Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][CH:4]=1.C(NC(C)C)(C)C.[Li]C.[CH:22](N1CCCCC1)=[O:23]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][C:4]=1[CH:22]=[O:23]
Reactant: COCOc1ccc(OC)cc1
Reactant: O=CN1CCCCC1
Agent: [Li]C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCOc1ccc(OC)c(C=O)c1
Temperature: -40 °C
Reaction time: 3 h

Procedure:
To a solution of 2-methoxy-5-(methoxymethoxy)benzene (20 g, 0.1 2 mol) in THF is added diisopropylamine (0.24 g, 2.4 mmol). The solution is cooled to −40° C. followed by addition of MeLi (3M/THF, 72 mL, 0.216 mol) slowly. The resulting mixture is warmed to 0° C., stirred at 0° C. for 3 h, cooled back down to −40° C. and added N-formylpiperidine (24 mL, 0.216 mol). After stirring at −40° C. for 2 h, the mixture is quenched with a mixed solution of HCl (37%, 120 mL) and THF (250 mL). The temperature is then raised to rt and diluted with water (200 mL) and EtOAc (200 mL). The pH of the mixture is adjusted to 8-9 with solid K2CO3 and extracted with EtOAc (300 mL) twice. The organic layer is combined, dried over Na2SO4, and concentrated. The residue is purified on silica gel with 25% EtOAc/hexanes as eluent to give 2-methoxy-5-(methoxymethoxy)benzaldehyde.
Reaction SMILES: [C:1]1([S-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[C:9]([O:13][C:14]([N:16]1[CH2:27][C@H:26](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][C@H:17]1[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].CN(C)C=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:27][C@@H:26]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:25][C@H:17]1[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: [S-]c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](C(=O)NC(C)(C)C)N(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Sc2ccccc2)CN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
0.45 g (3.41 mmol) of sodium thiophenolate was added to a solution of 1.23 g (3.08 mmol) of (4R)-1-t-butoxycarbonyl-4-(p-toluenesulfonyloxy)-N-t-butyl-L-prolinamide [prepared as described in Preparation 6(a)] in 10 ml of a 2:1 by volume mixture of dimethylformamide and ethyl acetate, and the mixture was stirred for 3 hours. At the end of this time, the reaction mixture was poured into a 10% w/v aqueous solution of sodium hydrogen-carbonate and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by preparative thin layer chromatography, using a 1:3 by volume mixture of ethyl acetate and hexane as the developing solvent, to give 1.0 g of the title compound as a colorless powder, melting at 119°-121° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24]/[CH:25]=[CH:26]\[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24]/[CH:25]=[CH:26]\[CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=4[O:38][CH3:39])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OC/C=C\CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OC/C=C\CN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 65.4 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (1.8 g, 13 mmol) and (Z)-1-[4-[(4-chloro-2-butenyl)oxy]-3-methoxyphenyl]ethanone (3.43 g, 9.7 mmol) in acetonitrile (100 ml) was heated at reflux for 11/2 hours. At the end of the reaction, the solvent was removed and the inorganics were filtered after addition of dichloromethane (250 ml). The dichloromethane solvent was removed again. The crude oil was purified on two flash chromatography columns to give a colorless oil (2.78 g). The oil was solidified by vigorously drying on a vacuum pump. Recrystallization from ethanol (10 ml) and hexane (2 ml) gave analytically pure (Z)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy-3-methoxy-phenyl]ethanone, 1.83 g,m.p.=57-59° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[NH2:15][C@H:16]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1)=[O:18]>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C@@H:16]([NH:15][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[C:17]([N:19]2[CH2:20][CH2:21][CH:22]([OH:25])[CH2:23][CH2:24]2)=[O:18])=[CH:28][CH:29]=1
Reactant: N[C@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: Cl
Product: O=C(N[C@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared according to EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-(R)-amino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl) propan-1-one hydrochloride (Preparation 84). Purification by chromatography using dichloromethane/methanol (92:8) as the eluent gave the title compound as a pale yellow powder. m/z (ES+)=445.34 [M+H]+; RT=3.10 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[CH:12]=[CH:13][C:14]([OH:16])=[O:15])[CH3:2].CCN(C(C)C)C(C)C>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:2]
Reactant: CCc1cc(C=O)cc(C)c1C=CC(=O)O
Agent: [Pd]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CO)cc(C)c1CCC(=O)O
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 3-(2-ethyl-4-formyl-6-methyl-phenyl)-acrylic acid (2.75 g, 12.6 mmol) and DIPEA (1.8 g, 13.8 mmol) in ethanol (80 mL), Pd/C (275 mg, 10% Pd, moistened with 50% water) is added. The mixture is stirred for 16 h at it under 1 atm of H2. The catalyst is filtered off and the filtrate is concentrated. The residue is dissolved in EA, washed with 2 N aq. HCl, followed by 1 N aq. HCl and brine. The organic extract is dried over Na2SO4, filtered and evaporated to give 3-(2-ethyl-4-hydroxymethyl-6-methyl-phenyl)-propionic acid (2.8 g) as a white solid; LC-MS: tR=0.76 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([NH2:13])=[N:9][NH:10][C:11]=1[NH2:12].[Br:14][CH:15]([CH:18]=O)[CH:16]=O>C(O)C.C(O)(=O)C>[Br:14][C:15]1[CH:16]=[N:12][C:11]2[N:10]([N:9]=[C:8]([NH2:13])[C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:18]=1
Reactant: Nc1n[nH]c(N)c1-c1ccccn1
Reactant: O=CC(Br)C=O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1nn2cc(Br)cnc2c1-c1ccccn1
Temperature: 25 °C
Yield: 19.5 %

Procedure:
4-(Pyridin-2-yl)-1H-pyrazole-3,5-diamine (2.54 g, 14.51 mmol) and 2-bromo-malonaldehyde (2.41 g, 15.97 mmol) were suspended in dry ethanol (35 mL). A small amount of glacial acetic acid (30 drops) was added and the mixture was heated at reflux for 3 hours. After allowing the reaction to cool to room temperature the mixture was concentrated under reduced pressure. The resulting solid was purified by silica gel chromatography eluting with EtOAc containing 2% NH3(aq) solution to afford the title compound as a yellow solid (0.82 g, 19% yield). MS (ES+) 290/292. δH (DMSO-d6) 7.2 (3H, m), 7.9 (1H, t), 8.5 (1H, d), 8.6 (2H, m), 9.3 (1H, s).
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]([O-:10])(C)[CH3:8].[K+].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1.C1OC1C>CCCCCC.C1COCC1>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[C:14]=1[CH2:6][CH:7]([OH:10])[CH3:8]
Reactant: Fc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)[O-]
Agent: CC1CO1
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)Cc1c(F)cccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.5 M of n-BuLi in hexane (4.4 mL) was added to THF (10.0 mL) at −78° C. under nitrogen, followed by the addition of 1.0 M of KOtBu in THF (11 mL). The mixture was stirred at −78° C. for 30 min, then 1-fluoro-3-(trifluoromethyl)benzene (1.5 g, 9.1 mmol) in THF (5 mL) was added slowly, and the resulting mixture was stirred at this temperature for 30 min. Then a solution of propylene oxide (640 mg, 11 mmol) in THF (5 mL) was added at −78° C. The mixture was allowed to slowly warmed to rt and stirred overnight. The mixture was quenched with water (10 mL), and then extracted with EtOAc (50 mL). The organic phase was washed with brine (10 mL), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield a brown oil. The crude material was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to give the desired product as a yellow solid. 1H NMR (CD3OD, 400 MHz): δ=1.22 (d, J=6.3 Hz, 3H), 2.90-2.97 (m, 1H), 3.06-3.13 (m, 1H), 4.05-4.13 (m, 1H), 7.37-7.44 (m, 1H), 7.47 (td, J=7.9, 5.7 Hz, 1H), 7.54-7.59 (m, 1H). 1H NMR (CDCl3, 400 MHz): δ=1.30 (d, J=6.1 Hz, 3H), 1.41 (d, J=6.1 Hz, 1H), 2.93-3.07 (m, 1H), 4.08-4.17 (m, 1H), 7.23-7.27 (m, 1H), 7.29 (s, 1H), 7.30-7.37 (m, 1H), 7.48 (d, J=7.8 Hz, 1H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26]>C1COCC1>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:25](=[O:26])[C:14]([CH3:19])([CH3:13])[C:15]([O:17][CH3:18])=[O:16])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COC(=O)C(C)C
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)C(=O)c1ccc(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
124 ml of diisopropylamine is dissolved in 500 ml of THF under a blanket of dry nitrogen and cooled to 0° C. and 550 ml n-BuLi (1.6M in hexane) is added dropwise. Next, the mixture is cooled to minus 40° C., using an acetone/N2 bath, and 100 ml methyl 2-methylproponate is added. The resulting mixture is stirred for an additional 15 min at minus 40° C., after which 160.5 g of 3,4-dimethoxybenzoyl chloride dissolved in 750 ml of THF is added dropwise in 60 min during which the temperature is kept below −40° C. The cooling bath is removed and stirring is continued for 60 min at RT. 150 ml of 4M hydrochloric acid is added and the THF layer is separated and washed with 100 ml of water, 200 ml 1M of sodium carbonate and 100 ml of brine, dried over MgSO4 and concentrated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21]([S:24]([N:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[N:22]=[CH:23][C:11]=2[N:10]=1.[Mn]([O-])(=O)(=O)=[O:31].[K+]>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]([OH:31])=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21]([S:24](=[O:25])(=[O:26])[N:27]([CH3:29])[CH3:28])[N:22]=[CH:23][C:11]=2[N:10]=1
Reactant: CN(C)S(=O)(=O)n1ncc2nc(-c3c(F)cccc3F)c3cc(C=O)ccc3c21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C)S(=O)(=O)n1ncc2nc(-c3c(F)cccc3F)c3cc(C(=O)O)ccc3c21
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A 250 ml round-bottomed flask is charged with 1.41 g of 5-(2,6-difluorophenyl)-7-formyl-N,N-dimethyl-1H-pyrazolo[4,3-c]isoquinoline-1-sulphonamide in 124 ml of acetone. 1.07 g of potassium permanganate in solution in 62 ml of water are added. After 1 h at RT, the acetone is evaporated and then the mixture is acidified to a pH of 1 by addition of 5N hydrochloric acid. The mixture is extracted with ethyl acetate and the organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP to give 1.46 g of 5-(2,6-difluorophenyl)-1-(dimethylsulphamoyl)-1H-pyrazolo[4,3-c]isoquinoline-7-carboxylic acid (yellow solid). LC-MS-DAD-ELSD: 433 (+)=(M+H)(+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1.C(=O)=O.CC(C)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C1COCC1>[CH2:35]([O:34][C:32]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1)=[O:33])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=C(O)Cc1cn(C(=O)OCc2ccccc2)c2ccccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Indole-3-acetic acid (13 g, 74 mmol) was taken up in 130 mL anhydrous THF in a flame-dried, 2-necked 1 L round-bottomed flask, under an inert atmosphere, and cooled to −78° C. (dry ice/acetone bath). A 1.0 M THF solution of LHMDS (163 mL, 0.163 mol) was added via syringe over 30 minutes, and the reaction mixture allowed to stir for an additional 30 minutes at −78° C. once the addition was complete. Next, benzyl chloroformate (11.7 mL, 13.9 g, 81.6 mmol) was added dropwise via syringe. Stirring was then continued for 1 hour. To work up the reaction mixture, it was quenched with 2 M HCl, and partitioned between 2 M HCl and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate, and the combined organic layers washed with brine, dried over anhydrous MgSO4, filtered, and evaporated to give a white solid with a pinkish tinge (22.49 g, 98% yield): 1H NMR (400 MHz, DMSO-d6) δ 3.71 (s, 2H) 5.47 (s, 2H) 7.27 (t, J=7.2 Hz, 1H) 7.32-7.47 (m, 4H) 7.54 (d, J=6.8 Hz, 2H) 7.58 (d, J=7.6 Hz, 1H) 7.68 (s, 1H) 8.08 (d, J=8.1 Hz, 1H) 12.43 (s, 1H); HRMS (ESI+) calcd for C18H16NO4 (MH+) 310.1074. found 310.1080.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:3]=1[CH2:4][O:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[CH2:8][C:9]1[C:10](=[O:17])[NH:11][NH:12][C:13]=1[CH:14]([CH3:16])[CH3:15].[H-].[Na+].[CH3:29][C:30]([O:32][CH2:33][C@H:34]1[O:39][C@H:38](Br)[C@H:37]([O:41][C:42]([CH3:44])=[O:43])[C@@H:36]([O:45][C:46]([CH3:48])=[O:47])[C@@H:35]1[O:49][C:50]([CH3:52])=[O:51])=[O:31].O>CN(C)C=O>[CH3:1][C:2]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:3]=1[CH2:4][O:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[CH2:8][C:9]1[C:10]([O:17][C@@H:38]2[O:39][C@H:34]([CH2:33][O:32][C:30](=[O:31])[CH3:29])[C@@H:35]([O:49][C:50](=[O:51])[CH3:52])[C@H:36]([O:45][C:46](=[O:47])[CH3:48])[C@H:37]2[O:41][C:42](=[O:43])[CH3:44])=[N:11][NH:12][C:13]=1[CH:14]([CH3:16])[CH3:15]
Reactant: Cc1ccc(C)c(COc2ccccc2Cc2c(C(C)C)[nH][nH]c2=O)c1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccccc2OCc2cc(C)ccc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-[2-(2,5-dimethylbenzyloxy)benzyl]-5-isopropyl-1,2-dihydropyrazol-3-one (152 mg) in N,N-dimethylformamide (1 mL) was added sodium hydride (60%, 18 mg), and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added a solution of acetobromo-α-D-glucose (214 mg) in N,N-dimethylformamide (1 mL), and the resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate/hexane=1/1-ethyl acetate) to give 4-[2-(2,5-dimethylbenzyloxy)benzyl]-5-isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole. To a solution of 4-[2-(2,5-dimethylbenzyloxy)benzyl]-5-isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole in tetrahydrofuran (1 mL) and methanol (0.5 mL) was added sodium methoxide (28% methanol solution, 0.400 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 2 mol/L hydrochloric acid and concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol=10/1–5/1) to give the title compound (33 mg).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][N:7]=1.O=C1N[C:15](=[O:17])[CH:14]=NN1>C(OC(=O)C)(=O)C>[C:15]([N:6]1[C:5](=[O:8])[NH:4][C:3](=[O:9])[C:2]([Br:1])=[N:7]1)(=[O:17])[CH3:14]
Reactant: O=c1[nH]nc(Br)c(=O)[nH]1
Reactant: O=c1cn[nH]c(=O)[nH]1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1nc(Br)c(=O)[nH]c1=O

Procedure:
The 6-bromo-3,5-dioxo-(2H,4H)-1,2,4-triazine (5 g) obtained from the 3,5-dioxo-(2H,4H)-1,2,4-triazine in accordance with the technique described in example 1b is treated with acetic anhydride (50 ml) for 7 hours under reflux. After concentration to dryness under vacuum and taking up in ethyl ether, the precipitate is filtered, centrifuged, and dried under vacuum at 50° C. to give compound 15a (4.6 g).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=2)[CH2:3][CH2:2]1.[N+:12]([O-])([OH:14])=[O:13]>CC(O)=O.CCOC(C)=O>[CH:1]1([C:4]2[N:9]=[C:8]([OH:10])[C:7]([N+:12]([O-:14])=[O:13])=[C:6]([OH:11])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Oc1cc(O)nc(C2CC2)c1
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)cc(C2CC2)nc1O
Temperature: 30 °C
Reaction time: 8 h
Yield: 514 %

Procedure:
6-Cyclopropyl-2,4-dihydroxy-pyridine (1 g, 6.6 mmol) was suspended in AcOH:EtOAc (4:1, 10 mL) at room temperature. The mixture was warmed to 30° C. and a small portion of fuming nitric acid (0.05 ml, 1.2 mmol) was added dropwise, keeping the temperature between 30 and 35° C. Upon addition the mixture became a clear solution. The remainder of the fuming nitric acid (0.25 ml, 6.3 mmol) was added dropwise. The clear solution was allowed to cool to room temperature upon which a precipitate started to form. The mixture was stirred at room temperature overnight. The solid was collected by filtration, washed with cold water and Et2O and dried in vacuo at room temperature over the weekend to give the title compound (1.21 g) as a yellow powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[N+:6]([O-:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.[OH-].[NH4+:12]>>[NH2:12][C:2]1[CH:7]=[N+:6]([O-:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1
Reactant: [NH4+]
Reactant: COc1c[n+]([O-])cc(Cl)n1
Agent: [OH-]
Product: COc1c[n+]([O-])cc(N)n1

Procedure:
2-Chloro-6-methoxypyrazine 4-oxide is treated with an excess of ammonium hydroxide in an autoclave at 150° C. for 14 hours. The reaction mixture is cooled and evaporated to dryness to give the crude product which may be used in the next step as is.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)([CH3:6])[CH3:5].[Cl:8][C:9]([Cl:11])=[CH2:10].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:5][C:4]([CH3:6])([CH2:3][CH2:2][Cl:1])[CH:10]=[C:9]([Cl:11])[Cl:8]
Reactant: CC(C)(Cl)CCCl
Reactant: C=C(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(C=C(Cl)Cl)CCCl

Procedure:
1,3-Dichloro-3-methyl-butane was reacted with 1,1-dichloroethene in the presence of aluminum chloride in the temperature range between -10° and +5° C. 3,3-Dimethyl-1,1,5-trichloro-1-pentene was thereby obtained and was purified by distillation. 1,1-Dichloro-3,3-dimethyl-1,4-pentadiene was obtained by splitting off hydrogen chloride with quinoline in the temperature range between 200° and 240° C. (See Application Ser. No. 281,614 filed July 9, 1981 now pending, corresponding to German Patent Application No. P 30 29 270.7 of 1.8.1980). ##STR6##
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:8][CH2:9][CH2:10]Br.O1CCOCC1>C(N(CC)CC)C>[N:5]1[N:6]2[CH2:8][CH2:9][CH2:10][NH:1][C:2]2=[CH:3][CH:4]=1
Reactant: BrCCCBr
Reactant: Nc1ccn[nH]1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: c1cc2n(n1)CCCN2
Temperature: 25 °C

Procedure:
5-Aminopyrazole (10 g) and 1,3-dibromopropane (13.4 ml) were added to 1,4-dioxane (20 ml) under stirring at ambient temperature. Triethylamine (40.1 ml) was added thereto. The mixture was refluxed under stirring for 4 hours. The reaction mixture was cooled to 0°-5° C. in an ice-bath and stirred for 30 minutes. An insoluble material was filtered off, and the filtrate was evaporated under reduced pressure to give 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (5.1 g).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([CH:15]=[O:16])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=1.[CH:19]1([NH:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH:19]1([N:24]([C:9]2[C:14]([CH:15]=[O:16])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=2)[CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CSc1ncc(C=O)c(Cl)n1
Reactant: COC(=O)CNC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CN(c1nc(SC)ncc1C=O)C1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
Triethylamine (10.9 mL, 78.2 mmol) was added to a solution of compound 224 (12.3 g, 65.2 mmol) and compound 225 (12.8 g, 81.5 mmol) in THF (200 mL). The reaction was stirred at room temperature. After 6 h, the reaction contents were poured into saturated sodium bicarbonate and extracted with ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo. The crude material was crystallized from ethyl acetate and hexanes to afford methyl 2-(cyclopentyl(5-formyl-2-(methylthio)pyrimidin-4-yl)amino)acetate (226) (17.55 g, 87.0% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:33]=[CH:32][C:12]2[C:13](=[O:31])[C:14]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@H:24]4[CH2:28][O:27]C(C)(C)[O:25]4)=[CH:18][C:15]=3[CH2:16][CH2:17][C:11]=2[CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:33]=[CH:32][C:12]2[C:13](=[O:31])[C:14]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@H:24]([OH:25])[CH2:28][OH:27])=[CH:18][C:15]=3[CH2:16][CH2:17][C:11]=2[CH:10]=1
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)CCc2cc(Nc4ccccc4N)ccc2C3=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Nc1ccccc1Nc1ccc2c(c1)CCc1cc(OC[C@H](O)CO)ccc1C2=O

Procedure:
For the synthesis of the title compound, 0.10 g (0.225 mmol) of (S)-2-(2-amino-phenylamino)-8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one and 0.0537 g (0.282 mmol) of p-toluenesulfonic acid monohydrate in 6 ml of methanol and 1.5 ml of water are reacted by method N. C24H24N2O4 (Mr=404.47)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Cl:10][CH2:11][C:12](O)=[O:13].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[Cl:10][CH2:11][C:12]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:13]
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)CCl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(NC(=O)CCl)cc1
Temperature: 30 °C
Reaction time: 3 h
Yield: 19.7 %

Procedure:
A mixture of 4-methoxyaniline (5.00 g, 40.6 mmol), chloroacetic acid (8.6 g, 91.5 mmol), EDCI (12.0 g, 61.2 mmol), HOBT (8.4 g, 61.3 mmol) and NMM (13 mL, 122 mmol) in anhydrous CH2Cl2 (50 mL) was stirred at 30° C. for 3 hours. The mixture was quenched with ice water, and then extracted with CH2Cl2 (30 mL×2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column (PE/EtOAc=5/1) to give the product (1.60 g, yield 20%).