Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:11][CH:10]([CH2:12][SH:13])[CH2:9][S:8]1)[CH3:2].[CH2:22]([C:25]1[C:35]([OH:36])=[C:34]([C:37](=[O:39])[CH3:38])[CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH2:29][CH2:30]Br)[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:37]([C:34]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH2:29][CH2:30][S:13][CH2:12][CH:10]2[CH2:9][S:8][C:7]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])[S:11]2)=[C:25]([CH2:22][CH2:23][CH3:24])[C:35]=1[OH:36])(=[O:39])[CH3:38]
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)SCC(CS)S1
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCSCC2CSC(CCC(=O)OCC)(CCC(=O)OCC)S2)ccc(C(C)=O)c1O

Procedure:
The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 31 (2.0 g, 0.0056 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopropane (prepared as described in U.S. Pat. No. 4,565,882, Example 14) (2.0 g, 0.006 mol) and anhydrous potassium carbonate (3.5 g) in methyl ethyl ketone (25 ml) at reflux overnight. The crude product was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 2.1 g (70%) of the product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH2:33][OH:34])[C:5]2=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:41])([CH3:40])[C:38]#[CH:39].C(N(CC)CC)C>CN(C)C=O.[Cu]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>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:39]#[C:38][C:37]([CH3:41])([CH3:40])[CH3:36])[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH2:33][OH:34])[C:5]2=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OCCO)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 80 °C
Yield: 29.6 %

Procedure:
A solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.15 g, 0.24 mmol) prepared in Example 190c in anhydrous N,N-dimethylformamide (10 mL) was added CuI (3 mg), 3,3-dimethyl-1-butyne (19.7 mg, 2.4 mmol) (Aldrich), and triethylamine (1 mL, 7.2 mmol). The mixture was degassed under nitrogen for 5 min, then dichlorobis(triphenylphosphine)palladium (8.4 mg, 0.012 mmol) (Strem) was added and the reaction mixture was heated at 80° C. under nitrogen for 0.5 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated. The residue was purified with chromatography to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-(3,3-dimethyl-1-butynyl)-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 41 mg, 30%).
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]/[C:14](=[C:21]2\[C:22](=[O:40])[NH:23][C:24]3[C:29]\2=[CH:28][C:27]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[CH:26][CH:25]=3)/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=[O:5])C.[OH-].[Na+]>CO.ClCCl>[C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]/[C:14](=[C:21]2\[C:22](=[O:40])[NH:23][C:24]3[C:29]\2=[CH:28][C:27]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[CH:26][CH:25]=3)/[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][CH:8]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1ccc(N/C(=C2\C(=O)Nc3ccc(NS(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=C(O)Cc1ccc(N/C(=C2\C(=O)Nc3ccc(NS(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
720 mg (1.3 mmol) of (Z)-3-[1-(4-ethoxycarbonylmethyl-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinone are dissolved in a mixture of 20 ml of methanol and 20 ml of dichloromethane. 4 ml of 1 N sodium hydroxide solution are added and the mixture is stirred for 18 hours at ambient temperature and for another 1 hour at 40° C. The reaction solution is evaporated down to half the volume and the pH is adjusted to 4–5 with 1 N hydrochloric acid. The precipitate formed is suction filtered, washed with water, a little isopropanol and ether.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:15]=[CH:14][C:13]=2[NH2:24])=[N:2]1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:37]=[CH:36][S:35][C:34]=1[C:38]([Cl:40])=[O:39].C(=O)([O-])O.[Na+]>C1COCC1>[ClH:40].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH:15]=[CH:14][C:13]=2[NH:24][C:38]([C:34]2[S:35][CH:36]=[CH:37][C:33]=2[CH3:32])=[O:39])=[N:2]1
Reactant: Nc1ccc(N2CCOCC2)cc1C=Cc1n[nH]c2ccccc12
Reactant: Cc1ccsc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccsc1C(=O)Nc1ccc(N2CCOCC2)cc1/C=C/c1n[nH]c2ccccc12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a similar manner to Example 1, (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (0.12 g, 0.25 mmol) was dissolved in methanol (6.0 mL) and crude 3-{2-[5-(morpholin-4-yl)-2-nitrophenyl]vinyl}-1H-indazole was obtained from 5-morpholino-2-nitrobenzaldehyde (65 mg, 0.25 mmol) and potassium carbonate (0.10 g, 0.75 mmol). In a similar manner to Example 2, crude 3-{2-[5-(morpholin-4-yl)-2-nitrophenyl]vinyl}-1H-indazole (0.80 g, 2.3 mmol) was dissolved in ethanol (25 mL) and the solution was added with tin (0.82 g, 6.9 mmol) and concentrated hydrochloric acid (4.0 mL) and heated from room temperature to 40° C. to obtain 2-[2-(1H-indazol-3-yl)vinyl]-4-(morpholin-4-yl)phenylamine. Further, in a similar manner to Example 29, 2-[2-(1H-indazol-3-yl)vinyl]-4-(morpholin-4-yl)phenylamine (0.45 g, 1.4 mmol) was dissolved in THF (10 mL) and the solution was added with triethylamine (0.61 ml, 4.2 mmol) and 3-methylthiophenecarbonylchloride (0.20 g, 1.4 mmol) and stirred at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure to obtain free base of Compound 225. Further, said free base was treated by 4 mol/L hydrogen chloride-methanol solution (1.0 mL) to obtain Compound 225 (0.40 g, 55%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]([NH2:25])[C:14]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][C:16]=32)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26]C(O)=O.C(OC=C(C#N)C#N)C.CO.C(Cl)Cl>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH2:19][CH:17]([C:16]3[CH:15]=[C:14]4[C:13](=[CH:12][C:11]=32)[N:25]=[CH:26][N:20]4[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCNc1cc2c(cc1N)C1CC2CN(C(=O)OC(C)(C)C)C1
Reactant: CC(=O)O
Agent: CCOC=C(C#N)C#N
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CCCCn1cnc2cc3c(cc21)C1CC3CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
4-Butylamino-5-amino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester (440 mg, 1.27 mmol) was dissolved in ethanol (20 mL) and HOAc (2 mL) and treated with ethoxymethylenemalononitrile (186 mg, 1.52 mmol). The resulting mixture was warmed to 60° C. and stirred 18 hours. The reaction was cooled, concentrated, treated with H2O and saturated aqueous Na2CO3 solution then extracted with ethyl acetate (3×50 mL) and dried (Na2SO4). After filtration and concentration, the residue was chromatographed to provide a yellow oil. (400 mg, 89%). (TLC 5% methanol/CH2Cl2 (NH3) Rf 0.70).
Reaction SMILES: [Na].[CH3:2][C:3]1[C:8]([CH3:9])=[C:7]([N+]([O-])=O)[C:6]([CH3:13])=[CH:5][N+:4]=1[O-:14].Cl.[CH2:16]([OH:18])[CH3:17]>C(OCC)(=O)C>[CH2:16]([O:18][C:7]1[C:6]([CH3:13])=[CH:5][N+:4]([O-:14])=[C:3]([CH3:2])[C:8]=1[CH3:9])[CH3:17]
Reactant: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Reactant: CCO
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Product: CCOc1c(C)c[n+]([O-])c(C)c1C

Procedure:
4.2 g of sodium were dissolved in 780 ml of ethanol under argon. 22.3 g of 2,3,5-trimethyl-4-nitropyridine 1-oxide were then added portionwise thereto and the solution was left to boil under reflux overnight. The pH was adjusted to 7 by means of 5N hydrogen chloride in ethyl acetate while cooling and the mixture was then evaporated in vacuo. The residue was taken up in 0.5 l of methylene chloride, the solution was filtered through silica gel, which was rinsed with 200 ml of methylene chloride, the combined filtrates were evaporated in vacuo and the residue was crystallized from petroleum ether. There was obtained 4-ethoxy-2,3,5-trimethylpyridine 1-oxide of melting point 59°-61°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH:11]C(O)=O)=[CH:4][CH:3]=1.C(O)C1C=CC=CC=1.CN(C=O)C>C(OCC)(=O)C>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)Nc1ccc(Cl)cc1C(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: OCc1ccccc1
Product: Nc1ccc(Cl)cc1C(=O)O
Yield: 59 %

Procedure:
1.0 g (5.1 mmol) of 5-chloroisatoic acid was heated under stirring in a mixed solvent of benzyl alcohol (5 mL) and DMF (5 mL) at 100° C. for 5 hours. After cooling, the reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was separated and purified using silica gel column chromatography to give 0.516 g of 2-amino-5-chlorobenzoic acid.benzylester (yield: 39%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.[C:20](=[O:23])([O-])[O-].[K+].[K+].O.CN([CH:30]=[O:31])C>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][CH2:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[C:20]([O:31][CH3:30])=[O:23]
Reactant: Oc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1cccc(COc2cccc(OCc3ccc4ccccc4n3)c2)c1
Temperature: 50 °C

Procedure:
A mixture of 3-(2-quinolinylmethyloxy)phenol (2.51 g, 0.01 mol), 1.85 g (0.01 mol) of methyl 3-chloromethyl benzoate, and 1.5 g of potassium carbonate in 30 ml of DMF is heated at 50° C. overnight. The reaction mixture is poured into water, extracted with ethyl acetate and the organic solution separated, dried and evaporated to dryness. Recrystallization from ethyl acetate gives methyl 3-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoate. (M.P. 93°-94° C.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:25](=[CH:26][CH:27]=1)[CH2:24][C:8]1[C:9]3[CH:15]=[CH:14][C:13]([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:12][C:10]=3[O:11][C:7]=1[C:6]2([CH3:29])[CH3:28].Cl([O-])=[O:31].[Na+].ON1C(=O)C2=CC=CC=C2C1=O.C(Cl)Cl>C(#N)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:31])[C:8]1[C:9]3[CH:15]=[CH:14][C:13]([O:16][S:17]([C:20]([F:21])([F:23])[F:22])(=[O:18])=[O:19])=[CH:12][C:10]=3[O:11][C:7]=1[C:6]2([CH3:29])[CH3:28]
Reactant: COc1ccc2c(c1)C(C)(C)c1oc3cc(OS(=O)(=O)C(F)(F)F)ccc3c1C2
Reactant: [O-][Cl+][O-]
Agent: O=C1c2ccccc2C(=O)N1O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)c1oc3cc(OS(=O)(=O)C(F)(F)F)ccc3c1C2=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
Trifluoromethanesulfonic acid 8-methoxy-6,6-dimethyl-6,11-dihydro-benzo[b]naphth[2,3-d]furan-3-yl ester (Compound Z11, 4.82 g) was dissolved in acetonitrile (48 mL) and water (24 mL), added with sodium chlorite (2.55 g) and N-hydroxyphthalimide (369 mg), and then the mixture was stirred at 40° C. for 1 hr. The reaction mixture was added with methylene chloride and the organic layer was washed with saturated brine. Thereafter, the organic layer was dried over magnesium sulfate. The residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (2.80 g, 56%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([Br:26])=[CH:4][C:5](C(C)(C)C)=[C:6]([C:9]2[C:10]([OH:21])=[C:11]([CH3:20])[C:12]([Br:19])=[CH:13][C:14]=2C(C)(C)C)[C:7]=1[OH:8].C1(C)C=CC=CC=1.FC(F)(F)S(O)(=O)=O.O>C(Cl)(Cl)Cl>[CH3:20][C:11]1[C:12]([Br:19])=[CH:13][CH:14]=[C:9]([C:6]2[C:7]([OH:8])=[C:2]([CH3:1])[C:3]([Br:26])=[CH:4][CH:5]=2)[C:10]=1[OH:21]
Reactant: Cc1c(Br)cc(C(C)(C)C)c(-c2c(C(C)(C)C)cc(Br)c(C)c2O)c1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(Br)ccc(-c2ccc(Br)c(C)c2O)c1O
Temperature: 5 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
The optically active 6,6′-dimethyl-5,5′-dibromo-3,3′-di(t-butyl)-2,2′-biphenol obtained in Example 1 (1.06 g, optical purity: >99% ee, 2.2 mmol), toluene (5 ml) and trifluoromethanesulfonic acid (750 mg, 5 mmol) were mixed followed by stirring the entire volume for 1 hour at 5° C. Water (10 ml) and chloroform (20 ml) were then added to the reaction mixture followed by extraction and liquid separation. The organic phase was then washed with water and dried with anhydrous magnesium sulfate followed by distilling off the solvent under reduced pressure. N-hexane (10 ml) was added to the remaining slurry followed by stirring at room temperature, washing and filtering to obtain optically active 6,6′-dimethyl-5,5′-dibromo-2,2′-biphenol (761 mg, yield: 93%, optical purity: >99% ee).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([OH:12])=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH3:13][C:14]1[C:15](B(O)O)=[CH:16][C:17]2[C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[C:22]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[CH3:13][C:14]1[C:15]([C:2]2[CH:3]=[C:4]([C:7]([OH:12])=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])=[CH:16][C:17]2[C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[C:22]=2[CH:23]=1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Reactant: COc1cc(O)c(C=O)cc1Br
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: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(O)c(C=O)cc1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 72.1 %

Procedure:
A mixture of 3-bromo-6-hydroxy-4-methoxy-benzaldehyde (2 g, 8.66 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid (3.18 g, 12.99 mmol), potassium carbonate (4.79 g, 34.63 mmol) and water (4 mL) in anhydrous 1,2-dimethoxyethane (140 mL) was degassed with argon for 15 minutes prior to the addition of tetrakis(triphenylphosphine)palladium(0) (2.0 g, 1.73 mmol). The reaction mixture was heated under reflux for 15 hours, allowed to cool to room temperature and extracted with ethyl acetate (2×100 mL). The organic extracts were successively washed with water (100 mL), a saturated aqueous solution of NH4Cl (100 mL), a saturated aqueous solution of NaCl (100 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography, using a Biotage 40M cartridge, eluting with 5% ethyl acetate/95% hexane, to give 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxy-6-hydroxybenzaldehyde as a white solid (2.2 g, 73%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]4/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:35][NH:36][CH3:37].C1COCC1.O>C1COCC1>[CH:11]1([C:9]2[N:10]=[C:3]3[C:2]([N:36]([CH3:37])[CH3:35])=[N:7][CH:6]=[CH:5][N:4]3[C:8]=2[CH2:14][C:15]2[CH:34]=[CH:33][C:18]3/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=4[O:22][CH2:23][C:17]=3[CH:16]=2)[CH2:12][CH2:13]1
Reactant: CNC
Reactant: C/C(C#N)=C1/c2ccc(Cc3c(C4CC4)nc4c(Cl)nccn34)cc2COc2cc(F)ccc21
Solvent: C1CCOC1
Solvent: O
Product: C/C(C#N)=C1/c2ccc(Cc3c(C4CC4)nc4c(N(C)C)nccn34)cc2COc2cc(F)ccc21
Temperature: 100 °C
Yield: 87.3 %

Procedure:
[step 6] (E)-2-{8-[(8-chloro-2-cyclopropylimidazo[1,2-a]pyrazin-3-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (0.2 g, 0.43 mmol) obtained in step 5 was dissolved in THF (1.4 mL), and 2 mol/L dimethylamine THF solution (1.7 mL, 3.4 mmol) was added. The mixture was stirred with heating at 100° C. for 1.5 hr in an Emrys Optimizer microwave synthesizer. Water was added to the mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=100/0 v/v-50/50 v/v) to give the title compound (0.18 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:18]=3)[S:13][C:6]=12.[BH4-].[Na+]>CCO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:29][C:27]1[CH:26]=[CH:25][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:15]=[CH:16][N:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:18]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:28]=1
Reactant: CCOC(=O)Cn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of thienopyridine 374 (0.25 g, 0.56 mmol) and nickel chloride hexahydrate (0.26 g, 1.1 mmol) in absolute EtOH (50 mL) was added sodium borohydride (0.085 g, 2.2 mmol) in small portions. The resulting mixture was stirred at r.t. for 1 h, then filtered through celite, run through a short plug of silica, eluting with 1:1 ethyl acetate/ethanol, and concentrated, affording title compound 375 (0.21 g, 91% yield). LRMS (M+H): 413.1.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].C(O)(=O)C(C(C(O)=O)O)O.C(=O)C1C=CC=CC=1>C(O)C>[CH3:1][CH2:2][O:3][C:4]([C@H:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CCOC(=O)C(N)c1ccccc1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: O=Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)[C@H](N)c1ccccc1
Reaction time: 0.08 h

Procedure:
A mixture of ethyl DL-phenylglycinate (5.021 g., 96% pure i.e. 27.0 mmole) and (+)-tartaric acid (2.027 g., 13.5 mmole, 0.5 equiv.) in ethanol (47 ml.) and benzaldehyde (2.75 ml., 2.88 g., 27.1 mmole, 1 equiv.) was stirred at 20°; crystallisation began within 5 minutes. After 10 days the mixture was filtered and the product washed with ethanol (2 × 7 ml.) and dried at 20°/4 mm. for 3 hours giving ethyl D-phenylglycinate (+)-hemitartrate solvated with 1.0 mole ethanol (3.922 g., 39% yield based on ester present or 78 % yield based on (+)-tartaric acid present), [α]D21 - 45.9° (c 2.506, H2O).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][CH:3]=1.[Mg].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:41])[CH:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:33][CH3:34])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:2]2[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][CH:3]=2)([OH:41])[CH:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:33][CH3:34])=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Reactant: CCC(C(=O)c1ccc(OCc2ccccc2)cc1)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(c1ccccc1)C(O)(c1ccc(OCc2ccccc2)cc1)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 0 °C
Yield: 93 %

Procedure:
A solution of 19.32 g of (4-bromophenoxy)-tert-butyldimethylsilane in 50 ml of tetrahydrofuran is added in drops to a suspension of 1.58 g of magnesium chips in 100 ml of tetrahydrofuran at 80° C. bath temperature, and it is refluxed for 1 hour. Then, it is cooled to 0° C., and 6.0 g of 1-(4-benzyloxyphenyl)-2-phenyl-butan-1-one [D. W. Robertson; J. A. Katzenellenbogen; D. -J. Ellen; A. Rorke; B. S. Katzenellenbogen, J. Steroid Biochem., 1982, 16, 1-13] is added, and it is stirred for 24 more hours at room temperature. For working-up, 60 ml of saturated ammonium chloride solution is added, diluted with ethyl acetate, washed neutral with water, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 9.1 g of 1-(4-benzyloxyphenyl)-1-(4-tert-butyldimethylsiloxy-phenyl)-2-phenyl-butan-1-ol is obtained as oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)[CH3:2].[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(=O)CC1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
1-Ethyl-4-piperidone (76 mg), 5-aminoindazole (67 mg), and acetic acid (0.02 ml) were dissolved in methanol (1 ml), and a borane-pyridine complex (0.06 ml) was added dropwise to the solution at room temperature. The reaction-mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give the title compound (50 mg, yield 41%).