Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[S:10][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].[H-].[Na+].Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C)C=O>[CH3:4][C:2]([NH:5][S:6]([C:9]1[S:10][C:11]([S:14]([NH:17][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)(=[O:16])=[O:15])=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(S(N)(=O)=O)s1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)NS(=O)(=O)c1ccc(S(=O)(=O)NCCN2CCOCC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
A solution of the product from Step B (1.05 g, 3.52 mmol), sodium hydride (60% dispersion in mineral oil, 310 mg, 7.75 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (0.721 g, 3.88 mmol) in anhydrous dimethylformamide (DMF) (20 mL) was heated at 110° C. for 2.5 h and then stirred at ambient temperature overnight. The reaction mixture was extracted with ethylacetate (3×100 mL), washed with brine, dried over molecular sieves and concentrated. The residue was chromatographed on silica, elution with 50% ethylacetate-hexane, to yield 0.32 g (22%) of the desired product.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]1([CH:21]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:22]2[C@@H:27]([NH2:28])[CH:26]3[CH2:29][CH2:30][N:23]2[CH2:24][CH2:25]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:37][O:38][C:39]([C:42]1[CH:43]=[CH:44][C:45]([O:50][CH3:51])=[C:46]([CH:49]=1)[CH:47]=O)([CH3:41])[CH3:40]>C(Cl)Cl>[CH3:51][O:50][C:45]1[CH:44]=[CH:43][C:42]([C:39]([O:38][CH3:37])([CH3:40])[CH3:41])=[CH:49][C:46]=1[CH2:47][NH:28][C@H:27]1[CH:26]2[CH2:29][CH2:30][N:23]([CH2:24][CH2:25]2)[C@H:22]1[CH:21]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc(C(C)(C)OC)cc1C=O
Reactant: N[C@H]1C2CCN(CC2)[C@H]1C(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(C)(C)OC)cc1CN[C@H]1C2CCN(CC2)[C@H]1C(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 43.9 %

Procedure:
Sodium triacetoxyborohydride (152 mg, 0.707 mmol) was added to a solution of (2S,3S)-2-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-amine(135 mg, 0.462 mmol) and 5-(1-methoxy-1-methylethyl)-2-methoxybenzaldehyde prepared in example 1 (92 mg, 0.442 mmol) dissolved in methylene chloride (4 ml) at room temerature, and the resulting solution was stirred for 4 h. The reaction mixture was diluted with methylene chloride, and washed with aq. sodium bicarbonate solution and brine. The extracts were dried over magnesium sulfate, and concentrated by evaporation. The residual oil was purified by crystallization from methylene chloride to yield analytically pure sample of the title compound as a white crystal (94 mg, 42%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[C:4]([CH3:17])[CH:3]=1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28].O>ClCCl>[Cl:25][CH2:26][C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][CH:13]=2)=[C:4]([CH3:17])[CH:3]=1)=[O:28]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(N)ccc1-c1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(NC(=O)CCl)ccc1-c1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 40.5 %

Procedure:
4'-Amino-2'-methylbiphenyl-4-carboxylic acid (D115, 2.45 g, 10.8 mmol) and triethylamine (3.8 ml, 27.3 mmol) were stirred in dichloromethane (50 ml) as chloroacetyl chloride (1.05 ml, 13.2 mmol) was added dropwise. This mixture was stirred for 3 h, when water (20 ml) was added. After vigorous stirring for 15 min and basification with potassium carbonate solution, the mixture was separated. The aqueous portion was washed with dichloromethane, and acidified with conc. hydrochloric acid. The precipitated solid was filtered off and dried, giving the title compound (1.33 g, 40%) as a grey powder.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1I)(=[O:3])[CH3:2].[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[C:1]([NH:4][C:5]1[N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1[C:30]#[C:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cn1nc(-c2ccccc2)c(I)c1NC(C)=O
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1nc(-c2ccccc2)c(C#Cc2ccccc2)c1NC(C)=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
Nitrogen was bubbled through a mixture of ethyl 2-(5-acetamido-4-iodo-3-phenyl-pyrazol-1-yl)acetate (34.95 g, 84.58 mmol), phenyl acetylene (18.6 mL, 169.16 mmol), triethylamine (300 mL) and DMF (120 mL) for 1.5 h. Copper iodide (1.61 g, 8.46 mmol) and bis(triphenylphosphine)palladium(II) dichloride (3 g, 4.23 mmol) were added and the reaction mixture was stirred at 90° C. under nitrogen for 2 h. The reaction mixture was concentrated in vacuo, and the residue was co-evaporated with toluene to remove excess DMF. The residue was diluted with ethyl acetate (300 mL) and washed with water (2×100 mL). The organic phase was filtered through celite, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated from ethyl acetate, yielding the title compound as a solid (25.67 g).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccc([N+](=O)[O-])cc3)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1ccc([N+](=O)[O-])cc1

Procedure:
The 2-trifluoroacetamido-3-(4-nitrophenyl)-6-benzoyl-imidazo[1,2-a]pyridine (8.59 g, 18.9 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 5.04 g. (74.4%). EA, MS(FD).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:18]([C:27]([N:29]3[CH2:34][CH2:33][CH:32]([CH2:35]Br)[CH2:31][CH2:30]3)=[O:28])[C:17]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][C:38]=3[O:47][CH2:48][CH3:49])=[N:16]2)=[CH:11][CH:10]=1>CN(C)C=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:19]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:18]([C:27]([N:29]3[CH2:34][CH2:33][CH:32]([CH2:35][N:4]4[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]4)[CH2:31][CH2:30]3)=[O:28])[C:17]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:39][C:38]=3[O:47][CH2:48][CH3:49])=[N:16]2)=[CH:11][CH:10]=1
Reactant: O=C1CNCCN1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(CBr)CC1
Solvent: CN(C)C=O
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(CN2CCNC(=O)C2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Piperazine-2-one (21 mg, 0.21 mmol) was added to a solution [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-bromomethyl-piperidin-1-yl]-methanone (48 mg, 0.07 mmol) in anhydrous dimethylformamide (2.0 mL). The mixture was stirred overnight at 70° C. The reaction mixture was cooled to ambient temperature and partitioned between methylene chloride and a saturated aqueous solution of ammonium chloride. The aqueous phase was extracted with methylene chloride and the combined organic extracts were washed with brine, and dried over anhydrous sodium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel using 1-5% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(piperazin-2-one-4-yl-methyl)-piperidin-1-yl]-methanone, which was dissolved in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to give [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(piperazin-2-one-4-yl-methyl)-piperidin-1-yl]-methanone hydrochloride as an off-white powder (23 mg, 45%). LR-MS (APCI): 702.4 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[Cl:24])[N:7]=[C:8]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[NH:9][C:10]=1[CH3:11])=[O:4].C1C(=O)N([Br:32])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[Cl:24])[N:7]=[C:8]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[NH:9][C:10]=1[CH2:11][Br:32])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (0.37 g, 1.0 mmol) in CCl4 (5 mL) was added NBS (0.20 g, 1.1 mmol) in portions. After the reaction mixture was stirred at room temperature for 1 hour, the solvent was removed in vacuo and the residue was purified by column chromatography to give 6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound C) as a yellow solid. MS: calc'd 429 (MH+), measured 429 (MH+).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][CH2:33]I)[C:27]([OH:29])=[O:28])[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.Cl[CH:36](Cl)[CH3:37]>N1C=CC=CC=1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][CH2:33][C:37]2[CH:36]=[CH:3][CH:2]=[CH:1][N:20]=2)[C:27]([OH:29])=[O:28])[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
Reactant: O=C(O)C(=NOCCI)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(O)C(=NOCCc1ccccn1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 60 °C
Reaction time: 56 h

Procedure:
A mixture of 5 g of syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-(2-iodoethoxyimino)-acetic acid solvated with dichloroethane (=4.27 g of pure product) and 30 ml of pyridine was heated at 60° C. for 24 hours and then stood at room temperature for 56 hours. The mixture was vacuum filtered and the recovered product was rinsed with pyridine and then ether and dried to obtain 1.66 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-(2-pyridylethoxyimino)-acetic acid (pyridinium internal salt) melting at 250° C. (decomposition).
Reaction SMILES: [OH-:1].[Na+].[CH3:3][C:4]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[CH2:7][C:6](=[O:13])[CH:5]=1.OO.O>CO>[CH3:3][C:4]12[O:1][CH:5]1[C:6](=[O:13])[CH2:7][C:8]([CH3:12])([CH3:11])[C:9]2=[O:10]
Reactant: CC1=CC(=O)CC(C)(C)C1=O
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)CC(=O)C2OC2(C)C1=O
Reaction time: 3 h
Yield: 81.5 %

Procedure:
2 ml of a 6N aqueous solution of NaOH have been added during a period of 15 minutes at 15° C. to a mixture of 3,5,5-trimethyl-cyclohex-2-en-1,4-dione (3.7 g) and hydrogen hydroperoxide (8.3 ml of a 30% solution) in 27 ml of methanol. The mixture was kept under stirring during 3 hours at 20°-25° C., treated with water and extracted with ether. The combined organic extracts were washed with water until neutrality, dried over MgSO4 and evaporated. 3.33 g (81.5%) of the desired product, b.p. 40° C./0.001 Torr, were thus obtained.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][C:15](O)=[S:16])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]1[CH2:28][CH2:27][N:26]2[C:21](=NC[CH2:24][CH2:25]2)[CH2:20][CH2:19]1.ClC(OCC(C)C)=O.C(NC1CCCCC1)C>O1CCCC1>[CH2:25]([N:26]([CH:21]1[CH2:20][CH2:19][CH2:18][CH2:28][CH2:27]1)[C:15](=[S:16])[CH2:14][CH2:13][CH2:12][C:11]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[N:9][N:10]=1)[CH3:24]
Reactant: C1CCC2=NCCCN2CC1
Reactant: OC(=S)CCCc1nnnn1-c1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: CCNC1CCCCC1
Solvent: C1CCOC1
Product: CCN(C(=S)CCCc1nnnn1-c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
4-(1-Phenyl-1,2,3,4-tetrazol-5-yl)thio-butyric acid (45 mmole) is dissolved in tetrahydrofuran (50 ml) and thereto is added DBU (50 mmole). To the mixture is added dropwise with stirring isobutyl chloroformate (50 mmole) under ice-cooling. The mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise N-ethylcyclohexylamine (54 mmole) and the mixture is further stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the residue is extracted with chloroform. The chloroform layer is washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. Chloroform is distilled off and the resulting residue is subjected to column chromatogrophy (Wakogel C-200, eluting solvent, chloroform) to isolate N-ethyl-N-cyclohexyl-4-(1-phenyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (yield: 43%), colorless liquid, nD18 =1.5590.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[OH:27]/[N:26]=[C:9](/[C:11]1[CH:12]=[CH:13][C:14](=[O:18])[N:15]([CH3:17])[CH:16]=1)\[CH2:8][CH:7]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1cc(C(=O)CC(c2ccccc2)c2ccccc2)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccccc2)c2ccccc2)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-(3,3-diphenyl-propionyl)-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a colorless solid, MS (ESI+): m/z=333.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[CH3:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O>C(OCC)C>[F:21][C:20]([F:22])([F:23])[C:17]1[CH:18]=[CH:19][C:14]([O:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH:4]([CH3:5])[CH2:3][OH:2])=[CH:8][CH:9]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(CO)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 35 °C
Yield: 79.3 %

Procedure:
6.6 g of methyl-α-[4-(4-trifluoromethylphenoxy)-phenoxy]propionate was dissolved in 15 ml of anhydrous diethyl ether, and the solution was added slowly to a dispersion of 0.4 g of lithium aluminum hydride in 50 ml of anhydrous diethyl ether while cooling. After completion of the addition, the mixture was refluxed at about 35° C. for 10 minutes to complete the reaction. The reaction mixture was poured into an appropriate amount of ice water to decompose any remaining unreacted lithium aluminum hydride, and 10% sulfuric acid was added to the mixture. The ethereal layer was separated, extracted twice with diethyl ether and dried over anhydrous sodium sulfate. The ether was removed from the dried extract and the resulting residue was distilled under reduced pressure to obtain 4.8 g of the desired product having a boiling point of 165° to 168° C./3 mmHg.
Reaction SMILES: [C:1]([O:14][CH3:15])(=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:22][CH2:23][O:24][C:25]([CH2:27]Br)=[O:26]>CC(C)=O>[CH3:15][O:14][C:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([O:8][CH2:27][C:25]([O:24][CH2:23][CH3:22])=[O:26])=[C:4]([O:5][CH3:6])[CH:3]=1
Reactant: COC(=O)c1cc(OC)c(O)c(OC)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(OC)cc(C(=O)OC)cc1OC
Yield: 74.6 %

Procedure:
To a mixture of methyl syringate (100 grams, 472 mmol), anhydrous K2CO3 (250 grams, 1.809 mol) in anhydrous acetone (1200 mL) was added Ethyl bromo acetate (113 grams, 677 mmol) and refluxed for 48 hours. Acetone was distilled and water (1200 mL) was added. Crude 11 was filtered, dried, and recrystallized from toluene to give pure 11 (105 grams, 75%) as a white powder. The melting point was found to be 90.5-92.5° C. The structure was confirmed by I.R and NMR. IHNMR (CDCl3) δ 1.32 (t, 3H,CH2CH3), 3.88(s, 3H,Ester), 3.90(s, 6H,OCH3), 4.25 (q, 2H,CH2CH3), 4.69(s,2H,OCH2), 7.24 (s, 2H,Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=2)SC)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][C:29]([NH2:33])([CH3:32])[CH2:30][CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=2)[NH:33][C:29]([CH3:32])([CH3:28])[CH2:30][CH3:31])[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(NC(SC)=C(C#N)S(=O)(=O)c2ccc(Cl)cc2)cc(OC)c1
Reactant: CCC(C)(C)N
Product: CCC(C)(C)NC(Nc1cc(OC)cc(OC)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Yield: 26 %

Procedure:
2-(4-Chlorophenylsulfonyl)-3-(3,5-dimethoxyphenylamino)-3-methylsulfanyl-2-propenenitrile (0.30 g, 0.7 mmol) was stirred in 1,1-dimethylpropylamine (1 ml) for 17 h at 100° C. in a sealed flask under nitrogen. Work-up as described in Example 17, 2) without chromatography gave 84 mg (26%) of the title compound. Mp 189-190° C. 1H NMR (200 MHz, CDCl3): δ=0.95 (t, 3H), 1.35 (s, 6H), 1.65 (q, 2H), 3.62 (s, 6H), 5.88 (d, 2H), 6.20 (t, 1H), 6.45 (br s, 1H), 7.0 (br s, 1H), 7.50 (dt, 2H), 7.83 (dt, 2H); Analysis: calc. for C22H26ClN3O4S; C, 59.96%; H, 5.65%; N, 9.06%. Found: C, 56.82%; H, 5.64%; N, 8.90%.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:17]=[CH:16][C:15]3[O:18][C:19]([Br:21])=[CH:20][C:14]=3[C:13]2=[O:22])=[CH:8][C:7]=1[CH3:23]>CC(O)=O.O>[Br:21][C:19]1[O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:8]=[C:7]4[C:6](=[CH:11][CH:10]=3)[NH:5][N:1]=[CH:23]4)[C:13](=[O:22])[C:14]=2[CH:20]=1
Reactant: O=N[O-]
Reactant: Cc1cc(-n2ccc3oc(Br)cc3c2=O)ccc1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1c2cc(Br)oc2ccn1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 44.8 %

Procedure:
NaNO2 (174 mg, 2.52 mmol) was added to a solution of crude 5-(4-amino-3-methylphenyl)-2-bromofuro[3,2-c]pyridin-4(5H)-one (800 mg, 2.52 mmol) in 5:1 AcOH/H2O (24 mL) and the resulting solution was stirred at 25° C. for 14 h. The solution was concentrated under reduced pressure. Flash chromatography on silica gel (49:1 CH2Cl2/MeOH) afforded the title compound (373 mg, 44%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 13.30-13.25 (br s, 1H, NH), 8.16 (s, 1H), 7.81 (d, J=1.8 Hz, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.35 (dd, J=8.7, 1.8 Hz, 1H), 7.19 (d, J=0.6 Hz, 1H), 6.85 (dd, J=7.5, 0.6 Hz, 1H).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[C:35]1([CH:34]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(O)CCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCCC=Cc1ccccc1
Yield: 44.3 %

Procedure:
This compound was synthesized from 10-carboxydecyltriphenylphosphonium bromide (10.55 g, 20 mmol) and benzaldehyde (2.12 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation (bp 152-155° C./0.03 torr) and crystallization afforded the product (2.43 g, 44%) as white crystals (mp 27-27.5° C.). IR: 3400-2500, 1720, 700 cm-1 ; 1H-NMR: 1.30 (m, 10H), 1.40 (m, 2H), 1.62 (m, 2H), 2.35 (m, 4H), 5.65 (m, 1H), 6.40 (m, 1H), 7.25 (m, 5H), 10.40 (bs, 1H). Anal. Calcd. for C18H26O2 : C, 78.79, H, 9.55%; Found: C, 78.66, H, 9.60%. Z:E=93:7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[C:19]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]O)[CH:27]=1)[CH3:17]>>[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[C:19]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][O:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:2]([F:1])[CH:7]=2)[CH:27]=1)[CH3:17]
Reactant: CCc1cccc(CC)c1-c1cccc(CO)c1
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Product: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(CC)cccc3CC)c2)cc1F
Yield: 80 %

Procedure:
The title compound was synthesized in the same manner as in Example 277 from ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate and (2′,6′-diethylbiphenyl-3-yl)methanol. a yellow oily substance (yield 80%).
Reaction SMILES: C([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:14]3[C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[C:16]4([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[CH2:15]3)[C:8]=2[C@H:7]([CH3:36])[CH2:6]1)(=O)C.C1COCC1.O[Li].O>O>[Cl:35][C:31]1[CH:30]=[C:29]2[C:16]3([CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]3)[CH2:15][N:14]([C:13]3[C:8]4[C@H:7]([CH3:36])[CH2:6][CH:5]([OH:4])[C:9]=4[N:10]=[CH:11][N:12]=3)[C:34]2=[CH:33][CH:32]=1
Reactant: CC(=O)OC1C[C@@H](C)c2c1ncnc2N1CC2(CCN(C(=O)OC(C)(C)C)CC2)c2cc(Cl)ccc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CC(O)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Reaction time: 4 h
Yield: 41.7 %

Procedure:
A solution of tert-butyl 1-((5R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5-chlorospiro[indoline-3,4′-piperidine]-1′-carboxylate (0.170 g, 0.331 mmol) in 2:1 THF:H2O (1.8 mL) was cooled to about 0° C. LiOH—H2O (0.034 g, 0.83 mmol) was added and the reaction was stirred at about room temperature for 4 hours. The reaction was quenched by the addition of 1N HCl to pH 6. The aqueous phase was extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by column chromatography (30-70% EtOAc/Hexane) to yield tert-butyl 5-chloro-1-((5R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.065 g, 42%). LCMS (APCI+) m/z 471, 473 [M+H]+; Rt=3.82 min.