Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:17]=2)=[C:10]([CH3:33])[CH:9]=1)=[O:6].[OH-].[K+]>CO.O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=2[OH:22])[O:15][C:11]2[C:12]([CH3:14])=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([OH:34])=[O:2])=[CH:9][C:10]=2[CH3:33])(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(NC(=O)CC(=O)O)cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of N-{4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-malonamic acid methyl ester (7.14 g, 14.6 mmol) in 50% aqueous methanol (56 mL) was added a 5 M solution of potassium hydroxide (8.8 mL, 44 mmol) to give a reddish-brown solution. The solution was stirred at RT for 45 min then diluted with water (200 mL). The solution was washed with EtOAc (3×50 ml) and the combined washings were extracted with 0.1 M KOH (50 mL). The combined basic aqueous solutions were acidified with concentrated HCl and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to a dark amber oil. The oil was dissolved in EtOAc (20 mL) and cyclohexane (100 mL) was added to give an oil, which slowly solidified on stirring at RT. The suspension was stirred 64 h at RT, then filtered. The solid was washed with cyclohexane (3×50 mL) and dried to give the title compound of Step F and Example 4-2 (6.26 g) as a solid. MS (APCl+) Calc.: 473.1, Found: 474.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.C(O)(=O)C(O)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:32]1[CH2:33][CH2:34][CH:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH2:31]1)=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: COc1ccc(C2CCNC2)cc1
Agent: O=C(O)C(=O)O
Product: COc1ccc(C2CCN(C(=O)c3cnoc3-c3ccccc3Cl)C2)cc1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(4-methoxyphenyl)pyrrolidine oxalat (16.0 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (5.4 mg). Calcd for C21H19ClN2O3: 382.1084, found 382.1083.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=2[Cl:18])=[C:6]([CH3:20])[CH:5]=1.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25]>>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([NH:25][C:24]3[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=3[F:22])=[CH:13][C:12]=2[Cl:18])=[C:6]([CH3:20])[CH:5]=1
Reactant: Nc1ccc(F)cc1F
Reactant: COC(=O)c1ccc(C(=O)c2ccc(Br)cc2Cl)c(C)c1
Product: COC(=O)c1ccc(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c(C)c1

Procedure:
Compound 534 (184 mg, 0.50 mmol) and 2,4-difluoroaniline (0.066 mL, 0.65 mmol) were treated as described for compound 529. Flash chromatography (ethyl acetate/petroleum ether: graduated from 0/100 to 20/80) gave the title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([NH2:16])[O:13][N:12]=3)[CH:9]=2)[N:4]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:3]=1.[CH:27]([O:30][C:31]1[CH:36]=[N:35][CH:34]=[C:33]([Sn](C)(C)C)[N:32]=1)([CH3:29])[CH3:28]>CN(C=O)C.[Cu]I.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>[CH:27]([O:30][C:31]1[N:32]=[C:33]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[N:15]=[C:14]([NH2:16])[O:13][N:12]=4)[CH:9]=3)[N:4]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:3]=2)[CH:34]=[N:35][CH:36]=1)([CH3:29])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4noc(N)n4)ccc32)cc1
Reactant: CC(C)Oc1cncc([Sn](C)(C)C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(OC(C)C)n3)c3cc(-c4noc(N)n4)ccc32)cc1
Temperature: 90 °C
Yield: 58.8 %

Procedure:
Argon gas was bubbled through a solution of 3-(3-iodo-1-tosyl-1H-indol-5-yl)-1,2,4-oxadiazol-5-amine (250 mg, 0.52 mmol) and 2-isopropoxy-6-(trimethylstannyl)pyrazine (188 mg, 0.62 mmol) in dry DMF (2.5 mL) for 15 min. To the mixture was added CuI (99 mg, 0.52 mmol) and Pd(PPh3)4 (60 mg, 0.052 mmol) and argon gas was further bubbled for additional 15 min. The reaction was heated at 90° C. for 1 h then cooled to RT. The reaction was quenched with ice cold water. The resulting suspension was filtered and washed with water. The solid was purified with basic alumina column chromatography (eluent: 20% EtOAc in petroleum ether) to give 3-(3-(6-isopropoxypyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-oxadiazol-5-amine (150 mg, 59%). MS (ESI, pos. ion) m/z: 491.1 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CS(O[CH2:19][CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]2[O:32][CH2:33][O:34][C:27]=12)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=O)=O.[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:19][CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]2[O:32][CH2:33][O:34][C:27]=12)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCCCCC(COS(C)(=O)=O)c1cccc2c1OCO2
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC(CC(C(=O)OCC)C(=O)OCC)c1cccc2c1OCO2
Yield: 39.4 %

Procedure:
To a suspension of 0.40 g of sodium hydride (60% oil dispersion, 10 mmol) in 10 ml of N,N-dimethylformamide was dropwise added 1.60 g (10 mmol) of diethyl malonate under ice cooling, and the resultant mixture was stirred for 30 minutes. To this mixture were added a solution of 3.14 g (10 mmol) of 2-(2, 3-methylenedioxyphenyl)heptyl methanesulfonate, intermediate in Reference Example 1. in 6 ml of N,N-dimethylformamide and 1.50 g (10 mmol) of sodium iodide, and the mixture was stirred at 100° C. for 2 hours. After cooling, the mixture was mixed with water and shaken with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo. The residue was chromatographed on a column of silica gel, eluting with ethyl acetate/hexane (1/10) to give 1.49 g of 2-(2, 3-methylenedioxyphenyl)heptylmalonic acid diethyl ester as an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[N:13]#[C:14]Br>CO>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=[C:14]1[NH2:13]
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Reactant: N#CBr
Solvent: CO
Product: Cn1c(N)nc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N1-methyl-4-nitro-benzene-1,2-diamine (200 mg, 1.20 mmol) in methanol (12 ml) was added cyanogen bromide (190.1 mg, 1.79 mmol). After stirring at room temperature for 16 h, the methanol was removed in vacuo and the resulting solid was stirred with diethyl ether (40 ml) for 5 minutes. The resulting hydrobromide salt of the title compound was filtered and air-dried.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[NH:14][C:13]=2[CH:12]=[C:11]([Br:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:23][O:24][CH3:25].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:23][O:24][CH3:25])[C:13]=2[CH:12]=[C:11]([Br:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2c(OCc3ccccc3)cc(Br)cc2[nH]1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCn1c(C)nc2c(OCc3ccccc3)cc(Br)cc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 26.4 %

Procedure:
2.0 g (6.3 mmol) 4-Benzyloxy-6-bromo-2-methyl-1H-benzimidazole were solved in dimethylformamide (10 ml) and the solution was cooled to 0° C. 151 mg (6.5 mmol) sodium hydride (60%) were added in portions and the reaction was stirred for 20 min. 435 μl (6.3 mmol) 1-Chloro-1-methoxy-methane were added and the reaction was stirred at 0° C. After 2 h the mixture was poured into water (200 ml) and extracted with ethyl acetate. The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (toluene/dioxane=6:1) to afford 0.6 g (26%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:51]=[CH:50][CH:49]=[CH:48][C:14]=1[C:15]([NH:17][C:18]1[CH:45]=[CH:44][C:21]([C:22]([N:24]([CH3:43])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](OCC)=[O:39])=[O:23])=[CH:20][C:19]=1[O:46][CH3:47])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:51]=[CH:50][CH:49]=[CH:48][C:14]=1[C:15]([NH:17][C:18]1[CH:45]=[CH:44][C:21]([C:22]([N:24]([CH3:43])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])=[O:23])=[CH:20][C:19]=1[O:46][CH3:47])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCCOc1cc(C)ccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2OCCCNC(=O)OC(C)(C)C)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCCO)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 121.2 %

Procedure:
To a solution of 4-[2-(3-tert-butoxycarbonylaminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-(5-ethoxycarbonylpent-1-yl)oxy-4-methylphenyl]benzamide (400 mg) in tetrahydrofuran (5 ml) was added lithium aluminum hydride (12 mg) at -23° C. and the mixture was stirred at 0° C. for 3 hours. The reaction was quenched with slow addition of 0.5N hydrochloric acid (15 ml) and the solution was stirred at ambient temperature for 20 minutes. The solution was extracted with chloroform (15 ml×3) and the organic layer was washed with aqueous saturated sodium bicarbonate solution and brine. The solution was dried over magnesium sulfate and the solvent was removed under reduced pressure to give 4-[2-(3-tert-butoxycarbonylaminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-(6-hydroxyhex-1-yl)oxy-4-methylphenyl]benzamide (456 mg).
Reaction SMILES: Cl[CH2:2][CH:3]=O.C(=O)(O)[O-].[Na+].[NH2:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=1>[Na+].[Cl-]>[N:10]1[CH:14]=[CH:13][N:12]2[CH:3]=[CH:2][CH:15]=[C:16]([NH2:17])[C:11]=12
Reactant: Nc1cccnc1N
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Product: Nc1cccn2ccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a solution of 50% aqueous chloroacetaldehyde (4.14 mL, 32.6 mmol) were added sodium bicarbonate (3.19 g, 40.0 mmol) and 2,3-diaminopyridine (3.56 g, 32.6 mmol). The reaction mixture was stirred at rt overnight, then diluted with saturated aqueous NaCl (100 mL) and extracted with n-butanol (3×200 mL). The organic layers were combined, dried (MgSO4), and concentrated. The crude residue was purified (FCC, 2 N NH3 in MeOH/DCM) to give imidazo[1,2-a]pyridin-8-ylamine (2.18 g, 51%). MS (ESI+): calcd for C7H7N3 m/z 133.06, found 134.1 (M+H)+. 1H NMR (d6-DMSO): 7.79-7.75 (m, 2H), 7.40 (d, J=1.1, 1H), 6.60 (s, 1H), 6.21 (dd, J=7.3, 1.1, 1H), 5.53 (br s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:7][CH2:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:7][CH2:6]2
Reactant: CCCCCCCC(=O)N1CCc2cc(OC)ccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCN1CCc2cc(OC)ccc2C1

Procedure:
The amide prepared under (a) is dissolved in 50 ml of dry diethyl ether and added dropwise to a suspension of 1.0 g of lithium aluminum hydride in 100 ml of dry diethyl ether. The mixture is then heated under reflux for 3 hours, 5 ml of water is added cautiously to cause decomposition, with cooling, and inorganic material is filtered off. The oil remaining after removal of the solvent in vacuo is reac-ted further without purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11](=[N:14][O:15][CH3:16])[O:12][CH3:13])=[C:9]([Cl:17])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]([C:11](=[N:14][O:15][CH3:16])[O:12][CH3:13])=[C:9]([Cl:17])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CON=C(OC)c1c(Cl)ccc(C(=O)O)c1Cl
Solvent: Cc1ccccc1
Product: CON=C(OC)c1c(Cl)ccc(C(=O)Cl)c1Cl
Yield: 99.8 %

Procedure:
A solution of 2.10 g (0.0076 mol) of 2,4-dichloro-3-(1'-(methoxy)imino-1'-methoxymethyl)benzoic acid and 20.00 g of thionyl chloride in 50 ml of dry toluene was stirred for 2 hours at 80° C. After the solvent had been removed in vacuo, 2.25 g of 2,4-dichloro-3-(1'-methoxyimino-1'-(methoxy)methyl)benzoyl chloride were obtained.
Reaction SMILES: O=[O+][O-].CC1(C)OC([CH2:10][O:11][C:12]([N:14]2[CH2:19][CH2:18][C:17]3[C:20]([C:32]#[N:33])=[C:21]([NH:23][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:25])[S:22][C:16]=3[CH2:15]2)=[O:13])CO1>>[N:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:10][O:11][C:12]([N:14]2[CH2:19][CH2:18][C:17]3[C:20]([C:32]#[N:33])=[C:21]([NH:23][C:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[O:25])[S:22][C:16]=3[CH2:15]2)=[O:13])=[CH:16][CH:15]=1
Reactant: CC1(C)OCC(COC(=O)N2CCc3c(sc(NC(=O)c4ccccc4)c3C#N)C2)O1
Agent: O=[O+][O-]
Product: N#Cc1c(NC(=O)c2ccccc2)sc2c1CCN(C(=O)OCCc1ccncc1)C2

Procedure:
MS: calc.: C23 H20 N4 O3 S (432.5) Fnd.: 433.1 [M+H]74. 3-Cyano-2-[(1-phenyl-methanoyl)-amino]-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:13]=1[NH:20][NH2:21]>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1>[I:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[N:20]([C:13]3[C:14]([F:19])=[CH:15][C:16]([F:18])=[CH:17][C:12]=3[F:11])[N:21]=[CH:4][C:3]=12
Reactant: O=Cc1c(I)ccnc1F
Reactant: NNc1c(F)cc(F)cc1F
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Product: Fc1cc(F)c(-n2ncc3c(I)ccnc32)c(F)c1
Temperature: 185 °C
Yield: 16.8 %

Procedure:
To a 15 mL pressure bottle was added 2-fluoro-4-iodonicotinaldehyde (530 mg, 2.112 mmol), (2,4,6-trifluorophenyl)hydrazine (359 mg, 2.215 mmol), DMAP (53 mg, 0.434 mmol), and anhydrous NMP (4 mL). The reaction mixture was flushed with argon, securely capped, and heated to 185° C. for 1.75 h. The reaction mixture was worked up according to the procedure described in Intermediate 69A and the product was purified by Biotage Silica gel chromatography using a 40 g Thompson Single Step™ silica cartridge with a linear gradient from 100% hexanes to 100% CH2Cl2 over 14 column volumes to give 133 mg (16.8%) of the title compound as a yellow solid. LC/MS (Condition B): ret. T=3.7 min, (M+H)+ 375.90 and 230 mg (27.6%) of the hydrazone intermediate as a pale yellow solid, LC/MS (Condition B): ret. T=3.7 min, (M+H)+ 395.90.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([OH:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[C:30](O)(=[O:52])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:7]([O:52][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCCCCCCCC

Procedure:
300 parts by mol of benzene, 200 parts by mol of docosanol (behenyl alcohol), 200 parts by mol of docosanoic acid (behenic acid), and further 10 parts by mol of p-toluenesulfonic acid were added to a reactor equipped with a Dimroth condenser, a Dean-Stark water separator and a thermometer, and sufficiently stirred and dissolved, and thereafter refluxed for 6 hours; and thereafter, a valve of the water separator was opened and azeotropic distillation was carried out. After the azeotropic distillation, the resultant was sufficiently cleaned with sodium hydrogencarbonate, and thereafter dried to thereby distil away benzene. An obtained product was recrystallized, and thereafter cleaned and refined to thereby obtain an ester wax 17 (behenyl behenate). The physical properties of the obtained ester wax 17 are shown in Table 2.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:10](F)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>O1CCCC1>[C:1]([C:4]1[CH:5]=[C:6]([S:10]([N:16]([CH2:17][CH3:18])[CH2:14][CH3:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCNCC
Reactant: CC(=O)c1cccc(S(=O)(=O)F)c1
Solvent: C1CCOC1
Product: CCN(CC)S(=O)(=O)c1cccc(C(C)=O)c1
Yield: 88.1 %

Procedure:
A solution of 40.4 g (0.20 mol) of 3-acetylbenzenesulfonyl fluoride, 32.2 g (0.44 mol) of diethylamine in 200 ml of dry tetrahydrofuran is stirred overnight at 23° C. and then refluxed for two days. Diethylamine (10 ml) is added and the solution refluxed for 24 hours and the solvent removed. The residue is dissolved in CH2Cl2 and the solution washed with 1NHCl and H2O. The CH2Cl2 layer is dried (MgSO4) and the solvent removed to give 45 g (88%) of thick oil. A sample is chromatographed (silica gel column) with CH2Cl2 to give a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[N+:12]=[N-:13])[C:5](=[O:11])[NH:6]2.[CH2:14]([OH:17])[C:15]#[CH:16]>CCOCC>[Cl:1][C:2]1[C:3]2[C:4]3[N:12]([N:13]=[C:15]([CH2:14][OH:17])[CH:16]=3)[C:5](=[O:11])[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: C#CCO
Reactant: [N-]=[N+]=C1C(=O)Nc2cccc(Cl)c21
Solvent: CCOCC
Product: O=c1[nH]c2cccc(Cl)c2c2cc(CO)nn12
Reaction time: 0.33 h
Yield: 54.4 %

Procedure:
2.0 g (0.0103 mole) of 4-chloro-3-diazooxindole, and 11.95 g (0.207 mole or 20 equivalents) of 97% propargyl alcohol are refluxed under N2 for hours. The reaction mixture is cooled, diluted with ether (200 ml) and stirred for 20 minutes. The cream-colored precipitates are filtered off, washed with ether and dried in vacuo over the weekend at 50°. Yield: 2.44 g, mp 295°-296°; 94.9% crude yield. The crude product is taken up in absolute ethanol, filtered while hot and the filtrate is concentrated to a volume of 150 ml. The solution is cooled and the precipitates filtered off, washed with ether and dried in vacuo at room temperature for 24 hours to give 1.4 g of title compound, mp 309°-311°.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]4[C:32]5[CH2:39][CH2:38][N:37](CC6C=CC(OC)=CC=6)[C:33]=5[N:34]=[CH:35][N:36]=4)[CH2:27][CH2:26]3)[N:18]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH:19]=2)=[CH:11][C:10]=1[C:49]([F:52])([F:51])[F:50].FC(F)(F)C(O)=O>>[N:34]1[C:33]2[NH:37][CH2:38][CH2:39][C:32]=2[C:31]([N:28]2[CH2:27][CH2:26][CH:25]([C:17]3[N:18]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH:19]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([F:8])=[C:10]([C:49]([F:50])([F:51])[F:52])[CH:11]=4)[N:16]=3)[CH2:30][CH2:29]2)=[N:36][CH:35]=1
Reactant: COc1ccc(CN2CCc3c(N4CCC(c5nc(-c6ccc(F)c(C(F)(F)F)c6)cn5CCN(C)C)CC4)ncnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc3c2CCN3)CC1
Temperature: 80 °C
Reaction time: 14 h
Yield: 99.3 %

Procedure:
To [2-(4-(4-fluoro-3-trifluoromethyl-phenyl)-2-{1-[7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-imidazol-1-yl)-ethyl]-dimethyl-amine trifluoroacetate (50.0 mg; 0.07 mmol; 1.0 eq.) in a seal tube was added trifluoroacetic acid (1.0 ml). The reaction mixture was stirred at 80° C. for 14 hours. LC-MS showed clean reaction with 99% purity by HPLC. After Removal of TFA, the residue was dissolved in small amount of acetonitrile, added water and then lyophilized to afford the title compound as off-white solid (35 mg, 70% yield); LC-MS (M+H=504, obsd.=504);
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6](N)[CH:5]=[CH:4][N:3]=1>CC(O)=O>[Cl:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)c1Sc1ccccc1
Solvent: CC(=O)O
Product: Clc1nccc2c1sc1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a 250 mL round flask was added 2-chloro-3-phenylthio-4-aminopyridine (2.7 g, 11.4 mmol), and 60 mL of glacial AcOH. To this clear solution, ButONO (1.36 g, 11.45 mmol) was added drop by drop. After stirring at room temperature for 1 h, another (1.36 g 11.45) mmol of ButONO was added. The mixture was continued to stir at room temperature for 18 h. The reaction was quenched by water, and the product was purified by a silica gel column. Yield (88%) of 1-chloro-benzothieno[2,3-c]pyridine was 2.2 g.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][C@@H:25]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C@H:22]1[CH2:23][OH:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]>CC(C)=O.O>[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][C@@H:25]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])[C@H:22]1[C:23]([OH:3])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.7 ml of Jones' reagent (chromium trioxide/4N aqueous sulfuric acid: Bowden, Heibron, Jones & Weedon, J. Chem. Soc., 1946, 39) was added, whilst ice-cooling, to a solution of 245 mg (0.74 mmol) of (3R)-1-t-butoxycarbonyl-3-t-butyldimethylsilyloxy-L-prolinol [prepared as described in step (a) above] in 10 ml of acetone, and the mixture was stirred at 0° C. for 2 hours. At the end of this time, the reaction mixture was diluted with water and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was triturated with hexane, to give 191 mg of the title compound as colorless crystals, melting at 146°-147° C.