Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-:4])C.[K+].[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)[CH3:8].[H][H]>C(O)C>[CH:13]1[CH:12]=[CH:11][C:10]([CH2:7][CH2:8][OH:4])=[CH:15][CH:14]=1
Reactant: CC(=O)c1ccccc1
Reactant: [H][H]
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: OCCc1ccccc1
Temperature: 40 °C
Reaction time: 19 h
Yield: 100 %

Procedure:
In an autoclave, 1.32 mg of RuBr2[(S,S)-xylskewphos] (3,5-Me2pica) (1.29×10−3 mmol, S/C=10000) and 5.79 mg of potassium tert-butoxide (5.16×10−2 mmol) are placed, and replaced with argon gas. Under argon gas flow, 1.5 mL of acetophenone (12.9 mmol) and 2.9 mL of ethanol was added while measuring by a syringe, pressurized with hydrogen to 10 atm, stirred at 40° C. for 19 hours, then the reduction of the hydrogen pressure was confirmed and phenylethanol was obtained at 100% yield. The optical purity was 88.0% ee as measured by GC (CP-Chirasil-DEX CB (0.25 mml. D×25 m, DF=0.25 μm, from VARIAN), constant at 110° C., pressure: 102.0 kPa, column flow: 1.18 mL/min, vaporizing chamber temperature: 250° C., detector temperature: 275° C., the retention time of each enantiomer was: (R): 11.7 min, (S): 12.4 min), and (S) isomer has predominantly been generated.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30]CC3C=CC=CC=3)=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>CCO.C1COCC1.[Pd]>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]2[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCN(c1ccc(NC(C)=O)cc1)C2Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(c1)CCN(c1ccc(NC(C)=O)cc1)C2Cc1ccc(O)cc1
Yield: 95.3 %

Procedure:
A solution of 2-(4-acetamidophenyl)-6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.190 g, 0.386 mmol) in 2 mL of EtOH/THF (1:1) was debenzylated with 10% Pd/C under an H2 atmosphere as described in Example 30.F to provide the title compound (0.148 g, 95% yield): ES-MS (m/z) 403 [M+H]+.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([OH:29])=O)[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][N:60]([C:63](=[O:70])[C@@H:64]([NH2:69])[CH2:65][O:66][CH2:67][CH3:68])[CH2:59][CH2:58]1)=[O:56])[CH2:51][CH2:52][CH3:53]>CN(C=O)C.C(Cl)CCl>[CH2:50]([O:54][C:55]([N:57]1[CH2:58][CH2:59][N:60]([C:63](=[O:70])[C@@H:64]([NH:69][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:29])[CH2:65][O:66][CH2:67][CH3:68])[CH2:61][CH2:62]1)=[O:56])[CH2:51][CH2:52][CH3:53]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)COCC)CC1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](COCC)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 75 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 5 ml DMF were added 37 mg HOAt, 53 mg EDC, 0.13 ml DIPEA and 55 mg 4-((S)-2-Amino-3-ethoxy-propionyl)-piperazine-1-carboxylic acid butyl ester. After stirring for 12 h it was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 86 mg MS (ES+): m/e=696.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[NH2:9][C:3]1[C:2]([F:1])=[CH:7][N:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5](=[O:8])[N:4]=1
Reactant: Nc1nc(=O)[nH]cc1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cn1cc(F)c(N)nc1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
5-Fluorocytosine (500 mg) and potassium carbonate (803 mg) were suspended in N,N-dimethylfoiliamide (5 mL) and ethyl bromoacetate (430 μl) was added to the suspension. The mixture was stirred at 100° C. overnight. The resulting precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=99:1 to 92:9) to give 329 mg (39% yield) of the desired product as a white amorphous.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH:12]([CH3:34])[CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[N:35]1[CH:40]=[CH:39][C:38]([CH:41]=O)=[CH:37][CH:36]=1.[H-].[Na+]>CS(C)=O.O1CCCC1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH:12]([CH3:34])[CH2:13][CH:14]=[CH:41][C:38]1[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=1
Reactant: COc1ccc(OC)c(C(C)CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=Cc1ccncc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1ccc(OC)c(C(C)CC=Cc2ccncc2)c1
Reaction time: 1 h

Procedure:
A mixture of 3-(2,5-dimethoxyphenyl)butyl triphenylphosphonium bromide (19.0 g., 35.4 mmoles) in dimethylsulfoxide (50 ml.) is added to 4-pyridinecarboxaldehyde (3.79 g., 35.4 mmoles) in tetrahydrofuran (40 ml.). The resulting mixture is then added dropwise to a slurry of 50% sodium hydride (1.87 g., 39 mmoles) in tetrahydrofuran (20 ml.) under a nitrogen atmosphere at 0°-5° C. Following completion of addition, the mixture is stirred for one hour at 0°-5° and then concentrated under reduced pressure. The concentrate is diluted with water (200 ml.) and then acidified with 6 N HCl. The aqueous acid solution is extracted with benzene (4×50 ml.). It is then made basic and extracted with ethyl acetate (3×50 ml.). Evaporation of the combined extracts after drying (MgSO4) affords 4-(2,5-dimethoxyphenyl)-1-(4-pyridyl)-1-pentene.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][C@@H:31]1[CH2:35][OH:36]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][C@@H:31]4[CH2:35][OH:36])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: OC[C@H]1CCCN1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: OC[C@H]1CCCN1CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 37 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and (R)-2-pyrrolidinemethanol to give the title compound in 37% yield; NMR Spectrum: 1.49-1.53 (m, 1H), 1.60-1.66 (m, 2H), 1.77-1.82 (m, 1H), 2.33-2.36 (m, 1H), 2.58 (br s, 1H), 2.77-2.79 (m, 1H), 3.13-3.15 (m, 1H), 3.26-3.29 (m, 2H), 3.37-3.41 (m, 1H), 4.39 (t, 2H), 4.44 (br s, 1H), 5.28 (s, 2H), 7.24 (d, 1H), 7.36 (t, 1H), 7.56 (s, 1H), 7.58 (s, 1H), 7.87 (t, 1H), 7.93 (d, 1H), 8.29 (s, 1H), 8.40 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 496 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[SH:12][CH:13](O)C.[C:16]([O-:19])([O-])=O.[K+].[K+]>CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([S:12][CH2:13][CH2:16][OH:19])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: CC(O)S
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCSc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
4-Chlorobenzotrifluoride (31.36 ml, 235.26 mmol) was dissolved in anhydrous DMF (200 ml), and mercaptoethanol (15.00 ml, 213.87 mmol) and K2CO3 (38.43 g, 278.06 mmol) were added thereto. The mixture was stirred for 30 minutes at room temperature and then refluxed. After 15 hours have passed, the reaction mixture was cooled to room temperature and the reaction was stopped by adding distilled water. The reaction mixture was extracted with diethyl ether, and the organic layer was washed with aqueous NH4Cl solution, dried over anhydrous MgSO4, and concentrated. The reaction solution thus concentrated was purified by silica gel column chromatography (EA/n-hexane=1/3, v/v) to give 2-(4-trifluoromethyl-phenylsulfanyl)-ethanol (32.11 g, 67.56%) of a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cc(F)cc(-c4ccccc4-c4ccccc4)c3O2)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cc(F)cc(-c4ccccc4-c4ccccc4)c3O2)cc1
Yield: 95.4 %

Procedure:
Treatment of ((2R)-8-(biphenyl-2-yl)-6-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (1.36 g, 2.79 mmol) with platinum (IV) oxide (84% Pt, 0.35 g) in ethanol (40 mL) and ethyl acetate (10 mL) according to the procedure described for Example 69, Step 8 provided 1.30 g (96%) of ((2R)-8-(biphenyl-2-yl)-6-fluorochroman-2-yl)methyl 4-methylbenzenesulfonate as an off-white solid. MS (ESI) m/z 489.2 ([M+H]+); m/z 506.2 ([M+NH4]+).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:38].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:38])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:29]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(CCc3ccccc3)cc2)C(=O)O1
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(CCc2ccccc2)cc1)C(=O)O
Reaction time: 3 h

Procedure:
5.15 g (10.31 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-{[p-(2-phenylethyl)phenyl]methyl}dihydrofuran-2-(3H)-one in 166 ml of dimethoxyethane and 85 ml of water are hydrolysed, under protective gas, with 41 ml of a 1M lithium hydroxide solution. After 3 h, the dimethoxyethane is evaporated off on an RE, and the residue is treated with an ice-cold mixture of 506 ml of sat. NH4Cl solution, 42 ml of 10% citric acid solution and 207 ml of methylene chloride. Methanol is added to dissolve the product completely. The aqueous phase is separated off and extracted 2× with methylene chloride/methanol, 10:1. The organic phases are washed with saline, dried with Na2SO4 and evaporated: tRet (II)=17.8 min.
Reaction SMILES: O1CCCCC1OC1C=C(C23CCC(CCCCC#[N:27])(CC2)CO3)C=CC=1.[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[O:34][C:35]1[CH:36]=[C:37]([C:41]23[CH2:48][CH2:47][C:44]([CH2:49][CH2:50][CH2:51]CO)([CH2:45][CH2:46]2)[CH2:43][O:42]3)[CH:38]=[CH:39][CH:40]=1.O1CCCCC1OC1C=C(C23CCC(CCO)(CC2)CO3)C=CC=1>>[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[O:34][C:35]1[CH:36]=[C:37]([C:41]23[CH2:48][CH2:47][C:44]([CH2:49][CH2:50][C:51]#[N:27])([CH2:45][CH2:46]2)[CH2:43][O:42]3)[CH:38]=[CH:39][CH:40]=1
Reactant: OCCCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Reactant: N#CCCCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Agent: OCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Product: N#CCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2

Procedure:
3-(1-(3-(Tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)propanenitrile was prepared using a procedure analogous to 5-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)pentanenitrile except that 4-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)butan-1-ol was replaced with 2-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethanol. The title compound was obtained (490 mg, 1.435 mmol, 87% yield) as a white solid. LCMS, [M+NH4]+=359.2. 1H NMR (500 MHz, CDCl3) δ 7.24 (t, J=8.0 Hz, 1H), 7.14-7.10 (m, 1H), 7.03-6.99 (m, 1H), 6.96 (ddd, J=8.2, 2.5, 0.8 Hz, 1H), 5.45 (t, J=3.2 Hz, 1H), 3.94 (ddd, J=11.3, 9.7, 3.2 Hz, 1H), 3.85 (s, 2H), 3.62 (m, 1H), 2.36-2.30 (m, 2H), 2.11-1.98 (m, 5H), 1.90-1.84 (m, 2H), 1.77-1.59 (m, 9H).
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(O)CC(C)C>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[N:4]=2)[CH2:24][CH2:23]1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Reactant: COc1ccccc1N1CCNCC1
Solvent: CC(C)CCO
Product: COc1ccccc1N1CCN(c2nc3c(c(=O)[nH]2)CCCC3)CC1

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol) and 1-(2-methoxyphenyl)piperazine (98 mg; 0.51 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 (reaction time 4 h) and worked up; yield: 52 mg (30%), crystals;
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([OH:18])=O)[CH:8]=2)[CH:3]=1.S(Cl)(Cl)=O.CN(C)[CH:25]=[O:26]>O1CCCC1>[OH:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([O:26][CH2:25][CH2:10][CH2:11][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:18])[CH:8]=2)[CH:3]=1
Reactant: COC(=O)c1cc2cc(C(=O)O)ccc2cc1O
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCOC(=O)c1ccc2cc(O)c(C(=O)O)cc2c1
Temperature: 50 °C

Procedure:
In 10.0 g of tetrahyrofuran, 1.00 g of 2-hydroxy-6-hydroxycarbonyl-3-methoxycarbonylnaphthalene is suspended. To this, 0.94 g of thionyl chloride and a small amount of N,N-dimethylformamide are added, and heated to 50° C. After allowing to proceed the reaction for about 3 hours, the solvent and other volatile are evaporated. To the residue, a solution of 1.27 g of n-decanol dissolved in 10.0 g of tetrahydrofuran is added, and reacted for about 20 hours under reflux. After evaporating the solvent, 15.0 g of N,N-dimethylformamide, 15.0 g of methanol, and 180.0 g of 5% aqueous sodium hydrogencarbonate are added, and reacted for 20 hours at 60° C. After removing insoluble matter, the pH of the reaction mixture is adjusted to pH 2 at 50° C., and the precipitate is recovered by filtration. The product was washed with warm water and methanol, and dried to yield 1.33 g of 2-hydroxy-3-hydroxycarbonyl-6-decyloxycarbonylnaphthalene as a white-yellow powder (melting/decomposing point: 269.2° C. (dec.)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:33][C:34]([CH3:39])([CH3:38])[C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:32][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:35](=[O:36])[C:34]([F:33])([CH3:39])[CH3:38])[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1([C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[O:23])[CH2:21][CH2:20]1)=[O:18]
Reactant: CC(C)(F)C(=O)O
Reactant: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(F)C(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (250 mg, 0.565 mmol) and 2-fluoro-2-methylpropanoic acid (108 mg, 1.02 mmol) in anhydrous CH2Cl2 (30 mL) was added HATU (323 mg, 0.85 mmol) and DIPEA (2.5 mL) under N2. This reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was poured into water (100 mL), extracted with ethyl acetate (3×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. This crude product was purified by silica gel chromatography to give N-(2,5-difluoro-4-((2-(2-fluoro-2-methylpropanamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (128 mg, 43% yield). 1H-NMR (400 MHz, Methanol-d4): δ 8.21-8.17 (m, 2H), 7.73 (d, J=2.4 Hz, 1H), 7.54-7.51 (m, 2H), 7.23 (dd, J=10.8, 7.2 Hz, 1H), 7.08-7.04 (m, 2H), 6.75 (dd, J=5.6, 2.4 Hz, 1H), 1.76-1.69 (m, 4H), 1.62 (s, 3H), 1.56 (s, 3H); MS (ESI): m/z 531.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](O)=[CH:7][N:6]=1)=[O:4].P(Br)(Br)([Br:14])=O>CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Br:14])=[CH:7][N:6]=1)=[O:4]
Reactant: O=P(Br)(Br)Br
Reactant: COC(=O)c1cnc(O)cn1
Solvent: CO
Product: COC(=O)c1cnc(Br)cn1

Procedure:
A solution of 5-hydroxy-pyrazine-2-carboxylic acid methyl ester (2.56 g, 16.61 mmol) in phosphorous oxybromide 9.9 g, 34.9 mmol) were heated at 90° C. for 70 mins. The reaction was allowed to cool and the resulting solid carefully dissolved in methanol and then the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and sat. NaHCO3 and the organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc:Hexanes 40:60) to afford the title compound.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[OH:20].FC(F)(F)[C:23](O)=[O:24]>>[F:11][C:12]1[C:13]([OH:20])=[C:14]([O:18][CH3:19])[CH:15]=[CH:16][C:17]=1[CH:23]=[O:24]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cccc(F)c1O
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1ccc(C=O)c(F)c1O
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a heated solution (80° C.) of hexamethylenetetramine (2.8 g, 20 mmol) in trifluoroacetic acid (10 mL) was added dropwise over a 50 minutes period 2-fluoro-6-methoxyphenol (1.42 g, 10 mmol) in trifluoroacetic acid (10 mL). The mixture was heated for an additional 1 hour, concentrated and water (50 ml) was added. The solution was stirred for 10 minutes and solid potassium carbonate was added until the solution was neutral. The solid that formed was collected to afford 1.1 g of 2-fluoro-3-hydroxy-4-methoxybenzaldehyde (65%). 1H NMR (500 MHz; DMSO-d6): δ 3.90 (s, 3 H); 6.98 (d, J=8.5 Hz, 1H); 7.31 (t, J=8.5 Hz, 1 H); 9.66 (br, 1 H); 10.02 (s, 1 H).
Reaction SMILES: [OH2:1].[OH:2][C@H:3]1[CH2:12][C@H:11]([O:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]2[C:5]([CH:6]=[CH:7][C@H:8]([CH3:31])[C@@H:9]2[CH2:21][CH2:22][C@H:23]2[O:28][C:27](=[O:29])[CH2:26][C@H:25]([OH:30])[CH2:24]2)=[CH:4]1.[OH-].[Na+:33]>O1CCOCC1>[OH:30][C@H:25]([CH2:24][C@H:23]([OH:1])[CH2:22][CH2:21][C@@H:9]1[C@@H:10]2[C:5](=[CH:4][C@@H:3]([OH:2])[CH2:12][C@@H:11]2[O:13][C:14](=[O:20])[CH2:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH:6]=[CH:7][C@@H:8]1[CH3:31])[CH2:26][C:27]([O-:28])=[O:29].[Na+:33]
Reactant: C[C@H]1C=CC2=C[C@@H](O)C[C@H](OC(=O)CC(C)(C)C)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O)CC(=O)O1
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@H]1C=CC2=C[C@@H](O)C[C@H](OC(=O)CC(C)(C)C)[C@@H]2[C@H]1CC[C@@H](O)C[C@@H](O)CC(=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.5 ml of water was added to a solution of 32 mg (0.076 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-hydroxy-8-(3,3-dimethylbutyryloxy)-2-methyl-1-naphthyl]ethyl}tetrahydro-4-hydroxy-2H-pyran-2-one [prepared as described in Example 28, above], in 1 ml of dioxane, after which 0.8 ml (0.08 mmol) of a 0.1N aqueous solution of sodium hydroxide was added to the mixture. The resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was lyophilized to give 35 mg of the title compound as a colorless powder.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4]1.S(Cl)([Cl:12])=O.[CH3:14]O>>[ClH:12].[CH3:14][O:8][C:7]([C:3]1([NH2:2])[CH2:6][CH2:5][CH2:4]1)=[O:9]
Reactant: NC1(C(=O)O)CCC1
Reactant: O=S(Cl)Cl
Reactant: CO
Agent: Cl
Product: COC(=O)C1(N)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
1-aminocyclobutanecarboxylic acid hydrochloride (5.2 g, 34.5 mmol) and methanol (120 ml) were charged. An ice bath was set, and thionyl chloride (3.7 ml, 51.7 mmol) was slowly added thereto. Then, the ice bath was removed, and the mixture was stirred at room temperature for 3 hours. The resultant product was vacuum-distilled to remove a solvent, and dried in a 60° C. oven so as to obtain methyl-1-aminocyclobutanecarboxylate hydrochloride (5.62 g, 37.1 mmol, 98%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[C:14](=[O:15])[N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=CC=3)[N:12]=[CH:11]2)[S:5][C:6]=1[C:7]([OH:9])=O.S1C(C(O)=[O:33])=CN=C1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][NH2:42])[CH:36]=1>>[CH3:1][C:2]1[N:3]=[C:4]([N:10]2[C:14](=[O:15])[N:13]([CH2:16][C:17]3[O:33][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[N:12]=[CH:11]2)[S:5][C:6]=1[C:7]([NH:42][CH2:41][C:37]1[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=1)=[O:9]
Reactant: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Reactant: O=C(O)c1cncs1
Product: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)o3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 57 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 4-methyl-2-(5-oxo-14(5-(trifluoromethyl)furan-2-yl)methyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 57% yield: mp 124-125° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.63 (s, 2H), 8.28 (s, 1H), 7.82-7.75 (m, 1H), 7.36 (s, 1H), 6.77-6.72 (m, 1H), 6.52 (t, J=5.5 Hz, 1 H), 6.47-6.42 (m, 1H), 5.04 (s, 2H), 4.66-4.60 (m, 2H), 2.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.6, 115.4, 150.9, 150.8, 149.7, 149.3, 149.2, 135.7, 131.4, 123.7, 121.8, 120.5, 116.9, 112.6, 112.5, 110.4, 42.1, 41.6, 17.2; MS (ES+) m/z 465.3 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH:5]([O:12][CH3:13])[CH2:6][CH:7]([CH2:10][OH:11])[CH2:8][OH:9].[H][H].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.C1COCC1.C(O)C>[CH2:16]([O:9][CH2:8][CH:7]([CH2:6][CH:5]([O:4][CH3:3])[O:12][CH3:13])[CH2:10][O:11][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: COC(CC(CO)CO)OC
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(CC(COCc1ccccc1)COCc1ccccc1)OC
Yield: 121.7 %

Procedure:
Sodium hydride (55% in oil, 32.72 g, 0.75 mol) was washed twice with n-hexane and suspended in 200 ml of THF. 4,4-Dimethoxy-2-(hydroxymethyl)butanol (49.26 g, 0.3 mol) was added dropwise to maintain a gentle evolution of hydrogen gas. Then benzyl chloride (94.94 g, 0.45 mol) was added during 30 min. and the mixture was refluxed over-night, cooled, diluted with 50 ml of ethanol, and evaporated in vacuum. The residue was suspended in about 200 ml of water and extracted with 3×100 ml of ether. The combined organic extracts were dried (MgSO4) and distilled in vacuum. The title compound (94.34 g, 91%) was obtained at 197°-200° C. (0.01 mm Hg).