Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10](=[O:24])[C:11]([C:13]1[C:21]2[C:16](=[N:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[NH:15][C:14]=1[CH3:23])=O>C(O)(C(F)(F)F)=O>[CH3:8][O:9][C:10](=[O:24])[CH2:11][C:13]1[C:21]2[C:16](=[N:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[NH:15][C:14]=1[CH3:23]
Reactant: COC(=O)C(=O)c1c(C)[nH]c2nc(Cl)ccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1c(C)[nH]c2nc(Cl)ccc12
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of triethylsilane (0.343 ml, 2.15 mmol) in TFA (2 ml) cooled to −10° C. is added portionwise (6-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-oxo-acetic acid methyl ester (0.155 g, 0.61 mmol). The reaction mixture is stirred at −10° C. for 1 hour and the solvent is removed in vacuo. The residue is washed with saturated sodium hydrogen carbonate solution and this aqueous portion is extracted with DCM (3×10 ml). The organics are combined, dried (Na2SO4) and concentrated in vacuo and the resulting crude is purified by chromatography on silica eluting with methanol/DCM (0-0.5% methanol) to yield the titled product as an off-white powder. (MH+ 239).
Reaction SMILES: [CH2:1]([SH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:8](#[N:11])[CH:9]=[CH2:10].C[O-].[Na+]>>[CH2:1]([S:7][CH2:10][CH2:9][C:8]#[N:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCS
Reactant: C=CC#N
Agent: C[O-]
Agent: [Na+]
Product: CCCCCCSCCC#N

Procedure:
β-n-Hexylmercaptopropionitrile was prepared according to the procedure of Example 1 using 1-hexanethiol (25.0 g; 0.21 moles), acrylonitrile (11.2 g; 0.21 moles) and sodium methoxide (0.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([I:11])[CH:3]=1.C(Cl)(=O)C([Cl:15])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([I:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1I
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)cc1I
Reaction time: 2 h

Procedure:
A catalytic amount of DMF (approximately 3 drops) was added to a stirred mixture of 4-chloro-2-iodobenzoic acid (24.47 g, 86.63 mmol) and oxalyl chloride (11.34 mL, 129.9 mmol) in DCM (100 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 2 hours and then concentrated in vacuo to give 4-chloro-2-iodobenzoyl chloride as a yellow oil that solidified upon standing (26.07 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[C:13]4[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=4[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13]4[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=4[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Cn1c(-c2ccc3c(c2)OCO3)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(O)Cn1c(-c2ccc3c(c2)OCO3)nc2ccccc21
Temperature: 25 °C

Procedure:
A solution of 0.5 g (1.42 mmol) of 1,1-dimethylethyl 2-(1,3-benzodioxol-5-yl)-1H-benzimidazole-1-acetate (the title compound of EXAMPLE 2) in 10 mL of chloroform was treated with 10 mL of trifluoro-acetic acid (TFA), and the reaction was stirred at rt until completion. Volatiles were evaporated in vacuo, and the residue was recrystallized from ether to give 2-(1,3-benzodioxol-5-yl)-1H-benzimidazole-1-acetic acid as a white solid: 1H NMR (DMSO, d6) δ 5.25 (s, 2H), 6.18 (s, 2H), 7.19 (d, J=8.1 Hz, 1H), 7.23-7.35 (m, 2H), 7.37-7.53 (m, 2H), 7.70-7.87 (m, 2H); HRMS (EI) Calc'd for M+ : 297.0875, found: 297.0885. Anal. Calc'd for [C16H12N2O4 +0.67 CF3CO2H]: C, 55.91; H, 3.43; N, 7.52. Found: C, 55.91; H, 3.52; N, 7.51.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:10]1([CH:16]=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:16]/[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CC1CCCCC1
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C/N=C/C1CCCCC1
Yield: 106.5 %

Procedure:
In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with cyclohexanecarbaldehyde (Aldrich) (0.6 g, 5 mmol) in CH2Cl2 at room temperature for 20 h to give {[1-cyclohexyl-meth-(E)-ylidene]-amino}-acetic acid tert-butyl ester as a colorless oil (1.2 g, 100%).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]3[CH:20]=[C:19]([C:21]4[CH:22]([CH2:28][CH3:29])[CH2:23][C:24](=[O:27])[NH:25][N:26]=4)[CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][CH:7]=1.Cl.O1CCOCC1>CC(=O)OCC>[CH2:28]([CH:22]1[CH2:23][C:24](=[O:27])[NH:25][N:26]=[C:21]1[C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]=[O:2])=[CH:7][CH:8]=3)[O:13][C:14]=2[CH:20]=1)[CH3:29]
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC(OC)OC)cc3)oc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC=O)cc3)oc2c1

Procedure:
22.2 mg (52 μmol) 6-{2-[4-(2,2-dimethoxy-ethoxy)-phenyl]-benzoxazol-6-yl}-5-ethyl-4,5-dihydro-2H-pyridazin-3-one, 130 μL (4 mmol/mL; 520 μmol) HCl and 2 ml dioxane are stirred for 3 h at 50° C. Then the mixture is diluted with EA, extracted with H2O and then with 10% sodium carbonate solution. The solv. of the org. phase is eliminated i.V.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([OH:35])[C:32]3[C:27](=[CH:28][C:29]([CH3:36])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:38]([O:45][C:46](=[O:50])[C@H:47](O)[CH3:48])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([O:35][C@H:47]([C:46]([O:45][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:50])[CH3:48])[C:32]3[C:27](=[CH:28][C:29]([CH3:36])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C[C@@H](O)C(=O)OCc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@@H](C)C(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 1 g of 4-{(S)-3-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester and 350 mg of (R)-2-Hydroxy-propionic acid benzyl ester in 20 ml of THF, 764 mg of Triphenyl-phosphane and 507 mg of Diethyl azodicarboxylate was added and stirred for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.3 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH2:23][NH:24][CH2:25][C:26](OCC)=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:31]([Si](C)(C)C)=[C:32]=[O:33].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:11][C@H:10]2[CH2:23][N:24]2[CH2:25][C:26](=[O:27])[NH:31][C:32]2=[O:33])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)CNC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN2CC(=O)NC2=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution (1.9 mL) of tert-butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-{[(2-ethoxy-2-oxoethyl)amino]methyl}-1,4-oxazepane-4-carboxylate (180 mg) in THF were added isocyanatotrimethylsilane (0.078 mL) and triethylamine (0.082 mL), and the mixture was stirred at room temperature for 2 hr. Then, isocyanatotrimethylsilane (0.156 ml) and triethylamine (0.164 mL) were added, and the mixture was stirred at 50° C. for 2 hr, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate). The obtained residue was diluted with methanol (1.4 mL), triethylamine (0.080 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (115 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([CH2:20][OH:21])[CH:9]=2)=[CH:4][CH:3]=1.P([O-])([O-])([O-])=[O:23]>C(#N)C.O.[O-]Cl.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:12][N:11]=[C:10]([C:20]([OH:23])=[O:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: OCc1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Temperature: 35 °C
Reaction time: 20 h

Procedure:
To a solution of [4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-methanol (17.4 g, 55 mmol) in acetonitrile (235 mL), phosphate buffer (pH 6.7, 220 mL) and 2,2,6,6-tetra-methylpiperidine 1-oxyl radical (TEMPO, 0.6 g) was added and the solution was warmed to 35° C. To this warm solution under argon was added with stirring over 2 h simultaneously a solution of NaOCl2 (12.4 g) in water (58 mL) and NaOCl (0.85 mL, 10% solution) in water (35 mL). Stirring was continued for 20 h at 35° C. after which time the solution was cooled to room temperature and quenched by addition of in sequence water (420 mL), 2 N NaOH solution (65 mL) and Na2SO3 solution (17.1 g in 285 mL water). This mixture was stirred for 30 min and acidified with 2 N HCl (175 mL). The mixture was extracted once with ethyl acetate/THF (800/150 mL), and once with ethyl acetate (500 mL). Organic phases were washed with brine (800 mL), pooled and dried with Na2SO4. The solvent phase was concentrated to a volume of ˜100 mL. n-Heptane (150 mL) was added and the solvent phase was concentrated again to ˜100 mL. This was repeated twice. n-Heptane (100 mL) was added. The product precipitated upon stirring, was filtered off and dried to give the title compound as a white solid (18.4 g, quant.), LC-MS (peak area/EIC) ˜100%, 332.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].[CH3:15]I.O>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH3:15])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CI
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(Cl)c(C=O)c2ccccc21
Reaction time: 0.5 h
Yield: 108.9 %

Procedure:
A solution of 2-chloro-1H-indole-3-carboxaldehyde (1.0 g, 5.5 mmol) in DMF (30 mL) is treated portionwise over 10 min with 60% sodium hydride (440 mg, 11 mmol). After stirring for 30 min, methyl iodide (685 μL, 11 mmol) is slowly added and the resulting mixture is stirred 3 hr at room temperature. Water (5 mL) is cautiously added and the solvents are removed. The residue is dissolved in ethyl acetate and washed with water, with brine, dried, filtered and concentrated to give 2-chloro-1-methyl-1H-indole-3-carboxaldehyde (1.16 g, 105%), mp 94.5-95.5° C., as a white solid. MS 194 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=2)[N:3]=1.[NH3:27]>O1CCCC1>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:5]=[C:4]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=3)[N:3]=[C:2]([NH2:27])[N:7]=2)[CH:13]=1
Reactant: N
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc(CN(C)C)cc2)n1
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1-c1nc(N)nc(Nc2ccc(CN(C)C)cc2)n1
Temperature: -78 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
A pressure bottle was charged with [4-chloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]-triazin-2-yl]-(4-dimethylaminomethyl-phenyl)-amine (0.305 g, 0.79 mmol) and tetrahydrofuran (20 ml) and cooled to −78° C. A slow stream of ammonia gas was passed into the solution for 2 minutes and the bottle was sealed. After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% methanol-ethyl acetate to provide the title compound (0.148 g, 49% yield). 1H NMR (CDCl3) δ 7.9 (s, 1H), 7.2-7.6 (m, 6H), 3.25 (d, 6H) 2.5 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([P:17]([OH:20])(=[O:19])[OH:18])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O>C([O-])([O-])=O.[Na+].[Na+].O.CO.[Pd]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([P:17]([OH:20])(=[O:18])[OH:19])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(P(=O)(O)O)cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(C(=O)Nc2ccc(P(=O)(O)O)cc2)cc1

Procedure:
Compound 3f (8.05 g) was dissolved in a mixture of 1 M Na2CO3 (15 ml), water (55 ml) and methanol (30 ml) (pH 8.0) and hydrogenated at room temperature at normal pressure using 10% Pd/C (200 mg) as catalyst. After absorption of the theoretical amount of hydrogen (about 4 hr), the filtrate of the reaction mixture was concentrated to 70 ml and acidified with 2 N HCl to pH 6.0. The monosodium salt of compound 5f precipitated. It was washed with water and dried at about 40° C. C13H13N2O4P (292.4); C13H12N2O4PNa (314.4) monosodium salt of compound 5f.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:23])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:23])=[CH:16][CH:17]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)C2CCCN2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(4-Cyano-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3 g, 8 mmol) was dissolved in 90 mL of a 1:2 mixture of trifluoroacetic acid and dichloromethane. The reaction was stirred at ambient temperature for one hour then concentrated to yield title compound as an amber oil which was carried onto next step as is. APCI (AP−): 214.1 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]#[N:15])[C:11]3[N:16]=[N:17][N:18]([CH3:19])[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][CH:33](O)[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN1C(=O)CCC1>[CH3:19][N:18]1[C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([O:1][CH:33]4[CH2:32][CH2:31][N:30]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=5)[CH2:35][CH2:34]4)=[C:3]([C:20]([F:23])([F:22])[F:21])[CH:4]=3)[N:13]=[C:12]([C:14]#[N:15])[C:11]=2[N:16]=[N:17]1
Reactant: OC1CCN(c2ccccn2)CC1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(O)c(C(F)(F)F)c3)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OC4CCN(c5ccccn5)CC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(4-hydroxy-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (0.940 mmol, 300 mg), 1-(pyridin-2-yl)piperidin-4-ol (1.410 mmol, 251 mg) and Triphenylphosphine (1.410 mmol, 370 mg) were suspended in NMP (1 ml) and DIAD (1.410 mmol, 0.278 ml, 285 mg) added. The mixture was stirred at room temperature overnight. The reaction mixture was passed down an SCX column to afford 1-methyl-6-(4-(1-(pyridin-2-yl)piperidin-4-yloxy)-3-(trifluoro-methyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile. (0.024 g)
Reaction SMILES: Cl.[NH+]1C=CC=CC=1.[C:8]([C:10]1[S:11][C:12]2[CH:18]=[C:17]([O:19]C)[CH:16]=[CH:15][C:13]=2[N:14]=1)#[N:9]>CO>[C:8]([C:10]1[S:11][C:12]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:13]=2[N:14]=1)#[N:9]
Reactant: COc1ccc2nc(C#N)sc2c1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CO
Product: N#Cc1nc2ccc(O)cc2s1
Temperature: 190 °C
Yield: 95.8 %

Procedure:
Dry pyridinium hydrochloride (34.0 g, 0,294 mol) and 2-cyano-6-methoxy-benzothiazole (Aldrich Chemical Co., 3.0 g, 0.016 mol) were added into a 500 mL round bottom flask which was preheated in an oil bath at 100 ° C. The bath temperature was increased to 190° C. and the reaction mixture was refluxed at this temperature for 2 h. After the completion of reaction, it was cooled to room temperature to obtain a yellow solid which was dissolved in methanol. Silica was added to this solution and evaporated to dryness. This material was then chromatographed using 30% ethyl acetate/hexane to obtain 2.7 g of the product as a white solid (95%): mp 120° C.; 1H NMR (CD3OD) δ5.68 (bs, 1H), 8.02-8.82 (m, 3H); 13C NMR (CD3OD) δ106.96, 114.26, 119.59, 126.53, 133.83, 138.93, 147.25, 160.23; MS m/e (rel intensity) 176 (100), 151 (3), 124 (5), 96 (15), 85 (4), 69 (7), 57 (5); Exact mass: calcd 176.0044, found 176.0047. ##STR24##
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:6]1[O:8][CH2:7]1>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][CH2:7][CH:6]([OH:8])[CH2:5][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCC(O)CCCCCCCCCCCOCC1CO1
Reactant: NCCO
Solvent: CCO
Product: CCCCCCC(O)CCCCCCCCCCCOCC(O)CNCCO
Temperature: 80 °C
Yield: 76.3 %

Procedure:
A 200-ml flask equipped with a stirrer, reflux condenser and dropping funnel was charged with 35.0 g (0.57 mol) of ethanolamine and 35 g of ethanol, and the mixture was heated to 80° C. with stirring in a nitrogen atmosphere. To this mixture, 13.0 g (38 mmol) of 12-hydroxyoctadecyl glycidyl ether were added dropwise over 3 hours. After the resultant mixture was stirred further for 3 hours, it was concentrated under reduced pressure and purified by column chromatography on silica gel, thereby obtaining 11.7 g (yield: 77%) of the title compound (Ia-1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:20][C:21]([C:23]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[O:22])[CH2:15][CH2:16][C:17](O)=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[C:36]([O:40][C:41](=[O:44])[CH2:42][NH2:43])([CH3:39])([CH3:38])[CH3:37].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:20][C:21]([C:23]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[O:22])[CH2:15][CH2:16][C:17]([NH:43][CH2:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:44])=[O:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)NCC(=O)OC(C)(C)C)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-methoxyquinoline (142 mg, 0.30 mmol) in tetrahydrofuran (THF) (5 mL) was added glycine t-butyl ester hydrochloride (44 mg, 0.33 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (64 mg, 0.33 mmol), 1-hydroxybenzotriazole (HOBT) (45 mg, 0.33 mmol) and diisopropylethylamine (DIEA) (0.43 g, 0.33 mmol). The reaction was stirred at ambient temperature overnight. The resultant solution was partitioned between water and ethyl acetate. The organic layer was concentrated in vacuo to afford an oil. The crude product was purified by elution through silica gel with 20:1 methylene chloride-methanol to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(((1,1-dimethylethoxycarbonyl)methyl)aminocarbonyl)propyl]aminocarbonyl-4-methoxyquinoline (62 mg, 35%); NMR (CDCl3) 1.25 (t, 3), 1.50 (s, 9), 2.00 (m, 1), 2.15–2.50 (m, 3), 3.31–3.95 (m, 9), 4.10–4.32 (m, 7), 5.40 (m, 1), 759 (t, 1), 7.63 (s, 1), 7.75 (t, 1), 8.14 (d, 1), 8.22 (d, 1), 9.41 (d, 1) ppm.
Reaction SMILES: IC.CN([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH:14]=2)[NH:9][CH:8]=1)C.[C-:24]#[N:25].[K+]>CS(C)=O>[C:24]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][S:18]([N:21]([CH3:22])[CH3:23])(=[O:19])=[O:20])[CH:14]=2)[NH:9][CH:8]=1)#[N:25]
Reactant: [C-]#N
Reactant: CN(C)Cc1c[nH]c2ccc(CCS(=O)(=O)N(C)C)cc12
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: CN(C)S(=O)(=O)CCc1ccc2[nH]cc(CC#N)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
Iodomethane (1.1 ml) was added to a stirred solution of the product of Stage (iii) (2.7 g) in dry dimethylsulphoxide (30 ml) and the resulting solution stirred at room temperature for 10 min. Potassium cyanide (2.7 g) was added, and the resulting mixture stirred at room temperature overnight. The mixture was partitioned between sodium carbonate, (2N, 300 ml) and ethyl acetate (2×100 ml). The combined extracts were dried (Na2SO4) and evaporated in vacuo to give an oil which was purified by `flash` chromatography (J, 5 cm col.) to give the title compound as a solid (1.3 g) m.p. 105°-107°.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:28]=[C:29]1[N:33]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:32](=[O:42])[CH2:31][S:30]1.N1CCCCC1>C(O)C>[O:28]=[C:29]1[N:33]([CH2:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[C:32](=[O:42])[C:31](=[CH:26][C:24]2[N:25]=[C:21]([NH:20][C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:22][CH:23]=2)[S:30]1
Reactant: O=Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)CN1C(=O)CSC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)CN1C(=O)SC(=Cc2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O

Procedure:
Following a procedure similar to that described in Example 17, the desired compound was prepared from 2 g of 2-tritylaminothiazole-4-carbaldehyde, 1.2 g of t-butyl 2,4-dioxothiazolidine-3-acetate, 0.88 g of piperidine and 20 ml of ethanol. The resulting product was a yellow powder having the following physical properties.