Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([O:31][CH3:32])([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]OS(C1C=CC(C)=CC=1)(=O)=O.[NH3:33]>CO>[CH3:1][O:2][C:3]([O:31][CH3:32])([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:33]
Reactant: COC(CCCCCCOS(=O)(=O)c1ccc(C)cc1)(OC)c1ccc(C(F)(F)F)cc1
Reactant: N
Solvent: CO
Product: COC(CCCCCCN)(OC)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Toluene-4-sulfonic acid 7,7-dimethoxy-7-[4-(trifluoromethyl)phenyl]heptyl ester (1.82 g, 3.835 mmol) was dissolved in a magnetically stirred solution of 7 M NH3 in methanol (30 ml) and stirred at room temperature for 72 hours. After removal of the solvent in vacuo, the residue was dissolved again in dichloromethane and washed with saturated aqueous NaHCO3. The organic layer was subsequently dried over Na2SO4, filtered and concentrated in vacuo to give crude 7,7-dimethoxy-7-[4-(trifluoromethyl)phenyl]heptylamine (1.43 g) which was not further purified. 1H-NMR (400 MHz, CDCl3) δ 0.88-0.95 (m, 2H), 1.12-1.16 (m, 4H), 1.33-1.38 (m, 2H), 1.83-1.88 (m, 2H), 2.59-2.65 (m, 2H), 3.10-3.26 (m, 8H, including —OMe singlet at 3.14), 7.56 (d, J˜8, 2H), 7.60 (d, J˜8, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11](N)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.BrC1C=C([NH2:22])C=CC=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([NH2:22])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Nc1cccc(Br)c1
Product: CN1CCN(c2cccc(N)c2)CC1

Procedure:
3-(4-Methyl-piperazin-1-yl)-phenylamine is prepared as described for 4-(4-methyl-piperazin-1-yl)-phenylamine (see Example 1) using 3-bromo-phenylamine.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9](B3OC(C)(C)C(C)(C)O3)=[CH:10][C:5]=2[N:4]=[CH:3]1.[NH2:20][C:21]1[C:30]2[C:25](=[C:26](Br)[CH:27]=[CH:28][CH:29]=2)[N:24]=[N:23][C:22]=1[C:32]([NH2:34])=[O:33]>C(O)=O>[NH2:20][C:21]1[C:30]2[C:25](=[C:26]([C:9]3[CH:8]=[CH:7][C:6]4[N:2]([CH3:1])[CH:3]=[N:4][C:5]=4[CH:10]=3)[CH:27]=[CH:28][CH:29]=2)[N:24]=[N:23][C:22]=1[C:32]([NH2:34])=[O:33]
Reactant: NC(=O)c1nnc2c(Br)cccc2c1N
Reactant: Cn1cnc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Solvent: O=CO
Product: Cn1cnc2cc(-c3cccc4c(N)c(C(N)=O)nnc34)ccc21

Procedure:
A formic acid salt of the title compound was prepared in a manner similar to EXAMPLE 1 using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole and 4-amino-8-bromocinnoline-3-carboxamide. 1H NMR (500 MHz, CD3OD) δ ppm 3.91 (s, 3 H), 8.54 (s, 1 H), 8.64 (d, J=8 Hz 1 H), 8.73 (d, J=8 Hz 2 H), 8.84 (d, J=16 Hz 1 H), 9.29 (d, J=8 Hz 1 H), 9.99 (s, 1 H); ESI-MS m/z [M+H]+ 319.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([O:13][CH3:14])=[CH:4][C:3]=1[O:15][CH3:16].C(=O)([O-])[O-].[Ca+2].Cl[C:23]([O:25][CH2:26][CH2:27][Cl:28])=[O:24].Cl>O1CCOCC1.O>[Cl:28][CH2:27][CH2:26][O:25][C:23]([NH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([O:13][CH3:14])=[CH:4][C:3]=1[O:15][CH3:16])=[O:24]
Reactant: COc1cc(OC)c([N+](=O)[O-])c(OC)c1N
Reactant: O=C(Cl)OCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)c([N+](=O)[O-])c(OC)c1NC(=O)OCCCl
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
0.26 moles (60 g) of 2-amino-4-nitro-1,3,5-trimethoxybenzene are dissolved in 270 ml of dioxane. 26.3 g of calcium carbonate are added and the temperature is then raised to about 90° C. 0.34 moles (48.6 g) of chloroethyl chloroformate are then added with stirring. When the addition is complete, stirring is continued for additional 30 minutes at 90° C. The reaction mixture is diluted with 600 ml of iced water and is then acidified by adding 25 ml of concentrated hydrochloric acid. The precipitate obtained is filtered off and washed with water. After drying, it melts at 133° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Cl[C:39]1[N:44]=[CH:43][C:42]([CH3:45])=[CH:41][N:40]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:39]3[N:44]=[CH:43][C:42]([CH3:45])=[CH:41][N:40]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: Cc1cnc(Cl)nc1
Product: COc1ccc(CC2c3cc(Oc4ncc(C)cn4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2-chloro-5-methyl-pyrimidine
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([F:8])[O:7][C:4]1([F:6])F.[F-:11].[K+]>>[C:2]([C:3]([C:4]([F:6])=[O:7])([F:8])[F:11])([F:10])([F:9])[F:1]
Reactant: [F-]
Reactant: FC(F)(F)C1(F)OC1(F)F
Agent: [K+]
Product: O=C(F)C(F)(F)C(F)(F)F

Procedure:
CF3CF2COF (b.p. -28° C.) is prepared by flowing hexafluoropropylene oxide through a stainless steel reactor tube containing active carbon carrying 3% by weight of potassium fluoride kept at 150° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.Cl.[CH2:26]([O:28][C:29](=[O:37])[CH2:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:27].C(N(CC)CC)C>CO>[CH2:26]([O:28][C:29](=[O:37])[CH2:30][CH:31]1[CH2:36][CH2:35][N:34]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:13]([O:23][CH3:24])[CH:12]=3)[N:3]=2)[CH2:33][CH2:32]1)[CH3:27]
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: CCOC(=O)CC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)CC1CCN(c2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc(OC)n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (100 mg, 0.29 mmol) and ethyl-2-(piperidin-4-yl)acetate hydrochloride (63 mg, 0.30 mmol) in 3 ml of methanol was treated with triethylamine (0.13 ml, 0.92 mmol). The mixture was stirred for 3 hours at room temperature, concentrated and the product purified by chromatography on silica gel using ethyl acetate as an eluent. The title compound was isolated as a colorless solid (137 mg, 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH2:14])([CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:21](Cl)(=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH:14][C:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:30])([CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(NC(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a mixture of 3-amino-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (5.0 g, 25 mmol) and potassium carbonate (3.8 g, 27 mmol) in THF (25 mL) and water (25 mL) was added benzyl carbonochloridate (4.6 g, 27 mmol) at 0° C. and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3×15 mL). The combined organic phase was washed with brine (25 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 4% EtOAc in petroleum) to give 3-benzyloxycarbonylamino-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (5.5 g, 70%). 1H NMR (400 MHz, CDCl3) δ 7.35 (s, 5H), 5.14-5.02 (m, 2H), 4.88-4.79 (m, 1H), 3.63-3.23 (m, 4H), 2.25 (m, 1H), 1.88-1.77 (m, 1H), 1.45 (s, 12H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)[C:4]([NH:6][CH:7]1[C:25](=[O:26])[N:9]2[C:10]([C:22]([OH:24])=[O:23])=[C:11]([CH2:14][S:15][C:16]3[N:20]([CH3:21])[N:19]=[N:18][N:17]=3)[CH2:12][S:13][C@H:8]12)=[O:5].[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([O:1][N:2]=[C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)[C:4]([NH:6][CH:7]1[C:25](=[O:26])[N:9]2[C:10]([C:22]([OH:24])=[O:23])=[C:11]([CH2:14][S:15][C:16]3[N:20]([CH3:21])[N:19]=[N:18][N:17]=3)[CH2:12][S:13][C@H:8]12)=[O:5])(=[O:36])[CH3:35]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3cccc(O)c3)[C@H]2SC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 7-[2-hydroxyimino-2-(3-hydroxyphenyl)-acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (9.83 g.) and acetic anhydride (200 ml.) was stirred for 5 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure. To the residue was added ether and the mixture was stirred overnight at ambient temperature. Precipitates were collected by filtration, washed thoroughly with ether and dried to give 7-[2-acetoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (8.5 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[N:6][CH:7]=1>C1COCC1.C(OCC)(=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-nitro-benzamide (2 g, 7.2 mmol) in THF (50 mL) and ethyl acetate (50 mL) was added Raney Ni (0.2 g) and the mixture was placed under hydrogen (4.1 bar) in a high pressure apparatus. After shaking overnight, the mixture was filter d and concentrated in vacuo and purified by flash chromatography to give 1.5 g (83%) of an off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]([CH3:31])[C:15]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C@@:32]12([CH2:42][S:43](O)(=[O:45])=[O:44])[C:39]([CH3:41])([CH3:40])[CH:36]([CH2:37][CH2:38]1)[CH2:35][C:33]2=[O:34]>CC(C)=O.CO>[C@@:32]12([CH2:42][S:43]([O:22][C@@:15]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])([C@H:14]([C:11]3[S:12][CH:13]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[N:10]=3)[CH3:31])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)(=[O:45])=[O:44])[C:39]([CH3:41])([CH3:40])[CH:36]([CH2:37][CH2:38]1)[CH2:35][C:33]2=[O:34]
Reactant: CC(c1nc(-c2ccc(C#N)cc2)cs1)C(O)(Cn1cncn1)c1cc(F)ccc1F
Reactant: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)=O
Solvent: CO
Product: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@@](Cn1cncn1)(OS(=O)(=O)C[C@@]12CCC(CC1=O)C2(C)C)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (10 g) in acetone (ca. 200 ml) a solution of (1R)-10-camphorsulfonic acid (3.9 g) in methanol (50 ml) was added and the mixture was heated shortly under reflux until a clear solution was obtained. The solution was then slowly cooled to rt, seeded with crystals of the desired enantiomeric salt and let overnight. The solid precipitate was collected by filtration, washed with acetone and dried to provide (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (1R)-10-camphorsulfonate as white solid. This salt was then taken up in methylenechloride and water and basified with aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous phase washed twice with methylenechloride. The organic phases were combined, dried with sodium sulphate, filtrated and the solvent removed under reduced pressure. The crude product was then dissolved in ethanol, the slurry heated for 20 min, small amount of water was added, the solution slowly cooled to 0° C. and stirred for ca. 2 hrs. The product was collected, washed with cold ethanol and dried under reduced pressure to provide the title enantiomerically pure compound (3.9 g, 39% yield, 96% ee). The analytical date were identical with published in U.S. Pat. No. 6,300,353 B1 and WO 99/45008.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][CH:9]1[C:14](=[O:23])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]([CH:9]2[CH2:10][C:11](=[CH2:13])[CH2:12][CH:8]2[NH2:7])=[O:23])=[CH:17][CH:18]=1
Reactant: C=C1CC(NC(=O)OC(C)(C)C)C(C(=O)Nc2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C1CC(N)C(C(=O)Nc2ccc(Cl)cc2)C1
Yield: 68.5 %

Procedure:
A solution of 0.98 g of 35c in 10 ml of CH2Cl2 and 1.07 ml of trifluoroacetic acid was stirred at 22° C. for 2 h. The solution was evaporated and the residue partitioned between H2O and CH2Cl2. The aqueous layer was treated slowly with NaHCO3 until pH═8, the suspension was filtered, the residue washed with H2O and dried to give 0.48 g (69%) of the title compound 35d. MS: 251.3 (M+H)+.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+]>>[CH:1](=[C:11]1/[C:10](=[O:15])[CH2:14][CH2:13][CH2:12]/1)\[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C1CCCC1
Reactant: CCCCCCCC=O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCC/C=C1\CCCC1=O

Procedure:
The procedure was similar to that in Example 1 by reacting n-octanal with cyclopentanone in the presence of 1% NaOH to give 2-(E)-octylidene cyclopentanone. The boiling point of this intermediate compound was determined to be 120°-125° C. at a pressure of 4 mm Hg. A subsequent Mannich reaction yielded the 2-Dimethylaminomethyl-5-(E)-octylidene cyclopentanone hydrochloride. The melting point of the product was determined to be 138°-140° C.
Reaction SMILES: [C:1]([N:3]1[CH2:8][C:7]2[C:9]3[C:18]([OH:19])=[CH:17][C:16]([CH:20]([CH3:28])[CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][C:10]=3[O:11][C:12]([CH3:14])([CH3:13])[C:6]=2[CH2:5][CH2:4]1)#[N:2].IC.[C:31](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([N:3]1[CH2:8][C:7]2[C:9]3[C:18]([O:19][CH3:31])=[CH:17][C:16]([CH:20]([CH3:28])[CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][C:10]=3[O:11][C:12]([CH3:14])([CH3:13])[C:6]=2[CH2:5][CH2:4]1)#[N:2]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(C#N)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCCCCC(C)C(C)c1cc(OC)c2c(c1)OC(C)(C)C1=C2CN(C#N)CC1
Reaction time: 7 h
Yield: 77.3 %

Procedure:
A mixture of 2.3 g (0.006 mole) of 2-cyano-5,5-dimethyl-8-(1,2-dimethylheptyl)-10-hydroxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, 2.8 g (0.02 mole) of iodomethane and 10 g (0.0725 mole) of potassium carbonate in anhydrous acetone was heated at reflux, with stirring, for 7 hours. After cooling, the solid was removed by filtration and discarded, and the mother liquor was concentrated on a rotary evaporator. The residual material was taken up in diethyl ether (70 ml) and washed with water, 1N HCl, and again with water. The organic layer was dried over sodium sulfate, filtered and concentrated to give 1.84 g (78%) of 2-cyano-5,5-dimethyl-8-(1,2-dimethylheptyl)-10-methoxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine as a yellow oil. The ir and nmr spectra confirmed the structure. The compound appeared pure by thin-layer chromatography (silica gel, chloroform solvent system).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([Br:11])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([NH2:14])=[O:13].[O:15]=[C:16](Cl)OC(Cl)(Cl)Cl.O>O1CCOCC1>[Br:11][C:6]1[C:5]2[NH:4][C:3]3[C:12](=[O:13])[NH:14][C:16](=[O:15])[NH:1][C:2]=3[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: NC(=O)c1[nH]c2c(Br)cccc2c1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)c2[nH]c3c(Br)cccc3c2[nH]1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
8.0 g (32 mmol) 3-amino-7-bromo-1H-indole-2-carboxylic acid amide was suspended in 50 ml dioxan, and refluxed after the addition of 3.8 ml (32 mmol) diphosgene for 3 h. Having cooled down to room temperature, 20 ml water was carefully added and the precipitate was then sucked off. 9.0 g (32%) 6-bromo-1H-pyrimido[5,4-b]indole-2,4(3H,5H)-dione was obtained. ESI-MS [m/z]: 278, 280 [M−H]−
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:10][N:6]1[C:5]2[CH:11]=[CH:12][C:2]([C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)=[CH:3][C:4]=2[S:8][C:7]1=[O:9]
Reactant: OB(O)c1cccnc1
Reactant: Cn1c(=O)sc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1c(=O)sc2cc(-c3cccnc3)ccc21
Yield: 131 %

Procedure:
A suspension of 6-Bromo-3-methyl-3H-benzothiazol-2-one (200 mg, 0.82 mmol), 3-pyridyl boronic acid (78 mg, 0.63 mmol), polymer-supported Pd(PPh3)4 (0.11 mmol/g, 115 mg, 0.0126 mmol) and Na2CO3 (2 M in water, 0.65 mL, 1.3 mmol) in DME (7 mL) was heated to reflux for overnight. After filtration and concentration, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 0-4%) and yielded the title compound (200 mg). MS (ESI) m/z 243.0 (M+H, 1H NMR (400 MHz, CD2Cl2) δ ppm 3.52 (s, 3H), 7.23 (d, J=8.4 Hz, 1H), 7.43-7.46 (m, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.93-7.96 (m, 1H), 8.62 (m, 1H), 8.88 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)[CH3:3].[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12>>[C:11]1(=[O:16])[N:1]([CH:2]([C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=2)[CH3:3])[C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccc(C(C)N)cc1
Product: Cc1ccc(C(C)N2C(=O)c3ccccc3C2=O)cc1
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
A mixture of 9.2 g of 4-(1-aminoethyl)toluene and 10 g of phthalic anhydride was stirred at 145° to 150° C. for 30 minutes. The reaction mixture was purified by silica gel column chromatography (eluted with benzene) to yield 10 g of 4-(1-phthalimidoethyl)toluene; m.p. 65°-66° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][NH2:15]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:15][CH2:14][CH2:13][O:12][CH3:11])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: COCCN
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Product: COCCNc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
One heats to reflux for 15 hours 0.3 mole of parachloronitrobenzene (47.35 g) in solution in 150 ml of β-methoxyethylamine. One then pours the cooled reaction mixture into 300 g of crushed ice. The intended product precipitates first in the form of a red oil which crystallizes rapidly. After recrystallization in ethanol and drying under vacuum the product melts at 86° C. Analysis gives the following results:
Reaction SMILES: C([O:3][P:4]([CH2:9][C@@H:10]1[C@H:15]([NH:16][C:17](=[O:19])[CH3:18])[C@@H:14]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:13]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:12]([CH2:36][O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:11]1)(=[O:8])[O:5]CC)C.N1C=CC=CC=1.C[Si](Br)(C)C>C(#N)C>[C:17]([NH:16][C@@H:15]1[C@@H:14]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:13]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:12]([CH2:36][O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:11][C@@H:10]1[CH2:9][P:4](=[O:3])([OH:5])[OH:8])(=[O:19])[CH3:18]
Reactant: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1NC(C)=O)OCC
Agent: C[Si](C)(C)Br
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1CP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 123.4 %

Procedure:
To a solution of diethyl(((2S,3R,4R,5S,6R)-3-acetamido-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phosphonate (0.40 g, 0.64 mmol, 1.0 equiv) in dry acetonitrile (23.5 mL) was added pyridine (0.6 mL, 7.36 mmol, 11.5 equiv) at 0° C. under argon atmosphere. Then, anhydrous TMSBr (1.65 mL, 10.2 mmol, 16.0 equiv) dissolved in 16.5 mL of dry acetonitrile was added dropwise at −5 to 0° C. The resulting mixture was stirred for 10 minutes. The resulting reaction mixture was allowed to warm to room temperature 4 hours and then the volatiles were removed in vacuo (bath temperature <15° C.). To the residue was added ice-cold water (10 mL), and the organic material was extracted into DCM (2×10 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo (bath temperature <15° C.) to obtain (((2S,3R,4R,5S,6R)-3-acetamido-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phosphonic acid (0.45 g) as a pale green solid. This material was directly taken forward to the next step without purification. ESI (M+1) 570.0; calc for C30H36NO8P 569.2.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:11][C@@H:12]([CH3:15])[CH2:13][CH3:14])=[C:7]([CH:10]=1)[C:8]#[N:9])=[O:2].B1([O-])O[O:17]1.O.O.O.O.[Na+]>C(O)(=O)C>[C:8]([C:7]1[CH:10]=[C:3]([CH:4]=[CH:5][C:6]=1[O:11][C@@H:12]([CH3:15])[CH2:13][CH3:14])[C:1]([OH:17])=[O:2])#[N:9]
Reactant: CC[C@H](C)Oc1ccc(C=O)cc1C#N
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC[C@H](C)Oc1ccc(C(=O)O)cc1C#N
Temperature: 50 °C
Yield: 103.5 %

Procedure:
To a solution of 5-formyl-2-{[(1S)-1-methylpropyl]oxy}benzonitrile (D35) (220 mg, 1.08 mmol) in acetic acid (20 ml) was added sodium perborate tetrahydrate (334 mg, 2.17 mmol), the reaction mixture was heated at 50° C. over the weekend. The reaction mixture was concentrated in-vacuo. Water (˜50 ml) was added, EtOAc (˜30 ml) was added and the layers partitioned, the aq layer was extracted twice more with EtOAc (˜30 ml) and the combined organics were evaporated to dryness under reduced pressure to give the title compound (245 mg) as an off white solid. δH (d6-DMSO, 400 MHz): 8.17 (2H, apparent d), 7.39 (1H, s), 4.68-4.74 (1H, m), 1.55-1.76 (2H, m), 1.31 (3H, d), 0.95 (3H, t). MS (ES): C12H13NO2 requires 219; found 220 (MH+).