Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[N:7]=[C:8]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:9]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:10]=3[N:16]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:28](C)=O.[Na+]>CO.[OH-].[Na+]>[CH:1]1([C:6]2[N:7]=[C:8]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:9]3[CH2:15][CH2:14][N:13]([CH3:28])[CH2:12][CH2:11][C:10]=3[N:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Fc1ccc(-c2nc(C3CCCC3)nc3c2CCNCC3)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCc2nc(C3CCCC3)nc(-c3ccc(F)cc3)c2CC1
Yield: 85.1 %

Procedure:
To a solution of 2-cyclopentyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (0.035 g, 0.112 mmol) in MeOH (1 mL) was added formaldehyde (37% in water; 0.10 mL) and NaBH(OAc)3 (0.032 g, 0.151 mmol). After the reaction was judged complete, the mixture was diluted with 1 N NaOH and extracted with CH2Cl2 (3×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO2 chromatography (1-7% 2 M NH3 in MeOH/CH2Cl2) to give 0.031 g (87%) of the title compound. MS (ESI): exact mass calcd. for C20H24FN3, 325.20; m/z found, 326.4 [M+H]+. 1H NMR (CDCl3): 7.47 (dd, J=5.4, 8.8, 2H), 7.15 (t, J=8.7, 2H), 3.38-3.30 (m, 1H), 3.20 (dd, J=4.1, 6.3, 2H), 2.97 (dd, J=4.2, 5.9, 2H), 2.71-2.70 (m, 2H), 2.60 (m, 2H), 2.41 (s, 3H), 2.12-2.05 (m, 2H), 1.99-1.91 (m, 2H), 1.87-1.79 (m, 2H), 1.73-1.63 (m, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:16][S-:17].[Na+]>CN(C)C=O>[CH3:16][S:17][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: C[S-]
Reactant: O=Cc1ccc(-c2ccccc2)cc1F
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(-c2ccccc2)ccc1C=O
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 84.8 %

Procedure:
To a solution of 2-fluoro-4-phenylbenzaldehyde (0.400 g) in N,N-dimethylformamide (4 mL) was added sodium methane-thiolate (0.210 g), and the resulting mixture was stirred at 50° C. for 2.5 hours. The reaction mixture was cooled to room temperature and then partitioned between diethyl ether (30 mL) and water (10 mL). The organic layer was washed successively with water (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.387 g).
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]2[C:10]3([CH2:27][O:28][C:4]=2[CH:3]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:11]3=[O:26].FC1C(C#[N:37])=CC2C3(COC=2C=1)C1C(=CC=CC=1)N(CC1C=CC=CC=1C(F)(F)F)C3=O>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2([C:5]3[CH:6]=[C:7]4[C:2](=[CH:3][C:4]=3[O:28][CH2:27]2)[NH:37][N:9]=[CH:8]4)[C:11]1=[O:26]
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ccccc2C(F)(F)F)c2ccccc21
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ccccn2)c2ccccc21
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3[nH]ncc3cc12

Procedure:
Following the procedure as described in EXAMPLE 46 and making non-critical variations using 6-fluoro-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile to replace 6-fluoro-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile, 1′-(pyridin-2-ylmethyl)-1H-spiro[furo[3,2-f]indazole-5,3′-indol]-2′ (1′H)-one was obtained (33%): mp 117-119° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 10.21 (br s, 1H), 8.60-7.59 (m, 1H), 7.79 (s, 1H), 7.70-7.65 (m, 1H), 7.31-6.89 (m, 7H), 5.24-4.77 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.5, 160.7, 155.4, 149.6, 142.3, 141.7, 137.1, 134.9, 132.3, 129.0, 126.3, 123.7, 123.6, 122.8, 121.7, 119.1, 115.6, 109.7, 89.6, 80.6, 57.3, 46.1; MS (ES+) m/z 369.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[CH:11][C:10]=2[CH3:21])=[N:6][CH:7]=1.Cl.[Cl:23][C:24]1[CH:45]=[CH:44][C:27]([O:28][CH2:29][CH2:30][C:31]2[CH:43]=[CH:42][C:34]([CH2:35][N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:33][CH:32]=2)=[CH:26][CH:25]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>O.CCN(CC)CC.CN(C=O)C>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][C:31]2[CH:43]=[CH:42][C:34]([CH2:35][N:36]3[CH2:37][CH2:38][N:39]([C:18](=[O:20])/[CH:17]=[CH:16]/[C:12]4[CH:11]=[C:10]([CH3:21])[C:9]([O:8][C:5]5[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N:6]=5)=[C:14]([CH3:15])[CH:13]=4)[CH2:40][CH2:41]3)=[CH:33][CH:32]=2)=[CH:44][CH:45]=1
Reactant: Cc1cc(/C=C/C(=O)O)cc(C)c1Oc1ccc(O)cn1
Reactant: Clc1ccc(OCCc2ccc(CN3CCNCC3)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(/C=C/C(=O)N2CCN(Cc3ccc(CCOc4ccc(Cl)cc4)cc3)CC2)cc(C)c1Oc1ccc(O)cn1
Yield: 94.3 %

Procedure:
To a DMF (26 mL) solution of (E)-3-{4-[(5-hydroxypyridin-2-yl)oxy]-3,5-dimethylphenyl}prop-2-enoic acid (1.300 g) and 1-{4-[2-(4-chlorophenoxy)ethyl]benzyl}-piperazine hydrochloride (2.116 g) were added HOBT (0.070 g), WSC (1.310 g), and Et3N (1.905 mL) at room temperature, then the resultant mixture was stirred at room temperature over night. The mixture was poured into water, and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1 to 1/0 and then AcOEt/MeOH=4/1) to afford (E)-1-(4-{4-[2-(4-chlorophenoxy)ethyl]benzyl}piperazin-1-yl)-3-{4-[(5-hydroxypyridin-2-yl)oxy]-3,5-dimethylphenyl}prop-2-en-1-one as a pale yellow amorphous powder (2.57 g).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]([C:17]([O:19]CC)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.CCO.O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:8]([C:17]([OH:19])=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(C(C)(C)C)nc1N1CCOCC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ncc(C(=O)O)c(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
To a stirring suspension of ethyl 2-tert-butyl-4-morpholinopyrimidine-5-carboxylate (0.36 g, 1.24 mmol) in 1:1:1 THF/EtOH/H2O (9 ml) at RT was added LiOH.H2O (130 mg, 4.95 mmol) and the mixture was stirred overnight at RT. The reaction mixture was checked by LC-MS and the completed reaction was concentrated to an aqueous residue, acidified (pH 3-4) with 3M HCl and the solution was extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried (MgSO4), filtered and concentrated in vacuo. The crude was dissolved in isopropanol and the solids (LiCl and NaCl) were filtered and washed with isopropanol. The filtrate was concentrated to obtain the desired product, 2-tert-butyl-4-morpholinopyrimidine-5-carboxylic acid (0.15 g, 46% yield). MS (ESI) m/z: 266.0 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]([F:38])([F:37])[C:28]1[C:33]([C:34](O)=[O:35])=[CH:32][N:31]=[CH:30][CH:29]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:34]([C:33]4[CH:32]=[N:31][CH:30]=[CH:29][C:28]=4[C:27]([F:38])([F:26])[F:37])=[O:35])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cnccc4C(F)(F)F)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 4-(trifluoromethyl)nicotinic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/diethyl ether/methanol=10:12:1) to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:18][S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19][CH3:18])=[CH:6][CH:5]=1)=[O:11]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: CSc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CO
Product: COC(=O)c1ccc(-c2ccccc2SC)cc1
Temperature: 0 °C
Yield: 814.9 %

Procedure:
To a stirring solution of 4-iodobenzoic acid methyl ester (5 g, 0.0019 mol), sodium carbonate (4.04 g, 0.038 mol) and Palladium acetate (4.2 mg, 0.00019 mol) in methanol (30 mL), was added 2-methylmercapto phenyl boronic acid (3.53 g, 0.02 mol) in one lot at 25-30° C. After reflux of 30 min., reaction mixture was poured in ice cold water (100 mL) and product was extracted in ethyl acetate (250 mL). Column purification (100-200 mesh silica gel, 5% hexane in ethyl acetate) gave 4 g of titled product in 81% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].O.[F:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1B(O)O.C(=O)([O-])O.[Na+].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.O>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:33]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]=2[F:27])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccncc1F
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: COCCOC
Solvent: O
Product: CN(Cc1cc(-c2ccncc2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 26.9 %

Procedure:
tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (215 mg), (3-fluoropyridin-4-yl)boronic acid hydrate (120 mg), sodium hydrogencarbonate (126 mg) and tetrakis(triphenylphosphine)palladium (87 mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 80° C. for 3 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow oil (yield 60 mg, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:17]>CCOC(C)=O>[CH2:16]([O:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:13]([C:11]2[O:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH:23]=1)[CH3:17]
Reactant: CCOC(=O)CCc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cccc(NC(=O)c2ccc(-c3ccc(Cl)cc3)o2)c1

Procedure:
Carboxylic acid (145) (58 mg, 0.26 mmol) was coupled to aniline (124) (50 mg, 0.26 mmol) using Method C. During this reaction, partial hydrolysis occurred. The acid was re-dissolved in EtOAc (2 ml) and the organic layer was washed with 1M HCl (2×1 ml), dried (Na2SO4), filtered and the solvent removed in vacuo to give a mixture of acid and ester, which was used without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:24])([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)C.C(O)(=O)C.[OH-].[Na+]>[Pd].O>[OH:24][C:11]1([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: OC1(c2ccc(C(F)(F)F)cc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: OC1(c2ccc(C(F)(F)F)cc2)CCNCC1

Procedure:
A mixture of 10.0 g. (0.03 mol) of 1-benzyl-4-hydroxy-4-(α,α,α-trifluoro-p-tolyl)piperidine and 1.0 g. of 10% Pd/C in 100 ml. of ethanol containing 2.0 ml. of acetic acid is shaken under hydrogen. The mixture is filtered and the filtrate is evaporated to give a white solid which is dissolved in 50 ml. of water and rendered alkaline by addition of 1N NaOH solution. Filtration gives white crystals, m.p. 136°-138°C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[C:11](/[CH3:15])=[CH:12]/[C:13]#[CH:14])[CH:6]=1.C([Li])CCC.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7](/[C:11](/[CH3:15])=[CH:12]/[C:13]#[C:14][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:8]=[CH:9][CH:10]=1
Reactant: C#C/C=C(\C)c1cccc(OCOC)c1
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C#C/C=C(\C)c1cccc(OCOC)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
764 mg (3.78 mmol) of 1-methoxymethoxy-3-((E)-1-methylbut-1-en-3-ynyl)benzene are dissolved in 20 ml of anhydrous THF and the solution is cooled to −78° C. 1.8 ml (4.5 mmol) of a 2.5M butyllithium solution are then added dropwise and the reaction medium is stirred for 30 minutes at this temperature. 0.43 ml (4.5 mmol) of ethyl chloroformate are then added dropwise and then the reaction medium is brought to room temperature and stirred for 2 hours. After treating with a saturated ammonium chloride solution and extracting with ethyl acetate, the organic phase is dried and then concentrated under reduced pressure. After purification by chromatography on a silica column (ethyl acetate 10-heptane 90), a yellow oil is obtained (m=836 mg; Y=81%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6]1\[CH2:7][CH2:8][O:9][C:10]2[C:15]\1=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:2].C(OC(=O)/C=C1/CCOC2C/1=CC=CC=2)C>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)/C=C1\CCOc2ccccc21
Agent: [Pd]
Agent: CCOC(=O)/C=C1/CCOc2ccccc21
Solvent: CCO
Product: CCOC(=O)CC1CCOc2ccccc21
Temperature: 45 °C
Reaction time: 18 h

Procedure:
To a solution of chroman-(4E)-ylidene-acetic acid ethyl ester and chroman-(4Z)-ylidene-acetic acid ethyl ester (1.68 g, 7.47 mmol, 1 eq.) in EtOH (91 mL) under N2, palladium on activated carbon (10 wt. %, 168 mg) was added. The flask was carefully evacuated and refilled with H2 (3×). The black suspension was stirred at 45° C. under an H2-atmosphere for 18 hours. The black suspension was filtered through Celite. The Celite was rinsed with EtOH. The filtrate was concentrated in vacuo to give (±)-chroman-4-yl-acetic acid ethyl ester as a grey oil. The product was used without further purification.
Reaction SMILES: Br.[CH:2]1[N:6]2[C:7]3[C:12]([N:13]=[CH:14][C:5]2=[N:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3.[BH4-].[Na+].O>C(O)C>[CH:2]1[N:6]2[C:7]3[C:12]([NH:13][CH2:14][C:5]2=[N:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: CCOC(=O)c1cn2c(cnc3ccccc32)n1
Agent: Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cn2c(n1)CNc1ccccc1-2
Yield: 99.3 %

Procedure:
To a stirred solution of 1.6 g of ethyl imidazo[1,2-a]quinoxaline-2-carboxylate hydrobromide (British patent application Ser. No. 79-26597, in 50 ml of ethanol was added portionwise 0.5 g of sodium borohydride and at the completion of the reaction (tlc), the mixture was poured into 250 ml of water. The mixture was extracted with ethyl acetate and the organic layer was washed with water, dried and evaporated to dryness to obtain 1.2 g (97% yield) of ethyl 4,5-dihydroimidazo[1,2-a]quinoxaline-2-carboxylate melting at 206°-8° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32])[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([O:24]CC)=[O:23])[C:12]1=[CH:11]2)#[N:2].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32])[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([OH:24])=[O:23])[C:12]1=[CH:11]2)#[N:2]
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(OCc3ccc(OC(C)C)c(C#N)c3)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCCC2CC(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of ethyl 2-(2-(3-cyano-4-isopropoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (70 mg, 0.157 mmol) in dioxane (1 mL) was added 1 M LiOH aqueous solution (0.627 mL, 0.627 mmol). The reaction was stirred at room temperature for 8 h, diluted with water, and acidified to pH 4 with 0.5 M aqueous citric acid solution. The light pink solid was collected to give the title compound (63 mg). LCMS m/z=419.4 [M+H]+; 1H NMR (400 MHz, CDCl3) 1.40 (d, J=6.1 Hz, 6H), 1.55-1.65 (m, 1H), 1.98-2.12 (m, 1H), 2.15-2.25 (m, 2H), 2.65 (dd, J=16.1, 8.6 Hz, 1H), 3.01 (dd, J=16.1, 5.3 Hz, 1H), 3.45-3.54 (m, 1H), 3.85-3.92 (m, 1H), 4.12-4.18 (m, 1H), 4.61-4.68 (m, 1H), 5.01 (s, 2H), 6.22 (s, 1H), 6.86 (dd, J=8.8, 2.4 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 7.58 (dd, J=8.7, 2.2 Hz, 1H), 7.65 (d, J=2.2 Hz, 1H).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:20])=O.CN(C)C=O>ClCCl>[C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:13][C:14]([Cl:20])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CN1C(=O)OC[C@@H]1c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CN1C(=O)OC[C@@H]1c1ccccc1
Reaction time: 0.75 h

Procedure:
To a solution of 1.31 gm (5.93 mMol) (4(S)-phenyloxazolidin-2-on-3-yl)acetic acid (Evans, U.S. Pat. No. 4,665,171) in 200 mL dichloromethane was added 0.67 mL (7.71 mMol) oxalyl chloride. To this solution was then added 0.5 mL anhydrous dimethylformamide which resulted in vigorous gas evolution. After 45 minutes all gas evolution had ceased and the reaction mixture was concentrated under reduced pressure. The title compound, recovered as an off-white solid, was dried at 0.5 mm Hg for 10 minutes before use in subsequent reactions.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:47])[C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([O:33][CH2:34][CH2:35]Br)=[C:19]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=3)[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[OH:54][C:55]1[CH:64]=[C:63]([OH:65])[CH:62]=[CH:61][C:56]=1[C:57]([O:59][CH3:60])=[O:58]>CC(C)=O>[CH3:60][O:59][C:57](=[O:58])[C:56]1[CH:61]=[CH:62][C:63]([O:65][CH2:35][CH2:34][O:33][C:20]2[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)=[CH:22][C:17]([C:16](=[O:47])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:18][C:19]=2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=2)=[CH:64][C:55]=1[OH:54]
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCBr)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCOc2c(-c3cccc(C(F)(F)F)c3)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1O
Temperature: 25 °C
Yield: 59.2 %

Procedure:
To a solution of N-(8-phenyloctyl)-4-(2-bromo-ethoxy)-3,5-bis(m-trifluoromethylphenyl)benzamide (1.48 g, 2.05 mmol, 1 eq) in acetone (21 mL) was added K2CO3 (1.42 g, 10.25 mmol, 5 eq) and methyl 2,4-dihydroxybenzoate (0.340 g, 2.05 mmol, 1.0 eq). The reaction was heated at reflux for overnight, cooled to rt and concentrated in vacuo. The residue was partitioned between EtOAc and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:hexane) to afford 2-hydroxy-4-{2-[5′-(8-phenyl-octylcarbamoyl)-3,3″-bis-trifluoromethyl-[1,1′:3′,1″]terphenyl-2′-yloxy]-ethoxy}-benzoic acid methyl ester (0.98 g, 60%) as a colorless oil. 1H NMR (CDCl3) δ 10.90 (s, 1H); 7.92–7.78 (m, 7H); 7.66–7.50 (m, 4H); 7.27–7.12 (m, 5H); 6.18–6.10 (m, 3H); 3.92 (s, 3H); 3.66–3.40 (m, 6H); 2.58 (t, 2H); 1.60 (m, 4H); 1.28 (m, 8H).
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[O:3][C:2]1=[O:12])[CH2:9]2.C[C:14](=O)[C:15](=[O:17])C.O=O>C(O)(=O)C>[C:15]([C:6]12[CH2:11][CH:1]3[CH2:9][CH:8]([CH2:10][CH:4]([O:3][C:2]3=[O:12])[CH2:5]1)[CH2:7]2)(=[O:17])[CH3:14]
Reactant: O=C1OC2CC3CC(C2)CC1C3
Reactant: CC(=O)C(C)=O
Agent: O=O
Solvent: CC(=O)O
Product: CC(=O)C12CC3CC(C1)OC(=O)C(C3)C2
Temperature: 80 °C
Reaction time: 4 h

Procedure:
In a flask were placed 3-oxatricyclo[4.3.1.14,8]undecan-2-one (16.6 g, 100 mmol), acetylacetonatocobalt [Co(acac)2] (50 mmol), 2,3-butanedione (600 mmol), and acetic acid (100 g). A condenser and an oxygen balloon were attached to the flask, and the mixture in the flask was vigorously stirred at 80° C. for 4 hours. After the completion of the reaction, the reaction mixture was concentrated, followed by addition of toluene and washing with water. The resulting organic layer was concentrated, the concentrate was subjected to silica gel column chromatography and thereby yielded the title compound 6-acetyl-3-oxatricyclo[4.3.1.14,8]undecan-2-one in a yield of 37%.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+]>CN(C=O)C.C(O)C.C(Cl)Cl>[OH:5][C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=1)=[CH:10][C:11](=[O:12])[CH:13]=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=1
Reactant: O=Cc1ccccc1O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: O=C(C=Cc1ccccc1)C=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of hydroxyl benzaldehyde in DMF was added K2CO3 (2 eq. each hydroxyl group) at 4° C. in an ice-bath and methyl chloromethyl ether (MOM chloride) (1.3 eq. each hydroxyl group). After the solution was stirred at room temperature and monitored by TLC for 3-5 hours, hexanes/dichloromethane (1:1) was added and allowed to stir for 30 min. The solid was filtered out and the filtrate was concentrated. The resulting residue was diluted with EtOAc and washed with H2O twice. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude was purified by a CombiFlash chromatography system using a Grace silica gel column and hexanes/ethyl acetate (as the eluent) to give MOM protected hydroxylbenzaldehyde. The resulting compound further reacted with excess acetone in ethanol catalyzed by 10% NaOH (1.2 eq. of NaOH). After stirred at room temperature and monitored by TLC for 1-5 hours, the reaction mixture was diluted with CH2Cl2, washed with H2O twice, and extracted with CH2Cl2 twice. The MOM protected hydroxy-phenyl-but-3-en-2-one was obtained after purification by a ConmbiFlash system using hexanes/ethyl acetate as the eluent. The resulting compound reacted with an appropriate MOM protected hydroxybenaldehyde to afford MOM protected hydroxyl 1,5-diphenyl-penta-1,4-dien-3-one, which was deprotected by heating in 50% acetic acid aqueous solution to afford the desired product.