Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-])=O)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].C(O)C.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[NH2:19][C:14]1[CH:13]=[C:12]([NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:22]([F:25])([F:23])[F:24])[CH:4]=2)=[O:10])[CH:17]=[CH:16][C:15]=1[CH3:18]
Reactant: Cc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1N
Temperature: 80 °C
Reaction time: 4 h
Yield: 60.7 %

Procedure:
1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-methyl-3-nitrophenyl)urea (7 g, 18.7 mmol) obtained in Step (1) above was stirred in a solvent of ethanol (100 mL). The reaction solution was added with tin chloride (II) dihydrate (12.68 g, 56.2 mmol), followed by stirring for about 4 hours at 80° C. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated solid was added with a mixed solution of ethyl acetate/hexane (1/1), and stirred for 2 hours or more. The resulting solid was filtered under reduced pressure, washed with diethyl ether, and the filtered solid was dried with warm wind in an oven (40° C.) for 3 hours or more to obtain the title compound (3.9 g, 61%).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([NH2:15])=[O:14])=[CH:10][CH:11]=2)[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:5]=1[CH2:24][CH2:25][CH3:26])(=O)[CH3:2].Cl.[NH2:28][OH:29].C([O-])(=O)C.[Na+]>C(O)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)[C:4]([C:1](=[N:28][OH:29])[CH3:2])=[C:5]1[CH2:24][CH2:25][CH3:26]
Reactant: CCCc1c(C(C)=O)c2ccc(C(N)=O)cc2n1Cc1ccccc1Cl
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCc1c(C(C)=NO)c2ccc(C(N)=O)cc2n1Cc1ccccc1Cl
Temperature: 100 °C
Yield: 86.1 %

Procedure:
To a suspension of 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxamide (36.5 mg) in ethanol (5 ml) was added hydroxylamine hydrochloride (70 mg) and sodium acetate (200 mg), and the mixture was heated in a sealed tube at 100° C. The reaction was evaporated in vacuo, then the residue was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 1-(2-chlorobenzyl)-3-(1-hydroxyiminoethyl)-2-propylindole-6-carboxamide (32.7 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[C:13](#[N:15])C.[C-]#N.[K+].O>C(O)C>[C:13]([CH2:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6])#[N:15]
Reactant: COc1ccc(C#N)c(CBr)c1
Reactant: CC#N
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C#N)c(CC#N)c1
Reaction time: 4 h

Procedure:
2-(Bromomethyl)-4-methoxybenzonitrile (36 g, example 235, step 1) was suspended in 200 ml of ethanol, 200 ml of acetonitrile was added followed by KCN (8.3 g) and 150 ml of water. Mixture was stirred and the colorless solution turned to yellow. The reaction was complete after 4 hours of stirring. The volatiles were removed under vacuum, and the residual solid was redissolved in ethyl acetate (200 ml) and washed with water (100 ml) and brine (100 ml). The organics were then dried over sodium sulfate. Ethyl acetate was removed and the residue was recrystallized from ethyl acetate and dichloride methane to provide 17 g of 2-(cyanomethyl)-4-methoxybenzonitrile.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].[N:6]1[C:13](Cl)=[N:12][C:10](Cl)=[N:9][C:7]=1Cl>N1C=CC=CC=1>[C:2](=[N:4][O:5][C:7]1[N:9]=[C:10]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[N:12]=[C:13]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[N:6]=1)([CH3:3])[CH3:1]
Reactant: CC(C)=NO
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: c1ccncc1
Product: CC(C)=NOc1nc(ON=C(C)C)nc(ON=C(C)C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.8 %

Procedure:
To a cold (0° C.) solution of acetone oxime (2.92 g, 0.04 mol) in dry pyridine (15 ml) is added cyanuric chloride (1.84 g, 0.01 mol). An exothermic reaction occurs and the temperature rises to 35° C. The solution is then stirred for 5 h at room temperature and then poured into 100 ml of ice-cold water. The resulting emulsion is extracted with dichloromethane (5×20 ml), the extracts are dried over MgSO4 and the solvent is evaporated. The residue is chromatographed (silica gel, CH2Cl2—C2H5O(CO)CH3 7:3) and the pure fraction is recrystallized from dichloromethane-hexane to afford 2.79 g of the title compound as a white solid, mp. 156-158° C.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1>ClCCl.N1C=CC=CC=1>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[O:13]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Cc1ccccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccccc1C
Yield: 3.9 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and o-toluidine (1.25 g, 11.7 mmol) in 10 mL of pyridine. The crude product was triturated with a hot mixture of ethyl acetate and ethanol and recrystallized from acetonitrile-DMF to yield 0.11 g of the title compound, mp 224°-225° C (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[NH:11][C:10](=[O:13])[CH2:9][CH2:8][C:7]=2[C:6]([CH:14]=[O:15])=[CH:5][CH:4]=1.[CH2:16](O)[CH2:17][OH:18].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:15]1[CH2:16][CH2:17][O:18][CH:14]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:13])[NH:11]2
Reactant: OCCO
Reactant: COc1ccc(C=O)c2c1NC(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2OCCO2)c2c1NC(=O)CC2
Yield: 70 %

Procedure:
8-Methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde (42 g) was suspended in toluene (400 ml), and ethylene glycol (33.7 ml) and p-toluenesulfonic acid monohydrate (0.78 g) were added, and the resulting mixture was heated under reflux in a Dean-Stark apparatus for 4.5 hours. The reaction mixture was cooled, and 10 ml of an aqueous solution containing 1.72 g of sodium bicarbonate was added. Stirring was carried out for some time, and the produced solid was collected by filtration. The solid was washed with water and toluene and dried at 60° C. to thereby obtain 35.5 g (yield: 70%) of 5-(1,3-dioxolan-2-yl)-8-methoxy-3,4-dihydro-1H-quinolin-2-one as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([C:23]([O:25]CC2C=CC=CC=2)=[O:24])[CH:17]=3)=[C:9]([CH3:33])[CH:8]=1)=[O:4]>[Pd].C(OCC)(=O)C.C(O)C>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH3:33])[C:10]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([C:23]([OH:25])=[O:24])[CH:17]=3)=[C:11]([CH3:13])[CH:12]=1)=[O:4]
Reactant: COC(=O)/C=C/c1cc(C)c(-c2cc3ccc(C(=O)OCc4ccccc4)cc3[nH]2)c(C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)CCc1cc(C)c(-c2cc3ccc(C(=O)O)cc3[nH]2)c(C)c1
Reaction time: 18 h

Procedure:
A mixture of benzyl 2-[4-((E)-2-methoxycarbonylvinyl)-2,6-dimethylphenyl]-1H-indole-6-carboxylate (950 mg, 2.16 mmol) and 10% palladium on carbon (95 mg) in 100 mL of 1:1 ethyl acetate/ethanol was stirred under a hydrogen balloon for 18 h. The catalyst was filtered through Celite and the filtrate was removed under reduced pressure to leave the title compound. MS: m/z 352.2 (M+1); Retention time=1.35 min (Method 10).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:14])[CH2:11][CH2:12]Cl)=[CH:4][CH:3]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:14])[CH2:11][CH2:12][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:4][CH:3]=1
Reactant: O=C(CCCl)CCc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1ccc(Cl)cc1)CCn1ccnc1

Procedure:
1-(4-Chlorophenyl)-5-chloro-3-pentanone (6.95 g.) is added to a well stirred, ice-cooled solution of 10.5 g. of imidazole in 10 ml. of dimethylformamide. The solution is stirred for 8 hours at 0° C. and then poured into 150 ml. of water. The product is collected by filtration and recrystallized from cyclohexane to yield 1-(4-chlorophenyl)-5-(1-imidazolyl)-3-pentanone.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH3:23])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:26]>>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH:4]([CH3:23])[C:3]([NH2:26])=[O:2])=[CH:9][CH:10]=1
Reactant: [NH4+]
Reactant: COC(=O)C(C)C(=O)Nc1ccc(OCc2cccc(F)c2)cc1
Agent: [OH-]
Product: CC(C(N)=O)C(=O)Nc1ccc(OCc2cccc(F)c2)cc1

Procedure:
The title compound is prepared in analogy to example 3 from N-[4-(3-fluoro-benzyloxy)-phenyl]-2-methyl-malonamic acid methyl ester and ammonium hydroxide. Colorless solid. Mp=206° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11]O.CC1C=CC(S([O-])(=O)=O)=CC=1.[CH3:24][C:25]1([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[O:29][CH2:28][CH2:27][O:26]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:33]1[CH2:32][CH2:31][CH:30]([C:25]2([CH3:24])[O:26][CH2:27][CH2:28][O:29]2)[CH2:35][CH2:34]1
Reactant: CC1(C2CCNCC2)OCCO1
Reactant: OCC1COc2ccccc2O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC1(C2CCN(CC3COc4ccccc4O3)CC2)OCCO1
Temperature: 75 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 22.5 parts of 2,3-dihydro-1,4-benzodioxin-2-methanol 4-methylbenzenesulfonate (ester), 11.1 parts 4-(2-methyl-1,3-dioxolan-2-yl)piperidine, 15 parts of sodium carbonate and 135 parts of N,N-dimethylacetamide was stirred overnight at 75° C. Water was added. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated, yielding 20.6 parts (100%) of 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-(2-methyl-1,3-dioxolan-2-yl)piperidine as an oily residue (intermediate 86).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:29]=[CH:28][CH:27]=[CH:26][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:4][CH2:5][C:6]1[CH:29]=[CH:28][CH:27]=[CH:26][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH2:2][CH3:3]
Reactant: CCCOCc1ccccc1Oc1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOCc1ccccc1Oc1ccc2c(c1)C=C(C(=O)O)CCS2(=O)=O
Temperature: 65 °C
Reaction time: 20 h
Yield: 64 %

Procedure:
Into a solution of methyl 7-(2-propoxymethylphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.37 g) in THF-methanol (10-5 ml) was added at room temperature a 1 M aqueous solution of potassium carbonate (1.8 ml), and the resulting mixture was stirred at 65° C. for 20 hours. After cooling to room temperature, 1 N hydrochloric acid (10 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-(2-propoxymethylphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (229 mg) as light yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(=O)CC.C(Cl)Cl>[C:22]1([CH2:21][CH2:20][CH2:19][CH2:18][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: BrCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: c1ccc(CCCCOc2ccc3[nH]ccc3c2)cc1
Temperature: 25 °C

Procedure:
A stirred mixture of 5-hydroxyindole (0.5 g, 3.8 mmol), anhydrous K2CO3 (1.58 g, 11.4 mmol), (4-bromobutyl) benzene (2.11 g, 11.4 mmol), and a catalytic amount of Kl in 2-butanone (40 ml) was heated at reflux overnight under nitrogen. After allowing to cool to room temperature, the reaction mixture was filtered, the flitrate then concentrated under reduced pressure to give an oil. The oil was taken up in CH2Cl2 (50 ml) and washed successively with 2N-NaOH (1×20 ml) and water (1×20 ml). The organic portion was dried (MgSO4) and the solvent was removed under reduced pressure to give an oil. The oil was purified by column chromatography using a solvent system of CH2Cl2 /Hexane (40:60) to give 5-(4-phenylbutyloxy)indole as an oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]=[C:16]([NH:20][NH2:21])[C:15]=3[CH2:22][CH2:23][CH3:24])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:25](OC(OCC)OCC)(=O)C.C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]4[CH:25]=[N:21][N:20]=[C:16]4[C:15]=3[CH2:22][CH2:23][CH3:24])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OC(C)=O
Reactant: CCCc1c(Cn2ccnc2-c2ncccc2F)ncnc1NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2cnnc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of 131 (30 mg, 0.09 mmol) and diethoxymethyl acetate (1 mL) is stirred at room temperature for 10 minutes. NaHCO3 (aq.) (10 mL) and dichloromethane (10 mL) are added. The organic layer is separated and the aqueous layer is extracted with dichloromethane (2×10 mL). The combined organic layers are dried (NaSO4) and solvent removed. The crude product is separated by PTLC (10% methanol in dichloromethane) to yield 187; LC-MS, M+1 338.15; 1H-NMR (CDCl3) δ: 8.87 (s, 1H), 8.83 (s, 1H), 8.42 (s, 1H), 7.54 (t, 1H), 7.23–7.34 (m, 3H), 5.79 (s, 2H), 3.02 (t, 2H), 1.66–1.76 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[C:32]([O:34][CH3:35])=[O:33].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:30]4[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=4[C:32]([O:34][CH3:35])=[O:33])[CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccccc1Br
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccccc1N1CCOc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc21
Reaction time: 1 h
Yield: 75.8 %

Procedure:
A mixture of N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate M; 500 mg, 1.196 mmol), methyl 2-bromobenzoate (687 mg, 2.99 mmol, Spectrochem), Pd2(dba3)2 (109 mg, 0.119 mmol), Xantphos (138 mg, 0.239 mmol) and sodium-tert-butoxide (229 mg, 2.392 mmol) in toluene (10 mL) was degassed for 10 minutes. The reaction mixture was subjected to microwave for 1 h at 100° C. After completion, reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combi flash column chromatography (column size: 12 g; elution: 0-20% ethyl acetate in hexane) to get methyl 2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)benzoate (500 mg, 75.7%) as a yellow solid. MS (ESI, positive ion) m/z; 552.1 (M+1)
Reaction SMILES: [C:1]([N:16]([CH3:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[Na+].[CH3:25]O>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:25][O:20][C:19](=[O:21])[CH2:18][CH2:17][N:16]([C:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:22]
Reactant: CO
Reactant: CCCCCCCCCCCCCC(=O)N(C)CCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCC(=O)N(C)CCC(=O)OC

Procedure:
313 g of N-myristoyl-N-methyl-β-alanine (manufactured by Kawaken Fine Chemical Co.) and 256 g of methanol were put into a 1000 ml flask, to which was added 2.85 g of p-toluenesulfonic acid as catalyst, and the mixture was heated for reaction under reflux for 5 hours. After its acid value was confirmed to be not larger than 10, the reaction mixture was neutralized with 1.2 g of an aqueous solution of sodium hydroxide (50%), and then the methanol was evaporated away under reduced pressure. The resulting residue was washed with water and dried to obtain N-myristoyl-N-methyl-β-alanine methyl ester. A 163 g portion of this N-myristoyl-N-methyl-β-alanine methyl ester and 379 g of decaglycerin (manufactured by Sakamoto Pharmaceutical Industry Co.), and then 1.1 g of sodium hydroxide were put into a 1000 ml flask, the atmosphere of which was then replaced with nitrogen. Then, the mixture was subjected to transesterification reaction by keeping it at 150° C. and not more than 60 mmHg for 6 hours to obtain 460 g of a pasty or oily product.
Reaction SMILES: 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.[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][CH:43](O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].[C:47]([OH:50])(=[S:49])[CH3:48]>C1COCC1>[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][CH:43]([S:49][C:47](=[O:50])[CH3:48])[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(O)=S
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 106.9 %

Procedure:
To a 0° C. solution of triphenylphosphine (2.1 g, 8 mmol) in THF (14 ml) was added dropwise (15 minutes) diisopropylazodicarboxylate (1.55 ml, 8 mmol). After 30 minutes stirring at 0° C., a solution containing (RS)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 5.34 mmol) and thioacetic acid (0.57 ml, 8 mmol) in THF (7 ml) was added dropwise. The reaction mixture was stirred 30 minutes at 0° C., 45 minutes at room temperature and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1 then 8:2 then 1:1) to provide (RS)-3-acetylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.4 g, 100%) as a slightly yellow oil, MS: m/e=246.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[C:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][CH:3]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:9][CH:10]=2)[C:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c2ccc(O)cc12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Br)c2ccc(O[Si](C)(C)C(C)(C)C)cc12

Procedure:
A mixture of 4-bromo-1-tert-butoxycarbonylaminonaphth-7-ol, as described above in Step C, (1.62 g, 4.80 mmol), tert-butyldimethylsilyl chloride (1.09 g, 7.20 mmol), and imidazole (0.82 g, 12 mmol), was stirred in dry DMF (40 mL) at ambient temperature for 18 hours. The solvent was removed under reduced pressure, and the residue was partitioned between H2O (100 mL) and Et2O (200 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with CH2Cl2—50% hexane to yield the desired product as a pale solid.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:27]4[CH:28]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: OB(O)c1cncnc1
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(-c4cncnc4)ccc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid isopropyl ester and pyrimidine-5-boronic acid following a procedure analogous to that described in Example 1. LC (method 5): tR=1.49 min; Mass spectrum (ESI+): m/z=368 [M+H]+.
Reaction SMILES: [C:1]1([C@H:7]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[O:17])[C:8]([O:10]C(C)(C)C)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[C:1]1([C@H:7]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)=[O:17])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)[C@@H](NC(=O)Nc1ccc(-c2ccncc2)cc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2ccncc2)cc1)N[C@H](C(=O)O)c1ccccc1

Procedure:
The solution of tert-butyl (2S)-phenyl[({[4-(4-pyridinyl)phenyl]amino}carbonyl)amino]acetate (50.0 mg) in dichloromethane (1.0 mL) and trifluoroacetic acid (954 μL) was stand at ambient temperature for 2 hours. The resulting mixture was concentrated in vacuo and the residue was diluted with chloroform (2 mL), then concentrated. To the residue was added ethyl acetate (2.0 mL) and the precipitated solid was collected by filtration, then washed with ethyl acetate (2.0 mL) to give (2S)-phenyl[({[4-(4-pyridinyl)phenyl]amino}carbonyl)amino]acetic acid trifluoroacetate (39 mg) as off-white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:21]=1B(O)O>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:21]2[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(F)c1B(O)O
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: COc1cccc(F)c1-c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 2-fluoro-6-methoxybenzene boronic acid according to the general procedure B. Obtained as a yellow solid (0.95 g).