Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]1[CH2:8][C:7]2[C:9]3[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH:21]([CH3:29])[CH:22]([CH3:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][C:10]=3[O:11][C:12]([CH3:14])([CH3:13])[C:6]=2[CH2:5][CH2:4]1)#[N:2].C[O-].[Na+].[Cl-].[NH4+].[CH2:35]([O:37]CC)C>CO>[CH3:13][C:12]1([CH3:14])[C:6]2[CH2:5][CH2:4][N:3]([C:1](=[NH:2])[O:37][CH3:35])[CH2:8][C:7]=2[C:9]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH:21]([CH3:29])[CH:22]([CH3:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][C:10]=2[O:11]1
Reactant: CCCCCC(C)C(C)c1cc(OC)c2c(c1)OC(C)(C)C1=C2CN(C#N)CC1
Reactant: CCOCC
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCCCCC(C)C(C)c1cc(OC)c2c(c1)OC(C)(C)C1=C2CN(C(=N)OC)CC1
Reaction time: 3 h
Yield: 59 %

Procedure:
A mixture of 198 mg (0.5 mmole) of 2-cyano-5,5-dimethyl-8-(1,2-dimethylheptyl)-10-methoxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine and 2.7 mg (0.05 mmole) of sodium methoxide in 8 ml of methanol was refluxed with stirring for 3 hours and allowed to stir overnight at ambient temperature. Ammonium chloride (29.4 mg; 0.55 mmole) was added and the stirring was continued for an additional 2 hours. The reaction mixture was concentrated on a rotary evaporator to give a residue to which was added 1 ml of diethyl ether. The solid was collected by filtration to give 138 mg in two crops (59%) of methyl 5,5-dimethyl-8-(1,2-dimethylheptyl)-10-methoxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine-2-carboximidate as a light yellow solid, m.p. 134°-36° C. The ir and nmr spectra confirmed the structure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N+:31]([O-:33])=[O:32])=[C:26]([CH:30]=1)[C:27](Cl)=[O:28]>ClCCl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N+:31]([O-:33])=[O:32])=[C:26]([CH:30]=1)[C:27]([NH:14][C:11]1[CH:12]=[CH:13][N:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[N:10]=1)=[O:28]
Reactant: Cc1ccc(-n2ccc(N)n2)cc1C
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3[N+](=O)[O-])n2)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 1-(3,4-dimethylphenyl)-1H-pyrazol-3-amine (408 mg, 2.18 mmol, 1.00 equiv) in dichloromethane (10 mL), pyridine (518 mg, 6.56 mmol, 3.00 equiv), and 5-chloro-2-nitrobenzoyl chloride (575 mg, 2.61 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The solution was adjusted to pH 7 with hydrochloric acid (1 mol/L). The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 600 mg (59%) of 5-chloro-N-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-yl)-2-nitrobenzamide as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=1.CO.C(Cl)Cl>COCCO>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:13]=[CH:12][C:5]3[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:16][CH:17]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCCNC2=O
Solvent: ClCCl
Solvent: COCCO
Solvent: CO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCNC3=O)ncc1Cl
Temperature: 120 °C
Yield: 25 %

Procedure:
7-Amino-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (21 mg, 0.12 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (36 mg, 0.12 mmol) were suspended in 2-methoxyethanol (1 ml), and heated to 120° C. for 5 hours. Concentration afforded a yellow solid. Preparative TLC (5% MeOH/CH2Cl2) gave the title compound the desired as a white solid, 13 mg. (25% yield) 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 9.68 (s, 1H), 8.68-8.77 (m, 2H), 8.30 (s, 1H), 7.80-7.86 (m, 1H), 7.71-7.78 (m, 1H), 7.59 (s, 2H), 7.43-7.51 (m, 1H), 7.34-7.39 (m, 1H), 7.12-7.18 (m, 1H), 2.85-2.97 (m, 2H), 2.79 (s, 3H), 2.60-2.71 (m, 2H), 1.80-1.90 (m, 2H); MS (m/e) 437 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH:29]1[CH2:32][CH:31]([C:33]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])[CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][N:2]1[C:10]([CH2:11][N:29]2[CH2:30][CH:31]([C:33]([N:35]3[CH2:36][CH2:37][CH2:38][CH2:39]3)=[O:34])[CH2:32]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: O=C(C1CNC1)N1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C(=O)N4CCCC4)C3)n(C)c2n1
Reaction time: 18 h
Yield: 35.9 %

Procedure:
A solution of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.27 mmol) and azetidin-3-ylpyrrolidin-1-ylmethanone (50 mg, 0.32 mmol) in DCE (3 mL) was stirred at ambient temperature for 90 min. Sodium triacetoxyborohydride (86 mg, 0.41 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; gradient from 100:0 to 70:30) to afford 348 as a white foam (50 mg, 37%). LCMS (Method G): RT=5.81 min, M+H+=516. 1H NMR (CDCl3, 400 MHz) δ 8.08 (m, 1 H); 7.71 (m, 1 H); 7.26 (m, 2 H); 4.35 (m, 4 H); 3.89-3.83 (m, 9 H); 3.66 (m, 2 H); 3.55-3.43 (m, 5 H); 3.31 (m, 2 H); 2.94 (s, 3 H) and 1.98-1.81 (m, 4 H)
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C([O:13][C:14]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[N:22]=[CH:21]2)=[CH2:15])CCC.O>C1COCC1>[Br:8][CH2:13][C:14]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[N:22]=[CH:21]2)=[O:15]
Reactant: C=C(OCCCC)c1cccc2cnc(Nc3ccccc3)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1cccc2cnc(Nc3ccccc3)nc12
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 125.1 %

Procedure:
NBS (58.2 mg, 0.327 mmol) was added to a solution 8-(1-butoxyvinyl)-N-phenylquinazolin-2-amine (104.5 mg, 0.327 mmol) in THF (2.4 mL) and water (0.094 mL, 5.23 mmol) at 0° C. and the resulting mixture was stirred at 0° C. for 2 min. The mixture was partitioned between Et2O (50 mL) and water (30 mL). The organic layer was separated, sequentially washed with saturated aq. NaHCO3 (20 mL), water (20 mL), and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide crude 2-bromo-1-(2-(phenylamino)quinazolin-8-yl)ethanone (140 mg) as a yellow-orange oil. NH4OAc (101 mg, 1.309 mmol) and piperidine-2,4-dione (44.4 mg, 0.393 mmol) were added to the resulting oil, and the mixture was taken up in EtOH (2.4 mL) and stirred under argon in a sealed flask at 50° C. for 15.5 h. The reaction was cooled to 25° C. and concentrated in vacuo. The residue was partitioned between DCM (50 mL) and saturated aq. NaHCO3 (30 mL). The aq. layer was extracted with DCM (3×30 mL), and the combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-10% MeOH/DCM) furnished 2-(2-(phenylamino)quinazolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (21.3 mg, 0.060 mmol, 18% yield) as a yellow-orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.99 (1H, br. s.), 9.97 (1H, s), 9.35 (1H, s), 8.14 (1H, d, J=7.6 Hz), 7.78 (3H, t, J=7.4 Hz), 7.34-7.45 (4H, m), 7.10 (1H, t, J=7.0 Hz), 7.03-7.07 (1H, m), 3.43 (2H, t, J=6.9 Hz), 2.79 (2H, t, J=6.6 Hz). m/z (ESI, +ve) 356.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]4[B:18]([OH:25])[O:19][C:20]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:16]=4[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(=O)CCCC1>CCC(=O)CC>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:28]([F:29])([F:31])[F:30])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]4[B:18]([OH:25])[O:19][C:20]5([CH2:23][CH2:24][CH2:22][CH2:21]5)[C:16]=4[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCC1(CC)OB(O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc21
Solvent: CCC(=O)CC
Solvent: O=C1CCCC1
Product: OB1OC2(CCCC2)c2cc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc21

Procedure:
The title compound was prepared by using the same method as described for 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-diethyl-benzo[c][1,2]oxaborol-1(3H)-ol with cyclopentanone to replace 3-pentanone. It was obtained as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.20 (s, 1 H), 7.80 (t, J=1.8 Hz, 1 H), 7.72 (s, 3 H), 7.61 (d, J=1.5 Hz, 2 H), 4.44 (d, J=18.3 Hz, 1 H), 4.31 (d, J=18.3 Hz, 1 H), 2.11-1.71 (m, 8 H) ppm.
Reaction SMILES: [CH:1]1(/[CH:6]=[CH:7]/[C@H:8]([C@@H:10]2[O:14][C:13](=[O:15])[C@H:12]([O:16][CH3:17])[C@@H:11]2[OH:18])[OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:20][C@H:21]1[CH2:27][CH2:26][C:25]2[CH:28]=[C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:30]=[CH:31][C:24]=2[NH:23][C:22]1=[O:38].C(C(CCCC)C([O-])=O)C.[Na+]>C1COCC1>[CH:1]1(/[CH:6]=[CH:7]/[C@@H:8]([OH:9])[C@H:10]([OH:14])[C@@H:11]([OH:18])[C@@H:12]([O:16][CH3:17])[C:13]([NH:20][C@H:21]2[CH2:27][CH2:26][C:25]3[CH:28]=[C:29]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:30]=[CH:31][C:24]=3[NH:23][C:22]2=[O:38])=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/C2CCCC2)[C@H]1O
Reactant: N[C@H]1CCc2cc(-c3ccccc3)ccc2NC1=O
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)N[C@H]1CCc2cc(-c3ccccc3)ccc2NC1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C1CCCC1
Yield: 46.4 %

Procedure:
100 mg of 19 (0.39 mmol), 112.6 mg of 14a (0.39 mmol) and 162 mg of sodium 2-ethylhexanoate (0.98 mmol) in 2.0 ml of THF are successively introduced into a Wheaton tube, with agitation and under an argon atmosphere. The agitation is maintained at AT for 24 h. The reaction medium is directly evaporated to dryness. The crude is chromatographed on a silica cartridge (12 g, eluent EtOAc). 92 mg of expected product Ex5 (white solid) are obtained.
Reaction SMILES: F[C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:11][O-:12].[Na+].O>CO>[F:10][C:3]1[CH:2]=[CH:9][CH:8]=[C:7]([O:12][CH3:11])[C:4]=1[C:5]#[N:6]
Reactant: N#Cc1cccc(F)c1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc(F)c1C#N
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
640.5 g (4.6 mol) of difluorobenzonitrile were dissolved in 3.5 l of methanol and then cooled to 0-5° C. 828.8 g of 30% strength sodium methoxide solution were added dropwise in this temperature range, and the reaction mixture was stirred at room temperature overnight. Then the reaction mixture was added to 20 l of water and the precipitate was filtered off with suction and washed twice with water and twice with heptane. The solid was dried in vacuo at 50° C. Yield: 740 g (99% of theory) of a white solid with a purity of >95% according to GC.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].Br[C:29]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[C:32]([NH2:33])=[C:31]([CH2:39]C)[CH:30]=1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[CH3:39][C:31]1[CH:30]=[C:29]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[C:32]=1[NH2:33]
Reactant: CCc1cc(Br)cc([N+](=O)[O-])c1N
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Product: Cc1cc(N2CCOCC2)cc([N+](=O)[O-])c1N
Temperature: 85 °C
Reaction time: 72 h

Procedure:
To a 800 ml pressure flask was added tris(dibenzylideneacetone)dipalladium (2.64 g, 2.88 mmol), 2-(di-t-butylphosphino)biphenyl (1.42 g, 4.75 mmol) and sodium tert-butoxide (17.5 g, 182 mmol). Then dry THF (500 mL), 4-bromo-2-ethyl-6-nitroaniline (30.0 g, 130 mmol) and morpholine (34 ml, 390 mmol) were added. Argon was bubbled through the solution for 1 minute and the flask was sealed. The reaction mixture was stirred at 85° C. for 3 days. THF was evaporated in vacuo and the crude product was preabsorbed on silica and this then transferred on top of a silica gel column. Elution with hexane-ethyl acetate (6:4 to 4:6 to 0:1 gradient) gave, after evaporation of solvents, the title compound (15.2 g red-brown solid, 49.3%). LCMS (M+H)+ m/z 238 (t=0.64 min.) 1H NMR (500 MHz, DMSO-d6) δ 7.32 (1H, s), 7.22 (1H, s), 6.96 (2H, s), 3.72 (4H, broad s), 2.96 (4H, broad s), 2.21 (3H, s). Procedure for the Preparation of 4-(3-amino-5-methyl-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([OH:23])[CH:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].COC(=O)[C@H](O)[C@H](C1C=CC=CC=1)NC(OCC1C=CC=CC=1)=O.CO[CH:51](OC)[C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][C:53]=1[O:60][CH3:61].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C@@H:4]1[O:23][CH:51]([C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][C:53]=2[O:60][CH3:61])[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[C@H:5]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:24]
Reactant: COC(=O)C(O)C(NC(=O)OCc1ccccc1)c1ccccc1
Reactant: COc1ccc(C(OC)OC)c(OC)c1
Agent: COC(=O)[C@H](O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1OC(c2ccc(OC)cc2OC)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1

Procedure:
N-Carbobenzyloxy-β-phenyl isoserine methyl ester (Preparation No. 19, 3C, 0.375 g, 1.14 mM) is dissolved in dry THF (10 mL) and the solution treated with 2,4-dimethoxy benzaldehyde dimethyl acetal (4, 0.300 g, 1.42 mM) and pyridinium p-toluenesulfonate (10 mg) and the solution heated to distill off the THF and methanol. After ½ the THF is distilled off, THF (10 mL) is added and the reaction distilled to ½ volume again. The process is repeated three times. The reaction is then concentrated in vacuo and the residue chromatographed over 75 g silica gel packed and eluted in acetone-hexane (300 mL of 20-80 and 300 mL of 25-75). Fractions of 20 mL are collected and analyzed by TLC. The following fractions are combined and evaporated under vacuum.
Reaction SMILES: [CH3:1][S:2][CH2:3][O:4]CSC.[P:8]([O-])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].IN1C(=O)CCC1=O>C1COCC1.C(OCC)(=O)C>[P:8]([O:4][CH2:3][S:2][CH3:1])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:9]
Reactant: CSCOCSC
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSCOP(=O)(OCc1ccccc1)OCc1ccccc1
Reaction time: 4 h
Yield: 75.8 %

Procedure:
To a solution of bis(methylthiomethyl)ether (30 mg, 2.34 mmol) and molecular sieves (300 mg) in THF (100 ml) at room temperature was added dibenzyl phosphate (2.74 g, 9.85 mmol) followed by N-iodosuccinimide (608 mg, 2.71 mmol) and the solution was stirred for 4 h. The reaction mixture was then diluted with ethyl acetate and filtered through a pad of celite. The filtrate was treated with a 1:1 (v:v) solution of saturated aqueous sodium bicarbonate and 5% aqueous sodium thiosulfate. The colorless organic extract was then washed with brine, dried over sodium sulfate and concentrated in vacuo to provide 600 mg (69%) of the title compound:
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14]CC)=[O:13])([O-:3])=[O:2].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C(=O)([O-])[O-]>>[N+:1]([C:4]1[C:9]([O:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([OH:14])=[O:13])([O-:3])=[O:2]
Reactant: Oc1ccccc1Cl
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Product: O=C(O)Cc1cccc(Oc2ccccc2Cl)c1[N+](=O)[O-]
Yield: 24.3 %

Procedure:
A mixture of ethyl 2-(2-nitro-3-chlorophenyl)acetate (15 g.), 2-chlorophenol (11.7 g.), anhydrous pottassium carbonate (12.8 g.) and cupric oxide (1.5 g.) was treated in a similar manner to the above Preparations to give 2-[2-nitro-3-(2-chlorophenoxy)phenyl]acetic acid (4.6 g.). mp 162° to 164° C. A mixture of thus obtained product, ethanol and a small amount of conc. sulfuric acid was treated in a similar manner to the above to give oily ethyl 2-[2-nitro-3-(2-chlorophenoxy)phenyl]acetate (5 g.).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2N)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(=O)(=O)(O)[OH:19].N([O-])=O.[Na+].[OH-].[Na+].C(Cl)(=O)C>O.CO.C(Cl)(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[OH:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)N1CCN(c2ccc(F)cc2N)CC1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)Cl
Solvent: CO
Product: CC(=O)N1CCN(c2ccc(F)cc2O)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-acetyl-4-(2-amino-4-fluorophenyl)piperazine (25 g) and conc. sulfuric acid (42 ml) in water (210 ml) was added dropwise a solution of sodium nitrite (13 g) in water (46 ml) under ice-cooling. This reaction mixture was stirred at the same temperature for 4 hr and at room temperature for 6 hr. To the reaction mixture was added an aqueous sodium hydroxide solution to make it alkaline and acetyl chloride was added dropwise. The mixture was stirred at the same temperature for 30 min, passed through Celite and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a black oil. The oil was subjected to silica gel column chromatography (developing solvent; chloroform:methanol=9:1) to give a black solid. This solid was recrystallized from ethyl acetate-isopropyl ether to give the title compound (0.66 g) as a pale-brown solid, m.p.=183-185° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][N:12]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][CH2:14][C:13]1=[O:24].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1)[CH:30]=O.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1)/[CH:30]=[C:14]1/[C:13](=[O:24])[N:12]([CH3:11])[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15]/1
Reactant: CN1C(=O)CCCC1c1ccccc1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CCC(c3ccccc3)N(C)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 1.1 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 1.59 mL) was added dropwise to a solution of 1-methyl-6-phenylpiperidin-2-one (200 mg) synthesized in accordance with a technique described in a document (see N. P. Baens et al., “Tetrahedron”, 1993, vol. 49, pp. 3193-3202, for example) in THF (5 mL) at −78° C., and the reaction solution was stirred at room temperature for 30 minutes. This solution was added dropwise to a solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (248 mg) and a boron trifluoride-dimethyl ether complex (134 μL) in THF at −78° C., and the reaction solution was stirred overnight while heating to room temperature. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to collect the part in which an aldol derivative eluted. The elution part was concentrated under reduced pressure. Methanesulfonyl chloride (33.9 mg), triethylamine (206 μL) and methylene chloride (25 mL) were added to the residue, and the reaction solution was stirred at room temperature for 3 days. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by LC-MS to obtain 4.54 mg of the title compound. Properties data of the compound are as follows.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13](I)[C:12]=2[C:22]#[N:23])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[Cl-].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][Zn+])=[CH:28][CH:27]=1>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([Cl:25])=[CH:27][CH:28]=3)[C:12]=2[C:22]#[N:23])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccnc(NC(C)=O)c2)c(C#N)c1I
Reactant: Clc1ccc(C[Zn+])cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-c2ccnc(NC(C)=O)c2)c(C#N)c1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a solution of ethyl 5-[2-(acetylamino)pyridin-4-yl]-4-cyano-3-iodothiophene-2-carboxylate (0.209 g, 0.474 mmol) in tetrahydrofuran (3.3 mL) was added 4-chlorobenzylzinc chloride (0.50M solution in tetrahydrofuran, 1.89 mL, 0.947 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.0182 g, 0.0355 mmol) under argon. The solution was stirred at 60° C. for 3 hours. The reaction was allowed to cool to room temperature and then the solvent was evaporated in vacuo. Column chromatography was performed to yield the title compound (0.159 g, 76%). LCMS: (FA) ES+ , 440. 1H NMR (400 MHz, CDCl3) δ: 8.66 (br s, 1H), 8.60 (br s, 1H), 8.38 (d, J=5.27 Hz, 1H), 7.51-7.47 (m, 1H), 7.33-7.23 (m, 4H), 4.51 (s, 2H), 4.39 (q, J=7.03 Hz, 2H), 2.24 (s, 3H), 1.39 (t, J=7.03 Hz, 3H).
Reaction SMILES: C([N:8]1[CH2:18][CH2:17][N:16]2[C@@H:10]([CH2:11][CH2:12][O:13][C:14]3[C:22]([Br:23])=[CH:21][CH:20]=[CH:19][C:15]=32)[CH2:9]1)C1C=CC=CC=1.C(Cl)(=O)OCCCl.CO>ClC(Cl)C>[Br:23][C:22]1[C:14]2[O:13][CH2:12][CH2:11][C@H:10]3[CH2:9][NH:8][CH2:18][CH2:17][N:16]3[C:15]=2[CH:19]=[CH:20][CH:21]=1
Reactant: Brc1cccc2c1OCC[C@H]1CN(Cc3ccccc3)CCN21
Agent: O=C(Cl)OCCCl
Solvent: CC(Cl)Cl
Solvent: CO
Product: Brc1cccc2c1OCC[C@H]1CNCCN21
Temperature: 85 °C

Procedure:
To a solution of Example 236A (60 mg, 161 mmol) in dichloroethane (0.5 mL) was add chloroethyl carbonochloridate (39.1 mg, 0.273 mmol). The mixture was heated for 2 hours at 85° C. Methanol (2 mL) was added, and the mixture cooled to room temperature. The solution was concentrated and NaOH (1 M, aqueous) was added until pH=10. The product was extracted with ethyl acetate. Purification via flash chromatography (0-70% methanol/dichloromethane) afforded the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.12 (dd, J=7.93, 1.53 Hz, 1H), 6.81-6.98 (m, 2H), 4.27-4.38 (m, 1H), 4.13-4.21 (m, 1H), 3.02-3.15 (m, 3H), 2.89-2.99 (m, 1H), 2.76-2.88 (m, 2H), 2.64-2.75 (m, 1H), 1.83-1.98 (m, 2H); MS (DCI+) m/z 283 (M+H)+.