Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH:27](O)(C)C>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH:14]=[CH:13][CH:12]=3)=[O:5])([CH3:27])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1cccc(Cc3ccccc3Cl)c12
Reactant: CC(C)O
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CC(C)OC(=O)c1cc2c(cn1)[nH]c1cccc(Cc3ccccc3Cl)c12

Procedure:
0.2 g (0.55 mmol) of 5-(2-chlorobenzyl)-β-carboline-3-carboxylic acid ethyl ester is refluxed for 4 hours with 0.16 g (0.57 mmol) of titaniumtetraisopropylate in 50 ml of isopropanol. The solution concentrated by evaporation to half, the isopropyl ester crystallizes out during cooling. Yield 164 mg (79% of theory), melting point 258°-260° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH:14]([OH:32])[CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][S:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:18][CH2:17]3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:33])[C:4]1=[O:34].[OH:35]O>O.C(Cl)Cl.CO.[NH4+].[OH-]>[CH3:2][N:3]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH:14]([OH:32])[CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][S:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:35])[CH2:18][CH2:17]3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:33])[C:4]1=[O:34]
Reactant: Cn1c(=O)c2c(ncn2CC(O)CN2CCN(CCCSc3ccccc3)CC2)n(C)c1=O
Reactant: OO
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cn1c(=O)c2c(ncn2CC(O)CN2CCN(CCCS(=O)c3ccccc3)CC2)n(C)c1=O
Temperature: 20 °C
Reaction time: 4 h

Procedure:
0.1 Moles of 1-[3-(1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-phenylthio-propyl)piperazine hydrochloride was dissolved in 200 ml demineralized water and maintained at 20° C. 120 ml hydrogen peroxide in 250 ml water was added dropwise. The mixture was stirred for four hours at room temperature. Completion of the reaction was checked by TLC using a mixture of 80/20/1 CH2Cl2 /methanol/NH4OH as eluent. When the reaction was completed, the reactive mixture was alkalinized, extracted with methylene chloride, washed with water, dried, and the solvent evaporated under vacuum to give the free base form of 1-[3-(1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-phenylsulfinylpropyl)piperazine. The dihydrochloride salt was prepared in the manner indicated in Example III, m.p. 260°-265° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][C:10]1[N:18]2[C:13]([C:14]([NH2:19])=[N:15][CH:16]=[N:17]2)=[C:12](Br)[CH:11]=1)=[O:5])[CH3:2].[CH2:21]([N:28]1[CH:36]=[C:35]2[C:30]([CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=[CH:34]2)=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][C:10]1[N:18]2[C:13]([C:14]([NH2:19])=[N:15][CH:16]=[N:17]2)=[C:12]([C:32]2[CH:33]=[CH:34][C:35]3[C:30]([CH:31]=2)=[N:29][N:28]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:36]=3)[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC1Cc1cc(Br)c2c(N)ncnn12
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC1Cc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Yield: 54 %

Procedure:
To a solution of 2-(4-amino-5-bromo-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-cyclopropanecarboxylic acid ethyl ester (1.33 g, 4 mmol) in degassed DMF (6.6 mL) was added 2-benzyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (2.1 g, 6.3 mmol), Pd(PPh3)4, and 2N Na2CO3 solution (5.3 mL). The reaction was irradiated in a microwave reactor at 150° C. for 10 min. After cooling the mixture was partitioned between EtOAc and H2O. The organic phase was separated and dried over Na2SO4, filtered, and evaporated in vacuo. The crude was purified by Biotage® (50-100% EtOAc/hexane) to give the title product as an off white solid, 1.0 g (yield 54%). 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 4.0 (m, 2 H), 3.0 (m, 2 H), 1.70 (m, 2 H), 1.2-1.0 (m, 5 H); ES-MS m/z 5467.27 [M+H]+, HPLC RT (min) 2.79.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]2[CH:28]=[CH:27][C:12]([O:13][CH2:14][C@@H:15]3[O:20][C:19]4=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:18]4[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.CC(C)=O.Cl>O>[N+:24]([C:22]1[N:21]=[C:19]2[N:18]([CH:23]=1)[CH2:17][CH2:16][C@H:15]([CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([N:6]3[CH2:5][CH2:4][C:3](=[O:2])[CH2:8][CH2:7]3)=[CH:28][CH:27]=1)[O:20]2)([O-:26])=[O:25]
Reactant: COC1(OC)CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
(R)-7-[4-(4,4-Dimethoxypiperidin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (5.16 g), acetone (100 ml) and water (17 ml) were mixed. A 6 N hydrochloric acid aqueous solution (41 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The remaining water layer was ice-cooled and neutralized by adding a 20% sodium carbonate aqueous solution. After being stirred at the same temperature for 10 minutes, the precipitated crystal was collected by filtration. The crystal thus obtained was dried at 60° C. to afford the title compound as a yellow solid (4.57 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16](=O)[CH:15]2[CH:10]([C:11]3([C:20]#[N:21])[CH2:19][CH2:18][CH:14]2[CH:13]=[CH:12]3)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:21][CH2:20][C:11]12[CH2:19][CH2:18][CH:14]([CH:13]=[CH:12]1)[CH:15]1[CH:10]2[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16]1
Reactant: N#CC12C=CC(CC1)C1C(=O)N(Cc3ccccc3)C(=O)C12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC12C=CC(CC1)C1CN(Cc3ccccc3)CC12

Procedure:
14.6 g (50 mmol) of 4-benzyl-1-cyano-4-azatricyclo-[5.2.2.02,6 ]undec-8-ene-3,5-dione are reduced with 5 g of LiAlH4 as described under Z 1-B and the mixture is worked up accordingly.
Reaction SMILES: FC1C=CC(CN2C(=O)N(C3SC(C(OCC)=O)=C(C)C=3)C=N2)=CC=1.[CH3:26][C:27]1[CH:31]=[C:30]([N:32]2[C:36](=[O:37])[N:35]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=3)[N:34]=[CH:33]2)[S:29][C:28]=1[C:49]([O:51]CC)=[O:50]>>[CH3:26][C:27]1[CH:31]=[C:30]([N:32]2[C:36](=[O:37])[N:35]([CH2:38][C:39]3[CH:40]=[CH:41][C:42]([S:45]([CH3:48])(=[O:46])=[O:47])=[CH:43][CH:44]=3)[N:34]=[CH:33]2)[S:29][C:28]=1[C:49]([OH:51])=[O:50]
Reactant: CCOC(=O)c1sc(-n2cnn(Cc3ccc(S(C)(=O)=O)cc3)c2=O)cc1C
Agent: CCOC(=O)c1sc(-n2cnn(Cc3ccc(F)cc3)c2=O)cc1C
Product: Cc1cc(-n2cnn(Cc3ccc(S(C)(=O)=O)cc3)c2=O)sc1C(=O)O
Yield: 74 %

Procedure:
Following the procedure as described in Example 30, making variations as required to replace ethyl 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylate with ethyl 3-methyl-5-(1-(4-(methylsulfonyl)benzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiophene-2-carboxylate, the title compound was obtained as a beige solid in 74% yield: 1H NMR (300 MHz, DMSO-d6) δ 13.02 (br s, 1H), 8.79 (s, 1H), 7.92 (d, J=7.1 Hz, 2H), 7.56 (d, J=7.1 Hz, 2H), 7.29 (s, 1H), 5.11 (s, 2H), 3.20 (s, 3H), 2.47 (s, 3H); MS (ES−) m/z 392.2 (M−1).
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7](=[O:21])[C:6]=1[CH2:22][CH:23]=[CH2:24])(=O)C.[OH-].[Na+]>C(O)C>[OH:4][C:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:7](=[O:21])[C:6]=1[CH2:22][CH:23]=[CH2:24]
Reactant: C=CCc1c(OC(C)=O)c2cccnc2n(-c2ccccc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCc1c(O)c2cccnc2n(-c2ccccc2)c1=O

Procedure:
A mixture of 6.0 g. of 4-acetoxy-1-phenyl-3-(2-propenyl)-1,8-naphthyridin-2(1H)-one, 200 ml. of ethanol and 40 ml. of 1N sodium hydroxide solution is stirred at room temperature for 22 hours. The ethanol is removed in vacuo and the remaining aqueous solution acidified with 1N hydrochloric acid. The product is filtered, washed with water and dried, weight 5.3 g., m.p. 248°-250° C. Recrystallization from chloroform yields the product of this example as a colorless solid, m.p. 250°-252° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:19][NH2:20]>C(O)CCC.COC(C)(C)C>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:20][N:19]=1
Reactant: NN
Reactant: O=C(Cc1ccccc1F)c1cccnc1Cl
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: Fc1ccccc1Cc1n[nH]c2ncccc12

Procedure:
A solution of 2.00 g (8.01 mmol) of 1-(2-chloropyridin-3-yl)-2-(2-fluorophenyl)ethanone from example 11A and 560 mg (11.2 mmol) of hydrazine hydrate in 6 ml of 1-butanol is heated in a microwave at 200° C. for 10 min. It is then diluted with tert-butyl methyl ether, washed with saturated sodium bicarbonate solution and dried over sodium sulfate. The solution is concentrated in vacuo. The crystalline residue is stirred with a little tert-butyl methyl ether and filtered off with suction. The mother liquor is concentrated and purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1). In total, 1.40 g (77% of theory) of the desired product are obtained as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([S:28]([CH3:27])(=[O:30])=[O:29])[CH2:19][CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24]
Reactant: O=C(NC1CCNCC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 199 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(piperidin-4-yl)thiophene-2-carboxamide (0.2 g, 0.46 mmol) and methanesulfonyl chloride (79.0 mg, 0.69 mmol). The title compound was obtained as a solid (40 mg, 17% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.73 (1H, m), 8.48 (1H, s), 3.80 (1H, m), 3.77 (2H, m), 2.84 (3H, s), 2.81 (2H, m), 1.89 (2H, m), 1.56 (2H, m). MS m/z: 509.25, 511.28 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[C:31]([O:35][C:36](=[O:39])[CH2:37][NH2:38])([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[C:31]([O:35][C:36](=[O:39])[CH2:37][NH:38][C:8]([C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)c1ncccc1O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(=O)c1ncccc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.5 %

Procedure:
To a solution of 3-hydroxypicolinic acid (0.20 g, 1.44 mmol) in DMF (5 mL) at 0° C. under N2 is added diisopropylethylamine (DIPEA) (0.75 ml, 4.3 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (EDCI) (0.412 g, 2.9 mmol) and 1-hydroxybenzo-triazole (HOBt) (0.019 g, 0.14 mmol). The resulting mixture is stirred for 5 min before glycine tert-butyl ester HCl (0.36 g, 2.9 mmol) is introduced. The resulting solution is stirred at room temperature for 3 days then concentrated under reduced pressure. The reaction mixture is diluted with EtOAc then washed with 1M HCl, sat. NaCl, and the organic layer is dried (MgSO4), filtered and concentrated under reduced pressure to a crude oil that is purified over silica (EtOAc/heptane 1:4) to afford 0.078 g (22% yield) of the desired compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 11.80 (1H, s), 8.39 (1H, br s), 8.02 (1H, dd, J=4.4, 1.5 Hz), 7.27 (1H, dd, J=8.8, 4.4 Hz), 7.25 (1H, dd, J=8.4, 1.5 Hz), 4.06 (2H, d, J=5.5 Hz), 1.44 (9H, s). HPLC-MS: m/z 197 [M-tBu]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[N:4]=1.[Br:10]N1C(=O)CCC1=O.C(Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:10][C:8]1[C:3]([O:2][CH3:1])=[N:4][C:5]([NH2:9])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccnc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1nc(N)ncc1Br
Reaction time: 5 h
Yield: 96 %

Procedure:
To a solution of 4-methoxypyrimidine-2-ylamine (1.84 g, 14.7 mmol) in chloroform (600 mL) was added N-bromosuccinimide (2.62 g, 14.7 mmol). After stirring in the dark for 5 hours, the solution was added to CH2Cl2 (200 mL) and 1N NaOH (100 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated yielding 2.88 g (96%) of 5-bromo-4-methoxypyrimidine-2-ylamine. LCMS (m/z): 204/206 (MH+). 1H NMR (CDCl3): δ 8.10 (s, 1H), 4.93 (bs, 2H), 3.96 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[C:11]([N+:19]([O-])=O)[CH:10]=1>[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:12]([CH2:15][C:16](=[O:17])[NH:19]2)=[CH:13][CH:14]=1
Reactant: COc1ccccc1-c1ccc(CC(=O)O)c([N+](=O)[O-])c1
Agent: [Fe]
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Yield: 66.2 %

Procedure:
Iron chips (5 g) were added in one portion to 9.8 g of 2′-methoxy-3-nitrobiphenyl-4-acetic acid in 50 hours. The reaction mixture was concentrated to dryness, sonicated in ethyl acetate and filtered to remove the insolubles. The filtrate was washed twice with 1N hydrochloric acid, water, brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel in ethyl acetate:hexane 1:2 to give 5.4 g (69 % yield based on-5-bromo-2-fluoronitrobenzene) of 6-(2-methoxyphenyl)-2-oxindole as a rose colored solid.
Reaction SMILES: [Mg].II.[CH2:4]([CH:6]([CH2:9][CH3:10])[CH2:7]Br)[CH3:5].[CH2:11]([Si:17](Cl)([Cl:19])[Cl:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>O1CCCC1.CCCCCC.C(OCC)C>[CH2:11]([Si:17]([CH2:7][CH:6]([CH2:9][CH3:10])[CH2:4][CH3:5])([Cl:19])[Cl:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC[Si](Cl)(Cl)Cl
Reactant: CCC(CC)CBr
Agent: II
Agent: [Mg]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC[Si](Cl)(Cl)CC(CC)CC

Procedure:
Anhydrous diethyl ether (100 mL) was put into a reactor with magnesium (5.0 g, 0.21 mol) which had been dehydrated and deaerated, followed by charging of argon gas. A small amount of iodine was slowly added to the mixture. 2-Ethylbutylbromide (29.5 g, 0.18 mol) was added dropwise to the slowly stirred mixture so that the reaction mixture was gradually refluxed. After the reaction was complete, the obtained Grignard reagent was transferred to a dropping funnel. The Grignard reagent was added dropwise to a solution being stirred containing n-hexyltrichlorosilane (38 g, 0.17 mol) in anhydrous tetrahydrofuran (100 mL) in another reactor which had been dehydrated and deaerated, followed by charging of argon gas, at 60° C.-70° C. The reaction mixture was then stirred overnight at room temperature. Hexane (500 mL) was added to the reaction mixture, and the resulting mixture was filtered under pressure, followed by fractional distillation of the filtrate to provide the desired product.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].O[CH2:11][CH:12]([CH2:14]O)O.[OH-].[Na+]>S(=O)(=O)(O)O.C1(C)C=CC=CC=1.[I-].[Na+]>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:4]=1[N:5]=[CH:14][CH:12]=[CH:11]2)[CH3:2]
Reactant: OCC(O)CO
Reactant: CCc1ccccc1N
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1cccc2cccnc12
Temperature: 142.5 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
A mixture of 2-ethylaniline (24.2 g, 200 mmol) and sodium iodide (0.40 g, 2.67 mmol) in 80% sulfuric acid (110 g) at 140° C. was added glycerine (22.0 g, 239 mmol) over a period of 30 m. The reaction mixture was stirred at 140-145° C. for 3 hours in an apparatus fitted with a Dean Stark trap. The reaction mixture was cooled to room temperature. The mixture was neutralized with 25% NaOH (aq) (210 g) to pH 7, and diluted with toluene. The mixture was extracted with ethyl acetate/ether. The pooled organic layers were washed with brine, and dried over magnesium sulfate. The mixture was filtered, to and the solvents were removed under vacuum. The residue was purified by chromatography on silica gel with 5 to 7% ethyl acetate in hexane to give 8-ethylquinoline (12) (24.5 g, 156 mmol, 78% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][N:5]([S:22](=[O:32])(=[O:31])[NH:23]C(OC(C)(C)C)=O)[C:6]1[C:11]([F:12])=[CH:10][C:9]([Br:13])=[CH:8][C:7]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:33])[CH2:4][N:5]([S:22](=[O:31])(=[O:32])[NH2:23])[C:6]1[C:11]([F:12])=[CH:10][C:9]([Br:13])=[CH:8][C:7]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CN(c1c(F)cc(Br)cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN(c1c(F)cc(Br)cc1OCc1ccccc1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1.25 g (2.28 mmol) of N-(t-butoxycarbonylsulfamoyl)-N-(2-benzyloxy-4-bromo-6-fluorophenyl)glycine methyl ester in 6 mL of methylene chloride is added 6 mL of TFA. The solution is stirred at room temperature for 20 min. then the solvent is removed under reduced pressure. The residual oil is purified by flash chromatography using 15% ethyl acetate in methylene chloride to elute the product as an oil: 1H NMR (CDCl3) δ 7.48-7.36 (m, 5H), 7.02-6.98 (m, 2H), 5.10 (d, J=4.30 Hz, 2H), 4.94 (s, 2H), 4.34 (q, 2H), 3.70 (s, 3H); MS (M−H)−=447.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19]C)=[O:18])[NH:5]CC1C=CC=CC=1)#[N:2].NC(NC1C=C(C=CC=1)C(OC)=O)=NC#N>>[NH2:5][C:4]([NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([OH:19])=[O:18])=[N:3][C:1]#[N:2]
Reactant: COC(=O)c1cccc(NC(=NC#N)NCc2ccccc2)c1
Agent: COC(=O)c1cccc(NC(N)=NC#N)c1
Product: N#CN=C(N)Nc1cccc(C(=O)O)c1
Yield: 92 %

Procedure:
The title compound was prepared as described in Example I except that the compound of Example E was replaced with an equivalent amount of the compound of Example G. This afforded the title compound (92%) as a white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:24]([C:26]1([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=O.C(C1(C(OC)=O)CCC1)=O>>[CH:1]1([O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:19][CH2:20][N:21]([CH2:24][C:26]5([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH2:22][CH2:23]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1cc(OC2CCCC2)c2c(OCC3CCNCC3)noc2c1
Reactant: COC(=O)C1(C=O)CCOCC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OC5CCCC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 4-(cyclopentyloxy)-3-(piperidin-4-ylmethoxy)-1,2-benzisoxazole (EXAMPLE 24, Step 2) and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (EXAMPLE 18, Step 1) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[C:7]([O:11]C)[C:8]=1[CH2:9][CH3:10].B(Br)(Br)Br>>[CH2:9]([C:8]1[C:7]([OH:11])=[CH:6][C:5]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:3]=1[OH:2])[CH3:10]
Reactant: CCc1c(OC)cc(C=Cc2ccccc2)cc1OC
Agent: BrB(Br)Br
Product: CCc1c(O)cc(C=Cc2ccccc2)cc1O
Yield: 91 %

Procedure:
This material was synthesized from 1-(3,5-dimethoxy-4-ethylphenyl)-2-phenylethene and BBr3 in 91% yield by the same method as described in Example 6. 1HNMR (CDCl3, ppm): δ 1.22 (t, J=7.5 Hz, 6H), 2.70 (q, J=7.5 Hz, 2H), 4.81 (s, 2H), 6.60 (s, 2H), 7.00 (s, 2H), 7.26 (m, 1H), 7.36 (m, 2H), 7.52 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9]Br.[C:11]([C:15]1[CH:16]=[C:17]([C:25](=[O:27])[CH3:26])[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[C:20]=1[OH:21])([CH3:14])([CH3:13])[CH3:12].C(OCC)(=O)C>CN(C)C=O>[Br:7][CH2:8][CH2:9][O:21][C:20]1[C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]([C:25](=[O:27])[CH3:26])=[CH:16][C:15]=1[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: BrCCBr
Reactant: CC(=O)c1cc([N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1cc([N+](=O)[O-])c(OCCBr)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.8 %

Procedure:
Potassium carbonate (4.65 g, 33.7 mmol) and 1,2-dibromoethane (31.7 g, 166.6 mmol) were added to a solution of 1-[3-(tert-butyl)-4-hydroxy-5-nitrophenyl]-1-ethanone (8.0 g, 33.7 mmol) in dimethylformamide (200 ml) and the mixture was stirred at room temperature for 12 hours. Ethyl acetate was added, the reaction mixture was washed with water and brine in that order and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield 1-[4-(2-bromoethoxy)-3-(tert-butyl)-5-nitrophenyl]-1-ethanone (8.1 g).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32](COCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3C)C=CC=2OC(F)F)CC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CCc3ccccc3)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCC[Si](C)(C)C)c1=O
Agent: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: C[Si](C)(C)CCOCn1ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(CCc3ccccc3)c2c1=O
Yield: 88.2 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(b) except for using 509 mg (0.729 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-phenethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 21-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 365 mg of the title compound was obtained as a pale yellowish foam. (Yield: 88%)