Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][N:27]=[CH:26][C:25]=2[CH2:29][CH2:30][C:31](O)=[O:32])=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:25]2[CH:26]=[N:27][O:28][C:24]=2[C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)cc1
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2cnoc2-c2ccc(Cl)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (0.37 g), 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.35 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.25 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.33 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-diethylphosphonomethylphenyl)-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.61 g, yield 92%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 138–139° C.
Reaction SMILES: [C:1](Cl)(=O)[O:2]C(C)C.[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:10]=1[C:11]([OH:13])=[O:12].C(Cl)(=O)C>O1CCOCC1>[Cl:18][C:14]1[C:10]2[C:11](=[O:13])[O:12][C:1](=[O:2])[NH:8][C:9]=2[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: CC(C)OC(=O)Cl
Solvent: C1COCCO1
Solvent: CC(=O)Cl
Product: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Temperature: 90 °C
Yield: 76 %

Procedure:
Under an atmosphere of nitrogen, isopropyl carbonochloridate (50 ml, 4.50 equiv) was added dropwise to a suspension of 2-amino-6-chlorobenzoic acid (20 g, 116.56 mmol, 1.00 equiv) in 1,4-dioxane (150 ml). The resulting solution was maintained at about 90° C. for 30 minutes, and then cooled to about 50° C. Acetyl chloride (50 ml, 6.00 equiv) was added in one portion, and the solution was maintained at about 50° C. for about 30 minutes. The resulting solids were collected by filtration and purified by silica gel chromatography (ethyl acetate/petroleum ether 10:1) to afford the title product as a gray white solid (17.6 g, yield: 76%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=C(N)[CH:8]=2)[N:3]=1.[H-].[Na+].CI.[CH3:17][N:18]([CH:20]=O)[CH3:19]>O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[C:20]([N:18]([CH3:19])[CH3:17])[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc2cc(N)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cc1ccc2cc(N(C)C)ccc2n1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A mixture of 2-methylquinolin-6-amine (2.4 g, 15.2 mmol) and NaH (2.4 g, 60.8 mmol) in DMF (60 mL) was stirred at 40° C. for 3 hrs. Then CH3I (3.8 mL, 60.8 mmol) was added by syringe. The reaction mixture was stirred at 40° C. overnight and then cooled to room temperature. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine and dried over anhydrous Na2SO4. After purified by column chromatography (hexane/EtOAc=25:1), compound 3 was obtained (1.1 g, 39%). MS [M++1]=187, LC-MS: tR=0.775 min.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH2:10].[O:11]1CCOC[CH2:12]1>>[N:10]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[C:12]=[O:11]
Reactant: C1COCCO1
Reactant: NC1Cc2ccccc2C1
Product: O=C=NC1Cc2ccccc2C1

Procedure:
A solution of 1.53 g (11.5 mmol) indan-2-ylamine and 1.39 mL (11.5 mmol) in 40 mL dry dioxane is stirred for 2 hours at 70° C. under argon atmosphere and then concentrated under vacuum.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)=[O:5].C(N(CC)CC)C>C(#N)C>[CH:10]1[N:9]=[CH:8][N:7]2[CH2:2][CH2:3][C:4](=[O:5])[C:6]=12
Reactant: O=C(CCBr)c1c[nH]cn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCn2cncc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
3-Bromo-1-(1H-imidazol-4-yl)-1-propanone (28.5 g) was suspended in acetonitrile (1100 ml) and the suspension was warmed to 70° C. A solution of triethylamine (15.3 ml) in acetonitrile (25 ml) was slowly added dropwise and the mixture was stirred at 70° C. for 2 h. Triethylamine (25 ml) was further added and the mixture was stirred for 30 min. The reaction mixture was cooled to room temperature and the insoluble material was filtered off. The solvent was evaporated and the residue was dissolved in ethyl acetate again. The insoluble material was filtered off and the solvent was evaporated. The resulting residue was subjected to silica gel column chromatography (eluent; dichloromethane:methanol containing ammonia (5%)=10:1) for purification to give the title compound (6.67 g) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([O:18][C:19]1[C:20](=[O:24])[C:21](=O)[CH:22]=1)CCC>C(O)C>[N:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[NH:1][C:21]2[C:20](=[O:24])[C:19](=[O:18])[CH:22]=2)=[CH:9][CH:10]=1
Reactant: Nc1cccc(-c2ccncc2)c1
Reactant: CCCCOc1cc(=O)c1=O
Solvent: CCO
Product: O=c1cc(Nc2cccc(-c3ccncc3)c2)c1=O
Yield: 76.8 %

Procedure:
A solution of 4-(3-aminophenyl)pyridine (0.81 g) and 3-n-butoxy-3-cyclobutene-1,2-dione (0.73 g) in ethanol (20 ml) is stirred at ambient temperature for 15 hours. The resultant precipitated solid is washed with methanol and ether and recrystallized from dimethyl formamide to give 0.91 g of the title compound, mp 252-255.5° C.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([CH2:13][CH:14]([N:16]3[CH2:20][CH:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[O:18][C:17]3=[O:28])[CH3:15])=[CH:12][C:5]=2[O:4]1.[CH3:29][S-:30].[Na+].[I-].[K+].O>CN(C)C=O>[Cl:27][C:23]1[CH:22]=[C:21]([CH:19]2[O:18][C:17](=[O:28])[N:16]([CH:14]([CH3:15])[CH2:13][C:11]3[CH:10]=[CH:9][C:6]4[O:7][CH2:8][CH:3]([CH2:2][S:30][CH3:29])[O:4][C:5]=4[CH:12]=3)[CH2:20]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CC(Cc1ccc2c(c1)OC(CCl)CO2)N1CC(c2cccc(Cl)c2)OC1=O
Reactant: C[S-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCC1COc2ccc(CC(C)N3CC(c4cccc(Cl)c4)OC3=O)cc2O1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
One equivalent of product from Example 6, 3-isomer, and 2 equivalents of sodium methyl mercaptide in dimethylformamide, containing a catalytic amount of potassium iodide, is stirred at 60° C. for 18 hours. The mixture is poured into water, the resulting product is collected and recrystallized from ethyl alcohol to give 6-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-3-methylthiomethyl-1,4-benzodioxane.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH2:20]([O:22][C:23](=[O:28])[C@H:24]([CH2:26][OH:27])[NH2:25])[CH3:21]>CO.C(Cl)(Cl)Cl>[CH2:20]([O:22][C:23](=[O:28])[C@H:24]([CH2:26][OH:27])[NH:25][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:21]
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H](CO)NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-serine ethyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp=179-181° C.). The reaction was monitored by tlc (Rf=0.2 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=O)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:37]=[CH:36][CH:35]=[C:32]([C:33]#[N:34])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(-c2ccc(NC(=O)OC(C)(C)C)c(N)c2)c1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: Cc1cccc(-c2ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c3cccc(C#N)c3)c2)c1

Procedure:
Prepared from (3-amino-3′-methyl-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G20) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a viscous orange oil (290 mg).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[C:14](#N)[CH3:15]>>[CH:7]1([CH2:6][CH:2]([N:1]2[CH2:15][C:14]3[C:2](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:3]2=[O:4])[C:3]([OH:5])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC#N
Reactant: NC(CC1CCCCCC1)C(=O)O
Product: O=C(O)C(CC1CCCCCC1)N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A solution of phthalic dicarboxaldehyde (248 mg; 1.80 mmol) and 2-Amino-3-cycloheptyl-propionic acid (318 mg; 1.72 mmol) in acetonitrile was heated to reflux for 18 h. The mixture was then allowed to cool to room temperature and the mixture stored in the refrigerator for 3 h. The solid was filtered off, rinsed with cold acetonitrile and air dried to give 424 mg (82%) of 3-Cycloheptyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid as a beige solid: EI-HRMS m/e calcd for C18H23NO3 (M+) 301.1678, found 301.1668.
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]O)=[CH:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[I:1][C:2]1[C:7]([O:8][CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][S:9][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1I
Reactant: OCCc1ccsc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Ic1ncccc1OCCc1ccsc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution containing 2-iodo-3-hydroxypyridine (1.85 g, 8.37 mmol), 2-(3-thienyl)ethanol (1.20 mL, 10.9 mmol), and triphenylphosphine (2.85 g, 10.9 mmol) in tetrahydrofuran (46.2 mL, 5.70 mmol) was added diisopropyl azodicarboxylate (2.14 mL, 10.9 mmol) dropwise. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated and purified by flash chromatography EtOAc/Hex (0-100%) eluted at 30% to give 2-Iodo-3-(2-thiophen-3yl-ethoxy)-pyridine (yield 90%). MS: (ESI+) 332.2
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:28]=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:30]=1[OH:31])[C:8]([O:10][C:11]1[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][C:12]=1[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:36]([OH:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:36]([O:54][C:15](=[O:16])[C:14]1[CH:18]=[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]([O:10][C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:30]([OH:31])=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:28]=2)=[C:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:13]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CC(C)(C)c1cc(C(=O)Oc2c(C(C)(C)C)cc(C(=O)Cl)cc2C(C)(C)C)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCCCCCCCO
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1cc(C(C)(C)C)c(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 102 %

Procedure:
10.0 grams of 4-(3,5-di-t-butyl-4-hydroxybenzoyloxy)-3,5-di-t-butylbenzoyl chloride (0.02 moles) 5.4 grams of n-octadecanol (0.02 moles) and 2.0 grams of triethylamine were stirred together in 100 ml. of benzene at room temperature for 2 hours and then heated for 1 hour at 60° to 70° C. The reaction mixture was cooled to room temperature and the precipitate filtered. The benzene solution was washed with water and dried over sodium sulfate. The benzene solution was then concentrated at reduced pressure yielding about 15 grams of the product. The product was crystallized twice from isopropanol yielding white crystals melting at 75° to 76° C.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH:9]=[CH:8][N:7]=2)=[N:4][N:3]=[N:2]1.[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([O:12][C:10]3[CH:9]=[CH:8][N:7]=[C:6]([C:5]4[NH:1][N:2]=[N:3][N:4]=4)[CH:11]=3)=[CH:18][CH:17]=2)=[O:30])=[CH:24][CH:23]=1)[CH3:21]
Reactant: CCc1ccc(N=C=O)cc1
Reactant: Nc1ccc(Oc2ccnc(-c3nnn[nH]3)c2)cc1
Product: CCc1ccc(NC(=O)Nc2ccc(Oc3ccnc(-c4nnn[nH]4)c3)cc2)cc1
Reaction time: 4 h

Procedure:
The title compound is prepared as described In Example 102 but using 4-[2-(1H-tetrazol-5-yl)-pyridin-4-yloxy]-phenylamine (Example 122) and 4-ethyl-phenyl-isocyanate. The reaction mixture is stirred for 4 h. The crude product is washed with a solution of CH2Cl2/MeOH (95/5) and dried in vacuo to afford the title compound as a beige solid: ES-MS: 402.0 [M+H]+; single peak at tR=7.73 min (System 2); Rf=0.20 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]=[CH:24][C:25]3[C:30]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)=[CH:29][CH:28]=[C:27]([C:41]#[N:42])[CH:26]=3)=[CH:17][C:16]=2[C:43]([F:46])([F:45])[F:44])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:48](=[O:56])[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([C:48]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[O:56])[CH2:22][CH:23]=[CH:24][C:25]3[C:30]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)=[CH:29][CH:28]=[C:27]([C:41]#[N:42])[CH:26]=3)=[CH:17][C:16]=2[C:43]([F:46])([F:44])[F:45])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: COc1ccc(COc2ccc(C#N)cc2C=CCNc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCC(=O)N(CC=Cc1cc(C#N)ccc1OCc1ccc(OC)cc1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To 4-(N′-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-((4-methoxybenzyl)oxy)-3-cyanophenyl)prop-2-en-1-yl)benzenamine (1.39 g) in 20 mL of CH2Cl2 was added ethyl 4-chloro-4-oxobutyrate (0.43 g) and pyridine (1 mL) at 0° C. The resulting solution was allowed to warm to ambient temperature for 30 minutes and then diluted with 100 mL CH2Cl2. The organic layer was washed with saturated copper sulfate, dried and concentrated to afford 4-(N′-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(ethoxycarbonyl)ethylcarbonyl)-N-(3-(6-((4-methoxybenzyl)oxy)-3-cyanophenyi)prop-2-en-1-yl)benzenamine as a blue solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]O)[CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)[CH:20]=1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: OCc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(OCc3cccnc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 103.6 %

Procedure:
Into a solution of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (500 mg), 3-pyridinemethanol (405 mg) and triphenylphosphine (0.98 g) in THF (10 ml) was added at 0° C. diethyl azodicarboxylate (a 40% solution in toluene) (1.62 g), and the resulting mixture was stirred at room temperature for 20 hours. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate) to obtain methyl 7-(3-pyridylmethoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (694 mg) as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:2]1=2.[S:15](Cl)([Cl:18])(=[O:17])=[O:16]>C(Cl)(Cl)Cl>[Cl:18][S:15]([N:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:2]1=2)(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1cnc2c(c1)NCCO2
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cnc2c(c1)N(S(=O)(=O)Cl)CCO2
Temperature: -78 °C
Yield: 88.5 %

Procedure:
A 100 mL round-bottomed flask was charged with methyl 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (4 g, 20.60 mmol) and CHCl3 (200 mL) was added to form a clear solution which was stirred and cooled to −78° C. To the resulting white suspension was added TEA (8.61 mL, 61.8 mmol). A solution of sulfuryl chloride (3.35 mL, 41.2 mmol) in CHCl3 (10 mL) was added dropwise and the reaction mixture was maintained at −78° C. for 1 h. The solution was warmed to 0° C. at which time the mixture turned clear yellow. The reaction was stirred at 0° C. for 2 h. The reaction was quenched with H2O (200 mL) and extracted with DCM (2×200 mL). The combined organics were washed with 1 N HCl (200 mL) then dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting solid was purified by flash column chromatography using a gradient elution with 0-25% acetonitrile in DCM to provide methyl 1-(chlorosulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (5.34 g, 18.24 mmol, 89% yield) as a white solid. 1H-NMR (CDCl3) δ 8.82. (br s, 1H), 8.63 (d, 1H), 4.72 (dd, 2H), 4.10 (dd, 2H), 3.92 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: COc1cccc(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cccc(CO)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
25.66 g (166.47 mmol) of 2-fluoro-3-methoxybenzaldehyde is dissolved in 140 ml of ethanol and mixed in portions at 0° C. with 3.15 g (83.35 mmol) of sodium borohydride. After one hour of stirring at room temperature, the reaction mixture is mixed with water and extracted three times with methyl tert-butyl ether. The combined organic extracts are shaken with water and brine, dried, the desiccant is suctioned off, and the solvent is spun off. The remaining residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 24.79 g (95.3%) of the desired compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[NH:16]([CH:23]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)(Cl)=O>>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([CH:23]([N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12](=[O:14])[CH2:11][NH:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:15])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:36][CH:35]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CC(C)(C)OC(=O)C(Nc1ccccc1)c1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)C(C(=O)OC(C)(C)C)c2ccc(Cl)cc2)c1
Yield: 51.1 %

Procedure:
The procedure is as in Example 8, but using 2.1 g of 2-[3-(3-methylphenyl)ureido]acetic acid, 3.18 g of tert-butyl (RS)-2-anilino-2-(4-chlorophenyl)acetate and 0.72 cm3 of thionyl chloride as starting materials. The product obtained is purified by chromatography on 250 g of silica (0.04-0.063 mm) contained in a column 4.2 cm in diameter [eluent: ethyl acetate/cyclohexane (30/70 by volume)], using an excess pressure of 40 kPa of nitrogen and collecting 10-cm3 fractions. Fractions 8 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. and the residue obtained is recrystallized from diisopropyl ether. 2.6 g of tertbutyl (RS)-2-(4-chlorophenyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate melting at 167° C. are then obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](Br)[C:5]([F:8])=[N:6][CH:7]=1.[CH2:10]([Sn](CCCC)(CCCC)C=C)[CH2:11]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH2:11])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1cnc(F)c(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(N)cnc1F
Temperature: 100 °C
Yield: 97.9 %

Procedure:
To a stirred solution of 5-amino-3-bromo-2-fluoropyridine (3.25 g, 17.0 mmol) in toluene (20 mL) was added tributyl(vinyl)tin (7.64 g, 20.4 mmol) followed by tetrakis(triphenylphosphine) palladium (Aldrich, 0.63 g, 1.7 mmol). The reaction mixture was heated at 100° C. for 24 h. The solvent was removed in vacuo and the residue was purified by column chromatography (silica gel; EtOAc/hexane, 4:6) to afford the title compound as a beige solid (2.30 g, 98%): 1H NMR (CDCl3, 300 MHz) δ 3.61 (br s, 2H), 5.44 (d, J=11.5 Hz, 1H), 5.83 (d, J=17.5 Hz, 1H), 6.66 (m, 1H), 7.18 (dd, J=3.0, 5.0 Hz, 1H), 7.52 (m, 1H); MS (CI/NH3) m/z 139 (M+H)+, 156 (M+NH4)+.