Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.[CH3:30][O:31][CH2:32][CH2:33]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:30][O:31][CH2:32][CH2:33][O:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=2)[CH:7]=1
Reactant: O=c1c(O)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cn(-c2cccc(C(F)(F)F)c2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
A suspension of 5-hydroxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (100 mg, 0.25 mmol), 2-bromoethyl methyl ether (0.070 mL, 0.75 mmol), and K2CO3 (104 mg, 0.75 mmol) in DMF (1 mL) was stirred for 24 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (1/2) to give the title compound (89.9 mg, 79% yield) as a pale yellow amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 3.45 (3H, s), 3.78-3.81 (2H, m), 4.42-4.44 (2H, m), 7.02 (1H, dd, J=1.9, 7.9 Hz), 7.20 (1H, s), 7.34-7.45 (7H, m), 7.55 (1H, d, J=7.9 Hz), 7.80 (1H, d, J=1.9 Hz), 8.29 (1H, s). LC-MS (ESI) m/z 457 [M+H]+. Anal. Calcd for C23H19F3N4O3.0.25H2O: C, 59.93; H, 4.26; N, 12.16. Found: C, 59.87; H, 4.09; N, 12.15.
Reaction SMILES: [CH3:1][C:2]([CH3:45])([C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=1[OH:44])[CH2:3][N:4]1[C:9](=[O:10])[N:8]([CH2:11][C:12]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[OH:22])([CH3:14])[CH3:13])[C:7](=[O:23])[N:6]([CH2:24][C:25]([C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=2[OH:35])([CH3:27])[CH3:26])[C:5]1=[O:36].OS(O)(=O)=O>[N+](C1C=CC=CC=1)([O-])=O.C(OCC)(=O)C>[CH3:14][C:12]([CH3:13])([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([C:12]([CH3:14])([CH3:13])[CH3:11])[C:16]=1[OH:22])[CH2:11][N:8]1[C:7](=[O:23])[N:6]([CH2:24][C:25]([C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([C:2]([CH3:1])([CH3:3])[CH3:37])[C:29]=2[OH:35])([CH3:26])[CH3:27])[C:5](=[O:36])[N:4]([CH2:3][C:2]([C:37]2[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([C:19]([CH3:21])([CH3:20])[CH3:18])[C:38]=2[OH:44])([CH3:45])[CH3:1])[C:9]1=[O:10]
Reactant: Cc1ccc(O)c(C(C)(C)Cn2c(=O)n(CC(C)(C)c3cc(C)ccc3O)c(=O)n(CC(C)(C)c3cc(C)ccc3O)c2=O)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)Cn2c(=O)n(CC(C)(C)c3cc(C)cc(C(C)(C)C)c3O)c(=O)n(CC(C)(C)c3cc(C)cc(C(C)(C)C)c3O)c2=O)c1
Temperature: 90 °C
Yield: 102.1 %

Procedure:
To a 50 ml 3-neck round bottom flask is charged 2 g product of Example 2 in 10 ml nitrobenzene. 0.1 ml H2SO4 is added and isobutylene is bubbled through the solution while warming to 90° C. After TLC shows the reaction to be complete, the mixture is diluted with an equal volume of ethyl acetate and washed 2 times with 50 ml 5% sodium bicarbonate. The organic layer is dried and concentrated in vacuo. The residue is purified by dry column chromatography (Et2O/hexane) to yield 1.3 g of product, mp 215°-217° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][N:9]([CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:25][I:26]>ClCCCl>[I-:26].[CH3:1][N+:2]1([CH3:25])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][N:9]([CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1CCCCC1CN(c1ccccc1)C1Cc2ccccc2C1
Reactant: CI
Solvent: ClCCCl
Product: C[N+]1(C)CCCCC1CN(c1ccccc1)C1Cc2ccccc2C1
Product: [I-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 17 (0.1 g, 0.31 mmol) in DCE (5 mL) was added methyl iodide (0.058 mL, 0.94 mmol) and the resulting mixture was stirred at rt for 16 hours. The reaction mixture was concentrated under reduced pressure and the crude material was purified by crystallization from methanol-ether to provide 1,1-dimethyl-2-[((indan-2-yl)(phenyl)amino)methyl]piperidinium iodide.
Reaction SMILES: CC(S([NH:7][C@@H:8]([C:10]1[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=1)[CH3:9])=O)(C)C.Cl>CO>[F:18][C:16]([F:17])([F:19])[C:13]1[N:12]=[CH:11][C:10]([C@H:8]([NH2:7])[CH3:9])=[CH:15][CH:14]=1
Reactant: C[C@@H](NS(=O)C(C)(C)C)c1ccc(C(F)(F)F)nc1
Agent: Cl
Solvent: CO
Product: C[C@@H](N)c1ccc(C(F)(F)F)nc1
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a solution of 2-methyl-N-{(1R)-1-[6-(trifluoromethyl)-3-pyridinyl]ethyl}-2-propanesulfinamide (41.6 g, 141 mmol) in methyl alcohol (470 mL) at 0° C. was added hydrogen chloride (4.0 Min dioxane; 106 mL, 424 mmol). After 30 min, the mixture was concentrated to dryness. The residue was recrystallized using ethyl alcohol (15 mL) and ether (40 mL). The white solid was filtered and dried under reduced pressure to give the hydrochloride salt of the title compound (26.3 g). MS 191.2 (M+1). 1H NMR (500 MHz, CD3 OD): δ 8.83 (d, J=2.2 Hz, 1H); 8.17 (d, J=8.2 Hz, 1H); 7.93 (d, J=8.2 Hz, 1H); 4.69 (q, J=6.9 Hz, 1H); 1.70 (d, J=6.9 Hz, 3H).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[NH:5]1[C:9]([C:10]2[CH:11]=[C:12]([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[C:21]([C:31]([NH:33][CH3:34])=[O:32])[C:20]=4[CH:35]=3)[CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]=[N:6]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[O:23][C:19]3[CH:18]=[CH:17][C:16]([C:12]4[CH:13]=[CH:14][CH:15]=[C:10]([C:9]5[N:8]=[N:7][N:6]([CH:2]([CH3:4])[CH3:3])[N:5]=5)[CH:11]=4)=[CH:35][C:20]=3[C:21]=2[C:31]([NH:33][CH3:34])=[O:32])=[CH:25][CH:26]=1
Reactant: CC(C)I
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn(C(C)C)n4)c3)cc12
Reaction time: 8 h
Yield: 31 %

Procedure:
2-Iodopropane (29 mg, 0.169 mmol) was added to a stirring solution of 5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (35 mg, 0.085 mmol) and Na2CO3 (18 mg, 0.169 mmol) in DMF (1 mL) at 100° C. It was allowed to stir overnight. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (12 mg, 30%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.49-8.57 (1H, m), 8.34 (1H, s), 8.08 (1H, d, J=7.32 Hz), 7.99-8.05 (2H, m), 7.87-7.94 (2H, m), 7.79-7.83 (1H, m), 7.72-7.78 (1H, m), 7.70 (1H, t, J=7.78 Hz), 7.41 (2H, t, J=8.70 Hz), 5.17-5.27 (1H, m), 2.87 (3H, d, J=4.58 Hz), 1.66 (6H, d, J=6.71 Hz). LC-MS retention time: 2.02 min; m/z (MH+): 456. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=15.35 min, purity=96%; Column: Waters XBridge phenyl column 4.6×150 mm, 3.5 μm, Rt=13.39 min, purity=97%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+].CCCCCC>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>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: OB(O)c1cccs1
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: [K+]
Solvent: CCCCCC
Solvent: COCCOC
Product: O=[N+]([O-])c1ccccc1-c1cccs1
Temperature: 80 °C
Yield: 107.7 %

Procedure:
14.07 g (110 mmol) of 2-thiophene-boronic acid, 24.9 g (100 mmol) of 1-iodo-2-nitrobenzene, and 5.78 g (5 mmol) of tetrakis(triphenylphosphine)palladium(0) were dissolved in 250 ml of ethylene glycol dimethyl ether (DME), and 70 ml of 2M K2CO3 aqueous solution was added to the solution, and then the mixture was refluxed at 80° C. for 12 hours. After the reaction was completed, an organic layer was isolated and concentrated, and then isolated by column chromatography using hexane, thereby obtaining 22.1 g (yield: 98%) of 2-(2′-nitrophenyl)-thiophene (A′).
Reaction SMILES: [CH3:1][C:2](=[CH2:7])[CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[S:15](Cl)([CH3:18])(=[O:17])=[O:16].O>C(Cl)Cl>[CH3:18][S:15]([O:6][CH2:5][CH2:4][CH2:3][C:2]([CH3:1])=[CH2:7])(=[O:17])=[O:16]
Reactant: C=C(C)CCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C)CCCOS(C)(=O)=O

Procedure:
4-Methyl-4-penten-1-ol (10.0 g, 0.10 mmol) is placed in 100 ml dry methylene chloride and cooled, with stirring and under nitrogen, in an acetone/dry ice bath to 0°. Triethylamine (42 ml, 0.30 mmol) is added all at once, followed by mesyl chloride (12 ml, 0.16 mmol) over a 15 min period. The mixture is stirred at 0° for 2 hr and then water is added, followed by stirring for 5 min. The mixture is worked up by extraction with water and the layers are separated. The aqueous phase is extracted with methylene chloride (2×); the organic layers are combined and washed with sat. NaHCO3, 2 N HCl, water and brine, dried over MgSO4, filtered and evaporated (not to dryness), giving 4-methyl-4-pentenyl methanesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[C:19]([CH3:23])([CH3:22])[CH:20]=[O:21])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[BH4-].[Na+]>CO>[OH:21][CH2:20][C:19]([C:18]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])=[CH:4][C:3]=1[O:2][CH3:1])([CH3:22])[CH3:23]
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1C(C)(C)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)OCc2ccccc2)ccc1C(C)(C)CO
Reaction time: 1 h

Procedure:
Benzyl 3-methoxy-4-(2-methyl-1-oxopropan-2-yl)benzoate (crude, from step 2) was then treated with MeOH (2 mL) followed by NaBH4 (190 mg, 5.03 mmol). The reaction mixture was stirred for 1 h before it was quenched with brine and extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and evaporated to give benzyl 4-(1-hydroxy-2-methylpropan-2-yl)-3-methoxybenzoate.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[C:8]([CH3:11])[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[C:5]=1OC)([O-:3])=[O:2].[Cl-].[Cl-].[Ca+2].[CH2:20]([CH:22]([NH2:25])[CH2:23][CH3:24])[CH3:21]>>[CH2:20]([CH:22]([NH:25][C:5]1[C:6]([N+:12]([O-:14])=[O:13])=[CH:7][C:8]([CH3:11])=[C:9]([CH3:10])[C:4]=1[N+:1]([O-:3])=[O:2])[CH2:23][CH3:24])[CH3:21]
Reactant: CCC(N)CC
Reactant: COc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Reaction time: 24 h
Yield: 86.6 %

Procedure:
To a suitable reaction vessel equipment with a thermometer and mechanical stirrer was introduced 24 g 2,6-dinitro-3,4-dimethylanisole 94% (0.1 moles), 0.55 g CaCl2 (0.005 moles), and 43.5 g (0.5 moles) 1-ethyl propylamine. The reaction mixture was stirred at a temperature of 25°-30° C. The progress of the reaction was followed by periodically withdrawing samples and analyzing for starting product and the new product formed. During 24 hours the starting product disappeared and the N-(1-ethylpropyl)-3,4-dimethyl-2,6-dinitroaniline is gradually formed. After completion of the reaction as indicated by vapor phase chromatography, the excess of 1-ethyl-propylamine was recovered from the reaction mixture by distillation. The residue was dissolved in dichloromethane and the solution was successively washed with 5% aqueous hydrochloric acid, 5% aqueous sodium hydroxide and then by water to neutral and dried. The solvent is next recovered by distillation leaving an oily product which solidified. (25.2 g 96.6%) with a yield of 86.6%.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:19]([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)[CH2:20][N:21]2C(=O)C3C(=CC=CC=3)C2=O)=[C:5]([C:14](OCC)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].NN>C(O)C.C(Cl)Cl>[N:8]1([C:7]2[S:6][C:5]3[C:14](=[O:15])[NH:21][CH2:20][CH:19]([C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH:33]=4)[C:4]=3[C:3]=2[C:1]#[N:2])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1C(CN1C(=O)c2ccccc2C1=O)c1ccc2ccccc2c1
Agent: NN
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1c(N2CCOCC2)sc2c1C(c1ccc3ccccc3c1)CNC2=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 77.4 %

Procedure:
To a solution of ethyl 4-cyano-3-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(2-naphthyl)ethyl]-5-(morpholin-4-yl)thiophene-2-carboxylate (0.126 g, 0.223 mmol) in ethanol (4.0 mL) and methylene chloride (1.0 mL) was added hydrazine (23.3 mg, 0.727 mmol). After 40 h of stirring at rt, hydrazine (25 mg, 0.78 mmol) was added and the mixture was stirred at rt for another 22 h. The mixture was filtered and concentrated. Purification on a silica gel column (continuous gradient of MeOH/DCM 0-20%) to afford a white solid product (0.0672 g, yield 77.1%). LCMS: (FA) ES+ 390. 1H NMR (400 MHz, d-chloroform) δ: 7.86-7.71 (m, 3H), 7.59 (s, 1H), 7.50-7.42 (m, 2H), 7.37 (dd, J=8.5, 1.8 Hz, 1H), 5.79 (d, J=4.0 Hz, 1H), 4.32 (d, J=3.5 Hz, 1H), 4.19-4.07 (m, 1H), 3.85-3.74 (m, 4H), 3.62 (ddd, J=12.5, 4.5, 2.3 Hz, 1H), 3.59-3.51 (m, 4H).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH2:8]([C:11]1[C:12]([OH:22])=[N:13][C:14]2[C:19]([C:20]=1[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH2:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:5][O:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([OH:22])[C:11]=1[CH2:8][CH:9]=[CH2:10]
Reactant: COS(=O)(=O)OC
Reactant: C=CCc1c(O)nc2ccccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1c(O)nc2ccccc2c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dimethyl sulfate (0.237 ml) was added to a mixture of 3-(prop-2-en-1-yl)quinoline-2,4-diol (1.0 g) and potassium carbonate (1.37 g) in acetone (100 ml) and the mixture was stirred at room temperature for 3 hours then warmed to 40° C. for 30 minutes. The reaction mixture was cooled and the solids were removed by filtration. The filtrate was concentrated in vacuo. Purification by flash chromatography (ISCO, 4-10% acetone/DCM) gave the desired product (0.70 g). LRMS (ES+) M/Z (M+H)+ 216.0.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[C:29](=[O:30])[CH2:28][CH2:27][C@@:26]2([CH3:31])[C:13]=1[CH:14]=[CH:15][C@@H:16]1[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]1[CH2:18][CH2:19][C@@H:20]2[C:32]([NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>O1CCCC1.O>[CH:1]([NH:11][C:12]1[C:29](=[O:30])[CH2:28][CH2:27][C@@:26]2([CH3:31])[C:13]=1[CH:14]=[CH:15][C@@H:16]1[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]1[CH2:18][CH2:19][C@@H:20]2[C:32]([NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:2]
Reactant: O=CO
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3C=CC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3C=CC4=C(NC=O)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
A solution of formic acid (0.22 mL, 5.84 mmole) and acetic anhydride (0.46 mL, 4.76 mmole) was heated at reflux temperature for 2 hours under a nitrogen atmosphere. The cooled solution was diluted with tetrahydrofuran (5 mL) and a solution of 4-amino-N-(1,1-dimethylethyl)-3-oxoandrosta-4,6-diene-17β-carboxamide, (0.35 g, 0.91 mmole) in tetrahydrofuran (10 mL) was added. The reaction was stirred overnight at room temperature and then diluted with water (25 mL). A gummy material separated which was extracted into diethyl ether-dichloromethane and washed with saturated aqueous sodium bicarbonate. The dried solution was concentrated to a yellow foam which was purified by flash chromatography (hexane-50% ethyl acetate, ethyl acetate) to give 4-formamido-N-(1,1-dimethylethyl)-3-oxoandrosta-4,6-diene-17β-carboxamide (0.25 g, 67.6%, diethyl ether). IR 3440, 3304, 3246, 1684, 1670, 1650 cm-1 ; MS (CI) m/z 413 (100%, M+ +1); (EI) m/z 412 (18%, M+), 57 (100%); 1H NMR (CDCl3) δ 0.78 (3H, s, C18 -Me), 1.14 (3H, s, C19 -Me), 1.37 (s, 3× tBu-Me's), 5.11 (1H, s, NHCOBu), 6.15-6.45 (2H, m, C6 -H+C7 -H), 7.07-7.20 (1H, d+s, NHCO), 8.12+8.29 (1H, d+s, CHO).
Reaction SMILES: [CH:1](=[N:19][OH:20])[C:2]1[CH2:3][O:4][C:5]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][C:6]=2[CH:7]=1.O.N.O.[OH-].[Na+]>C(Cl)Cl.FC(F)(F)C(O)=O>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][C:9]2[CH:10]=[CH:11][C:5]3[O:4][CH2:3][C:2]([CH2:1][NH:19][OH:20])=[CH:7][C:6]=3[CH:8]=2)[CH:14]=1
Reactant: ON=CC1=Cc2cc(Cc3cccnc3)ccc2OC1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: ONCC1=Cc2cc(Cc3cccnc3)ccc2OC1
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
13.1 ml of borane-pyridine complex was added dropwise to a mixture of 3.46 g (13.0 mmol) of 3-formyl-6-(3-pyridylmethyl)-2H-1-benzopyran oxime in methylene chloride (16 ml) and trifluoroacetic acid (16 ml) at −23° C. over 10 minutes and the mixture was stirred at the same temperature for 30 minutes, followed by addition of concentrated ammonia water to neutralize the acid. Then, water and an aqueous 10% sodium hydroxide solution were added to make the mixture basic, followed by extraction with ethyl acetate. After the organic layer was washed with water and brine, the solvent was evaporated in vacuo. The residue was purified by Florisil (Trademark) column chromatography (chloroform: methanol=50:1-15:1) to obtain 3.03 g (yield=86.9%) of the desired compound as an oil.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.[Cl:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31]>>[Cl:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[S:30]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)(=[O:32])=[O:31]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=S(=O)(Cl)c1cnccc1Cl
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cnccc1Cl)CC2

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 180 step C) and 4-chloro-pyridine-3-sulfonyl chloride. Off-white solid. MS (ESI): 490.2 (MH+).
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([OH:6])=[O:5].[C:15]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Li+].[Li+]>C(O)CC>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:2]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[C:3]=2[C:4]([OH:6])=[O:5])=[CH:24][CH:25]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CCCO
Product: CC(C)(C)c1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1
Reaction time: 20 h

Procedure:
A mixture of 2,6-dichloro-3-nitrobenzoic acid (4.72 g, 0.02 mol), 4-tertbutylaniline (4.47 g, 0.03 mol), lithium carbonate (1.48 g, 0.02 mol), and 1-propanol (10 mL) was refluxed with stirring for 20 h. The solvent was evaporated and to the residue, water (30 mL) and benzene (50 mL) were added. The mixture was made strongly basic with sodium hydroxide and stirred for 1h. Orange precipitate was collected by filtration and washed with benzene and ether. Dry precipitate was dissolved in water and acidified with diluted hydrochloric acid. Resulting precipitate was collected and crystallized from acetone-water to give 4.55 (65%) of the desired product, mp 201°-204° C. Anal. (C31H27N7O6) C, H, N.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH2:20])[N:19]=[C:15]4[CH:14]=[CH:13][N:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>C(#N)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH:20][C:31]([CH:28]5[CH2:30][CH2:29]5)=[O:32])[N:19]=[C:15]4[CH:14]=[CH:13][N:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2ccnc(-c3ccc4c(c3)OCCO4)n2n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1nc2ccnc(-c3ccc4c(c3)OCCO4)n2n1)C1CC1
Temperature: 25 °C

Procedure:
To a solution of 5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-ylamine (0.04 g, 0.148 mmol) in dry acetonitrile (2 mL) was added triethylamine (0.052 mL, 0.371 mmol) followed by cyclopropanecarbonyl chloride (0.034 mL, 0.371 mmol). The reaction mixture was then allowed to warm to ambient temperature, and the solvent removed under reduced pressure. The crude product was purified by preparatory HPLC. 1H NMR (300 MHz, DMSO): 1.84-1.88 (m, 4H), 2.00-2.08 (m, 1H), 4.31-4.36 (m, 4H), 7.06 (d, 1H), 7.64 (d, 1H), 8.21 (dd, 1H), 8.35 (d, 1H), 8.39 (d, 1H), 11.37 (s, 1H). LCMS Method: 2: RT: 3.51 min, MI: 338 [M+1].
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:12]C(=O)C.C([O-])(O)=O.[Na+]>Cl.CCO>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:12]
Reactant: CC(=O)Nc1ccc2ccccc2c1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc2ccccc2c1F
Temperature: 25 °C

Procedure:
A mixture of 1.31 g (6.43 mmol) of 1-fluoro-2-acetylaminonaphthalene in 15 mL of 6 N HCl and 15 mL of EtOH under a nitrogen atmosphere is heated to reflux for 3 hours and then allowed to cool to room temperature. The reaction is neutralized with saturated aqueous NaHCO3 and extracted 3 times with 30 mL of CH2Cl2. The combined organic layers are washed 2 times with 20 mL saturated brine, dried over MgSO4 and the solvents evaporated to give 1-fluoro-2-aminonaphthalene.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:20][C:12]2=[N:13][C:14](O)=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:22].P(Cl)(Cl)(Cl)=O>>[CH2:1]([S:8][C:9]1[S:20][C:12]2=[N:13][C:14]([Cl:22])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1c(O)nc2sc(SCc3ccccc3)nn2c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(Cl)nc2sc(SCc3ccccc3)nn2c1=O
Reaction time: 1.5 h
Yield: 72 %

Procedure:
A mixture of 18.3 g of the thus obtained 2-benzylthio-7-hydroxy-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one, 13.1 g of phosphorus pentachloride and 36.8 g phosphorus oxychloride was stirred at 85°-95° C. for 1.5 hours. Thereafter, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in toluene. The organic layer was washed with an aqueous potassium carbonate solution and water respectively, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography using an ethyl acetate/toluene (3:7) mixture as an eluent. Then the solvent was distilled off, and thus 14.0 g of 2-benzylthio-7chloro-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained m.p. 102°-104° C. Yield 72%.