Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[NH2:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:21][Si](Cl)(C)C>CO>[CH3:21][O:19][C:18](=[O:20])[C@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][C:6](=[O:8])[C@H:2]([CH:3]([CH3:5])[CH3:4])[NH2:1]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)C(C)C

Procedure:
The title compound is prepared by the procedure of Example 7 using 0.50 g of L-valine-L-phenylalanine, 10 ml of methyl alcohol and 0.564 ml of trimethylsilyl chloride to give 0.57 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:46])[CH:4]([Se]C1C=CC=CC=1)[CH2:5][CH2:6][CH2:7][C:8](=[O:38])[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:12][C@@H:11]1[OH:37].C(=O)(O)[O-].[Na+].OO>C(OCC)(=O)C.O1CCCC1>[CH3:1][O:2][C:3](=[O:46])/[CH:4]=[CH:5]/[CH2:6][CH2:7][C:8](=[O:38])[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:12][C@@H:11]1[OH:37]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](CC(=O)CCCC([Se]c2ccccc2)C(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](CC(=O)CC/C=C/C(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 2.333 g of (13E)-(9α,11α,15S)-2-phenylseleno-6-oxo-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)prost-13-enoic acid methyl ester [prepared as described in Reference Example 8(h)] in a mixture of 22 ml of ethyl acetate and 11 ml of tetrahydrofuran were added 733 mg of sodium bicarbonate and 1 ml of 30% (v/v) hydrogen peroxide at 34° C. and the mixture was stirred at that temperature for 30 minutes. The reaction mixture was then diluted with ethyl acetate, washed with water, an aqueous solution of sodium sulphate, water, an aqueous solution of ammonium chloride and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 1.524 g of the title compound having the following physical characteristics:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.C([O:14][C:15](=O)[C@@H:16]([C@@H:30]1[C@:47]2([CH3:48])[C@H:33]([C@H:34]3[C@H:44]([CH2:45][CH2:46]2)[C@:42]2([CH3:43])[C:37]([CH2:38][C@@H:39]([O:56][CH:57]4[CH2:62][CH2:61][CH2:60][CH2:59][O:58]4)[CH2:40][C@@H:41]2[O:49][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)=[CH:36][CH2:35]3)[CH2:32][CH2:31]1)[CH2:17][CH2:18][C@H:19]([F:29])[C:20]([O:23][CH:24]([O:26][CH2:27][CH3:28])[CH3:25])([CH3:22])[CH3:21])C>CCOCC>[O:51]1[CH2:52][CH2:53][CH2:54][CH2:55][CH:50]1[O:49][C@@H:41]1[C@@:42]2([CH3:43])[C:37](=[CH:36][CH2:35][C@@H:34]3[C@@H:44]2[CH2:45][CH2:46][C@@:47]2([CH3:48])[C@H:33]3[CH2:32][CH2:31][C@@H:30]2[C@H:16]([CH2:15][OH:14])[CH2:17][CH2:18][C@H:19]([F:29])[C:20]([O:23][CH:24]([O:26][CH2:27][CH3:28])[CH3:25])([CH3:22])[CH3:21])[CH2:38][C@@H:39]([O:56][CH:57]2[CH2:62][CH2:61][CH2:60][CH2:59][O:58]2)[CH2:40]1
Reactant: CCOC(=O)[C@H](CC[C@H](F)C(C)(C)OC(C)OCC)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 0.028 g. (0.00074 mole) of lithium aluminum hydride in 1 ml. of tetrahydrofuran at 0° C. was added 0.200 g. (0.00027 mole) of [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)-oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-oic acid ethyl ester in 3 ml. of tetrahydrofuran. The mixture was stirred at 50° C. for 1.5 hr, recooled to 0° C. and diluted with 12 ml. of ether. The mixture was then quenched with the dropwise addition of 0.06 ml. of water and 0.05 ml. of 10% aqueous sodium hydroxide. The mixture was stirred at 25° C. for 0.5 hr and was filtered. The solids were triturated with ether and filtered. Evaporation of solvent afforded [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)-oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:14]([O-])=O)[CH:4]=1.[H][H]>[Pd].COCCOC.CO>[NH2:14][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: COCCOC
Product: COc1cc(N)c(C(N)=O)cc1OC
Reaction time: 16 h

Procedure:
A suspension of 4,5-dimethoxy-2-nitrobenzamide (5.8 g, 25.6 mmol) in a 1:1 mixture of DME/MeOH (total volume 200 ml) and 10% Pd/C (0.7 g) was hydrogenated at RT using a balloon filled with hydrogen gas. The reaction was stirred for 16 h and the reaction mixture filtered through Celite®. The pad of Celite® was washed with a 1:1 mixture of MeOH/CH2Cl2 (200 mL). The filtrate was then concentrated in vacuo and dried under high vacuum overnight to give 2-amino-4,5-dimethoxybenzamide. (5.0 g, 25.5 mmol, 99%). HPLC retention time 2.303 mins.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.FC(F)(F)S(O[C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([CH3:33])=[CH:28][C:27]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[O:17][CH:2]3[CH:3]=[CH:4][C:5]4[C:10]([N:1]3[C:27]3[CH:28]=[C:29]([CH3:33])[C:30]([CH3:32])=[CH:31][C:26]2=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)c([Si](C)(C)C)cc1C
Reactant: c1ccc2ncccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C)N1c3ccccc3C=CC1OC2c1ccc(Cl)cc1
Yield: 65 %

Procedure:
Following the general procedure, treatment of quinoline (0.064 g, 59 μL, 0.50 mmol) and 4-chlorobenzaldehyde (0.105 g, 0.75 mmol) with 4,5-dimethyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.196 g, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=70/20) of the crude reaction mixture afforded 5-(4-chlorophenyl)-2,3-dimethyl-5H,6aH-benzo[4,5][1,3]oxazino[3,2-a]quinoline as inseparable mixture of diastereomers as a white solid (0.121 g, 65% yield, dr determined by 1H NMR analysis of crude reaction mixture is 10:1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[H-].[Na+].I[CH3:14]>O1CCCC1>[CH3:14][N:4]1[CH2:5][CH2:6][O:1][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]1=2
Reactant: c1ccc2c(c1)NCCO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCOc2ccccc21
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
Into a 250 mL 3-necked round bottom flask was placed a solution of 3,4-dihydro-2H-benzo[b][1,4]oxazine (4.8 g, 35.51 mmol) in tetrahydrofuran (50 mL). To the above was added NaH (2.3 g, 57.50 mmol) in several batches, while cooling to a temperature of 0-5° C. The mixture was stirred for 30 minutes at 0-5° C. To the above was added iodomethane (9.0 g, 63.41 nm not) dropwise with stirring, while cooling to a temperature of 0-5° C. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The residue was purified by eluting through a column with a 1:100 ethyl acetate/petroleum ether solvent system. This resulted in 3.0 g (50%) of 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine as yellow oil.
Reaction SMILES: [CH2:1]1[C:10]2=[CH:11][CH2:12][CH2:13][C:8]3=[C:9]2[N:3]([CH:4]=[CH:5][CH2:6][CH2:7]3)[N:2]1[C:14]([OH:16])=O.[NH2:17][CH:18]1[CH:23]2[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1.[OH-].[Na+].C(Cl)[Cl:29]>S(Cl)(Cl)=O>[ClH:29].[N:20]12[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21]1)[CH:18]([NH:17][C:14]([N:2]1[N:3]3[C:9]4[C:10](=[CH:11][CH2:12][CH2:13][C:8]=4[CH2:7][CH2:6][CH:5]=[CH:4]3)[CH2:1]1)=[O:16])[CH2:19]2
Reactant: O=C(O)N1CC2=CCCC3=C2N1C=CCC3
Reactant: ClCCl
Reactant: NC1CN2CCC1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: Cl
Product: O=C(NC1CN2CCC1CC2)N1CC2=CCCC3=C2N1C=CCC3
Temperature: 20 °C
Reaction time: 18 h

Procedure:
0.75 g (3.5 mmol) of 6,7,8,9-tetrahydro-pyrazolo[4,5,1-jk][1]benzazepine-2-carboxylic acid were boiled for 3 hours in 12 ml of thionyl chloride. Access of thionyl chloride was then removed by distillation under reduced pressure. 10 ml of toluene were added, and distillation under reduced pressure was repeated. The residue was dissolved in 10 ml of acetonitrile, and 0.83 g (6.6 mmol) of 3-amino-quinuclidine were added. The mixture was stirred for 18 hours at 20° C., then shaken with 2N sodium hydroxide and with methylene chloride. The methylene chloride layer was washed with water, dried and evaporated. The residue was dissolved in a mixture of 5 ml of absolute alcohol and 5 ml of ethyl acetate. The reaction mixture of 0.65 ml of acetyl chloride with 2 ml of absolute alcohol was added to the obtained solution and kept at 0° C. for 18 hours. The solid was then sucked off, washed with ethyl acetate and dried. In this manner 1.12 g of the desired product was obtained. The product decomposed slowly at 280° C. 13C NMR (CDCl3, ref: TMS)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[O:12][C:13]([CH:16]([O:19][CH3:20])[O:17][CH3:18])=[CH:14][CH:15]=1.[H][H]>[Ni].CO>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH:13]([CH:16]([O:17][CH3:18])[O:19][CH3:20])[O:12]1
Reactant: [H][H]
Reactant: COC(=O)CCCCCCCc1ccc(C(OC)OC)o1
Agent: [Ni]
Solvent: CO
Product: COC(=O)CCCCCCCC1CCC(C(OC)OC)O1
Yield: 93.6 %

Procedure:
8-(5-Dimethoxymethyl-2-furyl)-octanoic acid methyl ester (6.03 g, 0.02 mol), methanol (50 ml) and Raney nickel (3.0 g) were shaken under 100 atmospheres of hydrogen for 48 hours at 85°-100° C. After filtration, the methanol was distilled under reduced pressure from a water bath (60° C). Ether (50 ml) was added to the residue, and the turbid colourless solution was filtered. The ethereal solution was evaporated to dryness from a water bath under reduced pressure, at last under 15 mm Hg. The residual clear, colourless oil (6.07 g) was purified by distillation from a potassium acetate-coated flask giving 5.66 g (93%) of 8-(5-dimethoxymethyl-tetrahydro-2-furyl)-octanoic acid methyl ester, b0.1 126°-127° C, nD25 1.4504.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[CH3:26][S:27][C:28]1[N:33]=[CH:32][C:31]([CH:34]=[O:35])=[CH:30][N:29]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:26][S:27][C:28]1[N:33]=[CH:32][C:31]([CH:34]([C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)[OH:35])=[CH:30][N:29]=1
Reactant: CSc1ncc(C=O)cn1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cncnc21
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1ncc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncncc23)cn1
Temperature: 0 °C
Yield: 88.2 %

Procedure:
To a solution of 5-Iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine (38, 4.00 g, 9.97 mmol) in 5.00 mL of tetrahydrofuran at −20° C. under nitrogen, isopropylmagnesium chloride (5.80 mL, 2.0 M in tetrahydrofuran, 11.6 mmol) was added slowly. The reaction was allowed to warm to 0° C. over 70 minutes, then cooled to −20° C., followed by addition of 2-methylsulfanyl-pyrimidine-5-carbaldehyde (54, 1.12 g, 7.26 mmol) in 15.0 mL of tetrahydrofuran. The reaction was allowed to warm to room temperature over 1 hour, then poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (55, 2.75 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].CCN(C(C)C)C(C)C.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28](=[O:32])[C:29](Cl)=[O:30])=[CH:20]1>CN(C=O)C>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:29](=[O:30])[C:28]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:19][CH:20]=1)=[O:32])[CH3:2]
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Reactant: CCc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccccc1NC(=O)C(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
To a stirring solution of 2-ethyl-aniline (74 μL, 0.6 mmol) and DIEA (110 μL, 0.6 mmol) in DMF (1 mL) was added a solution of (1H-indol-3-yl)-oxo-acetyl chloride (62 mg, 0.3 mmol) in DMF (1 mL). The reaction was stirred at room temperature for 2 hours, then filtered and purified by HPLC (10-99% CH3CN/H2O) to yield the product N-(2-ethyl-phenyl)-2-(1H-indol-3-yl)-2-oxo-acetamide (34 mg, 39%). HPLC ret. time 3.50 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 10.14 (s, 1H), 8.79 (d, J=3.2 Hz, 1H), 8.30 (m, 1H), 7.57 (m, 2H), 7.33-7.21 (m, 5H), 2.67 (q, J=7.6 Hz, 2H), 1.17 (t, J=7.6 Hz, 3H); ESI-MS m/z 293.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:31]>O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Reactant: N
Solvent: O
Product: CC(C)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3,4-difluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 35 mg, 42%). mp 169–171° C. 1H NMR (300 MHz, DMSO-d6) δ 0.78 (d, 6H), 1.84, (m, 1H), 4.2 (d, 2H), 7.54 (m, 3H), 7.6 (m, 1H), 7.82 (m, 3H), 7.91 (d, 2H), 8.21 (s, 1H). MS (DCI/NH3) m/z 436 (M+H)+, 453 (M+NH4)+. Anal. calc for C20H19F2N3O4S.0.25 H2O: C, 55.17; H, 4.40; N, 9.65. Found: C, 54.19; H, 4.25; N, 9.35
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].Br[C:23]1[C:28]([C:29]2([OH:33])[CH2:32][CH2:31][CH2:30]2)=[CH:27][CH:26]=[CH:25][N:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:23]2[C:28]([C:29]4([OH:33])[CH2:32][CH2:31][CH2:30]4)=[CH:27][CH:26]=[CH:25][N:24]=2)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: OC1(c2cccnc2Br)CCC1
Agent: [Na+]
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1ncccc1C1(O)CCC1
Yield: 46.1 %

Procedure:
The title compound was prepared from sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (340 mg, 1.1 mmol) and 1-(2-bromopyridin-3-yl)cyclobutanol (228 mg, 1.0 mmol) according to the method of Example 6 Step 4. Purification by flash column chromatography eluting with a 0-10% diethyl ether/dichloromethane gradient gave 1-(2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}pyridin-3-yl)cyclobutanol (200 mg, 46%). 1H NMR (500 MHz, CDCl3) δ 8.61 (1H, s), 8.29 (1H, d, J=2.2 Hz), 8.10-8.04 (2H, m), 8.01 (1H, d, J=8.7 Hz), 7.95 (1H, dd, J=1.6, 8.6 Hz), 7.88-7.81 (2H, m), 7.73-7.64 (2H, m), 7.40 (1H, dd, J=4.5, 7.8 Hz), 7.23-7.15 (2H, m), 5.01 (1H, s), 2.78-2.68 (4H, m), 2.42-2.34 (1H, m), 1.86-1.78 (1H, m); m/z (ES+) 434 [MH+].
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.C(N(C(C)C)CC)(C)C.CC1C(C)=NC=CC=1N.[C:52](Cl)(=[O:54])[CH3:53]>ClCCl.O>[C:52]([O:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1)(=[O:54])[CH3:53]
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1[C@@H]1CCCC[C@H]1O
Reactant: CC(=O)Cl
Agent: Cc1nccc(N)c1C
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCCCC1n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reaction time: 0.33 h

Procedure:
(±)-2-(trans-2-Hydroxycyclohexyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 508, 50 mg, 0.11 mmol) was dissolved in dichloromethane (2 ml) and treated sequentially with diisopropylethylamine (0.028 ml, 0.16 mmol, 1.4 equiv), dimethyl-4-aminopyridine (1.4 mg, 0.011 mmol, 0.1 equiv) and acetyl chloride (0.014 ml, 0.19 mmol, 1.7 equiv). After stirring for 20 minutes, additional acetyl chloride (0.014 ml, 0.19 mmol, 1.7 equiv) was added and the mixture was stirred for an additional 20 minutes. The mixture was poured into water (15 mL) and extracted with dichloromethane (2×15 mL). The organic extracts were washed once with hydrochloric acid (10 mL, 1 N aqueous) and sodium bicarbonate (10 mL, aqueous saturated), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 80:20; dichloromethane:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.38 (1H, dd, J=6.1, 3.4 Hz), 8.36 (1H, s), 7.90 (1H, d, J=2.4 Hz), 7.72-7.70 (3H, m), 7.46-7.42 (2H, m), 7.39-7.36 (1H, m), 7.29-7.26, (2H, m), 6.47 (1H, dd, J=2.2, 1.9 Hz), 5.47 (1H, d, J=16.7 Hz), 5.42 (1H, d, J=16.2 Hz), 5.32-5.26 (1H, m), 4.56-4.49 (1H, m), 216-2.19 (2H, m), 2.13-1.99 (2H, m), 1.87 (3H, s), 1.89-1.81 (2H, m), 1.54-1.47 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 482.2202 [(M+H)+; calculated for C28H28N5O3: 482.2187].
Reaction SMILES: I[C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][CH:6]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[CH2:21]1COCC1>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]([OH:18])[C:2]2[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][N:5]([CH3:21])[CH:6]=2)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1n[nH]cc1I
Product: CCOC(=O)c1nn(C)cc1C(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a stirred solution of ethyl 4-iodo-1H-pyrazole-3-carboxylate (Step 10.1) (2 g, 7.14 mmol) in THF (40 mL) under Ar was added TurboGrignard (5.77 mL, 7.50 mmol) at −10° C. After 30 min, 4-chlorobenzaldehyde (1.004 g, 7.14 mmol) was added. The reaction mixture was stirred for 60 min at rt, quenched with a saturated aq. NH4Cl solution, and extracted EtOAc. The combined organic layers were washed a saturated aq. NH4Cl solution, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 35-55%) to afford the title product (1.73 g, 5.87 mmol, 82% yield) as a colorless oil. tR: 4.10 min (HPLC 1); tR: 0.89 min (LC-MS 2); ESI-MS: 277/279 [M-18] (LC-MS 2); Rf=0.15 (hexane/EtOAc 1:1).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[C:28]3[C:27]4[C@@H:26]([CH2:29][CH:30]=[O:31])[CH2:25][CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:32][Mg+].[Br-]>C1COCC1>[OH:31][C@H:30]([CH3:32])[CH2:29][C@H:26]1[CH2:25][CH2:24][C:23]2[S:22][C:21]3[N:20]=[CH:19][N:18]=[C:17]([O:16][CH:13]4[CH2:14][CH2:15][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH2:11][CH2:12]4)[C:28]=3[C:27]1=2.[OH:31][C@@H:30]([CH3:32])[CH2:29][C@H:26]1[CH2:25][CH2:24][C:23]2[S:22][C:21]3[N:20]=[CH:19][N:18]=[C:17]([O:16][CH:13]4[CH2:14][CH2:15][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH2:11][CH2:12]4)[C:28]=3[C:27]1=2
Reactant: C[Mg+]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC=O)CC4)CC1
Agent: [Br-]
Solvent: C1CCOC1
Product: C[C@@H](O)C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21
Product: C[C@H](O)C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 25 %
Yield: 33 %

Procedure:
A 50-mL round-bottom flask containing a solution of tert-butyl N-methyl-N-(4-[[(3R)-3-(2-oxoethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (500 mg, 1.12 mmol, 1.00 equiv) in anhydrous THF (20 mL) was cooled down to 0° C. under nitrogen. Then CH3MgBr (1 M in THF, 3.36 mL) was added dropwise via syringe and the resulting solution was stirred for 2 h at 0° C. The reaction was then quenched with saturated aqueous NH4Cl and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) to give the desired tert-butyl N-(4-[[(3R)-3-[(2R)-2-hydroxypropyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (192.1, 170 mg, 33%) as a colorless oil and tert-butyl N-(4-[[(3R)-3-[(2S)-2-hydroxypropyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (130 mg, 25%) as a colorless oil, respectively.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](F)[CH:3]=1.[CH2:12]([Mg]Br)[CH:13]([CH3:15])[CH3:14].[CH2:18](OCC)C>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:18])=[O:7])=[C:4]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CC(C)C[Mg]Br
Reactant: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Br)cc1CC(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-fluorobenzoic acid (2.0 g) in tetrahydrofran (15 ml) was added 2M isobutylmagnesium bromide in diethyl ether (13.5 ml) dropwise on ice-cooling, and the mixture was stirred at 0° C. for 1 hour. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. To the solution of the residue in N,N-dimethylformamide (20 ml) was added methyliodide (1.14 g) and potassium carbonate (1.89 g), and the mixture was stirred at 20° C. for 3 hours. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give methyl 4-bromo-2-isobutylbenzoate (1.5 g) as a colorless oil.