Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:14]2[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=2)[C:17]([O:19]C(C)(C)C)=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.II.O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[C:14]2[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=2)[C:17]([OH:19])=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: COc1ccc(CN(c2cccc(C(=O)OC(C)(C)C)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Agent: II
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COc1ccc(CN(c2cccc(C(=O)O)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A solution of 253B (100 mg, 0.20 mmol) in acetonitrile (5 mL) was treated with iodine (15.54 mg, 0.061 mmol) and water (50 μL, 2.78 mmol). The reaction mixture was stirred at 80° C. for 8 hours. The reaction mixture was diluted with ethyl acetate, and washed with water. The aqueous layer was extracted with ethyl acetate (4×20 mL). The pooled organic phase was dried over Na2SO4 and concentrated. The residue was triturated with DCM and filtered. The filtrate was concentrated, dissolved in DCM, and purified by flash chromatography, silica column (12 g, gradient elution from hexanes-ethyl acetate in 15 min.). The appropriate fraction was concentrated under reduced pressure and dried in vacuo to yield 253C (57.5 mg, 64.9% yield) as a yellow solid. HPLC: Rt=4.23 min. (PHENOMENEX® Luna C18 4.6×30 mm 3 u, A10-90% aqueous methanol containing 0.1% TFA in 2 min; 4 mL/min flow). MS (ES): m/z=434.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12]SC)=[CH:7][CH:6]=1)[CH3:3].[N+:16]([CH:19]=[C:20]([NH2:30])[NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][N:23]1[CH2:28][CH3:29])([O-:18])=[O:17]>>[CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12][NH:30][C:20]([NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][N:23]2[CH2:28][CH3:29])=[CH:19][N+:16]([O-:18])=[O:17])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CCN1CCCCC1NC(N)=C[N+](=O)[O-]
Reactant: CSCCSCc1ccc(CN(C)C)o1
Product: CCN1CCCCC1NC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1

Procedure:
24.54 grams of 2-[[5-[(dimethylamino)methyl]furfuryl]thio]ethylmethylsulphide are reacted with 40 grams of 2-nitro-N-(N-ethylpiperidinyl)-1,1-ethenediamine at 80° C. for 3 hours. The mixture is cooled and the procedure described in Example 1 is followed. The product melts at 95°-98° C.; spectrophotometric analyses confirm its structure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[O:21]=[C:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31].O>ClCCl>[O:21]=[C:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH2:28][CH2:29][C:30]([NH:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:31]
Reactant: O=C(Cl)CCCN1CCCC1=O
Reactant: Nc1ncccc1C(=O)c1cccs1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: O=C(CCCN1CCCC1=O)Nc1ncccc1C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 10 ml of dichloromethane are added 1.02 g of 2-amino-3-(2-thenoyl)pyridine and 0.48 ml of pyridine, whereto a solution of 1.1 g of 4-(2-oxopyrrolidin-1-yl)butyryl chloride in 5 ml of dichloromethane is added dropwise under ice-cooling. The mixture is stirred at room temperature for 2 hours. After the completion of the reaction, water is added to the reaction mixture. The dichloromethane layer is washed with water, and then the solvent is distilled off. The residue is recrystallized from a mixed solvent of ethyl acetate and ethanol to give 2-[4-(2-oxopyrrolidin-1-yl)butyrylamino]-3-(2-thenoyl)pyridine, m.p. 149°-151° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.[Br-:10].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[Br:10][C:5]1[C:6]([NH2:9])=[CH:7][N:8]=[C:3]([S:2][CH3:1])[N:4]=1
Reactant: [Br-]
Reactant: CSc1ncc(N)cn1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CSc1ncc(N)c(Br)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 4.8 %

Procedure:
A stirred solution of 2.0 g (14.2 mmol) of 2-methylsulfanylpyrimidin-5-ylamine in 50 mL of dichloromethane and 10 mL of methanol was cooled in an ice bath. 6.08 g (15.6 mmol) of benzyltrimethylammonium tribromide was added in portions over a period of 10 minutes. The mixture was stirred at 0° C. for 15 minutes and then at room temperature for 3 minutes. The mixture was quenched with saturated aqueous sodium bicarbonate solution until the pH was 8. The organic layer separated and was removed. The aqueous layer was extracted with two 200 mL portions of ethyl acetate. The organic layers were combined, washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude mixture was absorbed onto silica gel and chromatographed on silica gel using ethyl acetate-hexanes to afford 150 mg (5%) 4-bromo-2-methylsulfanylpyrimidin-5-ylamine.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][S:10][C:11](SC)=[CH:12][C:13]([C:15]1[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=1[Cl:26])=O>C(O)C>[Cl:21][C:20]1[CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=[C:16]([Cl:26])[C:15]=1[C:13]1[CH:12]=[C:11]([S:10][CH3:9])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: CSC(=CC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl)SC
Reactant: NNc1ccccc1
Solvent: CCO
Product: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1-c1ccccc1

Procedure:
Phenylhydrazine (0.11 ml) was added to a solution of 0.8 g of 3,3-bis[methylthio]-1-(2,6-dichloro-4-trifluoromethylphenyl)-2-propen-1-one in 10 ml of ethanol at room temperature, and the mixture was refluxed for 1 hour. The solvent was distilled of under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel (eluent: ether/hexane=1/6), giving 0.17 g of the desired compound in the form of a pale brown oil (yield 43.6%).
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].[C:6]([C:9]([CH3:11])=O)([CH3:8])=[CH2:7]>[OH-].[Na+]>[CH3:7][C:6]1([CH3:8])[CH2:3][CH:2]([CH3:4])[C:1](=[O:5])[CH:11]=[CH:9]1
Reactant: C=C(C)C(C)=O
Reactant: CC(C)C=O
Agent: [Na+]
Agent: [OH-]
Product: CC1CC(C)(C)C=CC1=O
Yield: 59 %

Procedure:
The procedure of example III was employed on 12 moles of isobutyraldehyde, 11 moles of methyl isopropenyl ketone and 800 ml of 0.8 M aqueous sodium hydroxide solution. After the reaction was completed the aqueous layer was removed. To the residual organic phase was added an equal volume of benzene and a catalytic amount (ca. 5 g) of p-toluenesulfonic acid. The reaction mixture was heated at reflux with concomitant removal of water via a Dean Stark trap. The usual workup and distillation afforded 897 g (59%) of the desired 4,4,6-trimethyl-2-cyclohexenone (II) with physical constants and spectral data identical with that isolated in Example III. Continued distillation afforded no material containing the 5-hydroxy-2,4,4-trimethylcyclohexanone isolated in Example III where the acid treatment step was omitted.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.I[CH:15]1[C:20](OC)([O:21]C)[CH2:19][CH2:18][O:17][CH2:16]1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH:15]2[C:20](=[O:21])[CH2:19][CH2:18][O:17][CH2:16]2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC1(OC)CCOCC1I
Product: O=C1CCOCC1c1ccc(C(F)(F)F)cc1

Procedure:
4-(trifluoromethyl)phenylboronic acid was reacted as described in Intermediate X(2) with 3-iodo-4,4-dimethoxytetrahydro-2H-pyran (Intermediate X(1)) to give 3-(4-(trifluoromethyl)phenyl)dihydro-2H-pyran-4(3H)-one (Intermediate Z(2)).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:14]1[S:15][CH:16]=[CH:17][N:18]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:8][C:5]1[N:6]=[CH:7][C:2]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nccs2)cn1
Temperature: 100 °C
Yield: 77.7 %

Procedure:
To a solution of 5-bromo-2-fluoropyridine (0.5 g, 2.857 mmol) in DMF (6 mL), 2-(tributylstannyl)thiazole (1.3 mL, 4.285 mmol) and Pd(PPh3)2Cl2 (0.2 mg, 0.2857 mmol) were added under argon. The mixture was degassed with argon for 10 min and heated to 100° C. for 30 min. The reaction mixture was filtered through Celite® reagent and the filtrate was diluted with EtOAc (2×100 mL) and water (100 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by Biotage IsoleraOne® column (5% ethyl acetate in hexane) to obtain 2-(6-fluoropyridin-3-yl) thiazole as off-white solid (0.4 g, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.80 (s, 1H), 8.52-8.47 (m, 1H), 7.98 (d, 1H), 7.87 (d, 1H), 7.33 (dd, 1H); LC-MS m/z calculated for [M+H]+ 181.02, found 180.8.
Reaction SMILES: C([O:5][CH2:6][CH:7]([CH2:12][CH3:13])[CH2:8][CH2:9][CH2:10][CH3:11])(=O)C=C.C(N1CCCC1=[O:21])=C.C(O)(=O)C=C.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)(=O)C>[CH3:11][CH2:10][CH2:9][CH2:8][CH:7]([C:6]([OH:5])=[O:21])[CH2:12][CH3:13]
Reactant: C=CN1CCCC1=O
Reactant: C=CC(=O)OCC(CC)CCCC
Agent: C=CC(=O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: CCCCC(CC)C(=O)O

Procedure:
Under an inert gas atmosphere, 72 parts by weight of 2-ethylhexyl acrylate, 25 parts by weight of N-vinyl-2-pyrrolidone, 3 parts by weight of acrylic acid, and 0.2 part by weight of azobisisobutyronitrile were added to ethyl acetate, and then the contents were mixed. The mixture was subjected to solution polymerization at 60° C. Thus, a solution (solid content: 28 w t %) of an acrylic copolymer (2-EHA/AA/N-VP=72/3/25) was obtained.
Reaction SMILES: IC[C:3]1[CH2:10][S:9][C@H:8]2[N:5]([C:6](=[O:23])[C@H:7]2[NH:11][C:12](=[S:22])[CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:24]([O-:26])=[O:25].[SH:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.N1C(C)=CC=C[C:35]=1C>C1COCC1.C(OCC)(=O)C>[N:31]1[CH:32]=[CH:33][C:28]([S:27][CH2:35][O:26][C:24]([C:4]2[N:5]3[CH:8]([S:9][CH2:10][CH:3]=2)[CH:7]([NH:11][C:12](=[S:22])[CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[Cl:21])[C:6]3=[O:23])=[O:25])=[CH:29][CH:30]=1
Reactant: Sc1ccncc1
Reactant: Cc1cccc(C)n1
Reactant: O=C([O-])C1=C(CI)CS[C@@H]2[C@H](NC(=S)Cc3cc(Cl)ccc3Cl)C(=O)N12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(OCSc1ccncc1)C1=CCSC2C(NC(=S)Cc3cc(Cl)ccc3Cl)C(=O)N12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(6R)-trans-3-Iodomethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, diphenylmethyl ester (3.00 g, 4.14 mmol) was dissolved in THF (50 mL) at 0° C. and treated with 4-mercaptopyridine (0.504 g, 4.54 mmol). A solution of 2,6-lutidine (0.576 g, 5.38 mmol) in THF (1 mL) was added next, and the reaction mixture was stirred at 0° C. for 0.5 h and then at 20° C. for 1 h. The mixture was diluted with ethyl acetate (500 mL) and the organic solution was washed with water (2×500 mL) and brine (100 mL). The solution was then dried (MgSO4) and evaporated under reduced pressure to give an oil which was treated with Et20 (50 mL) to give a solid. The solid was collected by filtration and purified by column chromatography on silica gel (CH2Cl2 to 30% EtOAc/CH2Cl2) to give 1.50 g of (6R)-trans-3-[(4-pyridylthiomethyl]-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylate, diphenylmethyl ester as a tan solid (49% yield), m.p. 122° C. 1H NMR (300 MHz, CDCl3) δ 3.37 (d, J=18 Hz, 1 H), 3.52 (d, J=18 Hz, 1 H), 3.68 (d, J=17 Hz, 1 H), 3.76 (d, J=17 Hz, 1 H), 3.96 (d, J=13 Hz, 1 H), 4.16 (d, J=13 Hz, 1 H), 4.93 (d, J=5 Hz, 1 H), 5.76 (dd, J=5, 9 Hz, 1 H), 6.95-7.42 (m, 16 H), 7.49 (d, J=9 Hz, 1 H), 8.29 (d, J=6 Hz, 2 H). Anal. Calcd. for C34H27N3O4S3Cl2 : C, 57.62; H, 3.84; N, 5.93. Found: C, 57.27; H, 3.68; N, 5.79.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[Al+3].[Cl-].[Cl-].C(OC([C@@H](N[C:25]([CH2:27][N:28]1[C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:32][N:31]([C:40](=O)[CH3:41])[CH:30]([CH:43]([CH3:45])[CH3:44])[C:29]1=[O:46])=O)CC1C=CC=CC=1)C#N)(=O)C.[OH2:47]>O1CCCC1>[C:40]([N:31]1[CH:32]=[C:33]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:28]([C@@H:27]([CH2:25][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]([C:30]2[NH:31][N:3]=[N:2][N:1]=2)[OH:46])[C:29](=[O:46])[CH:30]1[CH:43]([CH3:45])[CH3:44])(=[O:47])[CH3:41]
Reactant: O
Reactant: CC(=O)OC(C#N)[C@H](Cc1ccccc1)NC(=O)CN1C(=O)C(C(C)C)N(C(C)=O)C=C1c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1C=C(c2ccccc2)N([C@@H](Cc2ccccc2)C(O)c2nnn[nH]2)C(=O)C1C(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Sodium azide (75.3 mg) and aluminum chloride (386 mg) are added to a solution of (2RS,3S)-2-acetoxy-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutanenitrile (299 mg, Compound No. 18-1) in tetrahydrofuran (3.5 ml), and the mixture is stirred for two hours. The reaction mixture is warmed to 60° C. and stirred for three hours. The reaction mixture is cooled to room temperature, then water is added to the reaction mixture, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (242 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)=[CH:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](O)=[O:26])=[C:16]([C:29]([O:31]C)=[O:30])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[CH:7][CH:8]=2)=[O:26])=[C:16]([CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1ccc(-c2ccoc2)cc1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1ccc(-c2ccoc2)cc1

Procedure:
Using the same method as in Example 1-(ii), 4-(furan-3-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([4-(furan-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 84%).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[C:5](=[CH:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[NH2:6].ClN1C(=[O:21])CCC1=O.[OH-].[Na+]>C(Cl)Cl>[CH3:1][SH:2]1(=[O:21])[CH2:3][C:4]2[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:5]=2[NH:6]1
Reactant: CSCc1cc(C(F)(F)F)ccc1N
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C[SH]1(=O)Cc2cc(C(F)(F)F)ccc2N1
Temperature: 5 °C
Reaction time: 0.13 h

Procedure:
To 10.2 g. of α-methylthio-4-trifluoromethyl-o-toluidine predissolved in 50 ml. of methylene chloride and cooled to -38° C. is added dropwise, over 40 minutes, a solution of 6.2 g. of N-chlorosuccinimide predissolved in 250 ml. of methylene chloride, while the temperature is maintained between -28° and -38° C. After an additional 8 minutes, 13.3 ml. of a 15% aqueous sodium hydroxide solution is added, the cold bath is removed and the reaction mixture allowed to warm to 5° C. To the reaction mixture is added 100 ml. of water, the mixture is shaken, and the phases are separated. The methylene chloride layer is cooled to -20° C. and treated with a solution of 9.7 g. of m-chloroperoxybenzoic acid predissolved in 150 ml. of methylene chloride, added dropwise over 10 minutes. The cold bath is removed and the reaction mixture stirred for 20 minutes, after which time, it is washed successively with an aqueous solution of sodium sulfite and sodium bicarbonate and a saturated aqueous solution of sodium bicarbonate. The phases are separated and the methylene chloride layer is dried, evaporated in vacuo to dryness, and the residue recrystallized from chloroform/petroleum ether to yield 2-methyl-5-trifluoromethyl-2H,3H-2,1-benzisothiazole-S-oxide, m.p. 151°-154° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]2[C:10]([C:11]=1[C:12](=[O:16])[C:13]([NH2:15])=[O:14])=[C:9]([N+:17]([O-])=O)[CH:8]=[CH:7][CH:6]=2)[CH3:2].CCO>C1COCC1>[NH2:17][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:11]([C:12](=[O:16])[C:13]([NH2:15])=[O:14])=[C:3]([CH2:1][CH3:2])[N:4]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCc1c(C(=O)C(N)=O)c2c([N+](=O)[O-])cccc2n1Cc1ccccc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1c(C(=O)C(N)=O)c2c(N)cccc2n1Cc1ccccc1
Reaction time: 4 h
Yield: 30.2 %

Procedure:
A solution of 6.0 g (17.1 mmol) of 2-Ethyl-4-Nitro-α-oxo-1-(phenylmethyl)-1H-indole-3-acetamide in 140 ml of 1:1 THF:EtOH containing 1.0 g of 5% Pt/BaSO4 was hydrogenated at room temperature and 60 psi (4.22 Kg/cm2) for four hours. The catalyst was filtered and the filtrate evaporated in vacuo. The residue was chromatographed over silica gel eluting with Hexane/50 to 100% EtOAC to give 1.66 g (30%) of 4-Amino-2-Ethyl-α-oxo-1-(phenylmethyl)-1H-indole-3-Acetamide melting at 140-144° C.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[N:48]2[CH:49]=[N:50][N:51]=[C:47]2[CH:46]=[CH:45][CH:44]=1>O1CCOCC1.[Cu]I>[N:51]1[N:50]=[CH:49][N:48]2[C:43]([C:11]3[N:12]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:8]4[S:28][C:27]([CH2:29][N:30]5[CH2:31][CH2:32][N:33]([C:36]([CH3:40])([CH3:41])[C:37]([NH2:39])=[O:38])[CH2:34][CH2:35]5)=[CH:26][C:9]=4[N:10]=3)=[CH:44][CH:45]=[CH:46][C:47]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Reactant: Brc1cccc2nncn12
Agent: [Cu]I
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4cccc5nncn45)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Yield: 12.2 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (150 mg, 0.22 mmol), 5-bromo-[1,2,4]triazolo[4,3-a]pyridine (51 mg, 0.26 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium (II) (15 mg, 0.02 mmol) and copper(I) iodide (41 mg, 0.22 mmol) in dioxane (2.5 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the desired product was eluted with 2 M NH3 in MeOH. The appropriate fractions were combined and evaporated. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 690 as a white solid (14 mg, 12%). LCMS (Method F) RT 5.50 min; [M+H]+ 522. 1H NMR (400 MHz, CHCl3-d): δ 10.53 (d, J=0.9 Hz, 1 H); 8.08 (dd, J=7.0, 0.9 Hz, 1 H); 7.93 (d, J=9.1 Hz, 1 H); 7.41 (dd, J=9.1, 7.0 Hz, 1 H); 7.38 (s, 1 H); 7.08 (d, J=5.3 Hz, 1 H); 5.20 (d, J=5.3 Hz, 1 H); 4.07 (t, J=4.8 Hz, 4 H); 3.92 (t, J=4.8 Hz, 4 H); 3.88 (s, 2 H); 2.62 (m, 8 H);1.25 (s, 6 H)
Reaction SMILES: [C:1]1(=O)[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].Cl.[OH-:24].[Na+]>C(S)CCCCCCCCCCC>[OH:22][C:17]1[CH:18]=[CH:19][C:20]([C:13]2([C:1]3[CH:2]=[CH:3][C:6]([OH:24])=[C:5]([CH3:13])[CH:4]=3)[C:5]3[CH:4]=[CH:9][CH:8]=[CH:7][C:6]=3[C:11]3[C:12]2=[CH:1][CH:2]=[CH:3][CH:10]=3)=[CH:21][C:16]=1[CH3:15]
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Reactant: [OH-]
Reactant: Cc1ccccc1O
Agent: CCCCCCCCCCCCS
Agent: Cl
Agent: [Na+]
Product: Cc1cc(C2(c3ccc(O)c(C)c3)c3ccccc3-c3ccccc32)ccc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 156.9 %

Procedure:
A reaction was carried out by (a) feeding 23 g of fluorenone, 1.3 g of dodecyl mercaptan, and 161.0 g of 2-methyl phenol into a 500 ml glass reactor vessel equipped with a stirrer, a condenser and a thermometer, (b) dropping 13.0 g of 35% hydrochloric acid to a mixture, and (c) stirring the mixture at 50° C. for 2 hours. The amount of remaining fluorenone was determined by HPLC, and found to be 0.1% or less. To an obtained reaction mixture liquid, 18.5 g of 29% sodium hydroxide aqueous solution was added, and thereafter 94.0 g of 2-methyl phenol was distilled away from an organic phase by concentration under reduced pressure. To an obtained concentrated liquid, 161 g of toluene and 23 g of water were added, and the mixture liquid was stirred at 80° C. Thereafter, an aqueous phase was separated and removed, and a target substance partitioned in the organic phase was recovered. The organic phase was further washed twice with 23 g of water, and cooled to 10° C. Then, precipitated crystals were subjected to filtration and drying to obtain 37.9 g of 9,9-bis(4-hydroxy-3-methylphenyl)fluorene (yield: 84.3%, LC purity: 99.3%). Obtained 9,9-bis(4-hydroxy-3-methylphenyl)fluorene was dissolved by heat at 230° C. for 2 hours. The 9,9-bis(4-hydroxy-3-methylphenyl)fluorene thus dissolved had a hue of 1 in Gardner. The total amount of toluene used in the production was 4.2 parts by weight relative to 1 part by weight of the 9,9-bis(4-hydroxy-3-methylphenyl)fluorene.
Reaction SMILES: [C@@H:1]12[N:8](C)[C@@H:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[Cl:10]C(OC(Cl)C)=O>C1(C)C=CC=CC=1>[ClH:10].[CH:5]12[NH:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: CC(Cl)OC(=O)Cl
Reactant: CN1[C@@H]2CCC[C@H]1CC2
Solvent: Cc1ccccc1
Product: C1CC2CCC(C1)N2
Product: Cl
Temperature: 120 °C
Yield: 98.4 %

Procedure:
To an oven-dried, 100-mL, round-bottomed flask was added tropane (2.5 g, 19.96 mmol) followed by toluene (20 mL), and a-chloro-ethyl chloroformate (3.2 mL, 30 mmol). The flask was purged with N2 and the mixture was heated at 120° C. for 16 h. The reaction was allowed to cool to room temperature and the solvent was evaporated in vacuo. The resulting residue was dissolved in MeOH (20 mL) and heated to reflux at 85° C. for 3 h. The solvent was evaporated in vacuo and the product dried under vacuum to give 2.90 g (98% yield) of a light brown solid. MS m/z: 112.0 (M+1). 1H NMR (DMSO-d6; 400 MHz): d 1.64 (m, 4), 1.95 (m, 6), 3.92, (s, 2), 9.24 (br d, 2, J=7.3).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:10]=[C:11]1[N:16]2[CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:15]2[CH2:14][NH:13][CH2:12]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]1([C:7]([N:13]2[CH2:12][C:11](=[S:10])[N:16]3[CH2:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH:15]3[CH2:14]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C1CNCC2c3ccccc3CCCN12
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(C1CCCCC1)N1CC(=S)N2CCCc3ccccc3C2C1
Reaction time: 5 h
Yield: 15.5 %

Procedure:
Cyclohexanoyl chloride (0.16 g) was added to a mixture of 4-thioxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepin (0.24 g) and triethylamine (0.25 ml) in chloroform (20 ml, ethanol-free) at 0°. The mixture was maintained at 0° for 30 min then at room temperature for 5 hr. The solution was washed with, first, dilute hydrochloric acid, and secondly with sodium bicarbonate solution. The chloroform solution was dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, Et2O) and recrystallised from dichloromethane/40°-60° C. petroleum ether to give white crystals of the title compound (55 mg, 16%) m.p. 150°-151° C.