Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[O:2]=[C:3]1[N:8]2[CH:9]=[CH:10][S:11][C:7]2=[N:6][C:5]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4]1.[H-].[Na+].[CH:34]1([CH2:37][O:38][C:39]2[C:46]([O:47][CH3:48])=[CH:45][CH:44]=[CH:43][C:40]=2[CH:41]=O)[CH2:36][CH2:35]1>CS(C)=O.C(OCC)(=O)C>[CH:34]1([CH2:37][O:38][C:39]2[C:46]([O:47][CH3:48])=[CH:45][CH:44]=[CH:43][C:40]=2/[CH:41]=[CH:12]/[C:5]2[N:6]=[C:7]3[S:11][CH:10]=[CH:9][N:8]3[C:3](=[O:2])[CH:4]=2)[CH2:35][CH2:36]1
Reactant: O=c1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2sccn12
Reactant: COc1cccc(C=O)c1OCC1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cccc(/C=C/c2cc(=O)n3ccsc3n2)c1OCC1CC1
Reaction time: 0.5 h

Procedure:
To a stirred suspension of Step 2 intermediate (13.0 g, 28.08) was added NaH (1.2 g, 30.88) in dry DMSO (75 ml) and stirred for 0.5 h. A solution of 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (6.3 g, 30.88 mmol) in DMSO was added dropwise to this solution at room temperature and stirred for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4 to yield a crude solid which was purified by column chromatography using 10% ethyl acetate in DCM to afford 7.5 g of the desired compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 0.30-0.33 (m, 2H), 0.52-057 (m, 2H), 1.10-1.20 (br m, 1H), 3.72-3.90 (m, 5H), 6.29 (s, 1H), 7.00-7.11 (m, 3H), 7.34 (d, J=6.3 Hz, 1H), 7.44-7.50 (m, 1H), 7.90-8.00 (m, 1H), 8.14 (d, J=6.2 Hz, 1H); ESI-MS (m/z) 355.17 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].O>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1ccc(O)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1

Procedure:
4-Hydroxyphenylacetic acid (50 g, 0.32 m) in 300 ml of glacial acetic acid was cooled to 10° at which temperature 100 ml of nitric acid was slowly added. The mixture was allowed to reach room temperature, then was poured into 1 l of water. The separated solid was washed with water and recrystallized from ethanol to give 35 g of 4-hydroxy-3-nitrophenylacetic acid, m.p. 144-146° .
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH3:19])[CH:5]=1.FC(F)(F)S(O[C:27]1[CH:28]2[CH2:34][CH:31]([CH2:32][CH:33]=1)[CH2:30][CH2:29]2)(=O)=O>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:27]2[CH:28]3[CH2:34][CH:31]([CH2:32][CH:33]=2)[CH2:30][CH2:29]3)=[C:6]([CH3:19])[CH:5]=1
Reactant: O=S(=O)(OC1=CCC2CCC1C2)C(F)(F)F
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Product: COC(=O)c1ccc(C2=CCC3CCC2C3)c(C)c1
Yield: 57.6 %

Procedure:
3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester of Example 28, Step A (0.300 g, 1.09 mmol) and bicyclo[3.2.1]oct-2-en-2-yl trifluoromethanesulfonate (0.336 g, 1.31 mmol) were reacted in the manner of Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with 5% ethyl acetate in hexane, afforded the title compound (0.161 g) as a light yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:17])[CH2:15][OH:16])=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)[CH3:2]>C(O)C.[Ni]>[CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([CH:14]([CH3:17])[CH2:15][OH:16])[CH:12]=[CH:13][C:5]=2[O:4]1)[CH3:2]
Reactant: CCc1cc(=O)c2cc(C(C)CO)ccc2o1
Agent: [Ni]
Solvent: CCO
Product: CCC1CC(=O)c2cc(C(C)CO)ccc2O1
Reaction time: 2 h
Yield: 108.8 %

Procedure:
2-(2-Ethyl-4-oxo-4H-1-benzopyran-6-yl)propan-1-ol (4.1g) was taken up in ethanol (100 ml), Raney Nickel (5.0 g) was added and the mixture hydrogenated at 45 psi for 2 hours. The catalyst was removed by filtration (Hyflo supercel) and replaced with a fresh batch (5.0 g) and hydrogenation at 45 psi continued for a further 3 hours. The catalyst was removed by filtration and the filtrate evaporated to yield 2-(2,3-dihydro-2-ethyl-4-oxo-4H-1-benzopyran-6-yl)propanol as a pale green oil (4.5 g), I.R. carbonyl absorption 1690 cms-1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>CCOCC.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>[CH2:19]([O:26][C:27]1[N:28]=[CH:29][C:30]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=2[N+:16]([O-:18])=[O:17])=[CH:31][CH:32]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)OB(c2ccc(OCc3ccccc3)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)c([N+](=O)[O-])c1

Procedure:
A mixture of tert-butyl 4-chloro-3-nitrophenylcarbamate (818 mg, 3 mmol), 2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (933 mg, 3 mmol), tetrakis(triphenylphosphine)palladium (104 mg, 0.09 mmol), 10 mL of dioxane, and 6 mL of 1 M Na2CO3 was heated at reflux for 15 h. It was diluted with 50 mL Et2O and washed with brine (2×50 mL) and dried over MgSO4 and concentrated. The crude product was purified by silica chromatography (EtOAc/hexane) to afford tert-butyl 4-(6-(benzyloxy)pyridin-3-yl)-3-nitrophenylcarbamate (WZ02049) as a yellow wax (1.2 g, 95%). MS (ESI) m/z 444 (M+Na+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2-].[Na+].C[N:14](C)C1C=CC=CC=1>C(OCC)(=O)C>[NH2:14][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[CH:9][N:8]=1
Reactant: CC(C)(C)c1ccncc1
Reactant: CN(C)c1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccnc(N)c1
Temperature: 150 °C
Reaction time: 7 h
Yield: 45.6 %

Procedure:
To 100 g (0.73 mol) of 4-tert-butyl-pyridine and 31.0 g (0.79 mol) of sodium amide was added 181 mL (1.5 mol) of N,N,-dimethylaniline. The reaction mixture was heated with stirring under nitrogen for 7 hours at 150° C. After cooling, the reaction mixture was added to 400 mL of ice. ˜250 mL of ethyl acetate was added to the mixture to extract the organic phase. The organic phase was evaporated and fractional distilled. About ˜50 g (45% yield) of 2-amino-4-tert-butylpyridine was obtained. MS results confirmed the desired products.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=O)[CH2:11][C@H:10]2[C:15]([NH:17][CH2:18][CH:19]([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])=[O:8])=[CH:3][CH:2]=1.[CH3:33][N:34]([CH3:36])[NH2:35]>>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:35][N:34]([CH3:36])[CH3:33])[CH2:11][C@H:10]2[C:15]([NH:17][CH2:18][CH:19]([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])=[O:8])=[CH:5][CH:6]=1
Reactant: CN(C)N
Reactant: O=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CN(C)N=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 56 %

Procedure:
Following the general method as outlined in Example 17, starting from (2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-oxo-2-pyrrolidinecarboxamide and N,N-dimethylhydrazine, the resultant crude reaction mixture was purified by column chromatography using DCM/MeOH (30:1) to collect the desired product, e.g. (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(dimethylhydrazono)-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide as a mixture of two isomers as a light yellow oil in 56% yield (90.2% purity by HPLC).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH:13]([OH:21])[CH:12]2[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH:13]([O:21][C:28](=[O:30])[CH3:29])[CH:12]2[N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN(C1c2cc(OCc3ccccc3)ccc2OC(C)(C)C1O)S(C)(=O)=O
Solvent: c1ccncc1
Product: CC(=O)OC1C(N(C)S(C)(=O)=O)c2cc(OCc3ccccc3)ccc2OC1(C)C
Reaction time: 8 h

Procedure:
A solution of 4.5 g of N-(6-benzyloxy-3-hydroxy-2,2-dimethylchroman-4-yl)-N-methyl-methanesulfonamide and 37 ml of acetic anhydride in 74 ml of pyridine was left to stand at RT overnight. The batch was concentrated under reduced pressure and the residue was dissolved in EA, washed successively with dilute hydrochloric acid and saturated sodium bicarbonate solution and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave 4.7 g of N-(6-benzyloxy-3-acetoxy-2,2-dimethylchroman-4-yl)-N-methyl-methanesulfonamide, m.p. 124-125° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29]1)[CH3:27]>>[CH2:26]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:29]1)[CH3:27]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: CCN1CC[C@H](N)C1
Product: CCN1CC[C@H](Nc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1

Procedure:
Prepared by proceeding in a similar manner to Example 77, starting from (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67) and (S)-1-ethylpyrrolidin-3-ylamine (Intermediate 194).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([CH3:10])[CH2:5]1.[CH2:11]([O:13][C:14](=[O:27])[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:27])[C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH:4]3[O:8][C:7](=[O:9])[N:6]([CH3:10])[CH2:5]3)[CH2:25][CH2:26]2)=[CH:19][CH:20]=1)[CH3:12]
Reactant: CN1CC(CCCl)OC1=O
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Product: CCOC(=O)c1ccc(N2CCN(CCC3CN(C)C(=O)O3)CC2)cc1

Procedure:
Following the procedure of Example 2, the title compound is prepared from 5-(2-chloroethyl)-3-methyl-2-oxazolidinone and 4-(1-piperazinyl)benzoic acid ethyl ester.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1.NC(N)=[S:13].[OH-].[K+].Cl>C(O)C.O>[SH:13][C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1
Reactant: NC(N)=S
Reactant: FC(F)(F)c1nnc(Br)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1nnc(S)s1
Yield: 59.1 %

Procedure:
699 g (3 moles) of 2-bromo-5-trifluoromethyl-1,3,4-thiadiazole and 248 g (3.3 moles) of thiourea in a mixture of 600 ml of ethanol and 75 ml of water were heated for 2 hours under reflux. A solution of 223 g of potassium hydroxide in 2 liters of water was rapidly added dropwise to the reaction solution while it was still hot, and the mixture was once more heated under reflux, for 5 minutes. The cooled solution was adjusted to pH 5 with dilute hydrochloric acid and extracted repeatedly with methylene chloride. After drying and concentrating, the residue was recrystallized from a litte petroleum ether. The mother liquor yielded further product. 330 g (59% of theory) of 2-mercapto-5-trifluoromethyl-1,3,4-thiadiazole of melting point 73° C were obtained. ##STR85##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[C:8]([Cl:10])[CH:9]=1)[CH:6]=[O:7].C([O-])([O-])=O.[Cs+].[Cs+].[C:18]([O:21][CH2:22][CH2:23]Br)(=[O:20])[CH3:19]>CN(C=O)C.CCOC(C)=O>[C:18]([O:21][CH2:22][CH2:23][O:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[C:8]([Cl:10])[C:5]=1[CH:6]=[O:7])(=[O:20])[CH3:19]
Reactant: O=Cc1c(O)cc(Cl)cc1Cl
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1cc(Cl)cc(Cl)c1C=O
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To a solution of 4,6-dichlorosalicylaldehyde (3.72 mmol) in 5 mL DMF was added Cs2CO3 (3.72 mmol) followed by KI (3.72 mmol) and 2-bromoethyl acetate (8.68 mmol). The reaction mixture was heated to 100° C. for 4 h and then stirred at RT for 3 days. The mixture was diluted with EtOAc and washed 3 times with water and then with brine. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification with CC (KP-SIL™ from Biotage) using Hept/EtOAc (4/1) to EtOAc gives the desired compound as beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[F:19][C:20]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:19][C:20]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:25]=[CH:24][C:21]=1/[CH:22]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cccc(C(F)(F)F)c1F)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (100 mg, 0.404 mmol) in toluene 10 mL was added 2-fluoro-3-(trifluoromethyl)benzaldehyde 78 (77.7 mg, 0.404 mmol). PTSA (153.8 mg, 0.809 mmol) was added to the reaction mixture and stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 79 which was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-2-(2-fluoro-3-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 79 was eluted at 34% ethyl acetate in hexane to afford yellow coloured.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1)#[CH:2].I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]>>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:10]=2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: Oc1ccccc1I
Reactant: C#Cc1ccc(C=C)cc1
Product: C=Cc1ccc(-c2cc3ccccc3o2)cc1

Procedure:
The general procedure was used to convert 1-Ethynyl-4-vinyl-benzene and 2-iodophenol to the title product. Purification by flash chromatography (hexanes as the eluent) gave the analytically pure product as a white solid (300 mg, 68% yield). 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J=8.45, 2H), 7.56-7.44 (m, 4H), 7.29-7.19 (m, 2H), 6.98 (s, 1H), 6.74 (dd, J=10.93 and J=6.59, 1H), 5.78 (d, J=17.71, 1H), 5.28 (d, J=10.93, 1H). 13C NMR (75 MHz, CDCl3) δ 155.66, 154.87, 137.69, 136.26, 129.75, 129.22, 126.61, 125.02, 124.28, 122.94, 120.87, 114.40, 111.13, 101.37. Anal. Calcd. for C16H12O: C, 87.25; H, 5.49. Found C, 87.54; H, 5.62. m.p.: 164-165° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[H][H]>[Pd]>[CH3:1][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:4][CH2:3][OH:2]
Reactant: [H][H]
Reactant: c1ccc2c(c1)CCOC2
Agent: [Pd]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: Cc1ccccc1CCO
Temperature: 150 °C
Reaction time: 5 h

Procedure:
1250 Grams of isochroman having the structure: ##STR64## 25 grams of 5% palladium-on-carbon and 12.5 grams of citric acid are placed in a 4-liter autoclave. The autoclave is sealed, heated to 150° C. and pressurized with hydrogen at 200 psig. After five hours, 12.5 grams of additional citric acid is added to the autoclave and the autoclave is resealed. The autoclave is then heated at a pressure of 200 psig and 150° C. for an additional three hours. At the end of this additional three hour period, the autoclave is opened, the contents filtered and the filtrate is distilled over 2 grams of calcium carbonate through a 24" Goodloe column yielding the following fractions:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]1.Cl.C([BH3-])#N.[Na+]>CO>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: C1=CCNCC1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(CN2CC=CCC2)cc1
Reaction time: 96 h

Procedure:
A mixture of 4-hydroxybenzaldehyde (6.1 g.) and 1,2,3,6-tetrahydropyridine (8.3 g.) in methanol (70 ml.) was adjusted to pH7 by addition of ethereal hydrogen chloride. Sodium cyanoborohydride (3.15 g.) was then added in portions to the stirred solution at 25° C. The mixture was stirred at 20°-25° C. for four days, evaporated, and water (100 ml.) added to the resultant residue. The mixture obtained was adjusted to pH2 with dilute hydrochloric acid and extracted with ether (2×50 ml.). The extracts were discarded. The aqueous phase was separated and adjusted to pH9 with 10% w/v sodium carbonate solution, to give crude 1-(4-hydroxybenzyl)-1,2,3,6-tetrahydropyridine as a solid. This solid was dissolved in acetone (100 ml.) and the solution acidified to pH2 with ethereal hydrogen chloride to give 1-(4-hydroxybenzyl)-1,2,3,6-tetrahydropyridine hydrochloride (6.7 g.), m.p. 234°-236° C. (after recrystallisation from methanol/ethyl acetate.)
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[S:6][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19](=[O:21])[O:18][N:17]=2)=[C:12]([O:22][CH3:23])[CH:11]=1.ClCCl>CN(C)C=O.[O-2].[O-2].[Mn+4]>[CH3:23][O:22][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[C:16]1[NH:20][C:19](=[O:21])[O:18][N:17]=1)[O:9][CH2:8][C:7]1[S:6][C:5]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=2)=[N:4][C:3]=1[CH:2]=[O:1]
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CO)ccc1-c1noc(=O)[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C=O)ccc1-c1noc(=O)[nH]1
Temperature: 60 °C
Yield: 60.3 %

Procedure:
50 mg of 3-{4-[4-hydroxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one were dissolved in 2 mL of dimethylformamide by heating to 60° C. and 2 mL of dichloromethane was added. To the resulting solution was added 90 mg of manganese dioxide. The reaction mixture was heated to 60° C. overnight. 5 mL of dimethylformamide was added. The hot mixture was filtered through celite and washed with dichloromethane/methanol. The filtrate was concentrated under reduced pressure to give 30 mg of 5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-4-carbaldehyde which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH:6]=[CH:5]2.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:22]([O:21][C:17]([CH:18]=[CH:19][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH:6]=[CH:5]2)=[O:20])[CH3:23]
Reactant: C=CC(=O)OCC
Reactant: Brc1ccc2c(ccn2-c2cccnc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc2c(ccn2-c2cccnc2)c1

Procedure:
A solution of 0.75 g of 5-bromo-N-(3-pyridyl)indole and 0.5 g of ethyl acrylate in 20 ml of triethylamine is refluxed for 48 hours with 10.8 mg of palladium acetate and 30 mg of tri-o-tolylphosphine. The reaction mixture is cooled, evaporated and chromatographed on 20 g of silica gel with diethyl ether to yield 5-(2-ethoxycarbonylethenyl)-N-(3-pyridyl)indole. Saponification by refluxing for 15 hours in 30 ml of ethanol with 5 ml of 2N sodium hydroxide yields a solution which is evaporated to dryness. The residue is partitioned between 20 ml of ether and 10 ml of water. The aqueous phase is separated, brought to pH 5 and the resulting solid is filtered to yield 5-(2-carboxyethenyl)-N-(3-pyridyl)indole which melts with decomposition at 180°.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][C:18]4[C:21]([C:32]([F:35])([F:34])[F:33])=[N:22][N:23]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)[C:17]=4[C:16]3=[O:36])=[CH:11][CH:10]=2)[CH2:8][CH2:7]1.CCN(CC)CC.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[CH3:44][S:45]([N:3]1[CH2:4][CH2:5][N:1]=[C:2]1[C:6]1([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][C:18]4[C:21]([C:32]([F:33])([F:34])[F:35])=[N:22][N:23]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)[C:17]=4[C:16]3=[O:36])=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)(=[O:47])=[O:46]
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C5=NCCN5)CC4)cc2)CC3)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C5=NCCN5S(C)(=O)=O)CC4)cc2)CC3)cc1
Reaction time: 12 h

Procedure:
The product from Example 144 (0.017 g, 0.034 mmol) from was dissolved in CH2Cl2 (0.3 mL). Et3N (0.1 mL, 0.07 mmol) and MsCl (0.07 mL, 0.09 mmol) were added at rt under N2. The reaction was stirred for 12 h, concentrated to dryness, and purified via flash chromatography (silica, 100% EtOAc then 0.5% Et3N:10% MeOH:CH2Cl2) to afford the title compound. LC/MS (ESI+) 574.4 (M+H)+, tR=2.84 min (10–90% CH3CN/H2O in a 4-min run). 1H NMR ((CD3)2CO, 300 MHz) δ 7.50 (d, J=9.1 Hz, 2H), 7.33 (m, 4H), 6.98 (d, J=9.1 Hz, 2H), 4.16 (t, J=6.6 Hz, 2H), 3.83 (m, 7H), 3.16 (t, J=6.4 Hz, 2H), 2.42 (s, 3H), 1.47 (m, 2H), 1.18 (m, 2H) ppm.
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=CN=1)=[O:5].ClC1C=C[C:23]([NH2:24])=CC=1.C(O)(=O)C.[OH-].[Na+]>CS(C)=O>[OH:1][CH:2]=[C:3]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)[C:4]([NH:6][C:7]1[CH:23]=[N:24][CH:10]=[CH:11][CH:12]=1)=[O:5]
Reactant: Cc1cc(C(=CO)C(=O)Nc2ccccn2)on1
Reactant: Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Cc1cc(C(=CO)C(=O)Nc2cccnc2)on1

Procedure:
General method for the synthesis of α-[4-(chlorophenylamino)methylene]-3-methyl-N-pyridyl-5-isoxazoleacetamide: α-Hydroxymethylene-3-methyl-N-pyridyl-5-isoxazoleacetamide (0.25 g, 1.0 mmol) was stirred with 4-chloroaniline (0.13 g, 1.0 mmol) and acetic acid (200 μL) in DMSO (3 mL) at rt for 24 h. The resulting solution was mixed with 10 mL of an aqueous 0.5 N NaOH solution and extracted with CH2Cl2. The organic layer was dried over Na2SO4 filtered and concentrated. The residue was then recrystallized from MeOH.