Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC12CC3(C)OC(C)(CC(C)(O3)O1)P2C1C=CC=CC=1.[CH:21]([C:24]1[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[CH:27]=[C:26]([CH:33]([CH3:35])[CH3:34])[C:25]=1B(O)O)([CH3:23])[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Br:47][C:48]1[CH:53]=[C:52]([O:54][CH3:55])[C:51]([O:56][CH3:57])=[CH:50][C:49]=1Br>O.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]>[Br:47][C:48]1[CH:53]=[C:52]([O:54][CH3:55])[C:51]([O:56][CH3:57])=[CH:50][C:49]=1[C:25]1[C:24]([CH:21]([CH3:23])[CH3:22])=[CH:29][C:28]([CH:30]([CH3:32])[CH3:31])=[CH:27][C:26]=1[CH:33]([CH3:35])[CH3:34]
Reactant: COc1cc(Br)c(Br)cc1OC
Reactant: CC(C)c1cc(C(C)C)c(B(O)O)c(C(C)C)c1
Agent: [Pd]
Agent: CC12CC3(C)OC(C)(CC(C)(O1)P3c1ccccc1)O2
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: COc1cc(Br)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
To a 100-mL round bottom flask equipped with a magnetic stir bar was added tris(dibenzylideneacetone)dipalladium(0) (198 mg, 0.216 mmol, 0.02 equiv), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.13,7]decane (152 mg, 0.519 mmol, 0.048 equiv, CYTOP® 292) 2,4,6-triisopropylphenylboronic acid (4.02 g, 16.2 mmol, 1.5 equiv) and potassium phosphate (6.89 g, 32.4 mmol, 3 equiv). The flask was purged with nitrogen for 30 minutes, then anhydrous, degassed tetrahydrofuran (20 mL) was added. The reddish slurry was stirred at room temperature for 30 minutes, and then degassed water (2 mL), and 1,2-dibromo-4,5-dimethoxybenzene (3.20 g, 10.8 mmol, 1 equiv) was added. The reaction was stirred at reflux for 21 hours. The reaction mixture was cooled to room temperature and then diluted with water (30 mL). The phases were separated and the aqueous layer was washed with ethyl acetate (3×20 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The unreacted dibromoarene was removed by recrystallization from hot methanol. The product was further purified by column chromatography on an Isco CombiFlash system (120-g column; gradient: 1 column volumes heptane, ramp up to 98:2 heptane:ethyl acetate over 0.5 column volumes, hold at 98:2 for 2 column volumes, ramp up to 90:10 heptane:ethyl acetate over 7 column volumes, hold at 90:10 for 1 column volumes) to afford the title compound as a white solid (1.47 g, 99 area % by HPLC, 32% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.13 (s, 1H), 7.05 (s, 2H), 6.69 (s, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 2.96 (hept, J=7.0 Hz, 1H), 2.52 (hept, J=6.9 Hz, 2H), 1.32 (d, J=6.9 Hz, 6H), 1.20 (d, J=6.9 Hz, 6H), 1.07 (d, J=6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 148.0, 147.9, 147.6, 146.0, 135.3, 133.2, 120.5, 114.8, 114.8, 113.9, 56.2, 34.4, 30.9, 25.1, 24.3, 23.9.
Reaction SMILES: Cl.[S:2]1[C:6]2=[CH:7][CH:8]=[CH:9][NH:10][CH:5]2[CH2:4][CH2:3]1.[CH3:11][O:12][C:13](=[O:23])[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])Br.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:11][O:12][C:13]([C@@H:14]([N:10]1[CH2:9][C:8]2[CH:7]=[CH:6][S:2][C:3]=2[CH2:4][CH2:5]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[O:23]
Reactant: COC(=O)C(Br)c1ccccc1Cl
Reactant: C1=CNC2CCSC2=C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 82.5 °C

Procedure:
50 g (0.284 mole) of Tetrahydrothienopyridine hydrochloride (A) was reacted with 83 g (0.315 mole) of α-bromo-2-chlorophenyl acetic acid methyl ester (B) in 2.5 Lt. DMF in presence of 83 g. (0.6 mole) potassium carbonate. The reaction mixture was heated at 80-85°C under nitrogen atmosphere for 4 Hrs. The reaction mixture was filtered at RT and washed the residue with DMF. The DMF was concentrated under vacuum to obtain a viscous liquid. To this viscous liquid, water was added and the base was extracted from the aqueous layer using methylene dichloride. The methylene dichloride was concentrated under vacuum to get pure Clopidogrel base. Yield =92%
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][CH2:15][N:16]1[CH2:20][C@@H:19]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:18][C@H:17]1[C:31](=[O:34])[NH:32][CH3:33]>O1CCCC1>[CH3:8][S:9]([O:13][CH2:14][CH2:15][N:16]1[CH2:20][C@@H:19]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:18][C@H:17]1[C:31](=[O:34])[NH:32][CH3:33])(=[O:11])=[O:10]
Reactant: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1CCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
1.06 ml of triethylamine and subsequently 584 μl of methanesulfonyl chloride were added, whilst ice-cooling, to a solution of 2.13 g of (2S, 4S)-1-(2-hydroxyethyl)-4-(4-methoxybenzylthio)-2-methylcarbamoyl-pyrrolidine dissolved in 45 ml of dry tetrahydrofuran, and the mixture was stirred at 0° to 5° C. for 30 minutes. At the end of this time, the crystals which precipitated were collected by filtration and washed with tetrahydrofuran. The filtrate and washings were combined and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure, to afford 2.50 g of the title compound as an oil.
Reaction SMILES: [C:1]1([CH:7]([OH:16])[CH2:8]/[CH:9]=[CH:10]/[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]1([C:7](=[O:16])[CH2:8]/[CH:9]=[CH:10]/[N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(/C=C/CC(O)c1ccccc1)CC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCN(/C=C/CC(=O)c1ccccc1)CC
Reaction time: 0.17 h

Procedure:
To a solution of N-(4-phenyl-4-hydroxy-2-trans-butenyl)-N,N-diethylamine (44.04 g) in chloroform (1000 ml), manganese dioxide (350 g) was added portionwise with stirring at 15° to 20° C. for 10 minutes, and stirring was continued for 3 hours under ice-cooling. After filtration of inorganic materials, the filtrate was evaporated to afford N-(4-phenyl-4-oxo-2-trans-butenyl)-N,N-diethylamine, which formed its hydrobromide with a solution of hydrogen bromide (16.3 g) in anhydrous ether (200 ml), m.p., 92°-94° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([CH3:12])[C:3]=1[Cl:13].[CH3:14][O-:15].[Na+].[Cl-].[NH4+]>CO>[Cl:13][C:3]1[C:4]([CH3:12])=[N:5][CH:6]=[C:7]([C:2]=1[O:15][CH3:14])[C:8]([O:10][CH3:11])=[O:9]
Reactant: C[O-]
Reactant: COC(=O)c1cnc(C)c(Cl)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(C)c(Cl)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.4 %

Procedure:
Crude methyl 4,5-dichloro-6-methylnicotinate (380 mg) was dissolved in 3 ml of methanol and, in a nitrogen stream, sodium methoxide (120 mg) was then added to the solution under cooling on ice. The temperature of the reaction solution was gradually raised to room temperature, and it was stirred for 18 hours. After the disappearance of the materials had been confirmed, a saturated ammonium chloride aqueous solution was added to the reaction solution under cooling on ice, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away. The residue was purified by silica gel chromatography (ethyl acetate-hexane), so as to obtain the title compound (210 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH:4]=[O:5].BrN1C(=O)CCC1=O.[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[OH:24][CH2:23][C:22]([NH:21][C:4](=[O:5])[C:3]1[C:6]([O:11][CH3:12])=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=1[Cl:1])([CH3:26])[CH3:25]
Reactant: COc1cc(Cl)cc(Cl)c1C=O
Reactant: CC(C)(N)CO
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(Cl)cc(Cl)c1C(=O)NC(C)(C)CO
Temperature: 0 °C
Reaction time: 0.12 h

Procedure:
A suspension of 2,4-dichloro-6-methoxybenzaldehyde (3 g, 15 mmol) and N-bromosuccinimide (3.6 g, 20 mmol) in carbon tetrachloride (30 ml) was illuminated with a 150 W flood lamp under nitrogen with vigorous stirring on a steam bath for seven minutes. The cloudy mixture was cooled to 0° C., diluted with methylene chloride (30 ml) and treated dropwise with a solution of 2-amino-2-methylpropanol (3 ml, 30 mmol) in methylene chloride (30 ml). The ice bath was removed and the mixture was stirred at 20° C. for twenty hours.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([SH:18])=[CH:10][C:9]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].[CH:21]([Li])(CC)C.CN(C=O)C>C1COCC1>[C:1]([O:5][C:6]([N:7]1[C:8]2[C:9](=[CH:10][C:11]([SH:18])=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=2)[CH:19]=[CH:21]1)=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]C(C)CC
Reactant: Cc1cc(S)c(C(C)(C)C)cc1NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc2cc(S)c(C(C)(C)C)cc21
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
(5-tert-Butyl-4-mercapto-2-methyl-phenyl)-carbamic acid tert-butyl ester (prepared in Example EE; 20 g, 68 mmol) was dissolved in 100 mL of THF, cooled to −40° C., and treated dropwise with sec-butyllithium (1.3 M, 156 mL, 203 mmol). After the addition was complete, the reaction mixture was stirred at −30° C. to −45° C. for 30 minutes. To the mixture was added DMF (14.8 g, 203.39 mmol), and the solution was stirred at −35° C. for 30 minutes. The reaction mixture was slowly warmed to room temperature and was quenched with saturated NH4Cl solution. EtOAc (200 mL) was added; the organic layer was washed with brine, dried (MgSO4) and concentrated. The residue was dissolved in 100 mL of THF and 2 mL of concentrated HCl and stirred at room temperature for 1 hour. The solution was diluted with EtOAc, washed with NaHCO3 solution and brine, and dried (MgSO4). The crude product was purified by flash silica gel chromatography to give the title compound. MS(APCI): 304 (M−H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=2)=[C:5]([CH3:7])[N:6]=1.Cl.[NH2:20][OH:21].C(N(CC)CC)C>O1CCCC1.CO>[Br:1][C:2]1[S:3][C:4]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]([NH:20][OH:21])=[NH:15])=[C:12]([Cl:18])[CH:11]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(Br)sc1COc1ccc(C#N)c(Cl)c1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(Br)sc1COc1ccc(C(=N)NO)c(Cl)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
4-(2-Bromo-4-methyl-thiazol-5-ylmethoxy)-2-chloro-benzonitrile (200 mg, 0.6 mmol) was dissolved in a mixture of 4 ml tetrahydrofuran and 4 ml methanol. Hydroxylamine hydrochloride (1.0 g, 14.6 mmol) was added followed by the addition of 2.1 ml triethylamine. The reaction mixture was stirred at 65° C. overnight. The solvents were removed in vacuo and the resulting residue poured into water and extracted five times with ethylacetate. The combined organic extracts were washed with brine, dried over MgSO4 and the solvent was evaporated in vacuo to obtain 199 mg 4-(2-Bromo-4-methyl-thiazol-5-ylmethoxy)-2-chloro-N-hydroxy-benzamidine as an oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:33]=[CH:32][C:16]2[N:17]([CH3:31])[C:18]([NH:20][C:21]3[S:22][C:23]4[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=4[N:25]=3)=[N:19][C:15]=2[CH:14]=1)=[O:12])(C)(C)C.[ClH:35]>>[ClH:30].[ClH:35].[NH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:33]=[CH:32][C:16]2[N:17]([CH3:31])[C:18]([NH:20][C:21]3[S:22][C:23]4[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=4[N:25]=3)=[N:19][C:15]=2[CH:14]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCNC(=O)OC(C)(C)C)ccc21
Agent: Cl
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCN)ccc21

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-amino-ethyl)-amide dihydrochloride (225 mg) was prepared by following General Procedure L using (2-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]amino}-ethyl)-carbamic acid tert-butyl ester (250 mg) and hydrogen chloride (1.25 mL, 4.0 M solution in 1,4-dioxane).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([CH3:8])[CH3:7])C.Cl.[OH-].[K+].[Br:15][C:16]1[CH:17]=[C:18]([NH:23][C:24]2[C:25]3[CH:33]=[C:32]([NH:34][C:35](=[O:45])[CH2:36]P(=O)(OCC)OCC)[N:31]=[CH:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH:19]=[CH:20][C:21]=1[Cl:22].[Li+].[Cl-]>O.C(Cl)Cl.CO.CC(N(C)C)=O.C1COCC1>[Br:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[Cl:22])[NH:23][C:24]1[C:25]2[CH:33]=[C:32]([NH:34][C:35](=[O:45])/[CH:36]=[CH:4]/[CH2:5][N:6]([CH3:7])[CH3:8])[N:31]=[CH:30][C:26]=2[N:27]=[CH:28][N:29]=1
Reactant: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(Cl)c(Br)c3)ncnc2cn1)OCC
Reactant: CCOC(CN(C)C)OCC
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C/C=C/C(=O)Nc1cc2c(Nc3ccc(Cl)c(Br)c3)ncnc2cn1
Temperature: 40 °C
Reaction time: 21 h
Yield: 98.3 %

Procedure:
To a stirred mixture of 2,2-diethoxy-N,N-dimethylethanamine (2.11 g, 13.1 mmol) and water (2.2 mL) at room temperature and under a nitrogen atmosphere was added an aq. 37% HCl (2.19 mL, 26.1 mmol). After addition the mixture was stirred at 40° C. (bath) for 21 h. It was cooled to 0° C. (bath). This is called solution A. KOH (1.87 g, 33.4 mmol) was dissolved in water (10 mL) at room temperature under a nitrogen atmosphere. It was cooled to 0° C. (bath). This is called solution B. To a stirred heterogeneous mixture of compound 232 (2.76 g, 5.22 mmol) and THF (10 mL) at room temperature and under a nitrogen atmosphere was added minimum amount of DMA (5.5 mL) to give a homogeneous solution. LiCl (221 mg, 5.22 mmol) was added and stirred at 0° C. (bath) for 15 min, The cold solution B was added and stirred at 0° C. for 2 min. Then the cold solution A was added and the final reaction mixture was continued to stir at 0° C. under a nitrogen atmosphere. The reaction was monitored by TLC (DCM-MeOH=10:1). After 35 min, it was poured into water (300 mL). Petroleum ether (300 mL) was added and stirred at room temperature for 15 min. Petroleum ether layer was decanted. More petroleum ether (300 mL) was added and stirred for 15 min. The solid was collected by suction filtration; washed with water (4×30 mL); dried under reduced pressure over silica gel/KOH to give (2E)-N-[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]-4-(dimethylamino)-2-butenamide (5) (2.37 g, 98%) as a pale yellow solid, mp 168-171; HPLC: 96.8% pure; 1H NMR δ [(CD3)2SO] 10.92 (s, 1H), 10.34 (s, 1H), 9.10-8.95 (m, 2H), 8.67 (br s, 1 H), 8.38 (br s, 1 H), 7.97 (br d, J=8.3 Hz, 1H), 7.65 (d, J=8.8, 1H), 6.88 (dt, J=15.4, 6.0 Hz, 1H), 6.52 (br d, J=15.4 Hz, 1H), 3.09 (dd, J=6.0, 1.1 Hz, 2H), 2.19 (s, 6H). Anal. Calcd for C19H18BrClN6O.H2O: C, 47.57; H, 4.20; N, 17.52. Found C, 47.80; H, 4.25; N, 17.51.
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].[C:16]([O:25][CH2:26][CH3:27])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:19].N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>O>[ClH:1].[CH2:26]([O:25][C:16]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[CH2:12][CH2:11]1)=[O:15])=[O:24])[CH3:27]
Reactant: CCOC(=O)c1ccccc1N
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1ccccc1NC(=O)[C@H]1CC[C@H](CNC(=N)N)CC1

Procedure:
Trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride (10.0 g, 0.042 mole) (which is prepared by the method as disclosed in Japanese Patent First Publication No. 19694/1977, C.A., 87, 53269x) and ethyl anthranilate (10.4 g, 0.063 mole) are added to pyridine (50 ml), and the mixture is stirred for a while, and thereto is added dicyclohexylcarbodiimide (13 g, 0.063 mole), and the mixture is stirred at room temperature for 72 hours. After the completion of the reaction, water (30 ml) is added to the reaction mixture, and the mixture is stirred for 30 minutes, and the undissolved materials are filtered off. The filtrate is concentrated to dryness. The resulting residue is washed with ethyl acetate (300 ml) and recrystallized from water to give the title compound (6.74 g) as white crystals. m.p. 92°-95° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[H-].[Na+].Br[CH2:22][C:23]([NH2:25])=[O:24]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][CH2:22][C:23](=[O:24])[NH2:25])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OCC(N)=O)cc(C)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.2 g, 0.8 mmol) in anhydrous DMF (3 mL) was added sodium hydride (0.08 g, 2.0 mmol). After stirring for 15 minutes 2-bromo-acetamide (0.166 g, 1.2 mmol) was added and the resulting mixture stirred at room temperature for 18 hours then quenched with crushed ice. The pH was adjusted to 3 with 6M HCl and the mixture extracted with EtOAc. The organic extracts were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (0-5% MeOH in DCM) to give 6-carbamoylmethoxy-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.13 g, 53%). 1H NMR 400 MHz (DMSO-d6) δ 9.17 (s, 1H), 7.47 (s, 1H), 7.36 (s, 1H), 7.02 (s, 1H), 6.89 (s, 1H), 5.45 (m, 1H), 4.40 (s, 2H), 4.09-4.02 (m, 2H), 3.10 (dd, J=15.2, 2.4 Hz, 1H), 2.26-2.17 (m, 4H), 1.17-1.04 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH2:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].CC(C)([O-])C.[Na+]>>[CH2:9]([N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])[CH2:10][CH2:11][CH3:12]
Reactant: Cc1ccccc1Br
Reactant: CCCCNCCCC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CCCCN(CCCC)c1ccccc1C
Yield: 36 %

Procedure:
According to the general procedure B, 2-bromotoluene (171 mg, 1.00 mmol) reacted with N,N-di-n-butylamine (129 mg, 1.00 mmol) using 1 mol % of catalyst and sodium tert-butoxide (115 mg, 1.20 mmol) at 60° C. to give the title compound (79 mg, 37%) as an oil: 1H-NMR (300 MHz, CDCl3): δ 7.20-7.08 (m, 3H), 6.98 (app.t, 1H), 2.94 (t, 4H), 1.41 (m, 4H), 1.27 (m, 4H), 0.88 (t, 6H). GC/MS (EI): m/z 219 (M+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[C:8]1([C@@:14]2([C:19](O)=[O:20])[CH2:18][CH2:17][CH2:16][NH:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C(OCC)(=O)C>[C:8]1([C@@:14]2([CH2:19][OH:20])[CH2:18][CH2:17][CH2:16][NH:15]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)[C@]1(c2ccccc2)CCCN1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Product: OC[C@]1(c2ccccc2)CCCN1
Temperature: 0 °C

Procedure:
Lithium aluminium hydride (1M in tetrahydrofuran; 10.6 ml) was added to a cooled (0° C.) suspension of (±)-2-phenylproline hydrochloride (0.85 g) and the mixture heated at reflux for 1.5 h. After cooling to 0° C., water (1 ml) was added followed by 2M NaOH (1 ml) and water (2 ml). The reaction mixture was diluted with ethyl acetate (50 ml) then filtered through a pad of Hi-flo and the residue concentrated in vacuo to give (±)-2-phenylprolinol as a yellow oil which solidified on standing. 1H NMR (250 MHz, CDCl3) d 7.42-7.20 (5H, m, ArH), 3.60 (1H, d, J=10.0 Hz, CHHOH), 3.49 (1H, d, J=10.0 Hz, CHHOH), 3.07 (2H, t, J=5.7 Hz, CH2N), 2.43 (2H, br s, OH and NH), 2.19-1.75 (4H, m).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Br)=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)=[O:16].[F-].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:21]3[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=3)[C:15]([O:14][CH3:13])=[O:16])[N:5]=2)[CH:10]=[CH:11][C:2]=1[C:21]1[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=1)[C:15]([O:14][CH3:13])=[O:16]
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Brc1ccc2ccc(Br)nc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Product: COC(=O)c1cccc(-c2ccc3ccc(-c4cccc(C(=O)OC)c4)nc3n2)c1
Yield: 83 %

Procedure:
To a 250 mL Schlenk flask, 2,7-dibromo-1,8-naphthyridine (2.00 g, 6.94 mmol), 3-(methoxycarbonyl)phenylboronic acid (3.13 g, 17.40 mmol), CsF (4.00 g), and Pd(PPh3)4 (200 mg) were added. The flask was connected to a Schlenk line and evacuated of air then refilled with nitrogen gas. 130 mL of 1,2-dimethoxyethane (DME) was degassed (two hours) and added to the flask through a canula. The flask was equipped with a water condenser and refluxed under nitrogen gas atmosphere for 3 days. The solvent was removed on rotary evaporator. 100 mL of H2O was added and then extracted with CHCl3. The organic phase was dried with MgSO4. After removal of the CHCl3 solvent, the crude product was purified by column chromatography (silica, ethyl acetate/hexane, 20%) to give a white solid product with a yield of 83% (2.30 g) based on 2,7-dibromo-1,8-naphthyridine. 1H NMR (300 MHz, CD3Cl): δ 3.97 (s, 6H), 7.62 (t, 2H), 8.03 (d, 2H), 8.17 (d, 2H), 8.30 (d, 2H), 8.57 (d, 2H), 8.88 (s, 2H).
Reaction SMILES: C([Mg]Br)C.[C:5]([N:24]1[C:28](I)=[CH:27][N:26]=[CH:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cu]C#N.[Cl-].[Li+].Br[CH2:36][CH:37]=[CH:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[C:41]([C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=2)[CH:40]=1.[Cl-].[NH4+]>C1COCC1>[C:5]([N:24]1[C:28]([CH2:36]/[CH:37]=[CH:38]/[C:39]2[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[C:41]([C:49]3[CH:50]=[CH:51][C:52]([F:55])=[CH:53][CH:54]=3)[CH:40]=2)=[CH:27][N:26]=[CH:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(C=CCBr)cc1-c1ccc(F)cc1
Reactant: Ic1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#C[Cu]
Agent: CC[Mg]Br
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/Cc2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl magnesium bromide (3M solution in ether; 5.7 ml; 17 mmol) was added dropwise at 0° C. under argon atmosphere to a solution of N-trityl 5-iodoimidazole (6.1 g; 14 mmol). After stirring at 0° C. for 1 hour, a solution of copper (I) cyanide (0.27 g; 3 mmol) and lithium chloride (0.252 g; 6 mmol) in THF (5 ml) was added. The mixture was cooled down to −78° C. and a solution of methyl 4-(3-bromoprop-1-en-1-yl)-2-(4-fluorophenyl)benzoate (3.5 g; 10 mmol) in THF (10 ml) was added. After stirring at −78° C. for 15 minutes, the temperature was allowed to raise to room temperature. The mixture was stirred further overnight. After addition of aqueous ammonium chloride solution and evaporation to dryness, the residue was extracted with dichloromethane/distilled water. The organic layer was evaporated to give methyl 4-[(E)-3-(1-tritylimidazol-5-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate which was used in the next step without further purification.