Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:19])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O.[Cl:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([Cl:35])C=1Cl.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.CN1C(=O)CCC1.C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([Cl:35])[C:1]=1[N:8]1[CH2:9][CH2:10][C:11]([CH3:19])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(C)CCN(c2c(Cl)cncc2Cl)CC1
Temperature: 220 °C
Yield: 57 %

Procedure:
To a solution of ethyl N-Boc-4-methylpiperidine-4-carboxylate (130 mg, 0.47 mmol) in CH2Cl2 (8 mL) was added trifluoroacetic acid (0.86 mL, 11 mmol) and the reaction stirred at r.t. for 2 hr before evaporation and aziotrope with toluene (2×25 ml). The crude was dissolved in NMP (4.3 ml) and 3,4,5-trichloropyridine (135 mg, 0.74 mmol) was added followed by triethylamine (0.42 mL, 3.0 mmol) and the mixture was heated in a microwave reactor at 220° C. for 60 min. The mixture was poured into a saturated solution of sodium hydrogen carbonate (50 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water (2×50 mL), brine (50 mL), dried (MgSO4) and concentrated under reduced pressure to give a crude pale brown/orange oil (175 mg). The crude product was purified by flash column chromatography on silica gel (cyclohexane, EtOAc, 99:1-88:12, biotage 25+S) to furnish the title compound as a clear colourless oil (85 mg, 56%), LC-MS (ESI, 4 min) Rt 3.36 min, m/z 317 (100%, [M+H]+); m/z (ESI) C14H18N2O2Cl2 requires 316.0745, found [M+H]+ 316.0745.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.CO.O.[Li+].[OH-]>CC(O)C.C(Cl)Cl>[Cl:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:25]
Reactant: CCOC(=O)C1(NC(=O)c2c(C)cccc2Cl)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)O
Product: Cc1cccc(Cl)c1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 16 h
Yield: 119.2 %

Procedure:
A 100 mL round bottom flask containing the 2-(2-chloro-6-methyl-benzoylamino)-indane-2-carboxylic acid ethyl ester (0.255 g, 0.712 mmol) is charged with MeOH (15 mL) and a stirring bar is added. Stirring is initiated. After dissolution, water (5 mL) is added and starting material begins to precipitate out. Tetrahydrofuran is added to re-solubilize the starting material. LiOH (90 mg, 2.14 mmol) is added. After 16 h, tlc analysis (silica, 5% i-PrOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 3 by slowly adding dilute aqueous HCl (3%, ˜20 mL). The contents of the flask are poured into an addition funnel containing DCM (30 mL). The layers are separated. The aqueous layer is extracted with DCM (20 mL). The combined organic extracts are washed with water (30 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated to yield 280 mg of material. The material is purified by column chromatography (silica, 2% to 15% CH3OH in DCM) using an ISCO Companion and a 12 g cartridge. Fraction 2 is collected and evaporated. After pumping to constant weight, 130 mg of dry white powder is obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCc2ccc([N+](=O)[O-])cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To 2′,4′-dihydroxy-3′-propyl acetophenone (3.0 g, 15.4 mmol) and 4-nitrobenzyl bromide (3.6 g, 17 mmol) in acetone (62 mL) is added K2CO3 (3.2 g, 23 mmol). The reaction mixture is refluxed for 1 h and cooled to room temperature. The precipitate is filtered, washed with water (5×70 mL), and dried to give the title compound (4.8 g, 94%). LC-MS (m/z): 328 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][C@H:15]3[CH2:17][O:16]3)[C:7]=2[N:18]=1.[NH2:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1>C(O)C.O>[OH:16][C@@H:15]([CH2:14][CH2:13][N:8]1[C:9](=[O:12])[CH:10]=[N:11][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:18][C:7]1=2)[CH2:17][NH:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1
Reactant: COc1ccc2ncc(=O)n(CC[C@H]3CO3)c2n1
Reactant: N[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Solvent: CCO
Solvent: O
Product: COc1ccc2ncc(=O)n(CC[C@H](O)CN[C@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 31.4 %

Procedure:
In a mixed solvent (12 ml) of ethanol-water (9:1) were suspended 6-methoxy-4-{2-[(2S)-oxiran-2-yl]ethyl}pyrido[2,3-b]pyrazin-3(4H)-one (Reference Example 72; 290 mg, 1.17 mmol) and 6-[(4S)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Example 22; 291 mg, 1.17 mmol), and the suspension was stirred in a sealed tube at 80° C. for 16 hours. The solvent was removed from the reaction solution under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 182 mg (31%) of the title compound in the form of a yellowish solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.C1C=NC(NS(C2C=CC(N)=CC=2)(=O)=O)=NC=1.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39].O>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:38](=[O:39])[O:40][CH2:41][CH3:42])[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1nccc(-c2c[nH]nc2-c2ccc(F)cc2)n1
Agent: Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nccc(-c2c[nH]nc2-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinamine prepared in accordance with Example A-306 (0.26 g, 0.001 mol) in 5 mL of pyridine was added ethyl chloroformate dropwise. After the addition, the clear solution was stirred at room temperature for 6 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was trituated with ether to give 0.15 g of product, ethyl [4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]carbamate, as a white solid (46% yield), mp: 163–165° C.; Anal. Calc'd for C16H14FN5O2: C, 58.71; H, 4.31; N, 21.04. Found: C, 59.22; H, 4.51; N, 21.66.
Reaction SMILES: ClC1C(OCC2(C(F)(F)F)CCCCC2)=C[C:5](F)=[C:6]([CH:10]=1)[C:7](O)=O.[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[CH2:34][O:35][C:36]1[C:44]([Cl:45])=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[C:38]([F:46])[CH:37]=1)[CH2:31]2>>[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[CH2:34][O:35][C:36]1[C:44]([Cl:45])=[CH:43][C:39]([C:40]([O:42][C:6]([CH3:10])([CH3:7])[CH3:5])=[O:41])=[C:38]([F:46])[CH:37]=1)[CH2:31]2
Reactant: O=C(O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Reactant: O=C(O)c1cc(Cl)c(OCC2C3CC4CC(C3)CC2C4)cc1F
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 158 step 2, and making variations as required to replace 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)-methoxy)benzoic acid with 4-(adamantan-2-ylmethoxy)-5-chloro-2-fluorobenzoic acid, the title compound was obtained as a colorless oil (2.13. g, 48%): MS (ES−) m/z 393.2 (M−1).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:12])[CH:9]=[C:10](Br)[C:5]2=[N:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:12][C:8]1[CH:9]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:14]=2[CH3:13])[C:5]2[N:6]([C:2]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:14]=3[CH3:13])=[CH:3][N:4]=2)[N:7]=1
Reactant: Cc1ccncc1B(O)O
Reactant: Clc1cc(Br)c2ncc(Br)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1-c1cc(Cl)nn2c(-c3cnccc3C)cnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 24.7 %

Procedure:
A microwave vial was charged with a mixture of 3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (210 mg, 0.674 mmol), 4-methylpyridin-3-ylboronic acid (184 mg, 1.35 mmol), tetrakis(triphenylphosphine)palladium(0) (78 mg, 0.067 mmol), dioxane (6 mL), and K3PO4 (1 mL, 2.023 mmol) was stirred at room temperature for 5 min. under nitrogen. The resulting mixture was heated to 100° C. for 8 h in microwave. The reaction mixture was cooled to room temperature, quenched with water, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep. HPLC to give 56 mg (24%) product. 1H NMR (400 MHz, CD3OD) δ ppm 9.06 (1H, s), 8.93 (1H, s), 8.81 (2H, dd, J=15.23, 5.92 Hz), 8.17 (1H, s), 7.96-8.13 (2H, m), 7.68 (1H, s), 2.65 (3H, s), 2.58 (3H, s); LC/MS: Rt=0.88 min. LC/MS (Condition A): 336.14/338.15.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:13][O:14][CH:15]2[CH2:17][CH2:16]2)[C:8]([O:10]CC)=[O:9])[N:3]=1.Cl>[OH-].[Na+]>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:13][O:14][CH:15]2[CH2:17][CH2:16]2)[C:8]([OH:10])=[O:9])[N:3]=1
Reactant: CCOC(=O)C(=NOC1CC1)c1nsc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(C(=NOC2CC2)C(=O)O)ns1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.2 %

Procedure:
A suspension of ethyl 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(cyclopropyloxyimino)acetate (syn isomer)(763 mg) in 1N sodium hydroxide (6 ml) was stirred at ambient temperature for 2 hours to give a clear solution. The mixture was adjusted to pH 4.5 with 1N hydrochloric acid and washed with ethyl acetate. The aqueous solution was adjusted to pH 3 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated aqueus sodium chloride, dried over magnesium sulfate, and crystallized from diethyl ether to give 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-cyclopropyloxyiminoacetic acid (syn isomer) (110 mg) as a crystal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[C@H:37]([OH:39])[CH3:38])[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CCO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([CH2:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[C@H:37]([OH:39])[CH3:38])[N:16]=3)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To a solution of 3-{2-[2-((R)-1-hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene}azetidine-1-carboxylic acid tert-butyl ester (167 mg, 0.31 mmol) in EtOAc (5 mL) and EtOH (5 mL) was added 20% Pd(OH)2/C (160 mg) and the resulting mixture stirred under an atmosphere of H2 for 16 h. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo affording the title compound (156 mg, 93%). LCMS (method A): RT 3.07 min [M+H]+ 549.4
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]([CH2:12]Br)=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:9][N:8]=2)=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22](=[O:36])[CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH3:20].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]([CH2:12][N:24]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[O:34][CH3:35])[CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:36])=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1onc(-c2ccc(Br)o2)c1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(-c2ccc(Br)o2)noc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.4 %

Procedure:
Ethyl 3-(5-bromofuran-2-yl)-4-(bromomethyl)isoxazole-5-carboxylate (1.8 g, 4.75 mmol) was dissolved in 20 mL of DMF. N-(2,4-dimethoxybenzyl)glycine ethyl ester (1.2 g, 4.75 mmol) and potassium carbonate (1.3 g, 9.50 mmol) were added, and the mixture was stirred at room temperature for 16 h. EtOAc (50 mL) and water (50 mL) were added and the aqueous layer was extracted with additional EtOAc. The combined organic layer was washed with water and brine, and dried over MgSO4. After solvent was removed in vacuo, the crude was purified by flash chromatography (0-40% EtOAc/hexanes) to give 1.53 g of the title compound. MS: (+) m/z 551.44, 553.35 (M+1, 79Br/81Br).
Reaction SMILES: C[Si](Cl)(C)C.[Pb](I)I.I[CH2:10]I.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([C:22]2[N:23]([S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH:24]=[C:25]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[N:26]=2)=O)=[CH:15][CH:14]=1>O1CCCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([C:22]2[N:23]([S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH:24]=[C:25]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[N:26]=2)=[CH2:10])=[CH:15][CH:14]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(Br)cc1
Reactant: ICI
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[Si](C)(C)Cl
Agent: I[Pb]I
Solvent: C1CCOC1
Product: C=C(Cc1ccc(Br)cc1)c1nc(CC(C)(C)C)cn1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
TMSCl (0.1 mL) was added to a suspension of zinc (1.2 g, 18.3 mmol) and lead (II) iodide in tetrahydrofuran at room temperature. After stirring at room temperature for 10 min, diiodomethane (0.653 mL) was added dropwise maintaining the reaction at a gentle reflux. After stirring 1 h, the reaction mixture was cooled to 0° C., TiCl4 (1 M in DCM) (2.02 mL) was added dropwise. After stirring at room temperature for 1 h, a solution of intermediate 7 (238 mg, 0.54 mmol) in tetrahydrofuran was added and the reaction monitored by LCMS. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organics were washed with brine, dried (sodium sulfate) and concentrated in vacuo to afford 2-[1-(4-bromobenzyl)vinyl]-4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide which was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[NH:18][C:17]([C:20](O)=[O:21])=[CH:16]3)(=[O:9])=[O:8])=[CH:4][CH:3]=1.Cl.[C:24]([S:43][CH2:44][CH2:45][NH2:46])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([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.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[NH:18][C:17]([C:20]([NH:46][CH2:45][CH2:44][S:43][C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:21])=[CH:16]3)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3ccc(Cl)s3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cc2cccc(NS(=O)(=O)c3ccc(Cl)s3)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a mixture of 7-{[(5-chloro-2-thienyl)sulfonyl]amino}-1H-indole-2-carboxylic acid (0.84 g), 2-(tritylthio)ethylamine hydrochloride (0.85 g), 1H-1,2,3-benzotriazol-1-ol (0.35 g), triethylamine (0.36 mL) and N,N-dimethylformamide (20 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.50 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (1.41 g, yield 97%) was obtained as colorless crystals from a fraction eluted with ethyl acetate. melting point>197° C. (decomposition).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13]([C:15]2[C:24]([OH:25])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([O-:28])=[O:27]>>[CH3:9][O:8][C:7]1[C:2]([C:32]2[CH:33]=[CH:34][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=2)=[CH:3][C:4]([CH2:10][CH2:11][NH:12][C:13]([C:15]2[C:24]([OH:25])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[O:14])=[CH:5][CH:6]=1
Reactant: COc1ccc(CCNC(=O)c2cc3ccccc3cc2O)cc1Br
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Product: COc1ccc(CCNC(=O)c2cc3ccccc3cc2O)cc1-c1ccc([N+](=O)[O-])cc1
Yield: 61 %

Procedure:
The title compound (27 mg) was prepared from 0.05 g (0.1 mmol) of resin-bound N-2-(3-bromo-4-methoxyphenyl)ethyl-3-hydroxyl-2-naphthamide and 50.0 mg (0.3 mmol) of 4-nitro-phenyl boronic acid as described in Example 110.
Reaction SMILES: [NH2:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1)(=[O:18])[CH3:17]
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(N)S1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NN1NC=C(c2ncc([N+](=O)[O-])n2C)S1

Procedure:
The above compound is prepared by heating under reflux for 30 minutes a mixture of 14 gm. of 2-(2-amino-5-thiadiazolyl)-1-methyl-5-nitroimidazole in 280 ml. of acetic anhydride. The mixture is evaporated to dryness, and the solid residue is washed thoroughly with ether giving 16.4 gm. of a yellow solid having a melting point of 235° C. (decomposition).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH2:14]([Sn](CC)(CC)CC)[CH3:15]>CCOC(C)=O>[CH2:14]([C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1)[CH3:15]
Reactant: CC[Sn](CC)(CC)CC
Reactant: O=[N+]([O-])c1cc(Br)c2scnc2c1
Solvent: CCOC(C)=O
Product: CCc1cc([N+](=O)[O-])cc2ncsc12
Yield: 75.9 %

Procedure:
A solution of 7-bromo-5-nitrobenzothiazole (0.15 g, 0.58 mmol), tetraethyltin (0.18 mL, 0.87 mmol) and catalytic amount of Cl2 Pd(PPh3)2 in a sealed tube was stirred for 12 h at 90° C. The reaction mixture was diluted with EtOAc and washed with brine several times. Organic solution was dried over Na2SO4 and concentrated in vacuo, yielding an oil which was subjected to column chromatography (EtOAc, neat) to provide 91 mg (0.44 mmol, 75%) of the desired product.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[CH2:18]([N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:30](=[O:32])[CH3:31])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCN1CCN(c2cccc3c2C[C@H](NC(C)=O)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-pentylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (170 mg, 0.57 mmol) and triethylamine (86 μL, 0.86 mmol) in methylene chloride (30 mL) was added dropwise acetyl chloride (41 μL, 0.57 mmol) in methylene chloride (10 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The methylene chloride phase was dried (Na2SO4), filtered and evaporated in vacuo. The residue crystallized from diethyl ether/hexane. This gave 120 mg (62% yield) of the title compound as white crystals: mp 119-120° C. [α]21D +25° (c 0.97, chloroform); EIMS (70 eV) m/z (relative intensity) 343 (49, M+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]([CH2:15][C:16]2([OH:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[OH:22][C:16]1([CH2:15][C@H:5]2[CH2:4][CH2:3][C@H:2]([O:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:7][N:6]2[C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)CCC1CC1(O)CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)CC[C@@H]1CC1(O)CCOCC1
Temperature: 25 °C
Yield: 28.1 %

Procedure:
To a stirred solution of tert-butyl 5-hydroxy-2-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidine-1-carboxylate (1.92 g, 6.09 mmol, step 2 of Example 2), triethylamine (739 mg, 7.30 mmol) in dichloromethane (27 mL) was added methanesulfonyl chloride (836 mg, 7.30 mmol) at 0° C., and the mixture was allowed to warm to room temperature over 20 h. The mixture was quenched with water (50 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (1:5) to give 673 mg (28%) of the title compound as a white crystal. (cis isomer, 634 mg, 26% yield)
Reaction SMILES: [Cl-].[Li+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.O=[C:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1>CC#N>[C:15]([O:14][C:12](=[O:13])[CH:11]=[C:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Product: CCOC(=O)C1CCC(=CC(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a suspension of anhydrous lithium chloride (1.9 g, 45 mmol) in MeCN (100 ml) was added tert-butyl 2-(diethoxyphosphoryl)acetate (7.6 g, 30 mmol) at room temperature. The mixture was stirred for 30 min. TEA (6.4 ml, 45 mmol) was added and the mixture was stirred for another 30 min. Ethyl 4-oxocyclohexanecarboxylate (5.1 g, 30 mmol) was added and the mixture was stirred overnight. The precipitate was filtered off and the filtrate was concentrated to afford brown oil, which was purified by silica gel column (PE:EtOAc=10:1) to afford product (5 g, 62%).