1
Yield: 58.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (100 mg, 0.62 mmol) and 4-fluorobenzoyl chloride (99 mg, 0.62 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: 98/2 as eluent) to afford 103 mg of 4-fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 58%).
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[H-].[Na+].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21](OCC)=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[NH4+].[Cl-]>C1COCC1>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[O:5][N:4]=[C:1]([CH3:2])[N:3]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(N)=NO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1noc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70.3 %

Procedure:
A solution 1.30 g (17.49 mmol) of acetamide oxime in 55 ml THF was treated with 0.76 g (17.49 mmol) of NaH (55% in oil) and the corresponding suspension stirred for 45 min at RT. 3.00 g (11.66 mmol) of ethyl 1-tert-butoxycarbonylpiperidine-4-carboxylate dissolved in 15 ml of THF was added and heated at 65° C. for 2 h. The solution was cooled to RT, poured on aqueous saturated NH4Cl solution and extracted with Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3 and aqueous 10% KHSO4, dried (Na2SO4) and evaporated to give 2.19 g (70%) of the title compound as orange liquid. MS: 268.2 (MH+).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:13]([Br:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][N:9]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(#N)C>[Br:14][C:13]1[C:8]([NH:7][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9][CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncc([N+](=O)[O-])cc1Br
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Nc1ncc([N+](=O)[O-])cc1Br)c1ccccc1
Yield: 89.1 %

Procedure:
20 mλ of pyridine was added to 2-amino-3-bromo-5-nitropyridine (A) (21.8 g; 0.1 mole) in 300 ,λ of acetonitrile at room temperature in a stream of nitrogen followed by addition of benzoylchloride (24.4 g; 0.2 mole) and agitation for 3 hours. Then dilute hydrochloric acid (0.1N) was added to the resulting mixture. After extraction with ethyl acetate, the resulting ethyl acetate solution was dried over anhydrous sodium sulfate. The solvent was distilled off under a reduced pressure. The residue was recrystallized from methanol to give 3-bromo-2-benzoylamino-5-nitropyridine (B) (28.7 g; 89%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)S[C:8]3([CH:9]([C:19]#[N:20])[CH2:10]2)[N:3]1[CH2:4][CH2:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=13>C[O-].[Na+]>[O:1]=[C:2]1[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]([C:19]#[N:20])=[C:8]2[N:3]1[CH2:4][CH2:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=12
Reactant: N#CC1CC2(c3ccccc3)SC13c1ccccc1CCN3C2=O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1CC2

Procedure:
1.7 g of 1,2,3,4,6,7-hexahydro-4-oxo-3-phenyl-3,11b-epithio-11bH-benzo[a]quinolizine-1-carbonitrile were heated at reflux for 2 hours together with a sodium methylate solution (prepared from 156 mg of sodium in 40 ml of methanol). After cooling, the crystallized-out product was removed by filtration under suction and recrystallized from isopropanol. There was obtained pure 6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-carbonitrile of m.p. 204°-205°.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([CH3:21])=[C:14]([F:22])[C:13]=1[F:23])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([Si:5]([CH3:7])([CH3:6])[O:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([F:23])=[C:14]([F:22])[C:15]([CH3:21])=[C:16]([NH2:18])[CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c([N+](=O)[O-])cc(OCCO[Si](C)(C)C(C)(C)C)c(F)c1F
Agent: [Pd]
Solvent: CCO
Product: Cc1c(N)cc(OCCO[Si](C)(C)C(C)(C)C)c(F)c1F
Reaction time: 2 h
Yield: 60.4 %

Procedure:
To a solution of tert-butyl-[2-(2,3-difluoro-4-methyl-5-nitro-phenoxy)-ethoxy]-dimethyl-silane (1.16 g, 3.33 mmol) in EtOH (10 ml) was added 10% Pd/C (0.116 g) and the mixture was hydrogenated under balloon pressure for two hours. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. Purification of the crude product by flash chromatography (hexanes:EtOAc 7:3) gave 0.638 g of 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,4-difluoro-2-methyl-phenylamine as a tan solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[N:12]=1.[B-](F)(F)(F)[F:23].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:21])[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[C:8]1[S:9][C:10]([F:23])=[C:11]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[N:12]=1
Reactant: CC1(C)CCC(=O)N1c1nc(-c2ccc(C#N)cc2)cs1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)CCC(=O)N1c1nc(-c2ccc(C#N)cc2)c(F)s1
Reaction time: 16 h
Yield: 32 %

Procedure:
4-[2-(2,2-Dimethyl-5-oxopyrrolidin-1-yl)-1,3-thiazol-4-yl]benzonitrile (0.50 g, 1.7 mmol), prepared in step 2 of Example 88, was dissolved in acetonitrile (16 mL) and the Selectfluor® reagent (0.65 g, 1.9 mmol) was added. The mixture was stirred for 16 h, diluted with ethyl acetate, washed with H2O, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (10% acetone/hexane) afforded the title compound (0.17 g, 32%) as colorless crystals. HRMS: calcd for C16H14FN3OS+H+, 316.09144; found (ESI-FT/MS, [M+H]1+), 316.0916; Analytical HPLC purity 100% at 210-370 nm, 10.6 min; 98.4% at 296 nm, 10.6 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1[CH2:14][CH2:13][NH:12]C1=O.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[C:1]1([N:7]2[CH2:14][CH2:13][NH:12][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NCCO1
Reactant: O=C=Nc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1NCCN1c1ccccc1
Temperature: 195 °C
Yield: 48 %

Procedure:
A mixture of phenyl isocyanate (50 mmoles), 2-oxazolidinone (50 mmoles) and anhydrous AlCl3 (40 mg, 0.3 mmole) is heated at 195° C. for 6 hours with stirring. The reaction mixture is dissolved in dichloromethane and the resulting solution is washed with water twice. The dichloromethane solution is dried and evaporated and the residue distilled at reduced pressure. The distillate is recrystallized from hot hexane to give a yield of 48 percent of the desired product, m.p. 157° C.-159° C.
Reaction SMILES: ClC1C=CC(N)=CC=1.C([CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])C.Cl.C([OH:23])C>>[O:23]=[C:11]([CH2:17][CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(CC)C(C)=O
Reactant: CCO
Agent: Cl
Agent: Nc1ccc(Cl)cc1
Product: CCOC(=O)C(=O)CC

Procedure:
The p-chlorophenylhydrazone of ethyl 2-oxobutanoate was prepared by adaptation of the Japp-Klingemann reaction as described by Lions and Hughes (J. Proc. Roy. Soc. N. S. Wales 1939, 71: 445) to p-chloroaniline and ethyl 2-ethylacetoacetate. This phenylhydrazone was treated with HCl-ethanol according to the procedure of Lions and Hughes (J. Proc. Roy. Soc. N. S. Wales 1939, 71: 445) as applied therein to the corresponding bromophenylhydrazone. The title substance was collected by filtration as an orange solid after suspending the concentrated residue in water.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([F:30])[CH:23]=3)[CH:19]=[N:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[ClH:31].[ClH:31].[C:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:20]2[C:16]([CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:17][N:18]=[CH:19]2)=[CH:23][C:24]=1[F:30])#[N:29]
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2cncn2Cc2ccc(C#N)c(F)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cn2cncc2CCN2CCNCC2)cc1F
Reaction time: 1.5 h

Procedure:
A solution of the product from Step C (6.53 g, 15.8 mmol) in ethyl acetate (20 mL) was saturated with HCl gas. The solution was stirred for 1.5 hours and then concentrated in vacuo to yield the titled compound as a white solid.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[C:11]2[C:6]=1[CH:7]1[CH2:40][C:39](=O)[CH2:38][CH2:37][CH:8]1[C:9]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:29])N2)(=O)C.C(N)=O.C(O)=O.C(=O)([O-])[O-].[NH4+:52].[NH4+:53]>O>[NH2:52][CH:39]1[CH2:38][CH2:37][CH:8]2[C:9]([CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([CH3:29])[NH:53][C:11]3[C:6]([CH:7]2[CH2:40]1)=[C:5]([OH:4])[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH:12]=3
Reactant: [NH4+]
Reactant: CC(=O)Oc1cc(CCCSCCCCc2ccccc2)cc2c1C1CC(=O)CCC1C(C)(Cc1ccccc1)N2
Agent: O=C([O-])[O-]
Solvent: NC=O
Solvent: O
Solvent: O=CO
Product: CC1(Cc2ccccc2)Nc2cc(CCCSCCCCc3ccccc3)cc(O)c2C2CC(N)CCC21
Reaction time: 3 h

Procedure:
A mixture of 5.53 g. (0.01 mole) of dl-1-acetoxy-6-benzyl-6-methyl-3-(8-phenyl-4-thiaoctyl)-5,6,6a,7,10,10a-hexahydrobenzo[c]quinoline-9(8H)one, 5 ml. formamide and 10 ml. formic acid is heated at reflux under a nitrogen atmosphere while removing water as it forms in the reaction. Additional formic acid is added as required to control deposition of ammonium carbonate in the condenser. When the reaction temperature reaches 195° C., the mixture is cooled, diluted with water and extracted with ethyl acetate. The extract is evaporated to dryness, 5 ml. of concentrated hydrochloric acid is added and the mixture boiled for three hours, cooled, washed with ethyl ether. The aqueous phase is made alkaline with sodium hydroxide solution, extracted with ether and the extracts dried over anhydrous magnesium sulfate. The solvent is evaporated to afford the title compound as a mixture of isomers.
Reaction SMILES: ClC(Cl)C.[CH3:5][O:6][N:7]=[C:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[CH3:25][O:26][C:27](=[O:37])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:5][O:6]/[N:7]=[C:8](/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)\[CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:36][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][C:27]([O:26][CH3:25])=[O:37])=[CH:35][CH:34]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)CCc1ccc(N)cc1
Reactant: CON=C(COc1ccc(C=O)cc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CO/N=C(\COc1ccc(CNc2ccc(CCC(=O)OC)cc2)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged 5 mL of dichloroethane. To the stirred solvent was added 4-(2-methoxyimino-2-phenyl-ethoxy)-benzaldehyde (0.4 g, 1.5 mmol), 3-(4-amino-phenyl)-propanoic acid methyl ester (0.27 g, 1.5 mmol). RM was cooled to 0° C. and sodium triacetoxyborohydride (0.47 g, 2.25 mmol) was added portion wise over a period of 15 minutes. The reaction mixture was stirred at RT for 2 h. The RM was quenched with NaHCO3 solution (40 mL 10% solution in water) and extracted with ethyl acetate (20 mL×2). The organic layer washed with saturated brine solution (25 mL), dried over anhydrous Na2SO4 and evaporated in vacuum to dryness. The resulting crude compound was purified by column chromatography on silica gel (100/200 mesh), using petroleum ether (60-80) and ethyl acetate as eluent to give the product (0.450 g, Yield: 69.4%): MS (ESI, 120 eV): m/z=433.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2Cl.[NH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)-2-methylpropan-1-one (10 g, 32.0 mmol) was reacted with tert-butyl trans-4-aminocyclohexylcarbamate (10.3 g, 48.0 mmol) to afford the desired product (12.8 g, 81%) as an off-white solid: ESI MS m/z 491 [C24H32BrN3O3+H]+.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[Cl:13][C:14]1[C:15]([CH:20]=O)=[N:16][N:17]([CH3:19])[CH:18]=1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:20][C:15]1[C:14]([Cl:13])=[CH:18][N:17]([CH3:19])[N:16]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: Cn1cc(Cl)c(C=O)n1
Product: Cn1cc(Cl)c(C=NNC(=S)NC2CC3C=CC2C3)n1

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (35 mg, 0.21 mmol) and 4-chloro-1-methylpyrazole-3-carboxaldehyde (41 mg, 0.287 mmol) similar to Example 3 and isolated as a white solid (15 mg, 24%). 1H NMR (CDCl3): 11.91 (s, 1H), 7.24 (s, 1H), 7.45 (s, 1H), 7.35 (s, 1H), 6.10 (ddd, J=8.1, 5.1, 2.7 Hz, 2H), 4.26 (t, J=7.5 Hz, 1H), 3.99 (s, 3H), 3.02 (s, 1H), 2.93 (s, 1H), 1.88 (ddd, J=8.4, 7.0, 2.7 Hz, 1H), 1.61 (m, 1H), 1.52-1.38 (m, 2H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O1CCCC1.[NH:16]1[CH2:21][CH2:20][CH2:19][NH:18][C:17]1=[O:22].C(Cl)(Cl)Cl>C(N(CC)CC)C>[C:4]1([S:7]([N:16]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]2=[O:22])(=[O:9])=[O:8])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C1NCCCN1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C1NCCCN1S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
20.4 parts by weight of benzenesulfochloride in 20 parts by volume of tetrahydrofurane were added dropwise at 10°-15°C over the course of 15 minutes to a stirred mixture of 10 parts by weight of 1,3-diaza-cyclohexane-2-one, 80 parts by volume of tetrahydrofurane and 80 parts by volume of chloroform, followed by 10.1 parts by weight of triethylamine at the same temperature. The mixture was stirred at 10°-15°C for 30 minutes and then overnight at 50°C. Subsequently the mixture was evaporated to dryness; the residue was stirred with 100 parts by volume of water, filtered, stirred with water once more, filtered and washed with ethanol.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][C:10]1[N:11]2[CH:17]=[N:16][CH:15]=[C:12]2[S:13][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(=S)=S.ClCCl>[C:5]([C:15]1[N:16]=[CH:17][N:11]2[C:10]([CH3:9])=[CH:14][S:13][C:12]=12)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: Cc1csc2cncn12
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: ClCCl
Solvent: S=C=S
Product: CC(=O)c1ncn2c(C)csc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Aluminum chloride (16.0 g) was added to a solution of 10.0 ml of acetyl chloride in 100 ml of carbon disulfide at room temperature. The mixture was stirred for 30 min. A solution of 2.76 g of 3-methylimidazo[5,1-b]thiazole in 40 ml of dichloromethane was added dropwise thereto over a period of 15 min with stirring. The mixture was further stirred for 6 hr. The reaction solution was added to a mixture of 200 ml of dichloromethane with 100 g of ice with thorough stirring. After dissolution of the ice, 40 g of sodium carbonate and 50 g of sodium sulfate were added in that order with thorough stirring. The mixture was stirred under ice cooling for 30 min. After standing, the organic layer was separated by decantation. The gum residue was extracted with dichloromethane (100 ml, five times), and then combined with the organic layer. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated to dryness under the reduced pressure. Ethyl acetate (10 ml) was added to the concentrate. The resultant solid was triturated with 10 ml of ethyl acetate, collected by filtration, and washed with a minor amount of ethyl acetate. The washed product was dried under the reduced pressure to give 2.92 g of 7-acetyl-3-methylimidazo[5,1-b]thiazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:43])[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[O:32])=[C:26]([O:41][CH3:42])[CH:25]=3)=[CH:17][CH:16]=2)[CH2:11][C:12]([OH:14])=[O:13])=[O:8])[CH:2]=1.[OH:44]O>C(O)(=O)C>[O-:44][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:43])[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[O:32])=[C:26]([O:41][CH3:42])[CH:25]=3)=[CH:17][CH:16]=2)[CH2:11][C:12]([OH:14])=[O:13])=[O:8])[CH:2]=1
Reactant: OO
Reactant: COc1cc(CC(=O)Nc2ccc([C@@H](CC(=O)O)NC(=O)c3cccnc3)cc2)ccc1NC(=O)Nc1ccccc1C
Solvent: CC(=O)O
Product: COc1cc(CC(=O)Nc2ccc([C@@H](CC(=O)O)NC(=O)c3ccc[n+]([O-])c3)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of (R)-3-[(pyridine-3-carbonyl)amino]-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetylamino}phenyl)-propanoic acid [0.4 g, Example 5(e)], acetic acid (2.5 ml) and hydrogen peroxide (0.5 ml) was stirred at 80° C. for 6 hours. The reaction mixture was evaporated and the residue was triturated with water. The resulting solid was subjected to flash chromatography on silica gel eluting with a mixture of dichloromethane, methanol and acetic acid (9:1:0.5, v/v/v) to give the title compound as a light brown solid (50 mg), m.p. 190° C. (with decomposition). MS: MH+ 598.
Reaction SMILES: [NH2:1][C:2]1[C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:19](OCC)(OCC)(OCC)[CH2:20][CH3:21]>C(O)(=O)C>[CH2:20]([C:21]1[NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:2]=2[N:1]=1)[CH3:19]
Reactant: CCOC(CC)(OCC)OCC
Reactant: COc1ccc(COc2cccc(N)c2N)cc1
Solvent: CC(=O)O
Product: CCc1nc2c(OCc3ccc(OC)cc3)cccc2[nH]1
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a stirred solution of 2-amino-3-(4-methoxybenzyloxy)-aniline (1.15 g) in acetic acid (12 ml) was added triethyl orthopropionate (994 mg) at ambient temperature, and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo, and the residue was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo to give 2-ethyl-4-(4-methoxybenzyloxy)-1H-benzimidazole (900 mg) as pale yellow powder.