Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:16])[CH:4]=1)=O.[F:17][C:18]([F:33])([F:32])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=2)=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH3:16][C:5]1[CH:4]=[C:3]([CH2:1][NH:31][C:27]2[CH:26]=[C:25]([C:22]3[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:32])[F:33])=[CH:20][CH:21]=3)[CH:30]=[CH:29][CH:28]=2)[CH:15]=[CH:14][C:6]=1[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)COc1ccc(C=O)cc1C
Reactant: Nc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)COc1ccc(CNc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
To a solution of ethyl (4-formyl-2-methylphenoxy)acetate (0.2 g, 0.9 mmol) in anhydrous CH2Cl2 (8 mL) was added 4′-(trifluoromethyl)-1,1′-biphenyl-3-ylamine (0.214 g, 0.9 mmol). The resulting mixture was stirred under nitrogen at room temperature for 15 mins, prior to addition of sodium triacetoxyborohydride (0.267 g, 1.26 mmol) and acetic acid (0.052 mL, 0.9 mmol). The resultant mixture was stirred for 18 h prior to quenching by cautious addition of sat. sodium bicarbonate solution (20 mL) the reaction mixture was then extracted CH2Cl2 (20 mL). The organic extract separated by hydrophobic frit and the solvent removed in vacuo. Purification by Biotage™ chromatography (Silica, 40 g) eluting 9:1 cyclohexane:EtOAc afforded the title compound as a colourless oil (0.342 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=1.[Li]CCCC.[Si:21]([O:28][C:29]1[CH:30]=[C:31]([CH:38]=[CH:39][C:40]=1[F:41])[C:32](N(OC)C)=[O:33])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].Cl>CCOCC>[Si:21]([O:28][C:29]1[CH:30]=[C:31]([C:32]([C:2]2[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=2)=[O:33])[CH:38]=[CH:39][C:40]=1[F:41])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CON(C)C(=O)c1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: Fc1cc(Br)cc(OC(F)(F)C(F)F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reaction time: 1 h
Yield: 71 %

Procedure:
At −78° C. under argon, to a solution of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (2.04 g, 7.01 mmol) in anhydrous ether (20 mL) was added nBuLi (3.5 mL, 2.0 M in cyclohexane, 7.0 mmol) dropwise and the reaction mixture was stirred for 1 h. 3-(Tert-butyldimethylsilyloxy)-4-fluoro-N-methoxy-N-methylbenzamide (2.00 g, 6.38 mmol) was added in one portion and the reaction mixture was stirred at −78° C. for 1.5 h. The pale yellow solution was poured into 1 N HCl aqueous solution (30 mL) and ether (30 mL) was used to rinse the reaction flask. The aqueous phase was separated and extracted with ether (20 mL). The combined ether portions were dried over Na2SO4, filtered and concentrated. The resulting oil was purified by ISCO chromatography (120 g column) using hexanes/EtOAc (0-100% over 30 min) to give (3-(tert-butyldimethylsilyloxy)-4-fluorophenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone at a retention time of 7 min (2.11 g, 71% yield). LCMS: RT=2.41 min [M+H] 465.19 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDC3) 7.33 ppm, 3H, m; 7.28 ppm, 1H, m; 7.11 ppm, 2H, m; 5.86 ppm, 1H, t, J=53.39 Hz; 0.95 ppm, 9H, s; 0.15 ppm, 6H, s.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[CH2:13]([OH:35])[C@H:14]1[O:19][C@@H:18]([O:20][C@H:21]2[C@H:26]([OH:27])[C@@H:25]([OH:28])[C@H:24]([OH:29])[O:23][C@@H:22]2CO)[C@H:17]([OH:32])[C@@H:16]([OH:33])[C@@H:15]1[OH:34]>C([O-])(=O)C>[C@@H:18]1([O:12][CH2:11][C@H:9]([OH:10])[C@H:7]2[O:8][C:2](=[O:1])[C:3]([OH:4])=[C:5]2[OH:6])[O:19][C@H:14]([CH2:13][OH:35])[C@@H:15]([OH:34])[C@H:16]([OH:33])[C@H:17]1[OH:32].[C@@H:18]1([O:20][C:21]2[C:22]([O:28][C@H:25]([C@H:24]([CH2:2][OH:1])[OH:29])[C:26]=2[OH:27])=[O:23])[O:19][C@H:14]([CH2:13][OH:35])[C@@H:15]([OH:34])[C@H:16]([OH:33])[C@H:17]1[OH:32]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: CC(=O)[O-]
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: O=C1O[C@H]([C@@H](O)CO[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)C(O)=C1O
Yield: 0.8 %
Yield: 11.8 %

Procedure:
Twenty milligram of a cellulase preparation (Sigma) was dissolved in 1 ml of 20 mM acetate buffer (pH 5.0), and the solution was subjected to DOWEX® MARATHON WBA (resin 0.5 ml, manufactured by Dow Chemical) equilibrated with the same buffer to obtain a void fraction. This enzyme solution was added to 10 ml of 20 mM acetate buffer (pH 5.0) in which 0.35 g of ascorbic acid and 1 g of cellobiose were dissolved. The reaction at 37° C. for 2 days afforded a reaction solution of 11.8% of 6-O-(β-D-glucopyranosyl)ascorbic acid and 0.8% of 2-O-(β-D-glucopyranosyl)ascorbic acid. The solution was filtered with an UF membrane to recover and remove the enzyme, thereby to obtain a solution (pH 4.3, electrical conductivity 1.6 mS/cm). The solution was charged on a column of DOWEX® 1-X8 (acetate form, 1.5×12 cm) at SV=2.5. After the charge, washing with an about 10 column volume (200 mL) of distilled water, and elution with 0 to 0.1 M acetic acid linear gradient concentration (80 mL×2), and 0.1 to 1.0 M acetic acid linear gradient concentration (80 mL×2) were performed. A 6-O-(β-D-glucopyranosyl)ascorbic acid-enriched fraction (fractions 65 to 68), an unreacted ascorbic acid-enriched fraction, and a 2-O-(β-D-glucopyranosyl)ascorbic acid-enriched fraction (fractions 101 to 108) were fractionated in this order. The fractions 101 to 108 were collected as a 2-O-(β-D-glucopyranosyl)ascorbic acid-enriched fraction (2.4 mg, recovery rate 45%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[C:24]([OH:30])=[N:25][C:26]([Cl:29])=[N:27][CH:28]=1>CN(C=O)C>[Cl:29][C:26]1[N:25]=[C:24]([OH:30])[C:23]([NH:22][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=2)=[CH:28][N:27]=1
Reactant: Nc1cnc(Cl)nc1O
Reactant: O=C(O)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(Nc1cnc(Cl)nc1O)c1ccncc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5.88 g (47.7 mmol) isonicotinic acid and 7.74 g (47.7 mmol) 1,1′-carbonyldiimidazole in 30 mL DMF are stirred for 30 min at 45° C. prior to addition of 8.0 g (47.7 mmol) of 5-amino-2-chloro-pyrimidin-4-ol. The mixture is stirred for 12 h at rt, concentrated and purified by HPLC (reversed phase, water (+0.1% TFA)/MeOH) to yield N-(2-chloro-4-hydroxy-pyrimidin-5-yl)-isonicotinamide.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]1([C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[N:20]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(OCC)C>[C:8]1([C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[N:20]2[CH2:25][CH2:24][CH:23]([NH:26][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:22][CH2:21]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Brc1cccnc1
Reactant: NC1CCN([C@@H]2CCCC[C@@H]2c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: c1ccc([C@H]2CCCC[C@H]2N2CCC(Nc3cccnc3)CC2)cc1
Temperature: 70 °C
Yield: 20 %

Procedure:
The title compound, MS (ISP): m/e=440.4 (M+H+), was prepared as for example 209, steps (A) to (C). Step (B) was performed using 3-bromo-pyridine as follows: A suspension of (+/−)-[cis-1-(2-phenyl-cyclohexyl)-piperidin-4-yl]-amine (1.00 g, 3.88 mmol) in toluene (30 ml) was degassed with a flow of argon for 10 minutes. Tris-(dibenzylideneacetone)dipalladium chloroform complex (124 mg, 0.12 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (BINAP, 76.0 mg, 0.12 mmol), sodium tert-butoxide (0.470 g, 4.89 mmol) and 3-bromopyridine (0.483 g, 3.06 mmol) were added under argon. The flask was sealed and warmed to 70° C. for 3 hours. The mixture was diluted with ethyl acetate (30 ml) and diethyl ether (30 ml) and washed three times with saturated sodium chloride solution. The organic phase was dried with sodium sulphate and evaporated, yielding a red oil. Purification was achieved by flash chromatography (dichloromethane/methanol/25% NH3 90:10:1). (+/−)-[cis-1-(2-Phenyl-cyclohexyl)-piperidin-4-yl]-pyridin-3-yl-amine (0.260 g, 20%) was obtained as an orange foam, MS (ISP): m/e=336.3 (M+H+). This was reacted with benzoyl chloride in step (C).
Reaction SMILES: [CH:1]12[CH2:7][CH2:6][CH:5]1[C:4](=[O:8])[O:3][C:2]2=[O:9].C([Mg]Br)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1>C1COCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:4]([CH:5]2[CH2:6][CH2:7][CH:1]2[C:2]([OH:3])=[O:9])=[O:8])=[CH:12][CH:13]=1
Reactant: O=C1OC(=O)C2CCC12
Reactant: COc1ccc(C[Mg]Br)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCC2C(=O)O)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To 3-oxabicyclo[3.2.0]heptane-2,4-dione (8.00 g, 63.4 mmol) in THF (90.00 mL) at −78° C. was added 0.500 M of p-anisyl magnesium bromide (133 mL, 66.6 mmol) in THF (90 mL) dropwise. After stirring at −78° C. for 2 h, the reaction was quenched with ice cold water and concentrated. The aqueous layer was acidified and the white solid was filtered off and dried to obtain 9.72 g product (65%); MS m/z 233 (M−H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.C[Mg]Br.N1C=CC=C[CH:16]=1.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>O1CCCC1>[C:21]([O:11][C:2]1([CH3:16])[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: c1ccncc1
Reactant: C=C(C)C(=O)Cl
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: 50 °C
Reaction time: 3 h

Procedure:
30 g of 2-adamantanone was dissolved in tetrahydrofuran anhydride. Then, 200 ml of solution of methyl magnesium bromide dissolved in tetrahydrofuran in an amount of 1 mol/liter was added thereto at room temperature. After 3 hours, 5 g of pyridine was added, 26 g of methacrylic acid chloride was then added, and the resulting mixture was stirred at 50° C. for 3 hours. After the obtained reaction mixture was concentrated, hexane and a 1N ammonium chloride solution were added to the mixture, and the resulting mixture was shaken to separate an organic phase. Then, the organic phase was washed with a 5% sodium hydroxide solution and then with water, and it was confirmed that the pH of an aqueous phase became 8. The washed organic phase was concentrated so as to obtain crude 2-methyl-2-adamantyl methacrylate containing 90% by weight of 2-methyl-2-adamantyl methacrylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.CCN(CC)CC.[C:23]1([CH3:35])[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:24]=1[S:31](Cl)(=[O:33])=[O:32]>C(Cl)(Cl)Cl>[CH:4]1[C:3]2[C:8](=[N:9][C:10]3[C:15]([C:2]=2[NH:1][S:31]([C:24]2[C:25]([CH3:30])=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=2[CH3:35])(=[O:33])=[O:32])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Nc1c2ccccc2nc2ccccc12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)Nc2c3ccccc3nc3ccccc23)c(C)c1
Yield: 5.9 %

Procedure:
To a suspension of 4.00 g (20.6 mmol) of 9-aminoacridine 40 in 350 mL of CHCl3 was added 2.9 mL (20.8 mmol) of Et3N and 4.50 g (20.6 mmol) of mesitylenesulfonyl chloride. The reaction mixture was refluxed for 72 hr. Then the reaction mixture was filtered and the solvent was evaporated. The material was purified by column chromatography on silica gel by eluting first with 1% MeOH in CH2Cl2 and then with 5% MeOH in CH2Cl2 to yield 458.4 mg (6%) of sulfonamide 41 as an orange solid: 1H NMR (300 MHz, CDCl3, TMS) δ 9.25 (s, 1H), 8.77 (d, J=8 Hz, 2H), 7.46 (t, J=8 Hz, 2H), 7.21 (d, J=8 Hz, 2H), 7.15 (t, J=8 Hz, 2H), 7.02 (s, 2H), 2.78 (s, 6H), 2.36 (s, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[CH:23]=2)[N:18]=[CH:17]1.[CH:34]1([NH2:38])[CH2:37][CH2:36][CH2:35]1>N1C=CC=CC=1>[CH:34]1([NH:38][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][C:7]([CH3:6])=[C:8]([N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)[CH:23]=4)[N:18]=[CH:17]3)[CH:9]=2)[CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCC1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C(=O)NC2CCC2)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Temperature: 120 °C

Procedure:
Phosphorus oxychloride (0.08 ml) was added to a mixture of 4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid (0.30 g), cyclobutylamine (0.09 ml) and pyridine (5 ml) and the resultant was heated to 120° C. for 5 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The mixture was evaporated. The residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was dried (magnesium sulphate) and evaporated and the residue purified by column chromatography on a silica column using initially methylene chloride and then a 9:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.16 g); NMR Spectrum: (DMSOd6) 1.68 (m, 2H), 2.05 (m, 2H), 2.14 (s, 3H), 2.20 (m, 2H), 2.24 (s, 3H), 2.48 (m, 4H), 3.29 (m, 4H), 4.42 (m, 1H), 7.49 (d, 1H), 7.53 (d, 1H), 7.65 (m, 2H), 7.87 (d, 1H), 7.92 (m, 1H), 8.10 (s, 1H), 8.60 (d, 1H); Mass Spectrum: M+H+ 432.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][C:10]=2[N+:22]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C1COCC1.[Pd]>[CH:1]1([CH2:7][NH:8][C:9]2[C:10]([NH2:22])=[CH:11][C:12]([NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cc(Nc2ccccc2)ccc1NCC1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(Nc2ccccc2)ccc1NCC1CCCCC1
Reaction time: 0.05 h
Yield: 75.2 %

Procedure:
To a solution of N1-cyclohexylmethyl-2-nitro-N4-phenyl-benzene-1,4-diamine (0.06 g, 0.18 mmol) in THF (5.00 mL) was added 10% palladium on activated carbon (60 mg). The reaction flask was equipped with a septum and was placed under vacuum for 3 min. The flask was then placed under hydrogen atmosphere (balloon inflated with hydrogen) and the reaction mixture was stirred for 16 h. The palladium was filtered off through a plug of diatomaceous earth and washed with EtOAc. The solvent was removed via rotary evaporation. The resulting residue was flash chromatographed (30% EtOAc/hexanes), providing N1-cyclohexylmethyl-N4-phenyl-benzene-1,2,4-triamine as a purple foam (0.04 g, 75.6% yield). M+, 294.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)=[O:5].C(N(CC)C(C)C)(C)C.[CH3:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>C(Cl)Cl>[CH:17]1[C:8]2[CH2:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH2:12][N:6]([C:4]([C:3]3[CH:21]=[CH:22][C:23]([NH:25][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=4[CH3:35])=[CH:24][C:2]=3[Cl:1])=[O:5])[C:7]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)c(Cl)c1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.9 %

Procedure:
A mixture of 0.31 g of 5-(2-chloro-4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine and 0.15 g of N,N-diisopropylethylamine in 10 ml of methylene chloride is cooled in an ice bath while 0.18 g of 2-methylbenzoyl chloride is added. The bath is removed and the reactants stirred at room temperature for 18 hours. The mixture is washed with water, 1N HCl, water, 1M NaHCO3, brine and dried (Na2SO4). The methylene chloride is removed in vacuo to give 0.34 g of the desired product as crystalline solid, m.p. 138°-150° C. M+ =467.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=1.O(C)[Na].[NH2:12][C:13]#N.[NH4+:15].[Cl-]>CO>[Cl:1][C:2]1[S:6][C:5]([C:7](=[NH:15])[NH:8][C:13]#[N:12])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: N#CN
Reactant: N#Cc1ccc(Cl)s1
Agent: CO[Na]
Agent: [Cl-]
Solvent: CO
Product: N#CNC(=N)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-chlorothiophene-2-carbonitrile 1 in MeOH was added NaOCH3. The reaction mixture was stirred at room temperature for 4 h and then NH2CN was added. The reaction was allowed stir for overnight under N2. The mixture was then poured into NH4Cl (aq) and the precipitate collected and washed with water. The dried sample was confirmed as desired product 5-chloro-N-cyanothiophene-2-carboximidamide 2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.C([Li])CCC.[CH2:17]([O:24][C@@H:25]1[CH2:31][CH2:30][C@@H:29]2[C@@H:27]([O:28]2)[CH2:26]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>C1COCC1>[CH2:17]([O:24][C@H:25]1[CH2:26][C@H:27]([OH:28])[C@@H:29]([C:11]2[N:7]([CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[N:8]=[CH:9][CH:10]=2)[CH2:30][CH2:31]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COCCOCn1cccn1
Reactant: c1ccc(CO[C@@H]2CC[C@H]3O[C@H]3C2)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCn1nccc1[C@H]1CC[C@@H](OCc2ccccc2)C[C@@H]1O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 49.8 %

Procedure:
To a solution of the 1-[(2-methoxyethoxy)methyl]-1H-pyrazole (3.13 g, 20.1 mmol) prepared in Example 155a in THF (30 mL), butyl lithium (2.69 M solution in hexane; 7.46 mL, 20.1 mmol) and a boron trifluoride-diethyl ether complex (6.30 mL, 50.1 mmol) were added in that order at −78° C. The reaction solution was stirred at −78° C. for 10 minutes. Then, (1S*,3R*,6R*)-3-(benzyloxy)-7-oxabicyclo[4.1.0]heptane (J. Chem. Soc. Perkin Trans. 1 1997, 657; 3.41 g, 16.7 mmol) was added thereto, and the mixture was stirred at −78° C. for 5 hours. To the reaction solution, an aqueous sodium hydrogencarbonate solution (100 mL) was added, followed by extraction three times with ethyl acetate (100 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (ethyl acetate) to yield the title compound (3.00 g, 55%) as a mixture (3.00 g, 55%) with (1S*,2R*,4S*)-4-(benzyloxy)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanol.
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1>N1C=CC=CC=1>[O:1]([CH2:8][C:9]([O:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: O=c1cc(O)cc[nH]1
Solvent: c1ccncc1
Product: O=C(COc1ccccc1)Oc1cc[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
A 1.86 ml quantity of phenoxyacetyl chloride was added to a suspension of 1.00 g of 4-hydroxy-2-pyridone in 30 ml of pyridine, and the mixture was stirred at room temperature for four hours. The reaction mixture was concentrated and the concentrate was washed with ethyl acetate, water and chloroform in this order, thereby producing 500 mg of the title compound in a yield of 23%.
Reaction SMILES: [C:1]12([OH:13])[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.O1CCCC1.[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[CH2:28]>O>[C:26]([O:13][C:1]12[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2)(=[O:30])[C:27]([CH3:29])=[CH2:28]
Reactant: C=C(C)C(=O)Cl
Reactant: OC12CC3CC(O)(C1)CC(O)(C3)C2
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC12CC3CC(O)(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10 mmol of 1,3,5-adamantanetriol, 10 mmol of triethylamine, and 40 ml of tetrahydrofuran were mixed, and 10 mmol of methacrylic acid chloride was added dropwise to the mixture for about 30 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 24 hours. After the reaction had been completed, to the reaction mixture was added water, followed by purification by column chromatography to give 1-methacryloyloxy-3,5-dihydroxyadamantane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C)C=O.[Cl:13]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.[ClH:25]>C(Cl)(Cl)Cl>[ClH:13].[Cl:25][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: Cc1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: ClCc1ccccn1
Reaction time: 2 h
Yield: 87.4 %

Procedure:
A solution of 200 g (2.15 moles) of 2-methyl-pyridine and 14 g of dimethylformamide in 750 ml chloroform was heated at reflux while 300 g (1.29 mole) of trichloroisocyanuric acid (min. 90% available chlorine) were added thereto in portions without heating over 50 minutes as the reaction mixture remained under reflux by itself. The mixture was stirred for another 2 hours and was cooled and vacuum filtered. The filtrate was washed with 100 ml of 5% sodium hydroxide and the chloroform phase was dried over MgSO4, and filtered. 100 g (2.74 moles) of dry hydrogen chloride were added to the filtrate which was evaporated to dryness under vacuum. The residue was added to 250 ml of dry acetone and the mixture was stirred and vacuum filtered. The precipitate was washed with a little acetone and dried to obtain 185 g of 2-chloromethyl-pyridine hydrochloride. The acetone solution was cooled in the refrigerator to obtain another 42 g product for a total yield of 227 g (64.4%) melting at 120° to 122° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:14]([Sn](CCCC)(CCCC)CCCC)=[CH2:15]>CN(C=O)C.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>[CH:14]([C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[CH2:15]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1cccc(CC(=O)OCC)c1
Temperature: 90 °C

Procedure:
A mixture of 1.0 mmol of ethyl 3-bromophenylacetate, 1.5 mmol of vinyltributyltin, and 0.1 mmol of Pd(PPh3)4 in 4 mL DMF was stirred and heated at 90° C. for 1-16 h. Chromatography provided ethyl 3-vinylphenylacetate.