Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[Br:15][C:16]1[C:17]([CH3:23])=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[C:16]([Br:15])[C:17]=1[CH3:23])=[O:6]
Reactant: Cc1c(N)cccc1Br
Reactant: Nc1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1c(Br)cccc1NC(=O)c1ccccc1N
Reaction time: 0.25 h
Yield: 42.2 %

Procedure:
A solution of 2-aminobenzoic acid (5.00 g, 36.5 mmol) and thionyl chloride (8.68 g, 72.9 mmol) in toluene (50 mL) was heated at reflux for 60 min. The mixture was concentrated in vacuo, and the residue was suspended in THF (50 mL), cooled in an ice-water bath and treated with 3-bromo-2-methylaniline (20.35 g, 109 mmol). The resulting suspension was heated at reflux for 2 h. The cooled mixture was treated with 10% aqueous K2CO3 (50 mL), stirred vigorously for 15 min, and extracted with EtOAc. The organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel to give 2-amino-N-(3-bromo-2-methylphenyl)benzamide as a light yellow solid (4.70 g, 42% yield). Mass spectrum m/z 305, 307 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 7.72 (d, J=7.9 Hz, 1H), 7.67 (br. s., 1H), 7.54 (dd, J=8.3, 1.2 Hz, 1H), 7.48 (dd, J=7.9, 0.9 Hz, 1H), 7.36-7.31 (m, 1H), 7.15 (t, J=8.0 Hz, 1H), 6.81-6.73 (m, 2H), 5.59 (br. s., 2H), 2.45 (s, 3H).
Reaction SMILES: B.[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C:18](=[CH:19][CH2:20][CH2:21][CH2:22]1)[CH2:17][CH2:16]3.[OH-:28].[Na+].OO>O1CCCC1.O>[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([C@@H:19]([OH:28])[CH2:20][CH2:21][CH2:22]1)[CH2:17][CH2:16]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@]43C)[C@@H]1CC[C@@H]2OC1CCCCO1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CCC[C@H](O)[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC3CCCCO3)CC[C@@H]12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled solution (0° C.) of 5 ml. of 1 M borane in tetrahydrofuran in 2.7 ml. of dry tetrahydrofuran was added 500 mg. (1.4 millimole) of the product of Step C. in 2.0 ml. of dry tetrahydrofuran. The clear solution was stirred for 1 hr. at room temperature and then cooled to 0° C. and treated with 5 ml. of 2.5 N sodium hydroxide followed by 4 ml. of 30% hydrogen peroxide. The solution was stirred for 1 hr. at room temperature, diluted with water and extracted with ethyl ether, washed with water, brine, dried and evaporated to an oily crystalline material. The product was washed with cold methanol and pumped dry to give 175 mg. of final product having a m.p. of 167°-170° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:31]=O.N1CCCCC1>C(O)C>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:31]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: Cc1c(C(=O)N2CCCCC2)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2CCCCC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccncc3)c21
Temperature: 100 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
A mixture of 4-pyridin-4-yl-1,3-dihydroindol-2-one (60 mg, 0.3 mmol), 3-methyl-4-(piperidine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (75 mg, 0.34 mmol) and piperidine (0.14 mL) in ethanol (2 mL) was stirred at 100° C. overnight. The reaction was column chromatographed (2-3% methanol in dichloromethane) to give 20 mg (17%) of the title compound as a yellow orange solid.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1O.Cl.[CH3:13][CH:14]([CH2:16][CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][CH2:23][CH:24]([CH2:26][CH2:27][CH2:28][C:29]([OH:33])([CH:31]=[CH2:32])[CH3:30])[CH3:25])[CH3:20])[CH3:15]>[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C>[CH3:9][C:8]1[C:7]([OH:10])=[C:6]([CH3:11])[C:5]2[CH2:32][CH2:31][C@:29]([CH2:28][CH2:27][CH2:26][C@@H:24]([CH2:23][CH2:22][CH2:21][C@@H:19]([CH2:18][CH2:17][CH2:16][CH:14]([CH3:13])[CH3:15])[CH3:20])[CH3:25])([CH3:30])[O:33][C:3]=2[C:2]=1[CH3:1]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a mixture consisting of 23.3 g (0.153 mol) of 2,3,5-trimethylhydroquinone, 17.5 g (0.128 mol) of zinc chloride, 54 ml of ethyl acetate and 2.5 g of concentrated hydrochloric acid, 46.1 g (0.153 mol) of isophytol (purity: 98.3%) were added dropwise under stirring at 25°-30° C. over 3 hours. At the same temperature, the reaction mixture was stirred for additional 2 hours. After the reaction mixture was washed with 10 ml of water, the solvent was distilled off. Toluene (100 ml) was added to the residue to dissolve the same. The resulting solution was washed successively with water, alkaline water and a saturated aqueous solution of NaCl, dried over magnesium sulfate and then concentrated under reduced pressure, whereby 66.0 g of the title compound were obtained as a brown oil (yield: 95.2%, GLC purity: 95.1%, α-tocopheryl acetate content: 2.0, ethyl acethyl acetate recovery rate: 50%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:13])[N:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[CH:6][C:7]=1[OH:8].[CH2:14]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:13])[N:4]([C:9]([CH3:10])([CH3:12])[CH3:11])[N:5]=[CH:6][C:7]=1[O:8][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][CH2:18][O:17][CH2:14][CH2:15][CH3:16])=[CH:29][CH:28]=1
Reactant: CC(C)(C)n1ncc(O)c(Br)c1=O
Reactant: CCCOCCCOc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOCCCOc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Br)cc1
Reaction time: 3 h
Yield: 41.7 %

Procedure:
In 20 ml of N,N-dimethylformamide were dissolved 1.7 g of 4-bromo-2-t-butyl-5-hydroxy-3(2H)-pyridazinone and 2.0 g of 4-(3-propoxypropoxy)-benzyl bromide, and 1.3 g of anhydrous potassium carbonate was added thereto. The resulting mixture was heated under stirring on an oil bath at 80° to 90° C. for 3 hours. Then, procedures similar to those in Preparation Example 2 were carried out to obtain 1.3 g of the aimed compound as an oil.
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](C=O)=[C:3]1C1C=CC=CC=1.C(CC(OC)=O)#N.N1CCCCC1>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1c(-c2ccccc2)c(C=O)c2ccccc21
Agent: COC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CO
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 263.8 %

Procedure:
To 120 ml of methanol were added 23.5 g (0.10 mol) of 1-methyl-2-phenyl-1H-indole-3-carbaldehyde and 11.9 g (0.12 mol) of methyl cyanoacetate to produce a mixture. Subsequently, 2.5 g (0.03 mol) of piperidine was added to the mixture, reacted under reflux for 6 hours, and cooled to room temperature to precipitate a crystal. The obtained crystal was washed with a small amount of methanol, and then dried to give 30.9 g of a light-yellow crystalline indole compound A having a structure of the general Chemical Formula (1) in which R1 was methyl group and R2 was methyl group. The melting point of the obtained indole compound A was 193.7° C.
Reaction SMILES: [C:1](=[O:6])(OC)[O:2][CH3:3].[CH3:7][N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:18]([Si](C)(C)C)[CH:17]=[CH:16][N:15]([Si](C)(C)C)[CH:14]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:3][O:2][C:1]([N:15]1[CH:16]=[CH:17][CH2:18][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH3:7])=[CH:14]1)=[O:6]
Reactant: COC(=O)OC
Reactant: CN1CCCC1C1=CN([Si](C)(C)C)C=CC1[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)N1C=CCC(C2CCCN2C)=C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of dimethyl carbonate (0.05 mL, 0.6 mmol) in 2 mL of dry THF was slowly added 3-(1-methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1,4-dihydropyridine I (0.2 mL, 0.68 mmol). A solution of TBAF in THF (0.06 mL, 0.06 mmol) was then introduced dropwise and the reaction mixture was stirred at RT for 1 h. The reaction was quenched with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with ether (2 times), and the combined organic layers were washed with brine and dried over K2CO3. The solvent was removed under reduced pressure and the crude material was purified by RPLC hexanes) to afford 0.1374 g (91%) of 3-(1-methylpyrrolidin-2-yl)-4H-pyridine-1-carboxylic acid methyl ester II as a clear oil. IR (thin film, neat, NaCl): 2949, 2826, 2764, 1721, 1695, 1437, 1334, 1313, 1194, 983 cm−1. 1 HNMR (300 MHz, CDCl3): δ 6.68-6.51 (m, 2 H), 4.88-4.77 (m, 1 H), 3.65 (s, 3 H), 2.95-2.91 (m, 1 H), 2.64-2.62 (m, 2 H), 2.41-2.33 (m, 1 H), 2.05-1.93 (m, 5 H), 1.68-1.53 (m, 4 H); 13C NMR (CDCl3, 75 MHz) δ 151.81, 123.15, 122.74, 120.28, 119.63, 118.08, 117.71, 106.22, 105.94, 70.37, 56.60, 53.05, 40.16, 40.08, 28.76, 28.38, 22.37, 21.56, 21.05. HRMS Calcd for C12H18N2O2: 223.1447 [M+H]+. Found: 223.1434 [M+H]+. [α]24D−65.5 (c =8, CH2Cl2).
Reaction SMILES: [I:1][CH2:2][CH2:3][OH:4].Cl[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7].N1C=CC=CC=1.C(OCC)C>C1C=CC=CC=1>[C:6](=[O:7])([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:4][CH2:3][CH2:2][I:1]
Reactant: OCCI
Reactant: CCCCCCCCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCCCCCCOC(=O)OCCI
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a well-stirred solution consisting of 17.89 g. (0.104 mole) of 2-iodoethanol dissolved in 25 ml. of benzene precooled to 0° C. with the aid of an ice/water bath, there is added in a dropwise manner a solution consisting of 20 g. (0.104 mole) n-octyl chloroformate dissolved in 25 ml of benzene. Upon completion of this step, the reaction mixture is treated with 8.3 ml (0.104 ml.) of pyridine which is also added in a dropwise manner. The resulting suspension is then stirred for 30 minutes at 0° C. and thereafter for a period of five hours at room temperature while under a nitrogen atmosphere. At the end of this time, 100 ml. of diethyl ether is added to the mixture and the precipitated pyridine hydriodide is then removed by filtration. The organic filtrate is thereafter washed twice with 3N hydrochloric acid and once with brine, followed by drying over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there is obtained 2-iodoethyl n-octyl carbonate as the residual material.
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)C.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>O.O1CCCC1>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[O:19][CH2:8]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)cc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C2CO2)cc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A suspension of 4.84 g. of sodium hydride (57% mineral oil dispersion) in 70 ml. of dry dimethyl sulfoxide is heated at about 65° C. under argon with stirring for 1 hour. Dry tetrahydrofuran (75 ml.) is added and the resulting solution is cooled to -5° C. Trimethylsulfonium iodide (19 g., 92.8 mmole) is added very slowly and stirring is continued for about 5 minutes. A solution of 12.6 g. (92.8 mmole) of p-methoxybenzaldehyde in 120 ml. of tetrahydrofuran is added and the temperature is maintained at -5° C. After addition is completed the mixture is allowed to warm to room temperature, poured into water and extracted with ether. The extract is washed with saturated sodium chloride solution, dried and evaporated to give p-methoxystyrene oxide.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]#[C:9][NH2:10])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C(Cl)Cl>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:10][CH2:9][C:8]#[C:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[O:19])=[CH:16][CH:15]=1
Reactant: NC#CCCn1ccnc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCC#CCn1ccnc1)c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
A mixture of 2.68 g. of 4-(1H-imidazol-1-yl)-butynamine, 20 ml. of 1N sodium hydroxide and 75 ml. of methylene chloride was stirred and 2.6 ml. of 4-chlorobenzoyl chloride was added. The mixture was stirred for 18 hours, 5 ml. of 1N sodium hydroxide was added and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated to obtain the desired compound.
Reaction SMILES: C[O:2][C:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:12](=[O:14])[N:13]=[C:7]2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:12](=[O:14])[N:13]=[C:7]2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2nc(=O)cccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1cccc2c(O)cccc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.8 %

Procedure:
In 100 ml of methylene chloride was dissolved 25 g of the resulting 6-methoxybenzazepin-2-one, and 66 g of boron tribromide was added thereto dropwise at room temperature over 20 minutes. After stirring at room temperature for 1 hour, the reaction mixture was poured into ice-water, and the precipitated crystals were collected by filtration, washed with water, and dried to provide 18 g of 6-hydroxybenzazepin-2-one.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][CH2:20][OH:21])[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=2[O:21][CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1F)N(CCO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccc(Br)cc2OCCN1Cc1ccccc1
Temperature: 90 °C
Yield: 84 %

Procedure:
To a solution of N-benzyl-4-bromo-2-fluoro-N-(2-hydroxyethyl)benzamide (494 mg, 1.403 mmol) in DMF (14.00 mL) was added NaH (60% in oil) (61.7 mg, 1.543 mmol) slowly. After H2 gas evolved, the reaction mixture was heated at 90° C. for 24 h. After quenched with water, the reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine. After drying over anhydrous sodium sulfate and filtration, the organic layer was evaporated in vacuo. The oily crude 4-benzyl-8-bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one was purified by flash chromatography (gradient EtOAc in heptane) in 84% yield. LCMS (m/z): 332.1/334.1 (MH+), 0.94 min.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:23](I)[CH3:24].[H-].[Na+].C(OCC)(=O)C>C1COCC1.O>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:23][CH3:24])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCNC(=O)OCc1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 15 h
Yield: 80 %

Procedure:
3-Benzyloxycarbonylamino-1-propanol t-butyldimethylsilyl ether (10.1 g) was dissolved in THF (250 ml), and to the resulting solution were added under ice-cooling ethyl iodide (5.1 ml) and a 60% sodium hydride (as a mineral oil dispersion) (2.0 g). The resultant mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 15 hours. Ethyl acetate and water were added to the reaction solution obtained. The organic layer so separated was washed with water and then dried over magnesium sulfate. The solvent was evaporated off from the solution, and the residue was purified by a silica gel chromatography, thus affording the titled compound (8.5 g; 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[S:11].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:15])[CH3:14])[S:11][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)N=C(Nc1c(Cl)cccc1Cl)SCc1ccccc1
Reaction time: 4 h

Procedure:
5.2 g (0.02 M) of N-(2,6-dichlorophenyl)-N'-acetyl-thiourea, 1.7 g of (0.012 M) of ground potassium carbonate 2.6 ml (0.024 M) of benzylchloride and 80 ml of acetone are boiled in a reflux being energetically shaken for 4 hours. The acetone is distilled off. The product in the flask is washed with water and is filtered. After drying N-(2,6-dichlorophenyl)-N'-acetyl-S-benzylisothiourea is obtained with a melting point of 84°-95° C. After being recrystallized twice from ethanol it has a melting point of 99°-101° C., whereby 1.7 g are isolated (24% of the theoretical yield).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][O:11][C:10](=[O:14])[CH:9]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(C)C)(=O)C.C(#N)C>[CH2:1]([N:8]1[CH:13]=[CH:12][O:11][C:10](=[O:14])[C@@H:9]1[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC=CN(Cc2ccccc2)C1c1ccc(F)cc1
Solvent: CC(=O)OC(C)C
Solvent: CC#N
Product: O=C1OC=CN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.04 h

Procedure:
To a solution of N-benzyl-4-fluorophenyl-1,4-oxazin-2-one (10 g) in isopropyl acetate (110 ml) at room temperature was added a solution of (-)-3-bromocamphor-8-sulphonic acid ((-)-3-BCS) (12 g) in acetonitrile (24 ml). Crystallisation began after 2-3 minutes. The slurry was stirred for 1 hour at room temperature. Trifluoroacetic acid (7 ml) was added and the mixture stirred at 65° C. for 3 days. The mixture was cooled to 0°-5° C., aged for 1 hour and the solid collected, washed with isopropyl acetate and dried in vacuo at 40° C., to give the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3-BCS salt: yield 17.24 g, ee 98.6% (S) isomer.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:36]([NH:43][C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Reaction time: 8 h

Procedure:
N-t-Butoxycarbonyl-L-alanine (377 mg, 2.0 mmol), HOBT (283 mg, 2.1 mmol) and EDC hydrochloride (420 mg, 2.2 mmol) were dissolved in 5 mL of DMF. Benzylamine (230 μL, 2.1 mmol) was added followed by triethylamine (280 μL, 1.9 mmol). The mixture was stirred overnight and the solvent was evaporated. The residue was partitioned between ethyl acetate and 10% citric acid and the organic phase was washed sequentially with 10% sodium bicarbonate and brine. The solution was dried and evaporated to yield 498 mg of a waxy solid.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[CH:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=3)[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(C3=CCCCC3)nc3c2CCC3)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Nc2cc(C3CCCCC3)nc3c2CCC3)cc1
Yield: 107.3 %

Procedure:
To a solution of ethyl 2-(4-((2-(cyclohex-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.120 g, 0.32 mmol) in ethanol (10 mL) was added 10% palladium on carbon (0.020 g) and the mixture stirred at under an atmosphere of hydrogen at rt for 16 h. After this time, the mixture was filtered over celite, concentrated, and purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (0.130 g, 100%) as an off-white solid. MW=378.51. 1H NMR (CD3OD, 500 MHz) δ 7.17 (d, J=8.3 Hz, 2H), 7.06 (d, J=8.3 Hz, 2H), 6.57-6.54 (m, 1H), 4.06 (q, J=7.0 Hz, 2H), 3.53 (s, 2H), 2.80 (t, J=7.5 Hz, 2H), 2.69 (t, J=7.5 Hz, 2H), 2.45-2.36 (m, 1H), 2.02 (quin, J=7.5 Hz, 2H), 1.78-1.58 (m, 5H), 1.33-1.13 (m, 8H); APCI MS m/z 379 [M+H]+.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][C:12]([OH:14])=O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:15]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>>[N:1]1([CH2:10][CH2:11][C:12]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][CH:21]=2)=[O:14])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)CCn1cnc2ccccc21
Reactant: CC(C)(C)c1ccc(N)cc1
Product: CC(C)(C)c1ccc(NC(=O)CCn2cnc3ccccc32)cc1

Procedure:
Part C. The title compound was synthesized according to a procedure described in Example 98 starting from 3-benzoimidazol-1-yl-propanoic acid and 4-tert-butyl-aniline. Calculated for C16H23N3O m/z: 321.18, found 322.1 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2.[CH2:13]([O:15][C:16](=[O:21])[CH:17](Cl)[S:18][CH3:19])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:21])[CH:17]([O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[CH:3][C:2]([I:1])=[CH:11]2)[S:18][CH3:19])[CH3:14]
Reactant: Oc1ccc2ncc(I)cc2c1
Reactant: CCOC(=O)C(Cl)SC
Product: CCOC(=O)C(Oc1ccc2ncc(I)cc2c1)SC

Procedure:
In a similar procedure to Stage 2, Step 1 of Example 5, 3-iodo-6-hydroxy-quinoline was reacted with chloro-methylsulfanyl-acetic acid ethyl ester to give (3-iodo-quinolin-6-yloxy)-methylsulfanyl-acetic acid ethyl ester as a yellow coloured solid.