Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:6]=[C:5](B(O)O)[CH:4]=[C:3]1[C:19]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])C)[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]=1.[NH:36]1[CH:40]=[CH:39][N:38]=[CH:37]1>N1C=CC=CC=1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:30][SiH:28]([CH3:31])[CH2:27][CH2:26][O:25][CH2:24][N:23]1[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]=[C:19]1[C:3]1[C:2](=[O:1])[N:7]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:14])([CH3:13])[CH3:15])[N:6]=[C:5]([N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)[CH:4]=1
Reactant: C[Si](C)(C)CCOCn1nc(B(O)O)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Reactant: c1c[nH]cn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: c1ccncc1
Product: C[SiH](C)CCOCn1c(-c2cc(-n3ccnc3)nn(COCC[Si](C)(C)C)c2=O)nc2ccccc21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
100 mg of 6-oxo-1-(2-trimethylsilanylethoxymethyl)-5-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-2-yl]-1,6-dihydropyridazine-3-boronic acid (example 55), 35.5 mg of copper(II) acetate and 20 mg of imidazole are dissolved in dry pyridine, and the solution is stirred at 80° C. for 3 hours. For workup, it is diluted with 20 ml of water and extracted several times with ethyl acetate, the organic phases are dried using a silica gel cartridge, and the volatile components are distilled off. The crude product is purified by preparative RP-HPLC (0-100% acetonitrile (+0.05% formic acid) in water (+0.05% formic acid)).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)(C)C.[BH4-].[Na+].C(OCC)(=O)C.[H-].[Na+].[CH3:39][OH:40]>>[O:40]=[C:39]1[N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[CH:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:28]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)c2ccccc2)C1
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)OC(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
Bis(1,1-dimethylethyl)2-benzoyl-1,4-piperazinedicarboxylate (0.10 g, 0.26 mmol) was dissolved in methanol (2 mL), sodium borohydride (19 mg, 0.51 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added ethyl acetate, and the resulting mixture was washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (3 mL), 60% sodium hydride (12 mg, 0.30 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was extracted with ethyl acetate, washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=9:1 to 1:1) to obtain the title compound (47 mg, yield 57%) as a diastereomer mixture. Diastereomer ratio (α:β=1:5).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH2:24])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:29]([CH:26]4[CH2:28][CH2:27]4)=[O:30])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(N)sc3n2)c1
Reactant: O=C(Cl)C1CC1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of tert-butyl{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]phenyl}carbamate (1.00 g, 2.79 mmol) in pyridine (30 mL) was added cyclopropanecarbonyl chloride (327 μL, 3.63 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate (100 mL, 30 mL). The combined organic layer was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from tetrahydrofuran and hexane to give the title compound (1.02 g, 86%) as pale-yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:25][N:26]=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.CN.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14](=[O:15])[NH:26][CH3:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)O)CC1
Agent: CN
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
N-tert-butyloxycarbonyl-4-benzylpiperidine-4-carboxylic acid (3.0 g; 9.0 mmol) was dissolved in methylene chloride (25 ml) and EDAC (1.8 g; 9.0 mmol) and HOAt (1.3 g; 9.0 mmol) was added. The mixture was stirred for 15 min, then methyl amine (33% in ethanol; 2.3 ml; 18 mmol) and DIEA (1.6 ml; 9.0 mmol) was added and the mixture was stirred overnight. Methylene chloride (100 ml) was added and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and a aqueous solution of sodium hydrogensulfate (10%, 50 ml), dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica (90 g) using a mixture of aqueous ammonia/ethanol/methylene chloride (1:7:92) as eluent to afford 2.8 g of 4-benzyl-4-methylcarbamoylpiperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:7]2[CH2:8][CH:3]1[CH:4]=[CH:5][C:6]2(OC(=O)C)[O:9]C(=O)C.[CH3:18][C:19]([C:27]1[CH:28]=[C:29]([OH:34])[CH:30]=[C:31]([CH:33]=1)[OH:32])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].B(F)(F)F.CCOCC>>[OH:34][C:29]1[C:30]2[C@@H:4]3[CH2:5][C:6](=[O:9])[CH2:7][CH2:8][C@H:3]3[C:2]([CH3:17])([CH3:1])[O:32][C:31]=2[CH:33]=[C:27]([C:19]([CH3:18])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:28]=1
Reactant: CCCCCCC(C)(C)c1cc(O)cc(O)c1
Reactant: CC(=O)OC1(OC(C)=O)C=CC2CC1C2(C)C
Agent: FB(F)F
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(=O)C[C@@H]21

Procedure:
Following the same procedure as set forth above, (+)-6,6-dimethyl-2,2-diacetoxy-3-norpinene was reacted with 5-(1,1-dimethylheptyl)resorcinol in the presence of boron trifluoride diethyl etherate to afford (-)-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][C:13]#[N:14].[OH-:15].[Na+].OO>CO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:10])([F:11])[F:9])[C:3]=1[CH2:12][C:13]([NH2:14])=[O:15]
Reactant: N#CCc1c(F)cccc1C(F)(F)F
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)Cc1c(F)cccc1C(F)(F)F
Temperature: 40 °C

Procedure:
20 g (98.5 mmol) of 2-fluoro-6-trifluoromethyl-phenyl-acetonitrile is dissolved in 150 ml of methanol. It is adjusted to pH 10 with sodium hydroxide solution and heated to 40° C. Then, 15 ml (132.3 mmol) of hydrogen peroxide (30%) is instilled, diluted with 25 ml of water, and the pH is kept between 9-10 by simultaneous addition of sodium hydroxide solution. A solid precipitates with foaming. After completion of the addition, it is stirred for 30 more minutes, allowed to cool off, suctioned off from the solid, washed with water and dried in a vacuum. The title compound is obtained in crystalline form.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1[N:24]=[N:25][N:26]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)[C:27]=1[CH3:28].C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:31]4[CH2:32][CH2:33][CH:29]([N:26]5[C:27]([CH3:28])=[C:23]([CH3:22])[N:24]=[N:25]5)[CH2:30]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Cc1nnn(C2CCNC2)c1C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nnn(C2CCN(c3c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)c1C

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (100 mg, 0.36 mmol) was reacted with 3-(4 , 5-dimethyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride (182 mg, 0.9 mmol) in 8 ml of dry pyridine in the presence of 137 mg (0.9 mmol) of DBU at 115° C. for five days. The small amount of the solid was filtered off and the supernatant was evaporated to dryness. To the residue, water and a few drops of acetonitrile were added. The solid was collected to afford after drying 125 mg (81%) of the desired product as a gray solid. m.p. 230-232 ° C. (dec). 1H NMR (CDCl3) δ: 8.74 (s, 1H), 7.84 (d, J=13.2Hz, 1H), 5.07-4.8 (m, 1H), 4.4-3.85 (m, 5H), 2.8-2.14 (m, 8H, singlet at 2.29, 6H), 1.4-1.0 (m, 4H). Anal. calcd. for C21H12F2N5O3.1/2 H2O: C, 57.52; H, 4.83; N, 15.97. Found: C, 57.68; H, 4.81; N, 15.68.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH:42](OS(C)(=O)=O)[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)(=O)C>[CH2:22]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([CH2:38][CH2:39][CH2:40][CH2:41][C@@H:42]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[S:4][CH2:3]2)[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:36][CH2:37]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)OS(C)(=O)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 90 °C
Yield: 31.8 %

Procedure:
A mixture of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (2.05 g) and ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate (1.5 g) is heated at 90° C. for 1 day. After cooling, ethyl acetate (300 ml) is added to the mixture, and the resulting solution is washed with 5% phosphoric acid solution (30 ml×2) and water (20 ml) successively. The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuo to yield an oily residue, which is purified by silicagel column chromatography (hexane:ethyl acetate=2:1) to give tert-butyl 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (0.7 g) as a colorless oil. From the subsequent fraction, tert-butyl 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (0.55 g) is obtained as a colorless oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[C:25]1(O[Si](C)(C)C)[CH2:27][CH2:26]1)C.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH:25]1([N:19]2[CH2:18][CH2:17][N:16]([C:14]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH:13][CH:12]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:27][CH2:26]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: O=C(c1ccc(CN2CCOCC2)cc1)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(c1ccc(CN2CCOCC2)cc1)N1CCN(C2CC2)CC1
Temperature: 60 °C

Procedure:
A solution of (4-morpholin-4-ylmethyl-phenyl)-piperazin-1-yl-methanone (0.128 g) in methanol (7.5 mL) was treated with (1-ethoxy-cyclopropoxy)-trimethyl-silane (1.5 mL), acetic acid (0.2 mL), and NaBH3CN (˜400 mg). The mixture was heated at 60° C. for 18 h, and then was cooled to room temperature and concentrated. The residue was diluted with 1 N NaOH and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2) to yield the title compound.
Reaction SMILES: [F:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1(C)[O:12]C(=O)C[C:9](=O)[O:8]1.N1C=CC=CC=1>C(Cl)Cl>[F:1][CH2:2][C:3](=[O:4])[CH2:6][C:7]([O:8][CH3:9])=[O:12]
Reactant: O=C(Cl)CF
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC(=O)CF
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.4 %

Procedure:
Fluoroacetyl chloride (7.1 g, 73 mmoles) was added dropwise to a stirred solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (10.65 g, 74 mmoles) and pyridine (16.85 ml, 210 mmoles) in methylene chloride (75 ml) keeping the temperature below 10°. After stirring for 16 hours at room temperature the solution was diluted with methylene chloride (100 ml) and then washed with 1N hydrochloric acid (200 ml) and water (100 ml). The organic extract was dried (Na2SO4) and the solvent removed in vacuo. The residue was dissolved in methanol (150 ml) and the solution heated at reflux for 2.5 hours. Removal of the solvent followed by distillation at 60°-80° (bath temp)/14 mm Hg gave methyl 4-fluoro-3-oxobutanoate (6.4 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH2:10]Cl)=[C:5]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:4]=1.[CH3:18][NH:19][C@@H:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH2:10][N:19]([CH3:18])[C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][CH2:21]2)=[C:5]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:4]=1
Reactant: CN[C@H]1CCCc2ccccc21
Reactant: Cc1nc(Cl)cc(OC2CCCC2)c1CCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc(Cl)cc(OC2CCCC2)c1CN(C)[C@H]1CCCc2ccccc21
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 6-chloro-3-chloromethyl-4-cyclopentyloxy-2-methyl-pyridine hydrochloride salt, (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (3.0 g, 18.6 mmol), N,N-diisopropylethylamine (4.0 mL, 22.9 mmol), and anhydrous acetonitrile (50 mL) is stirred for 5 hours at 80° C. The reaction is cooled to ambient temperature and concentrated in vacuo. The obtained residue is dissolved in a mixture of hexane and ethyl:acetate (4:1, 100 mL) and filtered over a small pad of silica gel (35 g), which is subsequently rinsed with additional 100 mL of the same mixture of hexane and ethyl acetate. The filtered solution is concentrated in vacuo and the resultant residue is chromatographed on silica gel (hexane/ethyl Acetate 4:1) to afford (S)-(6-chloro-4-cyclopentyloxy-2-methyl-pyridin-3-ylmethyl)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine. 1H NMR: (CDCl3) 7.53 (m, 1H), 7.09 (m, 2H), 7.02 (m, 1H), 6.63 (s, 1H), 4.77 (m, 1H), 3.83 (d, 1H), 3.73 (dd, 1H), 3.56 (d, 1H), 2.73 (m, 2H), 2.63 (s, 3H), 2.07 (m, 2H), 2.04 (s, 3H), 1.98 (m, 2H), 1.82 (m, 4H), 1.68 (m, 4H).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[C:17](=[CH:18][C:19](I)=[CH:20][CH:21]=2)[N:16]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:14][C:15]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[C:17](=[CH:18][C:19]([S:1][C:2]3[CH:3]=[C:4]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=3)=[CH:20][CH:21]=2)[N:16]=1
Reactant: Clc1cc(-c2ccccc2)c2ccc(I)cc2n1
Reactant: CCC(O)(CC)c1cccc(S)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCC(O)(CC)c1cccc(Sc2ccc3c(-c4ccccc4)cc(Cl)nc3c2)c1
Temperature: 60 °C

Procedure:
10l (900 mg, 4.6 mmol), 2-chloro-7-iodo-4-phenyl-quinoline (10m, 1.6 g, 4.6 mmol), iPr2NEt (1.6 mL, 9.2 mmol), Pd2dba3 (104 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (132 mg, 0.2 mmol) were dissolved in 1,4-dioxane (15 mL) and degassed with N2 for 10 minutes. The reaction was heated to 60° C. for 1 hour, and then diluted with saturated aqueous NH4Cl and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (30% EtOAc in hexanes) to give the desired product, 10n.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:29]([Si:32]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[SH:33])([CH3:31])[CH3:30]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][S:33][Si:32]([CH:34]([CH3:36])[CH3:35])([CH:37]([CH3:39])[CH3:38])[CH:29]([CH3:30])[CH3:31])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CS[Si](C(C)C)(C(C)C)C(C)C)cc3)cc2)CC1
Reaction time: 8 h

Procedure:
1-[4′-(4-Bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (1.0 g, 2.27 mmol) and triisopropylsilanethiol (0.488 mL, 2.27 mmol) were dissolved in DMF (25 mL) and the solution was degassed with N2 for 10 minutes. Cesium carbonate was added and the reaction stirred overnight under N2 atmosphere. Standard aqueous workup afforded a mixture of the desired product plus de-protected free thiol which was taken directly to the next step.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9]>CN(C=O)C.CCOC(C)=O>[C:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9])#[N:3]
Reactant: COC(=O)c1ccc(C)c(Br)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(C#N)c1
Temperature: 140 °C
Reaction time: 12 h
Yield: 61.2 %

Procedure:
A mixture of copper (I) cyanide (510 mg, 5.69 mmol) and DMF (16 mL) was heated to 140 ° C. The reaction was added methyl 3-bromo-4-methylbenzoate (505 mg, 2.2 mmol) in DMF (10 mL) and heating was continued for 12 h. The reaction was cooled, diluted with EtOAc (125 mL) and washed with H2O (5×25 mL). The EtOAc layer was dried over MgSO4 and concentrated. The residue was chromatographed (40 g silica, 10% EtOAc/hexanes) to give the title compound as a solid (236 mg, 61%); IR(CHCl3): 1128, 1269, 1300, 1725, 2231, 3024 cm−1; NMR(300 MHz, CDCl3): 2.63 (s, 3H); 3.95 (s, 3H); 7.43 (d, 1H, J=8.1 Hz); 8.14 (d, 1H, J=8.1 Hz); 8.28 (s, 1H); MS(FD): 175.1.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:30])[NH:17][C:18]3[CH:23]=[C:22]([S:24](Cl)(=[O:26])=[O:25])[C:21]([CH3:28])=[CH:20][C:19]=3[CH3:29])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][NH2:38])[CH:32]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:30])[NH:17][C:18]3[CH:23]=[C:22]([S:24]([NH:38][CH2:37][C:33]4[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=4)(=[O:26])=[O:25])[C:21]([CH3:28])=[CH:20][C:19]=3[CH3:29])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)cc1NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: NCc1cccnc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)NCc2cccnc2)cc1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 9H-fluoren-9-ylmethyl[5-(chlorosulfonyl)-2,4-dimethylphenyl]carbamate (1.0 g, 2.3 mmol) in CH2Cl2 (23 mL) was added 1-pyridin-3-ylmethanamine (0.46 mL, 4.5 mmol) and pyridine (0.55 mL, 6.8 mmol). The bright yellow solution was then stirred at room temperature overnight and then quenched by the addition of sat. aq. NaHCO3 solution. The reaction was extracted with EtOAc and the organic extracted were dried over Na2SO4 and concentrated in vacuo. Purification by silica gel column chromatography (0-5% MeOH/DCM) afforded the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:12]([C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:13])([CH3:11])([CH3:10])[CH3:9].[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[C:28](O)=[O:29].CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:8]([N:12]([C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:13][C:28]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][N:22]=1)=[O:29])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Reactant: O=C(O)c1cnccn1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)N(NC(=O)c1cnccn1)C(=O)c1ccccc1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
Triethylamine (1.0 g, 0.01 mol) was added to a solution of N'-t-butyl-N'-benzoylhydrazine (0.86 g, 0.0031 mol) and pyrazine carboxylic acid (0.56 g, 0.0045 mol) in 10 ml of methylene chloride at 23° C. This mixture was added to a solution of methanesulfonyl chloride (0.6 g, 0.0052 mol) in 10 ml of methylene chloride at 0° C. The mixture was stirred at 23° C. for 3 hours and then allowed to stand at 23° C. overnight. Aqueous sodium bicarbonate was added and the layers were separated. The organic extracts were evaporated to give crude product which was triturated with ether to afford N'-t-butyl-N-(pyrazinecarbonyl)-N'-benzoylhydrazine as a white solid. m.p. 181-183° C.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[O:11]=[C:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1>CCCCCC.C1COCC1>[OH:11][C:12]1([C:7]2[S:6][CH:10]=[CH:9][N:8]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nccs2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
1.600 M of n-Butyllithium in hexane (1.0×10−1 mL) was added to 1,3-thiazole (0.958 mL, 0.0135 mol) in THF (20 mL) at −78° C. After 30 minutes, tert-butyl 3-oxopyrrolidine-1-carboxylate (2.50 g, 0.0135 mol) in THF (10 mL) was added, and the mixture was slowly warmed to room temperature overnight. The reaction was quenched with water, and the reaction mixture was extracted with ethyl acetate, dried with MgSO4, filtered and concentrated. The residue was purified by flash column (50% EtOAc/hexanes to pure EtOAc) to give the desired product (2.57 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH2:16][CH3:17])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cnc(Cl)c(Cl)c1

Procedure:
5,6-Dichloronicotinic acid (4.90 g) was dissolved in ethanol (40 mL), and thionyl chloride (2.0 mL) was added thereto under ice-cooling. The mixture was refluxed for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium hydrogencarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The extract was dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give ethyl 5,6-dichloronicotinate (4.85 g) as a white solid.