Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:28]=[CH:27][C:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:20]=4[CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:28]=[CH:27][C:21]4[CH2:22][CH2:23][N:24]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:25][CH2:26][C:20]=4[CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)cc1Cl
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCc2ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cc2CC1
Yield: 67.2 %

Procedure:
7-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (Example 17) (100 mg, 0.238 mmol), ethyl bromoacetate (0.043 ml, 0.391 mmol) and cesium carbonate (170 mg, 0.521 mmol) were stirred at room temperature in DMF for 5 hours. The reaction mixture was diluted with diethyl ether (˜20 ml) and washed with water (2×˜20 ml), the organic layer was passed through a phase separating cartridge to dry and concentrated in vacuo to yield the title compound (77 mg, 0.16 mmol, 60% yield) as a yellow oil. δH (d6DMSO, 400 MHz): 8.19 (1H, s), 8.11 (1H, dd), 7.81-7.85 (2H, m), 7.45 (1H, d), 7.34 (1H, d), 4.89 (1H, sept), 4.07 (2H, q) 3.42 (2H, s), 3.00-291 (4H, m), 2.77-2.72 (4H, m), 1.36 (6H, d), 1.19 (3H, t). MS (ES): C25H2835ClN3O4 requires 469; found 470 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[CH2:16][C:17]1[NH:21][C:20]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:19]=2[N:18]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:29]>CN(C)C=O.O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[CH2:16][C:17]1[N:18]([CH3:29])[C:19]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:20]=2[N:21]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCCC1Cc1nc2cc(F)c(F)cc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(CC2CCCCN2C(=O)OC(C)(C)C)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of sodium hydride (0.46 g, 60% dispersion in mineral oil) in dimethylformamide (30 ml) at 0° C., under argon, was added (RS)-2-(5,6-difluoro-1H-benzoimidazol-2-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester, D59 (2 g) and the reaction mixture stirred for a further 30 min. before the addition of iodomethane (0.78 ml). The reaction mixture was then stirred at room temperature for 18 h, a further equivalent of iodomethane (0.35 ml) was added and stirring continued for 24 h. Further portions of sodium hydride (0.23 g, 60% dispersion in mineral oil) and iodomethane (0.35 ml) were added and the reaction stirred for an additional 24 h. After diluting with water, the aqueous layer was extracted with diethyl ether (3×). The combined organics were dried (MgSO4) and solvent removed in vacuo to afford the title compound (0.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[O:20][N:19]=[C:18]([C:21]3[S:25][C:24]([CH2:26][N:27]4[CH2:30][CH:29]([C:31]([O:33]C)=[O:32])[CH2:28]4)=[CH:23][C:22]=3[CH2:35][CH3:36])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.[OH-].[Na+].C(O)(=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[O:20][N:19]=[C:18]([C:21]3[S:25][C:24]([CH2:26][N:27]4[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]4)=[CH:23][C:22]=3[CH2:35][CH3:36])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1
Reactant: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)c(Cl)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1cc(CN2CC(C(=O)O)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)c(Cl)c2)n1
Yield: 90.8 %

Procedure:
The title compound (0.14 g) was synthesized in a yield of 92% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 3 (3e) using methyl 1-[(5-{5-[3-chloro-4-(3-fluorophenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-4-ethyl-2-thienyl)methyl]azetidine-3-carboxylate (0.16 g, 0.30 mmol) that was obtained in Example 16 (16c), a 1 N aqueous solution of sodium hydroxide (0.89 mL, 0.89 mmol), and acetic acid (51 μL, 0.89 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][CH2:7][C:6](=[O:9])[O:5][C:3]1=[O:4].[OH:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCOCC1>[C:3]([C:2]([CH3:10])([CH3:1])[CH2:8][CH2:7][C:6]([O:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=1)=[O:9])([OH:5])=[O:4]
Reactant: COc1ccc(CO)cc1
Reactant: CC1(C)CCC(=O)OC1=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(COC(=O)CCC(C)(C)C(=O)O)cc1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A mixture of 2,2-dimethylglutaric anhydride (19.34 g), anise alcohol (22.08 g) and triethylamine (19.39 g) in dry dioxane (360 ml) was stirred at 80° C. for 3.5 hours. The reaction mixture was evaporated and the residue was diluted with water and adjusted to pH 9 with potassium carbonate. The aqueous layer was washed with benzene, acidified with dilute hydrochloric acid and extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give p-methoxybenzyl 4-carboxy-4-methylvalerate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35]([S:38](C)=O)=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35]([SH:38])=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(S(C)=O)cn2)cc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(S)cn2)cc1
Yield: 118.4 %

Procedure:
A solution of 4-tert-butyl-N-{6-[2-(5-methylsulfinylpyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (471 mg) in trifluoroacetic anhydride (5 ml) and methylene chloride (5 ml) is refluxed for 30 minutes, and the mixture is evaporated to remove the solvent. The residue is dissolved in methanol/triethylamine (1:1) (20 ml), and concentrated to dryness under reduced pressure. The residue is dissolved in chloroform, washed with saturated aqueous ammonium chloride solution and brine, dried over sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure to give 4-tert-butyl-N-{6-[2-(5-mercaptopyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide as pale yellow foam (529 mg).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([F:30])[CH:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[C:21]([F:30])[CH:20]=3)=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Reactant: CC(C)(C#N)c1ccc(CN)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1ccc(CNC(=O)Cn2cnc3cccc(C#N)c32)cc1F

Procedure:
2-(7-cyano-1H-benzimidazol-1-yl)-N-[4-(1-cyano-1-methylethyl)-3-fluorobenzyl]acetamide is synthesized according to example 14 with (7-cyano-1H-benzimidazol-1-yl)acetic acid (150 mg, 0.746 mmol) prepared according to scheme 3, 2-[4-(aminomethyl)-2-fluorophenyl]-2-methylpropanenitrile hydrochloride (205 mg, 0.896 mmol) prepared according to scheme 8, Et3N (250 μL, 1.79 mmol) and HATU (341 mg, 0.896 mmol) in DMF (3.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (50 21.2×50 mm, Mobile phase: A=water (0.075% TFA) B=MeCN (0.075% TFA). Yield=21 mg as TFA salt, 0.043 mmol, 6%); 1H NMR (400 MHz, DMSO-D6) δ ppm 1.62-1.71 (m, 6H), 4.32 (d, J=5.86 Hz, 2H), 5.26 (s, 2H), 7.13-7.25 (m, 2H), 7.29-7.41 (m, 2H), 7.71 (d, J=7.42 Hz, 1H), 8.00 (d, J=8.01 Hz, 1H), 8.36 (s, 1H), 8.84-8.93 (m, 1H). MS [M+H], calcd: 376.2. found: 376.0.
Reaction SMILES: [S:1]([C:5]1[S:13][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[CH2:14]1[O:16][CH2:15]1>CO.C(#N)C>[S:1]([C:5]1[S:13][C:8]2[CH2:9][N:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][C:7]=2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: C1CO1
Reactant: NS(=O)(=O)c1cc2c(s1)CNCC2
Solvent: CO
Solvent: CC#N
Product: NS(=O)(=O)c1cc2c(s1)CN(CCO)CC2
Reaction time: 18 h
Yield: 80 %

Procedure:
Into a solution of 2-sulfamoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (1.74 g, 8.0 mmol) in methanol (25 ml) and acetonitrile (50 ml) was bubbled ethylene oxide gas for 10 minutes. The reaction vessel was stoppered and the mixture was stirred for 18 hours. The precipitated product was collected by filtration. The filtrates were concentrated to provide additional product (total weight, 2.02 g). This material was crystallized from acetonitrile to give 1.67 g (80% yield) of pure product; m.p. 184°-186° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][CH:16]=[CH2:17].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:17]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=1)[CH2:16][CH:15]=[CH2:14]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C=CCCNc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 6.2 %

Procedure:
4-Trifluoromethoxy-phenylamine (2.5 g, 14 mmol), 4-bromobut-1-ene (2.0 g, 14 mmol) and Cs2CO3 (1.4 g, 4.2 mmol) were mixed together, and the mixture was stirred at ambient temperature for 7 days. The title compound (0.2 g, 6.1%) was obtained by silica gel column chromatography (eluting with petroleum ether/ethyl acetate=10/1). 1H NMR (300 MHz, CDCl3): δ 7.12-7.02 (m, 2H), 6.58-6.53 (m, 2H), 5.80-5.46 (m, 1H), 5.20-5.11 (m, 2H), 3.17 (t, 2H, J=6.6 Hz), 2.43-2.35 (m, 2H). LC-MS: [M+1]+ 232.2.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19](=[O:24])[CH2:20][C:21](Cl)=[O:22]>>[CH3:17][O:18][C:19](=[O:24])[CH2:20][C:21]([NH:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)=[O:22]
Reactant: Nc1ccc(OCc2ccc(F)cc2)cc1
Reactant: COC(=O)CC(=O)Cl
Product: COC(=O)CC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1
Yield: 75 %

Procedure:
The title compound is prepared in analogy to example 1 from 4-(4-fluoro-benzyloxy)-phenylamine and chlorocarbonyl-acetic acid methyl ester. Yield: 75%. Colorless solid. MS: m/e=318.2 (M++H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13]1
Reactant: O=c1[nH]c2ccccc2cc1C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=c1[nH]c2ccccc2cc1C1CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
3-(1-Benzylpiperidin-4-yl)quinolin-2(1H)-one (1.72 g, 5.40 mmol) was suspended in methanol (70 mL). A catalytic amount of palladium hydroxide (20% on carbon) was added to the mixture. The reaction vessel was placed on a Parr apparatus and charged with 55 psi of hydrogen. The reaction was shaken at room temperature for 5 h. The mixture was removed from the apparatus and filtered. The filtrate was concentrated to give the title compound as white solid in 90% yield. 1H NMR (300 MHz, DMSO-d6): δ 7.65 (s, 1H), 7.64 (d, J=10.61, 1H), 7.41 (t, J=7.50, 1H), 7.26 (d, J=8.05, 1H), 7.13 (t, J=7.32, 1H), 3.02 (d, J=11.71, 2H), 2.82 (t, J=11.89, 2H), 2.58 (t, J=11.71, 2H), 1.73 (t, J=11.71, 2H), 1.42 (m, 2H). Mass spec.: 229.4 (MH)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:4]([OH:6])=O.[C:21]([C:23]1([CH3:27])[CH2:26][NH:25][CH2:24]1)#[N:22].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:27][C:23]1([C:21]#[N:22])[CH2:26][N:25]([C:4](=[O:6])[C@H:3]([N:7]2[C:16](=[O:17])[C:15]3=[CH:18][NH:19][C:13]4[C:14]3=[C:9]([CH:10]=[CH:11][N:12]=4)[CH2:8]2)[CH:2]([CH3:20])[CH3:1])[CH2:24]1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2ccnc3[nH]cc(c23)C1=O
Reactant: CC1(C#N)CNC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)[C@H](C(=O)N1CC(C)(C#N)C1)N1Cc2ccnc3[nH]cc(c23)C1=O
Yield: 30.6 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoic acid (80 mg, 0.293 mmol). DMF (0.5 mL), 3-cyano-3-methylazetidine (85 mg, 0.439 mmol), HOBt (67.2 mg, 0.439 mmol), EDC (84 mg, 0.439 mmol) and N,N-dimethylpyridin-4-amine (53.6 mg, 0.439 mmol) were added and the solution was stirred at 25° C. for 4 h. The fractions were collected and lyophilized to afford the title compound as a white solid (31.5 mg, 30.6%). 1H NMR (400 MHz, DMSO-d6) δ 0.78 (dd, J=6.82, 3.28 Hz, 3 H) 0.96 (dd, J=8.59, 6.32 Hz, 3 H) 1.44-1.68 (m, 3 H) 2.26-2.44 (m, 1 H) 3.84 (dd, J=9.47, 5.18 Hz, 1 H) 3.99-4.14 (m, 1 H) 4.21 (dd, J=9.47, 5.68 Hz, 1 H) 4.34-4.65 (m, 1 H) 4.85 (dd, J=19.45, 5.56 Hz, 1 H) 4.96-5.11 (m, 2 H) 7.08 (d, J=5.05 Hz, 1 H) 7.86 (d, J=4.04 Hz, 1 H) 8.26 (dd, J=4.80, 3.28 Hz, 1 H) 12.22 (br. s., 1 H). [M+H] calc'd for C19H21N5O2, 352; found, 352.5.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].Br[C:34]1[CH:35]=[C:36]([C:40]2[CH:45]=[C:44]([NH:46][CH:47]3[CH2:49][CH2:48]3)[N:43]=[C:42]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=3)[CH:41]=2)[CH:37]=[N:38][CH:39]=1>COCCOC.C(Cl)Cl>[CH:47]1([NH:46][C:44]2[N:43]=[C:42]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=3)[CH:41]=[C:40]([C:36]3[CH:37]=[N:38][CH:39]=[C:34]([C:13]4[CH:14]=[C:15]5[C:10](=[CH:11][CH:12]=4)[CH2:9][NH:8][CH2:17][CH2:16]5)[CH:35]=3)[CH:45]=2)[CH2:49][CH2:48]1
Reactant: Brc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: c1ccc(-c2cc(-c3cncc(-c4ccc5c(c4)CCNC5)c3)cc(NC3CC3)n2)nc1

Procedure:
To a solution of 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butylester (Intermediate B26) (3 eq, 0.960 mmol, 0.344 g) in dry DME (1 ml) under an inert atmosphere of argon is added 2M Na2CO3 (2 eq, 0.640 mmol, 0.32 ml) followed by (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) (1 eq, 0.320 mmol, 100 mg) and PdCl2dppf (0.1 eq, 0.032 mmol, 23 mg). The reaction mixture is heated using microwave radiation at 90° C. for 2 hours. The reaction mixture is dissolved in DCM and washed with water. The organic solvent is reduced in vacuo and the residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 420.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CC1C=CC(S([CH2:20][N+:21]#[C-:22])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:22]=[N:21][CH:20]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Brc1cccc(-c2cnco2)c1

Procedure:
5-(3-Bromo-phenyl)-oxazole VI-a was prepared as described for intermediate I-c using 3-Bromo-benzaldehyde (10 g, 54 mmol), TosMIC (12.7 g, 65 mmol) and K2CO3 (8.97 g) in MeOH to give the desired intermediate VI-a as a brownish solid (12.1 g, 100%). 1H NMR (300 MHz, CDCl3) δ 7.92 (s, 1H), 7.80 (s, 1H), 7.57 (d, J=7.7 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.37 (s, 1H), 7.29 (d, J=7.9 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:13]([SiH:16]([Cl:18])[Cl:17])[CH:14]=[CH2:15].[Cl-].[Na+]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:14]([CH3:15])[CH2:13][SiH:16]([Cl:18])[Cl:17])[CH3:2]
Reactant: C=CC[SiH](Cl)Cl
Reactant: CCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: CCc1ccccc1C(C)C[SiH](Cl)Cl
Temperature: 50 °C
Yield: 77.6 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 27 g (255 mmol) of ethylbenzene and 1.1 g (9.0 mmol) of aluminum chloride were placed. The flask was then immersed in an ice water bath. To the reaction mixture was slowly added dropwise 12.0 g (85 mmol) of allyldichlorosilane and the solution was stirred for an hour. After confirming that no ethylbenzene was left by gas chromatography, 2.4 g, (413 mmol) of sodium chloride was added to reaction mixture, warmed up to 50° C. and stirred for two hours to deactivate the catalyst. Vacuum distillation of the reaction products gave 16.3 g (bp 80°-84° C./0.6 mmHg) of 3-(ethylphenyl)-1,1-dichloro-1-silabutane.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]([S:12]([CH2:15][CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17]([OH:19])=[O:18])(=[O:14])=[O:13])([CH3:11])[CH3:10])=[O:8].O.[CH2:28](O)[CH3:29]>>[OH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]([S:12]([CH2:15][C@H:16]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:17]([O:19][CH2:28][CH3:29])=[O:18])(=[O:14])=[O:13])([CH3:10])[CH3:11])=[O:8]
Reactant: CC(C)(C(=O)NCCO)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)[C@@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C(=O)NCCO

Procedure:
0.1N sodium hydroxide solution was added dropwise while stirring to a mixture of 0.86 g (2.23 mmol) of rac-α-[[[1-[(2 -hydroxyethyl)carbamoyl]-1-methylethyl]sulfonyl]methyl]hydrocinnamic acid and 200 mg of α-chymotrypsin in 5 ml of ethanol and 100 ml of water in such a manner that the pH value was held at 7.5. After sodium hydroxide solution was no longer consumed the working-up of the reaction mixture was effected by adjusting to pH 8 and extracting twice with 40 ml of ether each time. The combined organic extracts were washed with 15 ml of saturated sodium hydrogen carbonate solution, dried over sodium sulphate and evaporated under reduced pressure. There was obtained ethyl (R)-α-[[[1-[(2-hydroxyethyl)carbamoyl]-1-methylethyl]sulfonyl]methyl]hydrocinnamate as a yellowish oil.
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][NH:9][O:10][CH3:11].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:9]([CH3:8])[O:10][CH3:11])=[O:18])=[CH:15][CH:14]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Pyridine (4.40 mL, 54.2 mmol) was added dropwise to N,O-dimethylhydroxylamine hydrochloride (3.44 g, 35.2 mmol) dissolved in CH2Cl2 (100 mL) at RT. The reaction mixture was stirred for 30 min, and 4-bromobenzoyl chloride (5.95 g, 27.1 mmol) dissolved in CH2Cl2 (50 mL) was added dropwise. The mixture was stirred for 24 h and the volatiles were removed under reduced pressure. Water (200 mL) was added and the mixture was extracted with EtOAc (3×200 mL). The combined extracts were washed successively with 5% aqueous HCl (200 mL), 5% aqueous NaHCO3 (200 mL), water (200 mL), and brine (200 mL). The mixture was dried over MgSO4 and concentrated to afford 6.35 g (74%) of 80 as a colorless oil which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 3.35 (s, 3H), 3.53 (s, 3H), 7.54 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H).
Reaction SMILES: C(O)C.[BH4-].[Na+].C([O:8][C:9]([CH:11]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1)[C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)=O)C>O>[OH:8][CH2:9][CH:11]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1)[C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1
Reactant: CCOC(=O)C(Nc1ncnc2ccc(Cl)cc12)c1ccc2c(c1)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCC(Nc1ncnc2ccc(Cl)cc12)c1ccc2c(c1)OCO2
Yield: 16.8 %

Procedure:
10 ml of ethanol and 197 mg of sodium borohydride were added to 200 mg of 4-(α-ethoxycarbonyl-3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The obtained mixture was refluxed for 30 minutes, followed by the addition of 5 ml of water. The obtained mixture was concentrated under a reduced pressure, followed by the addition of 10 ml of water. The crystal thus precipitated was recovered by filtration. Thus, 30 mg of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl.CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:21][CH2:20]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CO
Solvent: ClCCCl
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCOCC4)CC3)cc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 118.7 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (2.0 g, 7.1 mmol) and 4-piperidin-4-yl-morpholine (1.4 g, 8 5 mmol) in DCE (40 mL) was stirred at room temperature for 1.5 hour then triacetoxyborohydride (2.2 g, 10.6 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours then diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge (70 g). The cartridge was washed with MeOH/DCM (1/1: v/v) and the desired product was eluted with (2M NH3 in MeOH)/DCM (1/1: v/v). The solvents were removed and the residue was triturated in hot IMS, filtered and dried at 60° C. for 1 hour under vacuum to give 2-Chloro-4-morpholin-4-yl-6-(4-morpholin-4-yl-piperidin-1-ylmethyl)-thieno[3,2-d]pyrimidine as a white solid (2.6 g, 84%). LCMS (Method C): RT 0.34 min and 1.67 min; [M+H]+ 438
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCCCCCCOCc1ccccc1
Reactant: O=C1CCNCC1
Product: O=C1CCN(CCCCCCOCc2ccccc2)CC1

Procedure:
1-(6-Benzyloxyhexyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-6-benzyloxyhexane essentially as described above in Example 38, Scheme C, step a.