Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.Cl[CH:13]([CH3:17])[C:14](=O)[CH3:15].[C:18]([NH:21][CH2:22][CH2:23][NH2:24])(=[O:20])[CH3:19]>>[C:18]([NH:21][CH2:22][CH2:23][N:24]1[C:14]([CH3:15])=[C:13]([CH3:17])[C:2]([C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[C:3]1[CH3:5])(=[O:20])[CH3:19]
Reactant: CC(=O)NCCN
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CC(=O)C(C)Cl
Product: CC(=O)NCCn1c(C)c(C)c(C(=O)OC(C)(C)C)c1C

Procedure:
By reaction of tert.-butyl acetoacetate with 3-chloro-2-butanone and 2-acetylaminoethylamine analogously to Example 1.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4]1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([NH:2][C@@H:3]1[C:9](=[O:10])[NH:8][C:7]3[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=3[O:5][CH2:4]1)=[O:26])=[CH:19]2
Reactant: N[C@H]1COc2ccccc2NC1=O
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1COc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
Alternatively, to a mixture of (S)-3-amino-2,3-dihydro-1,5-benzoxazepin-4(5H)-one hydrochloride salt (54 mg) (prepared in Itoh, et al., Chem. Pharm. Bull. 1986, 34, 1128–1147), tetrahydrofuran (10 mL), 5-chloroindole-2-carboxylic acid (39 mg), 1-hydroxy-7-azabenzotriazole (31 mg), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (57 mg) stirring at room temperature under argon was added diisopropylethylamine (65 mg). The resulting yellow suspension was stirred for 30 min, during which a solution formed. After evaporation under vacuum, the residue was redissolved in ethyl acetate (50 mL) and the resulting solution was washed sequentially with 1.0 M aqueous hydrochloric acid (25 mL), 1.0 M aqueous sodium hydroxide (25 mL), water (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum. The resulting solid crude product was triturated with diethyl ether (20 mL three times), followed by drying under vacuum to provide the title compound (63 mg).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][O:29][C:30]1[C:35]([CH:36]=O)=[CH:34][CH:33]=[C:32]([O:38][CH3:39])[N:31]=1.C([BH3-])#N.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(O)(=O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][CH2:36][C:35]4[C:30]([O:29][CH3:28])=[N:31][C:32]([O:38][CH3:39])=[CH:33][CH:34]=4)=[N:25][CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Reactant: COc1ccc(C=O)c(OC)n1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(CNc2ccc(Cc3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)cn2)c(OC)n1
Temperature: 100 °C
Yield: 72.7 %

Procedure:
To 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (120, 60.0 mg, 0.150 mmol) in 2.0 mL of ethanol and 0.1 mL of acetic acid, 2,6-dimethoxy-pyridine-3-carbaldehyde (121, 120 mg, 0.75 mmol) and silica supported cyanoborohydride (0.40 g, 0.484 mmol) were added. The reaction was heated to 100° C. for 18 minutes at 300 Watts in microwave, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (122, 60 mg).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([O:21][CH3:22])[C:8]([Cl:23])=[C:7]([CH3:24])[C:6]=1[C:25](=[O:27])[CH3:26].[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:23][C:8]1[C:7]([CH3:24])=[C:6]([C:25](=[O:27])[CH3:26])[C:5]([O:4][CH2:3][CH2:2][NH:33][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]=1[O:21][CH3:22]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCCc1ccccc1
Reactant: NC1CCCC1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCNC2CCCC2)c1OCCCc1ccccc1
Temperature: 65 °C
Yield: 68 %

Procedure:
Example 34b (217 mg, 0.48 mmol) was reacted with cyclopentylamine as described under General Procedure B (except heated to 65° C.) and the crude was purified by flash chromatography (silica-gel, MeOH/DCM 5:95) yielding the title compound (151 mg, 68%) as an oil. 1H NMR (300 MHz, CDCl3) δ 7.32-7.19 (m, 5H), 4.14 (t, J=5.1 Hz, 2H), 4.07 (t, J=6.3 Hz, 2H), 3.88 (s, 3H), 3.24-3.04 (m, 1H), 2.87-2.79 (m, 4H), 2.49 (s, 3H), 2.19 (s, 3H), 2.10-2.04 (m, 2H), 1.85-1.78 (m, 3H), 1.69-1.66 (m, 2H), 1.56-1.51 (m, 2H), 1.35-1.31 (m, 2H). MS (ES+) m/z 460 (M+H+).
Reaction SMILES: [OH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[NH:4][C:5](=[O:23])[C:6]2[N:11]=[N:10][N:9]([CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[N:8]=1.C(N(CC)CC)C>CS(C)=O.ClCCl>[C:2]([C:3]1[NH:4][C:5](=[O:23])[C:6]2[N:11]=[N:10][N:9]([CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:7]=2[N:8]=1)(=[O:1])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(C(O)c3ccccc3)nc21
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(C(=O)c3ccccc3)nc21
Temperature: 0 °C
Reaction time: 15 h
Yield: 48.3 %

Procedure:
384 mg (0.988 mmol) of 5-(hydroxy-phenyl-methyl)-3-(1-methyl-4-phenyl-butyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one are dissolved in a mixture of 3 ml of DMSO and 10 ml of dichloromethane, and the solution is cooled to 0° C. 1.37 ml (9.88 mmol) of triethylamine and 692 mg (4.35 mmol) of pyridine-SO3 complex are added, and the reaction mixture is then stirred at room temperature for 15 hours. For work-up, the mixture is diluted with 100 ml of dichloromethane and the organic phase is washed with 1N HCl and saturated sodium bicarbonate solution and then dried over sodium sulphate. The solvent is removed, and chromatographic purification gives 185 mg (48%) of a solid, m.p.: 105° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[O:4][N:3]=1.[CH3:11][CH2:12]O.OS(O)(=O)=O>>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:4][N:3]=1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(C)no1
Reaction time: 48 h
Yield: 97.3 %

Procedure:
To a solution of 2-(3-methylisoxazol-5-yl)acetic acid (7.28 g, 51.6 mmol) in EtOH (200 mL, 3425 mmol) was added concentrated H2SO4 (0.30 mL, 5.63 mmol) at room temperature. After 48 h, the reaction mixture was concentrated in vacuo to give a dark brown oil. The crude ester was filtered over a plug of silica (50 g) and the product was eluted with 40% Et2O:60% Hexanes (400 mL). The filtrate was subsequently concentrated to give the product ethyl 2-(3-methylisoxazol-5-yl)acetate (8.50 g, 50.2 mmol, 97% yield) as a clear oil. LC/MS m/z 170 [M+H]+.
Reaction SMILES: Br[CH:2](C)[C:3](OC)(OC)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C:17]([O-:20])(=[O:19])C.[K+]>C(O)CCC>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]([CH3:2])[C:17]([OH:20])=[O:19])=[CH:9][CH:8]=1
Reactant: COc1ccc(C(OC)(OC)C(C)Br)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CCCCO
Product: COc1ccc(C(C)C(=O)O)cc1
Temperature: 115 °C
Yield: 89 %

Procedure:
A mixture of 2-bromo-1,1-dimethoxy-1-(4'-methoxyphenyl)-propane (2.89 g; 0.01 mol), potassium acetate (1.2 g; 0.012 mol) and n-butanol (40 ml) is heated to 115° C. for 32 hours. By following the procedure of Example 1a, there is obtained the title product (1.60 g; 0.0089 mol). Yield, 89%; m.p. 56°-57° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]#[CH:12].I[C:14]1[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]([OH:24])=[CH:16][CH:15]=1.C1C=CC=CC=1.C(N(CC)CC)C>O=O.[Cu]I>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[C:14]([C:12]#[C:11][C:4]2[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:15]=[CH:16][C:17]=1[OH:24]
Reactant: C#Cc1cc(OC)ccc1OC
Reactant: COC(=O)c1cc(I)ccc1O
Agent: [Cu]I
Agent: O=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#Cc2cc(OC)ccc2OC)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon atmosphere 240 mg of 2,5-dimethoxyphenylacetylene and 493 mg of methyl 5-iodosalicylate are dissolved in 20 ml of oxygen-free and dry benzene. The mixture is treated with 85 mg of tetrakis (triphenylphosphine)palladium, 20 mg of copper(I)iodide and 450 mg of triethylamine, stirred at room temperature overnight and then poured onto 100 ml of aqueous pH 7 buffer. After extraction with ethyl acetate and purification by chromatography on silicagel, 5-[2-(2,5-dimethoxyphenyl)ethinyl]-2-hydroxybenzoic acid methyl ester is obtained (colorless crystals of M.P. 105°-108°).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][CH:12]=1.[CH:17]([CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)=[O:18]>C1COCC1>[OH:18][CH:17]([C:7]1[CH:12]=[N:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: FC(F)(F)c1ccc(Br)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(C(F)(F)F)nc2)CC1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A solution of isopropylmagnesium chloride (2.0 M in THF, 40.3 mL, 80.6 mmol) was added dropwise by syringe to a solution of 5-bromo-2-(trifluoromethyl)pyridine (19.5 g, 86.3 mmol) in dry THF (12 mL) at 2° C. After 30 minutes, tert-butyl 4-formylpiperidine-1-carboxylate (12.3 g, 57.3 mmol) was added to the Grignard solution at 2° C. as a solid. The reaction mixture was warmed to 10° C. over 1.5 hours after which it was quenched with saturated aqueous ammonium chloride solution. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate and washed with saturated aqueous NaCl solution. The organic phase was dried (MgSO4), filtered, and concentrated and used crude in the next step.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+:14]>C(O)C.O>[CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O-:7])=[O:6])[CH3:2].[Na+:14]
Reactant: CCOC(=O)C(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(OCC)C(=O)[O-]
Yield: 96.1 %

Procedure:
Ethyl diethoxyacetate (Ex. Fluka) (25 g) was added to sodium hydroxide (5.68 g) in ethanol (60 ml) and water (30 ml). After heating under reflux for 5 hours the solvents were removed at reduced pressure and the residue dried in vacuo to give sodium diethoxyacetate (23.2 g). The salt was then converted to diethoxyacetyl chloride and reacted with benzylamine to give N-benzyl diethoxyacetamide which was cyclised with conc. sulphuric acid according to Fukumi and Hideshi, Heterocycles, 9, 1197 (1978) to give 3-hydroxyisoquinoline.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH:11]([CH3:13])[CH3:12].Cl[S:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([OH:30])=[O:29])(=[O:24])=[O:23]>C1COCC1>[CH2:10]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([S:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28]([OH:30])=[O:29])(=[O:24])=[O:23])[CH2:17][CH2:16]1)[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)COC1CCNCC1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)COC1CCN(S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of N,N-Diisopropylethylamine (0.0078 ml, 0.045 mmol) in THF (1 ml) is added to 4-Isobutoxy-piperidine (0.008 g, 0.05 mmol) followed by a solution of 3-(Chlorosulfonyl)benzoic acid (9.93 mg, 0.045 mmol) and shaken at room temperature for 48 hours. The solution is evaporated under vacuum to afford 3-(4-Isobutoxy-piperidine-1-sulfonyl)-benzoic acid which is used without purification; [M+H]+ 342.00
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:13]#[N:14])=[CH:9][CH:10]=2)[NH:5]1.[Cl:15][C:16]1[N:21]=[CH:20][C:19]([S:22]([NH:25][CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.CO>CN1CCCC1=O>[ClH:15].[C:13]([C:8]1[CH:7]=[C:6]2[C:11]([C:12]([C:16]3[N:21]=[CH:20][C:19]([S:22]([NH:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)(=[O:24])=[O:23])=[CH:18][CH:17]=3)=[C:4]([OH:3])[NH:5]2)=[CH:10][CH:9]=1)#[N:14]
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Reactant: O=S(=O)(NCCN1CCCC1)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cl
Product: N#Cc1ccc2c(-c3ccc(S(=O)(=O)NCCN4CCCC4)cn3)c(O)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25 %

Procedure:
To a suspension of sodium hydride (97%, 0.036 g, 1.5 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was added 2-oxoindoline-6-carbonitrile (0.119 g, 0.75 mmol). The formed mixture was stirred for 5 min at room temperature and 6-chloro-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide (0.145 g, 0.5 mmol) was added. The resulting reaction mixture was set under an N2 atmosphere and stirred for 1 h at 90° C. Methanol (0.4 mL) was added and the solvents were removed in vacuo. The crude product was purified by preparative HPLC purification (XTerra®PrepMS C8 column 10 μm, 30×150 mm; 0.1 M NH4OAc buffer/acetonitrile, (80:20 to 40:60), as a eluent gradient). The collected product was stirred for 16 h in methanol/ethyl acetate, (5:1 mL), and the brownish red solid was collected by filtration affording 0.056 g (27% yield) of the title compound as the base. The base (0.046 g, 0.11 mmol) was dissolved in chloroform/methanol, (1:1), and treated with HCl in diethyl ether (1 M) at 0° C. The resulting brownish red crystals were collected by filtration and washed with diethyl ether to obtain 0.022 g (40% yield) of the title compound: 1H NMR (D2O, 400 MHz) δ 8.63 (s, 1H), 8.10 (d, J=9.2 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.80 (dd, J=9.2, 2.4 Hz, 1H), 7.22 (s, 1H), 7.21 (dd, J=8.0, 1.6 Hz, 1H) 2.91 (t, J=6.8 Hz, 2H), 2.51 (m, 6H), 1.61 (br s, 4H); MS (EI) m/z 412 (M++1).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=2)[N:10]=[CH:9][C:8]=1[C:19]#[N:20])[CH2:4][CH3:5])[CH3:2].COC1C=CC(/C=[C:36]2/[C:37]([NH:39][C:40]([S:42]/2)=[NH:41])=[O:38])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:41][C:40]1[S:42]/[C:36](=[CH:17]\[C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][C:8]([C:19]#[N:20])=[C:7]3[O:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])/[C:37](=[O:38])[N:39]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CCC(CC)Oc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC(CC)Oc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 4-(1-ethyl-propoxy)-6-formyl-quinoline-3-carbonitrile (example 64b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-(1-ethyl-propoxy)-quinoline-3-carbonitrile. LC-MS m/e 367 (MH+).
Reaction SMILES: ICI.[CH3:4][C:5]12[C:13]3([OH:17])[C:14]([CH3:16])([CH3:15])[CH:8]([CH2:9][CH:10]1[CH:11]=[CH:12]3)[CH2:7][CH2:6]2.[CH2:18](O)C=CCCCCCCC>CCOCC.[Zn]>[CH3:4][C:5]12[C:13]3([OH:17])[C:14]([CH3:16])([CH3:15])[CH:8]([CH2:9][CH:10]1[CH:11]1[CH:12]3[CH2:18]1)[CH2:7][CH2:6]2
Reactant: CC1(C)C2CCC3(C)C(C=CC13O)C2
Reactant: CCCCCCCC=CCO
Agent: [Zn]
Solvent: CCOCC
Solvent: ICI
Product: CC1(C)C2CCC3(C)C(C2)C2CC2C13O

Procedure:
A suspension of 19 g of zinc dust and 29 g of cuprous chloride powder in 125 ml of ether are stirred under reflux for thirty minutes. Diiodomethane (14.8 ml) is added dropwise over a twenty minute period. No external heat is required and the addition is carried out at a rate sufficient to maintain reflux (36°-41° C). 1.5 g of the product produced in Example VI, 9,10,10-trimethyl-tricyclo-(4.3.1.04,9)-dec-2-en-1-ol, is then added dropwise over a twenty minute period without external heating. Reflux is maintained (41°-46° C) throughout addition of the dec-2-en-1-ol. The reaction mass is refluxed daily for 8.5 hours for 5 days (42 hours in all) adding more ether and diiodomethane as required. The course of the reaction is followed by GLC (20 feet × 1/4 inch 5% SE-30 prog. 100°-220° C at [4°/min.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[C:6]([OH:13])[CH:5]=1)[CH3:2].[C:14](OCC)(=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].[O-]CC.[Na+].Cl>C(O)C.O.C(OCC)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:7]([C:10](=[O:12])[CH:11]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:13]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOc1ccc(C(C)=O)c(O)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1cc(=O)c2ccc(OCC)cc2o1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-ethoxy-2-hydroxyphenyl)ethanone (Aldrich, 5.0 g, 27.7 mmol) and diethyl oxalate (8.3 mL, 61 mmol) in ethanol (50 mL) was added sodium ethoxide (21% in EtOH, 31 mL, 83 mmol) and the mixture was refluxed for 1.5 hours. The mixture was cooled to ambient temperature, diethyl ether (150 mL), water (150 mL) and 12N hydrochloric acid (7 mL) were added. The separated organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and was concentrated under reduced pressure to afford ethyl 7-ethoxy-4-oxo-4H-chromene-2-carboxylate. The intermediate was dissolved in acetic acid (70 mL) and 12N hydrochloric acid (8.5 mL), heated to reflux for 2 hours, and cooled to ambient temperature. Water (300 mL) was added and the solids were collected by filtration, rinsed with water, and freeze-dried to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (t, 3H), 4.20 (q, 2H), 6.84 (s, 1H), 7.08 (dd, 1H), 7.19 (d, 1H), 7.92 (d, 1H). MS (APCI) m/z 235.04 (M+H)1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25](=[O:28])[CH2:26][OH:27])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[CH:12][C:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH:25]([OH:28])[CH2:26][OH:27])(=[O:18])=[O:17])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=C(CO)c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2)cc1)c1ccccc1C(O)CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-[2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]-2-hydroxyethanone (Example 167, 20 mg, 0.05 mmol) and sodium borohydride (10 mg, 0.26 mmol) in methanol (2 mL) and dichloromethane (0.5 mL) was stirred at room temperature for 30 minutes. The reaction was quenched with water and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. δH (500 MHz, d6 DMSO): 8.04 (1H, d, J=7.9 Hz), 7.84-7.79 (4H, m), 7.74 (1H, d, J=7.7 Hz), 7.70-7.67 (3H, m), 7.53 (1H, t, J=7.3 Hz), 7.44 (1H, d, J=16.3 Hz), 7.29 (1H, d, J=16.4 Hz), 7.23 (2H, t, J=8.6 Hz), 5.36 (2H, s), 4.71 (1H, s), 3.32 (1H, s), 3.17 (1H, s).
Reaction SMILES: [OH:1][C@H:2]1[CH2:26][C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:4]2([CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([O:22][CH3:23])[CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3]1.[H-].[Na+].IC.[C:37](OCC)(=O)C>CN(C=O)C.O>[CH:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([N:7]2[CH2:8][CH2:9][C:4]3([O:24][C@H:25]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:26][C@H:2]([O:1][CH3:37])[CH2:3]3)[CH2:5][CH2:6]2)=[O:11])=[CH:13][C:14]=1[O:22][CH3:23])([CH3:20])[CH3:21]
Reactant: COc1cc(C(=O)N2CCC3(CC2)C[C@@H](O)C[C@@H](c2ccccc2)O3)ccc1OC(C)C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C(=O)N2CCC3(CC2)C[C@@H](OC)C[C@@H](c2ccccc2)O3)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [cis-8-hydroxy-10-phenyl-11-oxa-3-azaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methoxy-phenyl)methanone (139 mg, 0.3 mmol) in DMF (4 mL) was added sodium hydride (34 mg, 1.5 mmol). The mixture was stirred at room temperature for 30 minutes. Iodomethane (187 μL, 3.00 mmol) was added. The mixture was stirred at room temperature overnight, then repartitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with water (3×), brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (50-60% ethyl acetate-Hex) to provide (4-isopropoxy-3-methoxy-phenyl)-[cis-8-methoxy-10-phenyl-11-oxa-3-azaspiro[5.5]undecan-3-yl]methanone (102 mg). 1H NMR (400 MHz, CDCl3) δ 7.48-7.33 (m, 4H), 7.33-7.28 (m, 1H), 7.01-6.90 (m, 2H), 6.86 (d, J=8.2 Hz, 1H), 4.66-4.46 (m, 2H), 4.12-3.90 (m, 2H), 3.86 (s, 3H), 3.76-3.61 (m, 1H), 3.48 (s, 1H), 3.37 (d, J=4.5 Hz, 3H), 3.21 (t, J=11.8 Hz, 1H), 2.28 (dd, J=39.8, 13.2 Hz, 2H), 2.00 (dd, J=12.6, 2.7 Hz, 1H), 1.85-1.62 (m, 3H), 1.59-1.44 (m, 1H), 1.42-1.33 (m, 7H). ESI-MS m/z calc. 453.25, found 454.5 (M+1)+; Retention time: 1.65 minutes (3 minute run).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:2]([CH3:5])([CH3:4])[CH3:3].[N+:12]([O-])(O)=O.[C:16]([O:19]C(=O)C)(=O)[CH3:17]>CO.[Pd]>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:16](=[O:19])[CH3:17])=[CH:10][CH:11]=1)[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])O
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1ccc(CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
To a solution of neopentylbenzene (9.20 g, 62 mmol) in acetic anhydride (30 mL) cooled in an ice bath was slowly added a solution of nitric acid (3.5 mL, 83 mmol) in acetic anhydride (10 mL). The reaction was allowed to warm to room temperature for 18 hours. The yellow reaction mixture was added to ice water and extracted with diethylether (3×). The organic layers were combined, washed with brine, dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. This provided a 1:1 mixture of ortho and para nitro substituted compounds as a yellow solid. To this yellow solid dissolved in methanol (100 mL) was added acetic anhydride (8.4 mL, 89 mmol) and 10% palladium on carbon (700 mg, 7 mmol) and the reaction mixture hydrogenated at a pressure of 40 psi for 3 hours. The reaction was filtered through celite, concentrated in vacuo, and purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/hexanes gradient. This provided the title compound (2.79 g, 22%) as a white solid.