Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2].[CH3:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([C:40](O)=[O:41])[C:29]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCN(CC)CC>[C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:40]([C:28]3[C:29]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:32][CH:31]=4)=[C:24]([CH3:23])[CH:25]=[CH:26][CH:27]=3)=[O:41])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2]
Reactant: N#Cc1cccc(CN2CCN(c3ccc(N)cc3)CC2)c1
Reactant: Cc1cccc(C(=O)O)c1-c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2ccc(N3CCN(Cc4cccc(C#N)c4)CC3)cc2)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.1 %

Procedure:
To a stirred solution of 4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (400 mg), 6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid (460 mg), HOBt (222 mg), and Et3N (166 mg) in CH2Cl2 (20 mL) was added at room temperature EDCl (315 mg) and the mixture was stirred at room temperature for 16 hours. The organic solution was then washed with water, with a saturated solution of NaHCO3 and dried over Na2SO4. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography eluting with CH2Cl2/MeOH (98/2) and crystallized from AcOEt to give the title compound (122 mg) as white crystals.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1.[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:5]([C:4]1[CH:3]=[C:2]([C:1]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:10]=2)[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: N#Cc1cccc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#Cc1cccc(-c2nc(=O)c3ccccc3s2)c1
Yield: 3.4 %

Procedure:
A mixture of isophthalonitrile (1.00 g, 07.8 mmol), methyl thiosalicylate (1.97 g, 12 mmol), triethylamine (1.34 g, 13 mmol) and toluene (5 ml) was heated and refluxed for 5 hours under a nitrogen flow. The precipitated crystals were taken by filtration and recrystallized from tetrahydrofuran-ethanol to give the title compound (0.07 g, 2%) as crystals.
Reaction SMILES: [N:1]1([CH2:6][C:7]([O:9]CC)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1>Cl>[N:1]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CN1CCCC1
Agent: Cl
Product: O=C(O)CN1CCCC1
Yield: 91 %

Procedure:
The solution of ethyl 2-(pyrrolidin-1-yl)acetate (2 g, 12.7 mmol, 1.0 eq) in 8 N HCl was stirred at 95° C. for 16 h. The mixture was concentrated and quenched and extracted as in Intermediate Example 15(b). The solvent was distilled off to afford the product in 91% yield (1.5 g). LC-MS (ESI): Calculated mass: 129.1; Observed mass 130.1 [M+H+] (rt: 0.26 min).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[NH:15][O:16][CH3:17])([O-:5])=[O:4].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C=O)C>[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]([O:16][CH3:17])[S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])([O-:5])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CONc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Yield: 20.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.24 g (6.00 mmol)) in DMF (8.0 ml), N-(2,4-dinitrophenyl)-O-methylhydroxylamine (0.85 g (3.99 mmol)) was added under ice-cooling with stirring. After 15 minutes' stirring under ice-cooling, p-toluenesulfonyl chloride (1.15 g (6.03 mmol)) was added. Then, the temperature of the reaction mixture was brought to room temperature and stirred at the same temperature for 18 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography with ethyl acetate-hexane (1:3) as eluent, to give 0.30 g (21%) of the title compound as orange crystals.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4].[OH:14][CH2:15][C@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1.CCN(C(C)C)C(C)C.O>C1COCC1>[OH:14][CH2:15][C@H:16]1[N:21]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)=[O:4])[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2cccc([N+](=O)[O-])c2)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-1-(3-nitrophenyl)ethanone (1.01 g, 4.14 mmol) was dissolved in THF (20 mL) and added (S)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.074 g, 4.97 mmol) followed by Hunig's base (1.45 mL, 8.28 mmol) then stirred at room temperature overnight. The reaction was poured into water and extracted with ETOAC (2×). The organic layer was separated, dried over Na2SO4, filtered and concentrated. The product was purified by chromatography through a 120 g ISCO Redi-sep column eluting with 0-70% ethyl acetate/hexane to yield the title compound.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:3].[CH2:15]([CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1)[C:16]#[CH:17]>>[CH2:15]([CH:18]1[CH2:23][CH2:22][N:21]([C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=2)=[O:3])[CH2:20][CH2:19]1)[C:16]#[CH:17]
Reactant: O=C(Cl)Oc1cccc(C(F)(F)F)c1
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Product: C#CCC1CCN(C(=O)Oc2cccc(C(F)(F)F)c2)CC1

Procedure:
3-(trifluoromethyl)phenyl chloroformate (5.0 g, 29.3 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (1.50 g, 6.72 mmol) according to general procedure 1. Yield=1.1031 g, 64%. m/z MH+=302.02. HPLC rt=10.8 min.
Reaction SMILES: [CH3:1][CH:2]([CH:9]1[C:25]2([CH3:26])[CH:12]([CH:13]3[CH:22]([CH2:23][CH2:24]2)[C:21]2([CH3:27])[C:16]([CH2:17][CH:18]([O:28][C:29](=[O:69])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([N:38]4[CH2:42][CH:41]([OH:43])[CH:40]([CH:44]([C:63]5[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=5)[O:45][CH:46]([C:55]5[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=5)[C:47]5[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=5)[CH2:39]4)=[O:37])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[C:70]1(=[O:76])[O:75][C:73](=[O:74])[CH2:72][CH2:71]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:54][O:53][C:50]1[CH:51]=[CH:52][C:47]([CH:46]([C:55]2[CH:56]=[CH:57][C:58]([O:61][CH3:62])=[CH:59][CH:60]=2)[O:45][CH:44]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:40]2[CH2:39][N:38]([C:36](=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:29]([O:28][CH:18]3[CH2:17][C:16]4[C:21]([CH3:27])([CH:22]5[CH:13]([CH2:14][CH:15]=4)[CH:12]4[C:25]([CH3:26])([CH:9]([CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])[CH2:10][CH2:11]4)[CH2:24][CH2:23]5)[CH2:20][CH2:19]3)=[O:69])[CH2:42][CH:41]2[O:43][C:70](=[O:76])[CH2:71][CH2:72][C:73]([OH:75])=[O:74])=[CH:48][CH:49]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(C(OC(c2ccccc2)C2CN(C(=O)CCCCCNC(=O)OC3CCC4(C)C(=CCC5C4CCC4(C)C(C(C)CCCC(C)C)CCC54)C3)CC2O)c2ccc(OC)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(OC(c2ccccc2)C2CN(C(=O)CCCCCNC(=O)OC3CCC4(C)C(=CCC5C4CCC4(C)C(C(C)CCCC(C)C)CCC54)C3)CC2OC(=O)CCC(=O)O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
Referring to scheme 17, Compound 66(12 g, 12.69 mmol) was mixed with succinic anhydride (1.9 g, 19 mmol) and DMAP (1.56 g, 13 mmol) and dried in a vacuum at 40° C. overnight. The mixture was dissolved in anhydrous dichloromethane (50 mL), triethylamine (2 g, 3.6 mL, 26 mmol) was added and the solution was stirred at room temperature under argon atmosphere for 16 h. It was then diluted with dichloromethane (100 mL) and washed with ice cold aqueous citric acid (5% wt., 100 mL) and water (2×100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography to afford compound 68 as white solid (12.1 g, 91% yield; Rf=0.5 in 10% MeOH/CHCl3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15](F)[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([NH:19][NH2:20])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: N#Cc1ccc(F)cc1OCc1ccccc1
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(NN)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A solution of 2-(benzyloxy)-4-fluorobenzonitrile (4.8 g, 21 mmol), in ethanol (80 mL) was treated with hydrazine monohydrate (2.6 g, 2.5 mL, 53 mmol) and heated to reflux for 3 days. The mixture was cooled to room temperature and concentrated. Water was added and the residue was extracted three times with ethyl acetate, dried over magnesium sulfate, filtered and condensed to give 2-(benzyloxy)-4-hydrazinylbenzonitrile (3.8 g, 15.8 mmol, 75% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.27 (s, 2H), 5.16 (s, 2H), 6.36 (dd, J=8.73, 1.75 Hz, 1H), 6.61 (d, J=1.61 Hz, 1H), 7.30 (d, J=8.59 Hz, 1H), 7.32-7.51 (m, 5H), 7.78 (s, 1H). ES-MS m/z 240 (M+H)
Reaction SMILES: [C:1]1([C:6]2[CH:7]=[N:8][N:9]([CH2:11][CH2:12][C@@:13]([CH3:23])([S:19]([CH3:22])(=[O:21])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:6]2[CH:7]=[N:8][N:9]([CH2:11][CH2:12][C@@:13]([CH3:23])([S:19]([CH3:22])(=[O:20])=[O:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(C2=CCCC2)cn1)S(C)(=O)=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@@](C)(CCn1cc(C2CCCC2)cn1)S(C)(=O)=O
Yield: 39.8 %

Procedure:
A solution of ethyl (2R)-4-[4-(cyclopent-1-en-1-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoate (250 mg, 0.734 mmol, 1 eq) in MeOH (30 mL) was subjected to hydrogenation conditions (10% Pd/C catcart, 10 bar H2 pressure) on a Thales nano H-cube. The mixture was concentrated to give ethyl (2R)-4-(4-cyclopentyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoate (100 mg, 40% yield) which was used without further purification. LC-MS M+H+343.4.
Reaction SMILES: N#N.[OH:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1.[CH3:14]I>C(Cl)Cl>[CH3:14][O:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1
Reactant: CI
Reactant: COC(=O)c1coc(CO)n1
Agent: N#N
Solvent: ClCCl
Product: COCc1nc(C(=O)OC)co1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methyl 2-(hydroxymethyl)oxazole-4-carboxylate (231 mg, 1.47 mmol) in CH2Cl2 (0.9 mL) was treated with MeI (0.11 mL, 1.76 mmol) followed by Ag2O (511 mg, 2.21 mmol) and the resulting mixture (protected from light) was stirred overnight at 40° C. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a colorless oil: TLC: rf (1:1 hept-EA)=0.33. LC-MS-conditions 07: tR=0.49 min, [M+H]+=172.20.
Reaction SMILES: [I-].[CH3:2][Li].[C:4]([C:7](Br)([CH2:19][CH2:20][CH2:21][CH:22]([O:28][C:29](=[O:31])[CH3:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:6])[CH3:5].[Cl-].[NH4+]>CCOCC>[C:4]([C:7]([CH3:2])([CH2:19][CH2:20][CH2:21][CH:22]([O:28][C:29](=[O:31])[CH3:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:6])[CH3:5]
Reactant: [Li]C
Reactant: CCCCCC(CCCC(Br)(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [I-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCC(CCCC(C)(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O
Reaction time: 0.5 h

Procedure:
Cupruous iodide (7.1 g., 0.037 mole) is suspended in ether (150 ml.) and a 1.66 M solution of methyl lithium in ether (45 ml., 0.075 mole) is added dropwise during 30 minutes. Ethyl 8-acetyl-8-bromo-12-acetoxyheptadecanoate (11.9 g., 0.025 mole) is added dropwise during 30 minutes. The temperature is kept at -4° C to -2° C. during these operations by means of a salt bath. Stirring is continued at this temperature for another 30 minutes; then the mixture is stirred for 2 hours without cooling. The reaction mixture is then treated with 200 ml. of saturated ammonium chloride solution. The organic layer is separated, washed with brine and dried over sodium sulfate. Distillation of the solvent in vacuo leaves the crude product as an orange oil weighing 9.2 g. The product is purified by column chromatography using 250 g. of silica gel and chloroform as the eluant. Ethyl 8-acetyl-8-methyl-12-acetoxyheptadecanoate is obtained as yellow viscous oil.
Reaction SMILES: [NH:1]=[C:2]1[C:10]2[C:5](=[C:6]([Cl:14])[C:7]([Cl:13])=[C:8]([Cl:12])[C:9]=2[Cl:11])[C:4](=[NH:15])[NH:3]1.S([O-])([O-])(=O)=[O:17].O[NH3+].O[NH3+]>CN(C)C=O>[N:15](=[C:4]1[C:5]2[C:10](=[C:9]([Cl:11])[C:8]([Cl:12])=[C:7]([Cl:13])[C:6]=2[Cl:14])[C:2](=[NH:1])[NH:3]1)[OH:17]
Reactant: N=C1NC(=N)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: O=S(=O)([O-])[O-]
Agent: [NH3+]O
Solvent: CN(C)C=O
Product: N=C1NC(=NO)c2c(Cl)c(Cl)c(Cl)c(Cl)c21

Procedure:
28.3 Parts, 1,3-diimino-4,5,6,7-tetrachloro-isoindoline and 8.5 parts hydroxyl-ammonium sulphate are stirred in 150 parts dimethylformamide for 1 hour at 80°. After cooling the product can be filtered and washed with dimethylformamide and water to obtain pure 1-oximino-3-imino-4,5,6,7-tetrachloroisoindoline in the form of colourless crystalls which up to 300° only darken but do not melt.
Reaction SMILES: [CH2:1]([P:3]([N:7]=[C:8]=[S:9])([CH2:5][CH3:6])=[O:4])[CH3:2].[F:10][C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH:32]3[NH:36][CH2:35][CH2:34][S:33]3)[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1>CC(C)=O>[CH2:1]([P:3]([NH:7][C:8]([N:36]1[CH2:35][CH2:34][S:33][CH:32]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[O:25][CH2:24][CH2:23][N:20]1[CH2:19][CH2:18][N:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=2)[CH2:22][CH2:21]1)=[S:9])([CH2:5][CH3:6])=[O:4])[CH3:2]
Reactant: Fc1cccc(N2CCN(CCOc3ccccc3C3NCCS3)CC2)c1
Reactant: CCP(=O)(CC)N=C=S
Solvent: CC(C)=O
Product: CCP(=O)(CC)NC(=S)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Reaction time: 24 h
Yield: 85.2 %

Procedure:
0.68 g of diethylphosphoryl isothiocyanate is added to a solution of 1.23 g of 2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine in 20 ml of acetone, and the mixture is stirred for one day. The mixture is concentrated under reduced pressure to remove solvent. The residue is extracted with chloroform, and the extract is washed with a saturated sodium chloride solution, dried and concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, chloroform:methanol=40:1), and the resultant product is recrystallized from ethyl acetate and ether. 1.49 g of N-diethylphosphoryl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carbothioamide are obtained. Yield: 81%.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21](=S)[NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2].C(O)(=[O:32])C>C(OCC)(=O)C>[CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]([NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:32])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2]
Reactant: CC(=O)O
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=S)NCC(C)C)cc21
Solvent: CCOC(C)=O
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=O)NCC(C)C)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of mercuric acetate (0.84 g) in glacial acetic acid (13 cc) is added dropwise during a period of 10 minutes to a solution of 10-[(2RS)-1-diethylamino-2-propyl]-N-(2-methylpropyl)-2-phenothiazinecarbothioamide (1.12 g) in glacial acetic acid (13 cc). The reaction mixture is stirred for 90 minutes at 25° C. and then filtered on sintered glass covered with celite. The celite is washed with acetic acid (2 cc) and the combined filtrates are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give a residue which is then diluted in ethyl acetate (50 cc). The organic phase is washed with normal caustic soda solution (25 cc) and distilled water (3×25 cc) and then with brine (1×25 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give a residue which is purified by chromatography on a column (height: 17.2 cm; diameter: 2.4 cm) of silica gel (0.04-0.06 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a 50:50 (by volume) mixture (1 liter) of cyclohexane and ethylacetate, collecting 60-cc fractions. Fractions 4 to 14 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-[(2RS)-1-diethylamino-2-propyl]-N-(2-methylpropyl)-2-phenothiazinecarboxamide (0.83 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:25])[CH:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][O:23][CH3:24])=[CH:17][CH:16]=3)[CH2:11][O:12]2)=[CH:7][CH:6]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI.CCCCCC.C(OCC)(=O)C>CC(C)=O.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:25])[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][O:23][CH3:24])=[CH:17][CH:16]=3)([CH3:26])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2=O)cc1
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 82.2 %

Procedure:
7-Methoxymethoxy-3-(4-methoxymethoxyphenyl)chroman-4-one(57.4 g, 0.167 mol) (see, Helv. Chim. Acta., 75, 2, 1992, 457-470) was dissolved in acetone(1100 ml), potassium carbonate(230 g, 1.67 mol) and methyl iodide(104 ml, 1.67 mol) were added thereto in order, and the resulting mixture was stirred for 5 days at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer thus obtained was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography(eluent:n-hexane/ethyl acetate=8/1, v/v) to give the title compound(49.2 g, Yield 82%) as a colorless oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[Cl-].[Li+].CS([Cl:33])(=O)=O.C(OC(=O)C)C.Cl>ClCCl.C(N(CC)CC)C>[Cl:33][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CO)cc3)c2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a mixture of (E)-N-[4-(hydroxymethyl)phenyl]-3-(4-methylphenyl)cinnamamide (3.00 g), lithium chloride (741 mg), triethylamine (3.06 ml), DMAP(catalytic amount) and dichloro-methane (300 ml) was added methanesulfonyl chloride (1.15 ml), and the mixture was stirred at room temperature for 13 hours. To the reaction mixture was added 4N hydrochloric acid ethyl acetate solution (3.3 ml), and the mixture was purified with column chromatography (ethyl acetate) and recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-(chloromethyl)phenyl]-3-(4-methylphenyl)cinnamamide (2.00 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]2[NH:21][CH2:20][CH2:19][C:12]3(C(=O)CCC3=O)[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)Cl.[OH-:25].[Na+]>Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]2[CH2:11][C:12](=[O:25])[CH2:19][CH2:20][NH:21]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CCC(=O)C12CCNC(Cc1ccc(F)c(F)c1)C2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCNC(Cc2ccc(F)c(F)c2)C1
Temperature: 75 °C

Procedure:
A mixture of intermediate 12 (0.032 mol) in HCl, (6N; 90 ml) was stirred at 75° C., then cooled. CH2Cl2 was added and the mixture was alkalized with NaOH at a temperature below 20° C. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was dried, yielding 7.2 g of 2-[(3,4-difluorophenyl)methyl]-4-piperidinone (intermediate 13).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8]C.[CH:23]1(C2C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)=NC(C)=CN=2)CC1>>[Br:1][C:2]1[N:3]=[C:4]([CH:21]2[CH2:22][CH2:23]2)[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH3:8]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: Cc1cnc(C2CC2)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: Cc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (1R,2S)-1-[(3-cyclopropyl-6-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.95-1.08, 1.69-1.78, 2.49, 3.04, 3.24, 4.78, 5.39, 5.58, 7.24-7.33; MS (ESI+) for C17H18BrN3O m/z 360 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.[Al]>O=[Mn]=O.O1CCOCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: O=[Mn]=O
Agent: [Al]
Solvent: C1COCCO1
Product: COc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 45 °C
Reaction time: 1.17 h

Procedure:
To a 100 mL flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanol (1.68 g, 3.53 mmol, Intermediate 49: step a) was added 1,4-dioxane (85 mL) to give a suspension at room temperature. Heating to approximately 45° C. formed a clear homogeneous solution. Then activated MnO2 (1.5 g, 17.2 mmol) was introduced and the mixture was heated to reflux in an aluminum heating mantle under an atmosphere of N2. After 70 minutes, the contents were cooled to 60° C. and then filtered through a Celite® pad and rinsed with THF. The resulting solution was concentrated and passed through a silica gel column (5% MeOH-DCM) to give the title compound as a white powder.