Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=4[CH:16]=3)[CH:13]=2)[CH:8]=[C:7]([C:29]([O:31]C)=[O:30])[CH:6]=1)(=O)C>O>[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:21]([CH3:25])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:27])([CH3:28])[C:17]=4[CH:16]=3)[CH:13]=2)[CH:8]=[C:7]([C:29]([OH:31])=[O:30])[CH:6]=1
Reactant: COC(=O)c1cc(OC(C)=O)c2cc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)ccc2c1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(-c3ccc4cc(C(=O)O)cc(O)c4c3)ccc21
Yield: 87.9 %

Procedure:
1.7 g (3.95 mmoles) of ester obtained in Example 1 are added to a mixture of 100 ml of methanolic soda (2M) and 50 ml of water. The mixture is heated for 4 hours, evaporated dry, and after 100 ml of water are added, extracted with ether (300 ml). The aqueous phase of the product is recuperated, brought to pH 1 with concentrated hydrochloric acid. After extraction of the precipitate with ether (300 ml), it is washed in water until neutral, then dried and evaporated. The solid obtained is recrystallized in acetonitrile. Thus is obtained 1.3 g (88%) of 4-hydroxy-6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-naphthoic acid which melts at 299° C.
Reaction SMILES: [Cl:1][CH2:2][S:3]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:16])=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1)=[O:4].ClC1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)Cl>[Cl:1][CH2:2][S:3]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:16])=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1)(=[O:23])=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1cc(S(=O)CCl)c(=O)c2ccc(F)cc21
Solvent: ClCCl
Product: Cn1cc(S(=O)(=O)CCl)c(=O)c2ccc(F)cc21
Yield: 77.6 %

Procedure:
6.33 g (0.0232 mole) of monochloroflosequinan (4) and 225 ml of methylene dichloride were placed in a 500 ml round bottom flask and stirred. Into this mixture a 5.98 g of 77% pure m-chloroperoxybenzoic acid (8) was added in four equal portions in 15 minute intervals and the mixture was stirred for an additional 30 minutes to complete oxidation. The reaction mixture was then concentrated to a final volume of 100 ml and the crystals which formed were filtered off and washed with two 10 ml portions of methylene dichloride. After high vacuum drying 5.2 g (77.6% yield) of white crystalline 3-chloromethylsulfonyl-7-fluoro-1-methyl-4-quinolone (9) were collected. The product was 99+% pure (by 1H NMR). 1H NMR, CDCl3, δ=8.52 dd, 1H, J=6.3 & 9.0 Hz, H at C5; 8.41 s, 1H, H at C2; 7.20 dd, 1H, J=2.1 & 9.6 Hz, H at C8; 7.32-7.26 m, 1H, H at C6; 5.03 s, 2H, CH2; 3.94 s, 3H, N—CH3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([C:13]([O:15]C)=O)[N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[NH3:24]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([C:13](=[O:15])[NH2:24])[N:8]=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1
Reactant: COC(=O)C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Reactant: N
Solvent: CO
Product: NC(=O)C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Yield: 74 %

Procedure:
10 g. of 7-chloro-3-methoxycarbonyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f]-1,4-diazepine and 200 ml. of a 13.6% solution of ammonia in methanol are left together overnight at room temperature. The solid rapidly dissolves and after several hours a precipitate gradually forms which increases in quantity with passage of time, until the whole mass has solidified. The solid is filtered by suction and washed with methanol. An additional small quantity of the same product is obtained by concentrating the solution to dryness. The two crops are combined and recrystallized from methanol. Colorless crystals are obtained (7 g.); m.p. 255°-256°C.; yield 74%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[Br:12]N1C(=O)CCC1=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][Br:12])[C:6]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2ccc(Cl)cc12
Product: Clc1ccc2scc(CBr)c2c1

Procedure:
Reaction of chloroacetone with 4-chlorothiophenol gave (4-chlorophenyl)thiomethyl methyl ketone, which was cyclized by reaction with polyphosphoric acid to 5-chloro-3-methylbenzothiophene. Bromination of the latter compound by photochemical reaction with N-bromosuccinimide provided 5-chloro-3-bromomethylbenzothiophene, which was reacted with sodium cyanide to give 5-chloro-3-cyanomethylbenzothiophene. The latter compound was hydrolyzed and esterified to give methyl α-(5-chloro-3-benzothienyl)acetate. Reaction of the ester with sodium methoxide and n-butyl nitrite afforded methyl α-hydroxyimino-α-(5-chloro-3-benzothienyl)acetate. Reduction of the oxime by reaction with zinc and formic acid and subsequent reaction with di-tert.-butyl carbonate gave N-tert.-butoxycarbonyl-(5-chloro-3-benzothienyl)glycine. NMR (CDCl3): δ 1.1-1.5 (broad s, 9H); δ 5.4-5.7 (broad s, 1H); δ 7.2-8.0 (m, 4H).
Reaction SMILES: O[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([OH:5])=[O:4].[Cr](Cl)([O-])(=O)=[O:23].[NH+]1C=CC=CC=1>C(Cl)Cl>[O:23]=[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:2][C:3]([OH:5])=[O:4]
Reactant: CCCCCCCCCCCCCCCCC(O)C(=O)O
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCCCC(=O)CCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.6 %

Procedure:
12-Hydroxystearic acid (2 g) dissolved in a 10% methanolic hydrochloric acid solution was stirred at room temperature for 2 hours. The mixture was then concentrated and distributed into chloroform and water, and the chloroform layer was washed with a 1% aqueous sodium hydrogen carbonate solution and water, dried with anhydrous sodium sulfate and concentrated to give the methyl ester of 12-hydroxystearic acid (2.0 g). To the methyl ester of 2-hydroxystearic acid (2.0 g) dissolved in methylene chloride (50 ml) were added Celite (4 g) and pyridinium chlorochromate (6 g), and the mixture was stirred at room temperature for 24 hours. Precipitates produced were removed by filtration. The filtrate mixed with silica gel (10 g) was concentrated and eluted with n-hexane-ethyl acetate (5:1) to give the methyl ester of 12-oxo-stearic acid (1.8 g). Then, the methyl ester of 12-oxo-stearic acid (1.8 g) was suspended into the mixed solvent of ethanol-water (1:1), and the potassium hydroxide (1.7 g) was dissolved in the suspension. The reaction mixture was heated to a temperature of 70° C. and stirred for 30 minutes. The reaction mixture was then cooled, adjusted to acidic range of pH by adding water and an excessive amount of citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give 12-oxostearic acid (1.6 g). After the 12-oxostearic acid (500 mg) was dissolved in N,N-dimethylformamide (DMF), para-nitrophenol (231 mg) and N,N'-dicyclohexylcarbodiimide (343 mg) were added, and the mixture was stirred for 12 hours. The reaction mixture was filtered, and the solvent was removed by distillation to give the active ester of 12-oxostearic acid. The active ester (438 mg) was dissolved in DMF, 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (400 mg) and triethylamine (2.0 ml) were added to the solution. The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK102 in the yield of 143 mg.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].I[CH3:14]>CN(C=O)C>[F:1][C:2]1[CH:9]=[C:6]([CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH3:14])[CH:7]=[O:8]
Reactant: COc1cc(C=O)cc(F)c1O
Reactant: CI
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(F)c1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
To a stirred solution prepared from 100 mL of DMF and 5-fluorovanillin (lit 1.0 g, 5.88 mmol). After 15 minutes, iodomethane was added, and stirring at room temperature continued for 16 hours. The reaction was terminated by the addition of water, the mixture was extracted with hexane (3×100 ML), and solvents were removed in vacuo. Purification by flash chromatography on a column of silica gel using hexane-ethyl acetate (4:1) as eluent afforded a colorless solid (1 g, 93% yield); mp 51–53° C. (Lit17 mp 52–53° C.) 1H-NMR (300 MHz, CDCl3) δ 3.94 (s, 3H), 4.05 (s, 3H), 7.24 (s, 1H), 7.26 (s, 1H), 9.82 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([O-:27])=[O:26]>>[CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:25]([O-:27])=[O:26])[CH:33]=3)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: O=[N+]([O-])c1cccc(-c2ccc3c(c2)C2(CCCCC2)C(=NOCc2ccccc2)N3)c1
Yield: 53.8 %

Procedure:
Prepared from 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′ (1′H)-one 2′(O-benzyloxime) (1.0 g, 2.6 mmol) and 3-Nitrophenyl boronic acid (0.86 g, 5.2 mmol) according to Example 45 procedure A. Purification by flash silica gel chromatography (eluant: 10:0.5 hexane:ethyl acetate) afforded the desired compound (0.60 g, 1.4 mmol, 55%) as a viscous oil. 1H NMR (500 MHz, DMSO-d6) δ 1.42-1.82 (8H, m), 2.02-2.04 (2H, q), 5.01 (2H, s), 6.88 (1H, d), 7.28-7.71 (8H, m), 8.08-8.13 (2H, m), 8.38 (1H, d), 9.69 (1H, s); MS (ESI(−ve)) m/z 426 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:12]=3[N:11]=2)=[CH:6][CH:5]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:34](O)=[O:35]>>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:14][C:13]3[C:15]([CH:34]=[O:35])=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:12]=3[N:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1ccc(-c2nc3ccc(OC)cc3[nH]2)cc1
Agent: C1N2CN3CN1CN(C2)C3
Product: COC(=O)c1ccc(-c2nc3ccc(OC)c(C=O)c3[nH]2)cc1
Temperature: 130 °C
Reaction time: 3 h
Yield: 21 %

Procedure:
A mixture of 4-(6-Methoxy-1H-benzoimidazol-2-yl)-benzoic acid methyl ester (1.50 g, 5.3 mmol), hexamethylenetetramine (1.50 mg, 10.60 mmol) and trifluoroacetic acid (12 mL) was stirred in a closed vessel under an argon atmosphere at 130° C. for 3 h. The resultant brown solution was poured onto 250 mL of crushed ice. The mixture was extracted with, chloroform-ethanol 95:5 (2×0.100 mL). The combined organic layers were dried (Na2SO4), and evaporated. The solid residue was purified by column chromatography over silica (Kieselgel 60) using chloroform as the eluent to give title compound (350 mg, 1.13 mmol, 21%) yellow crystals.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:32])[N:24]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:26][O:27][CH3:28])[CH:20]=[C:19]([Cl:33])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:33][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:26][O:27][CH3:28])=[O:32]
Reactant: COCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C(C)C
Yield: 80.7 %

Procedure:
A solution of {2-[3-chloro-5-(isopropyl-2-methoxy-ethyl-carbamoyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (Intermediate SS8) (0.056 g) and trifluoroacetic acid (0.6 ml) in dichloromethane (0.6 ml) was stirred at room temperature for 1 h then concentrated under vacuum. The residue was purified by flash chromatography eluting with dichloromethane:methanol:ammonia (94:6:1 then 92:8:1 v/v/v), to give the title compound as a colourless gum (0.036 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([C:9]([O:11]CC#C)=[O:10])=[CH:7][C:6]=1[O:17][CH3:18])[C:2]#[CH:3].[OH-].[Na+].Cl>CO>[CH2:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:17][CH3:18])[C:2]#[CH:3]
Reactant: C#CCOC(=O)c1ccc(OCC#C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CCOc1ccc(C(=O)O)cc1OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 107.7 %

Procedure:
To 50 ml of methanol were added 13.2 g of 2-propynyl 4-(2-propynyloxy)-3-methoxybenzoate and 40 ml of 15% aqueous sodium hydroxide solution and the mixture obtained was stirred at room temperature for 8 hours and at 50° C. for 2 hours. Then, the reaction mixture was added to hydrochloric acid for acidification. Crystals precipitated were collected by filtration and dried to obtain 12.0 g of 4-(2-propynyloxy)-3-methoxybenzoic acid represented by the formula:
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].C([O-])(O)=O.[Na+].[NH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>CO>[CH2:1]([NH:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1cccc(O)c1
Reactant: CCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCNc1cccc(O)c1
Yield: 57 %

Procedure:
0.11 mol of n-butyl bromide and 0.1 mol of NaHCO3 are added to 0.1 mol of m-aminophenol in 150 ml of methanol and the mixture is refluxed for 5 h. After cooling, the mixture is filtered and the solvent is removed in vacuo. The oil which remains is fractionated in vacuo, to give 3-(n-butyl-amino)phenol in a yield of 57%; b.p. 110° C. (6·10−5 torr), m.p. 35° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:8]1[C:15]([CH3:16])=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1)[CH:5]([CH3:7])[CH3:6]>CO>[OH:3][NH:2][C:12](=[NH:13])[C:11]1[CH:14]=[C:15]([CH3:16])[C:8]([CH2:4][CH:5]([CH3:6])[CH3:7])=[N:9][CH:10]=1
Reactant: Cc1cc(C#N)cnc1CC(C)C
Reactant: NO
Agent: Cl
Solvent: CO
Product: Cc1cc(C(=N)NO)cnc1CC(C)C
Temperature: 0 °C
Yield: 95.4 %

Procedure:
To an ice-cooled solution of potassium tert.-butylate (284 g, 2.53 mmol) in methanol (4 mL), hydroxylamine hydrochloride (151 mg, 2.17 mmol) is added. The suspension is stirred for 30 min before 6-isobutyl-5-methyl-nicotinonitrile (126 mg, 0.723 mmol) is added. The mixture is refluxed for 1 h before the solvent is evaporated. The residue is dissolved in sat. aq. NaHCO3-solution (10 mL) and extracted with EA (3×15 mL). The combined org. extracts are dried over MgSO4, filtered, concentrated and dried under HV to give N-hydroxy-6-isobutyl-5-methyl-nicotinamidine (143 mg) as a white solid; LC-MS: tR=0.56 min, [M+1]+=208.13; 1H NMR (CDCl3): δ 0.97 (d, J=6.8 Hz, 6H), 2.16 (hept, J=7.0 Hz, 1H), 2.36 (s, 3H), 2.72 (d, J=7.3 Hz, 2H), 4.91 (s, 2H), 7.70 (d, J=1.3 Hz, 1H), 8.66 (d, J=1.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[OH-].[NH4+:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH2:18])=[O:11])[CH2:7]1
Reactant: [NH4+]
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Reaction time: 18 h
Yield: 57.4 %

Procedure:
A solution of 5.6 g (0.02 mole) of 3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated while stirring with 3 ml (0.04 mole) of 57% ammonium hydroxide. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water and the solid which separated was collected by filtration, 6.6 g. Recrystallization from ethanol-water yielded 3.0 g of white granular crystals, m.p. 179°-184° C. A second recrystallization from isopropanol yielded 2.7 g (51.7%) of fine white crystals, m.p. 185°-187° C.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.Cl.[N:22]1([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[CH:26]=[CH:25][N:24]=[N:23]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[F:1][C:2]1[C:3]([N:29]2[CH2:30][CH2:31][CH:27]([N:22]3[CH:26]=[CH:25][N:24]=[N:23]3)[CH2:28]2)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: c1cn(C2CCNC2)nn1
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1COc2c(N3CCC(n4ccnn4)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 9.3 %

Procedure:
To a suspension of 76 mg (0.27 mmol) of (-) -9,10-difluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H -pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid and 118 mg (0.675 mmol) of 3-(1,2,3-triazol-1-yl) pyrrolidine hydrochloride in 10 ml of dry acetonitrile was added 121 mg (0.81 mmol) of DBU. The reddish brown solution was refluxed for 31 hr. The solvent was then removed under reduced pressure. To the residue water was added and extracted with chloroform. The organic layer was then evaporated to dryness, and to the residue, water was added and solid collected to yield 10 mg of the desired product, m.p. 225°-229° C. 1H NMR (TFA) δ: 9.17 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 7.99 (d, 13.3Hz, 1H), 5.9-5.18 (m, 1H), 5.22-4.07 (m, 7H), 3.13-2.63 (m, 2H), 1.82 (s, 3H), 1.79 (s, 3H). Anal. calcd. for C19H18N5O4F . 1/2 H2O: C, 55.86; H, 4.69; N, 17.16. Found: C, 55.93; H, 4.59; N, 16.37.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][CH2:27][O:28][CH2:29][CH3:30])[CH2:12]1)[C:8](=[O:31])[NH:7]2)=[O:5])C.C1COCC1.[Li+].[OH-]>CO>[CH2:29]([O:28][CH2:27][O:26][CH:11]1[CH2:10][CH:9]2[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]3[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]2=[O:31])[CH2:23]3)[CH2:12]1)[CH3:30]
Reactant: CCOCOC1CC2C(=O)NC3(C(=O)OCC)CC3C=CCCCCN(C)C(=O)C2C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOCOC1CC2C(=O)NC3(C(=O)O)CC3C=CCCCCN(C)C(=O)C2C1
Yield: 94.6 %

Procedure:
The ester 1e (2.26 g) was mixed with THF (20 ml), MeOH (20 ml) and a solution of LiOH (1N 20, ml) and stirred at 55° C. for ˜17 h. The reaction mixture was concentrated by rotary evaporation, diluted with water (30-50 ml) and acidified with 10% citric acid to pH 3-4. The cloudy solution was extracted into ethyl acetate (3×50 ml). The combined organic extracts were washed with water and brine, and dried over magnesium sulfate. The drying agent was removed by filtration and the ethyl acetate was removed by rotary evaporation. The residue was dried on high vacuum which gave 2 g of the title compound as a white foam. The product was used directly without further purification.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:21][C:16]1[CH:15]=[C:14]([CH:13]2[CH:9]([NH:7][CH3:6])[CH2:10][N:11]([C:22]([C:23]3[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[CH:27][CH:28]=3)=[O:31])[CH2:12]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)c2ccc(C#N)cc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CN(C(=O)c2ccc(C#N)cc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (414 mg, 0.87 mmol) in CH2Cl2 (8 ml) was added TFA (2 ml). The reaction mixture was stirred at RT for 2 hours, aqueous NaHCO3 was added until pH=8 and the product was extracted with CH2Cl2. The combined organic phase were dried over Na2SO4. Concentration under vacuo gave 302 mg (92%) of the title product as a colorless oil. ES-MS m/e: 374.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:21][CH3:22])[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[O:10])=[C:4]([F:23])[CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:11][C:9](=[O:10])[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH3:24])=[CH:3][C:4]=2[F:23])[O:21][CH3:22])=[CH:14][CH:15]=1)#[N:20]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(Br)cc1F
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(F)c1

Procedure:
In analogy to example 57.1, (RS)-2-(4-bromo-2-fluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide (example 41.2) was reacted with 2-methoxyphenylboronic acid to give (RS)-N-(4-cyano-benzyl)-2-(3-fluoro-2′-methoxy-biphenyl-4-yl)-2-methoxy-acetamide. Light yellow gum.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:13]([O:18][C@@H:19]3[O:36][C@H:35]([CH2:37][O:38]C(=O)C)[C@@H:30]([O:31]C(=O)C)[C@H:25]([O:26]C(=O)C)[C@H:20]3[O:21]C(=O)C)=[N:14][NH:15][C:16]=2[CH3:17])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C@@H:19]1([O:18][C:13]2[C:12]([CH2:11][C:8]3[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:6][CH:7]=3)=[C:16]([CH3:17])[NH:15][N:14]=2)[O:36][C@H:35]([CH2:37][OH:38])[C@@H:30]([OH:31])[C@H:25]([OH:26])[C@H:20]1[OH:21]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a solution of 4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (61 mg) in ethanol (3 mL) was added 1 mol/L aqueous sodium hydroxide solution (0.53 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (39 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=O.O.[NH2:13][NH2:14].C(O)(=O)C>>[N:1]1[C:2]2[C:10](=[O:11])[NH:13][NH:14][C:7](=[O:9])[C:3]=2[N:4]=[CH:5][CH:6]=1
Reactant: NN
Reactant: O=C1OC(=O)c2nccnc21
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH][nH]c(=O)c2nccnc12
Temperature: 25 °C

Procedure:
The title compound was prepared according to a literature procedure (Paul, D. B. Aust. J. Chem. 1974, 27, 1331). As described therein, 2,3-pyrazinedicarboxylic anhydride (5.00 g, 33.3 mmol), hydrazine hydrate (2.8 g, 56 mmol), and acetic acid (40.4 ml, 33.3 mmol) were mixed at RT. White precipitated crashed out. The reaction was heated under reflux for approximately 20 min. The reaction was cooled to RT and the solids were filtered, washed with water, and dried under vacuum. The product, 6,7-dihydropyrazino[2,3-d]pyridazine-5,8-dione was obtained as white solid. 1H NMR (Bruker, 400 MHz, D2O) ppm: 8.87 (s, 2H).