Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.C(Cl)(=O)[C:11]([Cl:13])=O.[N+](=C)=[N-].Cl>>[Cl:13][CH2:11][C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccsc1
Agent: C=[N+]=[N-]
Agent: Cl
Product: O=C(CCl)Cc1ccsc1
Yield: 100 %

Procedure:
The procedure described above for the synthesis of 1-chloro-3-[2-(3-methylbenzo[b]thiophen-2-yl)propan-2-one was followed, reacting thiophene-3-acetic acid (5.32 g, 37.4 mmol) with oxalyl chloride (3.6 mL, 5.2 g, 41 mmol, then ethereal diazomethane, then dry HCl gas. Work-up gave pure product, a brown oil which solidified upon refrigeration to a golden-brown, waxy solid (6.52 g, 100% yield): 1H NMR (400 MHz, CDCl3) δ 3.94 (s, 2H) 4.13 (s, 2H) 6.99 (d, J=5.1 Hz, 1H) 7.16 (dd, J=1.5, 0.8 Hz, 1H) 7.33 (dd, J=4.9, 2.9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12]O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:12])=[O:8]
Reactant: CO
Reactant: Nc1ccc(O)c(C(=O)O)c1
Product: COC(=O)c1cc(N)ccc1O
Yield: 76 %

Procedure:
To a solution of 5-aminosalicylic acid (3.00 g, 19.6 mmole) in methanol (80 ml) was added c-H2SO4 (8 ml) at 0° C. After the reaction mixture was refluxed for 6 hr, the solvent was removed in vacuo. The resulting residue was partitioned with ethyl acetate and water. The organic layer was washed with water (40 ml×3) and then dried over anhydrous MgSO4. After evaporation of the solvent, the residue was recrystallized from ethyl acetate/hexane to give 2.50 g (76% yield) of methyl 5-amino-2-hydroxybenzoate as a yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CCN(C(C)C)C(C)C.[C:24]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[C:24]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)=[O:33])=[CH:35][CH:36]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)c2ccc(C(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (8) (6.27 g, 33.5 mmol) in DCM (100 mL) was added DIEA (8.75 mL, 50.3 mmol) and then 4-tert-butylbenzoyl chloride (8.0 mL, 43.6 mmol) in drop-wise manner. The mixture was stirred for 3 h at RT, diluted with DCM, washed with 1N NaOH, dried, and concentrated. The residue was subjected to flash column chromatography with 0 to 10% EtOAc in DCM to give (R)-tert-butyl 3-(4-tert-butylbenzamido)piperidine-1-carboxylate (11.0 g, 91%). To a solution of (R)-tert-butyl 3-(4-tert-butylbenzamido)piperidine-1-carboxylate (850 mg, 2.36 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 190 mg, 4.72 mmol). The mixture was stirred at RT for 10 min and then iodomethane (0.44 mL, 7.08 mmol) was added. The mixture was stirred at RT for 1 h, and diluted with 150 mL EtOAc. The mixture was washed with water ×2, dried, and concentrated. The residue was subjected to flash column with 0 to 3% MeOH in DCM to afford (R)-tert-butyl 3-(4-tert-butyl-N-methylbenzamido)piperidine-1-carboxylate (9) in quantitative yield. It was treated with 15 mL 4N HCl in dioxane at RT for 1 h. The mixture was concentrated in vacuo to dryness to afford (R)-4-tert-butyl-N-methyl-N-(piperidin-3-yl)benzamide (10) HCl salt in quantitative yield.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[Li][CH3:18]>C1COCC1>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:18])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: [Li]C
Reactant: CCc1sc(C(=O)O)cc1-c1ccccc1
Solvent: C1CCOC1
Product: CCc1sc(C(C)=O)cc1-c1ccccc1
Reaction time: 1 h

Procedure:
At 5° C. a solution of 5-ethyl-4-phenyl-thiophene-2-carboxylic acid (180 mg, 0.775 mmol) in THF (4 mL) is treated with MeLi (0.9 mL, 1.6 M in diethyl ether). The reaction mixture is stirred at rt for 30 min before another portion of MeLi (0.5 mL) is added. Stirring is continued for 1 h, the reaction is quenched by adding water (50 mL) and extracted with EA. The organic extract is dried over MgSO4, the solvent is removed in vacuo, and the crude product is purified by CC on silica gel eluting with heptane:EA 30:1 to give 1-(5-ethyl-4-phenyl-thiophen-2-yl)-ethanone (64 mg) as a colourless oil; LC-MS: tR=1.03 min, [M+1+MeCN]+=272.15; 1H NMR (CDCl3): δ 7.60 (s, 1H), 7.47-7.32 (m, 5H), 2.91 (q, J=7.6 Hz, 2H), 2.54 (s, 3H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: F[H-]F.[NH4+].[C:5]1(=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH:7]=[CH:6]1.C([Si](CC)(CC)[C:20]([F:23])([F:22])[F:21])C.C1C2C(=CC=CC=2)C=CC=1>CN(C)C=O>[OH:16][C:5]1([C:20]([F:23])([F:22])[F:21])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH:7]=[CH:6]1
Reactant: CC[Si](CC)(CC)C(F)(F)F
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: F[H-]F
Agent: [NH4+]
Solvent: c1ccc2ccccc2c1
Solvent: CN(C)C=O
Product: O=C1C=CC(O)(C(F)(F)F)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 74 mg (1.3 mmol) of ground ammonium bifluoride, 174 mg (1.1 mmol) of 1,4-naphthoquinone, and 1 mL of N,N-dimethylformamide was treated with 239 mg (1.3 mmol) of triethyltrifluoromethylsilane and stirred vigorously at room temperature for one hour. Gas chromatographic analysis of the reaction mixture showed that the major naphthalene-desired product was 1,4-dihydro-4-hydroxy-1-oxo-4-trifluoromethylnaphthalene.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH:5]([O:13][CH:14]1[CH2:17][NH:16][CH2:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[N-]=C=O.ClC1C=CC=CC=1C(O[CH:37]1[CH2:40][N:39]([C:41](NC(C)(C)C)=[O:42])[CH2:38]1)C1C=CC=CC=1Cl>>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:5]([O:13][CH:14]1[CH2:17][N:16]([C:41]([NH:39][CH2:38][CH:37]=[CH2:40])=[O:42])[CH2:15]1)[C:4]1[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=1[Cl:2]
Reactant: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1
Agent: Cl
Agent: [N-]=C=O
Product: C=CCNC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1

Procedure:
This material was prepared from 3-(2,2′-dichlorobenzhydryloxy)azetidine hydrochloride (68) and the corresponding commercially available isocyanate using the procedure described for compound (69).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.CON(C)[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=[O:10]>O1CCCC1>[CH:1]1([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:3][CH2:2]1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Add cyclopropylmagnesium bromide (4.8 g, 33.0 mmol) to a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (7.5 g, 27.5 mmol) in tetrahydrofuran (120 mL) at 0° C. Remove the cooling bath and stir at ambient temperature overnight. Add an additional cyclopropylmagnesium bromide (20 mL) and stir an additional 4 hours. Pour into a solution of saturated sodium bicarbonate and extract once with diethyl ether and once with EtOAc. Combine organic extracts, dry over sodium sulphate; filter; collect the filtrate; and concentrate under vacuum. Purify via flash column chromatography using a gradient of 0-40% ethyl acetate in hexane to give the title compound (6.4 g, 91.7%). MS (m/z): 198 (M+1-tBu).
Reaction SMILES: C(S[C:4]1[C:13]2[C:8](=[C:9]([CH2:24][CH2:25][CH3:26])[C:10]3[O:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][C:14](=[O:23])[C:11]=3[CH:12]=2)[N:7]=[C:6]([C:27]([O-:29])=[O:28])[CH:5]=1)C.[CH2:30](O)[CH3:31]>>[O:23]=[C:14]1[C:11]2[CH:12]=[C:13]3[C:8](=[C:9]([CH2:24][CH2:25][CH3:26])[C:10]=2[O:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15]1)[N:7]=[C:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:5]=[CH:4]3
Reactant: CCCc1c2nc(C(=O)[O-])cc(SCC)c2cc2c(=O)cc(C(=O)OCC)oc12
Reactant: CCO
Product: CCCc1c2nc(C(=O)OCC)ccc2cc2c(=O)cc(C(=O)OCC)oc12

Procedure:
Ethyl 6-ethylthio-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline 2,8-dicarboxylate (2.85 g) was dissolved in ethanol (200 ml), and ethanol washed Raney nickel (30 g wet) added carefully. The mixture was refluxed for 11/2 hours, filtered to remove the catalyst, and concentrated, to give on cooling the title compound, (1.76 g) mp 168°-171° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[NH2:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20].O>CO>[OH:9][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([NH:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NCC(O)CO
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: CO
Solvent: O
Product: OCC(O)CNC(c1ccccc1)C(O)c1ccccc1
Temperature: 125 °C
Yield: 22.1 %

Procedure:
A mixture of trans-stilbene oxide (3.93 g, 0.20 mol) and 1-amino-2,3-propanediol (5.46 g, 0.060 mol) was heated at 125° C. for 18 hours in an oil bath. After cooling, the reaction mixture was dissolved in 20 mL of methanol and the solution poured into 150 mL of water. The product separated from the solution as a viscous cream-colored oil that slowly solidified. The solid was collected by filtration and vacuum dried at 40° C. for 18 hours to give 3.81 g (66% yield) of material. The product was recrystallized from methanol-isopropyl ether to give 1.75 g; mp 161°-163° C.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([CH2:36]Cl)[CH:31]=1>CN(C)C=O>[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)[CH:31]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Reactant: ClCc1cc(Cl)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4cc(Cl)ccn4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 11.4 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (21.2 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. An N,N-dimethylformamide (1 mL) solution of 4-chloro-2-chloromethyl-pyridine (34.3 mg, 0.21 mmol) described in Manufacturing Example 51-1-2 was added to a suspension of this solid in N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. This reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2), and then further purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (5.1 mg, 12%) as a trifluoro acetic acid salt.
Reaction SMILES: C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C[Si](Br)(C)C.[P:18]([CH2:22][CH2:23][O:24][N:25]=[C:26]([C:50]1[N:51]=[C:52]([NH:55]C=O)[S:53][CH:54]=1)[C:27]([NH:29][CH:30]1[C:48](=[O:49])[N:32]2[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]3[N:43]([CH3:44])[N:42]=[N:41][N:40]=3)[CH2:35][S:36][C@H:31]12)=[O:28])([OH:21])([OH:20])=[O:19]>C(Cl)Cl>[P:18]([CH2:22][CH2:23][O:24][N:25]=[C:26]([C:50]1[N:51]=[C:52]([NH2:55])[S:53][CH:54]=1)[C:27]([NH:29][CH:30]1[C:48](=[O:49])[N:32]2[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]3[N:43]([CH3:44])[N:42]=[N:41][N:40]=3)[CH2:35][S:36][C@H:31]12)=[O:28])([OH:21])([OH:20])=[O:19]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCP(=O)(O)O)c3csc(NC=O)n3)[C@H]2SC1
Agent: C[Si](C)(C)Br
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCP(=O)(O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 7-[2-{2-(O,O-diethylphosphono)ethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (6.2 g.) methylene chloride (90 ml.) and bis(trimethylsilyl)acetamide (9.2 g.) was stirred for 30 minutes at room temperature and thereto was added trimethylsilyl bromide (6.9 g.) over a period of 30 minutes with stirring at 20° to 25° C. and then stirring was continued for 5 hours at 25° to 27° C. The reaction mixture containing 7-[2-(2-phosphonoethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was concentrated and to the residue were added cold methanol (100 ml.) and cold conc. hydrochloric acid (4 ml.) followed by stirring for an hour at room temperature and a further addition of conc. hydrochloric acid (2 ml.). The resulting mixture was stirred for an hour at room temperature and then concentrated. To the residue was added water (300 ml.) and the mixture was adjusted to pH 2 to 3 with sodium bicarbonate and then subjected to column chromatography (non-ion adsorption resin, Diaion HP 20 prepared by Mitsubishi Chemical Industries) (200 ml.). The column was washed with water (1 l.) and then eluted successively with 10% methanol (1 l.), 20% methanol (1 l.), 30% methanol (1 l.) and 40% methanol (2 l.). The fractions containing the desired compound were evaporated to give the title compound (3.7 g.), mp. 180° to 210° C.) (dec.).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([OH:12])=O)[C:7]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[N:18][CH:19]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH:20]1([N:26]2[C:30]([NH2:31])=[CH:29][C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[N:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(C(C)C)C(C)C)C.CCCP(=O)=O>>[CH:20]1([N:26]2[C:30]([NH:31][C:10]([C:8]3[C:7]([NH:13][C:14]4[CH:15]=[N:16][CH:17]=[N:18][CH:19]=4)=[CH:6][CH:5]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:9]=3)=[O:12])=[CH:29][C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[N:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Nc1cc(-c2ccccn2)nn1C1CCCCC1
Reactant: O=C(O)c1nc(C2CC2)ccc1Nc1cncnc1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2ccccn2)nn1C1CCCCC1)c1nc(C2CC2)ccc1Nc1cncnc1
Reaction time: 8 h
Yield: 29 %

Procedure:
To a suspension of 6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid (50 mg, 0.2 mmol; intermediate A-5) at r.t under an argon atmosphere were added 2-cyclohexyl-5-pyridin-2-yl-2H-pyrazol-3-ylamine (47 mg, 0.2 mmol) and N-ethyldiisopropylamine (0.1 ml, 0.6 mmol). The yellow suspension was cooled to 0°, and propylphosphonic anhydride (0.31 ml, 1 mmol; 50% in AcOEt) was added. The suspension was stirred at 0° for 30 min. and at r.t overnight. The solvent was evaporated. After silica gel chromatography using a CH2Cl2/MeOH gradient, the product was obtained as yellow solid in 29% yield. MS: M=481.3 (M+H)+
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH:8]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:22][C:19]2[CH:18]=[CH:17][C:16]([S:13]([CH:8]3[CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]3[CH3:12])(=[O:15])=[O:14])=[CH:21][CH:20]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1CCN(C)C(S(=O)(=O)c2ccc(OCc3ccc(Cl)cc3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCC(C(=O)O)CC1S(=O)(=O)c1ccc(OCc2ccc(Cl)cc2)cc1

Procedure:
[4-(4-Chloro-benzyloxy)-benzenesulfonyl-1-methylpiperidine-4-carboxylic acid was prepared starting from [4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid ethyl ester (10.7 g, 24 mmol) dissolved in THF:Methanol (75: 75 ml) and 10N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.9 g (50%); off white solid; MS: 426.2 (M+H)+
Reaction SMILES: [CH2:1]([N:3]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH2:26][OH:27])=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:6])=[O:5])[CH3:2].O[C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:1]([N:3]([S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:6])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH2:26][O:27][C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=3)=[CH:24][N:25]=1)=[CH:17]2)[CH3:2]
Reactant: CCN(c1cccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCN(c1cccc2cc(-c3ncc(COc4ccc(C(=O)OC)cc4)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
N-ethyl-N-{2-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (420 mg) and methyl 4-hydroxybenzoate (153 mg) were dissolved in tetrahydrofuran (10 mL), and tri-tert-butylphosphine (263 mg) and 1,1′-(azodicarbonyl)dipiperidine (328 mg) were added. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtrated and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and eluted with a mixture of ethyl acetate-hexane (1:1) to give the title compound (200 mg, yield 36%) as pale-yellow crystals. melting point 191° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[NH:17][C:16]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:15]2.N1C=CC=CC=1.Cl>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[N:17]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:16]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:15]2
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)Cc1cc2cc(Br)ccc2c(=O)[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Cc1cc2cc(Br)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.8 %

Procedure:
Copper (II) acetate (67.5 mg, 0.371 mmol, 1.10 equiv.) and 4-fluorophenylboronic acid (95 mg, 0.675 mmol, 2.00 equiv.) were added to a stirred mixture of methyl 2-(6-bromo-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (100 mg, 0.338 mmol) and pyridine (54.6 μl, 0.675 mmol, 2.00 equiv.) in CH2Cl2 (3 mL) and the mixture was stirred in air at room temperature overnight in the presence of 4 Å molecular sieves. 1 N HCl (3 mL) was added to the reaction mixture and extracted with DCM (2×5 mL), dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0-15-20% EtOAc/hexanes to give 34 mg of methyl 2-(6-bromo-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][N:23]([CH3:28])[C:24](=[O:27])[CH:25]=[CH2:26])=[CH:14]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][N:23]([CH3:28])[C:24](=[O:27])/[CH:25]=[CH:26]/[C:2]2[CH:11]=[N:10][C:9]3[NH:8][C:7](=[O:12])[CH2:6][CH2:5][C:4]=3[CH:3]=2)=[CH:14]1
Reactant: C=CC(=O)N(C)Cc1c[nH]c2ccccc12
Reactant: O=C1CCc2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CN(Cc1c[nH]c2ccccc12)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 36.7 %

Procedure:
A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (0.64 g, 2.80 mmole), N-(1H-indol-3-ylmethyl)-N-methylacrylamide (0.60 g, 2.80 mmole), Pd(OAc)2 (0.06 g, 0.28 mmole), tri-ortho-tolylphosphine (0.17 g, 0.56 mmole) and diisopropylethylamine (0.73 mL, 4.2 mmole) in propionitrile (50 mL) was deoxygenated, then was heated to reflux under N2 overnight. The dark mixture was filtered through a pad of celite®, and the filter pad was rinsed with acetonitrile (250 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (10% MeOH/CHCl3). The title compound (0.37 g, 37%) was obtained as a light yellow solid after drying in vacuo: MS (ES) m/e 361 (M+H)+.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:22]([C:24]1[CH:29]=[C:28]([CH2:30]O)[CH:27]=[CH:26][N:25]=1)#[N:23]>C(Cl)Cl>[C:22]([C:24]1[CH:29]=[C:28]([CH2:30][Br:1])[CH:27]=[CH:26][N:25]=1)#[N:23]
Reactant: BrBr
Reactant: N#Cc1cc(CO)ccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1cc(CBr)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
Bromine (6.88 g, 43.1 mmol) is added dropwise to a solution of triphenylphosphine (11.3 g, 43.1 mmol) in 280 mL of CH2Cl2 at 0° C. The mixture is tirred for 30 minutes at 0° C. At this time, 2-cyano-4-(hydroxymethyl)-pyridine (4.82 g, 35.9 mmol) is added and the resulting mixture is stirred for 2 hours at room temperature. The reaction mixture is diluted with CH2Cl2 and washed with water (2x) and saturated NaCl solution. The organic layer is dried with MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting in a gradient of 20% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound (6.40 g, 32.5 mmol) as an oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[C:32]1([NH:38]N)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:38][C:32]3[C:37]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(I)cc3)CC2)c1
Reactant: NNc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(I)cc4)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenylhydrazine: ESMS m/e: 606.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[H-].[Na+].[CH3:12]OS(OC)(=O)=O.O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:12]
Reactant: Cc1cccc(Br)c1O
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)cccc1Br
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of 2-bromo-6-methylphenol (34.6 g, 0.18 mol) in THF (300 mL) was added NaH (9.6 g, 0.24 mol, 60%) in several portions. After the mixture was stirred for 1 h, Me2SO4 (28.0 g, 0.22 mol) was added dropwise. Then the mixture was stirred over night. Water (50 mL) was added, and the solvent was removed under reduced pressure. Then the residue was dissolved in Et2O (250 mL) and the organic layer was washed with NaOH (5%, 100 mL), brine (100 mL), and dried with Na2SO4. After removing the solvent, 35.3 g of the crude product was obtained (yield: 95%). 1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 3.81 (s, 3H), 6.88 (t, J=8.0 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H).