Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17](O)=[O:18])=[N:9]2)[CH:3]=1.[NH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:23][CH2:22][C:21]([NH:20][C:17]([C:10]1[C:11]2[CH2:12][C@H:13]3[CH2:16][C@H:14]3[C:15]=2[N:8]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][N:5]=2)[N:9]=1)=[O:18])([CH3:25])[CH3:24]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1nn(-c2cc(F)ccn2)c2c1C[C@H]1C[C@@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(CO)NC(=O)c1nn(-c2cc(F)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 23 °C
Reaction time: 0.33 h
Yield: 92.4 %

Procedure:
To a solution of (1aR,5aR)-2-(4-fluoro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (68 mg, 0.262 mmol), 2-amino-2-methylpropan-1-ol (23.38 mg, 0.262 mmol), and triethylamine (0.073 mL, 0.525 mmol) in DMF (1 mL) was added HATU (105 mg, 0.275 mmol). The reaction was stirred at 23° C. for 20 min then concentrated. The residue was purified by silica gel column chromatography to give the title compound (80 mg) as a white solid. LCMS m/z=331.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.46 (td, J=4.6, 3.4 Hz, 1H), 1.26 (td, J=7.8, 4.9 Hz, 1H), 1.41 (s, 3H), 1.42 (s, 3H), 2.24-2.30 (m, 1H), 2.79-2.84 (m, 1H), 2.91 (d, J=16.8 Hz, 1H), 3.00 (dd, J=16.6, 6.3 Hz, 1H), 3.70 (d, J=6.4 Hz, 2H), 4.69 (t, J=6.3 Hz, 1H), 6.93-6.98 (m, 2H), 7.63 (dd, J=10.1, 2.4 Hz, 1H), 8.43 (dd, J=8.5, 5.7 Hz, 1H).
Reaction SMILES: [CH:1]([C:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:5])[CH3:4])=[O:2].[CH3:17][Mg]Br.[Cl-].[NH4+]>C1COCC1>[OH:2][CH:1]([CH3:17])[C:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:5])[CH3:4]
Reactant: CC(C)(C=O)NC(=O)c1ccc(F)cc1F
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)C(C)(C)NC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of N-(1-formyl-1-methylethyl)-2,4-difluorobenzamide obtained in Example 32 (1.14 g, 5 mmol) in THF (10 ml) was added 0.9 M methyl magnesium bromide in THF (13 ml, 12 mmol) dropwise at −20° C. The reaction mixture was warmed gradually to room temperature over 2 hours and added to 10% aqueous ammonium chloride (100 ml). The resulting mixture was extracted with ethyl acetate, washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, concentrated under a reduced pressure and the residue was crystallized from hexane/ethyl acetate to give the title compound (1.05 g; 86%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([F:18])([F:17])[F:16])=[N:12]2)=[C:7]([CH3:19])[C:6]=1[N+:20]([O-:22])=[O:21])=[O:4].O.[OH-].[Li+].C(OCC)(=O)C.Cl>CO.O>[CH3:19][C:7]1[C:6]([N+:20]([O-:22])=[O:21])=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([C:15]([F:17])([F:16])[F:18])=[N:12]2
Reactant: COC(=O)c1cc2nc(C(F)(F)F)ccc2c(C)c1[N+](=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c([N+](=O)[O-])c(C(=O)O)cc2nc(C(F)(F)F)ccc12

Procedure:
5-Methyl-6-nitro-2-trifluoromethyl-quinoline-7-carboxylic acid methyl ester (3.78 g, 12.03 mmol) are dissolved in 200 ml of methanol/water (3:1 mixture), and treated with lithium hydroxide hydrate (1.06 g, 0.046 mol) at room temperature. After reaction completion the mixture is poured into ethyl acetate and 2 N hydrochloric acid, the organic phase is washed three times with water, dried with sodium sulphate, filtered and concentrated in vacuo. The residue is triturated with a little hexane. Filtration gives 3.50 g (97% of theory) of the title compound as white crystals. 1H NMR (d6-DMSO3, 400 MHz): δ ppm: 2.65 (s, 3H); 8.25 (d, 1H); 8.56 (s, 1H); 9.05 ppm (d, 1H).
Reaction SMILES: CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])([CH3:18])[C:14](OC)=[O:15].[OH-].[Na+]>O.O1CCCC1>[CH3:18][C:13]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:29][C:30]=1[CH3:31])([CH3:12])[CH2:14][OH:15]
Reactant: COC(=O)C(C)(C)OCCCCCCc1nc(-c2ccccc2)oc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCCCCCOC(C)(C)CO
Yield: 85.5 %

Procedure:
To 214 ml of dry ether, 1.35 g of lithium aluminum hydride was added, and a solution of 10.7 g of methyl 2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)hexyloxy]propionate/40 ml of dry ether was added dropwise with stirring under ice-cooling and stirred for 1 hour. To the mixture was added dropwise 43 ml of tetrahydrofuran/1.7 ml of water followed by addition of 6.3 ml of water and 1.7 ml of 1 N sodium hydroxide, and the mixture was stirred for 15 minutes and filtrated to remove insolubles. The filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=3:1) to provide 8.44 g of the objective compound.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(#N)C>[S:1]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: OCCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NS(=O)(=O)OCCCCc1ccccc1
Yield: 63 %

Procedure:
The title compound was obtained using the following procedure: The sulfamoyl chloride in acetonitrile solution prepared in (a) was reacted as in Example 12 with 17.7 g (0.118 mole) of 4-phenylbutanol, 46.4 g (0.459 mole) of triethylamine in 100 ml additional acetonitrile followed by using extracting, washing and concentration procedures of Example 12 through the first evaporation. The viscous residue was purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500A Prep Pak 500® silica. Eluting solvent used was methylene chloride at a flow rate of 200 ml/min). Fractions containing the title compound were combined and the solvent was evaporated under reduced pressure to give 19.3 g of colorless, viscous oil which solidified on standing. The solid was recrystallized from ethyl ether-petroleum ether (bp range 30°-60° C.) to give 16.9 g (63%) of title compound as white solid, mp 79°-81° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([CH:22]1[CH2:24][CH:23]1[C:25](O)=[O:26])#[N:21]>>[C:20]([CH:22]1[CH2:24][CH:23]1[C:25]([NH:19][CH2:18][C:12]1([C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[O:26])#[N:21]
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Reactant: N#CC1CC1C(=O)O
Product: N#CC1CC1C(=O)NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Yield: 29 %

Procedure:
This compound was synthesized from (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 2-cyanocyclopropanecarboxylic acid as described in example 8 step 6 (90 mg, yield 29%): 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.52-7.46 (m, 3H), 7.41-7.37 (m, 1H), 6.72 (t, J=5.3 Hz, 1H), 3.92-3.86 (m, 2H), 3.75-3.68 (m, 4H), 2.30-2.22 (dddd, J=13.2 Hz, 9.8 Hz, 6.5 Hz, 3.4 Hz, 2H), 1.99-1.89 (m, 4H), 1.52-1.47 (ddd, J=9.1 Hz, 5.8 Hz, 4.6 Hz, 1H), 1.38-1.33 (ddd, J=8.6 Hz, 6.1 Hz, 4.9 Hz, 1H). MS (ESI) m/z: Calculated for C20H21N3O2S: 367.14. found: 368.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@H:15]2[CH2:21][CH2:20][C@H:19]3[N:22](CC=C)[C@:16]2([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:17][CH2:18]3)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CN1C(=O)CC(=O)N(C)C1=O.[OH-].[Na+].O>ClCCl.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>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@H:15]2[CH2:21][CH2:20][C@H:19]3[NH:22][C@:16]2([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18]3)[CH:4]=[C:3]([C:2]([F:33])([F:1])[F:32])[CH:8]=1
Reactant: C=CCN1[C@@H]2CC[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@]1(c1ccccc1)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1cc(CO[C@H]2CC[C@@H]3CC[C@@]2(c2ccccc2)N3)cc(C(F)(F)F)c1
Temperature: 32.5 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (97 mg, 0.084 mmol) was added to a stirred mixture of (1S,2S,5S)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.1]octane (Example 182), 1,3-dimethylbarbituric acid (270 mg, 1.9 mmol) in dichloromethane (10 ml) at room temperature. The reaction mixture was stirred at 30-35° C. overnight and treated with 2M aqueous NaOH (5 ml). The mixture was stirred for 30 minutes, then treated with water (30 ml) and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel to give the title compound (166 mg, 81% two steps). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Cl.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]Cl.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CC(C)=O>[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=3)[N:10]=2)=[CH:3][C:2]=1[F:1]
Reactant: CN(C)CCCl
Reactant: COC(=O)c1ccc(CNc2nccc(-c3ccc(O)c(F)c3)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CNc2nccc(-c3ccc(OCCN(C)C)c(F)c3)n2)cc1
Yield: 97.6 %

Procedure:
To a solution of 39 (450 mg, 1.27 mmol) in acetone (25 mL) was added 2-(dimethylamino)ethyl chloride hydrochloride (220 mg, 1.53 mmol) followed by potassium iodide (53 mg, 0.32 mmol) and potassium carbonate (878 mg, 6.35 mmol). The reaction mixture was refluxed for 20 h, then saturated solution of NH4Cl was added, pH of the mixture was adjusted to 8 and acetone was removed under reduced pressure. The formed solid was collected by filtration, washed with water, dried and purified by flash chromatography on silica gel (MeOH/DCM/NH4OH: 10/89/1) to afford the title compound 40 (525 mg, 1.24 mmol, 97% yield).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:30]=[CH:29][CH:28]=[CH:27][C:6]=1[O:7][CH2:8][CH2:9][NH:10][CH:11]([CH3:26])[CH:12]([C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:19]=1)O)[CH3:3].S(Cl)([Cl:33])=O>C(#N)C>[ClH:33].[Cl:1][CH:12]([C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:19]=1)[CH:11]([NH:10][CH2:9][CH2:8][O:7][C:6]1[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=1[O:4][CH2:2][CH3:3])[CH3:26]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccccc1OCCNC(C)C(O)c1ccc(OC)c(S(N)(=O)=O)c1
Agent: Cl
Solvent: CC#N
Product: CCOc1ccccc1OCCNC(C)C(Cl)c1ccc(OC)c(S(N)(=O)=O)c1
Reaction time: 48 h
Yield: 84.8 %

Procedure:
In 1,000 ml of acetonitrile was suspended 17 g of 5-{2-[2-(2-ethoxyphenoxy)ethylamino]-1-hydroxy-2-methylethyl}-2-methoxybenzenesulfonamide hydrochloride and while stirring the suspension, 9 g of thionyl chloride was added dropwise to the suspension at room temperature, whereby the product first dissolved and then began to crystallize gradually. After stirring the mixture for two days, the crystals formed were recovered by filtration, washed with chloroform and dried to provide 15 g of 5-{1-chloro-2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2-methoxybenzenesulfonamide hydrochloride.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([OH:13])=O)=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[CH3:14][C:15]([NH2:18])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:18][C:15]([CH3:17])([CH3:16])[CH3:14])=[O:13])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-bromo-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (242 mg, 1 mmol), 2-methylpropan-2-amine (110 mg, 1.5 mmol), EDCI (382 mg, 2 mmol) and DMAP (244 mg, 2 mmol) in DMF (5 mL) was stirred at room temperature for 3 hours. Then the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude residue was used to the next step without further purification. MS: (M+H)+=297.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(OC([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc2nccc(Cl)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2nccc(N3CCNCC3)c2c1
Yield: 59.4 %

Procedure:
4,6-Dichloroquinoline (De, D., Byers L. D., Krogstad, D. J. J. Heterocyclic Chem. 1997, 34, 315) (0.34 g, 1.7 mmol) and 1-tert-butoxycarbonylpiperazine (1.58 g, 8.5 mmol) are reacted according to method A. The Boc group is cleaved with trifluoroacetic acid (5 mL) in CH2Cl2 (5 mL) giving 0.25 g of the product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5](F)=[CH:4][N:3]=1.[Cl:10]C1N=C(Cl)C(F)=CN=1>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Cl:10])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1nc(Cl)ncc1F
Product: Cc1nc(Cl)ncc1Cl

Procedure:
The title compound was prepared in a manner analogous to Intermediate 55, substituting 2,4,5-trichloropyrimidine for 2,4-dichloro-5-fluoropyrimidine. 1H NMR (500 MHz, CDCl3): 8.47 (s, 1H), 2.61 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[Cl:10])[NH2:6].N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21].CCCCCC>ClCCl>[Cl:10][C:9]1[CH:8]=[CH:7][C:5]([NH:6][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:4][C:3]=1[C:2]([F:1])([F:11])[F:12]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccccc1
Reaction time: 1.5 h
Yield: 89.2 %

Procedure:
3-trifluoromethyl-4-chloroaniline (25 g, 0.1278 mol) and pyridine (26 ml, 0.3195 mol) were dissolved in dichloromethane (250 ml). The reaction mass was cooled to 0° C. to −5° C. and a solution of phenyl chloroformate (22 ml, 0.1661 mol) in dichloromethane (100 ml) was added drop wise maintaining the temperature of the reaction mass below 0° C. The reaction mass was stirred at 0° C. to 5° C. for 1-2 hours and quenched with water (200 ml) below 10° C. The organic phase was separated and washed with water followed by 1N HCl. It was then dried over sodium sulfate and concentrated to obtain solid. This solid was agitated with hexane (350 ml) at ambient temperature for 2-3 hours and filtered. The obtained product was vacuum dried at 50° C. to give phenyl 4-chloro-3-(trifluoromethyl)phenylcarbamate (36 g) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]1[CH2:9][CH2:8][CH:7]([CH3:22])[CH2:6][C:5]2=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]3[C:5]([C:4]=2[CH:3]=1)=[CH:6][C:7]([CH3:22])=[CH:8][CH:9]=3
Reactant: CC1CCc2c(c3cc(Br)ccc3n2C(=O)OC(C)(C)C)C1
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)c1cc(Br)ccc1n2C(=O)OC(C)(C)C
Yield: 83.1 %

Procedure:
To a mixture of 6-bromo-9-tert-butoxycarbonyl-3-methyl-1,2,3,4-tetrahydrocarbazole obtained in Example 24 (2.0 g, 5.49 mmol), 2,3-dichloro-4,5-dicyano-1,4-benzoquinone (2.62 g, 11.5 mmol) and activated 3 Å molecular sieves was added anhydrous benzene (17 mL) under a nitrogen atmosphere, and the mixture was refluxed for 20 h. The cooled reaction mixture was filtered and the filtrate evaporated. The crude product was chromatographed (PS with gradient elution up to PS:DCM 3:1) to afford 3-bromo-9-tert-butoxycarbonyl-6-methylcarbazole (1.64 g, 4.56 mmol, 83%) as a colourless solid. By-products were also obtained—6-bromo-9-tert-butoxycarbonyl-4-ethoxy-3-methylcarbazole (12 mg, 0.030 mmol, 0.5%) was obtained as a colourless oil, and 6-bromo-9-tert-butoxycarbonyl-1,2-dihydro-3-methylcarbazol-4-(3H)-one (52 mg, 0.14 mmol, 2.5%) was obtained as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([O:14]C)=[O:13])=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[OH-].[Li+].Cl>CO>[OH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: COC(=O)c1ncc2cccnc2c1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ncc2cccnc2c1O
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a slurry of methyl 8-hydroxy-1,6-naphthyridine-7-carboxylate from Example 1, Step 2 (1.50 g, 7.35 mmol) in methanol (45 ml) was added lithium hydroxide (22.0 ml of a 1M aq. solution, 22.0 mmol) and the reaction was heated at 100° C. for 7 hrs. Upon cooling to room temperature, hydrochloric acid (22.0 ml of a 1M aq. solution, 22.0 mmol) was added and the reaction stirred for 16 hrs. The mixture was concentrated to a volume of 50 ml and neutralized with dilute NaHCO3 (pH=7). The resulting precipitate was collected by filtration and washed with water and dried in vacuo to afford the title compound.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:13][C:14]([OH:16])=O.O.[NH2:18][NH2:19]>C(O)C>[N:18]1[NH:19][C:14](=[O:16])[CH2:13][CH:3]2[CH2:4][CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2]=12
Reactant: NN
Reactant: O=C(O)CC1CCCc2ccccc2C1=O
Solvent: CCO
Solvent: O
Product: O=C1CC2CCCc3ccccc3C2=NN1

Procedure:
A mixture of the compound of formula (Dc), 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)acetic acid, (5.7 g, 26.1 mmol) and hydrazine hydrate (1.6 mL, 32.7 mmol) in 20 mL of ethanol was refluxed for 2 h, cooled and filtered (washed with small amount of EtOH) to give the compound of formula (Dd), 4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one, as a white solid (4.7 g, 84%); 1H NMR (300 MHz, CDCl3) δ: 8.61 (bs, 1H), 7.53-7.14 (m, 4H), 2.98-2.75 (m, 3H), 2.58 (dd, J=15.3, 16.8 Hz, 1H), 2.31 (dd, J=12.0, 16.8 Hz, 1H), 1.96-1.59 (m, 4H); LC-MS: purity: 100%; MS (m/e): 215 (MH+).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:15]([O:16]CC2C=CC=CC=2)[C@:14]2([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[CH:35][CH:34]=4)[CH:26]=3)[O:24][C@@:11]([CH:42]([OH:44])[CH3:43])([CH2:12][O:13]2)[C@@H:10]1[OH:45])C1C=CC=CC=1.Cl>[Pd].CO.O1CCCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C@@:14]23[O:24][C@@:11]([CH:42]([OH:44])[CH3:43])([CH2:12][O:13]2)[C@H:10]([OH:45])[C@H:9]([OH:8])[C@H:15]3[OH:16])=[CH:26][C:27]=1[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH3:41])=[CH:37][CH:38]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@H](O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
To a solution of (1R,2R,3S,4R,5S)-3,4-dibenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(1-hydroxyethyl)-6,8-dioxabicyclo[3.2.1]octan-2-ol 281 (140 mg, 0.22 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 20 mL) were added hydrochloric acid (0.03 mL, 1.1 lmmol) and Pd/C (23 mg, 0.02 mmol, 10%) at room temperature. The mixture was stirred at room temperature under H2 for 1 hour and filtered. The filtrate was adjusted with saturated aqueous sodium bicarbonate till pH becomes 7 and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with water (10 mL×3) and saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with EtOAc to give the title compound 28 as a white solid (14 mg, 14.1%, HPLC: 86.0%). The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, DMSO-d6) δ(ppm): 7.45 (s, 1H), 7.40 (m, 1H), 7.34 (m, 1H), 7.10 (d, 2H), 6.83 (d, 2H), 5.35-5.30 (m, 1H), 4.78 (d, 1H), 4.68 (s, 2H), 4.60 (d, 1H), 4.21-4.16 (m, 1H), 4.02-3.95 (m, 4H), 3.82-3.75 (m, 1H), 3.71 (d, 1H), 3.66-3.55 (m, 2H), 1.30 (t, 3H), 1.02 (d, 3H); and MS (ESI, pos. ion) m/z: 451.1[M+H]+.
Reaction SMILES: [N:1]([C@H:4]1[C:17]2[CH:16]=[CH:15][C:14]3[CH2:13][N:12]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH2:10][C:9]=3[C:8]=2[CH2:7][CH2:6][CH2:5]1)=[N+]=[N-]>CCOC(C)=O.CO.[Pd]>[CH2:18]([N:12]1[CH2:11][CH2:10][C:9]2[C:8]3[CH2:7][CH2:6][CH2:5][C@@H:4]([NH2:1])[C:17]=3[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CN1CCc2c(ccc3c2CCC[C@H]3N=[N+]=[N-])C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)CN1CCc2c(ccc3c2CCC[C@H]3N)C1
Reaction time: 8 h

Procedure:
A suspension of 30 mg of Pd/C (10% w/w) in a solution of (R)-7-azido-3-isobutyl-1,2,3,4,7,8,9,10-octahydrobenzo[f]isoquinoline (296 mg, 1 mmol) in 30 mL of EtOAc was stirred under H2 atmosphere overnight. The reaction mixture was then directly submitted to flash chomatograph (SiO2, EtOAc to EtOAc/2M NH3 in MeOH=100:15 to 100:25 to 100:35) to give (R)-3-isobutyl-1,2,3,4,7,8,9,10-octahydrobenzo[f]isoquinolin-7-amine as a colorless oil.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)=[CH:19][CH:18]=1>[Pd]>[CH:1]1([N:6]2[C:10]3=[N:11][C:28]([C:27]4[CH:30]=[CH:31][CH:32]=[C:25]([O:24][CH2:23][C:20]5[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=5)[CH:26]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: O=Cc1cccc(OCc2ccncc2)c1
Agent: [Pd]
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cccc(OCc4ccncc4)c3)nc(=O)c1-2
Yield: 21.6 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.7 g, 0.124 mol), 3-(4-pyridinylmethoxy)benzaldehyde (3.95 g, 0.0185 mol) and xylenes (100 ml) was refluxed overnight. Additional carboxamide (1 g) was added and the mixture was refluxed for another 2 days. 10% palladium on carbon (1 g) was added and the mixture was refluxed for another 3 hours. The catalyst was removed by filtration, the filtrate was concentrated in vacuo and the solid residue was collected by filtration. Additional product was obtained by concentration of the mother liquors and the combined product fractions were recrystallized from ethyl acetate to afford 1.66 g of 1-cyclopentyl-3-ethyl-6-[3-[4-pyridinylmethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 230-232° C.