Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[C:5]([O:8][CH2:9][CH2:10][CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1([CH3:18])[CH3:17])(=[O:7])[CH3:6]>C(Cl)Cl>[C:5]([O:8][CH2:9][CH2:10][CH:11]1[CH:16]=[CH:15][C:14]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][Cl:1])=[CH:13][C:12]1([CH3:18])[CH3:17])(=[O:7])[CH3:6]
Reactant: CC(=O)OCCC1C=CC=CC1(C)C
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClCCl
Product: CC(=O)OCCC1C=CC(C(=O)CCCCl)=CC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Charge a flask with aluminum chloride (223 g, 1.68 mol) and methylene chloride (200 mL). Place under a nitrogen atmosphere, cool to 0°-5° C. and add, by dropwise addition, ω-chlorobutyryl chloride (188.6 g, 1.34 mol). After acid chloride addition is complete, add, by dropwise addition, 2,2-dimethylphenethyl acetate (128.0 g, 0.67 mol), keeping the temperature at approximately 0° C. Continue stirring at 0° C. for 2 hours, quench by slowly pouring over approximately 2 L of crushed ice. Add methylene chloride (500 mL) and stir for 5 minutes. Separate the organic phase and extract the aqueous phase with methylene chloride (300 mL). Combine the organic phases and wash with saturated aqueous sodium hydrogen carbonate (3×200 mL), with deionized water (200 mL) and brine (200 mL). Dry (MgSO4) and stir for 30 minutes before filtering. Evaporate the solvent in vacuo and purify by chromatography (ethyl acetate/hexane) to give the title compound as an orange/brown oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:19][CH2:18][C:13]4([O:17][CH2:16][CH2:15][O:14]4)[CH2:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1>[Pd].C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:19][CH2:18][C:13]4([O:14][CH2:15][CH2:16][O:17]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: C1=C(c2ccc3c(c2)OCO3)CCC2(C1)OCCO2
Agent: [Pd]
Solvent: CCO
Product: c1cc2c(cc1C1CCC3(CC1)OCCO3)OCO2
Yield: 91 %

Procedure:
A mixture of 8-(1,3-benzodioxol-5-yl)-1,4-dioxaspiro[4,5]dec-7-ene and 10% palladium on charcoal in ethanol was reacted as described in example 3 to give the product (91%, mp: 115°-116° C.). Calc'd for C15H18O4 : C, 68.69%; H, 6.92%. Found: C, 68.35%; H, 6.84%.
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[N:18][N:10]3[C:9](=[O:22])[C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4].[OH-:23].[Na+]>O>[OH2:20].[CH2:1]([S:5]([C:6]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[N:18][N:10]3[C:9](=[O:22])[C:8]=2[CH:7]=1)=[O:23])[CH2:2][CH2:3][CH3:4].[CH2:1]([S:5]([C:6]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[N:18][N:10]3[C:9](=[O:22])[C:8]=2[CH:7]=1)=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: CCCCSc1ccc2[nH]c3cc(C(=O)O)nn3c(=O)c2c1
Agent: [Na+]
Solvent: O
Product: CCCCS(=O)c1ccc2[nH]c3cc(C(=O)O)nn3c(=O)c2c1

Procedure:
From 4,9-dihydro-7-(butylthio)-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid (3.17 g, 10 mmole), 1(N) NaOH soln (10 ml) in water (150 ml) and NaIO4 (2.14 g; 10 mmole) in water (50 ml); following the procedure of Example 7, there is obtained 4,9-dihydro-7-(butylsulfinyl)-9-oxo-pyrazolo[5,1-b]-quinazoline-2-carboxylic acid, hemihydrate (2.0 g); mp 205°-210° (d) remelts at 260° (d) after crystallization from aq. methanol.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[NH:7][CH2:6][CH2:5]2.C1(C)C=CC(S(O[CH2:24][CH:25]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=3)[CH2:26]2)(=O)=O)=CC=1>>[CH:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:41]=[CH:42][C:33]=1[CH2:32][CH2:31][CH2:30][N:27]1[CH2:28][CH2:29][CH:25]([CH2:24][N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][C:11]([CH3:12])=[C:2]([CH3:1])[CH:3]=3)[C:8]2=[O:13])[CH2:26]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(CCCc3ccc4ccccc4c3)C2)cc1
Reactant: CC1=C(C)CC2CCNC(=O)C2=C1
Product: Cc1cc2c(cc1C)C(=O)N(CC1CCN(CCCc3ccc4ccccc4c3)C1)CC2

Procedure:
Prepared from 6,7-dimethyl-1-oxo-1,3,4,5-tetrahydro-isoquinoline and 3-(p-toluenesulphonyloxymethyl)-N-[3-(naphth-2-yl)-propyl]-pyrrolidine analogously to Example 2.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[CH:10]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:2]1([CH2:1][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(Cn2cnc3ccccc32)cc1

Procedure:
To benzyl chloride (13 g, 0.103 mol), 1h-benzimidazole (11.81 g, 0.10 mol), K2CO3 (60 g, 0.434 mol) was added acetonitrile (200 mL) and the mixture was stirred and heated under reflux for 3 h, filtered hot, and washed with hot CH3CN (100 mL). The solvent of the filtrate was evaporated and the residual mass recrystallized as needles (16.5 g, 79%): mp 119°-120° C. (benzene)(lit1 mp 105° C.); 1H NMR (270 MHz, CDCl3) δ 5.40 (s, 2H, CH2), 7.20-7.41 (m, 8H), 7.85-7.89 (m, 1H), 8.02 (s, 1H, NCHN); IR (CDCl3) 3093 (w), 3065 (w), 3037 (w), 2929 (w), 1615 (w), 1496 (s), 1456, 1385 (w), 1361, 1331, 1285, 1261, 1204, 1181, 1007 (w), 963 (w), 947 (w) cm-1. MS (EI) m/e 208 (M+, 57.8), 91 (100); Anal. Calcd for C14H22N2 (208.26): C, 80.74; H, 5.81; N, 13.45; Found: C, 80.70; H, 6.02; N, 13.31.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]3[C:27]([Cl:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[Cl:30])=[CH:14][CH:13]=2)[C:9]#[N:10])=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1.[CH3:35][O:36][CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O>>[Cl:30][C:23]1[CH:24]=[C:25]([CH3:29])[CH:26]=[C:27]([Cl:28])[C:22]=1[O:21][CH2:20][CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:45]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH2:39][CH2:38][CH2:37][O:36][CH3:35])=[CH:3][C:4]=2[C:31]([F:34])([F:33])[F:32])[C:9]#[N:10])=[CH:13][CH:14]=1
Reactant: COCCCc1ccccc1B(O)O
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(C#N)c3ccc(Br)cc3C(F)(F)F)cc2)c(Cl)c1
Product: COCCCc1ccccc1-c1ccc(C(C#N)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using 2-[4-bromo-2-(trifluoromethyl)phenyl]-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}propanenitrile from step 1 and [2-(3-methoxypropyl)phenyl]boronic acid from EXAMPLE 3, step 1 as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (5 to 10%, in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [N:1]1C=CC=C[CH:2]=1.CN.[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1F)[N:16]([C:22]1[CH:27]=[C:26]([NH:28][CH3:29])[C:25]([F:30])=[CH:24][C:23]=1[F:31])[CH:15]=[C:14]([C:32]([OH:34])=[O:33])[C:13]2=[O:35]>C(OCC)C>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[NH:1][CH3:2])[N:16]([C:22]1[CH:27]=[C:26]([NH:28][CH3:29])[C:25]([F:30])=[CH:24][C:23]=1[F:31])[CH:15]=[C:14]([C:32]([OH:34])=[O:33])[C:13]2=[O:35]
Reactant: CNc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(C)c32)c(F)cc1F
Reactant: c1ccncc1
Agent: CN
Solvent: CCOCC
Product: CNc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NC)c(C)c32)c(F)cc1F
Temperature: 40 °C
Reaction time: 72 h
Yield: 24.3 %

Procedure:
Pyridine (300 mg) and a 40% aqueous solution (150 mg) of methylamine were added to 6,7-difluoro-1-(2,4-difluoro-5-methylaminophenyl)-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (80 mg), and the mixture was heated and stirred at 40° C. for 3 days. After the reaction mixture was allowed to cool, diethyl ether was added, followed by stirring. A supernatant liquid was removed, and ethanol (1 ml) was added to the residue to disperse solids therein. The solids were collected by filtration and washed with ethanol and dried to obtain the title compound (20 mg) as a pale yellow powder.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.Cl>N1C=CC=CC=1>[C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)CC=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 97.1 %

Procedure:
A mixture of diphenylacetaldehyde (19.6 g), malonic acid (10.9 g) and piperidine (0.4 mL) in pyridine (20 mL) was heated at reflux until the evolution of gas had subsided (1.25 h). The solution was cooled and poured into a stirred mixture of ice (100 g) and 2N hydrochloric acid (150 mL). The resulting solid was recovered by filtration, washed with water and dried to provide 23.1 g of 4,4-diphenyl-3-butenoic acid, mp 109°-111° C. A portion was crystallized from ethyl acetate-hexane to give the pure acid of 4,4-diphenyl-3-butenoic acid, mp 112.5°-114° C.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].C([O-])([O-])O[CH2:24][CH3:25]>>[CH2:24]([O:20][C:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10](=[CH:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][C:3]2=[O:21])[CH:11]=1)[CH3:25]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CCOC([O-])[O-]
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1

Procedure:
The process according to claim 1 wherein androst-4-en-3,17-dione is treated with ethyl orthoformate to yield 3-ethoxyandrosta-3,5(6)-dien-17-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH2:7][C:8]1=[O:12])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)NC(=O)C2
Product: COc1ccc2c(c1)N(C(C)=O)C(=O)C2

Procedure:
Prepared from 6-methoxy-2-indolinone (prepared according to Quallich, G. J.; Morrissey, P. M.; Synthesis 1993, 51) and acetic anhydride
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:25]3[CH:29]=[CH:28][N:27]=[CH:26]3)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: c1c[nH]cn1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCn1ccnc1

Procedure:
Using 3.9 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138) and 1.5 g of imidazole, a reaction similar to that conducted in Example 142 was carried out. As a result, 3.38 g of N-(trans-4-methylcyclohexyl)-4-[2-(1-imidazolyl)ethoxy]-3methoxycinnamamide (a compound of the present invention) was obtained as light-brownish white crystal, which had the following physiochemical properties:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1)([O-:3])=[O:2].Cl.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH2:29])[N:23]=2)=[CH:17][CH:16]=1.C(N(CC)C1C=CC=CC=1)C>O=P(Cl)(Cl)Cl>[NH2:29][C:24]1[N:23]=[C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)=[O:12])=[CH:16][CH:17]=2)[CH:27]=[C:26]([CH3:28])[N:25]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cn1
Reactant: Cc1cc(Nc2ccc(N)cc2)nc(N)n1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc([N+](=O)[O-])cn3)cc2)nc(N)n1
Temperature: 20 °C
Reaction time: 72 h
Yield: 33.9 %

Procedure:
5-Nitropyridine-2-carboxylic acid 18 (1.06 g, 6.31 mmol) was refluxed in POCl3 (10 mL) for 1 h. (clear solution obtained), cooled to 20° C. and excess POCl3 was removed under vacuum. The resulting residue was dissolved in 1,4-dioxane ((20 mL) and added slowly to a suspension of 17 (1.44 g, 5.72 mmol) and N,N-diethylaniline (2.0 mL, 12.62 mmol) in 1,4-dioane (20 mL). The reaction mixture was stirred at 20° C. for 3 days. The resulting white precipitate was filtered and washed with more 1,4-dioxane. The solid was stirred in aqueous NH3 (20 mL) and the resulting red precipitate was filtered, washed with water and recrystallized from MeOH to give 20 (708 mg, 31%); mp (MeOH)>290° C.; 1H NMR ([(CD3)2SO] δ 10.74 (1H, NH), 9.43 (dd, J=2.6, 0.5 Hz, 1H, H-6), 8.96 (s, 1H, NH), 8.81 (dd, J=8.6, 2.6 Hz, 1H, H-4), 8.38 (dd, J=8.6, 0.6 Hz, 1H, H-3), 7.81 (d, J=9.0 Hz, 2H-2′H-6′), 7.70 (d, J=9.1 Hz, 2H, H-3′, 5′), 6.09 (s, 2H, NH2), 5.87 (s, 1H, H-5″), 2.09 (s, 3H, CH3); HRMS (FAB+) calc. for C17H16N7O3 (M+1) m/z 366.1315, found 366.1314; Anal. calc. for C17H15N7O3.0.25 MeOH: C, 55.5; H, 4.4: N, 26.3; found, C, 55.7; H, 4.5; N, 26.2%.
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[N:15]2[CH:16]=[C:17]([C:21]3[CH:22]=[N:23][C:24]([N:27]4[CH2:32][CH2:31][C:30]([CH3:36])([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]4)=[N:25][CH:26]=3)[C:18]([F:20])=[CH:19][C:14]2=[N:13][C:12]=1[CH3:37]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O.CCOC(C)=O>[F:38][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[N:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[N:25][C:24]([N:27]4[CH2:32][CH2:31][C:30]([CH3:36])([C:33]([O:35][CH2:9][CH2:4][CH2:5][CH3:6])=[O:34])[CH2:29][CH2:28]4)=[N:23][CH:22]=3)[C:18]([F:20])=[CH:19][C:14]2=[N:13][C:12]=1[CH3:37]
Reactant: Cc1nc2cc(F)c(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cn2c1Cc1ccccc1OC(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCOC(=O)C1(C)CCN(c2ncc(-c3cn4c(Cc5ccccc5OC(F)F)c(C)nc4cc3F)cn2)CC1
Temperature: 180 °C
Yield: 81.4 %

Procedure:
A suspension of the sodium salt of Example 46 (207 mg, 0.38 mmol) and tetra-n-butylammonium chloride (42 mg, 1.5 mmol) in DMSO (2.5 mL) was heated under microwave irradiation, in a sealed tube, to 180° C. for 10 minutes. The reaction mixture was diluted with EtOAc (30 mL), and washed with HCl (1M, 20 mL), water (2×20 mL) and brine (20 mL), then the organic layers were dried over MgSO4 and the solvent was removed. The resulting crude yellow gum (270 mg) was purified by uv-directed preparative HPLC (pH 10 method eluting with 50-65% solvent B) to give the title compound (90 mg, 41%) as a colourless gum. δH (400 MHz, CD3OD) 8.39 (s 2H), 8.10 (d, 1H, J 7.3 Hz), 7.32-7.26 (m 2H), 7.21 (m, 1H), 7.16 (t, 1H, J 7.7 Hz), 7.10-7.08 (m, 1H), 6.92 (t, 1H, J 74 Hz), 4.42 (t, 2H, J 4.0 Hz), 4.38 (s, 2H), 4.18 (t, 2H, J 6.4 Hz), 3.40-3.37 (m, 2H), 2.42 (s, 3H), 2.17 (d, 2H, J 13.6 Hz), 1.69 (m, 2H), 1.51-1.42 (m, 4H), 1.26 (s, 3H), 0.99 (t, 3H, J 7.3 Hz). HPLC-MS (pH 10): MH+ m/z 582.8, RT 3.04 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([Cl:15])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:17][C:18]1[C:23]([CH2:24]O)=[CH:22][CH:21]=[C:20]([C:26]([F:29])([F:28])[F:27])[N:19]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([Cl:15])=[CH:11][C:12]([O:14][CH2:24][C:23]3[C:18]([CH3:17])=[N:19][C:20]([C:26]([F:29])([F:27])[F:28])=[CH:21][CH:22]=3)=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Reactant: COC(=O)Cc1csc2cc(O)cc(Cl)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2cc(OCc3ccc(C(F)(F)F)nc3C)cc(Cl)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
To a mixture of methyl(4-chloro-6-hydroxy-1-benzothiophen-3-yl)acetate (110 mg) and THF (dry) (5 mL) were added (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (82 mg), tri-n-butylphosphine (0.159 mL), and ADDP (130 mg) at room temperature. The mixture was stirred at room temperature for 12 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (164 mg). The compound was crystallized from IPE-hexane.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)[CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:8][CH:7]=1.[C-:23]#[N:24].[Na+]>O.Cl>[CH3:16][N:15]([CH2:14][CH2:13][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([C:23]#[N:24])=[CH:7][CH:8]=1)[C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)[CH3:17]
Reactant: [C-]#N
Reactant: CN(C)CCC(c1ccc(N)cc1)c1ncc[nH]1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CN(C)CCC(c1ccc(C#N)cc1)c1ncc[nH]1
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
A solution of sodium nitrite (0.3 g) in water (5 ml) was added dropwise to a stirred solution of 3-(4-aminophenyl)-N,N-dimethyl-3-(imidazol-2-yl) propanamine (1.0 g) in 2 N hydrochloric acid (6 ml) and water (6 ml), keeping the temperature at 3°-5°. After stirring for 30 min. the dark red solution was adjusted to pH 7-8 and treated with sodium cyanide (0.2 g) and cuprous cyanide (0.4 g) and heated on a steam bath for 3 h. The mixture was then adjusted to pH 11-12 and extracted with ethyl acetate (3×30 ml). The extracts were dried (Na2SO4) and concentrated to give the title compound as a gum (0.33 g) which was taken up into methanol (5 ml) and treated with a solution of maleic acid (0.15 g) in methanol (5 ml). Removal of the solvent and trituration of the residue with ether gave the dimaleate salt of the title compound as an off white solid that crystallised from ethanol-ether with m.p. 147°-148°; τ(D2O)2.06 to 2.35 (2H,m,aromatic),2.48(2H,br.s,imidazole), ##STR36## 6.5-7.5(4H,m,CH2CH2N(CH3)2),7.03(6H,s,N(CH3)2).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[OH:59][C:52]1[C:51]([CH2:50][NH:49][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:10][C:2]=2[CH3:1])=[C:56]([CH3:57])[CH:55]=[C:54]([CH3:58])[N:53]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1cc(CN2CCCCC2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(CN3CCCCC3)cc2C)c(O)n1
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
A solution of 2-methyl-4-(piperidin-1-ylmethyl)benzoic acid (100 mg, 0.43 mmol) in dichloromethane (50 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (35 mg, 0.1 mmol), triethylamine (32 mg, 0.3 mmol). The mixture was stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (27 mg, 0.2 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was washed with water (50 mL), dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-4-(piperidin-1-ylmethyl)benzamide as white solid (35 mg, 19%). LRMS (M+H+) m/z: calcd 367.23. found 367. HPLC purity (214 nm): 96%. 1H NMR (300 MHz, CD3OD): δ 7.54-7.46 (m, 3H), 6.26 (s, 1H), 4.62 (s, 2H), 4.17 (s, 2H), 3.10 (s, 4H), 2.54 (s, 3H), 2.53 (s, 3H), 2.39 (s, 3H), 1.93-1.89 (m, 4H), 1.77-1.75 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:26][C@H:27]([OH:30])[CH2:28][NH2:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:29][CH2:28][C@@H:27]([OH:30])[CH3:26])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: C[C@H](O)CN
Product: C[C@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and S-(+)-1-amino-2-propanol employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.82 (1H, br s), 10.35 (1H, br s), 8.50 (1H, s), 7.45 (1H, s), 7.31-7.27 (2H, m), 7.15 (2H, t, J=8.7 Hz), 4.93 (1H, d, J=4.2 Hz), 4.11 (2H, s), 3.80-3.75 (1H, m), 3.42-3.39 (1H, m), 3.20-3.14 (1H, m), 1.07 (3H, d, J=6.1 Hz); HRMS calcd for C19H18FN3O4+H+: 372.1360. Found 372.1355.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:24]1CCOCC1.C(OC(Cl)=O)C(C)C.N>C1COCC1>[C:19]([O:18][C:16](=[O:17])[NH:15][C@H:11]([C:12](=[O:13])[NH2:24])[CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(N)=O
Temperature: -15 °C
Reaction time: 0.03 h

Procedure:
To a solution of (S)-4-benzyloxy-2-tert butoxycarbonylamino butyric acid (1.16 g, 3.7 mmol) in anhydrous THF (15 mL) at −15° C. was added N-methylmorpholine (0.41 mL, 3.7 mmol) and isobutylchloroformate (0.51 mL, 3.7 mmol) under a nitrogen atmosphere. After 2 minutes, 33% aqueous ammonia (0.34 mL, 5.6 mmol) was added and the resulting mixture stirred at −15° C. for 2 h. The reaction mixture was left to warm to RT and was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The combined organic fractions were washed with aqueous 5% NaHCO3, water, dried (MgSO4) and concentrated in vacuo. The resulting white solid was used without further purification (quant. yield). 1H NMR (CDCl3, 300 MHz): δ 7.41-7.25 (5H, m), 6.38 (1H, br s), 5.75 (1H, br s), 5.38 (1H, br s), 4.55-4.45 (2H, m), 4.30 (1H, br s), 3.75-3.52 (2H, m), 2.10-2.00 (2H, m), 1.42 (9H, s).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18](Br)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Sn](CCCC)(CCCC)[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1)CCC>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([C:29]2[CH:28]=[N:27][CH:26]=[N:31][CH:30]=2)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cncnc2)c1
Yield: 77.8 %

Procedure:
To the solution of 3-(1-BOC-2-(S)-azetidinylmethoxy)-5-bromopyridine (580 mg, 1.69 mmol) in toluene (10 mL) was added tetrekis(triphenylphosphine)palladium (58 mg, 1%) and tributyl(pyrimidinyl)tin (0.75 g, 2.03 mmol). The mixture was stirred and heated under reflux for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 2:3) to afford an oil (450 mg, 78%): 1H NMR (CDCl3, 300 MHz) δ 1.40 (s, 9H), 2.30-2.44 (m, 2H), 3.88-3.96 (m, 2H), 4.22 (m, 1H), 4.44 (m, 1H), 4.58 (m, 1H), 7.44 (m, 1H), 8.44 (m, 2H), 8.98 (s, 2H); MS (CI/NH3) m/z 343 (M+H)+.