Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([BH3-])#N.[Na+].[H][H].[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: [H][H]
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN2
Reaction time: 3 h

Procedure:
To a solution of 50.0 g (340 mmol) of 5-methoxyindole in 700 ml of glacial acetic acid are added portionwise, at 15-20° C., 53.4 g (850 mmol) of sodium cyanoborohydride. The weakly exothermic addition is carried out over 3 hours and is accompanied by a slight evolution of hydrogen. The mixture is left stirring below 20° C. for 12 hours, 700 ml of water are then added and the pH of the reaction medium is adjusted to between 10 and 12 by addition of 1200 ml of 30% sodium hydroxide solution. The mixture is extracted twice with dichloromethane and the organic phase is then washed with 300 ml of water. The mixture is evaporated and the residue is purified by flash chromatography on a column of silica, the eluent used being a mixture of increasing polarity of methanol in dichloromethane. 41.84 g of colorless oil which becomes pale yellow on storage (to be stored under nitrogen atmosphere and sheltered from the light) are obtained.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Br)[CH:25]=1>CN(C=O)C.O>[Br:22][CH2:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:30][N:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=2)[C:2]1=[O:1]
Reactant: BrCc1cccc(CBr)c1
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2ccn(Cc3cccc(CBr)c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.15 g, 0.74 mmol) in DMF (7.5 mL) was added cesium carbonate (0.72 g, 2.2 mmol) and 1,3-bis(bromomethyl)benzene (0.29 g, 1.1 mmol). The reaction mixture was stirred at rt overnight. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 5% EtOAc/DCM) to afford methyl 2-[3-(bromomethyl)benzyl]-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.12 g, 42%). LC-MS: (FA) ES+ 388.
Reaction SMILES: N1C=CC=C(CN)C=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH2:14].[F:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][N:25]2[C@@H:29]([CH3:30])[CH2:28][N:27]([C:31]3[S:32][C:33]([C:37](O)=[O:38])=[C:34]([CH3:36])[N:35]=3)[C:26]2=[O:40])=[CH:22][CH:21]=1>>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH:14][C:37]([C:33]1[S:32][C:31]([N:27]2[CH2:28][C@H:29]([CH3:30])[N:25]([CH2:24][C:23]3[CH:41]=[CH:42][C:20]([F:19])=[CH:21][CH:22]=3)[C:26]2=[O:40])=[N:35][C:34]=1[CH3:36])=[O:38]
Reactant: NCc1ccc(F)c(F)c1
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccc(F)c(F)c1
Yield: 74 %

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with 3,4-difluorobenzylamine to react with (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as an off-white solid in 74% yield: mp 62-65° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 8.54 (t, J=5.9 Hz, 1H), 7.44-7.30 (m, 4H), 7.21-7.12 (m, 3H), 4.60 (d, J=15.6 Hz, 1H), 4.35 (d, J=5.9 Hz, 2H), 4.30 (d, J=15.6 Hz, 1H), 4.19 (dd, J=10.0, 9.1 Hz, 1H), 3.80-3.69 (m, 1H), 3.55 (dd, J=10.0, 6.2 Hz, 1H), 2.47 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.8, 161.5 (d, 1JC-F=244 Hz), 157.2, 154.9, 151.3, 150.4 (dd, JC-F=66, 13 Hz), 147.1 (dd, JC-F=66, 13 Hz), 137.6 (dd, JC-F=5, 4 Hz), 133.1 (d, 4JC-F=3 Hz), 130.0 (d, 3JC-F=8 Hz), 124.0 (dd, JC-F=7, 3 Hz), 117.6, 117.3 (d, JC-F=17 Hz), 116.3 (d, JC-F=17 Hz), 115.4 (d, 2JC-F=21 Hz), 49.4, 48.6, 43.7, 41.7, 18.4, 17.1; MS (ES+) m/z 474.8 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:24]([O-])([OH:26])=[O:25]>O>[N+:24]([C:6]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])([O-:26])=[O:25]
Reactant: CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]

Procedure:
To a mixture of 4-acetamido-1,1′biphenyl (21.1 g, 0.1 mol) and 150 mL of acetic anhydride maintained between 8° C. and 13° C. is slowly added dropwise over 32 minutes 12.7 mL of 70% nitric acid. The reaction mixture is added to 600 mL of a mixture of water and ice and the resultant precipitate is collected by filtration. The filter cake is washed with water and the residue is recrystallized from methanol (800 mL) to give 23.6 g of the title compound as a yellow crystalline solid melting at 129–132° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:22][C:23]([F:27])([F:26])[S:24]Cl>C1(C)C=CC=CC=1>[F:14][C:2]([F:1])([F:13])[O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[S:24][C:23]([F:27])([F:26])[F:22])=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1ccc2cn[nH]c2c1
Reactant: FC(F)(F)SCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: FC(F)(F)Oc1ccc2cnn(SC(F)(F)F)c2c1

Procedure:
20.2 g (0.1 mole) of 6-trifluoromethoxyindazole and 10.1 g (0.1 mole) of triethylamine in 125 ml of toluene are heated to 80° to 85° C., and 13.6 g (0.1 mole) of trifluoromethanesulphenyl chloride are then passed in the course of one hour and the mixture is stirred for a further hour at this temperature. After cooling, the precipitated triethylamine hydrochloride is filtered off with suction and rinsed with toluene. The filtrate, combined with the wash liquor, is washed twice with water. After drying (MgSO4) the volatile constituents are removed by distillation under a water pump vacuum. The oily crude product is purified by distillation under an oil pump vacuum. Boiling point 62°/0.05 mbar. Yield: 16.2 g (46% of theory).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=[C:13]2[O:24][CH3:25].CC([O-])=O.[K+].[Br:31]Br>CC(O)=O.O>[Br:31][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:22])([F:21])[F:23])[CH:14]=[C:13]2[O:24][CH3:25]
Reactant: COc1cc(C(F)(F)F)nc2ccc(-c3cc4ccccc4o3)cc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(F)(F)F)nc2ccc(-c3oc4ccccc4c3Br)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.6 %

Procedure:
To a stirred solution of 6-(1-benzofuran-2-yl)-4-methoxy-2-(trifluoromethyl)quinoline (0.930 g, 2.71 mmol) in HOAc (30 mL) at 0° C. was added KOAc (0.319 g, 3.25 mmol). The reaction was stirred at this temperature for 10 minutes, and then a solution of Br2 (0.154 mL, 2.98 mmol) in HOAc (5 mL) was added dropwise to it over a period of ˜10 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 2.5 hours. The reaction mixture was then diluted with H2O (10 mL). The solid that formed was filtered off and washed with excess H2O and hexane. This solid was then recrystallized from EtOAc:hexane to afford the product (0.750 g, 66%) as a solid. Mass spectrum (+ESI, [M+H]+) m/z 422/424. 1H NMR (500 MHz, DMSO-d6): δ 8.95 (s, 1H), 8.65 (d, 1H, J=8.9 Hz), 8.29 (d, 1H, J=8.9 Hz), 7.80 (d, 1H, J=8.1 Hz), 7.66 (d, 1H, J=8.1 Hz), 7.36-7.58 (m, 3H), and 4.26 ppm (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[CH2:19][O:20][CH3:21]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:19][O:20][CH3:21])[CH:3]=1
Reactant: COCCl
Reactant: Oc1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(Cl)c1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of 3-chlorophenol (50 g, 390.62 mmol, 1.00 equiv) in DCM (500 mL) was added DIEA (554 g, 4.29 mol, 11.00 equiv), followed by chloro(methoxy)methane (380 g, 10.00 equiv) at 20° C. The resulting mixture was allowed to react, with stirring, for 4 h at 20° C. The reaction mixture was then quenched with water. The separated organic phase was washed with water (2×), dried over Na2SO4 and then concentrated under vacuum to give 1-chloro-3-(methoxymethoxy)benzene as a white oil.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:5](=[C:6]([C@@H:14]([OH:17])[CH2:15][OH:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].ClCCl.N1C=CN=C1.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27]>O>[CH2:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:5](=[C:6]([C@H:14]([OH:17])[CH2:15][O:16][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1nc2c([C@@H](O)CO)cccc2cc1C
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CCc1nc2c([C@H](O)CO[Si](C)(C)C(C)(C)C)cccc2cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
1.72 g (7.45 mmol) of (−)-2-ethyl-3-methyl-8-(1(R),2-dihydroxyethyl)quinoline, 25 ml of dichloromethane and 0.75 g of imidazole are introduced into a 100 ml round-bottomed flask. The mixture is cooled to 0° C., 1.12 g (7.45 mmol) of tert-butyldimethylchlorosilane are added and the resulting mixture is stirred for 2 hours at 0° C. 50 ml of water are added and this mixture is extracted with ethyl acetate (3×80 ml). The organic phases are combined, dried over magnesium sulphate and concentrated. The residue is purified by chromatography on a column of silica (elution solvent: 10% ethyl acetate in hexane). 1.85 g (yield: 72%) of (+)-2-ethyl-3-methyl-8-(1(S)-hydroxy-2-[tert-butyldimethylsilyloxy]-ethyl)quinoline are obtained in the form of an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[Cl:13].[NH:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[Cl:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:14]1[CH2:15][CH2:16][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:18][CH2:19]1
Reactant: Fc1ccc(OCCCCl)c(Cl)c1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1C1CCN(CCCOc2ccc(F)cc2Cl)CC1

Procedure:
A mixture of 3.3 g of 2-(3-chloropropoxy)-5-fluorochlorobenzene, 3.3 g of 1-(4-piperidinyl)-2-oxobenzimidazoline, 0.9 g of sodium carbonate and 80 ml of dimethylformamide was heated at 80° - 90° C for 15 hours. After cooling, the reaction mixture was poured into water and extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was triturated with ether, cooled and filtered to give 1-{3-(2-chloro-4-fluorophenoxy)propyl}-4-(2-oxo-1-benzimidazolinyl)piperidine, m.p. 130° - 132° C; recrystallized from benzenecyclohexane, m.p. 149° - 149.5° C.
Reaction SMILES: [CH2:1]([C:8]1[C:9](Cl)=[N:10][C:11]([NH2:15])=[N:12][C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([NH2:22])[CH2:18][CH2:19][CH2:20][CH3:21]>O1CCOCC1>[NH2:15][C:11]1[N:10]=[C:9]([NH:22][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:13]([CH3:14])[N:12]=1
Reactant: CCCCCN
Reactant: Cc1nc(N)nc(Cl)c1Cc1ccccc1
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccccc1
Reaction time: 19 h
Yield: 89.7 %

Procedure:
A mixture of 5-benzyl-4-chloro-6-methylpyrimidine-2-ylamine (500 mg, 2.14 mmol) , amylamine (1.24 ml ) and dioxane (4 ml ) was kept at 95-100° C. for 19 hours. The reaction mixture was concentrated in vacuo, and the residue was extracted with chloroform and a saturated aqueous NaHCO3 solution. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (2%MeOH/CHCl3) to give the object compound (546 mg, 89.7%).
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.[C:15]1([CH2:21][C:22](O)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:22](=[O:23])[CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: c1ccc2c(c1)OCCc1ccsc1-2
Product: O=C(Cc1ccccc1)c1cc2c(s1)-c1ccccc1OCC2

Procedure:
Scheme 7 shows a general method for substitution at the 2-position of 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine intermediates 74 by acylation with a carboxylic acid such as 2-phenylacetic acid to give 1-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-2-phenylethanone intermediate 81. Bromination gives 2-bromo-1-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-2-phenylethanone intermediate 82. Cyclization with a thioamide compound gives 4-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-5-phenylthiazole 83.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[NH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.O>C1C=CC=CC=1>[CH:1](=[C:12]1[CH:13]=[C:8]([CH2:7][NH2:6])[CH:9]=[CH:10][NH:11]1)[CH:2]([CH3:4])[CH3:3]
Reactant: NCc1ccncc1
Reactant: CC(C)C=O
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C=C1C=C(CN)C=CN1
Yield: 91.7 %

Procedure:
227 g (3.15 mols) of isobutyraldehyde is added dropwise, within 1.5 hours, to a solution of 324 g (3.0 mols) of 4-aminomethylpyridine in 300 ml of benzene, the addition being made in a manner ensuring that the temperature in the solution does not exceed 35° C. The water which has formed (about 39 g) is separated, and the benzene (with residual water) is distilled off under a slight water-jet vacuum. The residue is distilled in an oil-pump vacuum. After a small preliminary fraction of 5 g, there is obtained 445 g (2.75 mols) of isobutylidene-4-aminomethylpyridine as a slightly yellowish main fraction, corresponding to a yield of 91.5% of theory; b.p. 81.5°-82° C./133 Pa; nD° =1.5105.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]2)=[CH:4][CH:3]=1.Cl[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1.N1C(C)=CC(C)=CC=1C>CN(C)C=O>[N+:26]([C:25]1[C:20]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]3)=[CH:4][CH:3]=2)=[N:21][CH:22]=[CH:23][CH:24]=1)([O-:28])=[O:27]
Reactant: CN1CCCC(c2cccc3ccc(N)cc23)C1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CN1CCCC(c2cccc3ccc(Nc4ncccc4[N+](=O)[O-])cc23)C1

Procedure:
A mixture of 7-amino-1-(1-methyl-3-piperidinyl)-naphthalene (0.252 g, 1.05 mmol from Example 61 ), 2-chloro-3-nitropyridine (0.333 g, 2.1 mmol) and collidine (0.139 mL, 1.05 mmol) in dimethylformamide (10 mL) was refluxed overnight. The reaction was concentrated at reduced pressure and the residue was taken up in methylene chloride. The organic phase was washed with 0.5N sodium hydroxide and brine, dried, concentrated onto silica gel and flash chromatographed (1×3 inches). Elution proceeded as follows: 50% ethyl acetate/hexane (500 mL) unweighed forrun; 75% ethyl acetate/hexane (400 mL) and ethyl acetate (100 mL) 0.151 g (51%) of red oil product. A sample crystallized from ether gave the title compound as red crystals. mp 107°-108° C. Analysis calculated for C21H22N4O2 ; C, 69.59; H, 6.12; N, 15.46. Found: C, 69.30; H, 5.91; N, 14.92.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N+:9]([O-])=O)=[C:6]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=1)(=[O:3])[NH2:2]>O1CCOCC1.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[NH2:9][C:7]1[S:8][C:4]([C:1](=[O:3])[NH2:2])=[CH:5][C:6]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)Cc1cc(C(N)=O)sc1[N+](=O)[O-]
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1cc(C(N)=O)sc1N
Yield: 95.9 %

Procedure:
Ethyl 5-carbamoyl-2-nitrothiophene-3-acetate (600 mg, 2.33 mmol) was dissolved in aqueous dioxan (7 ml, 4:1 dioxan/water) and treated with reduced iron powder (1.55 g, 27.77 mmol) and iron sulfate heptahydrate (200 mg, 0.68 mmol). The reaction mixture was refluxed for 1 hour then filtered through celite filter-aid and washed through with ethyl acetate. The organic phase was washed with saturated sodium aqueous hydrogen carbonate and saturated aqueous sodium chloride. The organic phase was dried over magnesium sulfate and evaporated to a red/black viscous oil and then chromatographed on silica gel using hexane/ethyl acetate (1:2) as eluent to give 510 mg of ethyl 2-amino-5-carbamoylthiophene-3-acetate. MS(ES): m/e 229 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Cl)cc1
Product: O=S(=O)(/C=C/c1ccc(F)cc1)Cc1ccc(Cl)cc1
Yield: 72 %

Procedure:
A solution of 4-chlorobenzyl sulfonylacetic acid (0.01 mol) and 4-fluorobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 72% yield.
Reaction SMILES: [F:1][CH:2]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][N:4]1[CH2:8][CH2:7][C@@H:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:5]1.[OH:25]OS([O-])=O.[K+]>CO>[F:1][CH:2]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][N:4]1[CH2:8][CH2:7][CH:6]([S:9]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:25])[CH2:5]1
Reactant: Oc1ccc(S[C@@H]2CCN(CC(F)CCc3ccccc3)C2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: O=S(c1ccc(O)cc1)C1CCN(CC(F)CCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 10.2 %

Procedure:
(2RS,3R)-4-[1-(2-Fluoro-4-phenyl-butyl)-pyrrolidin-3-ylsulfanyl]-phenol (0.56 g, 1.62 mmol) was dissolved in MeOH (50 ml), cooled to 0° C. and treated with oxone (0.5 g, 0.81 mmol). After 4 hours stirring at 0° C., reaction mixture was quenched with saturated NaHCO3 (65 ml). Aqueous phase was extracted with CH2Cl2 (6 times). Combined organic phases were dried over Na2SO4 and the solvent was evaporated. The residue was chromatographed by MPLC over silica gel (CH2Cl2—MeOH, 99:1 then 98:2) then by preparative HPLC (EtOH-heptane, 08:92, detection at 254 nm) to provide (2R,3R, S-oxide R)-4-[1-(2-fluoro-4-phenyl-butyl)-pyrrolidine-3-sulfinyl]-phenol (30 mg, first fraction, 5%), MS: m/e=362.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH2:24][C:25]([OH:27])=O)[C:11](=[O:28])[CH:10]=2)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[N:13][N:12]([CH2:23][CH2:24][C:25]([NH:42][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:27])[C:11](=[O:28])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(-c2cc(=O)n(CCC(=O)O)nc2-c2ccc(OC)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc(-c2cc(=O)n(CCC(=O)NCc3ccccc3)nc2-c2ccc(OC)cc2)cc1
Yield: 52.2 %

Procedure:
After 5,6-bis(4-methoxyphenyl)-2-(2-carboxyethyl)-2H-pyridazin-3-one was reacted with oxalyl chloride in a similar manner as in Example 113-(3), a further reaction was conducted with benzylamine, whereby the title compound was obtained in a yield of 52.2%.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2].FC(F)(F)S(O)(=O)=O.[CH2:72](OC(=N)C(Cl)(Cl)Cl)[CH:73]=[CH2:74].C1CCCCC1>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:74][CH:73]=[CH2:72])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:60])([CH3:61])[CH3:62])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: C=CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CC1OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (820 mg in 9 ml 33% methylene chloride in cyclohexane allyl trichloroacetimidate (366 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (16 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 17 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×15 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ether: hexane (2:3)) gave the title compound (800 mg). (1H NMR was consistent with the desired structure).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CO[C:13](=O)[CH2:14][O:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:20]1([CH3:24])[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][CH2:16][O:15][CH2:14][C:13]2[NH:6][C:4](=[O:5])[C:3]3[CH:7]=[CH:8][CH:9]=[N:10][C:2]=3[N:1]=2)[CH:19]=1
Reactant: NC(=O)c1cccnc1N
Reactant: COC(=O)COCCc1cccc(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(CCOCc2nc3ncccc3c(=O)[nH]2)c1

Procedure:
In analogy to example 91.3, 2-amino-nicotinamide and (2-m-tolyl-ethoxy)-acetic acid methyl ester (prepared from 2-m-tolyl-ethanol [1875-89-4] in analogy to example 91.1-91.2) reacted in the presence of LiHMDS in THF to yield after purification of the crude product with column chromatography (silica gel, EtOAc) and crystallization from EtOAc/heptane 2-(2-m-tolyl-ethoxymethyl)-3H-pyrido[2,3-d]pyrimidin-4-one as white solid. MS (m/e): 296.4 [M+H+].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Cl:10][SiH:11]([Cl:13])[Cl:12]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[CH2:2]([Si:11]([Cl:13])([Cl:12])[Cl:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCl
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: CCCCCCCC[Si](Cl)(Cl)Cl
Yield: 85.2 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.20 g (0.68 mmol) of tetrabutylphosphonium chloride, 1.00 g (6.73 mmol) of 1-chlorooctane and 2.71 g (20.0 mmol) of trichlorosilane were reacted at 170° C. for 2 hrs. The resulting mixture was distilled to give 1.42 g of n-octyltrichlorosilane (yield; 85%).