Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([NH:21][S:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)(=[O:24])=[O:23])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH:10]1[C:11]2[C:20]3[CH2:19][CH2:18][CH:17]([NH:21][S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:23])=[O:24])[CH2:16][C:15]=3[CH:14]=[N:13][C:12]=2[NH:8][N:9]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(NS(=O)(=O)c2ccccc2)CC4)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=S(=O)(NC1CCc2c(cnc3[nH]ncc23)C1)c1ccccc1
Temperature: 65 °C

Procedure:
To N-[3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-yl]-benzenesulfonamide (0.082 g, 0.18 mmol) was added trifluoroacetic acid (2 mL). The reaction mixture was heated at 65° C. for 5 h. On the completion of the reaction, toluene (5 mL) was added. The solvent was the removed under reduced pressure to give the crude product as a dark brown solid. The crude product was purified using reverse phase HPLC to give the desired product, N-(6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-yl)benzenesulfonamide was obtained as a white solid (0.038 g, 63%). M.p.=228-229° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.28 (s, 1H), 7.96 (s, 1H), 7.94-7.84 (m, 3H), 7.78 (s, 1H), 7.69-7.58 (m, 3H), 3.48 (br s, 1H), 3.04-2.72 (m, 4H), 1.95-1.7 (m, 2H); LCMS [M+H]: 329.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl.[Cl:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CS(C)=O.O>[ClH:21].[N:24]1([CH2:23][CH2:22][O:1][CH2:2][C:3]2[C:11]3[O:10][C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:8][C:7]=3[CH:6]=[CH:5][CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OCc1cccc2cc(-c3ccccc3)oc12
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(-c2cc3cccc(COCCN4CCCCC4)c3o2)cc1
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
7-Hydroxymethyl-2-phenylbenzofuran (1.57 g) is dissolved in dimethylsulfoxide (10 ml), and sodium hydride (60% oil dispersion) (0.57 g) is added thereto. After the mixture is stirred for 10 minutes, N-(2-chloroethyl)piperidine hydrochloride (1.35 g) is added to the mixture and the mixture is stirred at room temperature for 4 hours. The mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is converted to its hydrochloride and recrystallized from ethyl acetate, whereby 7-[(2-piperidinoethoxy)methyl]-2-phenylbenzofuran hydrochloride (1.32 g) is obtained. Yield: 51%.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][N:6]([CH2:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:12]=[N:11][N:10]=2)[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.Cl.O1CCOCC1>CO>[CH3:1][C:2]1([CH3:31])[NH:3][CH2:4][CH2:5][N:6]([CH2:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=3)[N:12]=[N:11][N:10]=2)[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2nnnn2-c2cccc(C(F)(F)F)c2)CC1(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC1(C)CN(Cc2nnnn2-c2cccc(C(F)(F)F)c2)CCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl 2,2-dimethyl-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-1-piperazinecarboxylate (567 mg, 1.287 mmol, Intermediate 11) in methanol was added 4M hydrogen chloride in 1,4-Dioxane (7 ml, 28.0 mmol). The reaction mixture was stirred at room temperature for 1 hour.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH:20]=O)=[CH:15][N:14]=1>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([NH2:11])=[N:19][C:17]2[N:18]=[C:13]([NH2:12])[N:14]=[CH:15][C:16]=2[CH:20]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: Cc1cccc(CC#N)c1C
Product: Cc1cccc(-c2cc3cnc(N)nc3nc2N)c1C

Procedure:
The title compound was prepared according to Example 1, starting from 2,3-dimethylphenylacetonitrile and 2,4-diamino-5-pyrimidine-carboxaldehyde; mp 330°-333° C.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[Cl:27][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1
Reactant: CCOC(=O)c1c(C)nc(SC)nc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1c(C)nc(SC)nc1Cl
Temperature: 100 °C
Yield: 82.8 %

Procedure:
Ethyl 4-hydroxy-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (0.2 g, 0.876 mmol), tetraethylammonium chloride (0.145 g, 0.876 mmol), and N,N-dimethylaniline (0.112 mL, 0.876 mmol) were dispersed in acetonitrile (10 mL). The reaction mixture was stirred briefly followed by the addition of phosphorous oxychloride (0.204 mL, 2.190 mmol). The reaction was heated at 100° C. for 4 h. The solvent was subsequently removed in vacuo. The residue was poured onto ice to give an off-white oil, which was extracted with DCM (2×15 mL), and dried over anhydrous Na2SO4. The solvent was removed in vacuo to give the title compound as a yellowish-green oil (0.179 g, 83%). [M+H] calc'd for C9H11ClN2O2S, 247; found, 247.
Reaction SMILES: C([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([Cl:17])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C@H:6]([O:24]C(=O)C(C)(C)C)[C@H:5]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)C.[OH-].[K+].O.NN>CO>[Cl:17][C:16]1[N:11]2[CH:10]=[CH:9][C:8]3[C@@H:7]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C@H:6]([OH:24])[C@@H:5]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[NH:4][C:13]=3[C:12]2=[N:14][C:15]=1[CH3:18]
Reactant: COCCO[C@@H]1c2ccn3c(Cl)c(C)nc3c2N(C(C)=O)[C@H](c2ccccc2)[C@H]1OC(=O)C(C)(C)C
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCO[C@@H]1c2ccn3c(Cl)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A suspension of 0.27 g (0.53 mmol) (7R,8R,9R)-10-acetyl-3-chloro-7-(2-methoxyethoxy)-2-methyl-9-phenyl-8-pivaloyloxy-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine, 0.10 ml (0.60 mmol) aqueous potassium hydroxide (6 N) and 0.20 ml (5.14 mmol) hydrazine hydrate in methanol is stirred at 60° C. for 4 h. The methanol is removed in vacuo and the reaction mixture is diluted with water. Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (toluene/dioxane/acetic acid: 8/1/1) to provide 0.34 g (0.88 mmol/51%) of the title compound as a colourless solid with a melting point of 123-126° C. (acetone).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:8](=[O:23])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:5].C(N(CC)CC)C.[CH3:38][N:39]=[C:40]=[O:41]>O1CCCC1>[CH3:2][O:3][C:4]([C:6]1[N:7]([CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:40](=[O:41])[NH:39][CH3:38])[CH2:27][CH2:26]2)[C:8](=[O:23])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:5]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1CC1CCNCC1
Reactant: CN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)N1CCC(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
To a solution of 6-bromo-1-oxo-4-phenyl-2-(piperidin-4-ylmethyl)-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester hydrochloride (100 mg) in tetrahydrofuran (5 ml) were added triethylamine (0.06 ml) and methylisocyanate (0.018 ml), and the mixture was stirred at room temperature for 24 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to give the title compound (34 mg, 33%).
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:24][C:25]1[O:29][N:28]=[C:27]([CH3:30])[C:26]=1[Br:31]>CO.C(Cl)(Cl)Cl>[Br:31][C:26]1[C:27]([CH3:30])=[N:28][O:29][C:25]=1[NH:24][S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)s1
Reactant: Cc1noc(N)c1Br
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)s2)c1Br
Yield: 34.2 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-[3,5 bis(trifluoromethyl)phenyl]thiophene-2-sulfonamide was prepared in the same manner as in Example 2. Reaction of 2-chlorosulfonyl-5-[3,5-bis(trifluoromethyl)phenyl]thiophene (250 mg, 0.63 mmol) with 5-amino-4-bromo-3-methylisoxazole (118 mg, 0.67 mmol) yielded, after column chromatography using 5% MeOH/CHCl3, 115.2 mg N-(4-bromo-3-methyl-5-isoxazolyl)-5-[3,5 bis(trifluoromethyl)phenyl]thiophene-2-sulfonamide as a white powder (34% yield). A portion of this sample was further purified by preparative HPLC, m.p. 140° C.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:13]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([F:26])=[CH:23][C:24]=2[F:25])=[CH:17][C:16]([C:27]([OH:29])=[O:28])=[C:15]([OH:30])[CH:14]=1.[CH:31](O)([CH3:33])[CH3:32].O>CN(C=O)C>[F:25][C:24]1[CH:23]=[C:22]([F:26])[CH:21]=[CH:20][C:19]=1[C:18]1[CH:13]=[CH:14][C:15]([OH:30])=[C:16]([C:27]([O:29][CH:31]([CH3:33])[CH3:32])=[O:28])[CH:17]=1
Reactant: CC(C)O
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
CDI (972 mg, 5.99 mmol) was added to a solution of diflunisal (1.50 g, 5.99 mmol) in DMF (30 mL). The reaction mixture was stirred at 50° C. for 2 h and isopropyl alcohol (1.15 mL, 14.97 mmol) was dropwise added. The reaction mixture was stirred at 50° C. for 3 h and allowed to reach r.t. It was poured into H2O (50 mL) and extracted with Et2O (2×60 mL). The organic layer was washed with NaHCO3 (20 mL, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (15% EtOAc/hexanes) to furnish 720 mg of isopropyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 41%).
Reaction SMILES: [CH3:1][CH:2](O)[C:3]#[CH:4].[CH3:6][O:7][CH2:8][CH2:9][NH:10][CH2:11][CH3:12]>>[CH2:11]([N:10]([CH2:9][CH2:8][O:7][CH3:6])[CH:2]([CH3:1])[C:3]#[CH:4])[CH3:12]
Reactant: CCNCCOC
Reactant: C#CC(C)O
Product: C#CC(C)N(CC)CCOC

Procedure:
In analogy to example 37.5 and 37.6, 3-Butyn-2-ol and N-(Methoxyethyl)ethylamine were converted to yield Ethyl-(2-methoxy-ethyl)-(1-methyl-prop-2-ynyl)-amine as colorless oil, MS: 155 (M).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][N:8]([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[C:17]1([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[C:25]2[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=2)[NH:19][C:18]1=[O:27]>ClCCl>[Cl:26][C:22]1[CH:21]=[C:20]2[C:25]([C:17]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)([C:12]3[CH:13]=[CH:14][C:9]([N:8]([CH3:15])[CH3:7])=[CH:10][CH:11]=3)[C:18](=[O:27])[NH:19]2)=[CH:24][CH:23]=1
Reactant: CN(C)c1ccccc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CN(C)c1ccc(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the suspension of cesium carbonate (0.147 g, 0.45 mmol) (Aldrich) in dichloromethane (2 mL) was added N,N-dimethylaniline (27.4 mg, 0.23 mmol) (Aldrich), followed by the addition of 3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (70 mg, 0.19 mmol) (from Example 60a supra) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched with water, extracted with dichloromethane three times. The combined organic layer was washed with water, brine, dried over MgSO4. After filtration, the solvent was removed. The residue was purified by chromatography to give rac-6-chloro-3-(3-chloro-benzyl)-3-(4-dimethylamino-phenyl)-1,3-dihydro-indol-2-one as a white solid. (Yield: 35 mg, 45%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:15])[CH3:14].[O:16]1[CH2:18][C@H:17]1[CH2:19]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[O:16]1[CH2:18][C@H:17]1[CH2:19][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)Nc1cc(C(F)(F)F)ccc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
A mixture of N-[2-hydroxy-5-(trifluoromethyl)phenyl]acetamide (282 mg, 1.28 mmol), (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (331.5 mg, 1.28 mmol) and Cs2CO3 (487.5 mg, 1.28 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-40% ethyl acetate in petroleum ether) to give the subtitled compound (150 mg).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[C:23]([N:27]1[CH2:30][CH:29](Cl)[CH2:28]1)([CH3:26])([CH3:25])[CH3:24].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:29]2[CH2:30][N:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:28]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc(O)cc1
Reactant: CC(C)(C)N1CC(Cl)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(OC2CN(C(C)(C)C)C2)cc1

Procedure:
A mixture of 3.98 g. (13.5 mmol.) of 2-n-butyl-3-(4-hydroxybenzoyl)benzofuran, 2.0 g. (13.5 mmol.) of N-t-butyl-3-chloroazetidine and 0.54 g. of sodium hydroxide in 75 ml. of ethanol was refluxed for five hours. The reaction mixture was cooled, filtered and 125 ml. of 10% aqueous sodium hydroxide solution was added. The mixture was extracted three times with chloroform, the combined extracts were evaporated to dryness and the residue was chromatographed on alumina with chloroform as eluant to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:50])[C:3](=[O:49])[CH2:4][C@@H:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41](O)=[O:42])=[CH:35][C:34]=3[O:44][CH3:45])=[CH:29][CH:28]=2)=[O:26])(=[O:23])=[O:22])=[CH:17][C:16]=1[N+:46]([O-:48])=[O:47])[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:51]([NH2:56])[C:52]([CH3:55])([CH3:54])[CH3:53].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C(=O)C.ClC(Cl)C>[CH3:45][O:44][C:34]1[CH:35]=[C:36]([CH2:39][CH2:40][C:41]([NH:56][CH2:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:42])[CH:37]=[CH:38][C:33]=1[C:30]1[CH:29]=[CH:28][C:27]([C:25]([NH:24][S:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C@@H:5]([CH2:6][S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:4][C:3]([N:2]([CH3:50])[CH3:1])=[O:49])=[C:16]([N+:46]([O-:48])=[O:47])[CH:17]=2)(=[O:23])=[O:22])=[O:26])=[CH:32][CH:31]=1
Reactant: COc1cc(CCC(=O)O)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@@H](CSc3ccccc3)CC(=O)N(C)C)c([N+](=O)[O-])c2)cc1
Reactant: CC(C)(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC(Cl)Cl
Solvent: CC(=O)N(C)C
Product: COc1cc(CCC(=O)NCC(C)(C)C)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@@H](CSc3ccccc3)CC(=O)N(C)C)c([N+](=O)[O-])c2)cc1

Procedure:
A solution of Example 126C (50 mg, 0.069 mmol), neopentylamine (21 mg, 0.20 mmol), EDCI (20 mg, 0.104 mmol), and HOBT (15 mg, 0.104 mmol) in N,N-dimethylacetamide (1 mL) and dichloroethane (0.5 mL) at room temperature was stirred for 16 hours. The mixture was concentrated, dissolved in 1:1 DMSO/methanol (1.0 mL) and purified by reverse phase preparative HPLC (using a C-18 column and a solvent system increasing in gradient from 20 to 95% acetonitrile/water containing 0.1% TFA) to provide the desired product. MS (ESI(−)) m/e 788 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ8.89 (br d, 1H), 8.57 (d, 1H), 7.90 (d, 2H), 7.85 (dd, 1H), 7.70(br t, 1H), 7.58 (d, 2H), 7.30-7.12 (m, 7H), 7.00 (d, 1H), 6.90 (dd, 1H), 4.45 (m, 1H), 3.75 (s, 3H), 3.42 (t, 2H), 2.90 (s, 3H), 2.79 (s, 3H), 3.00-2.70 (m, 8H), 0.80 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([O:5][CH3:6])=[O:4].Cl[CH:10]([OH:12])[CH3:11].CS(C)=O.[H-].[Na+]>O>[CH3:6][O:5][C:3]1([C:2]([F:8])([F:7])[F:1])[O:12][CH2:10][CH2:11][O:4]1
Reactant: COC(=O)C(F)(F)F
Reactant: CC(O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC1(C(F)(F)F)OCCO1
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of 42.0 g (0.33 mol) of methyl trifluoroacetate, 26.6 g (0.33 mol) of -chloroethanol, and 150 mL of dimethylsulfoxide (DMSO) was stirred at 10°-20° while 15.8 g (0.33 mol) of 50% NaH in mineral oil was added portionwise. The resulting mixture was stirred at 20° for 2 h, at 25° for several days, and then poured into 1 L of water. The resulting aqueous layer was extracted with 100 mL of ether. The organic layers were combined, then washed twice with water, dried over CaSO4, and distilled to give 35.6 g (63% yield) of 2-methoxy-2-trifluoromethyl-1,3-dioxolane, b.p. 60°-65° at 3.3 kPa (25 mm), and a residue containing about 4.8 g (7% yield) of by-product -(2-chloroethoxy)-2-trifluoromethyl-1,3-dioxolane (estimated by GC).
Reaction SMILES: CC1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[C:9]([O:12][C:13](=[O:15])[CH3:14])(=O)C.[Mn]([O-])(=O)(=O)=O.[K+]>O1CCCC1>[NH2:8][C:6]1[N:7]=[C:14]([C:13]([O:12][CH3:9])=[O:15])[CH:3]=[CH:4][CH:5]=1
Reactant: Cc1cccc(N)n1
Reactant: CC(=O)OC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N)n1
Temperature: 75 °C
Reaction time: 3 h
Yield: 17.9 %

Procedure:
A solution of 6-methylpyridin-2-amine (25 g, 231 mmol) and acetic anhydride (44 mL, 465 mmol) in tetrahydrofuran (188 mL) was heated under reflux for 12 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. This was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. Water (350 mL) was added to the obtained crystals, and the mixture was heated to 75° C., and potassium permanganate (87.1 g, 551 mmol) was gradually added over 45 min. The mixture was stirred for 3 hr, and filtered through celite, and the filtrate was concentrated. Hydrochloric acid/methanol solution (Tokyo Chemical Industry Co., Ltd., 350 mL) was added, and the mixture was heated under reflux for 24 hr. The reaction solution was concentrated, diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate. The obtained organic layers were mixed, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (6.28 g, yield 18%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:13][CH2:12]1)(C)(C)C.Cl.CCOC(C)=O>C(OCC)(=O)C>[C:18]1([CH3:23])[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:14]1[CH2:15][CH2:16][CH:11]([NH:10][CH2:9][CH2:8][NH2:7])[CH2:12][CH2:13]1
Reactant: Cc1ccccc1N1CCC(NCCNC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccccc1N1CCC(NCCN)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 15 (115 mg, 0.344 mmol) in ethyl acetate (2 mL) was treated with sat'd HCl/EtOAc solution (3 mL) at room temperature. The mixture was stirred at room temperature (1 h). The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium carbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound (16). The crude product was used directly.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12]2)[CH2:9][CH3:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].S(Cl)(Cl)=O.[CH3:24]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2([C:14]([O:16][CH3:24])=[O:15])[CH2:12][CH2:13]2)[CH2:9][CH3:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: CCC(c1ccc(Cl)c([N+](=O)[O-])c1)C1(C(=O)O)CC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCC(c1ccc(Cl)c([N+](=O)[O-])c1)C1(C(=O)OC)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
262 mg (about 0.93 mmol) of 1-[1-(4-chloro-3-nitrophenyl)propyl]cyclopropanecarboxylic acid were dissolved in 5 ml of methanol, the mixture was cooled to 0° C. and 0.14 ml (1.85 mmol) of thionyl chloride was added dropwise. The reaction solution was then slowly warmed to room temperature and stirred at this temperature overnight. The reaction mixture was then concentrated to dryness and the residue was taken up in 10 ml of dichloromethane. The solution was washed with water, dried over magnesium sulphate and concentrated under reduced pressure. This gave 224 mg of the target compound (81% of theory).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Cl[C:13]1[N:14]=[C:15]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:16]2[S:21][C:20]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([N:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]3)=[CH:19][C:17]=2[N:18]=1>CN(C=O)C.O>[N:1]1([C:13]2[N:14]=[C:15]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[C:16]3[S:21][C:20]([CH2:22][N:23]4[CH2:24][CH2:25][CH:26]([N:29]([CH3:31])[CH3:30])[CH2:27][CH2:28]4)=[CH:19][C:17]=3[N:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1CCN(Cc2cc3nc(-n4ccc5ccccc54)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 32.8 %

Procedure:
A solution of indole (0.117 g) in DMF (8 mL) was cooled to 0° C. then sodium hydride (0.06 g) was added. After 15 min, [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.395 g) was added. The reaction flask was sealed, heated at 150° C. for 1 h, cooled to room temperature, and diluted with water. The solid precipitate was collected by filtration then purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane) to furnish the title compound (0.156 g, 33%) as an off-white solid. MS m/e 477 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.27-1.57 (m, 2H) 1.55-1.79 (m, 2H) 1.95-2.13 (m, 3H) 2.16 (s, 6H) 2.75-3.06 (m, 2H) 3.74-3.89 (m, 6H) 3.91-4.08 (m, 4H) 6.71 (d, J=3.39 Hz, 1H) 7.18 (s, 1H) 7.30 (s, 1H) 7.36 (s, 1H) 7.61 (s, 1H) 8.30 (d, J=3.77 Hz, 1H) 8.78 (d, J=7.91 Hz, 1H)