Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]2)=[CH:9][C:5]=1[CH:6]=[N:7]O)[CH3:2].NO.C(OC(=O)C)(=O)C>O>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH2:18]2)=[CH:9][C:5]=1[C:6]#[N:7])[CH3:2]
Reactant: CCC[C@H]1CC[C@H](c2ccc(OCC)c(C=NO)c2)CC1
Agent: NO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCC[C@H]1CC[C@H](c2ccc(OCC)c(C#N)c2)CC1
Reaction time: 0.33 h

Procedure:
A mixture of 28.9 g of 2-ethoxy-5-(trans-4-propyl-cyclohexyl)-benzaldoxime (obtainable from the aldehyde and hydroxylamine) and 40 ml of acetic anhydride is heated until the exothermic reaction starts, and is then boiled for 20 minutes and poured into water to give 2-ethoxy-5-(trans-4-propyl-cyclohexyl)-benzonitrile of m.p. 32°.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:41]=[C:40]([C:42]([NH:44][CH:45]([CH3:47])[CH3:46])=[O:43])[CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[N:41]=[C:40]([C:42]([NH:44][CH:45]([CH3:47])[CH3:46])=[O:43])[CH:39]=[CH:38][CH:37]=2)=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)NC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)n1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)NC(=O)c1cccc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)n1
Yield: 35.9 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 6-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-N-isopropyl-2-pyridinecarboxamide (1.60 g) and pyridine hydrochloride (770 mg), the title compound (350 mg) was obtained as colorless powder crystals.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][N:3]([C:12](=[O:14])[CH3:13])[CH2:2]1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:33][C:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:1][CH2:2][N:3]([C:12](=[O:14])[CH3:13])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)N1CCc2ccccc2CC1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)N1C=C(Br)c2ccccc2CC1

Procedure:
reaction of the 1-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone [J. Heterocycl. Chem. (1971), 8(5), 779-831] with dibenzoylperoxide and N-bromosuccinimide in carbon tetrachloride at reflux yielded the 1-(5-bromo-1,2-dihydro-benzo[d]azepin-3-yl)-ethanone; hydrogenation of the 1-(5-bromo-1,2-dihydro-benzo[d]azepin-3-yl)-ethanone with tritium using Pd/C in methanol in the presence of triethylamine yielded the 1-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo [d]azepin-3-yl) -ethanone; treatment of the 1-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone with conc. aq. hydrochloric acid in methanol gave the 1,1,2-tritritio-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2C=[C:20]([NH:22][CH:23]([CH3:25])[CH3:24])[CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:25][CH:23]([NH:22][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)[CH3:24]
Reactant: [H][H]
Reactant: CC(C)Nc1cccc(Oc2ccc(OCc3ccccc3)cc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)NCCCCCOc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
A solution of 1-benzyloxy-4-[5-(1-methylethyl)aminophenoxy]benzene (24 g) in acetic acid (250 ml) was hydrogenated over 1 g 10% palladium on carbon. After shaking for 0.5 hours at room temperature, the theoretical amount of hydrogen was taken up. The solvent was removed by distillation in vacuo and the residue dissolved in water. The solution was basified with saturated sodium bicarbonate solution and the product was recovered by filtration to give 13.0 g (75%) of 4-[5-(1-methylethyl)aminopentoxy]phenol, mp 95°-99° (95.7% pure by gas chromatography). Mass spectrum was compatible with the expected product.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32](COCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][CH3:42])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3C)C=CC=2OC(F)F)CC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][CH3:42])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1
Reactant: CCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: CCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Yield: 79 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(b) except for using 9.35 g (containing an amount corresponding to 14.0 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-ethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one obtained in Example 5-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one, whereby 5.84 g of the title compound was obtained as a white solid. (Yield: 79%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18]3[C:17]4[CH:16]=[N:15][CH:14]=[CH:13][C:12]=4[C:11](=[O:19])[C:10]=3[C:9](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:8][C:7]=2[C:31]=1[CH3:32].[NH2:33][CH2:34][CH2:35][N:36]([CH3:45])[CH2:37][CH2:38][CH2:39][N:40]([CH2:42][CH2:43][NH2:44])[CH3:41]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18]3[C:17]4[CH:16]=[N:15][CH:14]=[CH:13][C:12]=4[C:11](=[O:19])[C:10]=3[C:9]([NH:44][CH2:43][CH2:42][N:40]([CH2:39][CH2:38][CH2:37][N:36]([CH2:35][CH2:34][NH:33][C:9]3[C:10]4[C:11](=[O:19])[C:12]5[CH:13]=[CH:14][N:15]=[CH:16][C:17]=5[C:18]=4[C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:31]([CH3:32])[C:7]=4[N:8]=3)[CH3:45])[CH3:41])=[N:8][C:7]=2[C:31]=1[CH3:32]
Reactant: CN(CCN)CCCN(C)CCN
Reactant: COc1ccc2c3c(c(OS(=O)(=O)c4ccc(C)cc4)nc2c1C)C(=O)c1ccncc1-3
Product: COc1ccc2c3c(c(NCCN(C)CCCN(C)CCNc4nc5c(C)c(OC)ccc5c5c4C(=O)c4ccncc4-5)nc2c1C)C(=O)c1ccncc1-3

Procedure:
In a similar manner to Example 4, 3-methoxy-6-{2-[(3-{[2-(3-methoxy-4-methyl-7-oxo-7H-5,10-diaza-benzo[c]fluoren-6-ylamino)-ethyl]-methyl-amino}-propyl)-methyl-amino]-ethylamino}-4-methyl-5,10-diaza-benzo[c]fluoren-7-one was obtained starting from toluene-4-sulfonic acid 3-methoxy-4-methyl-7-oxo-7H-5,10-diaza-benzo[c]fluoren-6-yl ester (the compound of Reference Example 2c-1) and N,N′-bis-(2-amino-ethyl)-N,N′-dimethyl-propane-1,3-diamine. The desired product was obtained as a reddish powder.
Reaction SMILES: [Na].[CH3:2][CH:3]([CH3:15])[CH2:4][C:5](=O)[CH2:6][C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:16][NH:17][NH2:18].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[CH2:4]([C:5]1[N:17]([CH3:16])[N:18]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=1)[CH:3]([CH3:15])[CH3:2]
Reactant: CNN
Reactant: CCOC(=O)C(=O)CC(=O)CC(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC(C)C)n(C)n1
Reaction time: 2 h
Yield: 96.9 %

Procedure:
A 1 L round bottom flask was charged with ethyl 6-methyl-2,4-dioxoheptanoate sodium salt (30.0 g, 135 mmol) and acetic acid (200 mL). Methylhydrazine (7.20 mL, 135 mmol) was added dropwise via syringe, and the resultant solution was allowed to stir under a nitrogen atmosphere for 2 hours. The pH was then adjusted to 9 by addition of saturated aqueous sodium carbonate, and the reaction mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to provide 27.5 g of ethyl 5-isobutyl-1-methyl-1H-pyrazole-3-carboxylate as a yellow oil. This material was utilized without any further purification.
Reaction SMILES: Br[C:2]1[C:3]([O:13]C(C)(C)C)=[N:4][C:5]([O:8]C(C)(C)C)=[N:6][CH:7]=1.C([Li])CCC.[CH2:23]([C:25]1[O:26][C:27]2[CH2:34][CH2:33][C:32]3[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:31]=3[C:30](=O)[C:28]=2[N:29]=1)[CH3:24]>O1CCCC1.[Cl-].[Na+].O>[CH2:23]([C:25]1[O:26][C:27]2[CH:34]=[CH:33][C:32]3[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:31]=3[CH:30]([C:2]3[C:3](=[O:13])[NH:4][C:5](=[O:8])[NH:6][CH:7]=3)[C:28]=2[N:29]=1)[CH3:24]
Reactant: CCc1nc2c(o1)CCc1cc(C)ccc1C2=O
Reactant: CC(C)(C)Oc1ncc(Br)c(OC(C)(C)C)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2c(o1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
To a solution of the product of step (vi) (1.74 g) in dry tetrahydrofuran (20 ml) at −78° C. was added n-butyllithium (2.3 ml of a 2.5M solution in hexanes) dropwise. After 0.5 hours a solution of the product from step (v) (1.26 g) in tetrahydrofuran (10 ml) was added. The reaction mixture was allowed to warm to room temperature and saturated brine was added. The mixture was extracted with ethyl acetate, the organic phase was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in acetic acid (20 ml) and the solution was heated at reflux for 64 hours. The solvent was evaporated under reduced pressure and the residue was then dissolved in trifluoroacetic acid (20 ml) and the solution heated at reflux for 64 hours. The solvent was evaporated under reduced pressure. Purification was by trituration with diethyl ether and filtration.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:21]([O:25][C:26]([N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CC(C)([O-])C.[Na+].C(OCC)(=O)C>CC1C=CC=CC=1C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:21]([O:25][C:26]([N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([O:14][C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: Brc1ccc(N2CCC(Oc3ccncc3)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNc2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCC(Oc4ccncc4)CC3)cc2)c2ccccc21
Temperature: 150 °C
Yield: 62.8 %

Procedure:
1.2 g of 4-[1-(4-bromophenyl)piperidin-4-yloxy]pyridine are placed in 20 ml of anhydrous o-xylene. 0.844 g of 3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is added, then 0.519 g of sodium tert-butoxide is added, followed by 0.032 g of palladium acetate, and then addition is completed with 0.029 g of tri(tert-butyl)phosphine. The reaction mixture is heated at 150° C. for 6 h. Heating is subsequently halted, the mixture is brought back to ambient temperature and ethyl acetate is added. The mixture is washed twice with water and then twice with a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of a dichloromethane/methanol (99/1 to 97/3) mixture. 1.1 g of 4-{4-[4-(pyridin-4-yloxy)piperidin-1-yl]phenyl}-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are obtained.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:27][CH:26]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:27][CH:26]=3)[C@H:8]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:17][CH:18]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccc(-c3ccccc3)cc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(c1)OC[C@@H](c1ccc(-c3ccccc3)cc1)[C@H]2c1ccc(OCCN2CCCC2)cc1

Procedure:
In an manner analogous to that described in step 5 for Example 10, (±)-cis-7-methoxy-3-(4-phenyl-phenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane (0.202 g, 0.399 mmol) was de-methylated by heating with pyridine hydrochloride to give the title compound as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][CH:22]=1>CN1CCCC1=O.O>[C:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:26][CH:25]=1)([CH3:30])([CH3:29])[CH3:31]
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(C)(C)Oc1ccc(CCBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(OC(C)(C)C)cc2)CCN(C)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 6.4 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 0.001 mol) was dissolved in N-methyl 2-pyrolidone (2.0 mL). Powdered potassium hydroxide (0.5 g, 0.0089 mol) was added and heated at 100° C. for 3 h. Reaction mass was cooled to RT and 1-(2-Bromo-ethyl)-4-tert-butoxy-benzene (0.245 g, 0.001 mol) was added at the same temperature and stir for 2 h at RT (TLC showed incomplete reaction). Reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (0.5% MeOH:DCM in neutral alumina, Diameter of column—2.5 cm, Height of alumina—approx. 5 inch) then further purified by preparative TLC to provide the desired compound as light yellow oil (0.024 g, 6% yield). 5-[2-(4-tert-Butoxy-phenyl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.024 g, 0.000063 mol) was dissolved in THF (1.0 mL), A solution of oxalic acid dihydrate (0.008 g, 0.000063 mol) in THF (1.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.020 g, 67% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:35]([NH:37]O)=[NH:36])=[CH:31][N:30]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:27][N:37]=[C:35]([C:32]5[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=5)[N:36]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: N=C(NO)c1cnc(N)nc1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4nc(-c5cnc(N)nc5)no4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) (195 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example B.5) (115 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane/hexane) as a yellow solid (143 mg, 56%). MS (EI) 506.1 [(M)+]; mp 272° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:36][NH2:37]>C(Cl)Cl.CCOCC>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:20])([CH3:21])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:36][NH2:37])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)OCCn2c1nc(C(=O)NN)c(OCc1ccccc1)c2=O
Reaction time: 3 h
Yield: 27 %

Procedure:
To a stirred suspension of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid (prepared according to the procedure in Naidu, B. N. et al WO2005118593) (0.66 g, 2 mmol) in CH2Cl2 (10 mL) containing catalytic DMF was added oxalyl chloride in CH2Cl2 (2 M, 2 mL, 4 mmol) at room temperature. After 3 h, the resulting clear reaction solution was concentrated to remove excess oxalyl chloride. The resulting residue was re-dissolved in CH2Cl2 (20 mL) and treated with anhydrous hydrazine (0.34 mL, 10 mmol). After 2 h at room temperature, the reaction mixture was concentrated and the residue was taken up in EtOAc (100 mL) and washed with sat. NaHCO3 (10 mL), water (10 mL), brine (10 mL) then dried (Na2SO4), filtered and concentrated to give a white solid. This was digested with Et2O (20 mL) and filtered. Concentration of filtrate provided the title compound (0.17 g, 27% yield). 1HNMR (500 MHz, CDCl3) δ: 8.35 (1H, s), 7.55 (2H, d, J=7.3 Hz), 7.38-7.31 (3H, m), 5.30 (2H, s), 4.03-3.97 (6H, m), 1.60 (6H, s). HRMS (M+H) calcd for C17H21N4O5: 345.1563. found: 345.1577.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[C:15]([N+:24]([O-])=O)=[C:16]([OH:23])[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1.C(O)(=O)C>C1C=CC=CC=1.[Fe]>[NH2:24][C:15]1[C:13]2[NH:14][C:10]([NH:9][C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:11][C:12]=2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[C:16]=1[OH:23]
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c([N+](=O)[O-])c1O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c(N)c1O
Yield: 95.5 %

Procedure:
To a solution of methyl 2-[(2-chloro-6-fluorophenyl)amino]-6-hydroxy-7-nitro-1H-benzimidazole-5-carboxylate (Step-2 of Intermediate-56, 0.500 g) in benzene (2.0 mL), were added iron powder (0.500 g) and acetic acid (4.0 mL). The reaction mass was refluxed for 3 h. Decant the reaction mass removed the solvent under vacuum. The obtained solid mass was washed with water. The reaction mass was extracted with MeOH:DCM (5%). The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.440 g of the desired product.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH2:13][CH3:14])[CH2:4][NH:5][CH2:6][CH:7]1[O:11][CH2:10][CH2:9][O:8]1.C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:27][CH2:28][C:29](Cl)=[O:30]>O>[CH3:1][O:2][CH:3]([O:12][CH2:13][CH3:14])[CH2:4][N:5]([CH2:6][CH:7]1[O:8][CH2:9][CH2:10][O:11]1)[C:29](=[O:30])[CH2:28][Cl:27]
Reactant: CCOC(CNCC1OCCO1)OC
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(CN(CC1OCCO1)C(=O)CCl)OC

Procedure:
N-(2-Methoxy-2-ethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and chloroacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2-methoxy-2-ethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:49]=[CH:48][CH:47]=[CH:46][C:14]=1[C:15]([NH:17][C:18]1[CH:43]=[CH:42][C:21]([C:22]([N:24]([CH3:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])=[O:23])=[CH:20][C:19]=1[O:44][CH3:45])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[NH2:64][N:65]1[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:49]=[CH:48][CH:47]=[CH:46][C:14]=1[C:15]([NH:17][C:18]1[CH:43]=[CH:42][C:21]([C:22]([N:24]([CH3:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([NH:64][N:65]2[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]2)=[O:39])=[O:23])=[CH:20][C:19]=1[O:44][CH3:45])=[O:16])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)O)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Reactant: CN1CCN(N)CC1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)NN2CCN(C)CC2)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 72.8 %

Procedure:
To a solution of 4-[2-(3-tert-butoxycarbonylaminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-(5-carboxypent-1-yl)oxy-4-methylphenyl]benzamide (250 mg) and N-methylmorpholine (37 mg) in dichloromethane (5 ml) was added pivaloyl chloride (45 mg) at -15° C. After being stirred at the same temperature for 5 minutes, to the mixture was added 1-amino-4-methylpiperazine (47 mg) and the mixture was stirred at -15° C. for 1 hour and then stirred at ambient temperature for additional 2 hours. The resulting mixture was poured into saturated aqueous sodium hydrogen carbonate solution (20 ml) and the solution was extracted with chloroform (15 ml×3). The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified on silica gel column chromatography (SiO3 30 g, 1-15% methanol in chloroform) to give 4-[2-(3-tert-butoxycarbonylaminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-[5-(4-methylpiperazine-1-yl)aminocarbonylpent-1-yl]oxy-4-methylphenyl]benzamide (208 mg).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]1[C@H:14]2[C:15](=[O:39])[CH:16]=[C:17]3[C@:36]([CH3:37])([C@@H:13]12)[C@@H:35]1[C@H:20]([C@H:21]2[C@:32]([CH3:38])([CH2:33][CH2:34]1)[C@@H:24]([CH:25]([CH3:31])[CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH2:23][CH2:22]2)[CH:19]=[CH:18]3>C(Cl)(Cl)Cl>[O:12]1[C:14]2=[C:13]3[C@:36]([CH3:37])([CH2:17][CH2:16][C:15]2=[O:39])[C@@H:35]2[C@H:20]([C@H:21]4[C@:32]([CH3:38])([CH2:33][CH2:34]2)[C@@H:24]([CH:25]([CH3:31])[CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH2:23][CH2:22]4)[C@@H:19]2[O:9][C@:18]123
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClC(Cl)Cl
Product: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4=O)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
A mixture of 0. 836 g (0.5 mmole) of m-chloroperbenzoic acid and 70 ml of chloroform was added to a mixture of 0.772 g (2.0 mmoles) of 1α,2α-epoxy-21,21-dimethoxy-20-methylpregna-4,6-dien-3-one and 20 ml of chloroform and the whole mixture was stirred at room temperature for 1 day. The reaction mixture thus obtained was worked up in the same manner as Example 7 to recover 0.498 g of 1α,2α;6α,7α-diepoxy-21,21-dimethoxy-20-methylpregn-4-en-3-one (yield: 62%).