Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:28][Si](C)(C)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([NH2:28])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A cooled (0° C.) solution of rac-(3,4-dichloro-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Example 4; 441 mg, 1.45 mmol) in dichloromethane (10 mL) and N,N-dimethylformamide (one drop) was treated with oxalyl chloride (2.0 M solution in dichloromethane, 1.01 mL, 2.02 mmol). The reaction was stirred at 0° C. for 1 h, then 1,1,1,3,3,3-hexamethyldisilazane (1.10 mL, 5.06 mmol) was added and the resulting cloudy mixture was stirred at 25° C. for 16 h. The reaction was quenched with methanol (10 mL), washed with an aqueous solution of 5% sulfuric acid (2×15 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine (1×10 mL), then were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) to provide rac-2-(3,4-dichloro-phenyl)-2-(tetrahydro-pyran-4-yloxy)-acetamide (278 mg, 63% yield) as a white solid, mp 81.9-83.6° C.; FAB-HRMS m/e calcd for C13H15NCl2O3 (M+H)+ 303.0428, found 303.0426.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:19]=1)[CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]Cl)[CH:23]=1.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:28][C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)=[C:6]([CH:19]=1)[CH2:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)ccc1O
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)ccc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-[5-chloro-2-hydroxy benzyl]isoindole-1,3-dione (300 mg, 1.04 mmol), and 3-picolylchloride hydrochloride (171 mg, 1.04 mmol) in anhydrous N,N-dimethylformamide (10 mL), cooled to 0° C., was added a 60% dispersion of sodium hydride in oil (104 mg, 2.6 mmol). The reaction was stirred at room temperature under anhydrous conditions for 15 h. The reaction was quenched by the addition of H2O (5 mL) and then poured into a separatory funnel, and aqueous saturated NaHCO3 solution (50 mL) was added. The aqueous layer was extracted 3×50 mL with CH2Cl2. The organics were combined and washed with saturated aqueous NaCl solution (100 mL), dried over MgSO4, filtered, and concentrated on a rotary evaporator triturated with ether, filtered and dried to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\[N+:22]#[C-:23])/[C:11](/[N+:20]#[C-:21])=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.[C:24](=O)([O-])[O-].[K+].[K+].CBr>CN(C=O)C>[CH3:24][O:19][C:16]1[CH:15]=[CH:14][C:13](/[CH:12]=[C:11](/[C:10](/[N+:22]#[C-:23])=[CH:9]/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[N+:20]#[C-:21])=[CH:18][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: [C-]#[N+]C(=C\c1ccc(O)cc1)/C(=C/c1ccc(OC)cc1)[N+]#[C-]
Agent: CBr
Agent: [K+]
Solvent: CN(C)C=O
Product: [C-]#[N+]C(=C\c1ccc(OC)cc1)/C(=C/c1ccc(OC)cc1)[N+]#[C-]
Yield: 110.3 %

Procedure:
13 mg of xanthocillin X monomethyl ether is dissolved in 2 ml of DMF and 40 mg of potassium carbonate is added thereto. Further, 50 μl of methyl bromide is added thereto and the mixture thus formed is extracted with 30 ml portions of ethyl acetate thrice. The extracts are combined, successively washed with water and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The sodium sulfate is filtered off, and the solvent is distilled from the filtrate. Thus, approximately 15 mg of xanthocillin X dimethylether is obtained in the form of a yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3].[CH2:12]([O:15][C:16]1([CH3:45])[CH2:21][CH2:20][N:19]([C:22]2[N:27]3[N:28]=[C:29]([CH2:31]I)[CH:30]=[C:26]3[N:25]=[C:24]([CH3:33])[C:23]=2[C@H:34]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:18][CH2:17]1)[CH:13]=[CH2:14].[H-].[Na+]>CN(C=O)C.O>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][O:11][CH2:31][C:29]1[CH:30]=[C:26]2[N:25]=[C:24]([CH3:33])[C:23]([C@H:34]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:22]([N:19]3[CH2:20][CH2:21][C:16]([O:15][CH2:12][CH:13]=[CH2:14])([CH3:45])[CH2:17][CH2:18]3)[N:27]2[N:28]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cccc(CO)c1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4cccc(CC=C)c4)nn23)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
To a mixture of (3-allylphenyl)methanol (33.0 mg, 0.222 mmol) in DMF (3 mL) at 0° C. was added (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (130 mg, 0.222 mmol) and NaH (8.90 mg, 0.222 mmol). The reaction mixture was stirred at 0° C. for 2 h. It was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 25% EtOAc/hexane to obtain (S)-ethyl 2-(2-(((3-allylbenzyl)oxy)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.083 mmol, 37.2% yield) as an oil. LCMS (M+1)=605.4.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:28])[O:13][C:14](=[O:27])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25]Cl)[CH:17]=2)=[CH:3]1.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:28])[O:13][C:14](=[O:27])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][N:29]=[N+:30]=[N-:31])[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cccc(OCCCCl)c3)C(=O)OC2=O)c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cccc(OCCCN=[N+]=[N-])c3)C(=O)OC2=O)c2ccccc21
Temperature: 75 °C
Yield: 113 %

Procedure:
To a solution of 3-(1-methylindol-3-yl)-4-[3-(3-chloropropyloxy)phenyl]furan-2,5-dione (1.0 g, 2.2 mmol) in DMF (15 mL) was added sodium azide (0.43 g, 3 eq.) and the resulting mixture was heated at 75° C. for 24 h. The reaction mixture was cooled to room temperature and quenched with water. The product was then extracted into EtOAc. The EtOAc layer was washed with H2O, NaCl (sat.), dried over Na2SO4, and concentrated in vacuo to give 3-(1-methylindol-3-yl)-4-[3-(3-azidopropyloxy)phenyl]furan-2,5-dione (1.0 g) which was used directly in the next step without any further purification.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]1[N:12]([CH3:31])[C:13](=[O:30])[C:14]([O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:16]=1.N1C=CC=CC=1.Cl.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45](Cl)=[O:46]>ClCCl.CN(C1C=CN=CC=1)C>[C:22]([O:21][C:14]1[C:13](=[O:30])[N:12]([CH3:31])[C:11]([CH:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]2[C:45]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=2)=[O:46])=[N:16][C:15]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: COC(=O)c1nc(C2CCc3ccccc3N2)n(C)c(=O)c1OC(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1nc(C2CCc3ccccc3N2C(=O)c2ccccn2)n(C)c(=O)c1OC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
The residue of Step 1 was dissolved in dichloromethane. Pyridine, picolinoyl chloride hydrochloride and a catalytic amount of DMAP were added. A further addition of the reactants was made after two hours. After evaporation of the solvent, the residue was diluted with EtOAc, the organic phase washed with water, dried (Na2SO4) and evaporated to afford the title product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[CH2:29][CH2:30][O:31][CH2:32][CH3:33].C(N(CC)CC)C>CN(C=O)C>[CH2:30]([O:31][CH2:32][CH2:33][N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[C:17]=2[N+:18]([O-:20])=[O:19])[CH2:23][CH2:24]1)[CH3:29]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: CCOCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOCCN1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 80 °C

Procedure:
Compound A2 (0.13 mmol, 50 mg), and 1-bromo-2-ethoxy-ethane (0.65 mmol, 99 mg) were dissolved in DMF (1 mL) and triethylamine (0.91 mmol, 127 μL). The reaction was heated in a microwave at 80° C. for 20 minutes. The mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvent in vacuo and purification by prep-TLC provided Compound A12 as a yellow solid (20 mg, 33%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.06 (s, 1H), 8.29 (s, 1H), 7.84 (d, 2H), 7.74 (d, 2H), 5.39 (s broad, 1H), 3.53 (m, 2H), 3.39 (q, 2H), 2.86 (s, 3H), 2.77 (m, 2H), 2.65 (m, 3H), 2.04 (m, 2H), 1.92 (m, 3H), 1.09 (m, 3H). LCMS (ESI), m/z 466.3 (M+H+, 100%).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][N:4]=[N:3]1.[NH2:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14]>>[N:2]1([CH2:7][C:8]([NH:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)=[O:14])=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: O=C(O)Cn1ccnn1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(Cn1ccnn1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 7 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 174, (S)-2-(2-(1H-1,2,3-triazol-1-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (17.6 mg, 7%). 1H-NMR (400 MHz, CDCl3): σ 8.37 (s, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.38-7.29 (m, 6H), 7.02 (t, 2H), 6.96-6.91 (m, 4H), 6.85 (d, 1H), 5.19-5.11 (m, 2H), 4.70-4.65 (m, 1H), 4.64 (d, 1H), 4.55 (d, 1H), 3.98 (dd, 1H), 3.58 (t, 1H). MS (EI) for C26H24FN5O4. found 490.2 (MH+).
Reaction SMILES: [Cl:1]/[CH:2]=[CH:3]\[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[Cl:1]/[CH:2]=[CH:3]\[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(C/C=C\Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1ccc(C/C=C\Cl)cc1
Reaction time: 1 h

Procedure:
The aldehyde (0.22 g) of Example 1 in ether (5 ml) is added to lithium aluminium hydride (0.08 g) in ether (5 ml), and the mixture stirred at 20° for 1 hour. After successive dropwise additions of water (80 l), 15% NaOH (80 l) and water (240 l), the resulting clear ether layer (+ washings) is evaporated to a residue of 4(Z-3-chloroallyl)benzyl alcohol yield 0.19 g (86%) nD20 1.5529.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Br.[Br:13][CH2:14][CH2:15][NH2:16].C(N(CC)CC)C>C(Cl)Cl>[CH2:5]([O:4][C:2](=[O:3])[NH:16][CH2:15][CH2:14][Br:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCBr
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCBr)OCc1ccccc1
Reaction time: 3 h
Yield: 88.1 %

Procedure:
Benzyl chloroformate (26 mL, 0.176 mole) was added in one portion to a stirring mixture of bromoethylamine hydrobromide (44 g, 0.21 mole), triethylamine (64 mL, 0.46 mole), and methylene chloride (1 L) at below −40° C. After the addition, the cooling bath was removed, and the reaction was allowed to stir for 3 h. The mixture was transferred to a 2 L separatory funnel, and sequentially washed with water (2×500 mL), 2N HCl (250 mL), and water (500 mL). The resulting solution was suction filtered through a 100 g pad of silica gel and washed with methylene chloride. Evaporation of the solvents afforded the product 14 (40 g, 89%) as an oil. 1H NMR (300 MHz, CDCl3) δ 3.46 (t, 2H), 3.60 (q, 2H), 5.11 (s, 2H), 5.20 (br s, 1H), 7.35 (m, 5H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[S:18][C:17]([C:19]([NH:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to aniline via General Procedure B. The product was purified via reverse phase HPLC to give 6.4 mg of 247. MS (Q1) 456.8 (M)+.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[CH:4]1[O:6][CH2:5]1.[CH3:15][Al](C)C>ClCCl.CCCCCC>[F:1][C:2]1[C:3]([CH:4]([CH3:15])[CH2:5][OH:6])=[C:7]([F:14])[C:8]([F:13])=[C:9]([F:12])[C:10]=1[F:11]
Reactant: C[Al](C)C
Reactant: Fc1c(F)c(F)c(C2CO2)c(F)c1F
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(CO)c1c(F)c(F)c(F)c(F)c1F

Procedure:
To a solution of 1.05 g of (+)-2,3,4,5,6-pentafluorostyrene oxide (over 95%ee) in 10 ml of dichloromethane, was added a 6 ml of 1.0M solution of trimethylalumimum in hexane, to react for one hour at 40° C. The similar work-up to Example 1 gave 1.10 g of (+)-2-(pentafluorophenyl)-1-propanol. The specific rotation was compared with that of Example 1, and the optical purity was determined to be 69%ee.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[F:22])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[C:4]([OH:29])[CH:3]=1.Br[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[F:22])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[C:4]([O:29][CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:3]=1
Reactant: N#Cc1ccc(Cn2c(-c3ccc(Cl)cc3O)nc3cc(F)c(F)cc32)c(F)c1
Reactant: BrCC1CCCC1
Product: N#Cc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 19, from 4-[2-(4-chloro-2-hydroxy-phenyl)-5,6-difluoro-benzoimidazol-1-ylmethyl]-3-fluoro-benzonitrile and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Brown sticky solid (78%). MS (Turbo Spray): m/z=496.0 (M+H).
Reaction SMILES: [NH2:1][CH:2]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[OH-].[Na+].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[C:24]([NH:1][CH:2]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CCCCC(N)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCOC(=O)CCCCC(NC(=O)c1ccccc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
While a solution (5 ml) of ethyl 6-amino-6-(2-naphthyl)hexanoate in acetonitrile (1.0 g) and a 1N aqueous solution of sodium hydroxide (4 ml) were vigorously stirred together under ice-cooling, benzoyl chloride (0.54 g) was added dropwise and the mixture was further stirred at room temperature for 1 hour. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The extract and the organic layer were combined, dried, and concentrated to provide ethyl 6-benzoylamino-6-(2-naphthyl)hexanoate (1.5 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][CH:11]=2)[CH2:6][C:5]1=[O:22].C([O-])(O)=O.[Na+].[O:28]=[C:29]1[CH2:34][S:33][C:32]2[CH:35]=[CH:36][C:37]([CH:39]=O)=[N:38][C:31]=2[NH:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[CH3:21][O:20][C:17]1[N:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[C:10]2[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][CH2:39][C:37]2[CH:36]=[CH:35][C:32]3[S:33][CH2:34][C:29](=[O:28])[NH:30][C:31]=3[N:38]=2)[C:5](=[O:22])[CH2:6]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2nccc(N3CCN(CCN)C(=O)C3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2nccc(N3CCN(CCNCc4ccc5c(n4)NC(=O)CS5)C(=O)C3)c2n1
Reaction time: 12 h
Yield: 66.7 %

Procedure:
To a solution of 1-(2-aminoethyl)-4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-piperazinone (46 mg, 0.15 mmol) in DCM-EtOH (2 mL, 1:1) were added NaHCO3 (32 mg, 0.38 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (29 mg, 0.15 mmol). After 12 h, NaBH(OAc)3 (38 mg, 0.15 mmol) was added. After an additional 2 h the solution was partitioned between NaHCO3 (sat)-DCM. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 0-7% MeOH in DCM (1% NH4OH)) yielding the title compound (48 mg, 67%) as a yellow solid: LCMS (ES) m/e 480 (M+H)+; 1H NMR (CD3OD, 400 MHz) δ 8.44 (d, J=5.3 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 6.96 (d, J=5.2 Hz, 1H), 4.21 (s, 2H), 4.19-4.22 (m, 2H), 4.03 (s, 3H), 3.82 (s, 2H), 3.69-3.74 (m, 4H), 3.67 (s, 2H), 2.90-2.93 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][CH2:6]2.Br[CH2:16][CH2:17][C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.O1CCOCC1.[I-].[K+]>[C:18]([CH2:17][CH2:16][N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)#[N:19]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: N#CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCCCO
Product: COc1cc2c(cc1OC)CN(CCC#N)CC2
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A suspension of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9.20 g, 40.1 mmol, 1.00 equiv, Aldrich), 3-bromopropionitrile (3.66 mL, 44.1 mmol, 1.10 equiv, Aldrich), potassium carbonate (33.25 g, 240.6 mmol, 6.00 equiv), and potassium iodide (266 mg, 1.60 mmol, 0.04 equiv) in n-butanol (70 mL) and 1,4-dioxane (70 mL) was stirred at reflux under argon for 48 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by flash chromatography (SiO2, MeOH-EtOAc 0:1 to 1:19) to afford 8.39 g of white solid (59%), which was characterized spectroscopically.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6]([F:16])=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][CH:9]=[CH:8]2.O.[NH2:19][NH2:20]>C(O)C>[F:16][C:6]1[C:5]([CH2:4][C:3]([NH:19][NH2:20])=[O:2])=[C:14]([F:15])[CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: NN
Reactant: COC(=O)Cc1c(F)cc2ncccc2c1F
Solvent: CCO
Solvent: O
Product: NNC(=O)Cc1c(F)cc2ncccc2c1F
Temperature: 30 °C
Reaction time: 24 h

Procedure:
To a solution of (5,7-difluoro-quinolin-6-yl)-acetic acid methyl ester (1.023 g, 4.32 mmol) in ethanol (15 mL) was added hydrazine monohydrate (2 mL) and the mixture was stirred at 30° C. for 24 h. The solvent was removed in vacuo to afford 1.024 g of the title compound as white solid, which was used without further purification. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.33 (s, 1H), 8.97 (d, 1H), 8.46 (d, 1H), 7.67 (d, 1H), 7.61 (dd, 1H), 4.27 (s, 2H). LCMS (method A): [MH]+=238, tR=3.24 min. (5,7-difluoroquinolin-6-yl)-acetic acid methyl ester was synthesized using the method described in WO2008/144767 p 108 (intermediate 2), followed by the method described for Intermediate 12, step 1 WO2008/144767 p 114.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[CH3:9][C:10](=O)[CH2:11][CH2:12][C:13](=O)[CH3:14].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[CH3:14][C:13]1[N:7]([CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])[C:10]([CH3:9])=[CH:11][CH:12]=1
Reactant: CCOC(=O)CN
Reactant: CC(=O)CCC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(C)ccc1C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Glycine ethyl ester HCl (22 g, 158 mmol) was added to a stirring mixture of hexane-2,5-dione (18 g, 158 mmol) in dichloromethane (100 mL) in an Erlenmeyer flask. To the stirring heterogeneous mixture was slowly added triethylamine (66 mL, 473 mmol). After 30 minutes, dichloromethane (50 mL) and NaHCO3 (sat. aq. 100 mL) were added and the mixture continued to stir for 20 minutes. The dichloromethane layer was injected directly onto a 330 g silica gel column and the product was eluted with 0-100% ethyl acetate in hexanes. Pertinent fractions were combined and concentrated to afford ethyl 2-(2,5-dimethyl-1H-pyrrol-1-yl)acetate as a white solid (16 g, 56%). 1H NMR (CDCl3/400 MHz) δ (ppm) 5.8 (s, 2H), 4.85 (s, 2H), 4.22 (q, 2H), 2.17 (s, 6H), 1.28 (t, 3H)
Reaction SMILES: [CH3:1][CH2:2][O:3][P:4]([SH:9])([O:6][CH2:7][CH3:8])=[S:5].[Br:10][C:11]1[CH:12]=[C:13]([C:17](=[O:23])[CH:18]=[CH:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][CH:16]=1>CC(C)=O>[Br:10][C:11]1[CH:12]=[C:13]([C:17](=[O:23])[CH:18]=[C:19]([S:5][P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:2][CH3:1])=[S:9])[C:20]([OH:22])=[O:21])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)C=CC(=O)c1cccc(Br)c1
Reactant: CCOP(=S)(S)OCC
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)SC(=CC(=O)c1cccc(Br)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
1.12 g (0.006 mole) of O,O-diethyldithiophosphoric acid were added dropwise to a solution of 1.28 g (0.005 mole) of 4-(3-bromophenyl)-4-oxo-2-butenoic acid in 20 ml of acetone, and then the mixture was stirred overnight at room temperature. At the end of this time, the solvent was distilled off and the residue was extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulphate, after which the solvent was distilled off. The residue was subjected to column chromatography through silica gel, eluted with a 4:1 by volume mixture of benzene and ethyl acetate. The resulting solid was recrystallised from a mixture of benzene and hexane, to give 1.54 g (yield 69.8%) of the desired 4-(3-bromophenyl)-2-diethoxyphosphinothioylthio-4-oxobutenoic acid, melting at 107°-111° C.