Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:17][C:9]2=[CH:10][CH:11]=[C:12]3[C:16]([NH:15][CH:14]=[CH:13]3)=[C:8]2[CH2:7][CH2:6]1)[CH2:2][CH3:3].P(Cl)(Cl)(Cl)=O.CN(C)[CH:28]=[O:29]>>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:17][C:9]2=[CH:10][CH:11]=[C:12]3[C:16]([NH:15][CH:14]=[C:13]3[CH:28]=[O:29])=[C:8]2[CH2:7][CH2:6]1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)C1CCc2c(ccc3cc[nH]c23)C1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCN(CCC)C1CCc2c(ccc3c(C=O)c[nH]c23)C1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A solution of di-n-propyl-(6,7,8,9-tetrahydro-1H-benzo[g]indol-7yl)amine, (3a, Chart 1)(0.90 g, 3.33 mmol) in dimethyl formamide (10 mL) was added dropwise to an ice-cooled solution of phosphorous oxychloride (1.2 ml, 0.73 g, 4.8 mmol) under an inert atmosphere. The solution was stirred for 10 minutes and was then heated to 50° C. After stirring for 3 hours, the solution was allowed to reach ambient temperature, stirred overnight and was then poured on ice. After basification, the mixture was heated to 80° C. for 10 minutes and then cooled. Extraction three times (dichloromethane), followed by drying (magnesium sulfate), filtering and evaporation several times with 99% ethanol, yielded 0.82 g (82%) of the material. This material was further purified on a silica column (dichloromethane/methanol, 3:1) to yield 0.53 g (53%) of the pure material as an oil.
Reaction SMILES: F.[CH3:2][N:3]([CH3:38])[C:4]([C:6]1[N:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:37])[CH2:25][O:26][Si](C(C)C)(C(C)C)C(C)C)[CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=1)=[O:5]>C1COCC1>[CH3:38][N:3]([CH3:2])[C:4]([C:6]1[N:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:37])[CH2:25][OH:26])[CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=1)=[O:5]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: F
Solvent: C1CCOC1
Product: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A solution of hydrogen fluoride (70% in pyridine, 3.25 mL) was added to methyl 3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-[(2S)-1-tripropan-2-ylsilyloxypropan-2-yl]oxy-benzoate in THF (300 mL) in a PTFE vessel and the resulting solution stirred for 18 hours at room temp. Further hydrogen fluoride solution (70% in pyridine, 3.25 mL) was added and the reaction stirred for an additional 66 hours. The reaction was quenched by the very careful addition of saturated aqueous sodium bicarbonate solution until the solution reached pH 8. The aqueous layer was extracted with ethyl acetate (2×500 mL) and the combined organics dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica eluting with 25 to 100% ethyl acetate in isohexane to afford the product (13.2 g, 98%). 1H NMR δ (CDCl3) 1.32 (3H, d), 1.93 (1H, d), 3.17 (6H, d), 3.74-3.79 (1H, m), 3.91 (3H, s), 4.54-4.60 (1H, m), 6.96 (1H, t), 7.43 (1H, d), 7.51 (1H, d), 8.36 (1H, d), 8.53 (1H, d); m/z 376 (M+H+)
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.[OH-].[Na+].[C:13]([OH:21])(=[O:20])[CH:14]([CH2:16][C:17]([OH:19])=[O:18])[OH:15].CC(C)=O>O>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:13]([O-:21])(=[O:20])[CH:14]([CH2:16][C:17]([O-:19])=[O:18])[OH:15]
Reactant: CN(C)C(=N)N=C(N)N
Reactant: O=C(O)CC(O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CN(C)C(=N)NC(=N)N
Product: O=C([O-])CC(O)C(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
20 g (2 molar equivalents) of metformin hydrochloride, 4.83 g (2 molar equivalents) of sodium hydroxide and 8.09 g (1 molar equivalent) of malic acid were stirred in 90 ml of water at 100° C., and acetone was added dropwise thereto at room temperature. Then, the produced crystal was stirred at room temperature for 1 hour, filtered and dried in hot air, thus obtaining 10.69 g (yield: 45.1%) of metformin malate.
Reaction SMILES: C(OC1C=C([CH:15]([N:30]([CH3:44])[C:31](=[O:43])[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:18]2)C=CC=1)C1C=CC=CC=1.[CH2:45]([OH:47])[CH3:46]>[OH-].[Pd+2].[OH-]>[C:26]([Si:23]([CH3:25])([CH3:24])[O:22][CH:19]1[CH2:20][CH2:21][CH:17]([CH:16]([C:18]2[CH:17]=[CH:16][CH:15]=[C:45]([OH:47])[CH:46]=2)[CH2:15][N:30]([CH3:44])[C:31](=[O:43])[CH2:32][C:33]2[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=2)[CH2:18]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CN(C(=O)Cc1ccc(S(C)(=O)=O)cc1)C(CC1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(OCc2ccccc2)c1
Reactant: CCO
Agent: [Pd+2]
Agent: [OH-]
Product: CN(CC(c1cccc(O)c1)C1CCC(O[Si](C)(C)C(C)(C)C)C1)C(=O)Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 16 h

Procedure:
To a solution of Example 39 (2.41 g, 3.8 mmol) in ethanol (220 mL) was added palladium hydroxide (20% on carbon) (0.15 g). This was hydrogenated at 30° C. for 16 hours, filtered through Celite, and the solvent removed in vacuo to give a white foam, 3.7 mmol, 97%. This was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[C:13]([O:17][C:18](=[O:29])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][O:27][CH3:28])=[CH:21][CH:20]=1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:29])[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][N:26]([C:8](=[O:9])[CH:7]=[C:5]2[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]2)[O:27][CH3:28])=[CH:23][CH:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CONCc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 93 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with 4-(methoxyamino-methyl)-benzoic acid tert-butyl ester as described in the preparation of compound 1-A gave the title amide as white crystals (93% yield): mp 137-138° C. (dichloromethane-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.58 (9H, s, t-Bu), 1.76 (6H, s, CH3), 3.67 (3H, s, OCH3), 4.87 (2H, s, NCH2), 6.40 (1H, s, CH), 7.39 (2H, d, J=8.2 Hz, aromatics), 7.95 (2H, d, J=8.2 Hz, aromatics). Anal. calcd for C20H25NO7: C, 61.37; H. 6.44; N, 3.58. Found: C, 61.23; H, 6.25; N, 3.52.
Reaction SMILES: [CH:1](OC(=O)C)=[O:2].C(O)=O.C(OC(=O)C)(=O)C.[CH3:17][O:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]=1[CH:29]([S:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][NH2:31]>C1COCC1>[C:33]1([S:32][CH:29]([C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:27]=[CH:28][C:19]=2[O:18][CH3:17])[CH2:30][NH:31][CH:1]=[O:2])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc2ccccc2c1C(CN)Sc1ccccc1
Reactant: CC(=O)OC=O
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: COc1ccc2ccccc2c1C(CNC=O)Sc1ccccc1
Temperature: 0 °C
Yield: 85 %

Procedure:
Acetic formic anhydride is generated by dropwise addition of 98% formic acid (1472 mg, 32 mmol) to 2655 mg (26 mmol) of acetic anhydride maintained at 0° C. followed by gentle heating at 50°-60° C. for 2 h. The mixture is cooled to -15° C. and 20 ml of THF are added. To the resulting solution is added dropwise at -15° C. a solution of 1-(2-methoxynaphth-1-yl)-1-(phenylthio)-2-aminoethane (3094 mg, 10 mmol) in THF (50 ml). The reaction mixture is allowed to warm to room temperature and the volatiles are removed in vacuo. The residue is taken up in ether. The ether solution is washed with water and NaHCO3 solution, dried over anhydrous K2CO3 and then evaporated in vacuo. The oily residue is triturated with ethyl acetate-hexane mixture to give crystalline title compound in 85% yield (2870 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31](=O)[C:32](O)=[O:33])([O-:23])=[O:22].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[C:11]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=[C:9]([N:8]2[C:32](=[O:33])[C:31]([CH2:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N+:21]([O-:23])=[O:22])=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[N:4][C:3]2=3)[CH:10]=1
Reactant: O=C(O)C(=O)Cc1ccccc1[N+](=O)[O-]
Reactant: Nc1cccnc1Nc1cccc(-c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1c(Cc2ccccc2[N+](=O)[O-])nc2cccnc2n1-c1cccc(-c2ccccc2)c1
Yield: 43 %

Procedure:
A mixture of 3-amino-2-(3-biphenylylamino)pyridine (196 mg) and 3-(2-nitrophenyl)pyruvic acid (188 mg) in ethanol (5 ml) was stirred under reflux for 1 hour. The mixture was cooled and then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from methanol to give 4-(3-biphenylyl)-2-(2-nitrobenzyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (140 mg).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[CH2:10]([Li])[CH2:11][CH2:12][CH3:13].[CH2:15]([N:18]([CH3:34])[CH2:19]/[CH:20]=[CH:21]/[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][C:25]=1[F:33])[CH:16]=[CH2:17].[CH2:35](Br)/[CH:36]=[C:37](/[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])\[CH3:38].C(=O)(O)[O-].[Na+]>C1COCC1.CCCCCC.CCOCC>[CH2:15]([N:18]([CH3:34])[CH2:19]/[CH:20]=[CH:21]/[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH:31]([CH2:35]/[CH:36]=[C:37](\[CH3:38])/[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])[CH2:10]/[CH:11]=[C:12](\[CH3:13])/[CH2:24][CH2:25][CH:26]=[C:27]([CH3:30])[CH3:28])=[CH:26][C:25]=1[F:33])[CH:16]=[CH2:17]
Reactant: C=CCN(C)C/C=C/COc1ccc(C(C)=O)cc1F
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: [Li]CCCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: C=CCN(C)C/C=C/COc1ccc(C(=O)C(C/C=C(\C)CCC=C(C)C)C/C=C(\C)CCC=C(C)C)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 0.92 ml of hexamethyldisilazane in 2.5 ml of THF is treated dropwise at 0° C. with 2.63 ml of 1.6M butyl-lithium in hexane. After 15 min. the mixture is cooled to -78° C. and 0.6g (Ex. Fa) of (E)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluorophenyl]-ethanone (Ha) in 1.9 ml of THF is added dropwise. After 1 hr. at -78° C. 0.5 ml of geranyl bromide in 1 ml of THF is added dropwise. The mixture is left to warm to room temperature, stirred for 1 hr. and poured into saturated sodium bicarbonate solution/ether. The organic phase is washed with 10% sodium chloride solution, dried and evaporated. After silica gel chromatography with (97.5%) methylene chloride/methanol the residue is dissolved in ethanol with 0.87 g of fumaric acid, evaporated and precipitated from ether with pentane. There is obtained 0.24 g of (E)-1-[4-[(E)-4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-2-[(E)-3,7-dimethyl-octa-2,6-dienyl]-5,9-dimethyl-deca-4,8-dien-1-one.fumarate (1:2), MS: m/e 549 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:19])=[N:11][CH:12]=[C:13]([C:17]=2[CH3:18])[C:14]([OH:16])=[O:15])[CH:5]=[CH:4][N:3]=1.[CH2:20](O)[CH3:21].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:19])=[N:11][CH:12]=[C:13]([C:17]=2[CH3:18])[C:14]([O:16][CH2:20][CH3:21])=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: CCO
Reactant: Cc1ncc(C(=O)O)c(C)c1Oc1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)c1cnc(C)c(Oc2ccnc(Cl)c2)c1C
Yield: 67 %

Procedure:
A three necked round bottom flask containing 5-(2-chloropyridin-4-yloxy)-4,6-dimethylnicotinic acid (11.7 g, 42.0 mmol) was charged with ethanol (250 mL), benzene (300 mL) and sulphuric acid (10 mL). The flask was fitted with Dean Stark apparatus and the reaction stirred at reflux overnight. The solution was cooled and carefully neutralized with saturated NaHCO3 solution. The material was extracted with EtOAc, dried, and concentrated to afford ethyl 5-(2-chloropyridin-4-yloxy)-4,6-dimethylnicotinate (8.6 g, 67%) as an oil which solidified to a white solid upon standing in a refrigerator (4° C.) overnight.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]1([CH2:19][CH3:20])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[CH:17][CH:16]=[CH:15][CH:14]=3)C.O.[OH-].[Li+].Cl>O1CCOCC1.O>[CH2:19]([C:6]1([CH2:5][C:4]([OH:21])=[O:3])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:20]
Reactant: CCOC(=O)CC1(CC)OCCc2c1[nH]c1ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC1(CC(=O)O)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
To a solution of (1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester (2.50 g, 8.7 mmol) in 1,4-dioxane was added a solution of lithium hydroxide monohydrate (1.50 g, 35.7 mmol) in water (5 mL). The mixture was stirred at room temperature overnight. It was neutralized with 5% HCl solution and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, and evaporated to dryness. Flash chromatography on silica gel provided 0.954 g (42%) of the title compound as a solid. mp. 135-136° C. 1H NMR (500 MHz, CDCl3) δ 10.0 (br, 1H), 8.55 (br, 1H), 7.51 (d, 1H), 7.34 (d, 1H), 7.18 (t, 1H), 7.12 (t, 1H), 4.12 (m, 1H), 4.06 (m, 1H), 3.01 (d, 1H), 2.99 (d, 1H), 2.85 (m, 2H), 2.10 (m, 1H), 2.03 (m, 1H), 0.86 (t, 3H); ESI (+) MS m/e=260 (MH+), ESI (−) MS m/e=258 (MH−).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[C:8]2[N:7]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]3=[C:5]([CH3:25])[C:4]=2[CH:3]=1.Br[C:27]1[S:28][C:29]([Cl:32])=[CH:30][CH:31]=1>>[Cl:32][C:29]1[S:28][C:27]([C:9]2[C:8]3[N:7]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]4=[C:5]([CH3:25])[C:4]=3[CH:3]=[C:2]([F:1])[CH:10]=2)=[CH:31][CH:30]=1
Reactant: Clc1ccc(Br)s1
Reactant: Cc1c2n(c3c(B4OC(C)(C)C(C)(C)O4)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)s4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light brown solid (15 mg, 22%), MS (ISP) m/z=335.4 [(M+H)+], mp 185° C., was prepared in accordance with the general method of example 171, step B from 8-fluoro-10-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (Example 171, step A) (68.8 mg, 0.2 mmol) and commercially available 2-bromo-5-chlorothiophene (59.2 mg, 0.3 mmol).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[C:15]([C:26]([NH:28][CH2:29][CH2:30][OH:31])=[O:27])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:32](Cl)(=[O:36])[O:33][CH2:34][CH3:35].N1C=CC=CC=1.O>C1COCC1>[C:32](=[O:36])([O:33][CH2:34][CH3:35])[O:31][CH2:30][CH2:29][NH:28][C:26]([C:15]1[N:14]=[N:13][N:12]([C:9]2[CH:8]=[CH:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)[C:16]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[O:27]
Reactant: CCOC(=O)Cl
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NCCO)c2COc2cccc(F)c2)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NCCOC(=O)OCC)c2COc2cccc(F)c2)cc1

Procedure:
To a solution of 1-{4-[(ethylamino)carbonyl]phenyl}-5-[(3-fluorophenoxy)methyl]-N-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxamide (600 mg) obtained in Example 498 in THF (15 ml) were added ethyl chlorocarbonate (0.15 ml) and pyridine (0.17 ml), and the mixture was stirred under ice-cooling for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=3/1 to ethyl acetate) and recrystallized from ethyl acetate to give the title compound as a colorless powder (520 mg).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[S:22](=[O:26])(=[O:25])([OH:24])[OH:23]>>[S:22]([O-:26])([O-:25])(=[O:24])=[O:23].[C:6]1([N+:5]#[N:1])[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[C:6]1([N+:5]#[N:1])[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: O=N[O-]
Reactant: O=S(=O)(O)O
Agent: [Na+]
Product: N#[N+]c1cccc2c1C(=O)c1ccccc1C2=O
Product: O=S(=O)([O-])[O-]
Temperature: 50 °C

Procedure:
To 150 cc of concentrated sulphuric acid were added under stirring 17 g of sodium nitrite over a period of 15 minutes. After a homogeneous solution had been obtained, there were added to it over a period of 1 hour 50 g of 1-aminoanthraquinone, maintaining the temperature at 30°-35° C. Thereupon, this mass was heated up to 50° C. for about 20 minutes; the homogeneous solution was then cooled down to 30° C. and poured slowly over 350 g of ice. The precipitated diazonium salt was then filtered, well squeezed out, washed with 30 cc of water and then again squeezed out. Thereby were obtained 120 g of humid anthraquinone-1-diazonium sulphate, which were added under stirring to a solution of 79 g of methacrylonitrile in 300 cc of methanol.
Reaction SMILES: [O:1]=[CH:2][C:3](Cl)(Cl)Cl.S([O-])([O-])(=O)=O.[Na+].[Na+].Cl.[NH2:15][OH:16].I[C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1C>O>[CH:18]1[CH:23]=[CH:22][C:21]([NH:24][C:2](/[CH:3]=[N:15]/[OH:16])=[O:1])=[CH:20][CH:19]=1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: NO
Reactant: Cc1cc(N)ccc1I
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(/C=N/O)Nc1ccccc1
Temperature: 95 °C
Reaction time: 0.08 h

Procedure:
Chloral hyrdate (17.40 g) is dissolved in water (256 mL) with sodium sulfate (108.75 g). The solution is warmed to 60° C. whereupon hydroxylamine hydrochloride (19.95 g) in water (124 mL) was added. In a separate flask a slurry of 2-iodo 5-aminotoluene (commercially available, Buttpark Ltd, U.K.) in water (139 mL) and CHCl (7.87 mL) was prepared at 80° C. The mixtures were combined and the reaction temperature increased to 95° C. for 20 min. then cooled to room temperature and then at 0° C. for 5 min. The solids were collected by filtration and washed with water (250 mL) and dried under vacuum to afford isonitrosoacetanilide 2.1 as a tan solid. Conc. H2SO4 (75 mL) was warmed to 50° C. and isonitrosoacetanilide 2.1 was added portionwise so that the temperature did not go above 70° C. After the addition the temperature was raised to 80° C. for 10 min. and then the mixture was allowed to cool to ambient temperature and poured onto ice water (10–12× volume). The isatin was filtered and washed with cold water (4×500 mL). The 1:1 isomeric mixture was taken up in 2N NaOH solution (316 mL) and stirred for 2 h then filtered. The filtrate was acidified to approx. pH 6 with acetic acid and refiltered to remove the undesired isatin isomer. The filtrate was acidifed to pH 1 with conc. HCl and filtered and the precipitate (desired isomer 2.7 g) was washed with water and dried by suction. Isatin 2 was converted to the corresponding aldehyde (3.1) as for isatin 1.1 above.
Reaction SMILES: C(OC(=O)C1C=CC(N[C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=CC=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(NC[C@H]3CC[C@H](C(O)=O)CC3)=O)C3C=CC(F)=CC=3N=2)=CC=1.[C:77]([O:81][C:82](=[O:93])[CH2:83][CH2:84][C:85]1[CH:90]=[CH:89][C:88]([NH2:91])=[C:87]([F:92])[CH:86]=1)([CH3:80])([CH3:79])[CH3:78]>CN(C)C1C=CN=CC=1>[C:77]([O:81][C:82](=[O:93])[CH2:83][CH2:84][C:85]1[CH:90]=[CH:89][C:88]([NH:91][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[C:87]([F:92])[CH:86]=1)([CH3:80])([CH3:78])[CH3:79]
Reactant: CC(C)(C)OC(=O)CCc1ccc(N)c(F)c1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)ccc21
Product: CC(C)(C)OC(=O)CCc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was synthesized in analogy to example 22, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (example 20, intermediate c), 3-(4-amino-3-fluoro-phenyl)-propionic acid tert-butyl ester and using 4-(dimethylamino)pyridine as base. Light brown foam (78%).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[F:11].C([Li])CCC.FC(F)(F)S(O[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])(=O)=O>C(OCC)C>[CH3:24][Si:23]([CH3:25])([C:26]([CH3:29])([CH3:28])[CH3:27])[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[F:11]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Fc1cc(F)c(F)c(Br)c1F
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)c1c(F)c(F)cc(F)c1F
Temperature: -78 °C

Procedure:
The compound, 1-bromo-2,3,5,6-tetrafluorobenzene, C6HBrF4, (14.8 g, 64.6 mmol) was dissolved in diethyl ether (200 ml) in a 500 ml flask and was cooled down to -78° C. Butyllithium (40 ml, 1.6M in hexanes) was then added to the flask dropwise while the solution was being stirred vigorously. After it had been stirred for one hour, t-butyldimethylsilyl trifluoromethane sulfonate (17.0 g, 64.6 mmol) was injected via a syringe. The reaction mixture was allowed to slowly warm up to room temperature over a period of eight hours, and the resulting suspension was filtered. After the solvent was removed from the filtrate at 25° C. under reduced pressure, the nonvolatile residue was distilled and a colorless liquid product was collected (45°C./0.8 mm Hg). Yield, 80%, 1H NMR(CCl2D2): δ0.40 (t, 6H), 0.93 (s, 9H), 7.10 (m, 1H); 13C NMR(CCl2D2): δ -3.7(t), 18.1(s) , 26.5(s) , 108.0(t), 144.8(m), 148.1(t), 151.4(t).
Reaction SMILES: [H-].[Na+].C1(C(C2[C:16]([CH2:17][O:18][CH2:19][C:20]3[C:25](C4C(=CC=C(O)C=4)O)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=[CH:13][CH:12]=2)=CC(=CC=1)O)O.Cl[C:35]1[N:40]=[CH:39][C:38]([C:41](=[O:43])[CH3:42])=[CH:37][CH:36]=1.Cl.[OH2:45]>CN(C=O)C>[CH2:19]([O:18][C:17]1[CH:12]=[CH:13][C:14]([O:45][C:35]2[N:40]=[CH:39][C:38]([C:41](=[O:43])[CH3:42])=[CH:37][CH:36]=2)=[CH:15][CH:16]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Reactant: O
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1
Reaction time: 0.17 h
Yield: 75 %

Procedure:
Dried DMF solution (50 ml) of sodium hydride (60% in oil, 7.24 g, 181 mmol) was cooled with ice in nitrogen atmosphere, dried DMF solution (50 ml) of hydroquinone monobenzyl ether (36.2 g, 181 mmol) was dropped into the above solution spending 10 minutes under ice cooling and the mixture was stirred for 1.5 hours under ice cooling. Dried DMF solution (110 ml) of 6-chloro-3-acetylpyridine (26.7 g, 172 mmol) was dropped into the above mixture spending 15 minutes and stirred for 2 hours under ice cooling. After completing the reaction, the reaction liquid was acidified with 6N hydrochloric acid, added with water, extracted with ethyl acetate, washed with water (400 ml×3), dried with magnesium sulfate and concentrated. The residue was recrystallized from 2-propanol (300 ml) to obtain the subject compound (43.3 g, 136 mmol). The result of 1H-NMR was consistent with the above structure.