Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([Cl:12])[C:4]=1[F:13].[CH2:14]([CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[CH2:15][CH2:16][CH2:17][CH3:18].Cl>C1COCC1.C1(C)C=CC=CC=1>[Cl:12][C:5]1[C:4]([F:13])=[C:3]([C:22]2([OH:25])[CH2:21][CH2:20][CH:19]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:24][CH2:23]2)[CH:8]=[CH:7][C:6]=1[O:9][CH2:10][CH3:11]
Reactant: CCOc1ccc(Br)c(F)c1Cl
Reactant: CCCCCC1CCC(=O)CC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(O)(c2ccc(OCC)c(Cl)c2F)CC1
Temperature: 43 °C
Reaction time: 1.5 h
Yield: 102 %

Procedure:
2.9 g of well dried magnesium and 20 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 43° C. 30.0 g of 1-bromo-3-chloro-4-ethoxy-2-fluoro benzene (1) dissolved in 80 mL of THF was slowly added dropwise thereto at a temperature range of from 38 to 46° C., followed by stirring for 90 minutes. Thereafter, 19.0 g of 4-pentylcyclo hexanone dissolved in 20 mL of THF was slowly added dropwise thereto at a temperature range of from 38 to 44° C., followed by stirring for 60 minutes. After cooling the resulting reaction mixture to 30° C., the reaction mixture was mixed with 100 mL of 3N hydrochloric acid and 100 mL of toluene in a vessel and separated into an organic layer and an aqueous layer by standing still, so as to attain extraction. The resulting organic layer was fractionated and washed with water, a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 39.5 g of 1-(3-chloro-4-ethoxy-2-fluorophenyl)-4-pentylcyclohexanol (3). The resulting compound (3) was a yellow oily matter.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]2[O:28][CH2:29][CH2:30][C:26]=2[CH:25]=1.C(N(CC)CC)C>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:22]([CH2:23][C:24]1[CH:32]=[CH:31][C:27]3[O:28][CH2:29][CH2:30][C:26]=3[CH:25]=1)[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccc2c(c1)CCO2
Reactant: O=C(O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Temperature: 50 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
A mixture of 6-bromo-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid (2.3 g), 5-aminomethyl-2,3-dihydrobenzo[b]furan (2.0 g), triethylamine (2.3 ml) and methanol (23 ml) was stirred at 50° C. for 24 hrs. The reaction mixture was concentrated, 1N-hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 4N-Hydrochloric acid-ethyl acetate solution (8 ml) was added to the residue at room temperature, and the mixture was stirred for 12 hrs. The reaction mixture was concentrated under reduced pressure and the obtained crystals were washed with diethyl ether to give the title compound (1.98 g).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[CH2:11]([O:15][C:16](=[O:20])[CH:17]([CH3:19])[NH2:18])[CH:12]([CH3:14])[CH3:13]>>[CH2:11]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)COC(=O)C(C)N
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)Nc1ccc(C#N)cc1

Procedure:
Following General Procedure AP above and using 4-fluorobenzonitrile (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example AA above), the title compound was prepared as an oil. The product was recovered by column chromatography on silica gel using 1:5 EtOAc/hexanes as the eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH2:34])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>ClCCl.CO>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:34][C:14](=[O:16])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: COc1cc(N)ccc1OCCN1CCOCC1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)ccc1OCCN1CCOCC1

Procedure:
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethylphenyl)propynoic acid and 3-methoxy-4-(2-morpholin-4-ylethoxy)phenylamine. Yield: 20 mg (6.9% of theory); melting point: 209° C.-211° C.; C23H22ClF3N2O4 (M=482.89); calc.: molecular ion peak (M+H)+: 483/485; found: molecular ion peak (M+H)+: 483/485; Rf value: 0.5 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][C:2]1=[O:12].[H-].[Na+].[CH3:15]I>CN(C=O)C>[CH3:15][N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][C:2]1=[O:12]
Reactant: CI
Reactant: O=C1CCNc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CCNc2ccccc21
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one (2.0 g, 12.3 mmol) in DMF (30 ml), at −10° C., was added sodium hydride (0.54 g, 60% dispersion, 13.6 mmol). The mixture was stirred at −10° C. for 15 min, then methyl iodide (0.77 ml, 12.3 mmol) was added. The mixture was stirred at −100° C. for a further 1 h and then concentrated in vacuo. The residue was taken up in EtOAc and washed with brine (3 times), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc) to give a white solid; yield 1.70 g (78%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]=[C:22]=[S:23]>C(Cl)Cl>[NH2:5][N:4]([CH2:3][CH2:2][OH:1])[C:22]([NH:21][C:15]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=1[Cl:13])=[S:23]
Reactant: NNCCO
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NN(CCO)C(=S)Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.61 g (0.10 mol) 2-hydroxyethylhydrazine was dissolved in 100 mL methylene chloride at 0°-5° C. After dropwise addition of 10.2 g (0.10 tool) triethylamine, 20.4 g (0.10 mol) 2,4-dichlorophenylisothiocyanate dissolved in 70 mL methylene chloride was added over a period of 4 h. The reaction mixture was left to warm up to room temperature, stirred for a further 2 h, the precipitate filtered off, washed with methylene chloride and the desired compound isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>ClCCl>[Cl:25][CH2:26][C:27]([N:12]1[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[S:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:13]1)=[O:28]
Reactant: Clc1ccc([C@@H]2CNc3ccccc3S2)cc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1C[C@@H](c2ccc(Cl)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 108.8 %

Procedure:
To a suspension of (R)-(+)-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (1.30 g, 0.005 mole) and triethylamine (1.66 ml, 0.012 mole) in dichloromethane (16 ml) is added dropwise a solution of chloroacetyl chloride (0.79 ml, 0.01 mole) in dichloromethane (4 ml) under ice cooling, and the mixture is stirred at room temperature for 45 minutes. After the solvent is distilled off, to the residue are added ethyl acetate and water, and the ethyl acetate layer is washed with aqueous sodium hydrogen carbonate solution, water and saline, dried over sodium sulfate and distilled to remove the solvent to give (R)-4-chloroacetyl-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (1.84 g) as caramel.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(O[K])C.Cl[CH2:13][CH:14]=[CH2:15]>C(O)C>[CH2:15]([S:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH:14]=[CH2:13]
Reactant: C=CCCl
Reactant: Sc1ncccn1
Agent: CCO[K]
Solvent: CCO
Product: C=CCSc1ncccn1
Yield: 90 %

Procedure:
10 mmole of 2-mercaptopyrimidine was dissolved in 20 ml of ethanol in stirring. 10 mole of EtOK was added to the solution, stirred for 5 minutes. At last, about 20 mmole (Not more than 30 mmole) of 3-chloropropylene was added, and stirred overnight. The white precipitate was removed by filtration, the solvent in the filtrate was removed in vacuum. The obtained viscous liquid was separated with a Si gel column (solvents: 1 ethylacetate/3 hexane). 1H NMR (CD3Cl): δ(ppm) 8.39 (2H, d, JH-H=4.74), 6.86 (1H, t, JH-H=4.74), 5.89 (1H, m), 5.20 (1H, d, JH-H=17.00), 5.00 (1H, d, JH-H=9.97), 3.71 (2H, d, JH-H=6.83). Yield: 90%.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[C:10]([O:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11].[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26].N1C=CN=C1>O>[O:6]([C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[C:10]([O:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:11])[Si:29]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCCOc1ccccc1)c1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCCOc2ccccc2)c1
Reaction time: 10 h

Procedure:
Into a 250 mL round bottom flask was added 30 mL of dry dimethyl formamide. Five parts of hydroxy ester (53) and 3.5 parts of tert-butyldimethyl silyl chloride were added. to the reaction flask with stirring. Three parts of Imidazole was added in portions and stirring was continued for 10 hours. The reaction mixture was diluted with 80 mL of water and the product was extracted with ethyl acetate. The organic layer was washed with water and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an oil, yield 6.80 parts. This material was pure enough for next step of the reaction. The reaction proceeded as follows:
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][C:9](=[O:21])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]=1.[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24].O>N1C=CC=CC=1>[C:22]([N:2]([C:3]1[S:4][CH:5]=[C:6]([CH2:8][C:9](=[O:21])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]=1)[CH3:1])(=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: CNc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Reactant: CC(C)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)C(=O)N(C)c1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Yield: 60.2 %

Procedure:
A solution containing 7.6 g (0.025 mole) of 2-methylamino-4-(3-trifluoromethylphenylcarbamoylmethyl)thiazole and 2.9 g (0.027 mole) of isobutyryl chloride in 25 ml of pyridine was heated at about 45° for 24 hours. The mixture was poured into water. The thick oil failed to crystallize. The aqueous phase was decanted and the residue was dissolved in benzene. The organic phase was washed with water, dried over sodium sulfate and cooled. With stirring, hexane was added and a crystalline product precipitated. There was obtained 5.8 g of the desired amide, m.p. 122°-23°. N.M.R. (dimethyl-d6 sulfoxide) ∂ 1.1-1.3 (2 × CH3), 2.7-3.4 (CH, septet), 3.6 (NCH3), 3.7 (CH2), 6.9 (hetero-aromatic), 7.3-8.1 (aromatic), 10.4 (HNC=O).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:22])[NH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:22])[N:10]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(-c3ccnc(Br)c3)n[nH]c(=O)c2cc1OC
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1nc(-c2ccnc(Br)c2)c2cc(OC)c(OC)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-4-(6,7-dimethoxyphthalazin-1(2H)-on-4-yl)pyridine (362 mg) in dimethylformamide (2 ml) is added sodium hydride (48 mg, 62.4% in oil,) with ice-cooling under nitrogen atmosphere, and the mixture is stirred at room temperature for 30 minutes. To the mixture is methyl bromoacetate (0.11 ml) under ice-cooling, and the mixture is stirred for 15 minutes. To the mixture is added water, and the mixture is extracted with ethyl acetate. The extract is washed, dried, and concentrated to give 2-bromo-4-(6,7-dimethoxy-2-methoxycarbonylmethylphthalazin-1(2H)-on-4-yl)pyridine (390 mg).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[CH:5][C:4]=1F)#[N:2].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[SH:25].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CS(C)=O>[C:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[CH:5][C:4]=1[S:25][C:19]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=1[Cl:17])#[N:2]
Reactant: Cc1nccn1Cc1ccc(C#N)c(F)c1
Reactant: Sc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nccn1Cc1ccc(C#N)c(Sc2ccc(Cl)cc2Cl)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of the product From Step C (417 mg, 1.94 mmol) and 2,4-dichlorothiophenol (348 mg, 1.94 mmol) in 7.0 mL of DMSO was added cesium carbonate (1.26 g, 3.88 mmol). The reaction was warmed to 60° C. under argon and stirred for three hours. The solution was poured into EtOAc and washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was purified by silica gel chromatography (3-4% MeOH/CH2Cl2) to provide the product as a brown foam.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH2:26][O:25]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>CN(C)C=O>[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH:35][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=4[Br:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:31]2)[CH2:26][O:25]1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccccc2Br)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Br)=CC1=O
Temperature: 0 °C
Yield: 74.6 %

Procedure:
To a solution of (S)-2-[4-(2-bromo-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.260 g, 0.71 mmol) in N,N-dimethylformamide (10 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.180 g, 0.91 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.663 g, 1.50 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.200 g, 1.55 mmol) was added. The mixture was stirred at room temperature for 5 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 20% to 100% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-bromo-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.290 g, 75%) as a yellow solid: HR-ES-MS m/z calculated for C25H31BrN4O5 [M+H]+ 547.1551, observed 547.1549, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.4 Hz, 3 H), 0.94 (d, J=6.4 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.37-1.50 (m, 1H), 1.50-1.65 (m, 1H), 1.69-1.83 (m, 1H), 3.73 (dd, J=8.4, 5.8 Hz, 1H), 4.00 (dd, J=8.4, 6.5 Hz, 1H), 4.11 (t, J=5.8 Hz, 2H), 4.20 (d, J=18.4 Hz, 1H), 4.35 (quin, J=5.8 Hz, 1H), 4.61 (d, J=18.4 Hz, 1H), 4.77 (s, 1H), 4.90 (dd, J=10.6, 4.8 Hz, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.24-7.35 (m, 1H), 7.50 (m, 2H), 7.60 (d, J=2.1 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 10.82 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]1([CH:22]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:23][N:24]([CH2:37][CH2:38][CH2:39]O)[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:27]=2[Cl:36])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:39][CH2:38][CH2:37][N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[C:27]=2[Cl:36])[CH2:23][CH:22]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
To a stirring solution of N-(3-Hydroxy-phenyl)-carbamic acid tert-butyl ester (1.9 g, 9.0 mmol) in anhydrous toluene (60 mL) was added N-(2,2-diphenylethyl)-N-(3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine (2.36 g, 5.3 mmol). Polymer bound triphenylphosphine (2.8 g, 8.4 mmol, 3 mmol/g, Fluka Chemie) was then added, and the mixture stirred for 15 minutes. The reaction mixture was then cooled to 0° C. and diisopropylazodicarboxylate (1.28 mL, 6.5 mmol) was added in a dropwise fashion. After stirring at room temperature for 60 hours, the crude reaction mixture was filtered and the resulting solid was washed with toluene. The filtrate was concentrated and the crude product was purified by silica gel chromatography (35 g Redisep column, silica, 40 um, 60 Å, 35 mL/min, A: hexanes, B: EtOAc, B: 0% for 5 min, B: 0% to 10% over 10 min; B: 10% for 10 min; B: 10% to 30% over 30 min; detection at 214 nm) to give 2.0 g (3.1 mmol, 59% yield) of the title compound as a white foam. MS (ESI) 639.4
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:11][C:12]([O:14]C)=O)[NH2:10])=[CH:5][CH:4]=1.[CH3:16][N:17]=[C:18]=[O:19].C[O-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:11][C:12](=[O:14])[N:17]([CH3:16])[C:18](=[O:19])[NH:10]2)=[CH:7][CH:8]=1
Reactant: CN=C=O
Reactant: COC(=O)CN(N)c1ccc(OC)cc1
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(N2CC(=O)N(C)C(=O)N2)cc1

Procedure:
Methyl [1-(4-methoxyphenyl)hydrazino]acetate (1.50 g) was treated with methyl isocyanate (0.85 ml) and then with sodium methoxide (from sodium (0.33 g) in methanol (15 ml)) according to the method of Example 1. The product was purified by recrystallisation from ethyl acetate to give the title compound (703 mg), m.p. 179°-181°, t.l.c. (ether) Rf 0.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[C:15]1([CH2:21][CH2:22][C:23](Cl)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:23](=[O:24])[CH2:22][CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCc1ccccc1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.1 %

Procedure:
To a mixture of 3-chloroaniline (8.3 ml, 78.4 mmol), DMAP (1.0 g, 7.8 mmol), and pyridine (6.9 ml, 86.2 mmol) in anhydrous DCM (150 ml) at 0° C., was added 3-phenylpropionyl chloride (12.8 ml, 86.2 mmol). The mixture was warmed to ambient temperature and stirred under N2 overnight. Excess DCM was added to the reaction mixture. The organic layer was washed with 1N HCl (3×), saturated NaHCO3 (3×), brine, dried over MgSO4, and the solvent was removed in vacuo to yield 21.6 g of N-(3-chlorophenyl)-3-phenylpropanamide 21 as a peach colored crude solid.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][N:6]=1.C(O)(=O)C.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[S:3][C:4]([CH2:7][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][N:6]=1
Reactant: O=Cc1cnc(Br)s1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1ncc(CN2CCCCC2)s1
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
2-Bromo-5-formylthiazole (198 mg, 1.034 mmol, available from Fluorochem) was mixed with acetic acid (0.148 mL, 2.58 mmol) and Piperidine (0.128 mL, 1.292 mmol), dissolved in Dichloromethane (DCM) (9.5 mL) and stirred under nitrogen for 30 minutes. sodium triacetoxyborohydride (411 mg, 1.938 mmol) was added and the reaction was allowed to stir under nitrogen for 45 minutes. A second sample of sodium triacetoxyborohydride (411 mg, 1.938 mmol) was added and the reaction was left to stir under nitrogen for 4.5 days. The reaction was loaded onto a 5 g SCX-column, eluting with MeOH (40 mL) followed by 2M MeOH/NH3 (40 mL). Product-containing fractions were evaporated to dryness to give a yellow solid. This was partitioned between sodium bicarbonate (20 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (70 mL) and the organic fractions were combined, washed (brine (50 mL)), dried (sodium sulfate), filtered and evaporated to dryness to give a yellow solid (214 mg). This was purified on a 25+S Biotage silica column, eluting with DCM:2M MeOH/NH3 (1:0 to 49:1, 22 CV). Product-containing fractions were evaporated to dryness to give a dark yellow solid (134 mg)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH3:20]>C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:19][CH3:20])=[CH:4][N:3]=1
Reactant: CCI
Reactant: Oc1cnc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cnc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of 1-chloroisoquinolin-4-ol (1.0 g, 5.5 mmole) in acetonitrile (10 mL) was added K2CO3 (2.3 g, 16.7 mmole) followed by ethyl iodide (0.87 mL, 11.0 mmole) at room temperature. The reaction mixture was stirred at room temperature for overnight. Solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced. The resulting residue was purified by silica gel chromatography to afford 1-chloro-4-ethoxyisoquinoline (700 mg, 62%) as an off-white solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.26-8.24 (m, 2H), 7.79 (s, 1H), 7.76-7.26 (m, 2H), 4.29-4.24 (q, J=6.8 Hz, 2H), 1.58-1.1.54 (t, J=6.8 Hz, 3H); MS: MS m/z 207.7 (M++1).