Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.[NH3:20].CO>O1CCCC1>[NH2:20][C:10]1[CH2:9][N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:6]2[CH:19]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[N:11]=1
Reactant: S=C1CN=C(c2ccccn2)c2cc(Br)ccc2N1
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: NC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
59.5 g of 7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepine-2(1H)-thione (J. B. Hester, jr., A. D. Rudzik & P.F . Von Voigtlander, J. Med. Chem., 1980,23, 392-402) in 800 ml of tetrahydrofuran were added to 1.0 l of 25% aqueous ammonia solution and 300 ml of methanol. The mixture was stirred at room temperature for 16 h., with the solution which formed being concentrated to about 500 ml in a vacuum. The crystals were filtered off, washed with water and dried. There were obtained 52 g of 2-amino-7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepine which was used without further purification for the next step. A sample recrystallized from dioxan melted at 213-215° C. (dec.).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([F:23])[C:19]([NH2:20])=[N:18][C:16]1=[O:17])(=[O:3])[CH3:2].Cl[C:25]([O:27][CH2:28][CH2:29][CH:30]([CH3:47])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:46])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[O:26].CO>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([F:23])[C:19]([NH:20][C:25]([O:27][CH2:28][CH2:29][CH:30]([CH3:47])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:46])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[O:26])=[N:18][C:16]1=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(F)c(N)nc1=O
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOC(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(F)c(NC(=O)OCCC(C)CCCC(C)CCCC(C)CCCC(C)C)nc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To the ice-cooled solution containing 2′,3′-Di-O-acetyl-5′-deoxy-5-fluoroocytidine (5) (9.76 g, 29.64 mmol) in dry CH2Cl2 (40 ml) and anhydrous pyridine (5 ml), phytanyl chloroformate (12 g, 33 mmol) (6a) was added dropwise in order to keep the low reaction temperature. After stirring the mixture for overnight at room temperature, MeOH (1.3 ml) was added in one portion to stop the reaction. The mixture was evaporated to a syrup mass under reduced pressure. To this residue, diethyl ether (50 ml) was added and the suspension was stirred for 30 min at room temperature. The insoluble precipitate was filtered through a glass filter. The precipitate was washed with 30 ml of diethyl ether. The filtrate and the washings were collected, dried over anhydrous Na2SO4, and evaporated to dryness. The crude target compound was further purified using silica column chromatography CH2Cl2:MeOH=5:1 to give 2′,3′-Di-O-acetyl-5′-deoxy-5-fluoro-N4-(phytanyloxycarbonyl)cytidine (16.7 g, 84.1%) (7a). 1H NMR in CDCl3: δ0.83, 0.85, 0.86, 0.88 (4s, each 3H, CH3), 0.91 (d, 3H, J=6.6 Hz, CH3), 0.96-1.88 (m, 24H, CH2+CH), 1.47 (d, 3H, J=6.6 Hz, H-5), 2.10, 2.12 (2s, each 3H, OMe), 4.13-4.37 (m, 3H, H-4+CH2OC═ONH), 5.01 (t, 1H, J=5.4 Hz, H-2), 5.29 (t, 1H, J=5.8 Hz, H-3), 5.96 (d, 1H, J=3.8 Hz, H-1), 7.39 (br s, 1H, N—CH═C—F).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[CH2:22][CH:21]([CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:26][CH2:25]3)[C:19](=[O:20])[C:14]2=[CH:15][C:16]=1[O:17][CH3:18]>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[CH2:22][CH:21]([CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:28][CH2:29]3)[C:19](=[O:20])[C:14]2=[CH:15][C:16]=1[O:17][CH3:18].[C:1]([O-:8])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5]
Reactant: O=C(O)CCC(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: O=C([O-])CCC(=O)[O-]
Temperature: 25 °C

Procedure:
Succinic acid (1.18 g, dissolved in 35 ml of acetone and 5 ml of water) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 168.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[Br:14][CH2:15][C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCCC1>[Br-:14].[C:17]([C:16]([CH2:15][N+:3]1[C:4]2[C:9](=[CH:8][C:7]([Cl:12])=[C:6]([Cl:13])[CH:5]=2)[N:10]=[CH:11][C:2]=1[NH2:1])=[O:22])([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Nc1cnc2cc(Cl)c(Cl)cc2n1
Reactant: CCOC(=O)C(=O)CBr
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C[n+]1c(N)cnc2cc(Cl)c(Cl)cc21
Product: [Br-]
Yield: 26.2 %

Procedure:
A solution of 0.2 g of the product of Step A, 0.2 g of ethyl bromopyruvate and 15 ml of anhydrous tetrahydrofuran was stirred at room temperature for 24 hours and was filtered to obtain 0.1 g of 1-carbethoxycarbonylmethyl-2-amino-6,7-dichloro-quinoxalinium bromide as a pale yellow crystalline solid. The filtrate was allowed to stand for several days and was then filtered to obtain 0.065 g of the said compound as a yellowish brown solid for a total yield of 0.165 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH:7](C(OCC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].CS(C)=O.[Cl-].[Na+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C(=O)OCC)c1ncccn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1ncccn1
Temperature: 142.5 °C
Reaction time: 0.33 h
Yield: 63.9 %

Procedure:
4.76 g of diethyl (2-pyrimidinyl)malonate and 20 ml of dimethyl sulfoxide were mixed. To the mixture was added 1.40 g of sodium chloride and 0.72 g of water. The mixture was stirred for about 20 minutes at an inner temperature of 140 to 145° C., and for about 20 minutes at an inner temperature of 145 to 148° C. The mixture was allowed to cool to room temperature, then, to the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure to obtain 2.12 g of ethyl (2-pyrimidinyl)acetate.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C@@H:11]([OH:15])[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[Cl:9].[CH3:16][CH2:17]O>>[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C@@H:11]([OH:15])[C:12]([O:14][CH2:16][CH3:17])=[O:13])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CCO
Reactant: O=C(O)[C@H](O)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CCOC(=O)[C@H](O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
50 mL ethanolic HCl were added to a solution of 3.5 g (14.9 mmol) of (R)-3-(3,4-dichloro-phenyl)-2-hydroxy-propionic acid in 50 mL EtOH and the reaction mixture was stirred for 4 h at RT. The reaction solution was evaporated down i. vac., the residue was combined with DCM, extracted with 15% K2CO3 solution and the organic phase was dried over Na2SO4. After the desiccant and solvent had been eliminated the product was obtained as an oil, which was further reacted without purification.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[F:29][CH:30]([F:40])[O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.O>C1COCC1>[F:29][CH:30]([F:40])[O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:2][O:3][CH3:4])=[CH:34][CH:33]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OC(F)F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COC=Cc1ccc(OC(F)F)cc1
Reaction time: 0.25 h
Yield: 53.3 %

Procedure:
A suspension of methoxymethyl triphenylphosphonium chloride (6.69 g, 19.5 mmol) in THF (200 mL) was cooled to ca. −20° C. n-BuLi (2.5 M in hexanes, 7.2 mL, 18 mmol) was added in portions over 5 min and the orange-red reaction mixture was stirred for an additional 15 min. 4-difluoromethoxybenzaldehyde (2.58 g, 15.0 mmol) in THF (50 mL) was added at −10° C. and the reaction mixture was stirred at this temperature for 30 min and then at room temperature for 19 h. Water (100 mL) was added and the mixture was concentrated under reduced pressure. The remaining aqueous phase was extracted with ethyl acetate (2×100 mL) and the combined organic phase was washed with water (2×100 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by three times repeated chromatography on silica gel. (Horizon™, flash system from Biotage™. Column: Flash 40+M, 40×150 mm. Eluent: 3% ethyl acetate in heptane. Combination of pure fractions and concentration in vacuo afforded 1.60 g (53%) of the title compound as a colourless oil.
Reaction SMILES: [OH:1][C@H:2]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C@H:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11][CH:10]=2)[N:4]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[OH-].[Li+]>CO.O.O>[C:22]([O:21][C:19]([N:4]1[C@@H:3]([C@H:2]([OH:1])[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:7][CH2:6][C@H:5]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:17])=[O:16])=[CH:13][CH:14]=1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3cccnc3)N2C(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a stirred solution of the title compound from Step A (8.51 g, 20.0 mmol) in methanol/water=4:1 (50 mL) was added lithium hydroxide (2.39 g, 100 mmol). The resulting mixture was stirred at RT overnight. The mixture was diluted with water and extracted with ether. The aqueous layer was acidified with 1N citric acid to PH 4.5, and then extracted with ethyl acetate. The organic layer was separated and washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by SFC (using an AD column 35% MeOH/65% CO2, 150 ml/min 100 bar) to afford 6.90 g (84%) of the title compound (i-4) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.53 (s, 2H), 8.00 (d, J=7.7 Hz, 2H), 7.77 (d, J=6.4 Hz, 1H), 7.32-7.29 (m, 1H), 7.21 (d, J=8.0 Hz, 2H), 5.22 (s, 1H), 4.51 (d, J=8.4 Hz, 1H), 4.13-4.11 (m, 1H), 4.09-4.01 (m, 1H), 3.07-3.04 (m, 1H), 2.58-2.56 (m, 1H), 1.68-1.51 (m, 2H), 1.42 (s, 9H). MS: m/z (ESI) 413 (M+1).
Reaction SMILES: [CH:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C)(C)N[Si](C)(C)C.[Li].[CH2:27](Br)[CH:28]=[CH2:29].Cl>O1CCCC1.O>[CH2:29]([C:1]1([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:28]=[CH2:27]
Reactant: O=C(OCc1ccccc1)C1CCCCC1
Reactant: C=CCBr
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC1(C(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl cyclohexanecarboxylate (1.44 g) in tetrahydrofuran (40 mL) was added a 1M solution of lithium hexamethyldisilazane in tetrahydrofuran (9.9 mL) under ice cooling. The solution was stirred at room temperature for 1 hour under ice cooling, to which hexamethylphosporamide (2.3 mL) was added. The solution was then stirred for additional 10 minutes. To the solution was added allyl bromide (1.4 mL). The solution was stirred under ice cooling for 1 hour, to which allyl bromide (1.4 mL) was further added. The solution was stirred at room temperature for 18 hours. Water and 3N hydrochloric acid were added to the solution, and it was extracted with diethyl ether. The organic layer was washed in turn with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=99:1) to give the title compound (550 mg). This product was subjected to the subsequent step without further purification.
Reaction SMILES: ClC1N=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1.[O:16]1CCCN(CCN)CC1.CCN(CC)CC.C[O:34][CH2:35][CH2:36]OC>>[N+:4]([C:5]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][CH2:12]2)=[CH:8][C:6]=1[NH:7][C:35](=[O:34])[CH3:36])([O-:15])=[O:16]
Reactant: NCCN1CCCOCC1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: COCCOC
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 20 °C

Procedure:
A solution of chloride 21 (2.0 g, 9.0 mmol), 2-(1,4-oxazepan-4-yl)ethylamine (292) (1.63 g, 11.3 mmol) and Et3N (1.3 mL, 9.9 mmol) in DME (140 mL) was stirred at reflux temperature for 20 h. The solution was cooled to 20° C., the solvent evaporated and the residue purified by column chromatography, eluting with a gradient (2-6%) of MeOH/DCM, to give (i) starting material 21 (0.5 g, 25%) and (ii) 1-oxide 48 (1.24 g, 42%) as a yellow solid: mp 119-120° C.; 1H NMR δ 8.08 (s, 1H, H-9), 7.40 (s, 1H, H-5), 5.82 (br s, 1H, NH), 3.81 (t, J=6.1 Hz, 2H, CH2O), 3.74 (t, J=4.7 Hz, 2H, CH2), 3.51-3.56 (m, 2H, CH2), 2.97-3.04 (m, 4H, H-6, H-8), 2.73-2.80 (m, 6H, 3×CH2), 2.15 (p, J=7.4 Hz, 2H, H-7), 1.88-1.94 (m, 2H, CH2); 13C NMR δ 158.7, 154.6, 148.8, 143.3, 129.8, 120.5, 114.7, 69.3, 68.7, 57.5, 55.8, 53.6, 38.7, 33.1, 32.3, 30.0, 25.7; HRMS (FAB+) calcd for C17H24N5O2 (MH+) m/z 330.1930, found 330.1937.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1(CO)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].[Na+].CC1(C)N([O])C(C)(C)CCC1.[C:41](=O)(O)[O-:42].[Na+]>C1COCC1>[C:1]([O:5][C:6]([CH:8]1[CH:14]([CH:41]=[O:42])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:16])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)N2CCCCCC2(CO)C(=O)OC(C)(C)C)cc1
Reactant: O=C([O-])O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2CCCCC(C=O)C2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C

Procedure:
To a solution of Hydroxymethyl-1-(4-methoxy-benzene sulfonyl)-azepane-2-carboxylic acid tert-butyl ester (0.5 g, 1.25 mmoL) in 1.25 mL in THF was added sodium bromide (19 mg, 0.19 mmoL). This suspention was cooled to 0° C. and TEMPO (25 mg, 5%) was added in followed by 1.41 mL of a 0.129M solution of sodium bicarbonate in Clorox bleach. The magnetic stirring was increased to obtain a biphasic solution and kept at that rate for three hours while the reaction gradually warmed to ambient temperature. The reaction was then quenched with sodium sulfite (1.26 g). After 20 minutes water and ethyl acetate were added in, the layers were separated, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent removed under reduced pressure, and the residue was purified by column chromatography (silica: 15% to 25% ethyl acetate in hexanes) to yield 3-Formyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid tert-butyl ester; MS: (M+H)+ =398, (M+NH4)+ =415.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1)=[O:14].Br[C:31]1[S:32][C:33]([C:36]([N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])=[CH:34][N:35]=1>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:31]2[S:32][C:33]([C:36]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:37])=[CH:34][N:35]=2)=[CH:17][CH:16]=1)=[O:14]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C(c1cnc(Br)s1)N1CCCC1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ncc(C(=O)N3CCCC3)s2)cc1
Yield: 14 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure A using [2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (199 mg, 0.5 mmol) and (2-bromo-thiazol-5-yl)-pyrrolidin-1-yl-methanone (120 mg, 0.46 mmol) to give 30 mg (14% yield). MS (ES+) 453.3 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.CCCCCC>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.8 %

Procedure:
A 100 mL of reactor equipped with magnetic stir bar was charged with 3.39 mg (0.00499 mmol) of {[(t-Bu)2P(OH)]PdCl2}2 (from Experiment 7), 1.57 g (10.0 mmol) of bromobenzene, 1.46 g (12.0 mmol) of PhB(OH)2 and 1.66 g (12.0 mmol) of K2CO3 in 7.0 mL of THF and 2.0 mL of H2O. The resulting mixture was stirred at room temperature for 5 h. The reaction was transferred to a separatory funnel, and diluted with 300 mL of hexane and 50 mL of H2O. The layers were separated, and organic layer was washed with H2O (2×100 mL), brine (100 mL), and dried over mgSO4, filtered, and the hexane and THF removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel using hexane as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to give 1.0 g (65% yield) of biphenyl.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH:10]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[O:9][CH2:8][CH2:7]3)[CH2:4][O:3]1.C(=O)(O)[O-].[Cl-].[OH:32][CH:33]([C:41]1[CH:50]=[CH:49][C:44]2[C:45](=[O:48])[O:46][CH2:47][C:43]=2[C:42]=1[CH3:51])[CH2:34][NH+:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)C>[OH:32][CH:33]([C:41]1[CH:50]=[CH:49][C:44]2[C:45](=[O:48])[O:46][CH2:47][C:43]=2[C:42]=1[CH3:51])[CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:15][CH:10]2[C:11]3[C:6](=[C:5]4[CH2:4][O:3][C:2](=[O:1])[C:14]4=[CH:13][CH:12]=3)[CH2:7][CH2:8][O:9]2)[CH2:37][CH2:36]1
Reactant: Cc1c(C(O)C[NH+]2CCNCC2)ccc2c1COC2=O
Reactant: Cc1ccc(S(=O)(=O)OCC2OCCc3c2ccc2c3COC2=O)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CC#N
Product: Cc1c(C(O)CN2CCN(CC3OCCc4c3ccc3c4COC3=O)CC2)ccc2c1COC2=O
Temperature: 120 °C

Procedure:
To a 5 mL microwave tube were added (3-oxo-3,6,8,9-tetrahydro-1H-furo[3,4-f]isochromen-6-yl)methyl-4-methylbenzenesulfonate (50 mg, 0.13 mmol), the free base generated by aqueous bicarbonate wash of 1-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-ium chloride (55 mg, 0.20 mmol), and a stir bar; the mixture was dissolved in acetonitrile (2.5 mL). The tube was capped, degassed and purged with N2. The tube was then placed in a microwave reactor and heated at 120° C. for 1 h; LC indicated formation of the desired product. The solution was concentrated to dryness, dissolved in MeOH (3.5 mL), filtered and was then subjected to mass-directed HPLC for purification to give 6-({4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-8,9-dihydro-1H-furo[3,4-f]isochromen-3(6H)-one, as a mixture of isomers which could be partially separated under the purification conditions. LC-MS (IE, m/z): 478 [M+1]+.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(O)(=O)C>[C:13]([O:3][C:2]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]=[CH2:9])=[CH:10][C:1]=1[O:11][CH3:12])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCc1ccc(O)c(OC)c1
Solvent: CC(=O)O
Product: C=CCc1ccc(OC(C)=O)c(OC)c1
Temperature: 140 °C
Yield: 100 %

Procedure:
Into a three-neck, 5000 ml round bottom flask equipped with an addition funnel, mechanical stirrer, condenser, thermometer, heating mantle and nitrogen inserting tube is charged eugenol (2,519 grams, 15.3 moles). The eugenol was heated to 75° C. The acetic anhydride (1554 grams, 15.2 moles) was added with stirring over a one-hour period. The reaction mixture was then heated to 140° C. and stirred for 3 hours. The acetic acid by-product from the acylation reaction was stripped from the reaction mixture at 36° C. and 0.15 mm Hg pressure. The reaction produced 3-(4-acetoxy-3-methoxyphenyl)propene (3134 grams, 99.3 percent yield.)
Reaction SMILES: Cl.O1CCOCC1.Cl[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[O:22][CH3:23])[C:12]([F:24])=[CH:11][N:10]=1.[CH3:25][S:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31]>C(O)CCC.C(OCC)(=O)C>[F:24][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[O:22][CH3:23])=[N:14][C:9]([NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:28]([CH2:27][S:26][CH3:25])[CH:29]=2)=[N:10][CH:11]=1
Reactant: CSCc1cccc(N)c1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCCCO
Product: COc1cc(F)ccc1-c1nc(Nc2cccc(CSC)c2)ncc1F
Temperature: 140 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
A 4N solution of hydrogen chloride in dioxane (0.61 mL; 2.45 mmol) was added to a stirred solution of 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine (630 mg; 2.45 mmol) and 3-[(methyl-sulfanyl)methyl]aniline (564 mg; 3.68 mmol) in 1-butanol (5.4 mL). The batch was stirred at 140° C. for 16 hours. After cooling the batch was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by chromatography (hexane/ethyl acetate 2:1) to give the desired product (662 mg; 1.77 mmol).
Reaction SMILES: CSC(=N)[N:4]([C:19]#[N:20])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:10]=1.[CH3:22][NH:23][NH2:24].[CH3:25][N:26](C)C=O>>[CH3:22][N:23]1[C:19]([NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:17])[CH3:18])[CH:10]=2)=[N:20][C:25]([NH2:26])=[N:24]1
Reactant: CSC(=N)N(C#N)CCCOc1cccc(CN(C)C)c1
Reactant: CN(C)C=O
Reactant: CNN
Product: CN(C)Cc1cccc(OCCCNc2nc(N)nn2C)c1

Procedure:
N-Cyano-N-[3-[3-[(dimethylamino)methyl]phenoxy]propyl]-carbamimidothioic acid methyl ester (1.5 g) and N-methylhydrazine (1.2 g) in dimethylformamide (15 ml) were heated at 40° for 24 hours. The solvent was removed, and the residue was triturated with ether to yield the title compound as a white solid (1.0 g) m.p. 95°-96.5°.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH:9]1[CH:13]=[CH:12][N:11]=[N:10]1.[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F>CS(C)=O.O>[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:9]1[CH:13]=[CH:12][N:11]=[N:10]1
Reactant: c1c[nH]nn1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2ccnn2)c(F)c1
Temperature: 90 °C
Yield: 50 %

Procedure:
A slurry of dibasic potassium phosphate, 38.0 g (0.218 mol), and 1H-1,2,3-triazole, 7.53 g (6.3 mL, 0.109 mol), in 325 mL dimethylsulfoxide was treated dropwise with 3,4-difluoronitrobenzene, 17.3 g (12.1 mL, 0.109 mol), with heating to 90° C. for 18 h. The mixture was cooled to room temperature, diluted with water (500 mL) and extracted with ethyl acetate (4×50 mL). Drying (Na2SO4) and concentrating in vacuo afforded a light yellow solid. This material was chromatographed over 600 g 230-400 mesh silica gel eluting with methylene chloride, 1% (v:v), 2% (v:v) and 5% (v:v) methanol-methylene chloride to afford 11.38 g (50%) of 3-Fluoro-1-nitro-4-(1H-1,2,3-triazol-1-yl)benzene as a light yellow solid, mp=123-124.5° C., along with 9.66 g (43%) of regioisomer 3-Fluoro-1-nitro-4-(2H-1,2,3-triazol-2-yl)benzene as a light yellow solid, mp 137-139° C.