Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]1[C@@H:9]2[O:10][C:11](=[O:13])[CH2:12][C@@H:8]2[C@@H:7]([CH2:14][O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:6]1)(=O)C.[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CCCCCC.CCOCC.CCOC(C)=O.ClCCl.C1(C)C=CC=CC=1>[C:16]([O:15][CH2:14][C@@H:7]1[C@@H:8]2[C@@H:9]([O:10][C:11](=[O:13])[CH2:12]2)[CH:5]([S:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:6]1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Sc1ccccc1
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@H]2CC(=O)O[C@@H]12
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C1C[C@@H]2[C@@H](COC(=O)c3ccccc3)OC(Sc3ccccc3)[C@@H]2O1
Temperature: -78 °C
Reaction time: 6.5 h
Yield: 72.6 %

Procedure:
To a suspension of 7 (35.7 g, 0.11 mol) and thiophenol (14.8 mL, 0.13 mol) in 220 mL of a 4:1 mixture of anhydrous toluene and dichloromethane at room temperature, boron trifluoride etherate (6.9 mL. 0.05 mol) was added dropwise. The resulting mixture was stirred at the same temperature for 6.5 h and then carefully poured into a biphasic mixture of 1000 mL of EtOAc and 100 mL of a saturated aqueous solution of NaHCO3 (sat. NaHCO3). The layers were separated and the organic layer was washed with 2×100 mL of saturated NaHCO3, 100 mL of water and 100 mL of brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated to afford a yellow liquid. This material was dissolved in 50 mL of CHCl3, and to it was added 200 mL of ether and 50 mL of hexane. The resulting solution was briefly cooled to -78° C. to induce crystallization. White powdery solid formed which was filtered off and washed with cold ether to afford 29.6 g of 8 (72% yield) as a mixture of two diastereomers: Rf 0.70 and 0.53 (minor and major isomers, respectively, 60% EtOAc/hexane); 1H-NMR (CDCl3) δ (for major isomer only) 8.01 (m, 2H), 7.42-7.70 (m, 5H), 7.27 (m, 3H), 5.89 (d, 1H, J=5.2 Hz), 5.29 (dd, 1H, J=7.7, 5.2 Hz), 4.55 (m, 2H), 4.48 (m, 1H), 2.60-3.12 (m, 3H).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([O:7][C@@H:8]([CH:10]([OH:19])[C:11]#[C:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH3:9])=[CH:3][CH:2]=1>C(OCC)(=O)C.[Pd]>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([O:7][C@@H:8]([CH:10]([OH:19])[CH2:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH3:9])=[CH:5][CH:6]=1
Reactant: C[C@@H](Oc1ccc(-c2ccccc2)cc1)C(O)C#Cc1cccnc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H](Oc1ccc(-c2ccccc2)cc1)C(O)CCc1cccnc1
Yield: 80.3 %

Procedure:
(2R, 3RS)-2-(Biphenyl-4-yloxy)-5-pyridin-3-yl-pent-4-yn-3-ol (4.86 g, Example 1c) was dissolved in ethyl acetate (100 ml) and hydrogenated at 5 atmospheres using 10% palladium on charcoal (0.5 g) as catalyst. The mixture was filtered through celite® and the filtrate concentrated under reduced pressure to give the title compounds (3.95 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[N:8][C@H:9]([C:14]([O-:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>>[CH2:24]([O:23][C:21]([N:8]1[C@@H:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:14](=[O:16])[O:15][C@H:7]1[C:6]1[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(C=N[C@@H](CC(C)C)C(=O)[O-])cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Product: COc1ccc([C@@H]2OC(=O)[C@H](CC(C)C)N2C(=O)OCc2ccccc2)cc1

Procedure:
(2S,4S)-N-Benzyloxycarbonyl-4-isobutyl-2-(4'-methoxyphenyl)-1,3-oxazolidin-5-one (15) was prepared from sodium N-(para-methoxybenzylidene)-(L)-leucinate (2.71 g, 10.0 mM) and benzyl chloroformate (1.43 mL, 10.0 mM) following general procedure C and obtained as a colourless oil after purification by flash column chromatography, using 25% ethyl acetate/petrol as eluant (3.21 g, 84%, single diastereomer): [α]D20 -30.0 (c 1.0, CHCl3); IR (CHCl3): 1795, 1715 cm-1 ; 1H NMR (200 MHz, CDCl3): δ 6.89-7.38 (m, 9H), 6.71 (s, 1H), 5.20 (s, 2H), 4.47 (t, J=7 Hz, 1H), 3.82 (s, 3H), 1.57-1.98 (m, 3H), 0.88-0.92 (m, 6H); 13C NMR (50.3 MHz, CDCl3): δ 172.5, 160.4, 154.0, 135.3, 129.2, 128.6, 128.3, 127.4, 113.9, 88.8, 68.1, 55.3, 54.4, 42.1, 24.5, 22.3, 22.2; LRMS (NH3): 384 (MH+); HRMS: calcd for C22H26NO5 (MH+): 384.1811; found: 384.1811.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:6]=[N:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][CH:10]=1.CI.N1C=CC=NC=1.[C:23](OCC)(=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl>O1CCCC1>[O:29]=[C:23]([C:5]1[CH:6]=[N:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][CH:10]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)(C)c1ncc(Br)cn1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: c1cncnc1
Solvent: CI
Product: CCOC(=O)C(=O)c1cnc(C(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.7 %

Procedure:
Magnesium turnings (1.9 g), a catalytic amount of iodine and dry tetrahydrofuran (50 cm3) were placed in a round-bottomed flask under an atmosphere of dry nitrogen. A portion of a solution of 5-bromo-2-(1,1-dimethylethyl)pyrimidine (15.2 g) in dry tetrahydrofuran (50 cm3) was added to the reaction vessel and the Grignard reaction was initiated by the addition of a small portion of methyl iodide, followed by heating the reaction contents to the reflux temperature. The remainder of the pyrimidine solution was added at such a rate so as to maintain reflux, and on completion of the addition and cessation of reaction, the so formed Grignard reagent was added to a solution of diethyl oxalate (20.4 g) in dry tetrahydrofuran, whilst the reaction temperature was maintained between -10° C. and -15° C. After the addition was complete, the reaction mixture was allowed to warm to the ambient temperature, at which point it was allowed to stir for 16 hours. Dilute aqueous hydrochloric acid was added to the reaction mixture which was then extracted into dichloromethane. The combined organic extracts were washed with water, and brine, and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure, and short-path distillation of the residue using a Kugelrohr apparatus gave ethyl 2-oxo-2-[2-(1,1-dimethylethyl)-pyrimidin-5-yl]-acetate (9.3 g).
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:13](=[O:31])[C:14]4[C:15]([O:23][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:16]([CH2:20][CH2:21]Cl)[N:17]=[CH:18][CH:19]=4)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.C(C1N=CC=C2C(=O)C(C3C=CC(C4(NC(=O)OC(C)(C)C)CCC4)=CC=3)=C(C3C=CC=CC=3)OC=12)C.Cl>O1CCOCC1>[NH2:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[C:13](=[O:31])[C:14]4[C:15]([O:23][C:24]=3[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:16]([CH2:20][CH3:21])[N:17]=[CH:18][CH:19]=4)=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(CCCl)nccc4c3=O)cc2)CCC1
Agent: CCc1nccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Agent: Cl
Solvent: C1COCCO1
Product: CCc1nccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 62 %

Procedure:
Following same procedure used to prepare 3-(4-(1-aminocyclobutyl)phenyl)-8-(2-chloroethyl)-2-phenyl-4H-pyrano[2,3-c]pyridin-4-one, tert-butyl 1-(4-(8-ethyl-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutylcarbamate was reacted with 4 M HCl in 1,4-dioxane to give the title compound (5 mg, 62%). 1H NMR (500 MHz, CD3OD): δ 8.61 (d, 1H), 7.95 (d, 1H), 7.51-7.30 (m, 9H), 3.42-3.35 (m, 2H), 2.75-2.67 (m, 2H), 2.55-2.42 (m, 2H), 2.28-2.12 (m, 1H), 1.98-1.88 (m, 1H). 1.5 (t, 3H). LCMS (Method I): RT=4.31 min, [M+2]+=398.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(C#N)cc(C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(C#N)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 124.4 %

Procedure:
To a solution of methyl 3-tert-butyl-5-cyanobenzoate (8.8 g, 0.0360 mol) in MeOH (76 mL) was added a solution of NaOH (2.0 g, 0.050 mol) in water (15 mL). The mixture was allowed to stir at rt for 2.5 h and then acidified with 1N HCl. The mixture was concentrated to remove methanol and the residue was extracted with EtOAc. The organic solutions were combined, washed with 1NHCl and brine, dried over Na2SO4, filtered, and concentrated to a small volume. Hexane was added and the product precipitated. The solid was filtered, washed with hexanes and dried to give 3-tert-butyl-5-cyanobenzoic acid (9.1 g, 73%). 1H NMR (400 MHz, d6-DMSO) δ: 8.19 (m, 1H), 8.13 (m, 1H), 8.10 (m, 1H), and 1.32 (s, 9H). LCMS: ES− 202.2.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([B:20]3[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]3)[C:15]=2[CH2:29][CH3:30])[CH2:10][CH2:9]1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH2:29]([C:15]1[C:16]([B:20]2[O:21][C:22]([CH3:27])([CH3:28])[C:23]([CH3:26])([CH3:25])[O:24]2)=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH3:30]
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cccc1C1=CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1c(B2OC(C)(C)C(C)(C)O2)cccc1C1CCNCC1
Reaction time: 12 h
Yield: 40 %

Procedure:
To a solution of 1-benzyl-4-[2-ethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,2,3,6-tetrahydro-pyridine (D118) (8 g, 19.83 mmol) in EtOAc (300 mL) was added dry Pd/C (8 g, 10%). The reaction mixture was hydrogenated under 55 psi at 50° C. for 12 hr, and then filtered. The filtrate was concentrated in vacuo. The residue was purified by Mass Directed AutoPrep to give 4-[2-Ethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-piperidine (D119) (2.5 g). MS (ES): C19H30BNO2 requires 315.2. found 316.2 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:9](=[O:48])[N:8]2[N:49]=[CH:50][CH:51]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]>CC(C)=O.O.CO.Cl>[CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:9](=[O:48])[N:8]2[N:49]=[CH:50][CH:51]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccnn2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: CCCCc1nc2ccnn2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 67.2 %

Procedure:
A solution of 700 mg of the product of Example 16 in 200 ml of 9:1 acetone-water, 50 ml of methyl alcohol and 2 drops of 5% HCl is refluxed for 16 hours. The reaction mixture is concentrated in vacuo to a residue which is extracted with 3:1 chloroform-methanol. The chloroform layer is dried with anhydrous Na2SO4, filtered and concentrated to a residue which is purified by column chromatography on silica gel by elution with 90% ethyl acetate-hexanes to give 300 mg of the desired product as a solid. M+H=426.
Reaction SMILES: Cl[C:2]([O:4][CH:5]=[CH2:6])=[O:3].C([N:14]1[CH2:18][CH:17]2[C:19]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:21][S:22](=[O:24])(=[O:23])[CH:16]2[CH2:15]1)C1C=CC=CC=1>ClCCCl>[C:31]1([C:19]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:17]3[CH:16]([CH2:15][N:14]([C:2]([O:4][CH:5]=[CH2:6])=[O:3])[CH2:18]3)[S:22](=[O:23])(=[O:24])[CH2:21][CH2:20]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=S1(=O)CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC21
Reactant: C=COC(=O)Cl
Solvent: ClCCCl
Product: C=COC(=O)N1CC2C(C1)S(=O)(=O)CCC2(c1ccccc1)c1ccccc1

Procedure:
0.16 cm3 of vinyl chloroformate is added to a solution of 0.7 g of (4aRS,7aRS)-6-benzyl-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide in 10 cm3 of 1,2-dichloroethane. The mixture is refluxed for 2 hours and then concentrated to dryness under reduced pressure (2.7 kPa) at 50° C. The crystalline solid is washed with ethyl ether, drained and then dried. 0.58 g of (4aRS,7aRS)-4,4-diphenyl-6-vinyloxycarbonylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide is obtained in the form of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]3[S:8][C:9]([CH3:16])=[CH:10][C:11]=3[C:12](SC)=[N:13][C:4]=2[CH:3]=1.[CH3:19][O:20][CH2:21][CH2:22][C@H:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>C(O)(C)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]3[S:8][C:9]([CH3:16])=[CH:10][C:11]=3[C:12]([N:27]3[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:22][CH2:21][O:20][CH3:19])[CH2:28]3)=[N:13][C:4]=2[CH:3]=1
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2sc(C)cc21
Reactant: COCC[C@H]1CNCCN1
Solvent: CC(C)O
Product: COCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3sc(C)cc32)CCN1
Temperature: 79.5 °C
Yield: 69 %

Procedure:
Combine 7-chloro-2-methyl-10-methylsulfanyl-4H-3-thia-4,9-diaza-benzo[f]azulene (42.74 g, 145 mmol) and (s)-2-(2-methoxy-ethyl)-piperazine (26.1 g, 181 mmol) in isopropyl alcohol (190 mL). Heat to 78-81° C. for 3-4 days, and then allow cooling to ambient temperature. Filter the solids and rinse with 1:1 MTBE/Ligroin (2×300 mL). Drying at 30° C. affords 39.1 g (69.5%) of the title compound: 1H NMR (500 MHz, DMSO-d6): δ 1.52 (bm, 2H), 2.27 (s, 3H), 2.45 (bt, 1H), 2.65 (bm, 2H), 2.75 (bt, 1H), 2.86 (bd, 1H), 3.20 (s, 3H), 3.38 (m, 2H), 3.80 (m, 1H), 3.90 (m, 1H), 6.33 (s, 1H), 6.67 (d, 1H), 6.75 (d, 1H), 6.82 (dd, 1H), 7.70 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 15.07, 25.49, 33.28, 45.11, 47.36, 52.55, 57.92, 69.18, 118.38, 119.81, 122.29, 122.56, 126.41, 126.99, 128.43, 142.54, 142.90, 152.84, 157.82. MS (ES+) M+H calcd for C19H23ClN4OS 390.94; found 391.96.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:24]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(C(F)(F)F)c(Cl)cc2N1

Procedure:
The title compound was prepared from {4-chloro-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M104) (0.23 g, 0.43 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light orange solid (150 mg, 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([Cl:9])=[N:7][OH:8])=[CH:4][CH:3]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C1C=CC=CC=1>[CH3:12][S:13]([O:8][N:7]=[C:6]([Cl:9])[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(C(Cl)=NO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccccc1
Product: Cc1ccc(C(Cl)=NOS(C)(=O)=O)cc1
Reaction time: 1 h
Yield: 62.1 %

Procedure:
In a second synthesis, 10 g of 4-methylbenzohydroximoyl chloride, 6.7 g of methanesulfonyl chloride, and 160 ml of benzene were mixed in a 250-ml, three-necked, round-bottomed flask equipped with a stirrer, thermometer, and drying tube. Triethylamine (8.8 g) was added dropwise during 6 minutes at 5°-10°, and the mixture was stirred at that temperature for 1 hour. The reaction mixture was filtered, the solid was washed with benzene, the washes and filtrate were combined and concentrated, and the concentrate was recrystallized from ethanol to give 9 g of N-(methanesulfonyloxy)-4-methylbenzimidoyl chloride, m.p. 100°-102°. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:42])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:16]([C:39]([NH2:41])=[O:40])[CH2:15]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:50](Cl)(=[O:53])[CH2:51][CH3:52]>ClC(Cl)Cl>[C:1]([C:4]1[CH:9]=[C:8]([NH:10][C:50](=[O:53])[CH2:51][CH3:52])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:42])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:16]([C:39]([NH2:41])=[O:40])[CH2:15]1)(=[O:3])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CC(=O)c1cc(N)ccc1NC(=O)CN1CCN(CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)C(C(N)=O)C1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc(NC(=O)CN2CCN(CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C(C(N)=O)C2)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
To a stirred solution of 4.5 parts of N-(2-acetyl-4-aminophenyl)3-(aminocarbonyl)-4-(5,5-bis(4-fluorophenyl)pentyl)-1-piperazineacetamide in 60 parts of trichloromethane were added 1.17 parts of N,N-diethylethanamine. A solution of 0.78 parts of propanoyl chloride in 45 parts of trichloromethane was added dropwise at room temperature (slightly exothermic reaction, the temperature rose from 24° C. to 30° C.). Upon completion, the whole was stirred for 3 hours at room temperature. The separated organic layer was washed with a sodium carbonate solution in water and water, dried, filtered and evaporated. The residue was crystallized from acetonitrile. After cooling to 0° C., the product was filtered off and dried in vacuo, first at 50° C. and then at 100° C., yielding 2.93 parts (57.7%) of N-[2-acetyl-4-[(1-oxopropyl)amino]phenyl]-3-(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl) pentyl]-1-piperazineacetamide; mp. 163.4° C. (compound 32).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:10](O)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(Cl)([Cl:28])=O>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:10]([Cl:28])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)N1CCC(C(=O)O)(c2ccccc2Sc2ccccc2)CC1
Product: CC(=O)N1CCC(C(=O)Cl)(c2ccccc2Sc2ccccc2)CC1

Procedure:
A suspension of 3.4 g of 1-acetyl-4-(2-phenylthiophenyl)piperidine-4-carboxylic acid, Example 15, in 5 ml of freshly distilled thionyl chloride is warmed on a steam bath for 5 minutes, effecting a clear solution. The excess thionyl chloride is removed at 50° C. under reduced pressure. The residue is recrystallized from a benzene-cyclohexane mixture to provide 1-acetyl-4-(2-phenylthiophenyl)piperidine-4-carbonyl chloride.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][C:24](O)=[O:25])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30]>C1COCC1.CO>[OH:25][CH2:24][CH2:23][CH2:22][C:17]12[CH2:16][CH2:15][C:14]([C:7]3[NH:6][C:5]4[C:4](=[O:27])[N:3]([CH2:28][CH2:29][CH3:30])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=4[N:8]=3)([CH2:21][CH2:20]1)[CH2:19][CH2:18]2
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CCC(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCCO)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 60 h
Yield: 85.7 %

Procedure:
To a solution of 3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-propionic acid (417 mg, 1.0 mmol) in THF (25 ml), cooled to 0° C. with the aid of an ice bath, was added BH3 (1.0 M in THF, 3.0 mmol). The resulting mixture was allowed to reach ambient temperature and stirred for a period of 60 h. Following the addition of MeOH (10 ml), the mixture was concentrated in vacuo to afford a white solid that was dissolved in MeOH (20 ml), stirred at rt for 2 h and evaporated to dryness in vacuo. The resulting white solid was recrystallized from EtOAc to afford 345 mg (86%) of a white powder. MS: 403 (MH+).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]([C:12]1[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[C:14]([CH3:22])[C:13]=1[O:23][CH3:24])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C-:25]#[N:26].[Na+].C(OC(C)C)(C)C.O>CS(C)=O>[CH3:24][O:23][C:13]1[C:14]([CH3:22])=[C:15]([CH3:21])[C:16]([O:19][CH3:20])=[C:17]([CH3:18])[C:12]=1[CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][CH2:3][CH2:2][C:25]#[N:26]
Reactant: COc1c(C)c(C)c(OC)c(C(CCCI)c2ccccc2)c1C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CS(C)=O
Solvent: O
Product: COc1c(C)c(C)c(OC)c(C(CCCC#N)c2ccccc2)c1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 163 %

Procedure:
To a solution of 4.19 g (5.0 mmole) of 1-iodo-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-4-phenylbutane in dimethylsulfoxide (30 ml) was added 0.74 g (5×3 mmole) of sodium cyanide, and the mixture was stirred at 50° C. for 2 hours. The reaction solution was cooled with ice, and isopropyl ether and water were added to it, followed by stirring. The isopropyl ether layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated. The residual solution was chromatographed on a silica gel column to perform purification (elution with isopropyl ether/hexane) to thereby give 1.65 g (98%) of 5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-phenylvaleronitrile. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 14.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([Cl:26])[CH:19]=3)=[N:14]2)=[O:9])[CH:4]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[Cl:26][C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][N:13]([CH2:12][C@@H:11]([NH:10][C:8]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[O:7][N:6]=3)=[O:9])[CH3:27])[N:14]=2)[CH:23]=[CH:22][C:21]=1[C:24]#[N:25]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(CN)on1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(CNS(C)(=O)=O)on1
Yield: 8.3 %

Procedure:
(S)-5-(aminomethyl)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)isoxazole-3-carboxamide (25 mg, 0.065 mmol) and DCM were added to a flask and stirred under nitrogen atmosphere. Methanesulfonyl chloride (9.05 μl, 0.065 mmol) was added and the reaction mixture was stirred at RT for 1 h. Methanesulfonyl chloride (6 μl) was added and the reaction mixture was stirred at RT overnight. Methanesulfonyl chloride (16 μl) was added and the reaction mixture was stirred at RT for 3 days. The reaction mixture was evaporated to dryness and the product was triturated using acetonitrile. Yield 8.3%. 1H-NMR (400 MHz; DMSO): δ 1.16 (d, 3H), 2.94 (s, 3H), 4.26-4.53 (m, 5H), 6.64 (s, 1H), 6.94 (d, 1H), 7.82 (d, 1H), 7.86 (m, 1H), 7.92 (dd, 1H), 7.98 (d, 1H), 8.09 (d, 1H), 8.81 (d, 1H)
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][Br:7].[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:30])[C:14]=1[NH:15][C:16]1[C:25]2[C:20](=[C:21]([OH:28])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[O:19][C:18](=[O:29])[CH:17]=1>>[Br:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:28][C:21]1[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[C:25]2[C:20]=1[O:19][C:18](=[O:29])[CH:17]=[C:16]2[NH:15][C:14]1[C:13]([Cl:30])=[CH:12][N:11]=[CH:10][C:9]=1[Cl:8]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: BrCCOCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCOCCBr

Procedure:
The title compound was prepared from 2-bromoethyl ether and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.64 (s, 1H), 4.13 (m, 2H), 3.93 (s, 3H), 3.80-3.74 (m, 4H), 3.55 (t, 2H); MS (ESI): 502.7.