Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].OO.[CH3:29][OH:30]>O.OS(O)(=O)=O>[CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[C:14](=[C:15]([CH2:29][OH:30])[C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CO
Temperature: 0 °C
Yield: 99 %

Procedure:
Camptothecin (20.0 g) was dissolved in mixture of methanol (750 mL), water (500 mL), conc. H2SO4 (500 mL) and finely ground FeSO4 (16.0 g) and hydrogen peroxide (100 mL 30% solution) was added dropwise over the course of 2 h and the reaction mixture was allowed to stir for another hour. The reaction mixture was then filtered through a sintered glass funnel to remove all undissolved material. The resultant filtrate was then cooled to 0° C. and NaOH (375 g) in 1 L water was added slowly with vigorous stirring. The yellow-brown solid was then filtered, washed with water and pumped to dryness. The resultant crude product was then placed in a 1 L erlenmyer flask, DMF (300 mL) added and warmed to 110° C. Once the solid is dispersed into small particles, acetonitrile (500 mL) was added and the mixture heated until boiling. The mixture was then allowed to cool to room temperature then 0° C., filtered and the solid washed with chloroform to provide 7-hydroxymethylcamptothecin (21.50 g, 99%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1/[CH:11]=[CH:12]/[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[O:14].[NH4+].[Cl-]>[Fe]>[NH2:33][C:31]1[CH:30]=[CH:29][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2/[CH:11]=[CH:12]/[C:13]([N:15]2[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:19][CH2:20]2)=[O:14])=[C:2]([F:1])[CH:32]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)/C=C/c2cnccc2Oc2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)/C=C/c2cnccc2Oc2ccc(N)cc2F)CC1

Procedure:
The title compound was prepared by the reduction of (E)-tert-butyl 1-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)acryloyl)piperidin-4-ylcarbamate (100 mg, 0.21 mmol) in a manner similar to that of Step E of Example 35 using Fe powder (55 mg, 2.7 mmol), NH4Cl (280 mg, 5.3 mmol). The product (90 mg, 95%) was obtained as a light brown solid which was used directly in the subsequent step. MS (ESI+): m/z 457.18 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:10]=[CH:11][C:12]=1[O:13]C)[CH3:2].Cl.N1C=CC=[CH:26][CH:25]=1>>[CH2:25]([O:20][C:18](=[O:19])[CH2:17][CH2:16][C:15](=[O:21])[C:9]1[CH:10]=[CH:11][C:12]([OH:13])=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH:8]=1)[CH3:26]
Reactant: c1ccncc1
Reactant: CCOC(=O)CCc1cc(C(=O)CCC(=O)O)ccc1OC
Agent: Cl
Product: CCOC(=O)CCC(=O)c1ccc(O)c(CCC(=O)OCC)c1
Yield: 4219.6 %

Procedure:
Starting with a mixture of 6.48 g (21.0 mmol) of 3-(3-ethoxy-3-oxopropyl)-4-methoxy-γ-oxobenzenebutanoic acid and 24.4 g (0.211 mmol) of pyridine hydrochloride, the title compound (2.87 g, 42.4%) was obtained as a light-tan oil, using the procedure of example 140.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[C:9]2[C:10]([CH3:17])=[CH:11][C:12]([O:15]C)=[C:13]([F:14])[C:8]=2[S:7][CH:6]=1.CN(C=O)C.CC([S-])(C)C.[Na+]>O.Cl>[F:14][C:13]1[C:8]2[S:7][CH:6]=[C:5]([CH2:4][C:3]([OH:18])=[O:2])[C:9]=2[C:10]([CH3:17])=[CH:11][C:12]=1[OH:15]
Reactant: COC(=O)Cc1csc2c(F)c(OC)cc(C)c12
Agent: CC(C)(C)[S-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O)c(F)c2scc(CC(=O)O)c12
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 122.7 %

Procedure:
To a mixture of methyl(7-fluoro-6-methoxy-4-methyl-1-benzothiophen-3-yl)acetate (248.4 mg) and DMF (dry) (7.5 mL) was added sodium 2-methyl-2-propanethiolate (415 mg) at room temperature. The mixture was stirred at 160° C. for 20 min. After cooling, the mixture was diluted with water and 1N HCl and extracted with EtOAc. The organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo to give the title compound (273 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[C:32](=[O:33])[C:31]4[CH:34]=[C:35]([CH3:37])[S:36][C:30]=4[NH:29][C:28]3=S)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[OH-].[K+].C([OH:43])C.OO>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][N:27]3[C:32](=[O:33])[C:31]4[CH:34]=[C:35]([CH3:37])[S:36][C:30]=4[NH:29][C:28]3=[O:43])[CH2:23][CH2:24]2)=[CH:6][CH:7]=1
Reactant: Cc1cc2c(=O)n(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)c(=S)[nH]c2s1
Reactant: CCO
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cc2c(=O)n(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)c(=O)[nH]c2s1
Reaction time: 8 h
Yield: 55 %

Procedure:
To a stirred mixture of 4.1 parts of 3-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2,3-dihydro-6-methyl-2-thioxothieno[2,3-d]pyrimidin-4(1H)-one, 5.6 parts of potassium hydroxide, 81 parts of ethanol and 8 parts of water were added dropwise 60 parts of a hydrogen peroxide solution 3%. The whole was stirred overnight. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanone. The product was filtered off and dried, yielding 2.2 parts (55%) of 3-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-6-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; mp. 187.6° C. (compound 135).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1>CCO>[C:10]1([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccco1
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccco2)cc1
Temperature: 140 °C

Procedure:
Furan-2-boronic acid (22) (3.6 g, 32.14 mmol) was coupled to bromobenzene (21) (4.2 g, 26.79 mmol) using Method E, except that Cs2CO3 (17.47 g, 53.58 mmol), Pd(PPha)4 (6.20 g, 0.54 mmol), toluene (25 mL) and EtOH (25 mL) were used and the reaction heated in a CEM Discover microwave at 140° C. (200 W, 200 psi). The crude product was purified by dry-flash chromatography eluting with EtOAc in heptane to yield the title compound. Yield: 2.94 g, 62%; LC tr 1.50 min; HPLC Purity: 84%
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:17])[C@@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH3:8])[CH:2]=[CH2:3].[C:18]([O:22][C:23]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](Br)=[CH:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:12]([O:11][C:10]([NH:9][C@@H:6]([CH2:7][CH3:8])[C:5]([NH:4][CH2:1]/[CH:2]=[CH:3]/[C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH:26]=1)=[O:17])=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)n1cc(Br)c2ccccc21
Reactant: C=CCNC(=O)[C@H](CC)NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)NC/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 90 °C

Procedure:
A 50 mL sealed tube was charged with (S)-tert-butyl 1-(allylamino)-1-oxobutan-2-ylcarbamate (500 mg, 2.07 mmol), 3-bromo-indole-1-carboxylic acid tert-butyl ester (620 mg, 2.09 mmol), palladium (II) acetate (59 mg, 0.263 mmol), tri-o-tolylphosphine (180 mg, 0.591), acetonitrile (10 mL), and triethylamine (0.6 mL, 4.30 mmol). The tube was flushed with argon and sealed, then stirred and heated to 90° C. for 24 h. The resulting mixture was concentrated in vacuo and the resulting residue purified via flash silica gel chromatography (Analogix IF-280, SF65-150 g column, gradient 90:10-50:50 Heptane:EtOAc) to yield (S,E)-tert-butyl 3-(3-(2-(tert-butoxycarbonylamino)butanamido)prop-1-enyl)-1H-indole-1-carboxylate. 1H NMR (300 MHz, CDCl3) δ 7.58 (s, 1H), 7.23-7.36 (m, 4H), 6.60-6.66 (m, 1H), 6.20-6.51 (m, 1H), 4.05-4.11 (m, 1H), 3.86-3.91 (m, 2H), 1.83-1.93 (m, 1H), 1.59-1.72 (m, 1H), 1.44 (s, 18H), and 0.95 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([Cl:21])=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Solvent: ClCCl
Product: Cc1ccc(Oc2ccc(C(=O)Cl)cc2)cc1

Procedure:
A solution of 2.0 g of 4-(4-methylphenoxy)benzoic acid in 30 ml of methylene chloride is added 1.67 g of oxalyl chloride and the mixture refluxed for 30 minutes with stirring under nitrogen. The reaction mixture is evaporated in vacuo to a residue which is evaporated with carbon tetrachloride(2×30 ml).
Reaction SMILES: [CH2:1](S)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[S:14](Cl)(Cl)(=O)=O.[CH2:19]([S:35]([OH:37])=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:12]([O:36][S:35]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=[O:37])=[S:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCS(=O)O
Reactant: CCCCCCCCCCCCS
Product: CCCCCCCCCCCCCCCCS(=O)(=S)OCCCCCCCCCCCC
Reaction time: 2 h

Procedure:
36 g of dodecane thiol are converted into the corresponding sulphenic acid chloride by reaction with sulphuryl chloride as described above. This compound is added to a suspension of 56 g of the compound obtainable under (a). The mixture is then stirred for 2 hours and concentrated by evaporation and the residue is recrystallized from ethanol. m.p. 56° to 57° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1([CH2:11][CH2:10][CH:9]([CH2:12][CH3:13])[CH2:8]1)[CH2:6][C:5]2=O.C[Si]([N:23]=[C:24]=[N:25][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1([CH2:11][CH2:10][CH:9]([CH2:12][CH3:13])[CH2:8]1)[CH2:6]/[C:5]/2=[N:25]\[C:24]#[N:23]
Reactant: CCC1CCC2(CC(=O)c3cc(Br)ccc3O2)C1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC1CCC2(C/C(=N\C#N)c3cc(Br)ccc3O2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a solution of 6-bromo-3′-ethylspiro[chroman-2,1′-cyclopentan]-4-one (226 mg, 0.73 mmol) in anhydrous DCM (5.7 mL) was added TiCl4 (1 M solution in DCM, 1.5 mL, 1.49 mmol) dropwise within 15 min at room temperature. The mixture was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (300 mg, 0.36 mL, 1.61 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (20 g) and extracted with DCM (3×20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give (E)-N-(6-bromo-3′-ethylspiro[chroman-2,1′-cyclopentane]-4-ylidene)cyanamide as light brown solid (225 mg), which was used in the next step without further purification.
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10]([NH:12][C@H:13]([CH3:20])[C@@H:14]([CH2:18][CH3:19])[C:15]([OH:17])=O)=[O:11])([CH3:8])([CH3:7])[CH3:6].Cl.[NH2:22][C@@H:23]([CH2:28][OH:29])[C:24]([O:26][CH3:27])=[O:25].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[C:5]([O:9][C:10]([NH:12][C@H:13]([CH3:20])[C@@H:14]([CH2:18][CH3:19])[C:15]([NH:22][CH:23]([CH2:28][OH:29])[C:24]([O:26][CH3:27])=[O:25])=[O:17])=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC[C@@H](C(=O)O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](C(=O)NC(CO)C(=O)OC)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (2.01 g, 10.51 mmol) was added in one portion to a solution of (2R,3R)-3-((tert-butoxycarbonyl)amino)-2-ethylbutanoic acid (1.62 g, 7.00 mmol), (S)-methyl 2-amino-3-hydroxypropanoate hydrochloride (1.64 g, 10.51 mmol), HOBT (1.61 g, 10.51 mmol) and triethylamine (3.42 ml, 24.51 mmol) in anhydrous dichloromethane (28.0 ml). The reaction mixture was allowed to stir at rt under a nitrogen atmosphere overnight before evaporating in vacuo. The residue was then taken up in ethyl acetate (50 mL) and washed with water (50 mL). The organic was then dried (MgSO4) and evaporated in vacuo. The residue was treated with MeOH to precipitate title compound (1.71 g, 74%) which was used immediately in the next reaction. 1H NMR (400 MHz, CCl3D) δ 6.56 (d, J=6.6 Hz, 1H), 4.68 (dt, J=7.2, 3.5 Hz, 1H), 4.09-3.98 (m, 2H), 3.98-3.91 (m, 1H), 3.86 (br. s., 1H), 3.81 (s, 3H), 1.83-1.67 (m, 1H), 1.67-1.52 (m, 1H), 1.44 (s, 9H), 1.18 (d, J=6.8 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:3]=1.[Cl:17][C:18]1[C:19](B(O)O)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.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>[Cl:17][C:18]1[C:19]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)[N:3]=2)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: Fc1cccc(COc2cccc(Br)n2)c1
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: CCOC(C)=O
Product: Fc1cccc(COc2cccc(-c3cc(F)ncc3Cl)n2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
A mixture of 2-bromo-6-(3-fluorobenzyloxy)pyridine (145 mg, 0.514 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (144 mg, 0.822 mmol), PalladiumTetrakis (71.3 mg, 0.062 mmol), DME (3 ml), and 12M sodium carbonate (1.028 ml, 2.056 mmol) was reaction mixture was stirred at 100° C. for 3 hr, followed by LCMS. The reaction mixture was cooled, diluted with 10 ml of ethyl acetate, filtered and concentrated to yield a crude product, which was purified by silica gel chromatography using a 12 g column eluting from 0%-20% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 100 mg of titled compound as a free base. LCMS (m/z): 333.1 (MH+), retention time=1.26 min.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C@H:21]([CH2:25][C:26]([O:28]CC)=[O:27])[CH2:20][CH2:19]4)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.O[Li].O>C1COCC1.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C@H:21]([CH2:25][C:26]([OH:28])=[O:27])[CH2:20][CH2:19]4)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc4c(ccn4C)c3)ccc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc2cc(OCCCOc3ccc4c(c3)CC[C@H]4CC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.2 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[(1-methyl-1H-indol-5-yl)oxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (51 mg, 0.13 mmol) (Example 48) in THF (1.8 mL) was added LiOH.H2O (6 mg, 0.15 mmol) in water (0.6 mL). The mixture was stirred for 12 h at rt, then the reaction mixture was concentrated under reduced pressure and the residue suspended in a small volume of water. The pH was adjusted to below 3 with HCl (1 N aqueous solution), and the aqueous layer was extracted with EtOAc. The organic layer was dried, filtered, and concentrated under reduced pressure to give 44 mg (93%) of the title compound as a solid. 1H NMR (400 MHz, CDCl3): δ 7.10 (d, 1H), 7.05-6.96 (m, 2H), 6.93 (d, 1H), 6.81 (dd, 1H), 6.72 (s, 1H), 6.65 (dd, 1H), 6.32 (d, 1H), 4.18-4.00 (m, 4H), 3.69 (s, 3H), 3.52-3.40 (m, 1H), 2.92-2.65 (m, 3H), 2.42-2.24 (m, 2H), 2.22-2.10 (m, 2H), 1.78-1.62 (m, 1H); LC-MS RT=3.45 min, (M+H)+ 380.1.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl-].[CH:13](=[N+:20]([CH3:22])[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][C:2]=2[CH:13]([N:20]([CH3:22])[CH3:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:27][CH:26]=1
Reactant: Oc1cccc2ccccc12
Reactant: COc1ccc(CCl)cc1
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: COc1ccc(COc2c(C(c3ccccc3)N(C)C)ccc3ccccc23)cc1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 and 5 from 1-naphthol and benzylidene-dimethyl-ammonium chloride and 4-methoxybenzyl chloride.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[C:12]1=[O:25].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH3:41][O:42][C:43]1[CH:44]=[C:45](/[CH:55]=[CH:56]/[C:57](O)=[O:58])[CH:46]=[CH:47][C:48]=1[N:49]1[CH:53]=[C:52]([CH3:54])[N:51]=[CH:50]1>C(Cl)Cl.O>[F:24][C:19]1[CH:18]=[C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][N:11]([NH:10][C:57](=[O:58])/[CH:56]=[CH:55]/[C:45]3[CH:46]=[CH:47][C:48]([N:49]4[CH:53]=[C:52]([CH3:54])[N:51]=[CH:50]4)=[C:43]([O:42][CH3:41])[CH:44]=3)[C:12]2=[O:25])[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Reactant: NN1CCCC(c2ccc(F)c(F)c2)C1=O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(/C=C/C(=O)NN2CCCC(c3ccc(F)c(F)c3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
IPEA (1.5 mL), 1-amino-3-(3,4-difluorophenyl)piperidin-2-one (420 mg) and BOPCl (0.53 g) were added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (450 mg) in methylene chloride (15 mL) at room temperature, and the reaction solution was stirred at room temperature for three hours. Water was added to the reaction solution, followed by extraction with chloroform. The resulting extract was washed with a saturated sodium chloride solution. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 572 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(C=P(CCCC)(CCCC)CCCC)#N.[CH3:44][C:45]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:48])[CH2:46]O>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:44][C:45]([CH3:48])([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH3:46])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(CO)c1ccccc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCCc1nc(C)n(CC(C)(C)c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 9.5 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), cyanomethylene tri-n-butylphosphorane (1 g), 2-methyl-2-phenylpropan-1-ol (0.63 g) and toluene (30 mL) was stirred at 100° C. for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.13 g, 10%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]3)=[CH:13][C:12]=2[N+:31]([O-])=O)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CO.[H][H]>C1COCC1.CCO.[Pd]>[NH2:31][C:12]1[CH:13]=[C:14]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]2)[CH:15]=[CH:16][C:11]=1[S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)(=[O:9])=[O:10]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(S(=O)(=O)c3cccc(F)c3)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(S(=O)(=O)c3cccc(F)c3)c(N)c2)CC1
Reaction time: 16 h
Yield: 98.2 %

Procedure:
A mixture of tert-butyl 4-{4-[(3-fluorophenyl)sulfonyl]-3-nitrophenyl}-1,4-diazepane-1-carboxylate (58.0 g, 121 mmol) and Pd/C (8.70 g, 15% by wt.) in 1.5 L of a 2:2:1 THF:MeOH:EtOH solvent is exposed to hydrogen gas (25 psi) in a Parr bottle. The pressure of hydrogen is constantly monitored and kept near 25 psi. After 16 h, the mixture is filtered, solids rinsed with MeOH and CH2Cl2, and filtrate concentrated to give a brown solid. The solid is triturated with EtOAc and hexane to give 53.4 g (98%) of the title compound as an off white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH3:11])[CH2:9][OH:10].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.O.C(Cl)(Cl)Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH3:11])[CH2:9][O:10][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](CO)OC1CCCCO1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](C)OC2CCCCO2)cc1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A solution of 2-O-tetrahydropyranyl-(R)-propane-1,2-diol(67.2 g, 0.42 mol) in pyridine (600 ml) was placed in a 2 l round-bottom flask with magnetic stirring rod and 500 ml dropping funnel with a side-tubing, protected by calcium chloride tube. 4-Dimethylaminopyridine (2 g) was added, the flask was placed in an ice-water cooling bath and a solution of p-toluenesulfonyl chloride (91 g, 0.477 mol) in pyridine (300 ml) was added over 1 hour under stirring. The mixture was stirred under ice-cooling for additional 3 hours and left to stand overnight in a refrigerator at 4° C. Water (20 ml) was then added to the mixture and, after standing for 1 hour, pyridine (approx. 300 ml) was distilled off in vacuo. The residue was diluted by ethyl acetate (2.5 l) and shaken with water (300 ml). After separation of the lower aqueous layer, the organic phase was washed with water (two 300 ml portions), evaporated in vacuo and the residue co-evaporated with toluene (four 250-ml-portions) in vacuo. The remaining amber oil was purified by chromatography over silica gel (eluting with chloroform) to afford 122 g (0.39 mol, 93%) of (R)-2-O-tetrahydropyranyl-1-O-p-toluenesulfonylpropane-1,2 diol as a thick colorless oil, RF 0.60 (TLC, chloroform). This product was stored at +4° C. for several months without obvious decomposition. For C15H22OS (MW 314,4) calculated: C,57.30; H,7.05; S,10.20. Found: C,57.15; H,7.22; S,10.52.