Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9](Cl)=[C:10]([N+:19]([O-:21])=[O:20])[C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:5])[CH3:2].CO.[CH2:26]([NH2:28])[CH3:27]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]([NH:28][CH2:26][CH3:27])=[C:10]([N+:19]([O-:21])=[O:20])[C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:5])[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NCCCN(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: CCNc1nc(C)c(C(=O)OCC)c(NCCCN(C)C)c1[N+](=O)[O-]

Procedure:
34.5 g. of 6-chloro-4-[[3-(dimethylamino)propyl]amino]-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.1 Mol.) are dissolved in 200 ml. of methanol. A mixture of 15 g. of triethylamine and 6 g. of ethylamine are added and the solution is refluxed for one hour with stirring. The solvent is distilled off in vacuo and the residue treated with about 100 ml. of water. The aqueous phase is extracted three times with 100 ml. portions of ether, the ether layers are combined, dried over calcium chloride and the solvent distilled off. The resulting yellow oil is recrystallized from ether/ligroin, yield 31 g. (88%), m.p. < 20°.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH2:6][CH2:7][NH:8][N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>C(OCC)(=O)C>[C:1]([N:8]([CH2:7][CH2:6][OH:5])[N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: OCCNN=Cc1ccccc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)N(CCO)N=Cc1ccccc1

Procedure:
0.78 g (10-2 moles) of acetyl chloride is added dropwise to a solution containing 10-2 moles of benzaldehyde (2-hydroxyethyl)hydrazone and 0.79 g (10-2 moles) of anhydrous pyridine in 20 ml of anhydrous ethyl acetate, with stirring in the cold.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([CH3:11])[CH:5]=1)=[C:2]=[O:3].[CH3:12][CH:13]([CH3:36])[CH:14]([NH:19][C:20]([C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=2)[N:26]=1)=[O:21])[C:15]([O:17][CH3:18])=[O:16]>>[CH3:11][C:6]1[CH:5]=[C:4]([NH:1][C:2](=[O:3])[NH:33][C:30]2[CH:31]=[CH:32][C:27]([C:25]3[N:26]=[C:22]([C:20]([NH:19][CH:14]([CH:13]([CH3:36])[CH3:12])[C:15]([O:17][CH3:18])=[O:16])=[O:21])[S:23][CH:24]=3)=[CH:28][CH:29]=2)[CH:9]=[CH:8][C:7]=1[CH3:10]
Reactant: Cc1ccc(N=C=O)cc1C
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Product: COC(=O)C(NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccc(C)c(C)c3)cc2)cs1)C(C)C
Yield: 75 %

Procedure:
The title compound was synthesized analogous to Example 23, using 4-isocyanato-1,2-dimethylbenzene and intermediate 3. Yield: 75%; 1H NMR (DMSO-d6, 300 MHz): δ 8.80 (s, 2H), 8.51 (s, 1H), 8.30 (s, 1H), 8.03 (d, 2H), 7.57 (d, 2H), 7.24 (s, 1H), 7.19 (d, 1H), 7.07 (d, 1H), 4.39 (t, 1H), 3.70 (s, 3H), 2.31 (m, 1H), 2.19 (s, 3H), 2.16 (s, 3H), 0.97 (t, 6H).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH3:17])[C:11]=1[C:18]1[N:23]=[CH:22][C:21]([CH:24]=[O:25])=[C:20]([O:26][CH3:27])[CH:19]=1)[CH3:9].[NH4+].[Cl-]>CCOCC>[CH2:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH3:17])[C:11]=1[C:18]1[N:23]=[CH:22][C:21]([CH:24]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:25])=[C:20]([O:26][CH3:27])[CH:19]=1)[CH3:9]
Reactant: [Li]c1ccccc1
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C=O)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCc1cccc(CC)c1-c1cc(OC)c(C(O)c2ccccc2)cn1
Reaction time: 2 h

Procedure:
Phenyllithium (1M in THF, 0.26 mL) is added dropwise to a solution of 6-(2,6-diethyl-phenyl)-4-methoxy-pyridine-3-carbaldehyde (70 mg, 0.26 mmol) in ether (4 mL) at room temperature. The mixture is stirred for 2 hours, then treated with aqueous NH4Cl solution (4 mL) and diluted with ether (10 mL). The organic layer is separated, dried and concentrated. The crude is purified by PTLC (4:1 hexane/EtOAc) to give [6-(2,6-diethyl-phenyl)-4-methoxy-pyridin-3-yl]-phenyl-methanol. 1H NMR (CDCl3) 8.51 (s, 1H), 7.26-7.43 (m, 6H), 7.15 (d, 2H), 6.76 (s, 1H), 6.06 (s, 1H), 3.82 (s, 3H), 3.21 (s, 1H), 2.32 (m, 4H), 1.05 (m, 6H).
Reaction SMILES: C([O:4][CH:5]([CH2:45][O:46]C(=O)C)[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[C:22](=[O:23])[CH2:21][O:20][CH2:19][CH:18]2[CH2:24][O:25]C(=O)C)[C:13]([I:29])=[C:12]([C:30]([NH:32][CH2:33][CH:34]([O:40]C(=O)C)[CH2:35][O:36]C(=O)C)=[O:31])[C:11]=1[I:44])=[O:9])(=O)C.C[O-].[Na+].[Na]>CO.O>[OH:40][CH:34]([CH2:35][OH:36])[CH2:33][NH:32][C:30]([C:12]1[C:13]([I:29])=[C:14]([N:17]2[C:22](=[O:23])[CH2:21][O:20][CH2:19][CH:18]2[CH2:24][OH:25])[C:15]([I:16])=[C:10]([C:8]([NH:7][CH2:6][CH:5]([OH:4])[CH2:45][OH:46])=[O:9])[C:11]=1[I:44])=[O:31]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2C(=O)COCC2COC(C)=O)c1I)OC(C)=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: O=C(NCC(O)CO)c1c(I)c(C(=O)NCC(O)CO)c(I)c(N2C(=O)COCC2CO)c1I
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of N,N'-bis[2,3-bis(acetyloxy)propyl]-5-[3-(Acetyloxy)methyl-5-oxo-4-morpholinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide (5.15 g, 5 mmol) in anhydroous methanol (100 ml), was added a solution of sodium methoxide, prepared from sodium (25 mg) and anhydrous methanol (5 ml), and the mixture was stirred for 3 hours. The solution was adjusted to pH 7 by a slow addition of Dowex-50 (H+) resin and then filtered. The filtrate was concentrated in vacuo to obtain the crude product (3.85 g) as a white solid. The material was dissolved in water (40 ml) and loaded onto a column of CHP-20 diaion resin. The column was first eluted with water (1L) and then with a stepwise gradient of ethanol in water (1-8%). The fractions containing the pure product were combined and the solvents removed in vacuo to obtain N,N'-Bis(2,3-dihydroxypropyl)-5-[3-(hydroxymethyl)-5-oxo-4-morpholinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as a white microcrystalline solid (2.45 g, 60% yield, 99% purity). Recrystallization from ethanol/isopropanol (95/5) afforded the analytical sample as a white solid, m.p. 227°-230°.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]([CH3:16])=[N:14][C:13]2[C:8](=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[NH:36][C:35]2[CH2:34][CH2:33][CH2:32][NH:31][C:30](=[O:37])[C:29]=2[CH:28]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CO.C(Cl)Cl>O1CCOCC1.O.C(Cl)Cl.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]>[C:1]([NH:5][C:6]1[C:15]([CH3:16])=[N:14][C:13]2[C:8]([N:7]=1)=[C:9]([C:27]1[NH:36][C:35]3[CH2:34][CH2:33][CH2:32][NH:31][C:30](=[O:37])[C:29]=3[CH:28]=1)[CH:10]=[CH:11][CH:12]=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc2cccc(B3OC(C)(C)C(C)(C)O3)c2nc1NC(C)(C)C
Reactant: O=C1NCCCc2[nH]c(Br)cc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCCNC4=O)c2nc1NC(C)(C)C
Temperature: 105 °C
Reaction time: 1.5 h
Yield: 94.6 %

Procedure:
A mixture of N-(tert-butyl)-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-amine (174b) (341 mg, 0.66 mmol), 2-bromo-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one (305b) (84.0 mg, 0.37 mmol), K2PO4 (420 mg, 1.98 mmol), X-Phos (Strem Chemicals, Inc., 17.5 mg, 0.037 mmol), and Pd2dba3 (Aldrich, 16.8 mg, 0.018 mmol) in a mixture of dioxane (3.0 mL) and water (0.60 mL) was stirred under argon at 105° C. for 1.5 h. The reaction mixture was subsequently diluted with DCM (10 mL) and concentrated onto silica gel. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one (128 mg, 0.35 mmol, 96% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.77 (1H, br. s.), 7.83 (1H, dd, J=7.4, 1.0 Hz), 7.56 (1H, dd, J=7.8, 1.0 Hz), 7.32 (2H, t, J=7.7 Hz), 7.09 (1H, d, J=2.7 Hz), 6.01 (1H, s), 3.21 (2H, dd, J=8.5, 4.6 Hz), 3.02 (2H, t, J=6.5 Hz), 2.55 (3H, s), 1.92-2.01 (2H, m), 1.58 (9H, s). m/z (ESI, +ve) 364.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][NH2:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)OC(=O)NCCCOCCOCCOCCCN
Product: CC(C)(C)OC(=O)NCCCOCCOCCOCCCNC(=O)CCC(=O)O

Procedure:
preparation from 1-(tert-butoxycarbonylamino)-4,7,10-trioxa-13-tridecanamine (5 g) and succinic anhydride (1.98) gave 7 g crude product. LCMS (Method 6): Rt 3.34 min; m/z (M+1) 421 Calcd: 421
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH:14][NH2:15])=[O:13])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([OH:29])=[C:24]([C:26](=O)[CH3:27])[CH:25]=1>CO.C(O)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([OH:29])=[C:24](/[C:26](=[N:15]/[NH:14][C:12](=[O:13])[C:11]2[CH:16]=[CH:17][CH:18]=[C:9]([S:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)(=[O:7])=[O:8])[CH:10]=2)/[CH3:27])[CH:25]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 41.8 %

Procedure:
3-(pyrrolidin-1-ylsulfonyl)benzohydrazide (105 mg, 0.390 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (66.5 mg, 0.390 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-(pyrrolidin-1-ylsulfonyl)benzohydrazide (70 mg, 0.163 mmol, 41.7% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.18 (m, 1H), 8.13 (m, 1H), 7.95 (d, 1H, J=7.6 Hz), 7.65 (t, 1H, J=7.6 Hz), 7.41 (m, 1H), 7.21 (m, 1H), 6.93 (d, 1H, J=8.8 Hz), 3.23 (m, 4H), 2.39 (s, 3H), 1.75 (m, 4H). Mass [M+H]+: 422.1
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[C:15]([O:16][CH3:17])=[C:14]([CH3:18])[C:13]([O:19][CH3:20])=[CH:12][C:7]=1[C:8]([O:10]C)=[O:9])([O-:5])=[O:4].Cl>CO>[N+:3]([C:6]1[C:15]([O:16][CH3:17])=[C:14]([CH3:18])[C:13]([O:19][CH3:20])=[CH:12][C:7]=1[C:8]([OH:10])=[O:9])([O-:5])=[O:4]
Reactant: COC(=O)c1cc(OC)c(C)c(OC)c1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)c([N+](=O)[O-])c(OC)c1C
Yield: 80.8 %

Procedure:
Potassium hydroxide (3.71 g, 66.31 mmol) was added to a stirred solution of 188 (4.83 g, 18.95 mmol) in anhydrous methanol (80 mL) and the reaction mixture heated at reflux for 3 h. The reaction mixture was allowed to cool and acidified to pH2 with 1 N HCl and the solid precipitate was filtered and washed with water (50 mL) and left to air dry to afford the product as a yellow-beige solid (189) (3.69 g, 15.31 mmol, 81%); 1H NMR (270 MHz, CDCl3) δ13.88 (br s, 1H), 7.23 (s, 1H), 3.90 (s, 3H), 3.75 (s, 3H), 2.14 (s, 3H); 13C NMR (67.8 MHz, CDCl3) δ164.09, 158.65, 150.09, 139.38, 125.70, 122.50, 107.24, 62.78, 56.34, 9.62.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][NH2:28])=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][C:10]([O:12]CC)=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=1>C(N(CC)CC)C>[N+:36]([C:35]1[C:30]([NH:28][CH2:27][CH2:26][CH2:25][O:24][C:20]2[CH:19]=[C:18]3[C:23]([C:15]([CH:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][C:10]([OH:12])=[O:11])=[CH:16][NH:17]3)=[CH:22][CH:21]=2)=[N:31][CH:32]=[CH:33][CH:34]=1)([O-:38])=[O:37]
Reactant: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(OCCCN)ccc12
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(O)CC(c1ccccc1)c1c[nH]c2cc(OCCCNc3ncccc3[N+](=O)[O-])ccc12

Procedure:
Analogously to Example 18, the compound 35, prepared in accordance with Example 14.2, is reacted with 2-chloro-3-nitropyridine and triethylamine, giving 3-{6-[3-(3-nitropyridin-2-ylamino)propoxy]-1H-indol-3-yl}-3-phenylpropionic acid. After preparative HPLC: 3-{6-[3-(3-nitropyridin-2-yl-amino)propoxy]-1H-indol-3-yl}-3-phenylpropionic acid trifluoroacetate.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.O.[NH2:22][NH2:23].O>C(O)C>[CH3:1][S:2][C:3]1[NH:23][N:22]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NN
Reactant: CSC(SC)=C(C(=O)c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: O
Product: CSc1[nH]nc(-c2ccccc2)c1-c1ccccc1
Yield: 89.3 %

Procedure:
To a suspension of 3,3-bis(methylthio)-1,2-diphenylprop-2-en-1-one (2.5 g, 8.32 mmol) in ethanol (20 mL), was added hydrazine hydrate (1.67 g, 33.3 mmol) at room temperature. The reaction was refluxed for 6 h. After cooling, the reaction was poured into water and extracted with ethyl acetate. The organic extract was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (1.98 g). LCMS m/z=267.0 [M+H]+.
Reaction SMILES: C([Si](CC)(CC)[O:4][C@H:5]([C@H:7]1[C@@H:10]([C:11]#[C:12][Si](C)(C)C)[N:9]([C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[C:8]1=[O:25])[CH3:6])C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(O)(=O)C>[OH:4][C@H:5]([C@H:7]1[C@@H:10]([C:11]#[CH:12])[N:9]([C@@H:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:18])[C:8]1=[O:25])[CH3:6]
Reactant: CC[Si](CC)(CC)O[C@@H](C)[C@@H]1C(=O)N([C@H](C)c2ccccc2)[C@@H]1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Product: C#C[C@@H]1[C@H]([C@H](C)O)C(=O)N1[C@H](C)c1ccccc1
Yield: 93.1 %

Procedure:
The same reaction as in Example 3 was carried out except that (3R,4S)-3-[(S)-1-(triethylsilyloxy)ethyl]-1-[(R)-1-phenylethyl]-4-[2-(trimethylsilyl)ethynyl]-2-azetidinone (826 mg, 1.92 mmol) was used instead of (3R,4S)-3-[(S)-1-(triethylsilyloxy)propyl]-1-[(R)-1-phenylethyl]-4-[2-(trimethylsilyl)ethynyl]-2-azetidinone in the Example 3, and, in addition 0.28 ml of acetic acid and 4.86 ml (4.76 mmol) of tetrabutylammonium fluoride (1M tetrahydrofuran solution) were used, to obtain 435 mg (yield 93%) of the title compound as colorless oily substance.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([F:10])([F:9])[F:8])=[N:3]1.[Li+].CC([N-]C(C)C)C.C[O:20][B:21](OC)[O:22]C.Cl>C1COCC1>[CH3:1][N:2]1[C:6]([B:21]([OH:22])[OH:20])=[CH:5][C:4]([C:7]([F:10])([F:9])[F:8])=[N:3]1
Reactant: Cn1ccc(C(F)(F)F)n1
Reactant: COB(OC)OC
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1nc(C(F)(F)F)cc1B(O)O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A solution of 1-methyl-3-trifluoromethylpyrazol (2 g) in 10 ml THF is cooled under an inert gas atmosphere to −78° C. A 2 M solution of LDA (9.75 ml) is added dropwise. The mixture is stirred to 10° C. for 1 h and cooled to −75° C. Trimethylborate (5.8 ml) is added and after stirring for 1 h at −75° C. the mixture is stirred overnight at ambient temperature. The resulting reaction solution is added to 10% hydrochloric acid (15 ml). The water phase is extracted 3 times with ethyl acetate and the combined organic phases are washed with water and a saturated sodium chloride solution. The organic phase is dried and evaporated and the residue is crystallized from water. After drying, one obtains the title compound as nearly colorless crystals (1.12 g) of mp. 138° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13]([CH3:14])=[O:23])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CSc1nccc(-c2ccc(Br)s2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2ccc(Br)s2)n1

Procedure:
4-(5-Bromo-thiophen-2-yl)-2-methylsulfanyl-pyrimidine (144 mg, 0.5 mmol) was dissolved in DCM (5 ml) and treated at 0° C. with mCPBA (content 70%, 112 mg, 0.65 mmol) for 15 minutes. The reaction mixture was washed with 2N-solution of sodium carbonate, the organic phase dried over sodium sulfate, filtered and evaporated to dryness and purified via chromatography on silicagel (acetone/hexanes:20/80 to 40/60) to give the title compound as white crystals. Yield: 120 mg (80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]1[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=1.[CH3:21][NH2:22]>O1CCCC1>[CH3:21][NH:22][S:17]([C:15]1[S:16][C:12]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[N:8]=[CH:7][N:6]=2)=[CH:13][CH:14]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Reactant: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
800 mg of 5-(6-bromoquinazolin-4-yl)-thiophen-2-sulfonyl chloride (compound in Production Example 377) was dissolved in 15 mL tetrahydrofuran, and 1.78 mL methylamine was added thereto and stirred at room temperature for 1 hour. The solvent was removed, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane), to give 752 mg of the title compound (pale skin-colored crystals).
Reaction SMILES: C(OP([CH:9]([O:15][CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.CC(C)([O-])C.[K+].[F:23][C:24]([F:46])([F:45])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33](=[O:44])[C:34]2[CH:39]=[C:38]([CH:40]=O)[CH:37]=[CH:36][C:35]=2[O:42][CH3:43])=[CH:27][CH:26]=1>O1CCCC1>[CH3:16][O:15][C:9](=[CH:40][C:38]1[CH:37]=[CH:36][C:35]([O:42][CH3:43])=[C:34]([C:33](=[O:44])[NH:32][CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:45])[F:46])=[CH:26][CH:27]=2)[CH:39]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: COc1ccc(C=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(OC)P(=O)(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)OC
Temperature: 0 °C
Yield: 75.4 %

Procedure:
Ethyl 2-(diethoxyphosphoryl)-2-methoxyacetate (265 mg, 1.10 mmol) was dissolved in 3 ml of dehydrated tetrahydrofuran and potassium t-butoxide (123 mg, 1.10 mmol) was added under stirring and cooling with ice under an atmosphere of argon, which was stirred for 30 minutes. Next, N-[[4-(trifluoromethyl)phenyl]methyl]-5-formyl-2-methoxybenzamide (338 mg, 1.00 mmol) dissolved in 2 ml of dehydrated tetrahydrofuran was added. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice water, which was extracted with ethyl acetate, washed with water and brine in sequence, then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=3:1 v/v) to obtain 330 mg (78%) of the title compound (mixture of geometrical isomers relevant to double bond) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:5]=[O:6])C.[CH3:13][O:14]C(C1C=CC=CC=1)C=O>>[CH3:1][O:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH2:13][OH:14])[CH2:5][OH:6]
Reactant: COC(C=O)c1ccccc1
Reactant: CCOC(C=O)c1ccccc1
Product: COC(CO)(CO)c1ccccc1

Procedure:
The procedure in Example 6 was repeated except that 2-ethoxy-2-phenylethanal was replaced with 2-methoxy-2-phenylethanal, to obtain 2-methoxy-2-phenyl-1,3-propanediol.
Reaction SMILES: [CH3:1][CH:2]([NH:8][C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[N:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CCCCCCC>[C@H:3]12[CH2:7][C@H:6]([CH2:5][CH2:4]1)[CH2:1][C@H:2]2[NH:8][C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[N:10]=1
Reactant: CCCCCC(C)Nc1cnc2cc(OC)c(OC)cc2n1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCCCCCC
Product: COc1cc2ncc(N[C@@H]3C[C@H]4CC[C@@H]3C4)nc2cc1OC

Procedure:
The (±)-bicyclo[2.2.]hept-2-yl-(6,7-dimethoxyquinoxalin-2-yl)-amine of Example 14 is resolved on a chiral HPLC column (Chiralpac AD, 25×2 cm, 60% heptane/40% ethanol with 10 mM (1S)-(+)-camphorsulfonic acid, 12 mL/minute) and the above titled product is obtained as the first eluent. The fractions collected are combined and washed with 50 mL of 1 N NaOH before drying (MgSO4). The solution after filtration is concentrated on a rotovap and then dried under a high vacuum. A yellow solid is obtained. [α]d2+19.5° (c=0.20, CH2Cl2) m.p. 184-186° C. Anal. calcd for C17H21N3O2×0.3H2O: C, 66.90; H, 7.15; N, 13.77. Found: C, 66.86; H, 7.01; N, 13.86.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([OH:18])[CH:17]=1.C(N(CC)CC)C>O1CCOCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:18][C:16]2[CH:17]=[C:12]([Cl:11])[CH:13]=[N:14][CH:15]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1cncc(Cl)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Oc2cncc(Cl)c2)cc1
Yield: 44.5 %

Procedure:
To a stirred solution of 4-fluoro-nitrobenzene (913 μL, 8.61 mmol, from Aldrich) in dioxane (1 mL) was added 3-chloro-5-hydroxypyridine (558 mg, 4.31 mmol, from Aldrich) followed by triethylamine (661 μL, 4.74 mmol). The solution was refluxed for 4.5 hours, evaporated and the crude solid was dissolved in ethyl acetate. The solution was washed three times with saturated K2CO3 solution, once with brine and then back-extracted with ethyl acetate. The two organic solutions were combined, concentrated and the residue was purified by chromatography (diethyl ether as eluant) to provide 481 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:15])[C:5]([F:14])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C:7]2=[N:12]O>CO.[Ni]>[Br:1][C:2]1[CH:3]=[C:4]([F:15])[C:5]([F:14])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[NH2:12]
Reactant: ON=C1CCOc2c(Br)cc(F)c(F)c21
Agent: [Ni]
Solvent: CO
Product: NC1CCOc2c(Br)cc(F)c(F)c21
Reaction time: 24 h

Procedure:
Raney-Ni (5 mL slurry in water) was added to a solution of 8-bromo-5,6-difluoro-2,3-dihydrochromen-4-one oxime (1.9 g) in 200 mL MeOH. The mixture was hydrogenated at 50 psi for 24 hrs to provide 8-bromo-5,6-difluoro-3,4-dihydro-2H-chromen-4-amine. Pd/C (0.3 g) was added to the mixture and hydrogenation was resumed at 50 psi for 4 hours. The title compound was obtained after filtration and concentration in vacuo. 1H NMR (300 MHz, 10% CD3OD in CDCl3): δ 7.15 (q, 1H), 6.6 (m, 1H), 4.6 (bm, 1H), 4.25 (bm, 2H), 2.2-2.4 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.OS(O)(=O)=O.[CH3:18]O>>[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:18])=[O:8])=[CH:5][CH:4]=1
Reactant: CO
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N(C)C)cc1

Procedure:
p-Dimethylaminobenzoic acid (50 g.) and concentrated H2SO4 (25 ml.) in 350 ml. methanol were refluxed 18 hours. The reaction mixture was cooled, quenched with ice and water (350 ml.), neutralized portionwise with KHCO3 until foaming ceased, and extracted 3×200 ml. CHCl3. The organic layers were combined, washed 1×150 ml. brine, dried (MgSO4) and reduced in volume to yield crystalline title product, 52 g.; 1H-nmr: 3.02 (s, 6H), 3.87 (s, 3H), 6.66 (d, J=16 Hz, 2H), 7.95 (d, J=16 Hz, 2H).