Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:18]=[C:19]([CH:21]=[C:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:20]=2)[O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=2)[CH2:3][CH2:2]1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35](=[O:43])OC2C=CC=CC=2)C=1.C([N:46](CC)CC)C>CS(C)=O.O>[CH:1]1([C:4]2[CH:20]=[C:19]([CH:18]=[C:6]([O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][N:9]=3)[CH:5]=2)[CH:21]=[C:22]2[CH2:23][CH2:24][N:25]([C:35]([NH:34][C:30]3[N:46]=[N:28][CH:33]=[CH:32][CH:31]=3)=[O:43])[CH2:26][CH2:27]2)[CH2:2][CH2:3]1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: CCN(CC)CC
Reactant: FC(F)(F)c1ccc(Oc2cc(C=C3CCNCC3)cc(C3CC3)c2)nc1
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cc(Oc3ccc(C(F)(F)F)cn3)cc(C3CC3)c2)CC1
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a solution of 2-(3-cyclopropyl-5-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine (0.15 g, 0.401 mmol) and phenyl pyridin-3-ylcarbamate (85.8 mg, 0.4 mmol) in DMSO (1.5 mL) was added triethylamine (0.55 mL, 4.0 mmol) and the mixture was stirred overnight. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4, and evaporated to dryness. The residue was purified by silica gel column chromatography (38% acetone in hexane) to give the title compound (0.13 g, 66%). 1H NMR (500 MHz, CDCl3): δ 8.77 (s, 1H), 8.45 (s, 1H), 8.41 (s, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.47 (t, J=4.5 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.81 (s, 1H), 6.77 (s, 1H), 6.70 (s, 1H), 6.38 (s, 1H), 3.70 (m, 2H), 3.60 (m, 2H), 2.60 (m, 2H), 2.47 (d, 2H), 1.87 (m, 1H), 0.98 (d, J=8 Hz, 2H), 0.70 (d, J=4.5 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 165.83, 156.60, 153.17, 146.31, 145.54, 138.65, 137.71, 136.70, 128.20, 124.83, 123.63, 118.77, 116.75, 111.30, 45.64, 44.62, 35.73, 29.21, 15.44, 9.51; m/z (496.2, M+ H+); HPLC: 98.6%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:37])[C:20]4[C:21]([O:29][C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:22]3[C:26](=[CH:27][CH:28]=4)[NH:25][N:24]=[CH:23]3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:41]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19](=[O:37])[C:20]4[C:21]([O:29][C:30]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:22]3[C:26](=[CH:27][CH:28]=4)[N:25]([CH3:41])[N:24]=[CH:23]3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]ncc54)c3=O)cc2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2c3oc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(=O)c3ccc21
Reaction time: 0.08 h
Yield: 60.5 %

Procedure:
To a solution of {1-[4-(4-oxo-2-phenyl-4,7-dihydro-pyrano[2,3-e]indazol-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (65 mg, 0.13 mmol) in DMF (3 mL) at 0° C. under an atmosphere of N2 was added sodium hydride (60% in mineral oil, 6 mg, 0.15 mmol). After 5 min, methyl iodide (10 μL, 0.16 mmol) was added and the mixture stirred for a further 2 hours. The reaction was quenched with H2O, partitioned between EtOAc and H2O and the phases separated. The organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 50 to 70% ethyl acetate in cyclohexane) to afford the title compound as an oil (41 mg, 60%). LCMS (Method B): RT=4.42 min, [M+H]+=522. Also obtained was {1-[4-(8-Methyl-4-oxo-2-phenyl-4,8-dihydro-pyrano[2,3-e]indazol-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester as a white solid (22 mg, 32%). LCMS (Method B): RT=4.26 min, [M+H]+=522.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21]([OH:23])=O)[CH:20]=1)[N:17]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:16]=[CH:15]2)=[O:10].CN(C(O[N:42]1N=N[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(N)CCCCC1>CN(C=O)C>[CH:43]1([NH:42][C:21]([C:19]2[CH:20]=[C:12]([NH:11][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:33])[F:32])=[O:10])[CH:13]=[C:14]3[C:18]=2[N:17]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[N:16]=[CH:15]3)=[O:23])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: C[Si](C)(C)CCOCn1ncc2cc(NC(=O)c3ccccc3C(F)(F)F)cc(C(=O)O)c21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: NC1CCCCC1
Product: C[Si](C)(C)CCOCn1ncc2cc(NC(=O)c3ccccc3C(F)(F)F)cc(C(=O)NC3CCCCC3)c21
Temperature: 25 °C
Yield: 105.1 %

Procedure:
To a solution of 5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-7-carboxylic acid (obtained in Step 5) (48 mg) in DMF (2 mL) were added HBTU (46 mg) and triethylamine (17 μL), and the mixture was stirred at room temperature, cyclohexylamine (12.5 μL) was added, and it was stirred at the same temperature overnight. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was triturated in n-hexane/ethyl acetate (10:1), and collected by filtration to obtain 59 mg of N-cyclohexyl-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1-[2-(trimethylsilyl)ethoxymethyl]-indazole-7-carboxamide as colorless powder. This was dissolved in MeOH (2 mL), 6N hydrochloric acid (2 mL) was added, and the solution was stirred on oil bath at 60-80° C. for 10 hours. The solvent was removed, and ice water was added to the residue. The precipitate was collected by filtration and dried to obtain the titled compound (33 mg) as colorless powder.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22].[O:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28](O)=[O:29].O>ClCCl.CN(C)C1C=CN=CC=1>[O:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][Cl:13])=[O:29]
Reactant: OCCCCCCCCCl
Reactant: O=C(O)C1CCCO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(OCCCCCCCCCl)C1CCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (5.7 g) in dichloromethane (100 ml) was slowly added to a solution of 8-chloro-1-octanol (4.1 g), tetrahydro-2-furancarboxylic acid (3.5 g) and 4-dimethylaminopyridine (1.5 g) in dichloromethane (50 ml) at 0° C. The mixture was stirred overnight at room temperature. The resulting solution was then added to water (500 ml) and extracted with dichloromethane (3×200 ml). The combined organic layers were washed with water (2×200 ml), dried over magnesium sulphate and filtered. The solvent removed in vacuum. The residue (7 g) was purified by column flash chromatography on silica gel using toluene/ethyl acetate (90:10) as eluent to give 8-chlorooctyl tetrahydro-2-furancarboxylate.
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[O:12][N:11]=2)[CH:5]=1.[C:24]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH3:25].[Li]>>[C:28]([O:27][C:24](=[O:26])[CH2:25][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[O:12][N:11]=2)[CH:5]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1

Procedure:
The title compound was prepared from (RS)-3-[5-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-benzoic acid methyl ester [prepared from (Z)-3-(hydroxyimino-methyl)-benzoic acid methyl ester [CAS-No. 91186-80-0] by treatment with NCS, cat. amount pyridine in CHCl3 followed by addition of (RS)-tetrahydro-2-(2-propynyloxy)-2H-pyran and slow addition of Et3N in CHCl3 at 23°C.] by treatment with lithium tert.-butyl acetate according to general procedure K (method b). Obtained as a yellow oil (3.00 g).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20][C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)[CH2:12][CH2:11]1)(=O)C.[OH-].[Na+]>C(O)C>[CH:24]1[CH:25]=[CH:26][C:21]2[S:20][C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=[C:16]([N:13]3[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][O:7][CH2:6][CH2:5][OH:4])[CH2:11][CH2:12]3)[C:22]=2[CH:23]=1
Reactant: CC(=O)OCCOCCN1CCN(C2=Nc3ccccc3Sc3ccccc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCCOCCN1CCN(C2=Nc3ccccc3Sc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
The residue of 11-(4-[2-(2-acetyloxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f]-1,4-thiazepine (7.8 g) was dissolved in ethanol (50 ml) and 1M NaOH solution (55 ml) was added. The mixture was stirred at room temperature for 30 min. The product was extracted into toluene (2×100 ml). Evaporation of the toluene phase gave quetiapine base (6.9 g).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.O1CCCC1.[Pt]=O>[CH:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc2cc(-c3ccccc3)oc12
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc2cc(C3CCCCC3)oc12
Yield: 60.1 %

Procedure:
2.5 g of 2-phenylbenzofuran-7-carboxylic acid is dissolved in a mixture of 80 ml of methanol and 16 ml of tetrahydrofuran and 0.5 g of platinum oxide is added to the solution. The mixture is subjected to catalytic hydrogenation under atmospheric pressure. The reaction mixture is filtered and the filtrate is evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=20:1) to give 1.54 g of 2-cyclohexylbenzofuran-7-carboxylic acid as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:27])[CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.Cl>C(O)C.[Fe]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:27])[CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc([N+](=O)[O-])c(OC)c2)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(N)c(OC)c2)cc1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a solution of methyl 4-(3′-methoxy-4′-nitro-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (670 mg, 1.80 mmol) in 85% aqueous ethanol (27 mL) was added iron powder (1.01 g, 18.04 mmol) and 2 N aqueous HCl (0.9 mL, 1.8 mmol), and the resulting suspension was heated at reflux for 2.5 h. The mixture was then cooled to rt, and filtered through a pad of Celite®. Water was added, the mixture was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure and the residue was triturated with ethyl acetate/hexane to afford methyl 4-(4′-amino-3′-methoxy-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (410 mg, 67%). LC-MS ret. time 2.58 min, m/z 342.1 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.31 (s, 6H), 3.28 (s, 2H), 3.66 (s, 3H), 3.90 (s, 3H), 6.75 (d, 1H), 7.02-7.09 (m, 2H), 7.59 (d, 2H), 7.94 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.Br[CH2:30][CH2:31][F:32].N>>[F:32][CH2:31][CH2:30][N:23]1[CH2:22][CH2:21][C@@H:20]2[N:15]3[C:16]4[C:11](=[CH:10][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=5[C:25]([F:28])([F:26])[F:27])=[CH:18][C:17]=4[C@@H:19]2[CH2:24]1)[CH2:12][CH2:13][CH2:14]3
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Reactant: FCCBr
Agent: N
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(CCF)CC[C@@H]2N4CCC3)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (32 mg, 96%) from (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) and 1-bromo-2-fluoroethane (30 mg, 0.23 mmol). MS (CI, NH3): 435.1 (base, M+H).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH2:19])[C@H:5]2[S:4]1.C(N(CC)CC)C.CN(C)C1C=CC=CC=1.[C:37]1([CH2:43][C:44](Cl)=[S:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:14])[Cl:15])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH:19][C:44](=[S:45])[CH2:43][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:5]2[S:4]1
Reactant: S=C(Cl)Cc1ccccc1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=S)Cc3ccccc3)[C@H]2S1
Temperature: -15 °C
Yield: 90.2 %

Procedure:
2,2,2-Trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (3.0 g) was suspended in dried dichloromethane (50 ml) and then dissolved by adding triethylamine (0.72 g) and dimethylaniline (1.9 g) under cooling at -15° C. To a mixture was dropwise added a solution of phenylthioacetyl chloride (2.2 g) in dried dichloromethane (10 ml) under stirring, and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, the reaction mixture was in turn washed with 5% hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water and then dried. After the solvent was distilled off, ether was added to the residue, after which the precipitated crystals were collected by filtration and dried to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylate (3.4 g), mp 140° to 142° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:10]([C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(O)c1
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(Oc2ccccc2C=O)c1
Yield: 56.5 %

Procedure:
2-Fluorobenzaldehyde (1.0 mg, 8.1 mmol) was dissolved in DMF (20 mL), 3-isopropylphenol (1.1 g, 8.9 mmol) and potassium carbonate (1.1 g, 8.1 mmol) were added thereto, and then microwave was irradiated at 180° C. for 5 minutes. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 70:30) to give the title compound (1.1 g, yield 57%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4](C)[CH:3]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:18][CH:17]=1.[Na]>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][CH:3]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:18][CH:17]=1
Reactant: CN1C(=O)c2ccccc2N(C)C1COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: [Na]
Product: CN1c2ccccc2C(=O)NC1COc1ccc(CC2SC(=O)NC2=O)cc1

Procedure:
5-[4-[[1,3-Dimethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidin-2,4-dione, sodium salt;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH:6]=[CH:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9].Br[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=1>>[C:29]([CH2:28][C:25]1[CH:26]=[CH:27][C:22](/[C:6](/[C:5]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:7]/[C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[O:9])=[CH:23][CH:24]=1)([OH:31])=[O:30]
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: COc1ccc(C=CC(=O)N2CCOCC2)cc1OC
Product: COc1ccc(/C(=C\C(=O)N2CCOCC2)c2ccc(CC(=O)O)cc2)cc1OC

Procedure:
This compound was obtained in analogy to the preceding Examples in the form of crystals, m.p. 192°-194° C., from 3,4dimethoxycinnamic acid morpholide and (4-bromophenyl)-acetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:20])[CH2:16][C:17]([OH:19])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[F:31][C:32]1[CH:33]=[C:34]([NH2:54])[CH:35]=[CH:36][C:37]=1[O:38][C:39]1[CH:44]=[CH:43][N:42]=[C:41]2[CH:45]=[C:46]([C:48]3[N:49]([CH3:53])[CH:50]=[CH:51][N:52]=3)[S:47][C:40]=12.C(Cl)CCl>>[F:31][C:32]1[CH:33]=[C:34]([NH:54][C:17](=[O:19])[CH2:16][C:15]([NH:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:20])[CH:35]=[CH:36][C:37]=1[O:38][C:39]1[CH:44]=[CH:43][N:42]=[C:41]2[CH:45]=[C:46]([C:48]3[N:49]([CH3:53])[CH:50]=[CH:51][N:52]=3)[S:47][C:40]=12
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)CC(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.4 %

Procedure:
To a solution of acid 42 (76 mg, 0.266 mmol) and HOBt (40 mg, 0.30 mmol) was added amine 9 (100 mg, 0.29 mmol) and the mixture was stirred at room temperature for 5 min. EDC (62 mg, 0.32 mmol) was added and combined mixture was stirred for additional 48 hours. Additional 42 (38 mg, 0.133 mmol) and EDC (31 mg, 0.16 mmol) were added and the reaction mixture was stiffed for a further 24 hours. Again additional 42 (38 mg, 0.133 mmol) and EDC (31 mg, 0.16 mmol) were added and the reaction mixture was stirred for 24 hours more then partitioned between EtOAc and NaHCO3 solution. The organic phase was washed with brine, dried over anhydrous Na2SO4 then filtered and concentrated. The residue was purified by preparative HPLC to afford tert-butyl 4-(3-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylamino)-3-oxopropanamido)piperidine-1-carboxylate 42a (20 mg, 13% yield) as a white solid. This material was dissolved in a solution of TFA/DCM (1 mL/2 mL), stirred for 20 min and concentrated. The residue was purified by preparative HPLC (column Aquasil C-18, gradient, MeOH 60% to MeOH 95% in water) to afford the title compound 43 as a tris-trifluoroacetate salt (31 mg, 99%), white solid. NMR (DMSO-d6) δ (ppm): 10.49 (s, 1H), 8.55 (d, 1H), 8.49 (bs, 1H), 8.27 (d, 1H), 8.00 (s, 1H), 7.86 (dd, 1H), 7.55 (s, 1H), 7.49 (t, 1H), 7.39 (dd, 2H), 7.26 (s, 1H), 6.74 (d, 2H), 4.00 (s, 2H), 3.83 (m, 1H), 3.24 (m, 2H), 3.00 (m, 2H), 1.92 (m, 2H), 1.56 (m, 2H). MS (m/z): 509.1 (M+H).
Reaction SMILES: BrC1C=CC(OC[C@H]2CC[C@H](OC3CCCCO3)CC2)=CC=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.[CH3:41][C:42]1([CH3:70])[C:46]([CH3:48])([CH3:47])[O:45][B:44]([C:49]2[CH:69]=[CH:68][C:52]([O:53][CH2:54][C@@H:55]3[CH2:60][CH2:59][C@H:58]([O:61][CH:62]4[CH2:67][CH2:66][CH2:65][CH2:64][O:63]4)[CH2:57][CH2:56]3)=[CH:51][CH:50]=2)[O:43]1>>[CH3:47][C:46]1([CH3:48])[C:42]([CH3:41])([CH3:70])[O:43][B:44]([C:49]2[CH:50]=[CH:51][C:52]([O:53][CH2:54][C@H:55]3[CH2:56][CH2:57][C@H:58]([O:61][CH:62]4[CH2:67][CH2:66][CH2:65][CH2:64][O:63]4)[CH2:59][CH2:60]3)=[CH:68][CH:69]=2)[O:45]1
Reactant: CC1(C)OB(c2ccc(OC[C@H]3CC[C@@H](OC4CCCCO4)CC3)cc2)OC1(C)C
Agent: Brc1ccc(OC[C@H]2CC[C@H](OC3CCCCO3)CC2)cc1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC1(C)OB(c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)OC1(C)C

Procedure:
The title compound (624 mg, 61.5 mmol) was prepared from (+/−)-2-({trans-4-[(4-bromophenoxy)methyl]cyclohexyl}oxy)tetrahydro-2H-pyran (900 mg, 2.44 mmol) and bis(pinacolato)diborane (742 mg, 2.92 mmol) by a procedure analogous to that described for (+/−)-2-[(cis-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclohexyl)oxy]tetrahydro-2H-pyran, Example 8, Step D. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.03-1.63 (m, 20H) 1.65-1.90 (m, 3H) 1.90-2.01 (m, 2H) 2.03-2.15 (m, 2H) 3.45-3.55 (m, 1H) 3.55-3.67 (m, 1H) 3.72-3.85 (m, 2H) 3.89-3.97 (m, 1H) 4.70-4.79 (m, 1H) 6.88 (d, J=8.78 Hz, 2H) 7.74 (d, J=8.78 Hz, 2H)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([OH:29])[CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH2:21]C)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([O:29][S:45]([C:42]1[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=1)(=[O:47])=[O:46])[CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(c1ccccc1)C(O)CCCCNC(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: COC(=O)C(c1ccccc1)C(CCCCNC(=O)OCc1ccccc1)OS(=O)(=O)c1ccc(C)cc1
Yield: 61.8 %

Procedure:
The same procedures as in Example 30 were performed except that 27.2 g (70.4 mmol) of methyl 7-(N-benzyloxycarbonylamino)-3-hydroxy-2-phenylheptanoate obtained in Example 9 was dissolved in 136 ml of pyridine; 1.27 g (10.39 mmol) of dimethylaminopyridine was added; and 20.1 g (105.6 mmol) of p-toluenesulfonyl chloride was added; to prepare the target compound as a pale yellow oil in an amount 23.5 g at a yield of 61.8%. The analytical results on the target compound are given below.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[H-].[Na+].FC(F)(F)S(O[CH2:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2)(=O)=O.O>CS(C)=O>[C:19]12([CH2:18][O:1][C:2]3[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=3)[CH:5]=[O:6])[CH2:20][CH:21]3[CH2:27][CH:25]([CH2:24][CH:23]([CH2:22]3)[CH2:28]1)[CH2:26]2
Reactant: O=S(=O)(OCC12CC3CC(CC(C3)C1)C2)C(F)(F)F
Reactant: O=Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cccc(OCC23CC4CC(CC(C4)C2)C3)c1
Reaction time: 0.17 h
Yield: 41.3 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (0.54 g, 4.42 mmol) in dimethyl sulfoxide (5 mL) was added sodium hydride (60%, 0.186 g) in portions. The mixture was stirred for 10 minutes and then was added a solution of Intermediate 34 (1.32 g, 4.42 mmol) in dimethyl sulfoxide (2 mL). The reaction mixture was stirred at 70° C. for 48 hours and the mixture was poured into water and extracted with ether. The organic layer was washed with a solution of sodium hydroxide 2N, water and brine. The solvent was removed under reduced pressure and the crude was purified by column chromatography with silica gel, eluting by hexane/ethyl acetate (10:1) to give the title compound as an oil (0.493 g, 41%).