Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=[O:3])C.C([O-])(=O)C.[Na+].[Br:10][C:11]1[CH:12]=[C:13]([CH2:29][C:30]([OH:32])=[O:31])[CH:14]=[C:15]([Br:28])[C:16]=1[O:17][C:18]1[N:19]=[N:20][C:21](Cl)=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=1>C1(C)C=CC=CC=1>[Br:10][C:11]1[CH:12]=[C:13]([CH2:29][C:30]([OH:32])=[O:31])[CH:14]=[C:15]([Br:28])[C:16]=1[O:17][C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:3])[NH:20][N:19]=1
Reactant: CC(=O)O
Reactant: CC(C)c1cc(Oc2c(Br)cc(CC(=O)O)cc2Br)nnc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)c1cc(Oc2c(Br)cc(CC(=O)O)cc2Br)n[nH]c1=O
Temperature: 120 °C
Yield: 73 %

Procedure:
A solution of 2-[3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-ethanol (12) (111.4 g, 247 mmol) in acetonitrile (223 mL), methylene chloride (343 mL) and sodium phosphate buffer (343 mL of a 0.67 M solution, pH=6.7) was treated with 2,2,6,6-tetramethyl-1-piperidinyloxy free group (2.35 g, 14.83 mmol) at room temperature. A solution of sodium chlorite (44.71 g, 395.5 mmol) in water (135 mL) and a solution of sodium hypochlorite (28 mL, 24.5 mmol) in water (50 mL) were then added simultaneously to the reaction mixture over 45 min. The temperature of the reaction mixture rose to 40° C. during the addition and a cold water bath was used to prevent the temperature from going any higher. The brown reaction mixture was stirred for 30 min. While cooling with cold water, a solution of sodium bisulfite (28.42 g, 297 mmol) in water (86 mL) was added dropwise to the reaction mixture over 5 min. The yellow solution was diluted with methylene chloride (223 mL) and extracted. The layers were separated and the organic layer was extracted with water (2×200 mL), dried with sodium sulfate, filtered and concentrated under vacuum to afford [3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-acetic acid (13). Glacial acetic acid (549 mL) and sodium acetate (40.56 g, 494 mmol) were added to [3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-acetic acid (13). The reaction mixture was heated to 120° C. for 24 h. At this time, the reaction mixture was cooled to room temperature, diluted with toluene (200 mL) and concentrated under vacuum two times. The resulting residue was diluted with tetrahydrofuran (223 mL) and isopropyl acetate (892 mL) and was washed with water (3×150 mL). The organic layer was separated and concentrated under vacuum to about 600 mL. Isopropyl acetate (180 mL) was added and the mixture was concentrated under vacuum to about 450 mL. Heptane (300 mL) was added in portions over 10 min. The mixture was stirred under reflux for 15 min and then was cooled to room temperature. The resulting solid was filtered, washed with 50% isopropyl acetate in heptane (200 mL), and dried under high vacuum overnight to afford [3,5-dibromo-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-acetic acid (14) (80.4 g, 73%) as a white solid; LRMS for C15H14Br2N2O4 (M+H) m/z=446. Molecular Weight=446.0978; Exact Mass=443.9320
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)#[CH:21]>>[C:20]([C:22]1[CH:23]=[C:24]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:27]=[CH:28][CH:29]=1)#[CH:21]
Reactant: C#Cc1cccc(C=O)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: C#Cc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-ethynylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-ethynylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C[O-].[Na+].[Cl:4][CH:5](Cl)[C:6]1[S:7][CH2:8][CH:9]([C:11]([O:13][CH2:14]C)=[O:12])[N:10]=1.C(Cl)Cl.O>CO>[Cl:4][CH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=1
Reactant: CCOC(=O)C1CSC(C(Cl)Cl)=N1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)c1csc(CCl)n1
Reaction time: 1 h
Yield: 87.4 %

Procedure:
Sodium methoxide (25% w/w in MeOH (44.62 g, 206.5 mmol)) was added slowly, (over 55 min.) whilst maintaining the temperature between 0 and 10° C., to ethyl 2-(dichloromethyl)-4,5-dihydro-1,3-thiazole-4-carboxylate (50.0 g, 206.5 mmol) in 50 mL of MeOH. An additional 50 mL of MeOH was added and stirred for 1 h. keeping the temperature below 10° C. DCM (125 mL) and water (71 mL) was added to the mixture and the organic layer was separated. The aqueous layer was extracted with a further 71 mL of DCM. The combined organic layers was dried over MgSO4 and evaporated in vacuo to give the crude product (34.6 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:35]=[C:36]([NH2:41])[CH2:37][CH2:38][O:39][CH3:40]>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:41]=[C:36]([CH2:37][CH2:38][O:39][CH3:40])[N:35]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Reactant: COCCC(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COCCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (500 mg, 1.70 mmol) in dichloromethane (30 ml) was treated with 1,1′-carbonyidiimidazole (272 mg, 1.70 mmol) and the solution was stirred at room temperature for 1 hour. N′-hydroxy-3-methoxypropanimidamide (J.Amer.Chem.Soc.; 80; 1958; 3769-3771) (201 mg, 1.70 mmol) was then added and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was heated neat at 120° C. under a nitrogen atmosphere for 2 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1) to afford the title compound as a colourless oil (410 mg).
Reaction SMILES: [OH:1][CH:2]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])/[CH:3]=[CH:4]/[C:5]1[N:10]=[C:9]([CH2:11][CH:12]2[O:16][C:15](=[O:17])[CH2:14][CH2:13]2)[CH:8]=[CH:7][CH:6]=1.[OH-:26].[Na+]>CO>[OH:16][CH:12]([CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5](/[CH:4]=[CH:3]/[CH:2]([OH:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:10]=1)[CH2:13][CH2:14][C:15]([OH:26])=[O:17]
Reactant: [OH-]
Reactant: CCCCCCCCC(O)/C=C/c1cccc(CC2CCC(=O)O2)n1
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/c1cccc(CC(O)CCC(=O)O)n1

Procedure:
Under the conditions of example 2, 30 mg of 5-(6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-2-pyridyl-methyl)-tetrahydrofuran-2-one in 2 ml of methanol is saponified with 1 ml of 1 n sodium hydroxide solution and worked up. 20 mg of the title compound is obtained as oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([O:13][Si](C)(C)C)[C:11]#N)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C(Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:13])[CH2:11][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: BrCc1ccccc1
Reactant: CSc1ccc(C(C#N)O[Si](C)(C)C)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccc(C(=O)Cc2ccccc2)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
The 3-fluoro-4-(methylthio)-a-[(trimethylsilyl)-oxy]-benzeneacetonitrile (40.1 g, 149 mmol) was cooled to −78° C. in tetrahydrofuran(400 mL). Lithium hexamethydisilazide (175 mL of 1.0 M in Hexanes, 175 mmol) was added dropwise over 1 hour. The solution was stirred for 1 additional hour at −78° C. Benzylbromide (24.5 g 149 mmol) was added as a solution in tetrahydrofuran (100 mL) over 25 minutes. The solution was kept at −78° C. for 1 hour, warmed to room temperature, and kept at room temperature for six hours. The solution was poured into ethyl acetate (300 mL). Aqueous 1 N hydrochloric acid (200 mL) was added and the solution stirred for 48 hours at room temperature. The layers were separated and the organic layer collected. The organic layer was mixed with aqueous 15% sodium hydroxide and stirred for 30 minutes. The organic layer was collected washed with saturated ammounium chloride(200 mL) and solution was dried over sodium sulfate and solvent removed at reduced pressure to afford a yellow oil. The product was isolated by preparative silica chromatography followed by crystallization from 2% ethyl acetate and hexanes (400 mL). 1-[3-fluoro-4-(methylthio)phenyl]-2-phenylethanone (21.5 grams, 82.0 mmol) was obtained as white crystals. (55% yield): Mp 77.1-77.2° C. 1H NMR (CDCl3/300 MHz) 7.77, (dd, 1H, J=8.0, 1.8 Hz), 7.64 (dd, 1H, J=10.7, 1.8 Hz), 7.20-7.40 (m, 6H), 4.22 (s, 3H), 2.51 (s, 1H).
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.[Br:27][C:28]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C(Cl)Cl>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:36]([N+:37]([O-:39])=[O:38])[C:28]=4[Br:27])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: CN(C)CCNc1ccnc2cc3c(cc12)OCO3
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCN(C(=O)c1cccc([N+](=O)[O-])c1Br)c1ccnc2cc3c(cc12)OCO3
Yield: 73.9 %

Procedure:
To a solution of compound 7 (259 mg, 1.0 mmol) and triethylamine (0.5 mL) in dry CH2Cl2 (20 mL) was added a solution of 2-bromo-3-nitrobenzoic acid chloride in 20 mL of CH2Cl2 (which was prepared by refluxing of 295 mg, 1.2 mmol of 2-bromo-3-nitrobenzoic acid in 10 mL of thionyl chloride for 4 h). The reaction mixture was heated to reflux for 6 h. The reaction mixture was allowed to cool and then washed with saturated NaHCO3 solution, water and brine and dried over Na2SO4. Solvent was removed in vacuo to give 360 mg of a yellow solid (73.9%); mp 96–97° C.; 1H NMR (CDCl3) δ 2.30 (s, 6H), 2.62 (t, 2H, J=6.6), 3.59–3.69 (m, 1H), 4.53–4.67 (m, 1H), 6.18 (d, 2H, J=5.2), 7.05 (d, 1H, J=7.8), 7.14 (d, 1H, J=7.4) 7.28–7.36 (m, 3H) 7.50 (dd, 1H, J=1.2, 7.8), 8.55 (d, 1H, J=3.8); 13C NMR (CDCl3) δ 45.4, 46.5, 56.4, 97.8, 102.3, 106.7, 112.2, 119.5, 122.6, 125.2, 127.7, 129.7, 140.8, 144.6, 148.3, 148.5, 149.5, 151.4, 166.9
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:19]1[C:30]2[C:29]3[CH2:28][CH2:27][CH2:26][C:25]=3[S:24][C:23]=2[N:22]=[CH:21][N:20]=1>O1CCCC1>[C:30]12[C:19]([O:1][CH:2]3[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]3)=[N:20][CH:21]=[N:22][C:23]=1[S:24][C:25]1[CH2:26][CH2:27][CH2:28][C:29]2=1
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Reactant: Clc1ncnc2sc3c(c12)CCC3
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (194 mg, 0.90 mmol, 1.40 equiv) in anhydrous tetrahydrofuran (5 mL) was added sodium hydride (60% dispersion in mineral oil, 77 mg, 1.92 mmol, 3.00 equiv) at 0° C. under nitrogen. After stirred at room temperature for 1 h, 12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraene (200 mg, 0.95 mmol, 1.00 equiv) was added and the resulting solution was stirred overnight at ambient temperature for additional 5 h. The reaction was then quenched with water and extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to give the resulted tert-butyl N-(4-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yloxy]cyclohexyl)carbamate (308 mg, 83%) as a yellow solid. MS (ES, m/z): 390 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3([CH2:16][CH2:15][CH2:14]3)[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34].C(O)(C(F)(F)F)=O>>[CH:17]1([N:7]2[CH2:8][C:9]3([CH2:16][CH2:15][CH2:14]3)[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C2(CCC2)CN(C2CCCC2)c2nc(Cl)ncc21
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CCC1)C(=O)N2C
Yield: 75.2 %

Procedure:
2′-Chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (Intermediate 4) (1.02 g, 3.18 mmol, 1 eq), 4-amino-3-methoxybenzoic acid (1.6 g, 9.5 mmol, 3 eq) and TFA (1.2 mL, 15.9 mmol, 5 eq) were heated to reflux in TFE (40 mL) for 24 hours. Solvent was evaporated in vacuo and the resulting residue was triturated with EtOAc to give 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (1.08 g, 75%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([CH:22]2[O:24][CH2:23]2)=[CH:20][CH:19]=1.[H-].[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:23][CH:22]([C:21]3[CH:25]=[CH:26][C:18]([CH3:17])=[CH:19][CH:20]=3)[OH:24])[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Reactant: Cc1ccc(C2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCc2c(c3cc(C)ccc3n2CC(O)c2ccc(C)cc2)C1
Yield: 14.3 %

Procedure:
2-Ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (214 mg, 1 mmol), 4-methylstyrene oxide (1 mL, 7.5 mmol) and NaH (120 mg, 3 mmol) were heated in DMF (4 mL) at 120° C. for 16 h (overnight) to obtain 50 mg of racemic-2-(2-ethyl-1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol as a TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL). 1H NMR (CDCl3, TFA salt) δ (ppm): 13.20 (bs, 1H), 7.4-7.0 (m, 7H), 5.05-4.97 (m, 1H), 4.70 (t, 1H), 4.25-4.10 (m, 3H), 3.70-3.60 (m, 1H), 3.40-3.10 (m, 5H), 2.5 (s, 3H), 2.38 (s, 3H), 1.41 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.[OH-].[K+]>CO.[Cu]>[CH3:12][O:11][C:5]1[CH:4]=[N:3][C:2]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2
Reactant: COc1cnc(Cl)c2[nH]ccc12
Reactant: c1nc[nH]n1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cnc(-n2cncn2)c2[nH]ccc12
Temperature: 160 °C
Yield: 57.6 %

Procedure:
A mixture of 7-chloro-4-methoxy-6-azaindole (1.029 g, 5.62 mmol), 1,2,4-triazole (11.6 g, 30 equiv), copper bronze (0.72 g, 11.2 mgatom) and finely pulverized KOH (0.63 g, 11.2 mmol) was heated in a sealed tube at 160° C. (oil bath temperature) for 18 h. The cooled mixture was taken up in MeOH and the resulting slurry was filtered through a pad of Celite. The filtrate was evaporated, the residue taken up in EtOAc and the resulting suspension was filtered. This process was repeated and the resulting solution was susequently adsorbed on silica gel and the volatiles were removed in vacuo. This solid was applied to the top of a silica gel chromatography column, which was eluted with 10-50% EtOAc—CH2Cl2 to give the title compound (0.697 g, 58%) as an off-white solid:
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:9](O)[C:10]#[C:11][C:12]([O:14]CC)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C>[C:22]([O:21][C:19]([NH:18][C@H:8]([C@H:9]1[O:14][C:12](=[O:13])[CH2:11][CH2:10]1)[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:20])([CH3:23])([CH3:24])[CH3:25]
Reactant: CCOC(=O)C#CC(O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1
Yield: 35 %

Procedure:
A solution of 9.25 g of the oily ethyl (4RS, 5S)-6-cyclohexyl-5-(t-butoxycarbonylamino)-4-hydroxy-2-hexynate (prepared as described in Preparation 4) in 100 ml of ethyl acetate was subjected to a catalytic hydrogenation reaction using a Paar's apparatus in the presence of 5 g of 5% w/w palladium-onbarium sulfate at about 4 atmospheres pressure for 4 hours. At the end of this time, the catalyst was removed by filtration, and the filtrate was condensed by evaporation under reduced pressure. The residue was then dissolved in 120 ml of toluene, 3 ml of acetic acid was added to the resulting solution, and the mixture was heated under reflux for 3 hours. The solvent was then removed by distillation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 2:1 by volume mixture of hexane and diethyl ether as eluent), to give 3.71 g [yield 35% from N-(t-butoxycarbonyl)-L-cyclohexylalaninol] of the title compound as the product of lesser polarity.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(Cl)CCl.[F:13][N+]1C(S([O-])(=O)=O)=CC=CC=1Cl>>[F:13][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7].[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)([O-])c1cccc(Cl)[n+]1F
Solvent: ClCC(Cl)Cl
Solvent: Oc1ccccc1
Product: Oc1ccccc1F

Procedure:
A 25 ml egg-plant type flask was flushed with argon, and 42.4 mg (0.45 mmol) of phenol, 2 ml of dry 1,1,2-trichloroethane and 95.3 mg (0.45 mmol) of N-fluoro-2-chloropyridinium-6-sulfonate were charged. The flask was immersed in an oil bath of 100° C. and heated for 49 hours. After completion of the reaction, the reaction solution was washed with water to remove 2-chloropyridine-6-sulfonic acid. The organic layer was quantitatively analyzed by gas chromatography. o-Fluorophenol was obtained at a conversion yield of 58%, and phenol was recovered at a recovery rate of 5%.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[N:9]2)[CH2:4][O:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:16])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](Cn2ccc([N+](=O)[O-])n2)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Yield: 98.5 %

Procedure:
1-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-3-nitro-1H-pyrazole (14.5 g) in ethanol (60 mL) was treated with 10% palladium on activated carbon (1.4 g). The mixture was placed on a Parr shaker and exposed to hydrogen (50 psi) for 16 h. After this time, the mixture was filtered through diatomaceous earth. The filtrate was concentrated in vacuo to afford 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (12.4 g, 98%) as an amorphous yellow oil; ESI-LRMS m/e calcd for C9H15N3O2 [M+H+] 198, found 198 [M+H+]. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.24 (s, 3H), 1.30 (s, 3H), 3.70 (dd, J=8.5, 6.0 Hz, 1H), 3.85-4.02 (m, 3H), 4.28 (quin, J=6.0 Hz, 1H), 4.56 (s, 2H), 5.36 (d, J=2.1 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([C:22]#[N:23])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C[Si]([N:35]=[N+:36]=[N-:37])(C)C.C([Sn](=O)CCCC)CCC>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]2[NH:37][N:36]=[N:35][N:23]=2)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21]
Reactant: Cc1nc2c(Cl)ccc(C#N)c2c(C)c1Cc1ccc(Cl)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc2c(Cl)ccc(-c3nnn[nH]3)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of 8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinoline-5-carbonitrile (0.048 g), toluene (1.5 mL), trimethylsilyl azide (0.081 g) and dibutyltin oxide (0.007 g) were sealed in a flask and heated at 100° C. for 66 hours. The mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution and the pH of the aqueous phase was adjusted to 5 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration, washed with diluted aqueous acetic acid solution and dried to afford title compound as a white solid, 0.017 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[O:12]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[CH:15][CH:14]=[N:13]1>C(#N)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:27]([NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[O:12][N:13]=[CH:14][CH:15]=2)(=[O:25])=[O:24])=[O:28])[N:7]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1-c1ccno1
Reactant: COc1cc(OC)nc(N)n1
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2ccno2)n1
Temperature: 40 °C
Reaction time: 10 h
Yield: 7.7 %

Procedure:
To a suspension of 2.5 g of 2-amino-4,6-dimethoxypyrimidine in 25 ml of acetonitrile was added 4 g of crude 2-(isoxazol-5-yl)benzenesulfonyl isocyanate prepared in Example 7. The resulting suspension was warmed at 40° C. for about 3 minutes to form a solution. The solution was stirred at room temperature for 10 hours, then concentrated in vacuo to give a viscous oil. The oil was chromatographed in a dry column of silica gel with ethyl acetate as eluant. The first fraction from the column was concentrated in vacuo to yield a solid. The solid was washed 1×10 ml of acetonitrile and suction dried to yield 0.5 g of the title compound; m.p. 183°-187° C. The IR spectrum showed a carbonyl absorption at 1710 cm-1 indicative of a sulfonylurea.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:6](=[O:23])[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=2.COC(=O)C.[C:30]([O:34][C:35](=[O:41])[NH:36][CH2:37][CH2:38][CH2:39]Br)([CH3:33])([CH3:32])[CH3:31]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:6](=[O:23])[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH2:39][CH2:38][CH2:37][NH:36][C:35]([O:34][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:41])[CH:9]=2
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: COC(=O)Cc1cc2ccc(O)cc2n(Cc2ccccc2)c1=O
Solvent: COC(C)=O
Product: COC(=O)Cc1cc2ccc(OCCCNC(=O)OC(C)(C)C)cc2n(Cc2ccccc2)c1=O

Procedure:
The title compound was prepared using the procedure of Example 75 and (1-benzyl-7-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl)-acetic acid methyl ester in place of 7-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)acetic acid methyl ester and (3-bromopropyl)carbamic acid tert-butyl ester in place of (2-bromoethyl)carbamic acid tert-butyl ester.