Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]1[CH2:16][N:15]2[C:17]3[CH:18]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:20]=[CH:21][C:22]=3[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:14]2[C:13]2[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:12]=2[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH3-]C#N.[Na+].[C:43]([NH:50][CH2:51][CH:52]=O)([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CO.CC(O)=O>[CH2:1]([N:8]([CH2:52][CH2:51][NH:50][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@@H:9]1[CH2:16][N:15]2[C:17]3[CH:18]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:20]=[CH:21][C:22]=3[C:23]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[C:14]2[C:13]2[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:12]=2[O:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](NCc1ccccc1)COc1cc(F)ccc1-3
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(CCNC(=O)OC(C)(C)C)Cc1ccccc1)COc1cc(F)ccc1-3
Temperature: 25 °C
Yield: 71 %

Procedure:
To the solution of methyl (7R)-7-(benzylamino)-14-cyclohexyl-3-fluoro-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate in MeOH/HOAc containing NaCNBH3 from the previous step was added N-Boc-2-aminoacetaldehyde (1.5 eq) and the solution was stirred at RT. After 1 h all volatiles were evaporated. The residual material was taken up with EtOAc and the resulting solution was washed with sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. The yellow residue was subjected to FC (PE:EtOAc, 8:2+1% NEt3). After evaporation of the solvents the product was obtained as a colourless solid (71%). (ES+) m/z 656 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([S:22]([CH2:25][CH2:26][OH:27])(=[O:24])=[O:23])=[CH:21][C:15]=3[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[CH2:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=1)=[O:31].CC#N.O>C(O)=O>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([NH:10][C:11]([C:13]2[N:17]([CH2:29][C:30](=[O:31])[NH:32][C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=3)[C:16]3[CH:18]=[CH:19][C:20]([S:22]([CH2:25][CH2:26][OH:27])(=[O:23])=[O:24])=[CH:21][C:15]=3[N:14]=2)=[O:12])[CH2:8][CH2:9]1)([CH3:3])[CH3:2].[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([NH:10][C:11]([C:13]2[N:14]([CH2:29][C:30](=[O:31])[NH:32][C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=3)[C:15]3[CH:21]=[C:20]([S:22]([CH2:25][CH2:26][OH:27])(=[O:23])=[O:24])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[O:12])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: CC(C)N1CCC(NC(=O)c2nc3cc(S(=O)(=O)CCO)ccc3[nH]2)CC1
Solvent: O=CO
Solvent: CC#N
Solvent: O
Product: CC(C)N1CCC(NC(=O)c2nc3cc(S(=O)(=O)CCO)ccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Product: CC(C)N1CCC(NC(=O)c2nc3ccc(S(=O)(=O)CCO)cc3n2CC(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-5-(2-hydroxy-ethanesulfonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide and 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-6-(2-hydroxy-ethanesulfonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide were prepared by a procedure according to example 29 starting from 1 g (2.5 mmol) crude 5-(2-hydroxy-ethanesulfonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide and 758.9 mg (3.04 mmol) 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide. Preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave a 1:1 mixture of both isomers described in the title. These isomers could be separated by NP-HPLC using a chiral stationary phase and a mixture of heptane, ethanol, methanol and diethyl amine as solvent. Structural assignment of both isomers was achieved by NOE-spectroscopy.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.O1CCCC1.CO.[BH4-].[Na+]>O>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(CO)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (200 mg) in a mixed solvent of tetrahydrofuran (1 mL) and methanol (1 mL) was added sodium borohydride (55.0 mg), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was m washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (166 mg, yield 83%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 467 (MH+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([OH:28])[C:17]3=[C:18]([F:27])[CH:19]=[N:20][C:21]4[CH:22]=[C:23]([Cl:26])[C:24](=[O:25])[N:15]([C:16]=43)[CH2:14]2)(=O)=O)=CC=1.[NH:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][CH2:30]1.[Na].O>C(O)C>[Cl:26][C:23]1[C:24](=[O:25])[N:15]2[CH2:14][C:13]([CH2:12][N:29]3[CH2:30][CH2:31][CH:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:33][CH2:34]3)([OH:28])[C:17]3=[C:18]([F:27])[CH:19]=[N:20][C:21]([CH:22]=1)=[C:16]23
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2(O)Cn3c(=O)c(Cl)cc4ncc(F)c2c43)cc1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(CC2(O)Cn3c(=O)c(Cl)cc4ncc(F)c2c43)CC1
Reaction time: 8 h

Procedure:
To a solution of crude ((4R/S)-8-chloro-3-fluoro-4-hydroxy-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl 4-methylbenzenesulfonate (˜2.5 g, assumed 6.10 mmol) in ethanol (50 mL), at room temperature, under argon was added 1,1-dimethylethyl 4-piperidinylcarbamate (1.22 g, 6.10 mmol) and sodium hydrogenocarbonate (1.94 g, 18.31 mmol). The reaction mixture was stirred for 8 hours. A further 0.5 equivalent of 1,1-dimethylethyl 4-piperidinylcarbamate (0.61 g, 3.05 mmol) and 1.5 equivalent of sodium hydrogenocarbonate (0.97 g, 9.15 mmol) were added. The reaction mixture was stirred for an additional 18 hours, treated with water (200 mL) and extracted with a 10% solution of methanol in dichloromethane (3×200 mL). The combined organic layers were dried over magnesium sulphate, evaporated and chromatograped affording an impure material which used crude in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH2:11])[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2.[CH3:18][N:19]([CH3:27])[CH:20]([CH2:25][CH3:26])[CH2:21][C:22](=O)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:23]3[CH2:26][CH2:25][CH:20]([N:19]([CH3:27])[CH3:18])[CH2:21][CH2:22]3)[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2
Reactant: CCC(CC(C)=O)N(C)C
Reactant: Nc1cc(Cl)cc2cc(-c3ccccc3)[nH]c12
Product: CN(C)C1CCC(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)CC1

Procedure:
7-Amino-5-chloro-2-phenyl-1H-indole prepared in Example 3 and 4-dimethylaminohexanone were reacted according to the same procedure as Step B of Example 1 to give the title compound.
Reaction SMILES: COC(=O)C1C(=CC=CC=1[N+:13]([O-])=O)C(O)=O.Br[C:18](Br)=[O:19].Br[CH2:22][CH:23]1[C:31]2[C:26](=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[CH:29][CH:30]=2)C(=O)[O:24]1>CC(C)=O>[OH:24][C:23]1([CH3:22])[C:31]2[C:26](=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[CH:29][CH:30]=2)[NH:13][C:18]1=[O:19]
Reactant: O=C1OC(CBr)c2cccc([N+](=O)[O-])c21
Reactant: COC(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: O=C(Br)Br
Solvent: CC(C)=O
Product: CC1(O)C(=O)Nc2c([N+](=O)[O-])cccc21

Procedure:
3-Substituted oxindoles can be prepared from 7-nitrophthalic anhydride 21, for example, which can be reacted with MeOH to give the 3-nitro-phthalic acid-2-methyl ester 22 by known procedures. The 3-nitro-phthalic acid-2-methyl ester 22 is converted to the corresponding acid chloride 23 then reacted with a methyl Grignard reagent to afford the methyl-ketone 24. The methyl-ketone 24 can be converted to the bromo-ketone 25 and cyclized to the 3-bromomethyl-7-nitro-3H-isobenzofuran-1-one 26 which can be reacted with an amine to afford the 3-hydroxy-3-methyl-7-nitro-oxindole 27. The 3-hydroxy-3-methyl-7-nitro-oxindole 27 can be reduced to the corresponding 7-amino-3-hydroxy-3-methyl-oxindole 28 which can then be alkylated by reductive amination to give compound 29. Alternatively, the 3-hydroxy-3-methyl-7-nitro-oxindole 27 can be reduced to the 7-amino-3-methyl-oxindole 30 under standard hydrogenation conditions and alkylated by reductive amination to give compound 31.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].[C:18]1([CH:24]=[CH:25][CH2:26][C:27](Cl)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>>[C:18]1([CH:24]=[CH:25][CH2:26][C:27]([O:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=3)[CH2:12][CH2:13]2)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)CC=Cc1ccccc1
Reactant: CN(C)Cc1ccc([C@H]2CC[C@H](O)CC2)cc1
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc([C@H]2CC[C@H](OC(=O)CC=Cc3ccccc3)CC2)cc1

Procedure:
from trans-4-(4-dimethylaminomethylphenyl)-cyclohexanol and 4-phenyl-3-butenoic acid chloride/triethylamine. White crystals.
Reaction SMILES: C[O-].[Na+].[C:4]([OH:12])(=[S:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[CH2:14][C:15]#[N:16]>C1COCC1.CCOCC>[C:4]([S:11][CH2:14][C:15]#[N:16])(=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CCCl
Reactant: OC(=S)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CCSC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Sodium methoxide (5.13 g; 0.095 mol) is added with stirring to an ice cold solution of thiobenzoic acid (13.8 g; 0.095 mol) in THF (100 ml). A yellow slurry forms. Next, chloroacetonitrile (6.45 ml; 0.10 mol) is added, and the reaction mixture stirred overnight at room temperature. It is then filtered, and the filtrate concentrated in vacuo to yield a yellow oil. This oil is dissolved in ether, the solution washed with saturated sodium bicarbonate solution, saturated salt solution, dried over sodium sulfate and concentrated in vacuo. The residual oil is distilled (boiling point 105°-106° C. at 10.5 mm) to afford 12.8 g (76%) of title product, a yellow oil.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:6]([OH:45])([CH3:44])[CH2:7][CH2:8][CH:9]([O:36][Si:37]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:38][CH3:39])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:35])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([OH:31])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2].[C:46](Cl)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:6]([OH:45])([CH3:44])[CH2:7][CH2:8][CH:9]([O:36][Si:37]([CH2:42][CH3:43])([CH2:38][CH3:39])[CH2:40][CH3:41])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:35])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([O:31][C:46](=[O:53])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)C=CC1C
Reactant: O=C(Cl)c1ccccc1
Agent: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CCC(OC(=O)c1ccccc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(OC(=O)c1ccccc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)C=CC1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(8E,12E,14E)-7-acetoxy-6,21-dihydroxy-6,10,12,16,20-pentamethyl-3-triethylsiloxy-18,19-epoxytricosa-8,12,14-trien-11-olide (101 mg, 156 μmol) was dissolved in methylene chloride (1 mL). 4-dimethylaminopyridine (59.7 mg, 48.9 μmol) was added to the solution, and the solution was cooled to 0° C. Benzoyl chloride (28.0 μL, 241.0 μmol) was added to the solution, and the solution was stirred at room temperature for two hours. The reaction solution was diluted with ethyl acetate (20 mL), and the dilution was washed with purified water (4 mL) twice and brine (4 mL). The resulting organic layer was dried over sodium sulfate, and then filtered. The filtrate was concentrated. The concentrate was purified by silica gel column chromatography (MERCK Silica gel 60, 63 to 200 μm; hexane:ethyl acetate=5:1→4:1) to obtain the title compound (107 mg, 142 μmol, 91.0%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](F)[N:10]=1>CN(C=O)C.C1COCC1.O>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)[N:10]=1
Reactant: Fc1cccc(F)n1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Fc1cccc(-n2cccn2)n1
Reaction time: 0.17 h
Yield: 61 %

Procedure:
Sodium hydride / 60 percent oil dispersion (0.80 g, 20 mmol) was added over 5 minutes to a solution of pyrazole (1.4 g, 20 mmol) in DMF (20 mL) and THF (6 mL). After 10 minutes, 2,6-difluoropyridine (1.9 mL, 21 mmol) was added in one portion. After stirring for 20 h, the reaction was diluted with water (250 mL) and extracted with ether (5×50 mL). The organics were combined, washed with water (3×50 mL), brine (50 mL) and dried (Na2SO4). Filtration and removal of solvent left a gold oil that was purified by reverse phase liquid chromatography, affording product as a colorless oil, 2.0 g, 12.3 mmol, 61 percent yield.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][N:14]([CH3:20])[C@@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(Cl)Cl>[CH3:13][N:14]([CH3:20])[C@@H:15]1[CH2:19][CH2:18][N:17]([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[CH2:16]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1ccc(CN2CC[C@@H](N(C)C)C2)cc1
Yield: 98.8 %

Procedure:
Methyl 4-(bromomethyl)benzoate 5 (0.5 g, 2.2 mmol), (R)—N,N-dimethylpyrrolidin-3-amine (0.523 g, 4.6 mmol) and potassium carbonate (0.392 g, 2.8 mmol) were stirred at room temperature for 18 h in ethyleneglycol dimethylether (3 mL) then diluted with DCM (20 mL), washed with brine, dried over MgSO4 and concentrated to give title compound 6 (0.57 g, 96% yield).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27]CC4C=CC=CC=4)[CH:23]=3)[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(CCO)(O)(=O)=O>[Pd].CO.O1CCCC1>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20]3)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2ccc3cc(OCCN4CCC(Cc5ccccc5)CC4)ccc3c2)cc1
Agent: [Pd]
Agent: O=S(=O)(O)CCO
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc2cc(OCCN3CCC(Cc4ccccc4)CC3)ccc2c1
Reaction time: 20 h
Yield: 95.3 %

Procedure:
A mixture of of 4-benzyl-1-[2-(6-benzyloxy-naphthalen-2-yloxy)-ethyl]-piperidine (0.67 g, 1.48 mmol) and 20% palladium on carbon (0.06 g) in methanol (8 ml) and tetrahydrofuran (8 ml) was shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (50 psi) for 20 h. After removal of the catalyst, the filtrate was evaporated and the white solid (0.51 g, 95%) was dissolved in tetrahydofuran (5 ml). A solution of isethionic acid in methanol (4.6 ml, 1.28 mmol) was added, and the solid precipitate was filtered off. The solid was washed with tetrahydofuran, and dried in vacuo overnight to give the title compound (0.51 g, 82%), mp139-141° C. Analysis calculated for C24H27NO2 ·C2H6O4S: C, 64.04; H, 6.82; N, 2.87; S, 6.58. Found: C, 63.88; H, 6.77; N, 2.70; S, 6.60.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:21])[CH:3]=1.C(Cl)[Cl:23]>FC(F)(F)C(O)=O>[ClH:23].[F:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1cc(F)nc(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)nc(N2CCNCC2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
tert-Butyl 4-(6-fluoro-4-methyl-2-pyridyl)piperazine-1-carboxylate (360 mg, 1.22 mmol) was dissolved in a mixture of DCM (20 ml) and trifluoroacetic acid (5 ml) and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, dissolved in THF, evaporated again and again dissolved in THF. Hydrochloric acid (4N in dioxan) was added, the precipitate was collected by filtration, washed with THF and dried under reduced pressure to give 265 mg of a solid (1.14 mmol, yield 93%) MS (multi-mode) m/z=196.1 [M+1]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:27])[O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].IC.[CH3:32]C(=O)OCC>C1COCC1>[Si:1]([O:8][CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([N:23]([CH3:32])[C:24](=[O:26])[CH3:25])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:27])[O:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(=O)Nc1ccc2c(c1)OC[C@H]1[C@H](CO[Si](C)(C)C(C)(C)C)OC(=O)N21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(=O)N(C)c1ccc2c(c1)OC[C@H]1[C@H](CO[Si](C)(C)C(C)(C)C)OC(=O)N21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.11 %

Procedure:
Compound N-((3R,3aS)-3-(((t-butyldimethylsilyl)oxy)methyl)-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-7-yl)-acetamide (0.685 g, 1.747 mmol) was dissolved in 20 ml of THF and cooled on ice-salt bath. 60% NaH (0.14 g, 3.495 mmol) was added. The ice bath was removed, and the reaction mixture was stirred at room temperature for 30 min, and then cooled on ice-salt bath. Iodomethane (0.496 g, 3.495 mmol) was added slowly in dropwise. The ice bath was removed, and the reaction mixture was stirred at room temperature for 3 h. TLC (PE/EA=1/1) was employed to monitor the reaction. After the reaction completed, the reaction was quenched by adding 10 ml of water and then extracted with EA (10 ml×3). The organic phase was combined, dried over anhydrous sodium sulfate, and the solvent was evaporated. Column chromatography (PE/EA=3/1) afforded white solid 0.618 g, yield: 87.11%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([CH2:21][CH2:22]CS([O-])(=O)=O)([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:9]1)=[O:7].[N:35]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([C:50]2([C:56]([OH:58])=[O:57])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:45]=1.C(OCC)(=O)C>CO.ClCCl>[N:35]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[Cl:20][C:15]1[CH:14]=[C:13]([C@@:10]2([CH2:21][CH2:22][N:53]3[CH2:52][CH2:51][C:50]([C:46]4[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=4)([C:56]([OH:58])=[O:57])[CH2:55][CH2:54]3)[CH2:11][CH2:12][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: O=C(O)C1(c2cccnc2)CCNCC1
Reactant: COc1cc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: NC(=O)N1CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(=O)O)(c4cccnc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 88.6 using (S)-2-[1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-(pyridin-3-yl)-piperidine-4-carboxylic acid morpholine-amide to give, after chromatography on silica gel eluting sequentially with ethyl acetate, 2% methanol/dichloromethane, 5% methanol/dichloromethane, and then 7% methanol/dichloromethane, the title compound: Rf =0.44 (silica gel, methanol/dichloromethane/concentrated ammonia 10/90/0.5).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6]1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>ClCCl>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]([OH:11])=[O:12])=[CH:16][CH:15]=1
Reactant: Fc1ccccc1
Reactant: O=C1CCCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)CCCC(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 57.5 %

Procedure:
A suspension of 22.32 g (0.167 mol) of aluminum chloride in 35 ml of dichloromethane is prepared. It is cooled to 0° C. and a mixture of 8.3 g (0.0728 mol) of glutaric anhydride (dihydro-2H-pyran-2,6(3H)-dione) and 8.4 ml (0.0895 mol) of fluorobenzene in 20 ml of dichloromethane is added slowly. The mixture is stirred for 15 hours at room temperature and then hydrolyzed in acidified iced water. The precipitated product is filtered off, washed with water and then dried under reduced pressure. The crude product is then recrystallized from 90 ml of ethyl acetate to give 8.8 g of the expected product in the form of beige crystals (yield=57.5%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:5]=1.[CH3:31][C@@H:32]1[CH2:37][CH2:36][C@H:35](O)[CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O.C1COCC1>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C@H:35]4[CH2:36][CH2:37][C@H:32]([CH3:31])[CH2:33][CH2:34]4)=[CH:20][CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(CN(c2nccc(-c3ccc(O)cc3)n2)C2CCCC2)c1
Reactant: C[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(CN(c2nccc(-c3ccc(O[C@H]4CC[C@H](C)CC4)cc3)n2)C2CCCC2)c1
Temperature: 25 °C

Procedure:
To a THF (2 mL) solution of 3-({cyclopentyl-[4-(4-hydroxy-phenyl)-pyrimidin-2-yl]-amino}-methyl)-benzoic acid methyl ester (39 mg, 0.10 mmol) (prepared in Example 172) was added cis-4-methyl-cyclohexanol (11 mg, 0.10 mmol) and triphenylphosphine (25 mg, 0.10 mmol). After the mixture was cooled 5 min. in an ice bath, diisopropyl azodicarboxylate (DIAD, 19.1 μL, 0.10 mmol) was added. The solution was stirred at room temperature until complete. Water was added, and the mixture was extracted with ethyl acetate (3×2 mL). The ethyl acetate layer was dried over Na2SO4 and concentrated. Purification was carried out by silica gel chromatography eluting with hexanes/ethyl acetate 9:1 then 4:1 to give 16 mg of 3-[(cyclopentyl-{4-[4-(trans-4-methyl-cyclohexyloxy)-phenyl]-pyrimidin-2-yl}-amino)-methyl]-benzoic acid methyl ester. LCMS m/z: 501 (M+1)+.