Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:34](OC)[O:35]C)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[C:20]([CH3:23])[CH:19]=[CH:18][C:17]=2[N:24]([CH3:33])[S:25]([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)(=[O:27])=[O:26])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O>O>[CH2:1]([S:8][CH:9]([CH:34]=[O:35])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[C:20]([CH3:23])[CH:19]=[CH:18][C:17]=2[N:24]([CH3:33])[S:25]([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)(=[O:27])=[O:26])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(CNC(=O)c1cc2c(C)ccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)NCC(C=O)SCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.7 %

Procedure:
A mixture of N-[2-(benzylthio)-3,3-dimethoxypropyl]-4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (4.75 g), Amberlyst (registered trade mark) 15 ion exchange resin (1.0 g), acetone (100 mL) and water (0.4 mL) was stirred at room temperature for 20 hr. Amberlyst (registered trade mark) 15 ion exchange resin was filtered off, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:3-3:2) to give the title compound (4.4 g, yield: 100%) as a colorless amorphous solid. MS: 528 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>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.O>[F:11][C:12]1[CH:17]=[C:16]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2cccc(F)c2)c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A 25 mL microwave vessel was charged with 1-bromo-3-nitrobenzene (XLVIII) (0.61 g, 3.0 mmol), 3-fluorophenylboronic acid (XLIX) (0.46 g, 3.3 mmol), potassium phosphate tribasic (0.95 g, 4.5 mmol), 1,4-dioxane (15.0 mL), and water (3.0 mL). Tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol) was added, and the reaction was placed in a microwave reactor for 1 h at 95° C. An additional 3-fluorophenylboronic acid (0.20 g) and tetrakis(triphenylphosphine)palladium(0) (0.05 g) were added, and the reaction was heated for another 1 h at 95° C. in a microwave reactor. The organic solvent was separated from the water and concentrated to a residue. The residue was then purified by flash chromatography using a 25 g Thomson normal phase silica gel cartridge (100% hexanes→1:99 EtOAc:hexanes) to afford 3′-fluoro-3-nitrobiphenyl (L) (0.63 g, 2.91 mmol, 97% yield) as a white solid. 1H NMR (DMSO-d6) δ ppm 8.48 (t, J=2.0 Hz, 1H), 8.26-8.24 (m, 1H), 8.20-8.18 (m, 1H), 7.78 (t, J=8 Hz, 1H), 7.70-7.68 (m, 1H), 7.67-7.65 (m, 1H), 7.59-7.56 (m, 1H), 7.32-7.28 (m, 1H).
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[N:11]=[C:10](F)[C:9]([C:13](=[O:29])[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:8][CH:7]=1)=O.C[C:33](C)([O-:35])C.[K+]>CO.O>[NH2:5][C:6]1[N:11]=[C:10]([O:35][CH3:33])[C:9]([C:13](=[O:29])[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]2)=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccc(NC(=O)C(C)(C)C)nc2F)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1nc(N)ccc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture of 1,1-dimethylethyl 4-(3-{6-[(2,2-dimethylpropanoyl)amino]-2-fluoro-3-pyridinyl}-3-oxopropyl)-1-piperidinecarboxylate (step 2, 360 mg, 0.827 mmol) and potassium tert-butoxide (278 mg, 2.48 mmol) in methanol (8 ml) was refluxed for 1 h. After cooling to room temperature, the mixture was diluted with water (20 ml) and extracted with diethyl ether (100 ml×2). The combined organic layer was washed with water (50 ml) and brine (50 ml), and dried over magnesium sulfate. Removal of the solvent gave 300 mg (100%) of the title compound as a colorless gum.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH3:19])[C:7]([OH:9])=O.[NH2:20][C:21](=[N:38]O)[C:22]1[CH:36]=[CH:35][C:25]([O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([F:37])[CH:23]=1>>[F:37][C:24]1[CH:23]=[C:22]([C:21]2[N:38]=[C:7]([C:6]3[CH:10]=[CH:11][C:12]([N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=3)[O:9][N:20]=2)[CH:36]=[CH:35][C:25]=1[O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: COCc1cc(C(=O)O)ccc1N1CCCCC1C
Reactant: CCOC(=O)CCCOc1ccc(C(N)=NO)cc1F
Product: CCOC(=O)CCCOc1ccc(-c2noc(-c3ccc(N4CCCCC4C)c(COC)c3)n2)cc1F

Procedure:
The title compound was prepared following procedure described for example 141, step 1, but starting from Intermediate 58 (158 mg; 0.60 mmol) and Intermediate 66 (162.04 mg; 0.57 mmol), the crude mixture was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1) to afford the title compound as a colorless oil. 1H NMR (CDCl3) δ 8.30 (d, J=2.1 Hz, 1H), 8.07 (dd, J=8.2, 2.0 Hz, 1H), 7.92-7.87 (m, 2H), 7.26 (d, J=8.4 Hz, 1H), 7.06 (t, J=8.5 Hz, 1H), 4.67-4.61 (m, 2H), 4.20-4.13 (m, 4H), 3.49 (s, 3H), 3.17 (br s, 1H), 3.06-3.03 (m, 1H), 2.65 (br s, 1H), 2.57 (t, J=7.3 Hz, 2H), 2.19 (quint, J=6.6 Hz, 2H), 1.86-1.70 (m, 4H), 1.51-1.48 (m, 2H), 1.27 (t, J=7.1 Hz, 3H), 0.90 (d, J=6.0 Hz, 3H). LC/MS (Method B): 512.4 (M+H)+. HPLC (Method A) Rt 4.62 min (Purity: 100.0%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:44])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:43])[CH2:9][CH2:10][C@@:11]3([C:27]([N:29]4[CH2:34][CH2:33][C:32]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)([C:35]#[N:36])[CH2:31][CH2:30]4)=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:46])[CH3:45].N1C=CC=CC=1.[CH3:53][C:54]1([CH3:61])[CH2:58][C:57](=[O:59])[O:56][C:55]1=[O:60]>C(OCC)(=O)C>[C:35]([C:32]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33][CH2:34][N:29]([C:27]([C@:11]23[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]2[C@@H:13]2[C@@:8]([CH3:43])([CH2:9][CH2:10]3)[C@@:7]3([CH3:44])[C@@H:16]([C@:17]4([CH3:20])[C@@H:4]([CH2:5][CH2:6]3)[C:3]([CH3:46])([CH3:45])[C@@H:2]([O:1][C:57](=[O:59])[CH2:58][C:54]([CH3:61])([CH3:53])[C:55]([OH:60])=[O:56])[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)=[O:28])[CH2:30][CH2:31]1)#[N:36]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(C#N)(c4ccccc4)CC3)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
Reactant: CC1(C)CC(=O)OC1=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(C#N)(c4ccccc4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of ((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl)-4-phenylpiperidine-4-carbonitrile (Example 76, 0.5 g, 0.80 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.2 g, 1.6 mmol) was added then 3,3-dimethyldihydrofuran-2,5-dione (0.82 ml) was added and the contents were refluxed for about 16 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, washed with water followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 19H); 1.23-1.78 (m, 23H); 2.15-2.59 (m, 11H); 2.77-3.58 (m, 16H); 4.33-4.70 (m, 4H); 5.58-5.60 (s, 1H); 5.78-5.80 (s, 1H); 7.44-7.47 (s, 1H); ES Mass: 753 (100%), [M+1].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](SC)[N:19]=3)[C:10]3[C:11]([N:17]=2)=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C([O-])([O-])=O.[Na+].[Na+].[C:43]1([C@@H:49]([NH2:51])[CH3:50])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl.CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:51][C@H:49]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH3:50])[N:19]=3)[C:10]3[C:11]([N:17]=2)=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[CH:4][CH:3]=1
Reactant: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(N)ccc32)n1
Reactant: C[C@H](N)c1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@H](Nc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(N)ccc32)n1)c1ccccc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
2-(4-Fluorophenyl)-1-(2-methylthio-4-pyrimidinyl)-5-aminoimidazo[4,5-b]pyridine (110 mg, 0.31 mmol) is dissolved in CH2Cl2/HOAc 1:1 (6.2 ml), combined at 0° C. with mCPBA (84 mg 70% 0.34 mmol) and stirred for 30 min. The reaction mixture is poured on 2N Na2CO3 and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the crude sulfoxide (110 mg). 50 mg are dissolved in 1-(S)-phenylethylamine (0.5 ml) and heated to 120° C. for 1 h. Purification over RP18 (CH3CN/Water 70/30 to 10/90) yielded the title compound as light brown foam (30 mg 52%)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][NH:25][CH2:24]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][N:25]([C:11]1[CH:12]=[C:13]3[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:15])[CH2:24]2
Reactant: Clc1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2cc(N3Cc4ccc(Cl)cc4C3)c(F)cc2c1=O
Temperature: 110 °C
Yield: 62.6 %

Procedure:
A mixture of 136 mg of 1-cyclopropyl-6,7-difluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 123 mg of 5-chloroisoindoline, 122 mg of DBU, and 1.5 ml of anhydrous DMF was heated at 110° C. for 1.5 hours while stirring. The resulting reaction mixture was evaporated under reduced pressure to dryness. 20 ml of chloroform and 10 ml of 5% acetic acid were added to the residue thus obtained, and the mixture was stirred. The deposited crystals were collected by filtration and washed with water and then ethanol. The chloroform layer was separated, and washed with water, dried over anhydrous sodium sulfate, and condensed. The residue was crystallized by the addition of hot ethanol. After cooling the mixture, the crystals were collected by filtration. These crystals, combined with the crystals obtained above, were recrystallized from a mixed solvent of chloroform, methanol, and ethanol to obtain 128 mg of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5][C:6](=[O:10])[CH:7]=[N+]=[N-].[CH:20]1C=CC=CC=1>CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][C:6](=[O:10])[CH2:7][CH2:20][N:11]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:19]
Reactant: c1ccccc1
Reactant: COC(=O)C(CC(=O)C=[N+]=[N-])NC(=O)OC(C)(C)C
Agent: [Rh+2]
Agent: CC(=O)[O-]
Product: COC(=O)C1CC(=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a refluxing mixture of rhodium acetate dimer (0.0093 g, 0.02 mmol) and 40 mL of benzene was added dropwise a solution of 2-tert-butoxycarbonylamino-5-diazo-4-oxo-pentanoic acid methyl ester (0.60 g, 2.1 mmol) in 4.5 mL of benzene. After stirring for 2 h at reflux, the mixture was cooled to room temperature, concentrated in vacuo, and filtered through a small pad of silica gel eluting with 1:1 ethyl acetate-hexane. Concentration of the filtrate afforded 0.53 g of 4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:11]1[NH:16][C:15](=[O:17])[C:14]2=[CH:18][N:19]=[C:20](I)[N:13]2[N:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:36]2[CH2:37][CH2:38][O:39][CH2:40][CH:41]=2)O1>O1CCOCC1.O.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>[CH2:1]([O:8][CH:9]([C:11]1[NH:16][C:15](=[O:17])[C:14]2=[CH:18][N:19]=[C:20]([C:36]3[CH2:41][CH2:40][O:39][CH2:38][CH:37]=3)[N:13]2[N:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(OCc1ccccc1)c1nn2c(I)ncc2c(=O)[nH]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(OCc1ccccc1)c1nn2c(C3=CCOCC3)ncc2c(=O)[nH]1
Temperature: 125 °C
Yield: 75.7 %

Procedure:
To a solution of compound 12 (300 mg, 0.75 mmol) in dioxane (2 mL) was added a solution of Cs2CO3 (492 mg, 1.51 mmol) in H2O (0.5 mL) dropwise, followed by addition of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (318 mg, 1.5 mmol) and Pd(PPh3)4 (86 mg, 0.075 mmol). The reaction mixture was degassed by purging with N2 for 15 min. Then the reaction was heated to 125° C. under microwave heating for 40 min. After removal of the solvent, the residue was purified by chromatography on silica gel column (eluted with PE/EtOAc=10:1 to 1:5) to afford compound 13 (200 mg, 75% yield) as white solid. LC-MS: m/z 353 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.82 (br. s, 1H), 7.91 (s, 1H), 7.37˜7.32 (m, 5H), 7.19 (br. s, 1H), 4.61 (m, 2H), 4.49 (q, J=6.8 Hz, 1H), 4.40 (m, 2H), 3.95 (t, J=5.2 Hz, 2H), 2.78 (m, 2H), 1.58 (d, J=6.4 Hz, 3H).
Reaction SMILES: B.C1COCC1.[CH:7]1([S:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.CO>C1COCC1>[CH:7]1([S:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][NH2:19])=[CH:20][CH:21]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: N#Cc1ccc(CSC2CCCC2)cc1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: NCc1ccc(CSC2CCCC2)cc1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
Add borane-THF complex (13.6 mL, 13.6 mmol, 1M solution in THF) dropwise to a solution of 4-(cyclopentylthiomethyl)-benzonitrile (1.5 g, 6.8 mmol) in anhydrous THF (8 mL) at room temperature and heat the mixture at reflux overnight. Cool to room temperature, add methanol cautiously and stir vigorously until gas evolution stops. Concentrate in vacuo and purify the crude mixture by SCX chromatography to obtain the title compound (0.86 g, 59%). MS (ES+) m/z: 205 (M-NH3+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]2[C:44]([CH:45]=1)=[N:43][N:42]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:41]=2>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:38]=[CH:39][C:40]3[C:44]([CH:45]=2)=[N:43][N:42]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:41]=3)=[CH:9][CH:10]=1
Reactant: COCCCn1cc2ccc(CCl)cc2n1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCn1cc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc2n1

Procedure:
Analogously to Method D, 0.178 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.090 g of 6-chloromethyl-2-(3-methoxypropyl)-2H-indazole are reacted. The title compound is obtained as a colourless oil. Rf=0.15 (2:1 EtOAc-heptane); Rt=5.80.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.C(N(CC)CC)C.[CH3:25][C@H:26]1[NH:31][CH2:30][CH2:29][NH:28][C:27]1=[O:32]>C(#N)C>[CH3:25][C@H:26]1[N:31]([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:6]=[N:5][N:4]=2)[CH2:30][CH2:29][NH:28][C:27]1=[O:32]
Reactant: FC(F)(F)c1ccc(-n2nnnc2CCl)cc1
Reactant: C[C@H]1NCCNC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H]1C(=O)NCCN1Cc1nnnn1-c1ccc(C(F)(F)F)cc1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[4-(trifluoromethyl)phenyl]-1H-tetrazole (500 mg, 1.90 mmol, commercially available from UkrOrgSynthesis, Kiev, Ukraine) in acetonitrile (8 mL) was added triethylamine (0.796 mL, 5.71 mmol) and (3R)-3-methyl-2-piperazinone (239 mg, 2.09 mmol, commercially available, for example from Sigma Aldrich, St Louis, USA). The reaction mixture was heated to 120° C. for 20 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]([OH:15])[CH2:10]2.N1C=CC=CC=1.[Cl:22][C:23]([C:33]([F:36])([F:35])[F:34])=[CH:24][C@@H:25]1[C@H:27]([C:28](Cl)=[O:29])[C:26]1([CH3:32])[CH3:31]>C1(C)C=CC=CC=1>[Cl:22][C:23]([C:33]([F:34])([F:35])[F:36])=[CH:24][C@@H:25]1[C@H:27]([C:28]([O:15][CH:9]2[CH2:8][C:7]3[C:11](=[CH:12][CH:13]=[CH:14][C:6]=3[C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH2:10]2)=[O:29])[C:26]1([CH3:32])[CH3:31]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: OC1Cc2cccc(-c3cccs3)c2C1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OC1Cc2cccc(-c3cccs3)c2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
A stirred solution of 0.54 g (0.003 mole) of 4-(2-thienyl)-2-indanol and 0.25 g (0.003 mole) of pyridine in 15 mL of toluene was cooled to 5° C., and 0.65 g (0.003 mole) of cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarbonyl chloride in 5 mL of toluene was added dropwise. Upon complete addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for 16 hours. The reaction mixture was filtered, and the filtrate concentrated under reduced pressure to give an oil residue. The oil was subjected to column chromatography on silica gel, eluting with 100% hexane then 1% ethyl acetatehexane. The appropriate fractions were combined and concentrated under reduced pressure to give 0.57 g of 4-(2-thienyl)-2-indanyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate as an oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.C(C(N)CC)C.[Cl:20][C:21]1[CH:58]=[CH:57][C:24]([C:25]2[C:30]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:41]5N(CC)[C:44]6[CH:48]=C[C:50](C(O)=O)=[CH:51][C:43]=6[N:42]=5)[CH:37]=4)[N:32]=3)=[CH:29][C:28]([O:55][CH3:56])=[CH:27][CH:26]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:58]=[CH:57][C:24]([C:25]2[C:30]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:41]5[N:42]([CH:43]([CH2:51][CH3:50])[CH2:44][CH3:48])[C:2]6[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=6[N:11]=5)[CH:37]=4)[N:32]=3)=[CH:29][C:28]([O:55][CH3:56])=[CH:27][CH:26]=2)=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Agent: CCC(N)CC
Product: CCC(CC)n1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21

Procedure:
The title compound was prepared from Resin 534a and 1-ethylpropylamine according to the procedure described in the preparation of Compound 534.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:4])=[O:3].[CH2:19](I)[CH2:20][CH3:21]>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH2:18]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:3])=[O:4]
Reactant: COc1ccc(N2CCNCC2)cc1S(C)(=O)=O
Reactant: CCCI
Product: CCCN1CCN(c2ccc(OC)c(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 1-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine and n-Pr-I, the title compound was recovered by the procedure described in Example 2;: MS m/z (rel. intensity, 70 eV)) 312 (M+, 38), 284 (17), 283 (bp), 70 (49), 56 (17).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([Cl:21])[C:12]=1[NH:22][NH2:23]>CCO>[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([F:19])([F:18])[F:20])[CH:14]=[C:13]([Cl:21])[C:12]=1[N:22]1[C:1]([CH3:2])=[C:4]2[CH2:8][CH2:7][CH2:6][C:5]2=[N:23]1
Reactant: CC(=O)C1CCCC1=O
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CCO
Product: Cc1c2c(nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl)CCC2
Yield: 75 %

Procedure:
2-Acetyl cyclopentanone (0.12 mL, 1 mmol) and 2,6-dichloro-4-trifluoromethylphenylhydrazine (245 mg, 1 mmol) in EtOH (10 mL) was heated under reflux for 12 hr. EtOH was removed under reduced pressure and the product purified by flash chromatography on silica (10% EtOAc:Hexane): yield 75%. 1H NMR (CDCl3) δ 7.8 (s, 2H), 2.6 (m, 6H each), 2.2 (s, 3H); MS (M+) 335.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([C:22]3([CH2:25][C:26]#[N:27])[CH2:24][CH2:23]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.C([Sn](=O)CCCC)CCC.[N:38]([Si](C)(C)C)=[N+:39]=[N-:40]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([C:22]3([CH2:25][C:26]4[NH:40][N:39]=[N:38][N:27]=4)[CH2:23][CH2:24]3)[O:13][N:12]=2)=[CH:9][CH:10]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COCOc1ccc(-c2noc(C3(CC#N)CC3)c2-c2ccccc2)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCOc1ccc(-c2noc(C3(Cc4nnn[nH]4)CC3)c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture consisting of {1-[3-(4-methoxymethoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropyl}-acetonitrile (the synthetic intermediate prepared in Example 42, Step A, 0.7 g) in toluene (10 mL) are added di-n-butyltin oxide (0.48 g) and azidotrimethylsilane (0.51 mL.) The stirring mixture is brought to reflux and continued stirring overnight. The mixture is subsequently cooled to room temperature, diluted with ethyl acetate (40 mL), and sequentially washed with water (20 mL) and brine solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography. Elution with hexanes-ethyl acetate (1:1 v/v) and further elution with ethyl acetate afforded the synthetic intermediate 5-{1-[3-(4-methoxymethoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropylmethyl}-1H-tetrazole (0.6 g.)
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([N:12]=[C:13]=[O:14])[CH2:4][CH2:3]1.[N-:15]=C=S.Cl.O=C1C2C(=CC=CC=2)C(N)CC1>>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1
Reactant: [N-]=C=S
Reactant: O=C=NC1CCC(=O)c2ccccc21
Agent: Cl
Agent: NC1CCC(=O)c2ccccc21
Product: NC(=O)NC1CCC(=O)c2ccccc21

Procedure:
The following formula I 1,2,3,4-tetrahydro-4-oxo-1-naphthylurea compounds are prepared by reacting 1,2,3,4-tetrahydro-4-oxo-1-naphthylisocyanate or isothiocyanate with the appropriately substituted amines, or by reacting 1,2,3,4-tetrahydro-4-oxo-1-naphthylamine hydrochloride with the appropriately substituted isocyanates, isothiocyanates or carbamoyl chlorides by the process of Example 6. The compounds obtained are listed in Table I below.