Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]([CH:8]([C:14](OCC)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])[CH2:2][CH2:3][CH3:4].C1(C(CCC)(CCC)C(C(C(OCC)=O)C(OCC)=O)=O)C=CC=CC=1>>[CH2:19]([C:5]1([CH2:1][CH2:2][CH2:3][CH3:4])[C:23]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]([OH:15])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]1=[O:7])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(CCCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccccc1
Agent: CCCC(CCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccccc1
Product: CCCCC1(CCCC)C(=O)C(C(=O)OCC)=C(O)c2ccccc21
Yield: 21 %

Procedure:
The title compound (1.2 g, 21%) was prepared following the procedure of Example 1F, substituting the product of Example 4E for the product of Example 1E. 1H NMR (300 MHz, CDCl3): δ 15.16 (d, J=13.97 Hz, 1 H), 8.22 (m, 1 H), 7.59 (m, 2 H), 7.36 (m, 2 H), 4.47 (m, 2 H), 2.25 (m, 2 H), 1.92 (m, 2 H), 1.71 (m, 2 H), 1.50 (m, 2 H), 1.24 (m, 2 H), 1.11 (m, 2 H), 0.89 (m, 1 H), 0.65 (m, 7 H).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>N1C=CC=CC=1.CCOC(C)=O>[S:11]([O:1][CH:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C1CC(O)C1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1CC(OS(=O)(=O)c2ccc(C)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-hydroxycyclobutanecarboxylate (10.2 g, 78.4 mmol) in dry pyridine (56.5 mL) at 0° C., TsCl (14.9 g, 78.4 mmol) was added portionwise. The resulting mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and the residue obtained was dissolved in EtOAc (100 mL) and sequentially washed with 2 N HCl (100 mL), saturated NaHCO3 (100 mL) and water (100 mL). The EtOAc layer was dried over Na2SO4, filtered, and concentrated to obtain ethyl 3-(tosyloxy)cyclobutanecarboxylate as a pale yellow oil, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl.CN(C=O)C>[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: OCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCCO)cc1
Reaction time: 2.5 h
Yield: 29.4 %

Procedure:
To a solution of 1,5-pentanediol (30 g, 0.29 mol) in dichloromethane/DMF (15/1, 320 ml) were added triethylamine (38.1 ml, 0.274 mol), dimethylaminopyridine (7.04 g, 57.6 mmol) and p-toluenesulfonic acid chloride (49.42 g, 0.259 mol) were in turn added at -30° C. and the mixture was stirred for 2.5 hours. To the reaction mixture was added purified water (200 ml) and the aqueous layer was extracted with chloroform (150 ml×3). The combined organic layer was washed succcessively with 5% aqueous hydrochloric acid (200 ml), saturated aqueous sodium hydrogen carbonate (200 ml) and saturated aqueous sodium chloride (200 ml), dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was chromatographed over silica gel and the fraction from ethyl acetate-hexane (1/1) gave 19.65 g of 5-hydroxypentyl p-toluenesulfonate. Yield=26%.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C:11]2([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[OH-].[Na+].[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:36]2[CH2:38][O:37]2)=[CH:30][C:29]=1[F:47])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[F:47][C:29]1[CH:30]=[C:31]([CH:32]=[CH:33][C:28]=1[O:27][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:34][C@H:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:43])[CH3:44])[C@H:36]([OH:37])[CH2:38][NH:17][C:11]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)c1cccc(C2(N)CCCCC2)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(F)c1)[C@H]1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C2(NC[C@@H](O)[C@H](Cc3ccc(OCc4ccccc4)c(F)c3)NC(=O)OC(C)(C)C)CCCCC2)c1
Reaction time: 72 h
Yield: 53.4 %

Procedure:
The free base (270 mg, 1.24 mmol) of 1-(3-isopropylphenyl)cyclohexanamine hydrochloride 3 is obtained as a colorless oil by neutralization of the salt with 1N NaOH, extraction into ethyl acetate, drying over Na2SO4, and concentration. This is dissolved in 10 mL of CH2Cl2, and to it is added compound 17 (280 mg, 0.73 mmol) and 1.25 g of silica gel. The solvent is removed in vacuo and the reactants on silica are allowed to stand at ambient temperature for three days. The product mixture is eluted from the silica with 10% methanol in CH2Cl2, concentrated, and chromatographed on silica gel, eluting with 4% methanol (containing 2% NH4OH) in CH2Cl2, to afford compound 18 (238 mg, 0.39 mmol, 54%) as a colorless oil: 1H NMR (CDCl3) δ 7.43-7.26 (m, 8H), 7.12 (m, 1H), 6.94-6.84 (m, 3H), 5.09 (s, 2H), 4.64 (d, J=9 Hz, 1H), 3.80 (br, 1H), 3.31 (br, 1H), 2.92-2.83 (m, 2H), 2.7 (m, 1H), 2.37 (m, 2H), 2.0-1.95 (m, 4H), 1.67-1.50 (m, 5H), 1.35 (s+m, 10H), 1.25 (d, J=7 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([O:32][CH2:33][CH3:34])[C:30]=1F)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:23]=[N:24][NH:25][N:26]=3)[CH:17]=2)[CH2:10][CH2:9]1)[CH3:2].C(OC1C=C(C=C(OCC)C=1[N:46]1[CH:50]=[N:49][CH:48]=[N:47]1)C=O)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([O:32][CH2:33][CH3:34])[C:30]=1[N:46]1[CH:50]=[N:49][CH:48]=[N:47]1)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:23]=[N:24][NH:25][N:26]=3)[CH:17]=2)[CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cncn1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cccc(-c4nn[nH]n4)c3)CC2)cc(OCC)c1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc(-c4nn[nH]n4)c3)CC2)cc(OCC)c1-n1cncn1

Procedure:
In analogy to the procedure described in example 50k), N-piperidin-4-yl-3-(1H-tetrazol-5-yl)-benzamide (example 178) was reacted with 3,5-diethoxy-4-[1,2,4]triazol-1-yl-benzaldehyde (example 129a), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as light yellow solid. MS: 518.2 (MH+).
Reaction SMILES: CN1CCOCC1.[C:8]([OH:11])(=[O:10])[CH3:9].Cl[CH:13]([O:15][C:16]([CH2:18][NH:19][CH2:20][C:21]([O:23][CH:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:49])[C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:47])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH3:46])=[CH:34][C:33]=2[CH3:48])[C:26]2[CH:50]=[CH:51][C:52]([Cl:54])=[CH:53][C:25]1=2)=[O:22])=[O:17])[CH3:14]>O>[C:8]([O:11][CH:13]([O:15][C:16]([CH2:18][NH:19][CH2:20][C:21]([O:23][CH:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:49])[C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:47])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH3:46])=[CH:34][C:33]=2[CH3:48])[C:26]2[CH:50]=[CH:51][C:52]([Cl:54])=[CH:53][C:25]1=2)=[O:22])=[O:17])[CH3:14])(=[O:10])[CH3:9]
Reactant: CC(=O)O
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)CNCC(=O)OC(C)Cl)c3cc(Cl)ccc32)c(C)c1
Solvent: CN1CCOCC1
Solvent: O
Product: CC(=O)OC(C)OC(=O)CNCC(=O)OC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.4 %

Procedure:
N-methylmorpholine (0.31 ml, 2.8 mmol) was added dropwise to an acetic acid (0.32 ml, 5.6 mmol) solution of 7-chloro-1-[2-methyl-4-(2-methylbenzamido)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl [(1-chloroethoxycarbonyl)methylamino]acetate (0.35 g, 0.56 mmol) under cooling with ice, and the mixture was stirred at room temperature for two days. Water was added to the reaction mixture, and then the resulted precipitates were collected by filtration and air-dried. The dried product was purified by silica gel chromatography (n-hexane:ethyl acetate) to obtain 0.26 g (72%) of 7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl [(1-acetoxy-ethoxycarbonyl)methylamino]acetate as amorphous.
Reaction SMILES: C[N:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([OH:11])=[O:10])=[CH:4][C:3]1=[O:12].Cl[Si](C)(C)[CH3:15]>CO>[CH3:15][O:11][C:9]([C:5]1[CH:6]=[C:7]([CH3:8])[NH:2][C:3](=[O:12])[CH:4]=1)=[O:10]
Reactant: Cc1cc(C(=O)O)cc(=O)n1C
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1cc(C)[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 75.5 %

Procedure:
1,6-Dimethyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (1.0 g, 6.5 mmol) was suspended in dry methanol (8 mL) and chlorotrimethylsilane (2.8 g, 26 mmol) was added at room temperature. The reaction was stirred for 36 hours at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of dichloromethane/methanol (25 mL) and saturated aqueous sodium bicarbonate (25 mL) was added. A precipitate formed which was filtered off and washed with water and MTBE and air-dried. The filtrate was diluted with methanol/dichloromethane and water and the layers were separated. The aqueous layer was extracted once more with dichloromethane. The combined organic layers were dried (sodium sulfate), filtered and concentrated. Both the previously precipitated material and the concentrated organic layer consisted of product and were combined to afford of the title compound (820 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.CN1CCOCC1.[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[S:30](Cl)(=[O:32])=[O:31])#[N:20]>CC#N>[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[S:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1)(=[O:32])=[O:31])#[N:20]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: CN1CCOCC1
Solvent: CC#N
Product: N#Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (2.98 g, 20 mmol) and NMM in MeCN (150 ml) was added 2-cyano-4-nitrobenzene-1-sulfonyl chloride (5.423 g, 22 mmol) at 0° C., then the solution was stirred at room temperature for overnight. The mixture was concentrated in vacuo at room temperature, and DCM and water was added to the residue. The organic layer was dried over Na2SO4 and concentrated to give the crude product. It was purified by prep. HPLC (column: Luna 300×50.0 mm, 10 u; liquid phase: [A-H2O+0.025% TFA; B-MeCN] B %: 25%-50%, 25 min) to give the title compound (2.0 g, 27.86%) as a yellow solid. 1H NMR: DMSO 400 MHz. δ11.05 (s, 1H), 9.22 (s, 1H), 8.88 (s, 1H), 8.62 (d, J=11.2 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.45 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.18 (d, J=10.0 Hz, 1H), 4.89 (s, 2H). ESI-MS m/z 360 (M+H, positive); HPLC purity: 93.07% (MaxPlot 190-370 nm), 98.72% (220 nm).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10].[I-:12].[Na+]>CC(CC)=O>[I:12][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1nccn1CCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1nccn1CCI
Yield: 82.9 %

Procedure:
163.4 g of 1-(2-chloroethyl)-2-nitroimidazole and 200.4 g of sodium iodide were heated under reflux for 4.5 hours in 1 liter of ethyl methyl ketone. After cooling, the mixture was filtered, the solvent was evaporated off, the residue was partitioned between 2 liters of dichloromethane and 1 liter of water and the organic phase was washed twice with 1 liter of water each time and evaporated. Crystallization from 1 liter of isopropanol yielded 206 g of 1-(2-iodoethyl)-2-nitroimidazole, m.p. 79°-82° C.
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:12]1[N:16]([CH3:17])[CH:15]=[N:14][C:13]=1[CH:18]=[O:19].CS(C)=O>C(OCC)(=O)C>[C:2]1([S:8]([C:12]2[N:16]([CH3:17])[CH:15]=[N:14][C:13]=2[CH:18]=[O:19])(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cnc(C=O)c1Br
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cn1cnc(C=O)c1S(=O)(=O)c1ccccc1
Temperature: 180 °C
Yield: 61.2 %

Procedure:
A mixture of benzenesulfinic acid sodium salt (0.065 g), 5-bromo-1-methyl-1H-imidazole-4-carbaldehyde (0.037 g) and dimethyl sulfoxide (2.0 mL) was heated by microwave irradiation at 180° C. for 10 minutes. The mixture was treated with additional benzenesulfinic acid sodium salt (0.065 g), and heated by microwave irradiation at 180° C. for 40 minutes. The mixture was diluted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was triturated with cyclohexane to afford a yellow solid. The solid was collected by filtration, washed with cyclohexane and dried to afford the title compound (0.030 g).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]([NH2:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].[OH-].[Na+].C([O:15][C:16](=O)[CH2:17][CH2:18][CH:19]=O)C>O>[CH2:4]([CH:3]1[N:2]2[C:16](=[O:15])[CH2:17][CH2:18][CH:19]2[NH:10][C:8]1=[O:9])[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)CC(N)C(N)=O
Reactant: CCOC(=O)CCC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CC1C(=O)NC2CCC(=O)N21
Yield: 74.7 %

Procedure:
To a solution of DL-leucinamide hydrochloride (1.5 g, 9 mmol) in water (40 ml), adjusted to pH 9.5 with 10% sodium hydroxide, ethyl-4-oxobutanoate (1g, 7.5 mmol) was added. The mixture was placed in a microwave oven and refluxed for 1 hour. Water was then evaporated under vacuum and the residue was chromatographated over silica gel (CH2Cl2/MeOH/NH4OH 98/2/0.1) to afford 1.1 g of the title compound.
Reaction SMILES: C([Li])CCC.[C:6]([NH:13][C@H:14]([CH2:16][OH:17])[CH3:15])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[S:18](Cl)(Cl)=[O:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:25]>CCCCCC.O1CCCC1.C(OCC)(=O)C>[C:9]([O:8][C:6]([N:13]1[C@@H:14]([CH3:15])[CH2:16][O:17][S:18]1(=[O:19])=[O:25])=[O:7])([CH3:11])([CH3:10])[CH3:12]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=S(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 0.75 h

Procedure:
120 ml of a ca 1.6 M solution of n-butyllithium in n-hexane was added with stirring during 15 min. to a solution of 17.5 g (S)-N-BOC-alaninol in 120 ml tetrahydrofuran at −78° C. The mixture was then stirred at −15° C. for 45 min. The mixture was then cooled to −78° C. and a solution of 7.3 mL thionyl chloride in 50 mL THF, cooled to −78° C. in a jacketed dropping funnel, was added at once with vigorous stirring. The temperature rose to ca −38° C. The mixture was then stirred at −15° C. for 1 h. The reaction mixture was distributed between 10% citric acid and ethyl acetate. The phases separated, the organic phase was washed with 10% sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was taken up in 150 mL ethyl acetate and a solution of 35 g sodium metaperiodate was added at 0° C. 0.20 g ruthenium dioxide hydrate was added to the well stirred mixture. The mixture was stirred at room temperature for 1.5 h. The phases were separated. The organic phase was purified by chromatography on silica gel with ethyl acetate: hexane=2: 1 to yield 13.79 g (S)-4-Methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester as white crystals melting at 121.1-121.8° C. after recrystallisation from t-butylmethylether.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH:15][C@H:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH:15][C@H:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: COC(=O)[C@H](NC(=O)c1cc(-c2ccc(N)cc2)no1)C(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](NC(=O)c1cc(-c2ccc(NS(=O)(=O)c3ccccc3F)cc2)no1)C(C)C
Reaction time: 0.17 h
Yield: 54.9 %

Procedure:
To a solution of 500 mg (1.57 mmol) of (R)-methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate (example 151, step 3) in DCM, 1.2 eq of pyridine was added and stirred for 10 minutes, then 368 mg (1.89 mmol) 2-fluorobenzene-1-sulfonyl chloride was added and the reaction mixture was stirred for 3 hours. DCM was removed under vacuum, the reaction mixture was washed with 1NHCl and extracted with EtOAc. The organic layer was concentrated and purified by precipitation using DCM and petroleum ether to yield 410 mg (86%) of title compound. MS (ESI): m/z 476(M+H)+; 1HNMR (DMSO-d6, 300 MHz): δ 11.039 (s, 1H), 9.215 (d, 1H), 7.942 (m, 1H), 7.805 (d, 2H), 7.718 (m, 1H), 7.625 (s, 1H), 7.465 (m, 2H), 7.271(d, 2H), 4.314 (t, 1H), 3.690 (s, 3H), 2.228 (m, 1H), 0.971 (d, 6H).
Reaction SMILES: [C:1]([C:3]12[CH:12]3[CH:13]=[C:14]([C:15]#N)[CH:9]([CH2:10][N:11]3[CH3:17])[CH:8]1[CH2:7][N:6]([CH3:18])[CH2:5][CH2:4]2)#[N:2].[C:19]1([Li])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.C1C[O:30]CC1>C(=O)=O.CC(C)=O.C1C=CC=CC=1>[C:15]([C:14]1[CH:9]2[CH2:10][N:11]([CH3:17])[CH:12]([CH:13]=1)[C:3]1([C:1]#[N:2])[CH:8]2[CH2:7][N:6]([CH3:18])[CH2:5][CH2:4]1)(=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [Li]c1ccccc1
Reactant: C1CCOC1
Reactant: CN1CCC2(C#N)C(C1)C1CN(C)C2C=C1C#N
Agent: Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CN1CCC2(C#N)C(C1)C1CN(C)C2C=C1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
A solution of 12.12 g (50 mM) of 7,11-dicyano-4,9-dimethyl-4,9-diazatricyclo[6.2.2.02,7 ]dodec-11-ene in 150 ml of dried THF is cooled in dry ice-acetone and treated with 26 ml of 1.67 molar (43.5 mM) phenyl lithium in benzene over a 15 minute period. The reaction mixture is allowed to stir at room temperature overnight and then treated with 50 ml of 2.5 N hydrochloric acid. The layers are separated and the tetrahydrofuranbenzene layer is extracted with 20 ml of 1 N hydrochloric acid. The combined product-containing hydrochloric acid layers are washed with methylene chloride and allowed to sit at room temperature for 2 hours. After making alkaline with 5 ml of 50% sodium hydroxide solution the product is extracted into a total of 125 ml of methylene chloride which after drying over MgSO4, and concentration yields 11.35 g of a crude product. By chromatography over silica gel 11-benzoyl-7-cyano-4,9-dimethyl-4,9 -diazatricyclo[6.2.2.02,7 ]dodec-11-ene is isolated analytically pure in an overall yield of 16%, m.p. 120°-139° C., NMR and IR spectrum are in accord with the structure.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(#N)C>[CH:14]1([NH:20][CH2:2][C:3]([N:5]2[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]2[C:12]#[N:13])=[O:4])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCC1
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.035 g, 0.178 mmol, Example 8D) in acetonitrile (3 mL ) at room temperature under nitrogen was added cyclohexylamine (0.041 mL, 0.356 mmol ), The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was flash chromatographed with 2-3% MeOH/CH2Cl2 to provide the desired compound as a pale yellow oil. MS (DCI) m/z 260 (M+H)+; 1H NMR (300 MHz, DMSO) δ 1.5-2 (10H, m), 2.13-2.31 (2H, m), 2.41-2.48 (2H, m), 3.76 (1H, d), 3.8-4.5 (2H, m), 4.53-4.55 (1H, t), 4.9 (1H, m), 5.05 (1H, m).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](O)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]1[O:22][C@@H:21]1[CH2:23]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O>>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:23][C@@H:21]2[O:22][CH2:20]2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cnn(Cc2ccccc2)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(Cn2cc(C[C@H]3CO3)cn2)cc1
Yield: 73.1 %

Procedure:
1-Benzyl-4-hydroxypyrazoLe (2 g, 11.5 mmol), potassium carbonate(3.2 g, 23 mmol), and (2s)-glycidyl-3-nitrobenzenesulfonate (2.98 g, 11.5 mmol) were slurried in actone (300 ml) at reflux for 17 hours. The acetone was removed in vacuo, the residue extracted from brine with chloroform, and dried over sodium sulfate. The solvent was removed again and the residue purified by column chromatography (silica gel, chloroform→1% methanol/chloroform) to yield product (1.8 g, 68%). MS, NMR.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCOCC1.O.[CH3:17][C:18]1[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([CH3:29])OC(=O)[CH:19]=1>C1(C)C=CC=CC=1>[CH3:29][C:22]1[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:18]([CH3:19])[CH:17]=[CH:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c(C)cc(=O)oc1C
Reactant: O=CCc1ccccc1
Solvent: O
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)ccc(-c2ccccc2)c1C
Yield: 55.6 %

Procedure:
A stirred solution of phenylacetaldehyde (77.0 g, 0.64 mole) and morpholine (56.0 g, 0.64 mole) in toluene (500 ml) was heated at reflux until the theoretical amount of water was collected in a Dean-Stark trap. The reaction mixture was cooled slightly, and ethyl 4,6-dimethyl-2-oxo-2H-pyran-5-carboxylate (125.0 g, 0.64 mole) was added. The solvent was distilled from the reaction mixture at atmospheric pressure to leave a residue. The residue was then heated at 200° for 2.5 hours. A Dean-Stark trap was used to collect the distilled morpholine. The remaining pot residue was cooled and slurried with a mixture of silica gel (700 g) and methylene chloride (1500 ml) for 45 minutes. The slurry was filtered and the filter cake rinsed with methylene chloride (500 ml). The combined filtrates were evaporated under reduced pressure to leave a thick brown residue. This residue was distilled under reduced pressure to give several fractions. All fractions which contained more than 73% product by gc analysis were combined to give a total of 90.5 g crude ethyl 2,4-dimethyl-[1,1'-biphenyl]-3-carboxylate.