Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH:5][C:6](=[O:8])[CH3:7].[H-].C([Al+]CC(C)C)C(C)C>COCCOC.C1(C)C=CC=CC=1>[C:6]([NH:5][C@H:4]([CH:3]=[O:2])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[CH3:7]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: CC(=O)N[C@H](C=O)Cc1ccccc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
N-Acetylphenylalanine methyl ester (4.2 g, 19 mmol) was dissolved in ethylene glycol dimethyl ether. The solution was cooled to -70° C. and diisobutylaluminum hydride (25.3 mL of a 1.5M solution in toluene, 39 mmol) was added. The resulting reaction mixture was stirred at -70° C. for 2 hours. The reaction was quenched by addition of 2N hydrochloric acid. The mixture was extracted 4 times with cold ethyl acetate and 4 times with toluene. The extracts were combined, washed with brine and dried over magnesium sulfate. Concentration in vacuo followed by silica gel chromatography furnished 2.7 g of a white solid. The NMR was identical to that reported in the literature, Biochemistry, 1979, 18, 921-926.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]4[CH2:20][CH2:19]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C@:28]([OH:32])([C:30]#[CH:31])[CH3:29])[CH:24]=1>>[CH:18]1([C:12]2[N:8]3[CH2:9][CH2:10][O:11][C:5]4[CH:4]=[CH:3][C:2]([C:31]#[C:30][C@@:28]([OH:32])([C:25]5[CH:24]=[C:23]([CH3:22])[O:27][N:26]=5)[CH3:29])=[CH:21][C:6]=4[C:7]3=[N:14][C:13]=2[C:15]([NH2:17])=[O:16])[CH2:20][CH2:19]1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: NC(=O)c1nc2n(c1C1CC1)CCOc1ccc(Br)cc1-2
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C4CC4)n2CCO3)no1

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-cyclopropyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol to give the titled compound. MS+419.2. 1H NMR (400 MHz, DMSO) δ 8.52 (d, J=2.2 Hz, 1H), 7.42 (br s, 1H), 7.31 (dd, J=8.5, 2.2 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 6.95 (br s, 1H), 6.45 (s, 1H), 6.35 (s, 1H), 4.50 (m, 4H), 2.40 (s, 3H), 1.80 (s, 3H), 1.76 (m, 1H), 0.98 (m, 2H), 0.84 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]2[CH2:17][CH:16]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.C[N:26]1[C:30](=[O:31])[CH2:29][CH2:28][CH2:27]1>CS(C)=O.CO>[C:30]([NH:26][CH:27]1[CH2:28][CH2:6][N:5]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)[CH2:4][CH2:3]1)(=[O:31])[CH3:29]
Reactant: Cc1cc2nc(NC(=O)C3CC3c3ccc(F)cc3)cc(Cl)n2n1
Reactant: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: CO
Product: CC(=O)NC1CCN(c2cc(NC(=O)C3CC3c3ccc(F)cc3)nc3cc(C)nn23)CC1
Temperature: 25 °C
Yield: 44 %

Procedure:
The title compound was prepared by combining N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-(4-fluorophenyl)cyclopropanecarboxamide (13B, 0.15 g, 0.435 mmol) and the N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-(4-fluorophenyl)cyclopropanecarboxamide (0.15 g, 0.435 mmol) in NMP (Volume: 1.450 ml) and heating the mixture at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory 60-70% HPLC ([1:1 MeCN/MeOH]/H2O+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a tan solid (86 mg, 44%). 1HNMR (DMSO-d6) δ: 10.95 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.18-7.29 (m, 5H), 7.03-7.17 (m, 4H), 6.08 (s, 1H), 4.30 (d, J=13.1 Hz, 2H), 3.16 (t, J=12.1 Hz, 2H), 2.38-2.48 (m, 2H), 2.35 (s, 3H), 2.24-2.32 (m, 1H), 1.88 (d, J=12.9 Hz, 2H), 1.82 (s, 3H), 1.44-1.62 (m, 4H), 1.35-1.43 (m, 2H), 1.25-1.35 (m, 1H); ESI-MS: m/z 451.3 (M+H)+. It was noted that rotamers were present.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=2[F:26])=[CH:14][CH:15]=1)=O)C.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:39][CH:40]=2)[CH2:30][CH2:29]1>C(Cl)Cl.CO>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=4[F:26])=[CH:14][CH:15]=3)=[O:3])=[N:39][CH:40]=2)[CH2:30][CH2:29]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Reactant: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2F)c2nccnc12
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1
Reaction time: 1 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 143.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), and stirring the reaction mixture for 1 h at reflux. Title compound: ESI-MS: 517.1 [M+H]+; tR=3.37 min (System 1); TLC: Rf=0.11 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[CH:16]=[C:17]([Cl:37])[C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:25]([OH:27])=O)=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:38][C:39]1[S:40][CH:41]=[C:42]([CH3:44])[N:43]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[CH:16]=[C:17]([Cl:37])[C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:25]([NH:38][C:39]3[S:40][CH:41]=[C:42]([CH3:44])[N:43]=3)=[O:27])=[N:19][CH:20]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: Cc1csc(N)n1
Reactant: O=C(O)c1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(O[C@H]2CCOC2)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1csc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(O[C@H]3CCOC3)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.70 mL, 0.53 mmol) was added to a solution of 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid (200 mg, 0.48 mmol) in DCM (6 mL) and stirred at RT for 2 hours. 2-Amino-4-methylthiazole (110 mg, 0.96 mmol) and pyridine (0.078 mL, 0.96 mmol) were added and the reaction stirred at RT for 16 hours. The solvent was removed in vacuo, water (20 mL) added and the mixture extracted with ethyl acetate (3×20 mL). The extracts were combined and washed with 2N hydrochloric acid (20 mL), saturated aqueous sodium bicarbonate solution (20 mL), water (20 mL), brine (20 mL), dried (MgSO4), filtered, and evaporated in vacuo. The residue was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (78 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([F:14])=[C:4](Cl)[N:3]=1.[CH:16]([O:19][C:20]1[NH:24][N:23]=[C:22]([NH2:25])[CH:21]=1)([CH3:18])[CH3:17].CCN(C(C)C)C(C)C>CCCCO>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([F:14])=[C:4]([NH:25][C:22]2[CH:21]=[C:20]([O:19][CH:16]([CH3:18])[CH3:17])[NH:24][N:23]=2)[N:3]=1
Reactant: CC(C)Oc1cc(N)n[nH]1
Reactant: CN(c1nc(Cl)nc(Cl)c1F)S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)Oc1cc(Nc2nc(Cl)nc(N(C)S(C)(=O)=O)c2F)n[nH]1
Temperature: 70 °C
Yield: 46.2 %

Procedure:
To a solution of N-(2,6-dichloro-5-fluoro-pyrimidin-4-yl)-N-methyl-methanesulfonamide (Method 21, 440 mg, 1.6 mmol) in n-BuOH (3 ml) was added 5-isopropoxy-1H-pyrazol-3-ylamine (227 mg, 1.6 mmol) and DIPEA (207 mg). The mixture was heated at 70° C. overnight. LC/MS showed the completion of the reaction. The solvent was evaporated and the residue was dissolved in DCM, which was then washed by aqueous NaHCO3, dried and concentrated. Flash chromatography was performed with EtOAc/Hex (50%) as eluent. A colourless solid (280 mg) was obtained, yield 46%. 1H-NMR (300 MHz, CD3OD) 5.84 (s, 0.8H), 4.61 (m, 1H), 3.32 (s, 3H), 3.27 (s, 3H), 1.36 (d, J=6.0; 6H). MS (ES+) m/z 378.86, 380.86 [MH+]. MS (ES−) m/z 376.88, 378.87 [M−].
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:10][Si:11](Cl)([CH3:13])[CH3:12].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][CH2:2]/[C:3](/[O:9][Si:11]([CH3:13])([CH3:12])[CH3:10])=[CH:4]/[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)CC(=O)CCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C(/CCl)O[Si](C)(C)C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of 4-chloro-3-oxobutanoic acid, methyl ester (60.4 g, 0.4 mol) and trimethylsilyl chloride (48.8 mL, 1.3 mol) in 500 mL dry ethyl acetate was cooled to -20° C. and triethylamine (17.42 mL, 1.25 mol) was added dropwise over 15 minutes under nitrogen atmosphere. The cold bath was removed and the heterogeneous mixture was stirred for two hours. The mixture was diluted with 200 mL dry hexane, stirred for five minutes and filtered under nitrogen. The filtrate was evaporated under vaccum. The product was redissolved in 100 mL hexane and filtered to remove a small amount of TEA.HCl. The filtrate was evaporated and the product was kept under pump vaccum for 0.5 hours to give the title compound (83.95 g, 94%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][CH2:17][C:16]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:15]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:23]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[CH2:1]([C:8]1[C:13]([I:23])=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][CH2:17][C:16]3([O:19][CH2:20][CH2:21][O:22]3)[CH2:15]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2cccc(N3CCC4(C3)OCCO4)n2)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1ccc(N2CCC3(C2)OCCO3)nc1Cc1ccccc1
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A mixture of 6.6 g of 2-benzyl-6-(3,3-ethylenedioxypyrrolidin-1-yl)pyridine and 60 ml of N,N-dimethylformamide was stirred in advance in an ice bath. 5.5 g of N-iodosuccinimide was added thereto and the resultant mixture was stirred as it was at room temperature overnight. To the reaction mixture was added 10 ml of a 1 M aqueous solution of sodium thiosulfate and the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography with 5–10% ethyl acetate/hexane, to give 6.7 g of the title compound.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:19][S:20]([CH3:23])(=[O:22])=[O:21].[OH-].[K+]>O>[CH3:5][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:8])[C:10]([CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:11]1
Reactant: CS(=O)(=O)Cc1cnc2ccccc2c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(CS(C)(=O)=O)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dimethyl sulphate (3.0 ml) was added to a stirred solution of 4-hydroxy-3-methylsulphonylmethylquinoline (1.9 g.) and potassium hydroxide (1.4 g.) in water (20 ml.) at 5°. The mixture was stirred at room temperature for 4 hours, then filtered to give the novel 1-methyl-3-methylsulphonylmethyl-4-quinolone, m.p. 204°-205° (from acetone).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].[C:21](OCC)(=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9](=[O:11])[CH:10]=[C:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)=CC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
3-(2-Fluoro-biphenyl-4-yl)-butan2-one (Japanese Patent Unexamined Publication No. 54-144347) (116 mg) was dissolved in toluene (2 ml), followed by adding thereto sodium hydride (29 mg, 60% oily), and the mixture was stirred at room temperature for 1 hour. Then, diethyl oxalate (105 mg) was added and the resulting mixture was stirred at 40° C. for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, and the extract solution was washed with water and dried. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography to obtain the desired compound (163 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[CH2:14][CH:13](Cl)[C:12]2=[O:18])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15](=[O:16])[CH:14]=[CH:13][C:12]2=[O:18])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(N2C(=O)CC(Cl)C2=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOc1ccc(N2C(=O)C=CC2=O)cc1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
N-(4-Allyloxyphenyl)chlorosuccinimide (265.5 g, 1 mole) was dissolved in dichloromethane (1300 ml) and cooled to 10° C. Triethylamine (101 g, 1 mole) was added in 10 min and the reaction was stirred for 10 min. The reaction mixture was washed with 1M hydrochloric acid and dried over sodium sulfate. The organic solvent was removed under reduced pressure and the solid was recrystallized from methanol.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.C([O-])([O-])=O.[K+].[K+].[CH3:21][C:22]1[CH:23]=[C:24]([SH:29])[CH:25]=[C:26]([CH3:28])[CH:27]=1.O>CN(C=O)C>[CH3:21][C:22]1[CH:23]=[C:24]([S:29][C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=2[C:6]#[N:7])[CH:25]=[C:26]([CH3:28])[CH:27]=1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: Cc1cc(C)cc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Sc2cccc([N+](=O)[O-])c2C#N)c1
Temperature: 0 °C
Yield: 73011.2 %

Procedure:
A mixture of 2,6-dinitrobenzonitrile (1.4 g 7.2 mmol) and K2CO3 (1.1 g, 7.9 mmol) in 10 ml of DMF was chilled to 0° C. A solution of 3,5-dimethylthiophenol (1.1 g 0.0079 mmol) in 10 ml of DMF, was added dropwise over 30 min with stirring under nitrogen. After stirring an additional 30 min, the reaction mixture was poured into 150 ml of water and stirred for 1 hr. The solid was collected by vacuum filtration. Chromatography on silica gel (flash; Hex/EtOAc 1:1) provided 1.64 g (80%) of 2-[(3,5-dimethylphenyl)thio]-6-nitrobenzonitrile: mp 155°-156° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]([N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[CH:25][C:18]=23)[CH:14]=[N:13]1)([CH3:11])[CH2:8][CH2:9][OH:10].C(Cl)Cl>>[CH3:1][S:2]([O:10][CH2:9][CH2:8][C:7]([CH3:6])([N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:31])[CH3:32])[CH:24]=[CH:25][C:18]=23)[CH:14]=[N:13]1)[CH3:11])(=[O:4])=[O:3]
Reactant: CC(C)(CCO)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(CCOS(C)(=O)=O)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
TEA (38.0 μL, 0.000273 mol) and methanesulfonyl chloride (21.1 μL, 0.000273 mol) were added sequentially to a solution of 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butan-1-ol (prepared as in Example 58) (81 mg, 0.00020 mol) in DCM (4 mL, 0.05 mol) at 0° C. The reaction mixture was held at this temperature for 1.5 hours, then was quenched by the addition of water. The reaction mixture was extracted with DCM four times. The combined extracts were dried over sodium sulfate, filtered and concentrated to afford crude 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butyl methanesulfonate (87 mg). MS (ES): 479 (M+1).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][C:29]([NH:33][S:34]([C:37]1[S:38][C:39]([Cl:43])=[C:40]([NH2:42])[CH:41]=1)(=[O:36])=[O:35])([CH2:31][OH:32])[CH3:30]>>[Cl:43][C:39]1[S:38][C:37]([S:34](=[O:36])(=[O:35])[NH:33][C:29]([CH2:28][OH:27])([CH3:30])[CH2:31][OH:32])=[CH:41][C:40]=1[NH:42][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:13]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(CO)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Product: CC(CO)(CO)NS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.7) according to general procedure II. Yellow solid. MS (ISP) 656.0 [(M−H)−]; mp 201° C.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([C:29](=O)[CH2:30][CH2:31][CH2:32][CH3:33])[C:23](=NOC)[C:24]#[N:25])=[C:17]([F:35])[CH:16]=1)(=[O:8])=[O:7])(C)(C)C.Cl.[NH:37]([C:39]1[CH:40]=[C:41]([CH:47]=[CH:48][C:49]=1[C:50]([F:53])([F:52])[F:51])[C:42]([O:44][CH2:45][CH3:46])=[O:43])[NH2:38]>>[CH2:30]([C:29]1[C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:16][C:17]=2[F:35])=[C:23]([C:24]#[N:25])[N:37]([C:39]2[CH:40]=[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:47]=[CH:48][C:49]=2[C:50]([F:51])([F:52])[F:53])[N:38]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F)C(C#N)=NOC
Reactant: CCOC(=O)c1ccc(C(F)(F)F)c(NN)c1
Agent: Cl
Product: CCCCc1nn(-c2cc(C(=O)OCC)ccc2C(F)(F)F)c(C#N)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F

Procedure:
The title compound is prepared by reaction of 3-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2-methoxyimino-4-oxooctanenitrile (from Step J) with ethyl 3-hydrazino-4-(trifluoromethyl)benzoate hydrochloride (from Step E) according to the procedure of Example 1, Step G.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[NH2:5].C(N(C(C)C)CC)(C)C.[Si:24](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][CH:12]=1)[NH2:5]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](N)Cc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Yield: 87.7 %

Procedure:
To a solution of L-tyrosine methyl ester (Sigma Chemical Company) (10.0 g, 51.3 mmol) and diisopropylethylamine (25.9 g, 200.0 mmol) in CH2Cl2 (400 mL) was added t-butyldiphenylsilyl chloride (TBDPS-Cl; 35.2 g, 128.2 mmol) at 23° C. The resultant mixture was stirred at 23° C. for 14 hours. The crude reaction mixture was dried over (MgSO4) and concentrated in vacuo. The resultant residue was purified by silica gel flash column chromatography. The polarity of the eluting solvent mixture was adjusted according to the Rf value of the product. The eluted fractions were combined, dried over MgSO4, concentrated and dried to give 19.5 g (87.8% yield) of O-(tert-butyldiphenylsilyl)-L-tyrosine methyl ester as a colorless syrup. Rf (hexanes/ethyl acetate (AcOEt)/methanol (MeOH) 20:20:1)=0.38.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17]([F:19])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[O:20][CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>O1CCOCC1>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17]([F:19])[C:15](=[O:16])[N:14]([C:40](=[O:41])[C:39]3[CH:43]=[CH:44][C:36]([O:35][CH3:34])=[CH:37][CH:38]=3)[C:12]2=[O:13])[CH2:8][C@@H:7]1[O:20][CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1cccs1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)n2c(=O)c(F)cn([C@H]3C[C@H](OCc4cccs4)[C@@H](COC(C)=O)O3)c2=O)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of 0.30 g of 5'-O-acetyl-2'-deoxy-5-fluoro-3'-O-(2-thienyl)methyluridine in 10 ml of dioxane were added 0.55 ml of triethylamine and 0.16 g of 4-methoxy-benzoyl chloride. The mixture was stirred at 80° C. for 2 hours. The solvent was distilled off and the residue was dissolved in 30 ml of ethyl acetate. The solution was washed with water. The ethyl acetate layer was dried over sodium anhydrous sulfate and concentrated. The residue was subjected to silica gel chromatography and purified by elution with chloroform, giving 0.37 g of 5'-O-acetyl-2'-deoxy-5-fluoro-3-(4-methoxybenzoyl)-3'-O-(2-thienyl)me thyluridine in a yield of 91%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([C@:15]12[CH2:23][CH2:22][C@@H:21]3[C@@H:24]4[C:29]([CH2:30][CH2:31][C@H:20]3[C@@H:19]1[CH2:18][CH2:17][C@@H:16]2[OH:33])=[CH:28][C:27](=[O:32])[CH2:26][CH2:25]4)[CH2:13][CH3:14]>C1C=CC=CC=1.N1C=CC=CC=1>[CH2:12]([C@:15]12[CH2:23][CH2:22][C@@H:21]3[C@@H:24]4[C:29]([CH2:30][CH2:31][C@H:20]3[C@@H:19]1[CH2:18][CH2:17][C@@H:16]2[O:33][C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:28][C:27](=[O:32])[CH2:26][CH2:25]4)[CH2:13][CH3:14]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(=O)CCc1ccccc1
Temperature: 0 °C

Procedure:
Add 3-phenylpropionyl chloride (2.9 g.) in benzene (10 cc.) to 13β-propyl-17β-hydroxy-gon-4-en-3-one (2.5 g.) in pyridine at -10°. Pour the mixture into ice water and extract with benzene-ether. Wash, dry and evaporate the extracts to a gum and purify by chromatography upon Florex. Recrystallize from ethyl acetate-hexane to obtain the title compound, m.p. 104°-108°. Ultraviolet absorption peak at 240 mμ (ε16,000); infrared absorption peaks at 5.76, 6.00 μ.