Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18](=[O:23])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9][C@@H:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1.C1C[O:33][CH2:32]C1>>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18]([C:19]2[O:20][C:32](=[O:33])[NH:22][N:21]=2)=[O:23])[CH2:9][C@@H:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C(=O)NN
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-hydrazinyl-2-oxoacetamido)-2-methylpentanoate, intermediate 24, (200 mg, 0.50 mmol) in THF (10 mL) is added CDl (86 mg, 0.53 mmol). The crude is stirred at room temperature for 4 hrs. The crude is heated to 60 deg C. for 30 mins. This reaction is quenched with water and diluted in EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The crude residue is purified via HPLC MeCN/water (0.1% TFA) to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)pentanoate (69 mg). HPLC retention time=1.79 minutes (condition A), MS 424.2 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.17 (d, J=7.1 Hz, 3H), 1.22 (t, J=7.1 Hz, 3H), 1.66 (ddd, J=14.3, 10.2, 3.8 Hz, 1H), 2.02 (ddd, J=14.2, 10.0, 3.8 Hz, 1H), 2.59 (m, 1H), 2.89 (dd, 1H), 2.96 (dd, 1H), 4.03-4.19 (q, 2H), 4.37-4.47 (m, 1H), 6.91 (d, J=8.8 Hz, 1H), 7.25 (d, 1H), 7.28-7.35 (m, 1H), 7.40 (t, J=7.6 Hz, 2H), 7.49-7.60 (m, 4H), 10.51 (br. s., 1H).
Reaction SMILES: Cl.Cl.Cl.Cl.[NH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH:17]=[C:16]([CH2:18][N:19]([CH3:30])[CH:20]2[C:29]3[N:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:23][CH2:22][CH2:21]2)[N:15]=[N:14]1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]=O.C(N(CC)CC)C.[BH4-].[Na+]>CO.[Cl-].[Na+].O>[CH3:30][N:19]([CH2:18][C:16]1[N:15]=[N:14][N:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][CH2:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=2)[CH:17]=1)[CH:20]1[C:29]2[N:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:23][CH2:22][CH2:21]1
Reactant: O=Cc1ccccn1
Reactant: CN(Cc1cn(-c2ccccc2CN)nn1)C1CCCc2cccnc21
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(Cc1cn(-c2ccccc2CNCc2ccccn2)nn1)C1CCCc2cccnc21
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of N-((1-(2-(aminomethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-N-methyl-5,6,7,8-tetrahydroquinolin-8-amine tetrahydrochloride, AD, (0.20 g, 0.43 mmol) in methanol (2 mL) was added 2-pyridine carboxaldehyde (0.04 mL, 0.43 mmol) and triethylamine (0.18 mL, 1.30 mmol). The reaction mixture was heated to 60° C. and stirred for 18 h. The reaction mixture was then cooled to room temperature and NaBH4 (0.05 g, 1.30 mmol) was added. The reaction stirred 1 h at room temperature. The reaction mixture was poured into brine (10 mL) and was extracted with ethyl acetate (2×10 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on basic alumina (0-5% methanol/dichloromethane) yielding AG. ESI+ MS: m/z (rel intensity) 440 (100, M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.C(N(CC)CC)C.C(C1[C:33]([OH:34])=[C:32](C(C)(C)C)[CH:31]=C(C)C=1)(C)(C)C.C(Cl)(=O)C=C>O.C(OCC)C>[C:33]([O:1][CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:34])[CH:32]=[CH2:31]
Reactant: OCc1c2ccccc2cc2ccccc12
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: C=CC(=O)OCc1c2ccccc2cc2ccccc12
Temperature: 0 °C

Procedure:
A mixture of 9-hydroxymethylanthracene (20.8 g, 0.1 mol) and triethylamine (11.1 g, 0.11 mol), containing 0.05 g of 2,6-di-tert.butyl-p-cresol, in 200 ml of freshly distilled diethyl ether was cooled with stirring to 0° C., and the temperature of the mixture was kept at about this level while acryloyl chloride (9.32 g, 0.103 mol) was added. The mixture was then warmed to refluxing temperature and heated to reflux for 2 hours. After the mixture had been cooled, 200 ml. of water was added, and the two layers were separated. The organic layer was washed twice with 50 ml portions of cold 10% sulphuric acid and then with a saturated aqueous solution of sodium bicarbonate, while the aqueous acid layer was extracted further with dichloromethane, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate. Finally, the two organic solutions were mixed, dried over anhydrous magnesium sulphate, and the solvents distilled off. There remained 11.1 g of the title compound as a yellow, semicrystalline oil. It solidified on standing and then had m.pt. 120°-125° C.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>>[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([N:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:16][CH:15]=2)[C:11]([C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)=[CH:12]1)=[O:28]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CN1CC=C(c2c[nH]c3ccc(OC4CCCCC4)cc23)CC1
Product: CN1CC=C(c2cn(C(=O)c3ccccc3Cl)c3ccc(OC4CCCCC4)cc23)CC1

Procedure:
(12.5 mg, 33%); from 5-cyclohexyloxy-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4c, 25.7 mg, 0.083 mmol) and 2-chlorobenzoyl chloride (25 uL, 0.20 mmol); HRMS-FAB+ for C27H29N2O2Cl: calculated MH+ : 449.19958; found: 449.19815.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N)(=O)C1C=CC=CC=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=O)=[CH:27][CH:26]=1>>[CH3:13][O:12][C:9]1[C:10]([CH3:11])=[C:2]2[C:3]([C:4]([OH:5])=[N:6][C:29]([C:28]3[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[N:1]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(C(N)=O)c(N)c1C
Agent: NC(=O)c1ccccc1
Product: COc1ccc(-c2nc(O)c3ccc(OC)c(C)c3n2)cc1
Yield: 92 %

Procedure:
The general procedure described in Example 31 was followed using 2-amino-4-methoxy-3-methyl benzamide as benzamide derivative [A] and 4-methoxybenzoic acid chloride as acid chloride [B], which gave the title compound (5.5 g, 92%). 1H-NMR DMSO-D6 δ 2.38 (s, 3H), 3.82 (s, 3H), 3.92 (s, 3H), 7.04 (d, 2H), 7.20 (d, 1H), 8.00 (d, 1H), 8.20 (d, 2H), 12.18 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[Cl:14].[I-:20].[Na+]>CC(C)=O>[Cl:14][C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=1[O:6][CH:5]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[CH2:4][CH2:3][CH2:2][I:20]
Reactant: [I-]
Reactant: ClCCCC(Oc1cc(Cl)ccc1Cl)c1cccs1
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1ccc(Cl)c(OC(CCCI)c2cccs2)c1
Yield: 95 %

Procedure:
2-[4-Chloro-1-(2,5-dichlorophenoxy)butyl]thiophene (2.4 g, 7.1 mmol) was dissolved in a saturated solution of sodium iodide in acetone (200 ml) and the reaction refluxed for 20 hours. The reaction mixture was cooled and the solid filtered off. The filtrate was evaporated in vacuo and the residue taken up in water (50 ml). The mixture was extracted with diethyl ether (3×70 ml) and the combined organic portions were washed with water (3×30 ml), dried (magnesium sulphate), filtered and evaporated in vacuo to give the title compound as a pale straw coloured oil (2.91 g, 95%).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:14]1[CH2:17][C:16](=O)[CH2:15]1.ClC1C=CC(C2C(C=O)=CC=CC=2)=CC=1>>[O:14]1[CH2:17][CH:16]([N:4]2[CH2:3][CH2:2][C@H:6]([NH:1][C:7](=[O:8])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH2:5]2)[CH2:15]1
Reactant: O=C1COC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=Cc1ccccc1-c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C2COC2)C1

Procedure:
The title compound was prepared by substituting (S)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate and 3-oxetanone for 4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].[NH2:32][CH:33](C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)[CH3:34].N1C2C(=CC(C(O)=O)=CC=2)C=C1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([NH:16][C:13]2[N:14]=[N:15][C:10]([CH:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]4[C:31](=[CH:30][CH:29]=3)[NH:32][CH:33]=[CH:34]4)=[O:6])[CH3:9])=[CH:11][N:12]=2)[CH:18]=[C:19]([O:27][CH3:28])[C:20]=1[O:25][CH3:26]
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1ccc2[nH]ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc4[nH]ccc4c3)nn2)cc(OC)c1OC
Yield: 64 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 1H-indole-5-carboxylic acid (140 mg, 0.85 mmol), diisopropylethylamine (0.34 mL, 1.95 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (350 mg, 0.92 mmol) in dimethylformamide (5 mL) gave N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1H-indole-5-carboxamide (187 mg, 64%) as a yellow solid. MS m/z 448 (M+1).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][C@H:9]([O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([CH3:29])=[CH:7][CH2:6]1)([O:3][CH3:4])=[O:2].C[O:31]CCOCCOC>>[Si:12]([O:11][C@@H:9]1[C@H:8]([CH3:29])[C@@H:7]([OH:31])[CH2:6][C@H:5]([C:1]([O:3][CH3:4])=[O:2])[CH2:10]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COCCOCCOC
Reactant: COC(=O)[C@H]1CC=C(C)[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Product: COC(=O)[C@@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H](C)[C@@H](O)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a stirred solution of this cyclohexene (110 mg, 0.27 mmol) in 2 ml of diglyme at 0° C. was added dropwise a borane-THF complex solution (1.0 M, 325 μL, 0.325 mmol, 1.5 eq). The resulting solution was stirred for 4 h at 0° C. THF was removed and TAO (trimethyl amine N-oxide, 90 mg, 0.81 mmol) was added. The mixture was heated and refluxed for 2 h. The resulting mixture was cooled to room temperature, extracted with EtOAc (4×40 ml) and dried over MgSO4. The residue was separated by flash chromatography on silica, then was purified by HPLC (Cyclohexane/EtOAc: 9:1) to afford compound 3.2.c (R=Me, P=TBDPS, A=COOCH3) (46 g, 40.5%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].[C:12](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)=O)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a solution of 4′-hydroxy-3′-methylacetophenone (25.0 g) in N,N-dimethylformamide (120 ml) were added potassium carbonate (69.1 g) and methyl iodide (11.4 ml) under ice-cooling, and the mixture was stirred for 2 hr under ice-cooling and further at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (27.5 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.Cl>CO>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:17][CH3:18])[N:8]=[CH:7][CH:6]=[C:5]2[O:4][C:3]1[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:2]=1[F:1]
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Agent: Cl
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of A1 (230 mg, 0.67 mmol, 1.0 eq.) in MeOH (50 mL) Pd/C (10% w/w, 23 mg) and aq. HCl-solution (1N, 1.34 mL, 2.0 eq.) were added. The reaction mixture was stirred under hydrogen atmosphere (1 atm) at RT for 48 h. The suspension was filtered through a pad of Celite®. The solvent was removed in vacuo and the crude product was purified using an Isolute® SPE column SCX, loading the reaction mixture as a MeOH solution and then eluting the desired compound with 2N NH3 in MeOH. The title compound A2 was isolated after evaporation of the solvent under reduced pressure as a white solid (200 mg, 0.64 mmol, 95%). 1H NMR (400 MHz, d6-DMSO, 300K) δ 3.92 (s, 6H), 4.97 (br s, 2H), 6.38 (d, J=5.3 Hz, 1H), 6.45 (dd, J=2.4 Hz, J=8.5 Hz, 1H), 6.53 (dd, J=2.4 Hz, J=13.2 Hz, 1H), 7.05 (t, J=9.0 Hz, 1H), 7.36 (s, 1H), 7.49 (s, 1H), 8.44 (d, J=5.3 Hz, 1H). MS (ES) C17H16FN2O3 requires: 314. Found: 315 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH:14](C#N)[C:15]([O:17]CC)=[O:16])=[CH:9][CH:8]=1.C(O)(=O)C>C(OCC)(=O)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(C#N)C(c1ccc(Br)cc1)c1ccccc1C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(CC(=O)O)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 21.9 %

Procedure:
Sulfuric acid (940 g, 9.59 mol) was added over 30 min under ice cooling to a mixture of ethyl 3-(4-bromophenyl)-2-cyano-3-o-tolylpropanoate (200 g, 494 mmol) in acetic acid (1.06 kg, 17.7 mol), while keeping the internal temperature below 27° C., then the reaction mixture was heated at reflux for 20 h. After cooling to 40° C. ice (500 g) and ethyl acetate (1500 mL) were added, the precipitate collected by filtration and washed with water to produce the title compound (34.5 g). The filtrate was partitioned between ethyl acetate and water, the organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was stored in the refrigerator for 1 h. Then the precipitate was collected by filtration and washed with acetic acid and heptane to afford a second crop of product (96.2 g). Total yield: 130.7 g (83%). Off-white solid, MS: 319.0 [M−H]−.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:8][CH:9]=1)([O-])=O>C(O)(=O)C>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][S:10][C:7]1[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(SCc2ccccn2)nc1
Solvent: CC(=O)O
Product: Nc1ccc(SCc2ccccn2)nc1
Temperature: 25 °C
Reaction time: 240 h
Yield: 34.7 %

Procedure:
5-nitro-2-[(2-pyridinylmethyl)sulfanyl]pyridine (6.0 g) was dissolved in acetic acid (60 ml), reduced iron (18 g) was added to the mixture, and the mixture was stirred for 240 hours at room temperature. The mixture was filtered with. Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 6-[(2-pyridinylmethyl)sulfanyl]-3-pyridineamine (1.83 g).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:22])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:21])[C@H:17]([CH2:19][OH:20])[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:22])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:21])[C@H:17]([CH2:19][OH:20])[NH:18][S:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:38])=[O:37])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@H](CO)NS(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 90.6 %

Procedure:
L-seryl-L-proline benzylester hydrochloride (1.64 g, 5 mmole) was dissolved in methylene chloride (30 ml), and triethylamine (1.11 g, 11 mmole) was added thereto at -30° C. Methylene chloride (10 ml) solution of benzene sulfonyl chloride (0.86 g, 5 mmole) was added dropwise thereto. The mixture was stirred for 1 hour at less than 0° C. and then for 5 hours at room temperature, and methylene chloride (60 ml) was added thereto. The mixture was washed with 5% aqueous sodium bicarbonate (100 ml, twice), 1N aqueous hydrochloric acid (100 ml, twice) and water (100 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-benzenesulfonyl-L-seryl-L-proline benzylester (yield: 1.96 g, 90.6%).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].N1C=CC=CC=1>ClCCl>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH:18][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH3:14]
Reactant: CCOC(=O)CN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
Tosyl chloride (14.75 g, 77.37 mmol) was added to a stirring mixture of glycine ethyl ester hydrochloride (9.0 g, 64.48 mmol) and pyridine (11.45 mL, 141.85 mmol) in 100 mL of dichloromethane. After stirring overnight, the mixture was washed with water and dilute NaOH. The combined organics were dried with Na2SO4, filtered, evaporated under reduced pressure to give 16.0 g (96%) of 81, which was used without purification in the next reaction. 1H-NMR (400 MHz, CDCl3): δ 1.18 (t, 3H), 2.42 (s, 3H), 3.76 (d, 2H), 4.08 (q, 2H), 5.22 (m, 1H), 7.30 (d, 2H), 7.75 (d, 2H) ppm. 13C-NMR (100 MHz, CDCl3): δ 13.99, 21.55, 44.19, 61.89, 127.28, 129.76, 136.20, 143.81, 168.87 ppm. □ DEPT (100 MHz, CDCl3): CH3 carbons: 13.99, 21.55; CH2 carbons: 44.19, 61.89; CH carbons: 127.28, 129.76 ppm. LC/MS: 95%, m/z=257.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[C:17]12([NH2:27])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>>[C:17]12([NH:27][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1ccccc1NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 62.8 %

Procedure:
A mixture of 2-chloronitrobenzene (10 g), potassium carbonate (17.5 g) copper (I) iodide (609 mg) and 1-adamantanamine (19.2 g) was heated at 180° under nitrogen for 6 h. The mixture was allowed to cool to room temperature and was adsorbed onto silica. This was chromatographed with hexane-EA (9:1) as eluent to give the title compound (10.86 g) as an orange/brown crystalline solid containing 29% 2-chloronitrobenzene. T.l.c. (99:1 hexane-EA) Rf 0.23
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:14][CH2:13]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C.ClCCl.O=[Mn]=O>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][C@H:15]1[CH2:16][CH2:17][C@H:12]([O:11][C:5]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=2[CH:3]=[O:2])[CH2:13][CH2:14]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)c1cc(Cl)ccc1O[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: O=[Mn]=O
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](Oc2ccc(Cl)cc2C=O)CC1

Procedure:
In a manner similar to the method described in example 94c, trans-2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-benzoic acid methyl ester (2.7 g, 6.76 mmol) was reacted with LiAlH4 (1 M, 6.76 mL, 6.76 mmol) in ethyl ether, then oxidized with activated MnO2 (4.64 g, 54 mmol) in dichloromethane to give trans-2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-benzaldehyde as a white solid (Yield 1.12 g, 44%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:5]=[CH:6][C:7]([CH:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11][C:10]1=[O:17])=[O:8]>[Pd].O1CCOCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][CH2:6][C:7]([CH:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11][C:10]1=[O:17])=[O:8]
Reactant: COc1ccc(C=CC(=O)C2C(=O)C=C(C)OC2=O)cc1O
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1ccc(CCC(=O)C2C(=O)C=C(C)OC2=O)cc1O

Procedure:
The hydrogenation of 3-(3-hydroxy-4-methyoxycinnamoyl)-6-methyl-2H-pyran-2,4(3H)-dione as prepared in the above step of Claisen-Schmidt condensation was carried out in the following way. The condensation product (1.39 g.) obtained in the above step was dissolved in 150 ml. of dioxane, and the hydrogenation was effected in the presence of 0.1 g. of 5% palladium-charcoal at room temperature and under the atmospheric pressure. One mole equivalent of hydrogen was absorbed in 8 hours. After removal of the catalyst and the solvent, the remaining crystalline product was subjected to silica gel chromatography for purification. Upon recrystallization from a mixed solvent of ethanol and n-hexane, 1.11 g. of 3-(3-hydroxy-4-methoxyhydrocinnamoyl)-6-methyl-2H-pyran-2,4(3H)-dione was obtained, showing mp. 115-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[F:11].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[F:11]
Reactant: CC(O)c1ccc(Cl)c(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of the above alcohol (1 eq) in CH2Cl2 (0.3M) at rt was added Dess-Martin periodinane (1.5 eq). The reaction mixture was stirred for 45 minutes at rt and H2O (10 eq) was added. The mixture was stirred for 30 minutes and filtered through silica gel pad eluted with 30% EtOAc/hexane and concentrated. The residue was purified by flash chromatography on silica gel eluted with 20% EtOAc/hexane to give the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH3:27])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C[O-].[Na+].[C:31](OCC)(=[O:33])C>CO>[CH3:31][O:33][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH3:27])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(F)c1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1C#N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
280 mg 2-Fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-benzonitrile (intermediate example 1) were dissolved in 10 ml methanol. 390 mg sodium methoxide were added and the reaction mixture stirred at a temperature of 60° C. for two hours. The cooled reaction mixture was diluted by adding 200 ml ethyl acetate and washed three times with portions of 50 ml water. The organic layer was dried over MgSO4 and the solvent removed in vacuo to provide 140 mg 2-Methoxy-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzonitrile as pale yellow solid.