Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:10][CH:9]=1.[CH:42]([N:45]=[C:46]=[O:47])([CH3:44])[CH3:43]>>[CH3:43][CH:42]([NH:45][C:46]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:12][CH:13]=1)=[O:47])[CH3:44]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3N)cc2)C1=O)NC(=O)OC(C)(C)C
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)Nc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1

Procedure:
Prepared from N-[1-[[(2'-amino)[1,1'-biphenyl]-4-yl]-methyl]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-t-butoxycarbonylamino-3-methylbutanamide (Example 2, Step B) and isopropyl isocyanate by the procedure described in Example 2, Step C. 1H NMR (400 MHz, CDCl3): δ 1.06 (d, 3H) 1.07 (d, 3H), 1.32 (s, 3H), 1.39 (s, 9H), 1.88 (m, 1H), 2.48 (dd, 1H), 2.50 (m, 1H), 2.62 (m, 2H), 3.80 (m, 1H), 4.52 (m, 1H), 4.98 (d, 1H), 5.10 (d, 1H), 5.28 (br s, 1H), 6.08 (br s, 1H), 6.68 (br s, 1H), 7.22 (m, 11H), 7.70 (d, 1H).
Reaction SMILES: C(OC(N[C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][CH:13]=2)=O)(C)(C)C.N([O-])=O.[Na+].C(Cl)Cl.[BrH:28]>O>[Br:28][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][CH:13]=2
Reactant: COc1cccc2ncc(NC(=O)OC(C)(C)C)cc12
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cccc2ncc(Br)cc12
Reaction time: 1 h

Procedure:
To a solution of 3-(tert-butoxycarbonylamino)-5-methoxyquinoline (2.74 g, 10 mmol) in aqueous 48% HBr (40 mL), NaNO2 (2.1 g, 30 mmol) in water (20 mL) is added at 0° C. The reaction mixture is stirred 1 hour. The reaction mixture is extrated with CH2Cl2 (3×30 mL). After drying over MgSO4, dichloromethane is evaporated affording the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.Cl[CH:10]([CH3:12])[CH3:11]>>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:10]([CH3:12])[CH3:11])[CH:3]=1
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)Cl
Product: CC(C)Oc1cncc(Br)c1

Procedure:
Prepared according to the procedure described in Example 167, Step 1, using 5-bromo-pyridin-3-ol and 2-chloro-propane.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].O1CCCC1.[CH3:15][NH:16][CH3:17]>C1(C)C=CC=CC=1>[CH3:15][N:16]([CH3:17])[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6]
Reactant: CNC
Reactant: N#Cc1ccnc(Cl)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN(C)c1cc(C#N)ccn1
Temperature: 190 °C

Procedure:
A mixture of 10 g. (72 mmoles) of 2-chloroisonicotinonitrile, 30 ml. of tetrahydrofuran, 100 ml. of toluene and 20 ml. (0.3 mole) of dimethylamine was placed in a steel bomb and heated at 190° C. for 4 hours. The bomb was cooled and the mixture removed and filtered. The residue, remaining after the filtrate was concentrated, was dissolved in water, which was subsequently extracted with ether (3×40 ml.). The combined extracts were dried and concentrated to the crude product. Recrystallization from petroleum ether gave 7.4 g. (69%) of the pure product, m.p. 63°-66° C.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH:13]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:14]([F:17])([F:16])[F:15])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CS(C)=O.[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([NH2:39])(=[O:38])=[O:37])#[N:29].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([NH:39][C:2]1[C:11]([O:12][CH:13]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:14]([F:17])([F:16])[F:15])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)(=[O:38])=[O:37])#[N:29]
Reactant: FC(F)(F)C(Oc1nc2ccccc2nc1Cl)c1cccnc1
Reactant: N#Cc1ccccc1S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: N#Cc1ccccc1S(=O)(=O)Nc1nc2ccccc2nc1OC(c1cccnc1)C(F)(F)F
Temperature: 25 °C
Yield: 68.7 %

Procedure:
According to Example 132, by use of 2-chloro-3-[2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy]-quinoxaline (Compound BJ) (70 mg, 0.21 mmol), dimethyl sulfoxide (2 mL), 2-cyanobenzenesulfonamide (38 mg, 0.21 mmol) and potassium carbonate (28 mg, 0.21 mmol), the mixture was stirred and reacted at 150° C. for 1.5 hours. The reaction mixture was allowed to cool down to room temperature, a 1% aqueous acetic acid solution was added thereto, and extraction with ethyl acetate was performed. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was evaporated off under reduced pressure. The residue was subjected to slurry purification using methanol, to give 2-cyano-N-{3-[2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy]-quinoxalin-2-yl}benzenesulfonamide (Compound 145) (70 mg, 70%).
Reaction SMILES: Cl.Cl[C:3]1[N:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]2=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=3)[C:6]2[CH:19]=[CH:20][N:21](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]=2[N:4]=1.[NH2:32][C:33]1[C:34]([O:48][CH3:49])=[CH:35][C:36]([CH3:47])=[C:37]([N:39]([CH3:46])[C:40](=[O:45])[CH2:41][N:42]([CH3:44])[CH3:43])[CH:38]=1.[OH-].[NH4+:51]>FC(F)(F)CO.C1COCC1.C(OCC)(=O)C>[CH3:43][N:42]([CH3:44])[CH2:41][C:40]([N:39]([CH3:46])[C:37]1[C:36]([CH3:47])=[CH:35][C:34]([O:48][CH3:49])=[C:33]([NH:32][C:3]2[NH:4][C:5]3=[N:21][CH:20]=[CH:19][C:6]3=[C:7]([NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:18])[C:14]=3[C:15]([NH2:51])=[O:17])[N:16]=2)[CH:38]=1)=[O:45]
Reactant: COc1cc(C)c(N(C)C(=O)CN(C)C)cc1N
Reactant: [NH4+]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Cl)n2c(=O)c4c(F)cccc4nc32)cc1
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: OCC(F)(F)F
Product: COc1cc(C)c(N(C)C(=O)CN(C)C)cc1Nc1nc(Nc2cccc(F)c2C(N)=O)c2ccnc-2[nH]1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one HCl salt (0.5 g, 1.04 mmol) in 2,2,2-trifluoroethanol (10 mL) was added N1-[5-amino-2-methyl-4-(methyloxy)phenyl]-N1,N2,N2-trimethylglycinamide (0.275 g, 1.10 mmol). The resulting mixture was let stir at 50° C. for 90 min. Solvents were then removed under reduced pressure to afford a brown residue. Half of this material was then dissolved in THF (10 mL) and aqueous ammonium hydroxide (27%) (30 mL, excess) was added. After stirring at 30° C. for 24 h and rt for 18 h, the reaction was diluted with ethyl acetate and the organic layer was washed with water and a saturated brine solution and dried over sodium sulfate. Solvents were removed under reduced pressure and the residue purified by chromatography on SiO2. This material was dissolved in dioxane (6 mL) and 2N NaOH (4 mL) was added in a microwave safe vessel. The reaction was then heated in a microwave at 120° C. for 15 min. The reaction was diluted with EtOAc and the organic layer was washed with water and saturated brine solution and dried over sodium sulfate. Solvents were removed under reduced pressure and the residue purified by chromatography on SiO2 to afford 2-[(2-{[5-[(N,N-dimethylglycyl)(methyl)amino]-4-methyl-2-(methyloxy)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide (95 mg, 0.182 mmol) as a light green solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.10 (s, 6 H) 2.13 (s, 3 H) 2.62 (d, J=15.57 Hz, 1 H) 2.83 (d, J=15.57 Hz, 1 H) 3.04 (s, 3 H) 3.91 (s, 3 H) 6.29 (dd, J=3.20, 1.74 Hz, 1 H) 6.91-7.00 (m, 2H) 7.00-7.07 (m, 1 H) 7.45 (d, J=6.78 Hz, 1 H) 7.54 (s, 1 H) 7.96-8.11 (m, 2 H) 8.23-8.34 (m, 2H) 10.38 (s, 1 H) 11.47 (br. s., 1 H). ESIMS (M+H)+=521.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].[O:10]1[C:19]2[C:14](=[C:15]([NH2:20])[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:10]1[C:19]2[C:14](=[C:15]([NH:20][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(CBr)OCC
Reactant: Nc1cccc2c1CCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(CNc1cccc2c1CCCO2)OCC
Temperature: 100 °C

Procedure:
Bromoacetaldehyde diethyl acetal (11.8 ml) was added to a mixture of chroman-5-yl-amine (5.85 g) (prepared according to J. Heterocyclic Chem., (1973), Vol 10 (4) page 623), and potassium carbonate (10.84 g) in dry DMF (70 ml) at room temperature under N2. The mixture was heated at 100° C. for 60 h. The cooled mixture was partitioned between water (800 ml) and ether (3×200 ml). The combined organic extracts were washed with brine/water 1:1 (2×200 ml) and dried. The solvent was evaporated and the residue purified by flash column chromatography on silica. Elution with cyclohexane/ethyl acetate 6:1 gave the title compound as a pale yellow oil (8.0 g).
Reaction SMILES: [CH2:1]([N:17]=[C:18]=[S:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:20]=[C:21]([CH2:24][OH:25])[CH2:22][OH:23]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH2:1]([NH:17][C:18]([O:23][CH2:22][C:21](=[CH2:20])[CH2:24][OH:25])=[S:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=C(CO)CO
Reactant: CCCCCCCCCCCCCCCCN=C=S
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C=C(CO)COC(=S)NCCCCCCCCCCCCCCCC

Procedure:
Hexadecyl isothiocyanate (9.65 g) and 2-methylenepropane-1,3-diol) (3.0 g) were heated with pyridine (17 ml) and 4-dimethylaminopyridine (0.8 g) to 104° C. for 6.5 hours. The mixture was evaporated to dryness in vacuo and chromatographed on a Waters PrepLC®/System 500A using a PrepPAK®-500/SILICA cartridge with ether/chloroform/hexane 2:2:9 as eluent.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.[CH3:30][NH:31][C:32]([CH3:35])([CH3:34])[CH3:33]>ClCCl>[C:32]([N:31]([C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1)[CH3:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CNC(C)(C)C
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N(C)C(C)(C)C)nc2c1C#N
Yield: 92.9 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.20 g, 0.70 mmol) was dissolved in dichloromethane (10 ml), and diisopropylethylamine (0.15 ml, 0.88 mmol) and N-methyl-tert-butylamine (0.10 ml, 0.84 mmol) were added. After heating under reflux for 3 hours, N-methyl-tert-butylamine (50.0 μl, 0.42 mmol) was added, followed by heating under reflux for 2 hours. This was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane) to obtain a pale yellow solid (0.22 g, 0.65 mmol, 93%).
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[C:10]([CH3:13])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[O:14](S(C(F)(F)F)(=O)=O)[S:15]([C:18]([F:21])([F:20])[F:19])(=O)=[O:16]>ClCCl.N1C=CC=CC=1>[F:19][C:18]([F:21])([F:20])[S:15]([O:12][C:11]1[C:2]([Br:1])=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:13])[N:7]=[CH:6][CH:5]=[CH:4]2)(=[O:16])=[O:14]
Reactant: Cc1cc2ncccc2c(Br)c1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2ncccc2c(Br)c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
To the solution of 5-bromo-7-methylquinolin-6-ol (238 mg, 1.0 mmol) in dichloromethane (10 mL) and pyridine (2 mL) was added Tf2O (0.34 mL, 2.0 mmol) at −30° C. The mixture was stirred and warmed to 0° C. over a period of 2 hours. The reaction was quenched with slow addition of NaHCO3 solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give 5-bromo-7-methylquinolin-6-yl trifluoromethanesulfonate. LCMS-ESI+ (m/z): 369.9, 371.9 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[CH:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].[H][H]>C(O)(=O)C.[Pd]>[OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: [H][H]
Reactant: Cc1cc(C)c(C(O)CCCCCO)c(O)c1C
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cc(C)c(CCCCCCO)c(O)c1C

Procedure:
A solution of 1-(2'-hydroxy-3',4',6'-trimethylphenyl)-1,6-hexanediol (formula III-3 wherein R=H3C, X=H, Y=OH, n=4, in the free form) (5.43 parts) in acetic acid (150 volume parts) was stirred with 5% palladium on carbon (4.79 parts) under a stream of hydrogen gas at room temperature until the uptake of hydrogen ceased. The catalyst was filtered off and the filtrate was concentrated in vacuo. The resulting residue was subjected to column chromatography on silica gel and eluted with chloroform-methanol (100:1). From the 1st fraction, 6-(2'-hydroxy-3',4',6'-trimethylphenyl)hexanol (formula III-2, wherein R=H3C, X=H, Y=OH, n=4, in the free form) (0.872 part) was obtained as colorless needles melting at 81°-82° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[CH:27]=[N:28][CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:23][C:24]2[CH:25]=[C:26]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH:27]=[N:28][CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1
Product: COc1cc(-c2cncc(CN(c3ccc(Cl)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-chlorophenyl)amino]piperidine (621 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [C:1]([O:13]C)(=[O:12])[C:2]1[C:3](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:4]([O:6][CH3:7])=[O:5].[OH-].[Na+]>C(O)C>[CH3:7][O:6][C:4](=[O:5])[C:3]1[C:2](=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:1]([OH:13])=[O:12]
Reactant: COC(=O)c1ccccc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1ccccc1C(=O)O

Procedure:
Dimethyl phthalate (15.73 mmol) is stirred for 24 hours at ambient temperature in 60 ml of ethanol with 15.73 ml of 1N sodium hydroxide solution. The solvent is evaporated off under reduced pressure at 40° C. and the reaction mixture is then diluted with water before bringing the pH to 3. The mixture is extracted with ethyl acetate, dried (MgSO4) and evaporated to yield the title product in the form of an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]2[CH2:8][CH2:9][CH:10]3[C:15]([C:6]=2[CH:5]=1)=[N:14][N:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12](=[O:22])[CH2:11]3)([O-])=O.Cl>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]2[CH2:8][CH2:9][CH:10]3[C:15]([C:6]=2[CH:5]=1)=[N:14][N:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12](=[O:22])[CH2:11]3
Reactant: O=C1CC2CCc3ccc([N+](=O)[O-])cc3C2=NN1c1ccccc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)C1=NN(c3ccccc3)C(=O)CC1CC2
Temperature: 25 °C

Procedure:
To a mixture of 9-nitro-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one in ethanol and water is added iron powder with stirring at room temperature. The mixture is heated up to 50° C. on a water bath with stirring and concentrated hydrochloric acid is added dropwise carefully. The resulting mixture is further stirred with heating at 80° C. and the filtrate is concentrated. To the residue is added an aqueous sodium hydroxide solution, and the alkaline solution is extracted with chloroform. The extract is washed with water, dried over magnesium sulfate anhydride and the chloroform is distilled off to give 9-amino-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.
Reaction SMILES: C([O:5][C:6](=[O:45])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([N:28]([C:30](=[O:42])[CH2:31][CH:32]2[CH2:37][CH2:36][CH:35]([CH2:38][N:39]([CH3:41])[CH3:40])[CH2:34][CH2:33]2)[CH3:29])[B:15]2[O:23]C3C(C)(C4CC(C3)C4(C)C)[O:16]2)[C:8]=1OC)(C)(C)C.B(Cl)(Cl)Cl>>[CH3:40][N:39]([CH2:38][C@H:35]1[CH2:36][CH2:37][C@H:32]([CH2:31][C:30]([N:28]([C@H:14]2[CH2:13][C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:6]([OH:5])=[O:45])[C:8]=3[O:16][B:15]2[OH:23])[CH3:29])=[O:42])[CH2:33][CH2:34]1)[CH3:41]
Reactant: COc1c(CC(B2OC3CC4CC(C4(C)C)C3(C)O2)N(C)C(=O)CC2CCC(CN(C)C)CC2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: CN(C)C[C@H]1CC[C@H](CC(=O)N(C)[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1

Procedure:
Prepared from 3-[2-{[2-(4-Dimethylaminomethyl-cyclohexyl)-acetyl]-methyl-amino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester and BCl3 following the procedure described in step 2 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 403 (MH)+.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[F:34]C(F)(F)S([O-])(=O)=O.ClC1C=CC=C(Cl)[N+]=1F>ClCCl.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=4)=[C:23]([F:34])[CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(O)c1cnc(-c2[nH]c(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)cc2F)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazol-5-yl]ethanol (420 mg) in dichloromethane (5 mL) was added 2,6-dichloro-1-fluoropyridinium trifluoromethanesulfonate (410 mg), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give a mixture of the title compound and a positional isomer thereof (35.0 mg). The mixture of the obtained positional isomers was dissolved in hexane-ethanol (850:150, volume ratio, 114 mL), and the solution was subjected to HPLC using TSK GEL SHILICA-60 (20 mm ID×250 mL, manufactured by Tosoh Corporation silica). Using hexane-ethanol (850:150, volume ratio) as a mobile phase, the solution was eluted at flow rate 20 mL/min and at room temperature, and the fraction was separated at retention time 39.0 min, and concentrated. The obtained solid was dissolved in ethyl acetate and the insoluble material was filtered off. The filtration was concentrated to give the title compound (26.8 mg, yield 4%) as a colorless amorphous solid. MS: 505 (MH+).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:50])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:49])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:48])[NH:31][C@@H:32]4[CH2:35][C@H:34]([C:36]([N:38]5[CH2:43][CH2:42][N:41]([CH2:44][CH3:45])[CH2:40][CH2:39]5)=[O:37])[C:33]4([CH3:47])[CH3:46])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:52])[CH3:51])(=O)C.[OH-].[Na+]>CO.C1COCC1>[CH2:44]([N:41]1[CH2:42][CH2:43][N:38]([C:36]([C@H:34]2[CH2:35][C@@H:32]([NH:31][C:30]([C@:14]34[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]3[C@@H:16]3[C@@:11]([CH3:49])([CH2:12][CH2:13]4)[C@@:10]4([CH3:50])[C@@H:19]([C@:20]5([CH3:23])[C@@H:7]([CH2:8][CH2:9]4)[C:6]([CH3:51])([CH3:52])[C@@H:5]([OH:4])[CH2:22][CH2:21]5)[CH2:18][CH2:17]3)=[O:48])[C:33]2([CH3:46])[CH3:47])=[O:37])[CH2:39][CH2:40]1)[CH3:45]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCN(CC)CC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCN(CC)CC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3S)-3-(4-ethylpiperazine-1-carbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 69, 550 mg) in MeOH:THF (2:1) at 0° C. temperature 2N NaOH (4 mL) was added and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatiles was evaporated, the aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine and dried with Na2SO4. The solvent was evaporated and the resulting crude was stirred in hexane to get crude solid. The solid crude was purified over silica-gel column chromatography to afford the title compound. Wt: 200 mg, Yield: 93.3%. 1H NMR (300 MHz, CDCl3): δ 5.86 (d, 1H, J=8.1 Hz), 4.72 (s, 1H), 4.57 (s, 1H), 4.18-4.06 (m, 1H), 3.78-3.68 (m, 1H), 3.52-3.30 (m, 3H), 3.23-3.08 (m, 2H), 2.92-2.86 (m, 1H), 2.52-2.20 (m, 3H), 2.01-1.88 (m, 2H), 1.80-1.12 (m, 33H), 0.96, 0.93, 0.87, 0.81, 0.74 (s, 18H); Mass: [M+1]+ 649 (5%), [M+Na]+ 671 (100%); IR (KBr, cm−1): 3353, 2937, 2858, 1635, 1618, 1533, 1459, 1390, 1262, 1250, 1148, 1048, 1033, 1020, 983, 883; M.R: 177° C.-188.7° C.; HPLC: 95.72%.
Reaction SMILES: C(O[C:4]([NH:6][C:7]1[N:17]=[CH:16][CH:15]=[CH:14][C:8]=1[C:9]([O:11]CC)=O)=[O:5])C.NC1N=CC=CC=1C(OCC)=O.ClC(OCC)=O.C(N(CC)C(C)C)(C)C.[NH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][CH:51]([C:54](=[O:62])[C:55]2[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=2)[CH2:50][CH2:49]1>C1(C)C=CC=CC=1.CO>[F:61][C:58]1[CH:57]=[CH:56][C:55]([C:54]([CH:51]2[CH2:50][CH2:49][N:48]([CH2:47][CH2:46][N:45]3[C:9](=[O:11])[C:8]4[CH:14]=[CH:15][CH:16]=[N:17][C:7]=4[NH:6][C:4]3=[O:5])[CH2:53][CH2:52]2)=[O:62])=[CH:60][CH:59]=1
Reactant: NCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CCOC(=O)Nc1ncccc1C(=O)OCC
Agent: CCOC(=O)Cl
Agent: CCOC(=O)c1cccnc1N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3ncccc3c2=O)CC1

Procedure:
A mixture of 2.06 g of ethyl 2-ethoxycarbonylaminonicotinate (m.p. 60°, obtainable by boiling ethyl 2-aminonicotinate with ethyl chloroformate for 5 h in the presence of N,N-diisopropylethylamine in toluene) and 2.54 g of 1-(2-aminoethyl)-4-p-fluorobenzoylpiperidine (Rf 0.43 on silica gel with butanol/ethanol/water/ethyl acetate/acetic acid 50:50:50:25:25) is heated at 190° for 1 h. The mixture is cooled and taken up in methanol and, on cooling, 3-[2-(4-p-fluorobenzoylpiperidino)ethyl]-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine is obtained, m.p. 237°. Hydrochloride m.p. 297°-298°. Fumarate m.p. 253°-255°.