Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1([CH3:21])[C:19](=[O:20])[N:7]2[C:8](=[O:18])[C:9]3[CH:10]=[C:11]4[CH:17]=[CH:16][O:15][C:12]4=[N:13][C:14]=3[C:6]2=[N:5]1)([CH3:3])[CH3:2].C[O-].[Na+].[C:25](O)(=[O:27])C>CO>[CH:1]([C:4]1([CH3:21])[C:19](=[O:20])[NH:7][C:6]([C:14]2[N:13]=[C:12]3[O:15][CH:16]=[CH:17][C:11]3=[CH:10][C:9]=2[C:8]([O:27][CH3:25])=[O:18])=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)C1(C)N=C2c3nc4occc4cc3C(=O)N2C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2ccoc2nc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84 %

Procedure:
The compound prepared in Example 40 (10.5 g, 0.037 mol) is suspended in 150 mL absolute methanol and 4.0 g sodium methoxide is added. After stirring for 72 hours at room temperature the mixture is poured onto ice containing acetic acid to maintain the pH at 3-4. A white solid forms and is filtered yielding 9.8 g (84%) of the title compound with mp 134°-137° C.
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]2[NH:7][C:8]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1.B(Br)(Br)Br.O.[K+].[Br-]>CN(C)C=O>[OH:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]3[CH:15]=[CH:14][C:13](=[O:16])[CH:12]=[C:9]3[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCc1cc(OC)ccc1N2
Agent: BrB(Br)Br
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C=CC2=Nc3ccc(O)cc3CCC2=C1
Temperature: 0 °C
Reaction time: 3.75 h

Procedure:
A solution of 2,8-dimethoxy-10,11-dihydro-5H-dibenz[b,f]azepine (7) (1.0 g; 3.9 mmol) in CH2Cl2 (23.5 mL; dried over molecular sieve 4A), maintained under a CaSO4 drying tube, was cooled to 0° C. and treated with BBr3 (1.85 mL; 19.6 mmol; 5 eq). After 5 minutes the reaction was warmed and allowed to stir at ambient temperature for 3.75 hours. The mixture was carefully blended into H2O (350 mL) and this was then extracted four times with EtOAc (100 mL each). The combined EtOAc layers were washed with brine (50 mL) then transferred to a 3-neck round bottom flask equipped with a mechanical stirrer and rapidly stirred for 15 minutes with a solution of NaIO4 (3.0 g) in H2O (200 mL). The phases were separated and the aqueous layer was washed with EtOAc (25 mL). The combined EtOAc layers were washed four times with H2O (100 mL each) then the combined H2O washes were backwashed with EtOAc (50 mL). The combined EtOAc layers were then washed with brine (100 mL), dried over Na2SO4 and evaporated to dryness under reduced pressure. The residue was taken up in hot EtOAc (ca. 150 mL), concentrated by boiling to ca. 50 mL and diluted with hexane (20 mL). Upon cooling the title compound (2) separated as a red powder that was isolated by filtration and vacuum dried overnight at 60° C. The yield after two crops was 0.80 g (90%); the first crop was analytically pure and decomposed at temperatures above 200° C., the exact decomposition point dependant upon the rate of heating: IR (KBr) cm-1 1630, 1612, 1556, 1480, 1463, 1295, 1222, 1207, 1107, 888, 827; 1H NMR (DMSO-d° ) δ2.77 (br. s, 4H), 6.2-6.9 (v. br. m, 4H), 7.1-7.5 (v. br. m, 2H), 10.43 (br. s, lH); 13C NMR (DMSO-d6) ppm 186.9, 160.6, 160.4, 151.5, 146.4, 144.9, 138.4, 137.6, 129.4, 128.2, 116.0, 114.9, 33.1, 31.2; mass spectrum, m/e 225 (base), 196. 167; λmax =478 nm (19,760) (pH=4.5; 0.1 M acetate) λmax=602 nm (65,000) (pH=10.61; 0.1 M glycine), pKa =6.95.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[C:21]1([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccccc3)cn2)CC1
Yield: 80.7 %

Procedure:
A mixed solution of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (1.00 g, 2.92 mmol), phenylboronic acid (535 mg, 4.38 mmol), ethanol (2.5 ml), 2N aqueous solution of sodium carbonate (12 ml), tetrakis(triphenylphosphine)palladium (404 mg, 0.350 mmol) and toluene (23 ml) was stirred at 95° C. for 12 hours under a nitrogen atmosphere, and the solvent was distilled away under reduce pressure. The residue was poured into water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the titled compound 800 mg (80.7%) as solid product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([Br:15])[CH:12]=[C:11]([C:16]([NH2:18])=[O:17])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[Cl:19][CH2:20][CH2:21][O:22][CH2:23][C:24](Cl)=[O:25]>C1(C)C=CC=CC=1>[Br:15][C:13]1[CH:12]=[C:11]([C:16]([NH2:18])=[O:17])[C:7]2[NH:8][C:9]3[CH:10]=[C:2]([NH:1][C:24](=[O:25])[CH2:23][O:22][CH2:21][CH2:20][Cl:19])[CH:3]=[CH:4][C:5]=3[C:6]=2[N:14]=1
Reactant: O=C(Cl)COCCCl
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1cc(N)ccc12
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(Br)nc2c1[nH]c1cc(NC(=O)COCCCl)ccc12
Temperature: 100 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
A mixture of 7-amino-2-bromo-5H-pyrido[3,2-b]indole-4-carboxamide (200 mg, 0.655 mmol) and 2-(2-chloroethoxy)acetyl chloride (113 mg, 0.721 mmol) in toluene (1.5 mL) was stirred at 100° C. for 12 hr. The solvent was removed and preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA, 10-60% B at 42 mL/min over 20 min) followed by SCX capture and release with 2 N NH3 in MeOH left 2-bromo-7-(2-(2-chloroethoxy)acetamido)-5H-pyrido[3,2-b]indole-4-carboxamide (80 mg, 0.19 mmol, 29% yield) as a yellow solid. MS (ESI) m/z 426.97 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.73 (1H, s), 9.99 (1H, s), 8.44 (1H, br. s.), 8.24 (1H, s),8.09 (1H, d, J=8.55 Hz), 7.98 (1H, s), 7.91 (1H, br. s.), 7.49 (1H, d, J=9.46 Hz), 4.21 (2H, s), 3.86 (4H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][C@H:17]2[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][C@H:17]2[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]2)[C:13]([Cl:27])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC(F)(F)C2)C(=O)O)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC(F)(F)C2)C(=O)Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-propionic acid (240 mg, 0.65 mmol) was dissolved in methylene chloride (10 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 376 μL, 0.75 mmol) which produced gas evolution and was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for 1 h. After this time, the reaction was concentrated in vacuo to about 2 mL and then another portion of methylene chloride (˜2 mL) was added to produce a roughly 0.16 M solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-propionyl chloride which was used.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>C(O)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([NH:7][C:8](=[O:10])[CH3:9])[S:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(Br)cs1
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(Br)cs1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A solution of 4-bromothiazol-2-amine (0.500 g, 2.81 mmol), acetic anhydride (0.43 mL, 4.50 mmol) and acetic acid (5 mL) was refluxed for 2 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 25% ethyl acetate-petroleum ether) to afford N-(4-bromothiazol-2-yl)acetamide (0.300 g, 49%) as a white solid. MS (ESI, pos. ion) m/z 221, 223 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(#N)C>[Br:16][C:8]1[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:10][C:9]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cn2c(C)cccc2n1
Solvent: CC#N
Product: CCOC(=O)c1nc2cccc(C)n2c1Br
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
A solution of ethyl 5-methylimidazo[1,2-a]pyridine-2-carboxylate (5.0 g, 25 mmol) in acetonitrile (94 mL) was treated with N-bromosuccinimide (4.8 g, 27 mmol) in acetonitrile (47 mL) dropwise and stirred at 20° C. for 30 min. The reaction mixture was concentrated, diluted with dichloromethane (200 mL), and washed with saturated sodium bicarbonate (150 mL) and brine (50 mL). The organic layer was dried with sodium sulfate, filtered, and concentrated to a crude solid. Purification by flash column chromatography gave the desired product (4.0 g, 58%). LCMS for C11H12BrN2O2 (M+H)+: m/z=282.9, 284.9.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.[CH3:26][C:27]12[O:34][C:31]([CH3:35])([CH2:32][CH2:33]1)[CH2:30][C:29](=[O:36])[CH2:28]2>>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([C:29]3([OH:36])[CH2:28][C:27]4([CH3:26])[O:34][C:31]([CH3:35])([CH2:32][CH2:33]4)[CH2:30]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: CC12CCC(C)(CC(=O)C1)O2
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Product: CC1(C)CC=C(c2cc(C3(O)CC4(C)CCC(C)(C3)O4)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g)) and 1,5-dimethyl-8-oxa-bicyclo[3.2.1]octan-3-one (J. Org. Chem., 64(10), 3398-3408 (1999)). 1H-NMR (DMSO-d6; 400 MHz): d 14.25 (bs, 1H), 9.72 (s, 1H), 8.29 (s, 1H), 7.90 (d, 1H, J=8.3 Hz), 7.33 (dd, 1H, J=2.3, 8.6 Hz), 7.27 (m, 1H), 5.65 (m, 1H), 4.88 (s, 1H), 2.42-2.37 (m, 2H), 2.26-2.22 (m, 2H), 1.95 (m, 2H), 1.81-1.71 (m, 4H), 1.53-1.47 (m, 4H), 1.23 (s, 6H), 1.00 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C28H34N4O3, 475.2 (M+1). found 475.1.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:11].[C:12]([CH:15]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:16]([O:18][CH3:19])=[O:17])(=O)[CH3:13]>>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:11][C:12](=[C:15]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:16]([O:18][CH3:19])=[O:17])[CH3:13]
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Reactant: Nc1ccc2c(c1)CCCC2
Product: COC(=O)CC(C(=O)OC)=C(C)Nc1ccc2c(c1)CCCC2
Reaction time: 72 h
Yield: 65.6 %

Procedure:
The 5,6,7,8-tetrahydronaphthalen-2-amine (10 g; 68 mmol) and dimethyl acetylsuccinate (11.6 g; 62 mmol) were mixed together, placed in a dessicator and the homogeneous mixture was stirred under vacuum (3 mbars) for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (1 to 20%) in heptane furnished 12.9 g (60%) of dimethyl 2-(1-(5,6,7,8-tetrahydronaphthalen-2-ylamino)ethylidene)succinate as a deep orange oil.
Reaction SMILES: Cl.C([NH:5][C:6]([CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([NH2:28])=[C:20]([Cl:29])[CH:19]=1)(C(OCC)=O)[C:7]([O:9]CC)=[O:8])(=O)C>CC(O)=O.O>[ClH:29].[NH2:5][CH:6]([CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:26])([F:27])[F:25])[C:21]([NH2:28])=[C:20]([Cl:29])[CH:19]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)(NC(C)=O)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(Cl)cc(CC(N)C(=O)O)cc1C(F)(F)F
Temperature: 140 °C
Reaction time: 0.25 h

Procedure:
50 mL conc. HCl were added to a solution of 40.0 g (94.16 mmol) of diethyl 2-acetylamino-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-malonate in 110 mL AcOH and 150 mL of water and the reaction mixture was heated to 140° C. for 4 h. The precipitate formed was filtered off and discarded. The filtrate was evaporated down i. vac., combined with 100 mL of EtOH and stirred for 15 min at RT. The precipitate formed was filtered off, washed with EtOH and dried i. vac. The crude product was used in the next reaction step without any further purification.
Reaction SMILES: C1([N:7]2[CH2:12][CH2:11][C:10]3([C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][O:13]3)[CH2:9][CH2:8]2)C=CC=CC=1.Cl>[Pd].C(O)C>[C:15]1([CH:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]3([CH2:9][CH2:8][NH:7][CH2:12][CH2:11]3)[O:13]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(N2CCC3(CC2)OCc2ccccc23)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(C2OC3(CCNCC3)c3ccccc32)cc1

Procedure:
A mixture of 2.9 G. of 1'-benzyl-1,3-dihydro-3-phenylspiro[phenylspiro[isobenzofuran-1,4'-piperidine], (Example 4), 0.4 g. of 10% palladium on carbon, 20 ml. of 95% ethanol, and 2 ml. of conc. hydrochloric acid is hydrogenated at 50 p.s.i. and 50°. After hydrogen uptake ceases, the mixture is filtered and the filtrate concentrated. Recrystallization of the residue from cyclohexane provides colorless crystals, m.p. 119°-123°.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]4[CH2:33][C:32](=[O:34])[C:29]5([CH2:31][CH2:30]5)[CH2:28]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:35])[NH:6]2.[H-].[Na+].S(OC)([C:41]1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]4[CH2:33][CH:32]([O:34][CH3:41])[C:29]5([CH2:31][CH2:30]5)[CH2:28]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:35])[NH:6]2
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCCN1CC(=O)C2(CC2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCCN1CC(OC)C2(CC2)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The above product from Example 2 (60 mg) was dissolved into DMF (4 ml) and cooled at 0° C. NaH (1.1 eq) was added to the reaction and stirred for 10 minutes. To the reaction was added TsOMe (1.2 eq), the solution was heated at 80° C. for two hours. The reaction was quenched with water and extracted with EtOAc followed by washing with water, then brine and dried over Na2SO4. The solution was evaporated and purified by silica column to give the titled product. Mass: (M+1), 492
Reaction SMILES: [NH:1]([C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:5]=2[N:4]=1)[NH2:2].[C:24]([O-])([O-])(OCC)[CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:24][C:25]1[N:4]2[C:5]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:6]=3[C:7]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[N:8][CH2:9][C:3]2=[N:1][N:2]=1
Reactant: NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1
Reactant: CCOC(C)([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1)=NC2

Procedure:
To a mixture of 9,5 parts of 2-hydrazino-5-phenyl-7-trifluoromethyl-3-H-1,4-benzodiazepine prepared in Example 4, 29 parts of ethyl orthoacetate and 150 parts by volume of chloroform, is added dropwise 23 parts of p-toluenesulfonic acid with stirring under ice-cooling below 10° C and then the mixture is stirred at room temperature for 7 hours. After completion of the reaction, the reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate and the chloroform layer is separated, washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue is treated with a mixture of benzene and isopropyl ether, whereby 1-methyl-6-phenyl-8-trifluoromethyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine is yielded as crystals containing benzene of crystallization. Recrystallization from a mixture of benzene and n-hexane yields colorless needless melting at 129° C to 130° C (sintering), 133° C to 134° C (effervescence).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O>CC(O)=O>[Cl:1][CH2:2][C:3]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=2[N:5]=1
Reactant: O=C(CCl)Nc1ccc(F)cc1Nc1ccccc1
Solvent: CC(=O)O
Product: Fc1ccc2nc(CCl)n(-c3ccccc3)c2c1
Temperature: 70 °C

Procedure:
2-Chloro-N-(4-fluoro-2-phenylaminophenyl)acetamide (740 mg, 2.62 mmol) was dissolved in AcOH (20 mL) and the mixture heated at 70° C. under a nitrogen atmosphere for 5 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with DCM (×3). The combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford the title compound as a brown oil which crystallised on standing (570 mg, 84%). LCMS (Method C): RT 3.40 min [M+H]+ 261.2. 1H NMR (CDCl3, 400 MHz): δ 7.75 (1H, dd, J=8.87, 4.76 Hz), 7.66-7.54 (3H, m), 7.47 (2H, d, J=7.38 Hz), 7.07 (1H, td, J=9.21, 2.41 Hz), 6.84 (1H, dd, J=8.54, 2.41 Hz), 4.66 (2H, s). 1
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Br[CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27].C(=O)([O-])O.[Na+]>CN(C)C=O>[F:27][C:26]([F:29])([F:28])[CH2:25][CH2:24][N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CCC(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperazine (5.00 g) and N,N-diisopropylethylamine (4.68 ml) in N,N-dimethylformamide (13 ml) was added 1-bromo-3,3,3-trifluoropropane (5.00 ml) at 60° C. The mixture was stirred at 60° C. for 4 hours. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with hexane. The organic layer was washed successively with saturated aqueous ammonium chloride solution, aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated to give the title compound (5.38 g) as a pale yellow solid.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][C:14](=O)[C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[C:17](=O)[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>C(O)C>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3C(=O)C[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: NN
Solvent: CCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 90 °C
Yield: 73.6 %

Procedure:
To 3β-benzoyloxy-5α-cholest-8(14)-ene-7,15-dione 10 (180 mg, 0.35 mmol) dissolved in ethanol (14 mL) was added anhydrous hydrazine (12 μl, 0.38 mmol) and the mixture was heated to 90° C. for 0.75 h. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on 4 g of silica gel 60 using EtOAc/CHCl3 (4:6) yielding 127 mg (71%) of pyridazine 12, which crystallized from CH2Cl2 /EtOAc, mp 215°-216° C. 1H NMR: δ8.06 (d, 2H, J=8.2 Hz), 7.57 (dd, 1H, J=7.4, 7.4 Hz), 7.45 (dd, 2H, J=7.5, 7.8 Hz), 5.09 (m, 1H), 3.18 (dd, 1H, J=5.5, 17.9 Hz), 3.11 (dd, 1H, J=6.9, 16.3 Hz), 2.96 (dd, 1H, J=10.8, 16.3 Hz), 2.64 (dd, 1H, J=12.6, 17.9 Hz), 2.34 (dd, 1H, J=5.7, 10.9 Hz), 2.25 (ddd, 1H, J=2.9, 3.5, 13.1 Hz), 2.05-2.14 (m, 2H), 1.07 (s, 3H), 1.00 (d, 3H, J=6.3 Hz), 0.89 (d, 6H, J=6.6 Hz), 0.87 (s, 3H). IR (Nujol): 1715, 1602, 1318, 1276, 1116 cm-1. Anal. (C34H46N2O2): C, H.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH3:17][C:18]1[S:22][C:21]([CH2:23][C:24](O)=[O:25])=[CH:20][CH:19]=1>>[CH3:17][C:18]1[S:22][C:21]([CH2:23][C:24]([NH:1][N:2]2[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:16])=[O:25])=[CH:20][CH:19]=1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: Cc1ccc(CC(=O)O)s1
Product: Cc1ccc(CC(=O)Nn2nc(C(F)(F)F)c3ccccc3c2=O)s1

Procedure:
The product of Example 11B and 2-(5-methylthiophen-2-yl)acetic acid were treated using a method similar to that described in Example 5 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.85-11.96 (m, 1H), 8.43 (d, J=6.9 Hz, 1H), 8.10-8.17 (m, 1H), 8.01-8.08 (m, 2H), 6.81 (d, J=3.4 Hz, 1H), 6.66-6.68 (m, 1H), 3.84-3.85 (bs, 2H), 2.41 (d, J=0.8 Hz, 3H); MS (ESI+) M/Z 368 (M+H)+, 385 (M+NH4)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:11]([O:19][CH3:20])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:18][S:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=1[O:19][CH3:20])(=[O:16])=[O:17]
Reactant: COc1cc(OCc2ccccc2)ccc1S(C)(=O)=O
Agent: [Pd]
Solvent: CO
Product: COc1cc(O)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
Dissolve 4-benzyloxy-1-methanesulfonyl-2-methoxy-benzene (5.57 g, 19.09 mmol) in MeOH (200 mL), under N2, and add 5% Pd—C (900 mg). Evacuate the reaction vessel and flush with hydrogen gas (3 times). Stir the reaction mixture at room temperature for 3 hours, under 1 atmosphere of hydrogen gas. Filter, concentrate, and purify the reaction mixture by flash column chromatography (silica gel, 30-60% of EtOAc/hexane) to give 3.24 g of 4-methanesulfonyl-3-methoxy-phenol (100%).