Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:16].C(OOC(=O)C1C=CC=CC=1)(=[O:24])C1C=CC=CC=1.C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[OH:24][CH:5]1[C:4]2[C:9](=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[C:8](=[O:16])[CH2:7][CH2:6]1
Reactant: COc1ccc([N+](=O)[O-])c2c1CCCC2=O
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc([N+](=O)[O-])c2c1C(O)CCC2=O
Temperature: 25 °C

Procedure:
2.0 gm of 5-methoxy-8-nitro-1-tetralone (described in Japanese Patent Laid-open (ko-kai) 279891/1989 and also in U.S. Pat. No. 4,939,255) and 2.05 gm of N-bromosuccinic imide were dissolved in 50 ml of carbon tetrachloride. After the addition of a catalytic amount of benzoyl peroxide, the mixture was heated under reflux for 4 hours and then cooled to room temperature, followed by the addition of 50 ml of chloroform. The mixture was washed with 10% aqueous solution of sodium hydroxide, water, and saturated brine in this order, and dried over anhydrous sodium sulfate. To the residue obtained by removing the solvent were added 5 ml of tetrahydrofuran, 5 ml of ethanol, 8 ml of water, and 250 mg of calcium carbonate, and the mixture was heated under reflux. A residue was obtained by removing the solvent from the reaction mixture, which, after the addition of 50 ml of water, was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography using chloroform-ethyl acetate (4:1) as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 1.49 gm of light yellow powder of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:9])[CH2:5][C:6](Cl)=[O:7])C.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:6](=[O:7])[CH2:5][C:4]([OH:3])=[O:9])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: CCOC(=O)CC(=O)Cl
Product: COc1ccc(N2CCN(C(=O)CC(=O)O)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 127 using chlorocarbonyl-acetic acid ethyl ester and 3(S)-benzyl-1-(3-cyclobutoxy-4-methoxy-phenyl)-piperazine (Example 7, Compound 95) as starting material. Product as an oil (25 mg, 65%). LC/MS (Method B) 2.56 min, [M+1]+ 439. Potency class A.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[CH2:8][CH2:7][C:6]([CH3:13])([CH3:12])[C:5]=2[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:3]1.C(O[CH:24](OC(C)(C)C)[N:25]([CH3:27])[CH3:26])(C)(C)C>CN(C)C=O>[CH3:24][N:25]([CH:27]=[C:8]1[C:9](=[O:11])[C:10]2[N:2]([CH3:1])[N:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]=2[C:6]([CH3:13])([CH3:12])[CH2:7]1)[CH3:26]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: CCOC(=O)c1nn(C)c2c1C(C)(C)CCC2=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C)c2c1C(C)(C)CC(=CN(C)C)C2=O
Yield: 87.1 %

Procedure:
A solution of ethyl 1,4,4-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (4.8 g, 19.18 mmol) in anhydrous dimethylformamide (30 mL) was treated with dimethylformamide di-tert-butylacetal (9.19 mL, 38.35 mmol) at 65° C. for 2 hours. The mixture was evaporated to dryness and the crude material was crystallized from hexane to give the title compound (5.1 g, 87% yield).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.CN.[N+:18]([C:21]1[CH:30]=[CH:29][C:24]([CH2:25][N:26]=[C:27]=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19].[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][NH:26][C:27]([N:2]([CH:3]2[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]2)[CH3:1])=[O:28])=[CH:29][CH:30]=1)([O-:20])=[O:19]
Reactant: O=C=NCc1ccc([N+](=O)[O-])cc1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)NCc1ccc([N+](=O)[O-])cc1)C1CCNCC1

Procedure:
The title compound was prepared by the reaction of 4-(N-methylamino)-1-tert-butoxycarbonylpiperidine (prepared by the method described in Example 1, Step A, using methylamine in place of ethylamine) with (4-nitrobenzyl)isocyanate (prepared from phosgene and (4-nitrobenzyl)amine), followed by treatment of the product with 50% TFA in CH2Cl2 to remove the tert-butoxycarbonyl group, affording the title compound. ESI-MS: 293.1 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]([CH2:25][CH2:26][CH2:27][CH2:28]Br)[N:18]3[C:23]=2[C:22]([NH2:24])=[N:21][CH:20]=[N:19]3)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C>CN(C=O)C.[I-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]([CH2:25][CH2:26][CH2:27][CH2:28][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:18]3[C:23]=2[C:22]([NH2:24])=[N:21][CH:20]=[N:19]3)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Nc1ncnn2c(CCCCBr)cc(-c3cccc(OCc4ccccc4)c3)c12
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CCCCN3CCCC3)cc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 55 °C
Yield: 94.5 %

Procedure:
To a solution of 5-[3-(benzyloxy)phenyl]-7-(4-bromobutyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (129 mg, 0.29 mmol) in DMF (1.5 mL) was added pyrrolidine (26 μL, 0.31 mmol), triethylamine (120 μl, 0.86 mmol), and sodium iodide (0.4 mg, 0.003 mmol). The reaction was heated (55° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and water (25 mL). The layers were separated and the organic was washed with water (2×20 mL), brine, dried (Na2SO4) and evaporated to afford 121 mg (96%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ7.87 (s, 1 H), 7.46-7.41 (m, 2 H), 7.41-7.28 (m, 4 H), 7.08-7.04 (m, 1 H), 7.02-6.97 (m, 2 H), 6.55 (s, 1 H), 5.14 (s, 2H), 2.87 (t, 2 H), 2.42-2.33 (m, 6 H), 1.76-1.66 (m, 2 H), 1.67-1.60 (m, 4 H), 1.56-1.46 (m, 2 H); ES-MS m/z 442.2 [M+H]+, HPLC RT (min) 2.30.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH2:10].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O>[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH:10][S:19]([CH3:18])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 72.8 %

Procedure:
To 334 ml of a pyridine solution containing 52.1 g of 2-fluoro-5-nitroaniline was added 42.1 g of methanesulfonyl chloride under ice-cooling, followed by stirring at room temperature for 7 hours. Water was added to the reaction solution, the precipitate was collected by filtration, and the crude crystals were recrystallized from ethanol to give 56.9 g of N-(2-fluoro-5-nitrophenyl)methanesulfonamide as pale yellow needles.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7].[BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+]>O1CCCC1.C(O)C>[Br:1][C:2]1[C:3]([CH:9]([OH:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)C(=O)c1c(C)sc(C)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(O)c1c(C)sc(C)c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a solution of ethyl 2-(4-bromo-2,5-dimethylthiophen-3-yl)-2-oxoacetate (28c) (1 g, 3.56 mmol) in tetrahydrofuran (22.5 mL) and ethanol (5.6 mL) cooled to 0° C. is added sodium tetraborohydride (121.2 mg, 3.20 mmol). The mixture is stirred at 0° C. for 1 hour. The mixture is quenched with HCl (1N) and extracted with ethyl acetate. The organic extract is washed with brine, dried over sodium sulfate, filtered and concentrated to afford the desired alcohol (28d) as a white solid (836 mg, 2.85 mmol, 89%) which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([CH:29]([CH3:31])[CH3:30])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH3:33]I>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[C:21]([CH:29]([CH3:31])[CH3:30])[CH:20]=3)(=[O:18])=[O:17])[CH3:33])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(C(C)C)cc(C(F)(F)F)c1
Reactant: CI
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(C(C)C)cc(C(F)(F)F)c1
Yield: 82.9 %

Procedure:
Starting with [(R)-4-(3-isopropyl-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (Example 12-1) and methyl iodide, using the method analogous to the one described for example 2-1, {(R)-4-[(3-isopropyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (30 mg, 82.9%) was obtained as an off-white semisolid. MS cald. for C22H28F3N3O4S 487, obsd. (ESI+) [(M+H)+] 488
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][C:10]([CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:11][C:4]=2[N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[N:6]([CH3:7])[C:5]4[CH:8]=[CH:9][C:10]([CH2:12][N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)=[CH:11][C:4]=4[N:3]=3)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Cn1c(I)nc2cc(CN3CCCC3)ccc21
Product: Cn1c(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)nc2cc(CN3CCCC3)ccc21

Procedure:
Prepared according to general working method I from 2-iodo-1-methyl-5-pyrrolidin-1-ylmethyl-1H-benzimidazole (100 mg, 0.29 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (68 mg, 0.32 mmol).
Reaction SMILES: Cl.CN([CH2:5][CH:6]1[C:18](=[O:19])[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:20])[C:9]=2[CH2:8][CH2:7]1)C.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1>O>[CH3:20][N:10]1[C:9]2[CH2:8][CH2:7][CH:6]([CH2:5][N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH3:21])[C:18](=[O:19])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: CN(C)CC1CCc2c(c3ccccc3n2C)C1=O
Reactant: Cc1ncc[nH]1
Agent: Cl
Solvent: O
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Yield: 82.2 %

Procedure:
A solution of 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride (1.7 g) in water (17 ml) was treated with 2-methylimidazole (1.4 g) and then heated under reflux for 20 h. The cooled mixture was filtered and the residue washed with water (3×15 ml) to give crude product (1.7 g) m.p. 221°-221.5°. This material was recrystallized from methanol to give the title compound (1.4 g) m.p. 231°-232°.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]=[C:20]1[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][N:21]1[CH2:38][C:39](O)=[O:40].C(N(C(C)C)CC)(C)C>ClCCl>[C:13]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:12][CH2:11][CH2:10][N:9]([C:39](=[O:40])[CH2:38][N:21]3[CH2:22][CH2:23][CH2:24][C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:19])[CH2:8]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(C2(c3ccccc3)CNCCO2)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCOC(c2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,2-diphenylmorpholine (0.075 g, 0.313 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.097 g, 0.313 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.131 g, 0.345 mmol) in dichloromethane (1 mL) was added diisopropylethylamine (0.082 mL, 0.470 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was loaded directly onto a silica gel column (Analogix®, SF15-24) and the product was eluted with a gradient of 5% to 100% ethyl acetate/hexanes over 25 minutes with a flow rate of 30 mL/minute. 1H NMR (300 MHz, CDCl3) δ ppm 7.18-7.60 (m, 20H), 4.43 (s, 2H), 3.50-3.70, m, 6H), 3.05-3.10 (m, 2H), 2.40-2.50 (m, 2H), 1.55-1.70 (m, 2H); MS (DCI+) m/z 531 (M+H)+.
Reaction SMILES: [N:1]#[C:2][NH2:3].[C:4]12([C:14](Cl)=[O:15])[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2>[OH-].[Na+].CCOCC>[C:4]12([C:14]([NH:1][C:2]#[N:3])=[O:15])[CH2:11][CH:10]3[CH2:9][CH:8]([CH2:7][CH:6]([CH2:12]3)[CH2:5]1)[CH2:13]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: N#CN
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: N#CNC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a solution of cyanamide (2.52 g, 0.06 mol) in 24 ml of sodium hydroxide (10%) was added slowly to a solution of 1-adamantanecarbonylchloride (4 g, 0.02 mol) in ether (15 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with ether and the aqueous layer was cooled in ice bath and acidified with hydrochloric acid (10%) to pH 2. The precipitated white solid was filtered, washed with water, later hexanes and dried under high vacuum to give the N-(1-adamantancarbonyl)cyanamide (3.2 g, 78%); m.p. 164–166° C. (lit m.p. 168–170° C.); purity 94% HPLC; 1H-NMR (CD3OD) δ 1.45–2.16 (m, 15H, CH2 and CH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](N)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.N(OC(C)(C)C)=O.[I:23]I>C(Cl)(Cl)(Cl)Cl>[I:23][C:12]1[CH:11]=[N:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:14][N:13]=1
Reactant: COc1ccc(-c2cnc(N)cn2)cc1
Reactant: II
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2cnc(I)cn2)cc1
Temperature: 0 °C

Procedure:
In a light protected flask, 4.10 g (20.4 mmol) 5-(4-methoxyphenyl)-pyrazin-2-amine are added to 140 mL carbon tetrachloride. After cooling down to 0° C. 4.12 mL (34.6 mmol) tert-butyl nitrite and 6.72 g (26.5 mmol) iodine are added sequently. Then cooling is removed and the reaction mixture is stirred at ambient temperature over night. The reaction mixture is diluted with DCM and washed sequently with aq. Na2S2O5 solution and water. The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The residue is triturated with TBME and purified by column chromatography (silica gel, PE/EtOAc 6/4).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[S:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[OH-].[Na+].Cl>O1CCCC1.O>[OH:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:12]([S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24])(=[O:15])=[O:14])[C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:33])=[O:2])=[CH:7][CH:8]=1
Reactant: COC(=O)C=Cc1ccc(N(Cc2cccc(O)c2)S(=O)(=O)c2c(C)cc(C)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(O)c2)c2ccc(C=CC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-{4-[(3-hydroxy-benzyl)-(2,4,6-trimethyl-benzenesulfonyl)-amino]-phenyl}-acrylic acid methyl ester (0.040 g, 0.08 mmol) in 0.5 mL tetrahydrofuran was added sodium hydroxide (0.010 g, 0.25 mmol) in 0.5 mL water. The reaction was stirred at room temperature for 24 hr. The reaction mixture was adjusted to a pH of 4 with 1N HCl and water was added. The aqueous solution was washed with methylene chloride and the organic layer was dried (magnesium sulfate) and concentrated. Preparative TLC afforded 3-{4-[(3-hydroxy-benzyl)-(2,4,6-trimethyl-benzenesulfonyl)-amino]-phenyl}-acrylic acid. 1H NMR (CDCl3) δ 7.58 (d, 1H, J=16 Hz), 7.29 (d, 2H, J=8.4 Hz), 7.04 (d, 2H, J=8.4 Hz), 7.05–7.00 (m, 1H), 6.86 (s, 2H), 6.70–6.60 (m, 3H), 6.28 (d, 1H, J=16 Hz), 4.77 (s, 2H), 2.45 (s, 6H), 2.25 (s, 3H).
Reaction SMILES: [Mg].II.Br[CH:5]=[C:6]([CH3:8])[CH3:7].[CH2:9]([Sn:13](Cl)([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12]>O1CCCC1.IC>[CH:5]([Sn:13]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:9][CH2:10][CH2:11][CH3:12])=[C:6]([CH3:8])[CH3:7]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)=CBr
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CI
Product: CCCC[Sn](C=C(C)C)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
A suspension of magnesium (2.64 g, 110 mmol) in dry tetrahydrofuran (60 mL) was treated with a small amount of iodine and then 1-bromo-2-methylpropene (13.5 g, 100 mmol) in tetrahydrofuran (30 mL) was added in several portions. The mixture was heated under reflux for 3 min. The mixture was cooled to 25° C. and then treated with iodomethane (0.2 mL, 3.0 mmol). The reaction mixture was stirred at 25° C. for 30 min and then heated under reflux for 2 h until all the magnesium was consumed. The mixture was cooled to 25° C. then treated with a solution of tributyltin chloride (27 mL, 100 mmol) in tetrahydrofuran (30 mL). The mixture was heated under reflux for 19 h and then cooled to 25° C. The solution was extracted with diethyl ether and a saturated aqueous ammonium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford isobutenyltri-n-butyltin (31.95 g) as a crude oil. The 1H-NMR data of the crude oil indicated 58% purity of the desired isobutenyltri-n-butyltin.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16](F)[CH:15]=1>O1CCCC1>[CH2:1]([NH:5][C:18]1[CH:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=1[N+:20]([O-:22])=[O:21])[CH:2]([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CC(C)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CNc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Add a solution of isobutylamine (14 mL, 0.138 mol), potassium carbonate (10.4 g, 0.075 mol) and water (50 mL) to a solution of 4-chloro-2-fluoro-nitrobenzene (11.0 g, 0.063 mol) in tetrahydrofuran (0.3 L) and stir at ambient temperature for 3 hours. Separate phases and wash organic layer with 1:1 solution of 1N HCl (aq)/saturated sodium chloride. Dry organic phase with solid magnesium sulfate, filter and concentrate under reduced pressure to give 14.5 g (0.063 mol) of the desired compound as an orange oil that solidifies upon standing.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:12]([Mg]Cl)[C:13]([CH3:16])([CH3:15])[CH3:14]>C1COCC1.CCCCCC>[CH3:12][C:13]([CH3:16])([CH3:15])/[CH:14]=[CH:8]/[C:7]1[CH:10]=[CH:11][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)C[Mg]Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)/C=C/c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) and well stirred suspension of 4-carboxy benzaldehyde (2.0 g, 13.32 mmol) in anhydrous THF (90 mL) is added 33.3 mmol of neopentyl magnesium chloride in hexane during 20 minutes and the mixture is stirred at the same temperature for an additional two hours before being quenched with satyrated ammonium chloride solution. Most of the THF is evaporated and the aqueous mixture is treated with conc. HCl (50 mL) and the mixture is heated to reflux for 2 hours. The mixture is then cooled to ambient temperature and extracted with methylene chloride (2×100 mL), the organic layer is dried over sodium sulfate and concentrated to obtain the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12]O>[Ni]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[CH3:12]
Reactant: CO
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: [Ni]
Product: CC1C(=O)Nc2ccc(F)cc21

Procedure:
3.0 g (20 mmol) 5-fluoro-1,3-dihydro-indol-2-one were stirred with 2.0 g Raney nickel in 50 mL methanol for 1.5 h at 200° C. in an autoclave. The catalyst was filtered off and the filtrate was concentrated to dryness by rotary evaporation. The residue was recrystallised from methanol, suction filtered and dried.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][C:12]([OH:17])([CH3:16])[CH2:13][CH2:14]O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[C:1]([O:9][CH2:10][CH2:11][C:12]([OH:17])([CH3:16])[CH2:13][CH2:14][Br:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)(CCO)CCOC(=O)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(CCBr)CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.5 %

Procedure:
To a solution of 3,5-dihydroxy-3-methylpentyl benzoate (1.0 g) and carbon tetrabromide (2.78 g) in tetrahydrofuran (30 mL) was added dropwise a solution of triphenylphosphine (2.20 g) in tetrahydrofuran (10 mL) under ice-cooling. After stirring at room temperature for 3 days, water was added, and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=9:1→6:4) to give the title compound (979 mg) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24](=[O:34])[N:23]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)[CH:22]=[CH:21]2>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:27]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:24](=[O:34])[N:23]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[CH:22]=[CH:21]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cn2ccc3cc(F)c(-c4ccccc4)cc3c2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2ccc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
168 mg (0.83 mmol) 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 5 mL of dimethylacetamide and 20 mg (0.83 mmol) of sodium hydride (60%) were added. The mixture was stirred at room temperature. After 30 minutes a solution of 240 mg (0.67 mmol) 6-fluoro-2-(4-methoxy-benzyl)-7-phenyl-2H-iso-quinolin-1-one (315) in 5 mL of dimethylacetamide was added and stirring was continued at room temperature. After standing overnight, 20 mg (0.83 mmol) of sodium hydride (60%) were added and the solution was stirred at 100° C. After 1 h, the solvent was removed i. vac. and saturated sodium bicarbonate solution was added. The aqueous phase was extracted three times with dichloromethane. The organic layers were dried with MgSO4 and evaporated. The crude product was purified by preparative HPLC. Rt=1.98 min (Method C). Detected mass: 541.7 (M+H+).