Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]#[C:24][CH2:25][OH:26])[CH:8]=2)[N:3]=1>O1CCCC1.[O-2].[Mn+4].[O-2]>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]#[C:24][CH:25]=[O:26])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(C#CCO)ccc2n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(C#CC=O)ccc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
860 mg of 2-amino-6-(3-hydroxyprop-1-ynyl)-4-(1,3-dihydroisoindol-2-yl-carbonyl)quinazoline are dissolved in 2 ml of tetrahydrofuran and, after addition of 1.736 g of manganese(IV) oxide, stirred at room temperature for 16 h. After addition of a further 434 mg of manganese(IV) oxide, the mixture is stirred for a further 12 h, filtered through kieselguhr, and the filtrate is evaporated to dryness. Drying in vacuo gives 402 mg of “A965”.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](SC)[N:5]=[N:6][C:7]=1[CH3:8].[OH-:11].[K+].[BH4-].[Na+]>>[CH3:1][CH:2]1[C:7]([CH3:8])=[N:6][NH:5][C:4](=[O:11])[NH:3]1
Reactant: CSc1nnc(C)c(C)n1
Reactant: [OH-]
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Product: CC1=NNC(=O)NC1C
Yield: 35.4 %

Procedure:
5,6-Dimethyl-3-methylthio-1,2,4-triazine (2.48 g) was reacted with potassium hydroxide (1.792 g), and the reaction mixture was reduced by sodium borohydride (0.907 g) in a similar manner to that of Example 32-(3). The above reaction mixture was concentrated, and the residue was treated with 10% hydrochloric acid and then evaporated under reduced pressure. The resultant solid was extracted with a mixture of chloroform and methanol. The extract was evaporated, and the resultant residue was dissolved in a small amount of water. The solution was passed through a column of DIAION NP-20 (Trademark, manufactured by Mitisubishi Chemical Industries Ltd.) (100 ml) using water and then a mixture of methanol and water (1:1) as eluents. The eluate with aqueous methanol was evaporated under reduced pressure and the residue was dissolved in acetone under reflux. The solution was treated with activated charcoal and filtered. The filtrate was evaporated and resultant residue was recrystallized from ethanol to give 5,6-dimethyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.719 g), m.p. 200°~102.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:19]=1)=[O:13].CCN(CC)CC.[CH3:39][N:40]1[CH2:43][CH:42]([C:44](O)=[O:45])[CH2:41]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:44]([CH:42]3[CH2:43][N:40]([CH3:39])[CH2:41]3)=[O:45])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: CN1CC(C(=O)O)C1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CN(C)C4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was dissolved in DMSO, to which Et3N (3 equiv.) and 1-methylazetidine-3-carboxylic acid (2 equiv.) was added. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equiv.) was added to it and stirring was continued overnight. After completion of the reaction, water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired product.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C@@H:18]2[C@H:12]([CH:13]=[CH:14][C:15]3[C:16]4[N:17]2[C:19]2[CH:28]=[CH:27][N:26]=[CH:25][C:20]=2[C:21]=4[CH2:22][CH2:23][CH:24]=3)[CH2:11][CH2:10][CH2:9]1.C(Cl)(Cl)Cl.[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH:36]=[CH:35][CH2:34]1>O>[CH:33]1([C:39]([CH:10]2[CH2:11][CH:12]3[CH:13]=[CH:14][C:15]4[C:16]5[N:17]([C:19]6[CH:28]=[CH:27][N:26]=[CH:25][C:20]=6[C:21]=5[CH2:22][CH2:23][CH:24]=4)[CH:18]3[CH2:8][CH2:9]2)=[O:40])[CH2:38][CH2:37][CH:36]=[CH:35][CH2:34]1
Reactant: C1=C[C@@H]2CCCC[C@H]2n2c3c(c4cnccc42)CCC=C13
Reactant: O=C(Cl)C1CC=CCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(C1CC=CCC1)C1CCC2C(C=CC3=CCCc4c3n2c2ccncc42)C1

Procedure:
Triethylamine (10 ml.) was added with stirring to a solution of 5.5 g. (±)-trans-1,2,3,4,4a,8,9,14a-octahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine in 100 ml. chloroform, followed by addition, with stirring, of 5.76 g. (0.04 moles) 3-cyclohexene-1-carbonyl chloride in 10 ml. chloroform. The mixture was refluxed 2 hours then cooled and water was added. The organic layer was separated, dried over K2CO3, and evaporated to dryness in vacuo. Trituration of the residual oil in hexane gave (±)-trans-3-[(3-cyclohexen-1-yl)carbonyl]-1,2,3,4,4a,8,9,14a-octahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine, m.p. 156.5°-158.5° .
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27]([C:29]2[S:30][C:31]([C:34]([NH:36][NH2:37])=[O:35])=[CH:32][CH:33]=2)=[O:28])=[CH:21][CH:20]=1>CS(C)=O>[N:19]1[CH:20]=[CH:21][C:22]([CH2:25][NH:26][C:27]([C:29]2[S:30][C:31]([C:34]([NH:36][N:37]=[C:15]([C:11]3[C:10]([OH:18])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[N:13]([CH3:14])[N:12]=3)[CH3:16])=[O:35])=[CH:32][CH:33]=2)=[O:28])=[CH:23][CH:24]=1
Reactant: CC(=O)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: NNC(=O)c1ccc(C(=O)NCc2ccncc2)s1
Solvent: CS(C)=O
Product: CC(=NNC(=O)c1ccc(C(=O)NCc2ccncc2)s1)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Reaction time: 10.5 h
Yield: 52.6 %

Procedure:
1-[5-(3,4-Dichlorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (40 mg, 0.14 mmol) in dimethyl sulfoxide (1.0 mL) was mixed with 5-hydrazinocarbonylthiophene-2-carboxylic acid 4-picolylamide (39 mg, 0.14 mmol) prepared in Reference Synthetic Example 4 and left at 100° C. for 10.5 hours. The solvent was evaporated, and the residue was dissolved in chloroform (1.0 mL). After addition of n-hexane (2.0 mL), the resulting crystals were recovered by filtration to give 40 mg of the desired product (yield 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:21]=1.C(N(CC)C(C)C)(C)C.CC1CCCO1.CCCP(=O)=O>O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([NH:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:21]=1)=[O:6]
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Reactant: O=C(O)c1cc(-c2ncccc2F)c(Cl)cc1Cl
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC1CCCO1
Solvent: O
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
To a refluxing mixture of 2,4-dichloro-5-(3-fluoropyridin-2-yl)benzoic acid (Preparation 27A, 159 g, 0.554 mol), ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (154 g, 0.665 mol), N,N-diisopropylethylamine (215 g, 1.66 mol) and 2-methyltetrahydrofuran (4.8 L), was added propylphosphonic anhydride solution (989 mL, 1.66 mol, >50% by weight in EtOAc) and the reaction maintained at reflux for 6 hours. After cooling to room temperature, the reaction was diluted with water (6 L) and extracted with 2-methyltetrahydrofuran (2×1.5 L). The combined organic layers were concentrated in vacuo to provide a slurry which was filtered and the solid washed with ethyl acetate (3×200 mL) to give the title compound as a white solid (215 g, 79%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5][C:4]=2[C:3]=1[OH:18].Br[CH:20]1[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:1][C:2]1[C:3]([O:18][CH:20]2[CH2:23][CH2:22][CH2:21]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2
Reactant: C[C@H]1CCc2c(ccc(Br)c2O)N1C(=O)C1CC1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@H]1CCc2c(ccc(Br)c2OC2CCC2)N1C(=O)C1CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 85.1 %

Procedure:
A 250-mL round-bottom flask was charged with (2S)-6-bromo-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol (2.00 g, 6.45 mmol), bromocyclobutane (1.81 mL, 2.60 g, 19.3 mmol), cesium carbonate (6.3 g, 19.34 mmol) and acetonitrile (100 mL). The resulting mixture was stirred for 6 h at 80° C. The reaction mixture was filtered through a pad of Celite and concentrated under vacuum. The residue was purified via column chromatography on silica gel (gradient elution with 0-10% ethyl acetate-petroleum ether) to afford (2S)-6-bromo-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinoline (2.00 g, 85%) as a colorless oil. MS (ES, m/z): 364, 366 [M+H]+
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[OH:24])[N:8]=2)[CH2:3]1.C(N(CC)CC)C.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>O.C(Cl)Cl>[CH2:36]([O:35][C:33](=[O:34])[NH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[OH:24])[N:8]=2)[CH2:3]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To (R)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol (50.8 mg, 0.16 mmol) was added 500 μL of CH2Cl2 and the solution was cooled to 0° C. To this solution was added sequentially triethylamine (33.2 μL, 0.24 mmol) and benzyl chloroformate (29.2 mg, 0.17 mmol). The reaction mixture was stirred from 0° C. to 5° C. over 45 min, then diluted with water and CH2Cl2 (10 mL). The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give (R)-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamic acid benzyl ester. LC/MS: m/z 455.2 (M+H)+ at 2.81 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13]C(C)(C)C)(=[O:12])=[O:11]>FC(F)(F)C(O)=O>[Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:13])(=[O:11])=[O:12]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1CCBr
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccccc1CCBr

Procedure:
A solution of 6.3 g of the product from Example 10 in 30 ml trifluoroacetic acid was stirred at room temperature for one hour. The desired product was insoluble in the reaction mixture and was isolated by filtration. Washing with diethyl ether and drying gave 4.5 g of 2-(2-bromoethyl)benzenesulfonamide as a white solid, m.p. 169°-171° C. (dec.).
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][O:6][C:7]1[C:8]([N+:14]([O-:16])=[O:15])=[C:9](N)[CH:10]=[CH:11][CH:12]=1.C([O-])(O)=O.[Na+].[ClH:22]>O>[Cl:22][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH3:5])[C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: Cl
Reactant: COc1cccc(N)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cccc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
A solution of sodium nitrite (180 mg, 2.60 mmol) in water (0.5 mL) was added dropwise to a solution of 3-methoxy-2-nitro-phenylamine (400 mg, 2.38 mmol, Example 86(A)) in HCl (37%, 3.9 mL) at 0° C. over one hour period. Then the reaction mixture was added to a cold (0° C.) solution of CuCl2 (640 mg, 4.76 mmol) in HCl (6 N, 3.5 mL). The resulting green solution was stirred at room temperature for 2 days. Then, the reaction mixture was poured onto ice and neutralized carefully with a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The resulting organic phase was washed with brine, dried over MgSO4, filtered and evaporated to yield 293 mg (1.56 mmol, 66%) of 1-chloro-3-methoxy-2-nitrobenzene as a brown oil.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[O:9]=[C:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:12]([CH:13]=[CH:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2C(F)(F)F)=[O:30])=[CH:11]1>CS(C)=O>[CH3:28][C@:25]12[CH2:26][CH2:27][C:10](=[O:9])[CH:11]=[C:12]1[C@H:13]1[CH2:4][C@H:14]1[CH:15]1[CH:24]2[CH2:23][CH2:22][C@:20]2([CH3:21])[C@@H:19]([C:29]([NH:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:30])[CH2:18][CH2:17][CH:16]21
Reactant: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Nc1ccccc1C(F)(F)F
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@]12CCC(=O)C=C1[C@H]1C[C@H]1C1C2CC[C@@]2(C)C1CC[C@@H]2C(=O)Nc1ccccc1
Reaction time: 1.5 h

Procedure:
To a suspension of NaH (0.25 g, 6.18 mmol) in 7.4 mL DMSO (dried over molecular sieves) at room temperature under N2 was added trimethylsulfoxonium iodide (1.50 g, 6.85 mmol). The mixture was stirred for 1.5 hr. A solution of (17β)-3-oxo-N-[2-(trifluoromethyl)phenyl]androsta-4,6-diene-17-carboxamide (5-1) (0.68 g, 1.49 mmol) in 10 mL DMSO was added slowly. The solution was stirred at room temperature overnight. The reaction was then quenched by dropwise addition of 10% KHSO4 solution and extracted with CHCl3. The organic phase was washed with 10% KHSO4 solution, saturated NaHCO3 solution, and brine, then dried with MgSO4. After removal of the solvent, the residue was purified by chiral preparative HPLC (Chiralpak AD, 85% Hexanes (0.1% diethylamine); 15% 2-propanol) to yield the desired resolved products 6-6and 6-2.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[NH:13][C:12]2=[O:21])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:21])[C:11]2=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:31](=[O:33])[CH3:32])[CH:10]=2)[CH2:6][O:7]1
Reactant: CC(=O)Cl
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-5-chloro-1,3-dihydro-indol-2-one (56.5 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.5 mL THF was added acetyl chloride (13.4 μL, 0.189 mmol). After stirring at room temperature for 3 h, the mixture was filtered and rinsed with isopropanol and hexanes/EtOAc (7:3) to give the title compound (46.9 mg, 73%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[N:16][C:17]([CH:20]([NH:22][C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=O)[CH3:21])=[CH:18][N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].P(Cl)(Cl)(Cl)=O>ClCCCl>[CH:25]1([C:23]2[N:16]3[C:17]([CH:18]=[N:19][C:14]([NH:13][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)=[N:15]3)=[C:20]([CH3:21])[N:22]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)C3CCCCC3)nn2)cc(OC)c1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1cc(Nc2ncc3c(C)nc(C4CCCCC4)n3n2)cc(OC)c1OC
Yield: 25.9 %

Procedure:
Applying the Cyclization Procedure 1, using N-[1-(3-{[3,4,5-tris(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]cyclohexane-carboxamide (Intermediate 68) (140 mg, 0.34 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.25 mL, 2.68 mmol), to afford 7-cyclohexyl-5-methyl-N-[3,4,5-tris(methyloxy)phenyl]-imidazo[5,1-f][1,2,4]triazin-2-amine (35 mg) as a yellow solid. MS m/z 398 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([OH:31])[C@@H:16]([N:18]2[CH2:23][CH2:22][C:21]([OH:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH3:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:32][S:33](O)(=[O:35])=[O:34].[H][H]>[Pd].C(O)C>[OH2:8].[OH2:34].[OH2:8].[CH3:32][S:33]([O:31][C@@H:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)[C@@H:16]([N:18]1[CH2:23][CH2:22][C:21]([OH:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[CH3:17])(=[O:35])=[O:34]
Reactant: CS(=O)(=O)O
Reactant: [H][H]
Reactant: C[C@@H]([C@@H](O)c1ccc(OCc2ccccc2)cc1)N1CCC(O)(c2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]([C@@H](OS(C)(=O)=O)c1ccc(O)cc1)N1CCC(O)(c2ccccc2)CC1
Product: O
Temperature: 52.5 °C
Reaction time: 5 h
Yield: 256.2 %

Procedure:
Five percent palladium on carbon catalyst (0.75 g, 50% water-wet), (1S,2S)-1-(4-benzyloxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol (5.0 g, 12.0 mmol), ethanol (62.5 mL), and methanesulfonic acid (1.15 g, 12.0 mmol) were combined in a Parr pressure reactor under a nitrogen atmosphere. The nitrogen atmosphere was exchanged for hydrogen (3×25 psi) and then the hydrogen pressure was increased to 50 to 55 psi. The mixture was heated and stirred at 50 to 55° C. for 5 hours when HPLC indicated that the reaction was complete. The hydrogen gas was slowly vented, the reactor flushed with nitrogen, and then the warm (50° C.) reaction mixture was filtered through Celite. The Celite filter cake was washed with ethanol (5 mL). The combined wash and filtrate were concentrated in vacuo to 10 mL. Water (17.5 mL) was added and the solution was concentrated at atmospheric pressure until a distillate temperature of 76° C. was obtained. The clear solution was slowly cooled over 1 hour to 15 to 20° C. and then cooled further to 0 to 5° C. After granulating for 1 hour at 0 to 5° C., the thick slurry was filtered and the cake washed with cold water (5° C., 2.5 mL). The solid was dried for 18 hours at 20 to 25° C. to give 4.71 g of the title compound for an 83% yield. The product was identical to an authentic sample of the title compound. If low-pyrogen water and pyrogen-free conditions are employed in the above procedure, isolated title compound is suitable for parenteral applications.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[C:8](=[O:11])[C:7]1[C:12]([OH:20])=[C:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[CH:15][C:6]=1[O:5]2.[Cl-].Cl[CH:23]=[N+:24]([CH3:26])[CH3:25].C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[CH2:23][N:24]([CH3:26])[CH3:25])[C:8](=[O:11])[C:7]1[C:12]([OH:20])=[C:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[CH:15][C:6]=1[O:5]2
Reactant: CCCc1c(O)cc2oc3cc(Cl)cn3c(=O)c2c1O
Reactant: C[N+](C)=CCl
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCc1c(O)cc2oc3cc(Cl)c(CN(C)C)n3c(=O)c2c1O
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To 60 mg (0.20 mmol) of 2-chloro-6,8-dihydroxy-7-propyl-9H-pyrrolo [2,1-b][1,3]benzoxazin-9-one in 20 mL of CH2Cl2 was added 157 mg (1.22 mmol) of chloromethylene dimethylammonium chloride and the reaction stirred for 1 hr. The mixture was concentrated, diluted with 50 mL of dry MeOH and 1.0 g (15.9 mmol) of sodium cyanoborohydride was added. After 24 hr the mixture was quenched with saturated NaHCO3 and the mixture extracted with ethylacetate which was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (Silica Gel EtOAc 100% to acetone 100%) to give 50 mg of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[CH2:7][C:8]([C:18]1([Cl:21])[CH2:20][CH2:19]1)([OH:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1>CN(C)C=O>[F:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:8]([C:18]2([Cl:21])[CH2:19][CH2:20]2)([OH:17])[CH2:7][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:15][CH:14]=1
Reactant: OC(CCl)(Cc1ccc(F)cc1)C1(Cl)CC1
Reactant: c1nc[nH]n1
Solvent: CN(C)C=O
Product: OC(Cc1ccc(F)cc1)(Cn1cncn1)C1(Cl)CC1
Temperature: 80 °C
Yield: 36.7 %

Procedure:
65 g (0.94 mol) of 1,2,4-triazole and 71 g (0.63 mol) of potassium tert.-butylate are taken in 160 ml of absolute dimethylformamide under a nitrogen atmosphere and are heated to 80° C. A solution of 70.6 g (0.26 mol) of 1-chloro-2-(1-chlorocyclopropyl)-3-(4-fluorophenyl)-propan-2-ol in 90 ml of absolute dimethylformamide is added dropwise at this temperature, with stirring. The mixture is subsequently stirred at 100° C. for 6 hours and is then concentrated by stripping off the diluent under reduced pressure. The residue is taken up in ethyl acetate, the mixture is washed with water and, after drying over sodium sulphate, the solvent is stripped off under reduced pressure. The product which remains is chromatographed over a silica gel column with chloroform as the mobile phase. 28.2 g (39% of theory) of 1-(4-fluorophenyl)-2-(1-chloro-cyclopropyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol are obtained in this manner in the form of a solid substance of melting point 111° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]3[C:14]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]3[C:14]([N:18]4[CH2:19][CH2:20][N:21]([CH2:25][C:26]5[CH:31]=[CH:30][C:29]([F:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=5)[CH2:22][CH2:23]4)=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=[N+]([O-])c1cc(CBr)ccc1F
Reactant: CCc1ccc(-c2nc3cccc(N4CCNCC4)c3[nH]2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccc(-c2nc3cccc(N4CCN(Cc5ccc(F)c([N+](=O)[O-])c5)CC4)c3[nH]2)cc1
Reaction time: 1 h
Yield: 33.8 %

Procedure:
2-(4-Ethyl-phenyl)-7-piperazin-1-yl-1H-benzoimidazole (200 mg, 0.65 mmol) and 4-bromomethyl-1-fluoro-2-nitro-benzene (152 mg, 0.65 mmol) were stirred together with DIEA (83 mg, 0.6.5 mmol) in DMF (4 ml) at room temperature. After 1 h, the reaction is complete and it was purified by HPLC Method E to yield the title product (100 mg (34%), 0.22 mmol). 1H NMR (DMSO-d6): δ=12.71 (s, 1H), 8.15 (m, 1H), 8.04 (d, J=8.2 Hz, 2H), 7.83 (m, 1H), 7.59 (m, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.08 (m, 2H), 6.52 (dd, J=6.64, 1.94 Hz, 1H), 3.69 (s, 2H), 3.65 (bs, 4H), 2.75 (bs, 6H), 1.32 (t, J=7.6 Hz, 3H). Calculated mass=457.43, [M+H]+=458.