Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].[H-].[Na+].[Cl:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][CH:20]=1>C1COCC1>[Cl:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:21][CH:20]=1
Reactant: COCCOCCOCCOCCO
Reactant: ClCc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCCOCCOCCOCc1ccc(CCl)cc1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of tetraethylene glycol monomethyl ether (2.00 g, 9.61 mmol) in THF (15 mL) at room temperature was added NaH (276.7 mg, 11.53 mmol). The reaction mixture was stirred for 30 min, followed by the addition of 1,4-bis(chloromethyl)benzene (2.01 g, 11.5 mmol). The reaction mixture was stirred at room temperature overnight and subsequently the solvent was evaporated. The reaction mixture was then dissolved in CH2Cl2 and washed with water. The organic phase was dried with Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography to give the desired compound (2.56 g, 7.40 mmol, 77%) as a colorless liquid. 1H NMR (300 MHz, CDCl3) δ 7.26-7.40 (m, 4H), 4.55 (s, 2H), 4.54 (s, 2H), 3.69−3.56 (m, 14H), 3.53−3.50 (m, 2H), 3.34 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.7, 136.8, 128.7, 128.0, 72.8, 71.9, 70.7, 70.6, 70.5, 69.6, 59.1, 46.1; MS (ESI) m/z calculated for C22H35N6O11 [M+H]+ 347.1 found [M+H2O]+ 364.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[C:6]=2[CH:16]=1.[H-].[Na+].[CH3:28]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][N:18]([CH3:28])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[C:6]=2[CH:16]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)cc2c1ncn2C1CCCCO1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1cc(Cl)cc2c1ncn2C1CCCCO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of tert-butyl (6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-4-yl)methylcarbamate (300 mg, 0.82 mmol) in DMF (10 mL) at 0° C. was added NaH (60% in mineral oil, 98.4 mg, 2.46 mmol). After stirring at RT for 30 min, CH3I (349 mg, 2.46 mmol) was added and the reaction mixture was stirred at RT overnight and then quenched with H2O at 0° C. The mixture was extracted with EtOAc (100 mL) and the extract washed with H2O (50 mL×3), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (1:1) to afford tert-butyl (6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-4-yl)methyl(methyl)carbamate as yellow oil (310 mg, 99%). MS (ESI): m/z=380.3 [M+1]+.
Reaction SMILES: C(O)(C)C.[ClH:5].CNOC.Br[CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C(=O)(O)[O-].[Na+]>C(N(CC)CC)C>[Cl:5][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Cl
Agent: CNOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C1c2ccccc2C(=O)N1CCCl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.4 %

Procedure:
To a suspension of 50 ml of isopropanol containing N,O-dimethylhydroxylamine hydrochloride (3.90 g, 40.0 mmol) was added dropwise 5.56 ml of triethylamine. The resulting mixture became homogeneous after 5 minutes. Thereto was added 2.45 g (10.0 mmol) of N-(bromoethyl)phthalimide and the mixture was refluxed for 29 hours. This was cooled to room temperature, then poured into 200 ml of a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was separated and was washed with water and dried over magnesium sulfate. Chloroform was distilled off and the residue was purified by column chromatography on silica gel. Development with 30% hexane-chloroform resulted in elution of 1.37 g of N-(2-chloroethyl)-phthalimide and further development with chloroform resulted in 0.964 g (yield: 41%) of white cyrstals of N-[2-(N-methoxy-N-methylamino)ethyl]phthalimide.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH3:12][N:13](C)[CH:14]=[O:15]>>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:14]([NH:13][CH2:12][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])=[O:15]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CN(C)C=O
Product: Cc1nc[nH]c1CSCCNC(=O)NCCSCc1[nH]cnc1C

Procedure:
A mixture of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (1.6 g.) and 1,1-carbonyl di-imidazole (0.5 g.) in dimethyl formamide (12 ml.) was heated to reflux temperature whereupon the mixture solidified. After cooling, a small quantity of dimethyl formamide was added and the slurry was filtered to give the solid product which was washed with water, ethanol and ether and finally recrystallised from dimethyl formamide. Yield 0.5 g., m.p. 230°-234°.
Reaction SMILES: [ClH:1].[CH:2]([C:5]1[CH:18]=[C:17]2[C:8]([N:9]3[C:14]([CH2:15][O:16]2)=[N:13][NH:12][C:11](=[O:19])[C@H:10]3[CH3:20])=[CH:7][C:6]=1[C@H:21]([C:23]1([CH3:27])[CH2:26][NH:25][CH2:24]1)[CH3:22])([CH3:4])[CH3:3].[Si]([O:35][CH2:36][CH:37]=O)(C(C)(C)C)(C)C.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[ClH:1].[OH:35][CH2:36][CH2:37][N:25]1[CH2:24][C:23]([C@@H:21]([C:6]2[CH:7]=[C:8]3[C:17](=[CH:18][C:5]=2[CH:2]([CH3:3])[CH3:4])[O:16][CH2:15][C:14]2[N:9]3[C@H:10]([CH3:20])[C:11](=[O:19])[NH:12][N:13]=2)[CH3:22])([CH3:27])[CH2:26]1
Reactant: CC(C)c1cc2c(cc1[C@@H](C)C1(C)CNC1)N1C(=NNC(=O)[C@H]1C)CO2
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)c1cc2c(cc1[C@@H](C)C1(C)CN(CCO)C1)N1C(=NNC(=O)[C@H]1C)CO2
Temperature: 70 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of (R)-7-isopropyl-4-methyl-6-[(R)-1-(3-methyl-azetidin-3-yl)-ethyl]-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloric acid (Example #133, Step G, 0.083 g, 0.233 mmol) in MeOH (3 mL) and acetic acid (0.3 mL) was added 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (0.122 g, 0.699 mmol) and the reaction mixture was stirred at 70° C. overnight. NaBH3CN (0.073 g, 1.164 mmol) was added and the reaction mixture was stirred at 70° C. for 1 h. The reaction mixture was cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by prep-HPLC (Table 3, Method 26) to give (R)-6-{(R)-1-[1-(2-hydroxy-ethyl)-3-methyl-azetidin-3-yl]-ethyl}-7-isopropyl-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloric acid (0.0291 g, 31%) as a solid. 1H NMR (CD3OD-d4, 400 MHz): δ 7.04 (s, 1H), 6.84 (s, 1H), 4.81-4.78 (m, 1H), 4.62 (s, 2H), 4.15 (d, J=10.8 Hz, 1H), 4.04 (d, J=10.8 Hz, 1H), 3.93 (d, J=10.8 Hz, 1H), 3.86 (d, J=10.8 Hz, 1H), 3.77-3.69 (m, 2H), 3.38 (m, 2H), 3.12-3.04 (m, 2H), 1.56 (s, 3H), 1.45 (d, J=6.8 Hz, 3H), 1.42-1.35 (m, 3H), 1.34-1.27 (m, 3H), 1.19-1.12 (m, 3H). LC/MS (Table 1, Method 4) Rt=1.761 min.; MS m/z: 401 [M+H]+. SFC (Table 1, Method 28) Rt=5.52 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[N+:15]([C:18]1[CH:19]=[C:20]2[C:25](=O)[O:24][C:22](=[O:23])[C:21]2=[CH:27][CH:28]=1)([O-:17])=[O:16].Cl>>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([N:1]2[C:25](=[O:24])[C:20]3=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:28][CH:27]=[C:21]3[C:22]2=[O:23])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1C1CCN(Cc2ccccc2)CC1

Procedure:
9.51 Grams of 4-amino-1-benzylpiperidine and 9.66 grams of 4-nitrophthalic anhydride were reacted in a similar manner to that described in Example 14 to give 9.19 grams of the title compound as the monohydrochloride quarterhydrate. Melting Point: 240°-2° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:15]([O-])=O)=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][C:9](=[O:13])[CH2:8][C:7]=2[CH:14]=1>CO.[Pd]>[NH2:15][C:4]1[C:3]([O:2][CH3:1])=[CH:14][C:7]2[CH2:8][C:9](=[O:13])[NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCNC(=O)C2
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N)CCNC(=O)C2
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of 8-methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (360 mg, 1.5 mmol) in methanol (30 mL) was added palladium 10% wt on Carbon (50% wet; 50 mg). The mixture was shaken in a Parr apparatus under an atmosphere of hydrogen (50 PSI) for 30 minutes. Filtration through Celite and evaporation of the solvent provided 7-amino-8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (300 mg, 95%) as a tan solid. 1H-NMR (CDCl3) δ 6.54 (s, 1H), 6.47 (s, 1H), 5.80 (br s, 1H), 3.82 (s, 3H), 3.73 (s, 2H), 3.71 (br s, 2H), 3.53 (q, J=6.3 Hz, 2H), 2.96 (t, J=6.1 Hz, 2H); LC/MS (ESI+): 207.13 (M+H).
Reaction SMILES: [OH:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:51])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:50])[CH2:37][CH2:38][CH2:39][CH2:40][CH:41]2[CH:48]3[CH:44]([NH:45][C:46](=[O:49])[NH:47]3)[CH2:43][S:42]2)[CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.C(N=C=NC(C)C)(C)C.O[N:62]1[C:66](=[O:67])[CH2:65][CH2:64][C:63]1=[O:68]>CN(C=O)C>[C:63]1(=[O:68])[N:62]([O:8][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([C:2]([OH:1])([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:51])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:50])[CH2:37][CH2:38][CH2:39][CH2:40][CH:41]4[CH:48]5[CH:44]([NH:45][C:46](=[O:49])[NH:47]5)[CH2:43][S:42]4)[CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][CH:10]=2)[C:66](=[O:67])[CH2:65][CH2:64]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(CCCCC1SCC2NC(=O)NC21)NCCCCCC(=O)NCCCOc1cccc(C(O)(c2ccccc2)c2ccc(C(=O)O)cc2)c1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: O=C(CCCCC1SCC2NC(=O)NC21)NCCCCCC(=O)NCCCOc1cccc(C(O)(c2ccccc2)c2ccc(C(=O)ON3C(=O)CCC3=O)cc2)c1
Reaction time: 0.08 h

Procedure:
To a solution of biotinylated trityl acid (5, 175 mg, 0.244 mM) in anhydrous DMF (3 mL) was added 1,3-diisopropyl carbodiimide (4 mg, 0.35 mM) and stirred the reaction mixture for 5 min. To this reaction mixture was added N-hydroxy succinimide (40 mg, 0.32 mM) and stirred for over night at room temperature. The solvent was removed under high vacuum and the residue obtained was purified by silca gel column chromatography using CH3OH/CH2Cl2, 3:7) mixture as a solvent system. Evaporation of the solvent gave 6 as a white crystalline solid. Yield: 80 mg (41%). 1H-NMR (CD3OD) δ ppm:
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([NH2:42])[CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:2]3[N:22]=[C:5]4[C:6]([C:10]5[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=5[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2)CC1
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3cccc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)nc12

Procedure:
4-(3-[8-(2-methoxy-5-trifloromethylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl)-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.150 g, 0.5 mmol), and 4-(3-amino-phenyl)piperazine-1-carboxylic acid tert-butyl ester (0.152 g, 0.548 mmol) in a manner analogous to Example 2d. Product was isolated as a foam (0.19 g, 73%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (d, J=6.1 Hz, 1H), 7.93 (s, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.56 (d, J=6.1 Hz, 1H), 7.46-7.40 (m, 2H), 7.31-7.28 (m, 1H), 7.13 (d, J=8.1 Hz, 1H), 7.00-6.94 (m, 1H), 6.87 (s, 1H), 6.84 (d, J=8.1 Hz, 1H), 3.88 (s, 3H), 2.89-2.75 (m, 2H), 2.73-2.63 (m, 1H), 1.92-1.79 (m, 2H), 1.73-1.63 (m, 4H), 1.52 (s, 9H). MS=568 (MH)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]([CH3:48])[C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41]>>[CH3:38][N:39]([CH3:48])[C:40]([N:42]1[CH2:43][CH2:44][N:45]([C:35]([N:15]2[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=[C:14]2[C:8]2[C:9]([O:11][CH2:12][CH3:13])=[N:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[N:6][CH:7]=2)=[O:36])[CH2:46][CH2:47]1)=[O:41]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)N(C)C)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazine-1-carboxylic acid dimethylamide (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C35H44N7O3Cl2 [(M+H)+] 680.2877, observed 680.288.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:17]([CH2:16][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:18][CH:19]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(OC)cc3)cc2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: COc1ccc(COc2ccc(CSc3ccc(OCC(=O)O)c4c3CCC4)cc2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 68A. mp 183-185° C.; IR (KBr) cm−1: 3015, 2588, 1742, 1716, 1514, 1243; 400 MHz 1H NMR (DMSO-d6): δ 12.97 (br(s), 1H), 7.26-7.34 (m, 2H), 7.06-7.13 (m, 2H) 7.04 (d, 1H, J=8.5 Hz), 6.80-6.92 (m, 4H), 6.56 (d, 1H, J=8.5 Hz), 4.92 (s, 2H), 4.60 (s, 2H), 3.93 (s, 2H), 3.69 (s, 3H), 2.75 (t, 2H, J=7.3 Hz), 2.67 (t, 2H, J=7.3 Hz), 1.89 (pentet, 2H); MS m/z 449 (M−1). Anal. Calc'd for C26H26O5S: C, 69.31; H, 5.82. found: C, 69.00; H, 5.74.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([CH2:7][N:8]1[C:12]([NH:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[N:9]1)=[O:6].C(OCC)(=O)C.Cl>O1CCOCC1.O1CCCC1>[C:5]([CH2:7][N:8]1[C:12]([NH:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[N:9]1)([OH:6])=[O:4]
Reactant: COC(=O)Cn1nccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O)Cn1nccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4N Sodium hydroxide aqueous solution (125.79 ml) was added to a solution of 1-methoxycarbonylmethyl-5-triphenylmethylaminopyrazole (100 g) in dioxane (100 ml) and the mixture was stirred for three hours at ambient temperature. The reaction mixture was added to a mixture of ethyl acetate (300 ml) and tetrahydrofuran (300 ml), and 1N hydrochloric acid was added thereto to adjust to pH 3. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-carboxymethyl-5-triphenylmethylaminopyrazole.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([OH:11])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:6]=[N:5]1>CC(C)CCO>[F:21][C:2]([F:1])([F:20])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:11][CH2:9][CH2:8][CH:7]([CH3:12])[CH3:6])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:6]=[N:5]1
Reactant: CSc1ccc(-c2cnn(CC(F)(F)F)c(=O)c2O)cc1
Solvent: CC(C)CCO
Product: CSc1ccc(-c2cnn(CC(F)(F)F)c(=O)c2OCCC(C)C)cc1

Procedure:
The intermediate, 2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone prepared in Example 90C was reacted with 3-methyl-1-butanol to provide 2-(2,2,2-trifluoroethyl)-4-(3-methylbutoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone according to the method of Example 90D.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]2=3)[CH2:4][CH2:3]1.C1C(=O)N([Br:26])C(=O)C1>CN(C=O)C.O>[Br:26][C:16]1[CH:17]=[CH:18][C:9]2[N:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CCC(N2CCCCc3ccccc32)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(N2CCCCc3cc(Br)ccc32)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A solution of compound 3 (0.73 g, 2.99 mmol) in DMF (5 mL) was treated with a solution of NBS (0.53 g, 2.99 mmol) in DMF (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours and stored at 0° C. overnight. The reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (25 mL), dried (Na2SO4) and concentrated. The product was filtered through a short plug of silica gel (2.0 N NH3 in MeOH:CH2Cl2, 2.5:97.5) to give compound 4 (0.915 g, 95.3%) as a yellow oil. 1H-NMR (DMSO-d6) δ 1.56 (m, 4H), 1.72 (m, 4H), 1.96 (td, 2H, J=10.9, 2.2 Hz), 2.15 (s, 3H), 2.65 (m, 2H), 2.76 (m, 2H), 2.93 (m, 2H), 3.14 (m, 1H), 6.83 (d, 1H, J=8.5 Hz), 7.19 (td, 2H, J=8.6, 2.4 Hz); EI-MS (m/z, %) 324 (M+, 14) 322 (M+, 14), 98 (25), 97 (100), 96 (25), 71 (38).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)[C:23]([N:25]=C=O)=[O:24]>C1COCC1.N>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:16][CH2:17][N:18]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc(C2CCNCC2)cc1OC1CCCC1
Agent: N
Solvent: C1CCOC1
Product: COc1ccc(C2CCN(C(N)=O)CC2)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)piperidine (3.63 mmol, 1.00 g) in dry THF (40 mL) at 0° C. was added trichloroacetylisocyanate (4.72 mmol, 0.889 mg; 563 μL) dropwise over 5 minutes. The resulting solution was stirred at 0° C. for 1 hour and at room temperature for 30 minutes. The reaction was diluted with NH3 saturated CH3CN solution (40 mL) and stirred at room temperature over the weekend. The volatiles were removed in vacuo and the residue partitioned between EtOAc (100 mL) and water (100 mL). The aqueous phase was extracted with EtOAc (1×100 mL), the combined organics washed with water (1×100 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2 :EtOAc) to afford the title compound as a white solid, mp=149°-150° C. (0.800 g, 70%).
Reaction SMILES: BrC1SC2C=C(C(OCC)=O)C=CC=2N=1.FC1(F)CCNCC1.C([O-])([O-])=O.[Cs+].[Cs+].[F:30][C:31]1([F:51])[CH2:36][CH2:35][N:34]([C:37]2[S:38][C:39]3[CH:45]=[C:44]([C:46]([O:48]CC)=[O:47])[CH:43]=[CH:42][C:40]=3[N:41]=2)[CH2:33][CH2:32]1.Cl>CC#N.O>[F:51][C:31]1([F:30])[CH2:36][CH2:35][N:34]([C:37]2[S:38][C:39]3[CH:45]=[C:44]([C:46]([OH:48])=[O:47])[CH:43]=[CH:42][C:40]=3[N:41]=2)[CH2:33][CH2:32]1
Reactant: CCOC(=O)c1ccc2nc(N3CCC(F)(F)CC3)sc2c1
Agent: CCOC(=O)c1ccc2nc(Br)sc2c1
Agent: Cl
Agent: FC1(F)CCNCC1
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccc2nc(N3CCC(F)(F)CC3)sc2c1
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of ethyl 2-bromo-benzo[d]thiazole-6-carboxylate 49a (1.75 mmol, 500 mg), 4,4-difluoropiperidine 49b (1.92 mmol, 303 mg), and Cs2CO3 (5.24 mmol, 1.71 g) in 15 mL of CH3CN was refluxed overnight. The suspension was cooled to room temperature and 15 mL of water was added to the mixture (containing ethyl 2-(4,4-difluoropiperidin-1-yl)benzo[d]thiazole-6-carboxylate 49c). The reaction mixture was heated at 60° C. for 18 h. After cooling, the mixture was acidified using 3N aqueous HCl and the resulting precipitate was filtered to give 575 mg (99%) of 49d. MS m/z (M+H+) 299.1.
Reaction SMILES: [BH4-].[Na+].[C:3]1([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21](=O)[CH3:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)(C(F)(F)F)=O.O>[C:3]1([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][CH3:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCc1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
To magnetically stirred TFA (1600 mL) was added at 0° C. sodium borohydride (64 g, 1.69 mol) over 1 h. To this mixture was added dropwise a solution of 1-(1-benzenesulfonyl-2,3-dihydro-1H-indol-5-yl)-ethanone (40 g, 0.13 mol) in TFA (700 mL) over 1 h. The mixture was stirred overnight at 25° C., diluted with H2O (1600 mL), and basified with sodium hydroxide pellets at 0° C. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 1-benzenesulfonyl-5-ethyl-2,3-dihydro-1H-indole (16.2 g, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:6]2.[H-].[Na+].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1)=[C:8]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:6]2
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc2c(O)c(-c3ccccc3)c(CC(C)C)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(CC(C)C)cc2c1
Yield: 83 %

Procedure:
6-(Methyloxy)-3-(2-methylpropyl)-2-phenyl-1-naphthalenol (105) (0.66 g, 2.16 mmol) was treated with NaH in DMF followed by addition of 4-fluorobenzaldehyde to give 0.74 g (83%) of the title compound (106) as a light yellow foam. 1H NMR (400 MHz, CDCl3): δ 0.75 (d, J=6.8 Hz, 6H), 1.60-1.70 (m, 1H), 2.47 (d, J=7.1 Hz, 2H), 3.94 (s, 3H), 6.67 (d, J=8.8 Hz, 2H), 7.05 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.07-7.12 (m, 2H), 7.15-7.25 (m, 4H), 7.56 (s, 1H), 7.61 (d, J=8.6 Hz, 2H), 7.67 (d, J=9.1 Hz, 1H), 9.79 (s, 1H). LCMS (ESI): m/z 411 (M+H)+.