Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24].O>CN(C)C=O.C(OCC)(=O)C>[CH2:24]([O:4][C:3](=[O:5])[CH:2]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:1])[CH:23]=[CH2:22]
Reactant: CC(Oc1cccc2[nH]ccc12)C(=O)O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C(C)Oc1cccc2[nH]ccc12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methylindol-4-yloxyacetic acid (2 g) in N,N-dimethylformamide (20 ml) was added anhydrous potassium carbonate (2.02 g) and allyl bromide (1.27 ml), and the mixture was stirred at 80° C. for 2 hours. To the reaction mixture was added water and ethyl acetate, then separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane-ethyl acetate) to give the title compound (1.88 g) having the following physical data.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]([CH3:18])[CH3:17])/[CH:10]=[CH:11]/[C:12]([OH:14])=O)=[O:7])([CH3:4])[CH3:3].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:55]1[C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH2:57][CH2:56]1>CN(C=O)C.O>[N:55]1([C:12](=[O:14])/[CH:11]=[CH:10]/[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH2:57][CH2:56]1
Reactant: c1ccc2c(c1)CCN2
Reactant: CC(C)C[C@@H](/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](/C=C/C(=O)N1CCc2ccccc21)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.8 %

Procedure:
To a solution of (2E,4S)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-6-methyl-2-heptenoic acid (4.70 g, 18.26 mmol) in DMF (30.0 mL) were added BOP reagent (8.08 g, 18.26 mmol) and DIPEA (6.38 mL, 36.5 mmol). After stirring at RT for 5 min, 2,3-dihydro-1H-indole (2.053 mL, 18.26 mmol) was added and stirring continued overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by flash column chromatography (0-20% EtOAc/hexanes) to afford the title compound (4.83 g, 74%) as a white solid. LC-MS m/z 359 (M+H)+, 1.18 min (ret time).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5]C=CC=1.B(F)(F)F.C[CH2:13][O:14][CH2:15][CH3:16].C(C1[O:21]C1)Cl.[OH-].[Na+]>O.C1(C)C=CC=CC=1>[CH2:16]([O:7][CH2:1][CH:6]1[O:21][CH2:5]1)[CH:15]1[O:14][CH2:13]1
Reactant: CCOCC
Reactant: ClCC1CO1
Reactant: Oc1ccccc1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C(OCC1CO1)C1CO1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
A reaction vessel was charged with 94.1 g (1 mol) of phenol, 1.5 g of boron trifluoride-etherate and 100 ml. of toluene, and with good stirring, the temperature was maintainined at 55° to 65°C., and 277.5 g (3 mols) of epichlorohydrin was added dropwise over the course of 3 hours and 20 minutes. The mixture was further stirred for 1 hour at this temperature to complete an addition polymerization reaction of these monomers. At this point, a part of the addition polymer was withdrawn, and analysis of it showed no presence of epichlorohydrin. 400 ml. of toluene was added to the reaction mixture, and the mixture stirred thoroughly. While maintaining the inside temperature of the reactor at 40° to 45°C., 67.3 g (1.2 mols) of solid sodium hydroxide was added over the course of 1 hour. The mixture was further stirred at this temperature for 1 hour, and then cooled to about 30°C. 440 ml. of water was added to remove the resulting potassium chloride. The organic layer was further washed with 150 ml. of water, and the toluene was evaporated off at reduced pressure. The residue was filtered to afford phenylpolyepichlorohydrin monoglycidyl ether as a transparent light yellow liquid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[N:16]2[N:17]=[C:18]([NH2:20])[N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1.C(OCC)C>C(Cl)Cl>[Br:10][C:11]1[N:16]2[N:17]=[C:18]([NH:20][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Nc1nc2cccc(Br)n2n1)c1ccccc1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
Benzoyl chloride (4.40 g; 31.4 mmol; 2.0 eq.) was added to a suspension of 5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A3), 3.34 g; 15.7 mmol; 1.0 eq.) in pyridine (2.53 mL; 31.4 mmol; 2.0 eq.) and DCM (60 mL). The reaction mixture was then heated at reflux for 4 hours, after which it was cooled down to rt. Diethyl ether was added to the reaction mixture and the solid which precipitated was filtered off. The precipitate was resuspended in an aqueous mixture (pH 4/5), filtered and dried under vacuum to give the title compound as a white powder (4.97 g, quant. yield). HPLC, Rt: 2.40 min. (purity 93.4%), LC/MS, M+(ESI): 317.1, M−(ESI): 315.1.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].Br[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.CCN(CC)CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:4]1([CH2:1][CH:2]=[CH:3][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:4]1([CH:1]=[CH:2][CH2:3][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: C=CCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(C=CCc2ccccc2)cc1
Product: O=C(O)c1ccc(CC=Cc2ccccc2)cc1
Yield: 19.9 %

Procedure:
Allylbenzene (255 μL, 1.9 mmol), 4-bromobenzoic acid (523 mg, 2.6 mmol), Et3N (0.91 mL, 6.5 mmol), Palladium (II) Acetate (16 mg, 0.052 mmol), triphenylphosphine (60 mg, 0.21 mmol) and acetonitrile (5 mL) were stirred at reflux overnight in a round bottom flask. Added HCl 1N, extracted with EtOAc, dried the organic layer on anhydrous MgSO4, filtered, evaporated solvent under vacuum. Purified by column chromatography using 10% MeOH/CH2Cl2 yielded 90 mg (14%) of mixture of two regioisomers 54. The mixture was then submitted for hydrogenation without further characterization.
Reaction SMILES: [C:1]([C:3]([CH3:8])([CH3:7])[C:4]([NH2:6])=[O:5])#[N:2].C(Cl)(=O)[C:10](Cl)=[O:11].[CH3:15][N:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=3)[CH:24]=[CH:23][N:22]=2)[CH:18]=[N:17]1.N1C=CC=CC=1>ClCCCl.C1COCC1>[C:1]([C:3]([CH3:8])([CH3:7])[C:4]([NH:6][C:10](=[O:11])[NH:34][C:31]1[CH:30]=[CH:29][C:28]([O:27][C:25]2[CH:24]=[CH:23][N:22]=[C:21]([C:19]3[CH:18]=[N:17][N:16]([CH3:15])[CH:20]=3)[CH:26]=2)=[CH:33][N:32]=1)=[O:5])#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Reactant: CC(C)(C#N)C(N)=O
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C#N)nc3)ccn2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
A suspension of Example B9 (0.076 g, 0.673 mmol) in DCE (4 mL) was treated with oxalyl chloride (0.059 mL, 0.673 mmol), stirred at RT for 1 h, then heated to 80° C. for 1.5 h. The mixture was cooled to RT, added drop-wise to a solution of Example A2 (0.15 g, 0.561 mmol) and pyridine (0.226 mL, 2.81 mmol) in THF (4 mL) and stirred at RT overnight. The mixture was treated with satd. Na2CO3, extracted with EtOAc (4×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 2-cyano-2-methyl-N-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)propanamide (178 mg, 78%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 10.71 (s, 1H), 8.38 (d, J=5.7 Hz, 1H), 8.28 (d, J=2.9 Hz, 1H), 8.26 (s, 1H), 8.04 (m, 1H), 7.96 (s, 1H), 7.76 (dd, J=9.0, 2.9 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 6.71 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 1.66 (s, 6H); MS (ESI) m/z: 406.1 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[Cl:27][C:28]1[CH:29]=[C:30]([C:36]2([C:54]([F:57])([F:56])[F:55])[CH2:40][C:39]([C:41]3[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[C:43]([C:50]([F:53])([F:52])[F:51])[CH:42]=3)=[N:38][CH2:37]2)[CH:31]=[C:32]([Cl:35])[C:33]=1[Cl:34]>CN(C)C=O.C(OC)(C)(C)C>[Cl:27][C:28]1[CH:29]=[C:30]([C:36]2([C:54]([F:55])([F:57])[F:56])[CH2:40][C:39]([C:41]3[CH:49]=[CH:48][C:44]([C:45]([NH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])=[O:46])=[C:43]([C:50]([F:51])([F:52])[F:53])[CH:42]=3)=[N:38][CH2:37]2)[CH:31]=[C:32]([Cl:35])[C:33]=1[Cl:34]
Reactant: O=C(O)c1ccc(C2=NCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1ccc(C2=NCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of methyl glycinate hydrochloride (0.36 g, 2.89 mmol) in N,N-dimethylformamide was added triethylamine (0.59 g, 5.78 mmol) at 0° C. Then 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.40 g, 1.73 mmol), 4-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]-2-(trifluoromethyl)benzoic acid (0.73 g, 1.44 mmol) was added to the solution. Reaction mixture was stirred for overnight at room temperature. The reaction mixture was diluted with t-BuOMe, washed with H2O, and dried over MgSO4. After evaporation, the residue was purified by column chromatography (0.13 g, 16%).
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-])=O.Cl.[NH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)C(C)C)(C)C>C(#N)C.[Zn]>[NH2:1][CH2:4][CH:5]([NH:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: [Zn]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCNC(CN)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 148.3 %

Procedure:
trans-β-Nitrostyrene (4.04 g, 27.1 mmol) was added to a solution of ethyl 3-aminopropanoate hydrochloride (4.16 g, 27.1 mmol), and N,N-diisopropylethylamine (9.43 mL, 54.2 mmol) in acetonitrile (70 mL). After 15 min, anhydrous hydrochloric acid gas was bubbled into the solution until acidic. The mixture was concentrated, redissolved in ethanol (60 mL) and aqueous hydrochloric acid (12M; 30 mL), and cooled to 0° C. Zinc dust (8.80 g, 134 mmol) was added in portions over 5 min. After 0.5 h, the mixture was concentrated to remove ethanol and saturated aqueous sodium carbonate was added. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated to give the title compound (9.5 g). MS 237 (M+1).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C(COC)OC.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[CH:7][C:8]([CH3:12])=[N:9]3)=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cc1cc(N2CCCC2)c2ccc(I)cc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1cc(N2CCCC2)c2ccc(-c3cccc(Cl)c3)cc2n1
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
A mixture of 1.5 g 7-iodo-2-methyl-4-pyrrolidin-1-yl-quinoline (Example 3.1), 256 mg tetrakis(triphenylphosphine)palladium and 30 ml Dimethoxyethane is stirred under argon for 15 min. 1.04 g 3-Chlorophenylboronic acid and 7 ml Ethanol are added. The resulting red solution is stirred for another 10 min. at room temperature and treated afterwards with 19 ml of a 2M aqueous solution of sodium carbonate. The mixture is refluxed for 1.5 h under vigorous stirring. After the reaction is complete, the reaction mixture is concentrated on a rotary evaporator. The residue is taken up in 50 ml water and extracted twice with 50 ml ethyl acetate. The combined organic phases are washed with 50 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate and filtered. The filtrate is evaporated and the residue is chromatographed on silica gel (eluent: Dichloromethane/Methanol 19:1 then 4:1). The pure fractions are combined and evaporated. 1.235 g of 7-(3-Chloro-phenyl)-2-methyl-4-pyrrolidin-1-yl-quinoline are obtained as a colorless oil. MS (ISP): 323.3 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[F:33][C:34]1([F:40])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)CC)C>C(#N)C>[F:33][C:34]1([F:40])[CH2:39][CH2:38][N:37]([C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[CH:4][CH:3]=2)[CH2:36][CH2:35]1
Reactant: FC1(F)CCNCC1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Br)nc3)cc2)CCN1C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(N4CCC(F)(F)CC4)nc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 150 °C

Procedure:
A mixture of 1,1-dimethylethyl (2S)-4-({4-[[(6-bromo-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D108) (0.050 g, 0.0993 mmol), 4,4-difluoropiperidine (0.141 g, 0.894 mmol) and triethylamine (0.138 mL, 0.993 mmol) in acetonitrile (4 mL) was heated in a microwave at 150° C. for 12 h. Further portions of 4,4-difluoropiperidine (4 eq.) and triethylamine (5 eq.) were added and the reaction heated at 150° C. for 1 h. The reaction mixture was concentrated and the residue dissolved in DCM/water. The aqueous layer was further extracted with DCM (×3) and the combined organics were dried (Na2SO4) and concentrated to give a yellow gum which was purified by column chromatography. Elution with 0-100% EtOAc/hexane gave a colourless gum which was a mixture (˜9:1) of the title compound and unreacted D109 (0.0485 g). MS (ES): MH+ 544.2.
Reaction SMILES: [CH3:1][C:2]1([CH2:19][C:20]([F:23])([F:22])[F:21])[C@@:7]2([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=3)[CH:5]([O:6]2)[C:4](=[O:18])[O:3]1.[K].[Br:25][C:26]1[CH:27]=[CH:28][C:29](O)=[N:30][CH:31]=1.[OH-].[K+]>CN(C)C=O.C(O)(C)C>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([O:6][C:5]2[C:4](=[O:18])[O:3][C@:2]([CH3:1])([CH2:19][C:20]([F:23])([F:22])[F:21])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[N:30][CH:31]=1
Reactant: CC1(CC(F)(F)F)OC(=O)C2O[C@]21c1ccc(S(C)(=O)=O)cc1
Reactant: Oc1ccc(Br)cn1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: C[C@]1(CC(F)(F)F)OC(=O)C(Oc2ccc(Br)cn2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
To a 0° C. mixture of the epoxide(0.930 g) from step 1 in dimethylformamide(3 mL) and isopropanol(12 mL) was added the potassium salt of 5-bromo-2-hydroxypyridine, prepared from 5-bromo-2-hydroxypyridine and one equivalent of 8N KOH followed by evaporation to dryness with toluene and high vacuum drying, (0.742 g, 3.5 mmol) and the mixture was warmed up slowly to reflux for 16 hrs. It was then cooled to room temperature and poured on icy dilute ammonium chloride and ethyl acetate; the organic layer was separated and the aquous further extracted ounce with ethyl acetate. The combined organic layers were washed with brine, dried with MgSO4 and the solvents were removed in vacuo to yield after purification on silica gel(10% acetone/toluene) the title compound (0.380 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[O:8][CH:7]([CH3:12])[CH2:6]1.[H-].[Na+].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][C:21]#[N:22])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1>CN(C=O)C>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([CH:20]([CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH:9]([CH3:11])[O:8][CH:7]([CH3:12])[CH2:6]2)[C:21]#[N:22])=[CH:18][CH:17]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CC1CN(CCCCl)CC(C)O1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1CN(CCCC(C#N)c2ccc(Cl)cc2)CC(C)O1

Procedure:
This intermediate (2.0 g.) was prepared using the procedure described in Example 2a except using 2.3 g. (11 moles) of 4-(3-chloropropyl)-2,6-dimethylmorpholine, 0.48 g. of sodium hydride, and 1.69 g. (11 mmoles) of 4-chlorobenzyl cyanide in 15 ml. of a 2 to 1 mixture of toluene and DMF and was isolated as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16].O=[C:26]([CH3:35])[CH2:27][C:28]([O:30][CH2:31][CH2:32][C:33]#[N:34])=[O:29]>C1COCC1>[C:33]([CH2:32][CH2:31][O:30][C:28]([C:27]1[CH:21]([C:20]2[CH:23]=[CH:24][C:17]([C:15]#[N:16])=[CH:18][CH:19]=2)[NH:12][C:10](=[O:11])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)[C:26]=1[CH3:35])=[O:29])#[N:34]
Reactant: CC(=O)CC(=O)OCCC#N
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: C1CCOC1
Product: CC1=C(C(=O)OCCC#N)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
9.87 g (48.3 mmol) N-[3-(trifluoromethyl)phenyl]urea, 12.68 g (96.68 mmol) 4-cyanobenzaldehyde, 15 g (96.68 mmol) (2-cyanoethyl) 3-oxobutanoate and 37.5 g polyphosphoric acid ethyl ester are suspended in 250 ml of THF. The mixture is stirred at reflux for 18 hours. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate as eluent.
Reaction SMILES: [NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH2:19])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O.C(Cl)Cl>[NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCN)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCNC(=O)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
4-Amino-N-(1-(3-aminopropyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (0.70 g) was dissolved in dimethylformamide (10 ml). Triethylamine (0.30 ml) was added, and a solution of benzoyl chloride (0.25 ml) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature. Insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.15 g of 4-amino-N-(1-(3-benzoylaminopropyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:24][N:23]=[CH:22]2)=[CH:17][CH:16]=1.CI>O1CCCC1>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:24][N:23]=[C:22]2[CH3:1])=[CH:19][CH:20]=1
Reactant: COc1ccc(-n2cncc2-c2ccncc2)cc1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(-n2c(-c3ccncc3)cnc2C)cc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
A solution of diisopropyl amine (0.51 mL, 3.6 mmol) in tetrahydrofuran (12 mL) at −20° C., was treated with n-butyl lithium (2.5 M in hexanes, 1.45 mL, 3.6 mmol) and the solution was stirred for 10 minutes. A solution of Preparation 80 (4-(1-(4-methoxyphenyl)-1H-imidazol-5-yl)pyridine, 730 mg, 2.9 mmol) in tetrahydrofuran was added and the solution became dark orange. The solution was stirred for 30 minutes as the temperature was allowed to rise to 0° C. After cooling to −20° C., methyl iodide (0.54 mL, 8.7 mmol) in tetrahydrofuran (12 mL) was added and the solution was stirred for 30 min at −20° C. and for 2 hr at 23° C. The solvent was removed in vacuo, the residue was diluted with brine and was extracted with ethyl acetate. The organic layer was then dried (MgSO4), was filtered, and was concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate-hexanes-methanol (63:32:5 to 72:18:10) to afford 555 mg (72% yield) of the title compound; diagnostic 13C NMR signals (100 MHz, CDCl3) δ 160.144, 150.034, 149.197, 137.749, 131.265, 129.463, 128.985, 128.828, 120.849, 115.233, 55.78, 14.203; MS (AP/Cl) 266.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH:7]=[O:8].[Na+].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([O-:18])=[O:17]>>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH:7]=[O:8])(=[O:18])=[O:17]
Reactant: O=Cc1ncsc1Cl
Reactant: O=S([O-])c1ccccn1
Agent: [Na+]
Product: O=Cc1ncsc1S(=O)(=O)c1ccccn1

Procedure:
The title compound was prepared by the method of Preparation 5a using 5-chloro-thiazole-4-carbaldehyde and pyridine-2-sulfinic acid sodium salt.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)(Cl)Cl.[C:24](Cl)([Cl:26])=[O:25]>C(Cl)Cl>[Cl:26][C:24]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:25]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCCO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC(=O)Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 270 parts of n-octadecanol in 150 parts of chloroform is added during 90 mins to a stirred solution of 300 parts of phosgene in 450 parts of methylene dichloride at 0°-5° C. The reaction mixture is then stirred a further 2 hours at 0°-5° C., 2 hours at 10° C. and 12 hours at 25° C. Excess phosgene and hydrogen chloride are removed by passing a stream of dry nitrogen. The residue is evaporated to constant weight at 100° C. under reduced pressure to give 327 parts of n-octadecyl chloroformate as a pale yellow oil.