Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:24]O>>[N:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][CH2:13][CH:14]([C:17]([O:19][CH3:24])=[O:18])[CH2:15][CH2:16]1
Reactant: CO
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
1-(Benzyloxycarbonyl)piperidine-4-carboxylic acid (48.5 g) in methanol (485 ml) was cooled to 0° C. and thionyl chloride (13.34 ml) was added dropwise. The mixture was then refluxed for 20 min (TLC control). When the reaction was complete, the methanol was distilled off, the residue was taken up in water (15 ml) and extracted with ethyl acetate (2×150 ml). The combined organic phases were extracted with water and sat. sodium chloride solution and the extract was dried (Na2SO4) and concentrated in vacuo. Yield: 38 g (67%)
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][O:14][CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[N:8]=1.[OH:27]O.[OH-].[Na+]>CO>[F:26][C:2]([F:1])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][O:14][CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]([NH2:21])=[O:27])=[CH:18][CH:17]=2)[N:8]=1
Reactant: OO
Reactant: N#Cc1ccc(COCCn2ccc(NC(N)=NCC(F)(F)F)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1ccc(COCCn2ccc(NC(N)=NCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 31 %

Procedure:
To a solution of 4-(2-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]ethoxymethyl)benzonitrile (650 mg.) in MeOH (5 ml.) was added hydrogen peroxide (30%, 100 volume) (2 ml.) followed by N aqueous NaOH (1 ml.). The mixture was then stirred at room temperature for 2.25 hours. The solvent was then evaporated in vacuo to give a yellow gum (700 mg.). This gum was purified by medium pressure chromatography using EtOAc/EtOH/triethylamine 96:3:1 v/v/v as eluant to give 4-(2-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]ethoxymethyl)benzamide (210 mg.; 31%) having the following n.m.r. in d6DMSO: 7.5 (m, 4H); 7.5 (d, 1H); 5.8 (d, 1H); 5.0 (s, 2H); 4.0 (m, 4H); 3.7 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH:5]([CH:16]1[CH2:18][CH2:17]1)[C:6]([O:8]CC1C=CC=CC=1)=[O:7])(=[O:3])[CH3:2]>CO>[C:1]([O:4][CH:5]([CH:16]1[CH2:17][CH2:18]1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C(=O)OCc1ccccc1)C1CC1
Solvent: CO
Product: CC(=O)OC(C(=O)O)C1CC1
Yield: 130.1 %

Procedure:
1.40 g of benzyl acetoxy(cyclopropyl)acetate was added to 280 mL of methanol, followed by filtration. The filtrate was subjected to reduction using a continuous hydrogenation reactor (H-Cube (registered trademark); manufactured by ThalesNano) under the condition of CatCart (registered trademark), 10% palladium on carbon (manufactured by ThalesNano), a flow rate of 1.0 ml/min, and a pressure of 4 bar (Full H2 mode). The solvent was evaporated under reduced pressure to obtain 1.16 g of acetoxy(cyclopropyl)acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15](SC)[N:14]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH2:34][C:35]1[C:36]([F:43])=[CH:37][C:38]([CH3:42])=[C:39]([OH:41])[CH:40]=1.C([O-])([O-])=O.[K+].[K+]>ClCCl.CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([O:41][C:39]4[C:38]([CH3:42])=[CH:37][C:36]([F:43])=[C:35]([NH2:34])[CH:40]=4)[N:14]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COc1ccc(Cn2cc(-c3ccnc(SC)n3)cn2)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3ccnc(Oc4cc(N)c(F)cc4C)n3)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine from Example A18 (200 mg, 0.64 mmol) in dichloromethane was added m-CPBA (220 mg, 1.28 mmol). The reaction was stirred for 2 hour at RT. Water was added, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organics were washed with brine and concentrated in vacuo. The residue was combined with 5-amino-4-fluoro-2-methylphenol (180 mg, 1.28 mmol) and K2CO3 (176 mg, 1.28 mmol) in DMF (5 mL) and the resultant mixture was heated at 90° C. overnight. After filtration and concentration, the residue was purified by silica gel column chromatography to give 5-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluoro-4-methylbenzenamine (210 mg, 84% yield). MS (ESI) m/z: 406.2 (M+H+).
Reaction SMILES: [OH-].[Na+].O.C[O:5][C:6](=[O:42])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:38][CH3:39])([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:40])=[CH:10][C:9]=1[F:41].Cl>CO>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][C:6]([OH:42])=[O:5])=[C:9]([F:41])[CH:10]=2)=[C:15]([CH3:40])[CH:16]=1)([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:34])([CH3:35])[CH3:33])=[C:25]([CH3:37])[CH:24]=1)[CH2:38][CH3:39])[CH3:22]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)O)c(F)c2)c(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.4 %

Procedure:
A mixed solution of a 6 N sodium hydroxide aqueous solution (0.011 mL) with water (0.032 mL) was added to a solution of (4′-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-fluoro-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 60-(2); 8.5 mg, 0.016 mmol) in methanol (0.22 mL) at room temperature, and the mixture was stirred at room temperature for six hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (8 mg, 100%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][CH:36]4[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]4)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:2][CH2:3]1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c14) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]4[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=4)[N:22]=3)[N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=2)[N:22]=[C:21]([C:17]2[N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)n2)n1
Temperature: 23 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
To N-tert-butyl-3-{6-[4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide (Example 26) (0.092 g, 0.174 mmol) was added TFA (2 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as an off-white solid (0.080 g, 98%). MS (ISP) 472.0 [(M+H)+]; mp 254° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:26])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.6 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate (11.0 g, 29.7 mmol) in methanol (90 ml) was added 1N aqueous sodium hydroxide solution (59.6 ml, 59.6 mmol), and the mixture was stirred at room temperature for 6 hrs. The reaction solution was evaporated under reduced pressure, diluted with 1N hydrochloric acid (100 ml), and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization from ethyl acetate-hexane gave (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (8.6 g, 85%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH:14]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([O:23]CC3C=CC=CC=3)=[CH:18][C:17]=2[F:31])Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:16]2[CH:21]=[C:20]([F:22])[C:19]([OH:23])=[CH:18][C:17]=2[F:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](C(Br)c2cc(F)c(OCc3ccccc3)cc2F)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cc(F)c(O)cc2F)C1
Yield: 16.1 %

Procedure:
A suspension of palladium on carbon (10%, 0.47 g) in a solution of 4.7 g of (S)-2-[(4-benzyloxy-2,5-difluoro-phenyl)-bromo-methyl]-morpholine-4-carboxylic acid tert-butyl ester in ethanol (400 ml) was hydrogenated at room temperature and normal pressure till the theoretical amount of hydrogen had been consumed. Solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was partitioned with ethyl acetate and saturated sodium bicarbonate solution. Organic phases were pooled, washed with brine and dried with Na2SO4 before being concentrated in vacuo. The residue was then purified by column chromatography (dichloromethane-diethyl ether (19:1)/silica gel) to give 0.5 g of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][NH:35][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: NC1CCCC1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCNC2CCCC2)c1OCCC(C)c1ccc(F)cc1

Procedure:
Example 8a (100 mg, 0.21 mmol) was reacted with cyclopentylamine (6.0 eq.) as described under General Procedure G. The title compound was afforded as an oil (65 mg, 65%). 1H NMR (300 MHz, CDCl3) δ 7.17-7.13 (m, 2H), 6.99-6.93 (m, 2H), 4.07 (t, J=5.2 Hz, 2H), 3.92 (t, J=6.7 Hz, 2H), 3.81 (s, 3H), 3.06 (quintet, J=6.6 Hz, 1H), 3.01-2.93 (m, 1H), 2.81 (t, J=5.2 Hz, 2H), 2.46 (s, 3H), 2.16 (s, 3H), 2.03-1.96 (m, 2H), 1.84-1.76 (m, 2H), 1.68-1.49 (m, 4H), 1.33-1.23 (m, 2H), 1.27 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[N:20]2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCOCC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][NH:9][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[N:20]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1ccc2nccnc2c1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(C(=NNc2ccc3nccnc3c2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 20.3 %

Procedure:
In toluene (8 mL) was placed 1-(diphenylmethylene)hydrazine (1.00 g, 5.10 mmol), palladium acetate (10.4 mg, 0.0464 mmol) and 2-(diphenylphosphino)-1-(2-(diphenylphosphino)naphthalen-1-yl)naphthalene (44 mg, 0.0696 mmol) and the reaction was stirred at 100° C. under Ar for 5 min and then cooled to RT. To this dark purple solution was added 6-bromoquinoxaline (970 mg, 4.64 mmol), sodium t-butoxide (624 mg, 6.50 mmol) and toluene (2 mL). The reaction was placed under Ar and warmed to 100° C. for 5 hrs, cooled to RT and stirred overnight. The reaction was diluted with ether (50 mL) and water (30 mL) and filtered through a Celite pad. The pad was washed with ether (20 mL) and water (20 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), concentrated in vacuo and purified by chromatography (ethyl acetate/hexanes) to give 1-(diphenylmethylene)-2-(quinoxalin-6-yl)hydrazine (305 mg, 20% yield) as a bright yellow foam. 1H NMR (300 MHz, DMSO-d6) δ 7.35-7.41 (m, 5H), 7.51-7.53 (m, 2H), 7.58-7.65 (m, 3H), 7.75 (s, 1H), 7.89 (s, 2H), 8.61 (s, 1H), 8.74 (s, 1H), 9.60 (s, 1H); MS (ESI) m/z: 325.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][Zn+].NC1C=CC(CC2C=CC=CC=2)=CC=1C#N>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[Cl:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Clc1ccccc1C[Zn+]
Reactant: N#Cc1cc(I)ccc1N
Agent: N#Cc1cc(Cc2ccccc2)ccc1N
Agent: [Cl-]
Product: N#Cc1cc(Cc2ccccc2Cl)ccc1N

Procedure:
From 9 (488 mg, 2 mmol) and 2-chlorobenzylzinc chloride (0.5 Min THF, 10 mL, 5 mmol) by the same methods as 10a; white powder (272 mg, 62%), mp 79-80° C.; 1H NMR (CDCl3) δ 3.96 (s, 2H, CH2), 4.79 (br s, 2H, NH2), 6.69 (d, J=8.8 Hz, 1H, H-3), 7.12-7.19 (m, 5H, aromatic protons), 7.20 (s, 1H, H-6).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:28](OC)[O:29]C)[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[NH:13]2)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:28]=[O:29])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[NH:13]2)(=[O:3])[CH3:2]
Reactant: COC(OC)c1cc(OC(C)=O)c2c(c1)N1CC3NC3C(OC(C)=O)(O1)C2COC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)Oc1cc(C=O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2NC21

Procedure:
8-Carbamoyloxymethyl-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate is reacted with p-toluenesulfonic acid according to a similar manner to that of Example 38 to give 8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate. Further, this product is subjected to catalytic reduction according to a similar manner to that of Example 17 to afford 8-carbamoyloxymethyl-4-hydroxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate.
Reaction SMILES: [NH2:1][C:2]1[C:11](Br)=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:13]([O:15][CH3:16])=[O:14].[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(#N)C>[NH2:1][C:2]1[C:11](/[CH:19]=[CH:18]/[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1c(N)c(Br)cc2c1CCCC2
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1c(N)c(/C=C/C(=O)OC(C)(C)C)cc2c1CCCC2
Temperature: 200 °C
Yield: 30.2 %

Procedure:
A mixture of Example 476A (0.327 g, 1.2 mmol), tert-butyl acrylate (0.203 mL, 1.40 mmol), acetonitrile (1.5 mL), tri(ortho-tolyl)phosphine (0.035 g, 0.12 mmol), palladium diacetate (0.013 g, 0.06 mmol), and triethylamine (0.32 mL, 2.3 mmol) was sealed and heated in a microwave reactor for 10 minutes at 200° C. The reaction mixture was concentrated and purified by flash chromatography (15% ethyl acetate/hexanes) to provide the desired product (0.12 g, 32%); MS (DCI) m/e 332 (M+H)+.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>C(O)(=O)C>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:19]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:16][CH:15]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 90 °C
Yield: 87 %

Procedure:
A mixture of phthalic anhydride (10 g, 0.067 mmol) and 4-methoxybenzylamine (9.7 ml, 0.074) in glacial acetic acid (60 ml) was stirred in a 90° C. oil bath for 2½ hr, cooled to room temperature and the excess acetic acid removed under reduced pressure. The residual mixture was diluted with water (50 ml) and poured slowly into a saturated NaHCO3 solution (150 ml). The mixture was stirred at room temperature overnight and the precipitate collected by filtration, rinsing further with water. The precipitate was then dried under reduced pressure to provide a white solid product (15.7 g) 87%.
Reaction SMILES: [CH2:1]([N:3]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=2)[CH2:22]1)[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].Cl.[CH2:34]([N:36]([CH2:40][CH3:41])[CH2:37][CH2:38]Cl)[CH3:35]>>[CH2:34]([N:36]([CH2:40][CH3:41])[CH2:37][CH2:38][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([N:3]([CH2:1][CH3:2])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=3)[CH2:22]2)=[O:12])=[CH:10][CH:9]=1)[CH3:35]
Reactant: CCN(CC)CCCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Product: CCN(CC)CCOc1ccc(C(=O)N(CC)c2cc(OC)ccc2C2CCc3cc(OC)ccc3C2)cc1
Yield: 72.5 %

Procedure:
Synthesized from N-ethyl-4-hydroxy-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide (250 mg) and 2-diethylaminoethyl chloride hydrochloride (130 mg) according to an analogous synthetic method to Preparation Example 40, the title compound (223 mg) was obtained.
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.CCCCCC>ClCCl>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:1]=[N:3][CH2:4][CH2:5]2
Reactant: COc1cccc(CCNC=O)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccc2c(c1)CCN=C2
Temperature: 0 °C
Yield: 87 %

Procedure:
A solution of 29.4 Kg of N-formyl-3-methoxyphenethylamine in 30 litres of dichloromethane was added over 90 minutes to a well-stirred slurry of 38.4 Kg of phosphorus pentachloride in 30 litres of dichloromethane. An exothermic reaction ensued, causing the solvent to reflux at 35°-38° C. After addition was complete, the reaction mixture was hydrolysed by the addition of a mixture of 90 Kg of ice and 30 litres of hexane. After cooling the aqueous layer was separated, made basic with 144 Kg of 45% potassium hydroxide and extracted twice with 50 Kg of dichloromethane. After drying the organic layer with sodium sulfate the solvent was removed under reduced pressure to give 23 Kg of 6-methoxy-3,4-dihydroisoquinoline as an oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C:12](=[O:14])[CH3:13])(=O)[CH3:9].[OH:15][C@@H:16]1[CH2:27][CH2:26][C@:25]([OH:29])([CH3:28])[C@@H:24](O)[CH:23]=[CH:22][C@H:21]([CH3:31])[C@@H:20](/[C:32](/[CH3:36])=[CH:33]/C=C)[O:19][C:18](=[O:37])[CH2:17]1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.ClCCl>[C:12]([O:11][C@@H:8]1[C@@:25]([OH:29])([CH3:28])[CH2:26][CH2:27][C@@H:16]([OH:15])[CH2:17][C:18](=[O:37])[O:19][C@H:20](/[C:21](/[CH3:31])=[CH:22]/[CH:23]=[CH2:24])[C@@H:32]([CH3:36])[CH:33]=[CH:9]1)(=[O:14])[CH3:13]
Reactant: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O)CC[C@@](C)(O)[C@@H](O)C=C[C@@H]1C
Reactant: CC(=O)OC(C)=O
Agent: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O)CC[C@@](C)(O)[C@@H](O)/C=C/[C@@H]1C
Agent: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O)CC[C@@](C)(O)[C@@H](OC(C)=O)/C=C/[C@@H]1C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O)CC[C@@](C)(O)[C@@H](OC(C)=O)C=C[C@@H]1C
Reaction time: 1 h

Procedure:
Triethylamine (35.6 μl, 246 μmol), acetic anhydride (11.6 μl, 123 μmol) and 4-dimethylaminopyridine (3.0 mg, 24.6 μmol) were added to an anhydrous dichloromethane (2 ml) solution of (4R,7R,8S,9E,11S,12S)-4,7,8-trihydroxy-7,11-dimethyl-12-[(1E)-1-methylbuta-1,3-dien-1-yl]-oxacyclododec-9-en-2-one (40.0 mg, 123 μmol) at 0° C. and the reaction solution was stirred at the same temperature for one hour. The reaction solution was poured into a saturated sodium hydrogen carbonate aqueous solution, and the reaction solution was diluted with ethyl acetate and washed with distilled water and brine sequentially, and after dried over anhydrous sodium sulfate, the drying agent was filtered off and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane:diethyl ether=1:2) to obtain the title compound (42 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH2:17])=[N:14][C:13]=2[CH3:18])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:19](N1C=CN=C1)([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:20]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:19]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)=[O:20])=[N:14][C:13]=2[CH3:18])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 40 °C

Procedure:
A suspension of 5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (17.5 mmol) and 1,1′-carbonyldiimidazole (4.26 g, 26.3 mmol, 1.5 equivalents) in CH2Cl2 (100 ml) was heated at 40° C.-reflux under argon until no starting material remains (30 min-5 hours) as determined by HPLC and NMR. When cool the solid precipitate was removed by filtration.