Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClC(Cl)(Cl)[C:31]([N:33]=C=O)=[O:32]>ClCCl.O1CCCC1>[C:31](=[O:32])([O:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:4]2[C:5]([CH3:18])=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:2]([Br:1])[C:3]2=[O:28])=[CH:21][CH:22]=1)[NH2:33]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccc(CO)cc1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccc(COC(N)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
Compound of Example 206 (0.868 g, 1.93 mmol) was suspended in dichloromethane (7.0 mL). Trichloroacetyl isocyanate (4.00 mL, 0.53 M in toluene, 2.12 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours then diluted with tetrahydrofuran (50 mL) and Al2O3 (5.0 g) was added and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through a pad of Celite® washing with methonal. The filtrate was then concentrated and the residue was redissolved in tetrahydrofuran (30 mL). Al2O3 (5.0 g) was added and the mixture was heated to 40° C. for 3 hours. After cooling to room temperature, the reaction was filtered through a pad of Celite ® washing with methanol. The filtrate was concentrated and the resulting solid was washed with diethyl ether to give an off-white solid (0.831 g, 87%). 1H NMR (400 MHz, CDCl3) δ 7.54 (app q, J=7.7 Hz, 1H), 7.25 (d, J=8.2 Hz, 2H), 7.13 (d, J=8.2 Hz, 2H), 6.25 (app dt, J=2.0, 8.3 Hz, 1H), 6.86-6.30 (m, 1H), 5.97 (s, 1H), 5.32 (s, 2H), 5.18 (s, 2H), 5.02 (s, 2H), 4.81 (br s, 2H), 2.25 (s, 3H). ES-HRMS m/z 493.0580 (M+H calcd for C22H20BrF2N2O4 requires 493.0569).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:26][C@@H:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2ccc(F)cc2)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: Fc1ccc(-c2ccc(CN[C@H]3CCCc4ccccc43)cc2)cc1

Procedure:
4′-Fluoro[1,1′-biphenyl]-4-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:7][C:6]3[CH:16]=[CH:17][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=3)=[CH:9][CH:10]=2)=[CH:23][CH:22]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Fc1ccc(CNCc2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)cc1
Reaction time: 0.5 h
Yield: 26.1 %

Procedure:
To a mixture of 4-(4-(trifluoromethyl)phenoxy)benzaldehyde (1.4 g, 5.2 mmol) in anhydrous dichloroethane (10 mL), at room temperature under nitrogen, was added (4-fluorophenyl)methanamine (0.6 mL, 52 mmol). The mixture was stirred for 3 minutes before acetic acid (0.42 mL, 7.3 mmol) was added dropwise via syringe. After an additional 30 minutes, sodium triacetoxyborohydride (1.6 g, 7.3 mmol) was added to the reaction mixture. After 20 h, the reaction was quenched with 1 N aqueous NaOH (30 mL) then extracted with chloroform. The organic extracts were combined, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (ISCO system, eluting with 0-5% MeOH in CHCl3) to afford the desired compound (0.51 g, 24%) as a colorless oil. MS (ESI): 376.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH:20]([CH3:22])[CH3:21])[N:13]=2)[CH:3]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>CN1C(=O)CCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH:20]([CH3:22])[CH3:21])[N:13]=1)(=[O:9])[NH2:10]
Reactant: COc1ccc(Nc2cc(Cl)nnc2C(N)=O)nc1C(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)nc1C(C)C
Temperature: 140 °C
Yield: 32.4 %

Procedure:
To a solution of 6-chloro-4-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazine-3-carboxamide (199 mg, 618 μmol) in NMP (2.06 mL) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (532 mg, 2.47 mmol) in four portions approximately every 12 h while heating at 140° C. After a total heating time of 48 h, the mixture was cooled, diluted with ethyl acetate and brine, then the phases were separated and the organic phase washed twice more with brine. The organic phase was concentrated in vacuo then purified by chromatography (silica, 1 to 5% methanol in dichloromethane) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (100 mg, 200 μmol, 32%) as a brown solid. MS (EI/CI) m/z: 500.4 [M+H].
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH2:7][CH2:6][NH:5]1.[N:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=[O:37])=[CH:31][CH:30]=3)=[O:27])=[CH:25][C:20]=2[NH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[N:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:5]4[CH2:6][CH2:7][N:8]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=5[CH3:16])[CH2:9][CH:4]4[CH2:3][CH2:2][OH:1])=[O:37])=[CH:31][CH:30]=3)=[O:27])=[CH:25][C:20]=2[NH:19][CH:18]=1
Reactant: O=C(O)Cc1ccc(NC(=O)c2ccc3nc[nH]c3c2)cc1
Reactant: Cc1ccccc1N1CCNC(CCO)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(C(=O)Cc2ccc(NC(=O)c3ccc4nc[nH]c4c3)cc2)C(CCO)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-(2-hydroxyethyl)-4-(2-methylphenyl)piperazine from Step 2 of Example 20 (0.20 g; 0.91 mmol), 4-(5-benzimidazolylcarbonylamino)phenylacetic acid (0.299 g; 1.00 mmol), HOBT (0.14 g; 1.0 mmol), and EDC (0.210 g; 1.09 mmol) in DMF (30 mL) was added DIEA (0.23 mL; 1.3 mmol). The reaction was stirred at ambient temperature for 18 h and the solvent was evaporated under reduced pressure. The residue was partitioned between CH2Cl2 and saturated aqueous NaHCO3. The organic phase was separated and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 95:5:0.5 CH2Cl2 : MeOH:NH4OH as eluant. Trituration in EtOAc gave the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][NH2:16].[BH4-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:16][CH3:15])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(C)=O)cc1OC
Reactant: CN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC(C)Cc1ccc(OC)c(OC)c1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of 15.1 g (78 mmol) of (3,4-dimethoxyphenyl) acetone (1) in 102 mL of methanol was cooled to 4° C. and was treated with 35 mL of 40% aqueous methylamine. To the reaction mixture, 3.5 g (92.5 mmol) of sodium borohydride was then added, and the temperature of the reaction was maintained at 4° C. The reaction mixture was allowed to stir for an additional 30 minutes, then concentrated under reduced pressure. To the residue, 60 mL of water was added, and the resulting reaction mixture was acidified to pH 1 using 6N HCl. The aqueous layer was extracted with 5×50 mL of dichloromethane, and the pH was adjusted to pH 13 using 6N NaOH. The aqueous layer was extracted with 4×75 mL of dichloromethane. The organic layers were combined, dried and concentrated to give 15 g (72 mmol, 92%) of 1A as a colorless oil (M+H, 210).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:8][CH:9]2[CH2:12][CH:11]([NH:13]C(=O)OC(C)(C)C)[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[ClH:21]>CO>[ClH:21].[Br:1][C:2]1[C:3]([O:8][CH:9]2[CH2:10][CH:11]([NH2:13])[CH2:12]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CC(Oc2ncccc2Br)C1
Agent: Cl
Solvent: CO
Product: NC1CC(Oc2ncccc2Br)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To tert-butyl (3-((3-bromopyridin-2-yl)oxy)cyclobutyl)carbamate (see PREPARATION 7B; 342 mg, 1 mmol) was added 4 M HCl in MeOH (50 mL). The solution was stirred at RT for 2 hours. The solvent was removed under reduced pressure to give 3-((3-bromopyridin-2-yl)oxy)cyclobutanamine hydrochloride (223 mg, 0.95 mmol, yield 95%). ESI-MS (M+1): 243 calc. for C9H11BrN2O 242.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:12]=[C:13]=[S:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:15]([NH2:18])[CH2:16][NH2:17]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:12][C:13]([NH:17][CH2:16][CH2:15][NH2:18])=[S:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: NCCN
Reactant: Cc1c(N=C=S)ccc2cccnc12
Solvent: ClCCl
Product: Cc1c(NC(=S)NCCN)ccc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 8-methyl-7-quinolinylisothiocyanate (1.36 g) in CH2Cl2 (50 mL) is added dropwise to ethylene diamine (2.26 mL) in solution in CH2Cl2 (50 mL). The mixture is stirred for 30 minutes at room temperature then rotary evaporated. The residue is suspended in CH2Cl2 (50 mL) and ether (50 mL) and filtered. The precipitate is dried in vacuo to afford N-(8-methyl-7-quinolinyl)-N'-2-aminoethylthiourea as a white powder.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[C:12]2=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1(C)C=CC=CC=1.P(Br)(Br)[Br:32]>C1COCC1>[Br:32][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=2)[CH2:19][CH2:20][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc2c(c1)CCC(c1ccc(S(C)(=O)=O)cc1)C2=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCC(c1ccc(S(C)(=O)=O)cc1)=C2Br
Temperature: 25 °C
Yield: 74 %

Procedure:
Add 2-(4-methanesulfonyl-phenyl)-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (1.0 eq.), hyflo (20 wt %), and toluene (7.5 vols) to a three neck flask with a reflux condenser and nitrogen vent purge. While stirring at room temperature, add PBr3 (1.75 eq.) in one portion. Heat the reaction to reflux (˜110° C.) overnight allowing it to vent through a caustic scrubber. After refluxing for 15 hours, cool the yellow solution to 45° C. and slowly add THF (20 vols). Stir this mixture for 30 minutes at 45° and filter it, while warm, over a pad of Hyflo. Wash the pad with 45° C. THF (2×2 vols). Concentrate the filtrate at reduced pressure to remove all of the THF. Carefully add water (7.5 vols) to the remaining mixture keeping the temperature below 40° C. Cool the slurry to room temperature and stir it for 2 to 3 hours. Filter the slurry over a polypropylene pad and wash it with water (2×2 vols). Dry the resulting filter cake in a vacuum oven overnight at 50° C. to provide the title compound (74%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:6].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[S:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29](=[S:30])[NH:1][C:2]2[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)=[O:6])[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccc(F)cc2)cc1N
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Product: COc1ccc(C(=O)Nc2ccc(F)cc2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Yield: 76.5 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-N-(4-fluorophenyl)-4-methoxy-benzamide from Example 8 (0.520 g, 2.00 mmol) and 3,5-dichlorophenyl isothiocyanate (0.409 g, 2.00 mmol). Filtration afforded the product (0.71 g) in two crops; m.p. 175-178° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[O:24])=[CH:19][CH:18]=1>>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([C:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:18][CH:19]=2)=[O:24])=[CH:26][CH:27]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(C)(C)c1ccc(C(=O)c2ccc(O)cc2)cc1
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 10.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (341 mg) and 4-t-butylphenyl 4-hydroxyphenyl ketone (775 mg) obtained in Example 30 were mixed and stirred at 150° C. for 15 minutes. The reaction mixture was then purified by column chromatography on silica gel eluting with hexane/acetone to obtain 72 mg of the title compound (yield: 11%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[C:5]([C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)=O)[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[OH:20][N:19]=[C:9]([C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1)[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[N:2]([CH3:17])[CH3:1]
Reactant: CN(C)c1cccc(C(=O)c2nnnn2C)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)c1cccc(C(=NO)c2nnnn2C)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 99.6 %

Procedure:
To a stirred solution of [3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methanone (3.84 g, 17 mmol) in dry pyridine (30 mL) was added hydroxylamine hydrochloride (2.89 g, 42 mmol). The reaction mixture was stirred at 70° C. for 6 h, then concentrated in vacuo and diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer was separated, washed with water (50 mL) and dried over MgSO4. Evaporation of the solvent in vacuo afforded 3-[(hydroxyimino)(1-methyl-1H-tetrazol-5-yl)methyl]-N,N-dimethylaniline as a yellow solid [4.48 g, yield 99.6%; HPLC/MS m/z=247 (M+H); logP(HCOOH)=1.17].
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:35]([O:36][CH3:37])=[CH:34][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[CH:6]=1)[N:14]=[CH:13][C:12]([C:17]#[N:18])=[C:11]3[NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]2[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=2)=[C:22]([Cl:33])[CH:21]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.[I-].[Na+].C(=O)(O)[O-].[Na+]>COCCOC>[Cl:33][C:22]1[CH:21]=[C:20]([NH:19][C:11]2[C:10]3[C:15](=[CH:16][C:7]4[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[C:35]([O:36][CH3:37])=[CH:34][C:8]=4[CH:9]=3)[N:14]=[CH:13][C:12]=2[C:17]#[N:18])[CH:25]=[CH:24][C:23]=1[S:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1
Reactant: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCCl
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCN1CCOCC1

Procedure:
A mixture of 1.27 g (2.3 mmol) of 8-(2-chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxybenzo[g]quinoline-3-carbonitrile, 4.0 mL of morpholine and 0.1 g of sodium iodide in 10 mL of 1,2-dimethoxyethane is heated under reflux for 16 hours. After allowing the reaction to cool, the solvent is evaporated to yield a residue, which is stirred with saturated sodium bicarbonate. The solid is collected by filtration, is washed with water and dried. The crude product is purified by silica gel chromatography, utilizing a gradient of 98:2 to 90:10 of methylene chloride/methanol to give 0.53 g of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile as a yellow solid, mp>300° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.C(Cl)Cl.[C:13]1([CH3:22])[C:14]([C:19](Cl)=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1.O>CCOCC>[CH3:22][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1)=[O:20]
Reactant: COC(=O)c1cc[nH]c1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(C(=O)c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Under nitrogen at room temperature, methyl pyrrole-3-carboxylate (2.5 g., 20 mmoles) was combined with 75 ml. of methylene chloride. o-Toluoyl chloride (3.09 g., 20 mmoles) in 25 ml. of methylene chloride was added, followed by stannic chloride (4.6 ml., 40 mmoles) added at a fast dropwise rate via a needle and syringe. Progress of the reaction was followed by thin layer chromatography (silica gel with ethyl acetate-1/hexane-5/5% acetic acid as eluant). After stirring at room temperature for 2.5 hours, the reaction was cooled with an ice-water bath while 75 ml. of water was added dropwise. After addition was complete, the mixture was stirred for 15 minutes at room temperature, approximately an equal volume of ether was added, the organic layer separated, washed in sequence with water, 1N sodium hydroxide, water and saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to yield methyl 5-(2-methylbenzoyl)pyrrole-3-carboxylate.
Reaction SMILES: [OH-:1].[Na+].CC(C)=[O:5].[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][OH:24])=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)(Cl)Cl.[OH2:29]>>[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][OH:24])=[N:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1.[OH:1][C:17]([CH3:16])([CH3:22])[C:18]([OH:5])=[O:29]
Reactant: [OH-]
Reactant: CC(C)=O
Reactant: O
Agent: OCc1nn(Cc2ccccc2)c2ccccc12
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(O)C(=O)O

Procedure:
Into a round-bottomed flask, provided with a vigorous stirrer, 1.9 g of NaOH, 10 g of acetone and 2.38 g of 1-benzyl-3-hydroxymethyl-indazole, prepared as described above, are successively added. 1.6 g of chloroform are then added (exothermic reaction) and the mixture is heated for two hours on a water bath. Water is added, the reaction mixture is washed with ethyl acetate and the aqueous solution is acidified. The residue is recrystallized from a mixture of hexane/ethyl acetate 1:1. The ether of 1-benzyl-3-hydroxymethyl-indazole with 2-hydroxy-2-methyl-propionic acid is thus obtained (Compound I, R=R'=CH3, R'"=H), m.p. 132°-134° C.
Reaction SMILES: C(OC([CH2:8][NH:9][CH2:10][C:11]1[S:15][CH:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([O:28][CH2:29][CH3:30])[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=2)[CH:12]=1)=O)(C)(C)C.O>ClCCl.FC(F)(F)C(O)=O>[CH2:29]([O:28][C@@H:23]([CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:12]=[C:11]([CH2:10][NH:9][CH3:8])[S:15][CH:14]=2)=[CH:17][CH:18]=1)[C:24]([O:26][CH3:27])=[O:25])[CH3:30]
Reactant: CCO[C@@H](Cc1ccc(-c2csc(CNCC(=O)OC(C)(C)C)c2)cc1)C(=O)OC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCO[C@@H](Cc1ccc(-c2csc(CNC)c2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.5 %

Procedure:
5 g (11.5 mmol) of methyl 3-(4-{5-[(tert-butoxycarbonylmethylamino)methyl]thiophen-3-yl}phenyl)-2(S)-ethoxypropanoate are placed in 80 ml of dichloromethane and 4.4 ml of trifluoroacetic acid. After stirring at room temperature for 24 hours, water is added and the reaction medium is extracted with dichloromethane. The dichloromethane phase is washed with aqueous 30% sodium hydroxide solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with a 50/50 heptane/ethyl acetate mixture. 3.2 g (84%) of methyl 2(S)-ethoxy-3-[4-(5-methylaminomethylthiophen-3-yl)phenyl]propanoate are obtained.
Reaction SMILES: CN(C)C=O.[CH3:6][N:7]([CH3:12])[CH2:8][C:9]([OH:11])=[O:10].C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1.[CH2:34]([O:52][CH2:53][CH:54]([CH2:74]O)[O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63]/[CH:64]=[CH:65]\[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]>C(Cl)Cl>[CH3:6][N:7]([CH2:8][C:9]([O:11][CH2:74][CH:54]([O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63]/[CH:64]=[CH:65]\[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:53][O:52][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:10])[CH3:12]
Reactant: CN(C)CC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCCOCC(CO)OCCCCCCCC/C=C\CCCCCCCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCOCC(COC(=O)CN(C)C)OCCCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
In a solvent mixture of 22 ml N,N-dimethylformamide and 11 ml methylene chloride was suspended 572 mg (5.547 mmol) of N,N-dimethylglycine followed by addition of 1736 mg (8.414 mmol) of N,N'-dicyclohexylcarbodiimide and the mixture was stirred at ambient temperature overnight. The solvent was then distilled off under reduced pressure and the residue was dissolved in 12 ml of pyridine containing 327 mg (0.551 mmol) of dissolved 1,2-O-dioleylglycerol. Then, 80 mg (0.388 mmol) of N,N'-dicyclohexylcarbodiimide (DCC) was added and the reaction was conducted at 50° C. overnight. After completion of the reaction, the solvent was distilled off and the residue was dissolved in methylene chloride, washed with saturated aqueous sodium hydrogen carbonate solution, dried, and concentrated. The residue was subjected to column chromatography (silica gel/ethyl acetate-n-hexane) to provide 251 mg (67.2%) of the title compound of the invention.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH:16][C:17](=[O:31])[C:18]2[CH:23]=[C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:21]=[C:20]([F:30])[CH:19]=2)=[CH:8][CH:7]=1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][C:33]1=[O:38]>>[F:30][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:21]=1)[C:17]([NH:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][NH:32][C:33](=[O:38])[CH2:34]2)=[CH:7][CH:8]=1)=[O:31]
Reactant: O=C1CNCCN1
Reactant: O=C(Nc1ccc(OCCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Product: O=C1CN(CCCOc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)CCN1

Procedure:
Compound is prepared from N-[4-(3-chloropropoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide and 2-piperazinone according to conditions described in general procedure L. A white powder is produced (0.102 g, 60%). Mp: 90-92° C. 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.24 (d, J=6.3 Hz, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.75 (s, 1H), 7.56 (m, 2H), 7.45 (s, 1H), 7.42 (d, J=8.1, Hz, 1H), 7.16 (d, J=9.6 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 6.93 (s, 1H), 4.22 (br s, 2H), 3.31 (m, 4H), 3.17 (br s, 2H), 2.98 (s, 2H), 2.61 (m, 4H), 2.06 (m, 2H), 1.60 (brs, 6H). MS: 505.2 (M+1).