Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Br:37])[C:5]([C@@H:8]([NH:18][C:19](=[O:36])[CH2:20][N:21]2[C:25]3[C:26]([F:31])([F:30])[C@@H:27]4[CH2:29][C@@H:28]4[C:24]=3[C:23]([C:32]([F:35])([F:34])[F:33])=[N:22]2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[Br:37][C:4]1[C:5]([C@@H:8]([NH:18][C:19](=[O:36])[CH2:20][N:21]2[C:25]3[C:26]([F:31])([F:30])[C@@H:27]4[CH2:29][C@@H:28]4[C:24]=3[C:23]([C:32]([F:33])([F:34])[F:35])=[N:22]2)[CH2:9][C:10]2[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=2)=[N:6][CH:7]=[C:2]([NH:1][S:45]([CH3:44])(=[O:47])=[O:46])[CH:3]=1
Reactant: Nc1cnc([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)c(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cnc([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Compound 41C (35.6 mg, 0.06 mmol) was dissolved in 1 mL of methylene chloride and cooled to 0° C. To it was added 0.2 mL of pyridine followed by methanesulfonyl chloride (0.007 mL, 0.09 mmol). The reaction mixture was stirred at 0° C. for one hour. LCMS showed complete reaction. It was then partitioned between EtOAc and brine. The organic layer was separated, dried and concentrated to afford the title product. MS (m/z) 670.27 [M+H]+.
Reaction SMILES: [Li+].[OH-].[Br:3][C:4]1[CH:32]=[CH:31][C:7]2[N:8]([C:18]([C:20]3[CH:21]=[CH:22][C:23]4[O:28][CH2:27][C:26](=[O:29])[NH:25][C:24]=4[CH:30]=3)=[O:19])[CH:9]([CH2:12][C:13]([O:15]CC)=[O:14])[CH2:10][O:11][C:6]=2[CH:5]=1.CCOC(C)=O.Cl>O.C1COCC1>[Br:3][C:4]1[CH:32]=[CH:31][C:7]2[N:8]([C:18]([C:20]3[CH:21]=[CH:22][C:23]4[O:28][CH2:27][C:26](=[O:29])[NH:25][C:24]=4[CH:30]=3)=[O:19])[CH:9]([CH2:12][C:13]([OH:15])=[O:14])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: CCOC(=O)CC1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)CC1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 108 %

Procedure:
LiOH (55.3 mg, 2.31 mmol) dissolved in water (3 mL) was added to a solution of ethyl {7-bromo-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate (Intermediate 28, 366 mg, 0.77 mmol) in THF (6.0 mL). The mixture was stirred at rt for 1.5 h. EtOAc (40 mL) was added followed by 1 M HCl (3.1 mL, 3.1 mmol) and water (20 mL). The phases were separated and the organic layer was washed with brine (30 mL), dried over Na2SO4 and evaporated to give crude title compound (372 mg, 108%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([CH2:15][CH3:16])=[C:13]([CH3:17])[N:12]=[C:11]([C:18]3[S:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:10]=2)=[CH:4][C:3]=1[CH2:24][OH:25].[C:26](Cl)(=[O:28])[CH3:27].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[C:26]([O:25][CH2:24][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[C:14]([CH2:15][CH3:16])=[C:13]([CH3:17])[N:12]=[C:11]([C:18]3[S:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:10]=2)[CH:6]=[CH:7][C:2]=1[Br:1])(=[O:28])[CH3:27]
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Br)c(CO)c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Br)c(COC(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
A 18-mL vial was charged with [2-bromo-5-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]methanol (93 mg, 0.21 mmol), acetyl chloride (100 mg, 1.27 mmol, 6 eq.). Pyridine (1 ml) was added followed by 4-(dimethylamino)pyridine (5 mg, 0.2 eq.). The resulting mixture was stirred at rt for 2 hr. Then water was (5 ml) added. The precipitate was collected and washed with water. The crude product was purified by chromatography on silica gel using dichloromethane as eluent to give the tile compound (73 mg, 72% yield).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][OH:6])=[CH2:2].C1(C)C=CC=CC=1.[H-].[Na+].[Br:16][C:17]1[CH:22]=[CH:21]C=C(Br)[N:18]=1>O>[Br:16][C:17]1[N:18]=[C:1]([O:3][CH2:4][CH2:5][OH:6])[CH:2]=[CH:21][CH:22]=1
Reactant: Brc1cccc(Br)n1
Reactant: C=COCCO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: OCCOc1cccc(Br)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
8.81 g of ethylene glycol monovinyl ether was added to toluene (100 mL) suspension of 2.4 g of sodium hydride (55% to 72%), and 9.48 g of 2,6-dibromopyridine was added thereto and stirred overnight at 110° C. The reaction liquid was left cooled to room temperature, and water was added thereto to separate the organic layer. This was washed with saturated saline water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. 100 mL of methanol and 576 mg of p-toluenesulfonic acid hydrate were added to the resulting residue, and stirred for 5 hours. After this was concentrated under reduced pressure, aqueous saturated sodium hydrogencarbonate solution was added to it, and extracted with ethyl acetate. This was washed with saturated saline water, dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1 to 2/1) to obtain 7.74 g of the entitled compound as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[Si:11]([CH3:14])([CH3:13])[CH3:12]>>[CH3:12][Si:11]([CH3:14])([CH3:13])[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: C[Si](C)(C)Cl
Product: Cc1cc(C)cc([Si](C)(C)C)c1

Procedure:
In the same manner as described in preparation 1, 5-bromo-m-xylene was allowed to react with chlorotrimethylsilane, and afforded TSIX. The yield and properties of product are summarized in Table 1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[NH2:20].C(O)C.S([O-])(O)(=O)=O.[K+]>O>[CH:16]1[CH:17]=[CH:18][C:10]([OH:9])=[C:11]([C:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 72.5 °C
Reaction time: 0.75 h

Procedure:
2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one (1.0 kg) and 4-Hydrazino benzoic acid (0.699 kg), Ethanol (9.0 lit), Water (1.0 lit) was stirred at 25-35° C. in round bottom flask. Followed by addition of Potassium hydrogen sulphate (0.15 kg) into the reaction mass and heated the reaction mass at 70-75° C. for two hrs. Cooled the reaction mass at 25-30° C. and stirred for 45 minutes. Filtered off the solid and washed with ethanol. Obtained solid and water (1.0 lit) stirred at 25-30° C. for 15 minutes and then heated at 50-55° C. for 1 hr. The solid was filtered at 50-55° C. and washed with water. Charge this wet cake in DMF (5.0 lit) and stirred at 25-30° C. In this solution 30% H2O2 was added at 25-30° C. within 1 hr. Followed by addition of water at 25-30° C. and stirred for 30 minutes. Filtered off the solid and washed it with water. The obtained solid was added in pre heated water and stirred at 45-50° C. Gradually increased the temperature up to 65-75° C. & stir it for 60 min. cooled the reaction mass at 45-50° C. and stirred it for 40 minutes. The precipitated Deferasirox filtered off and washed with water. Dry the solid at 65-75° C. in vacuum tray drier.
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1)C>O1CCCC1.O>[O:4]=[CH:5][CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1
Reactant: CCOC(COc1ccc(CC2SC(=O)NC2=O)cc1)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=CCOc1ccc(CC2SC(=O)NC2=O)cc1
Reaction time: 8 h
Yield: 75.2 %

Procedure:
20 ml of 6N aqueous hydrochloric acid were added to a solution of 10.07 g of 5-[4-(2,2-diethoxyethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Preparation 46) in 80 ml of tetrahydrofuran, and the resulting mixture was allowed to stand overnight at room temperature. At the end of this time, the reaction reduced pressure. The residue was diluted with water, after which it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 2:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 5.92 g of the title compound having Rf=0.37 (on silica gel thin layer chromatography using a 1:2 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[NH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[F:22])[N:15]([CH3:23])[N:14]=1>>[F:22][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:21]=1[C:13]([NH:12][C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5])=[N:14][N:15]2[CH3:23]
Reactant: Cn1nc(N)c2c(F)cccc21
Reactant: COC(=O)c1ccncc1Br
Product: Cn1nc(Nc2cnccc2C(=O)O)c2c(F)cccc21
Yield: 34 %

Procedure:
The title compound was prepared in 34% yield from methyl 3-bromoisonicotinate and 3-amino-4-fluoro-1-methyl-indazole according to the general procedure for Example 6. 1H NMR (400 MHz, DMSO-d6): δ 4.00 (3H, s), 6.84-6.89 (1H, m), 7.39-7.42 (2H, m), 7.80 (1H, d, J=5.0 Hz), 8.21 (1H, d, J=5.0 Hz), 9.90 (1H, s), 10.88 (1H, br s), 14.22 (1H, br s). [M+H] calc'd for C14H11FN4O2, 287; found 287.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[O:32][CH3:33])=[O:11])=CC=1)([O-])=O.[H][H]>CO.O1CCCC1.[Pd]>[O:23]([CH2:22][C:21]([NH:20][C@@H:19]1[C:18](=[O:31])[N:17]2[C:12]([C:10]([OH:11])=[O:9])=[C:13]([O:32][CH3:33])[CH2:14][S:15][C@H:16]12)=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [H][H]
Reactant: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 1 h

Procedure:
A solution of 250 mg (0.5 mmol) of 7β-phenoxyacetamido-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 2 ml of methanol/tetrahydrofurane, 1:1, is added to a mixture of 5% palladium/charcoal in 2 ml of the same solvent, which mixture has been prehydrogenated for one hour under atmospheric pressure, and the reaction mixture is hydrogenated for 3 hours at room temperature and under atmospheric pressure. After this time, about 90% of the calculated amount of hydrogen has been taken up. The catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is taken up in 10 ml of methylene chloride and extracted with twice 10 ml of 5% strength aqueous sodium bicarbonate solution. The combined bicarbonate extracts are neutralised at 0° C. with dilute hydrochloric acid and extracted with 3 times 10 ml of methylene chloride. The organic phase is dried over sodium sulphate and freed from the solvent in vacuo. After crystallisation from chloroform/pentane, the residue gives 7β-phenoxyacetamido-3-methoxy-3-cephem-4-carboxylic acid of melting point 173°-174° C.
Reaction SMILES: C1([N:7]=C=NC2CCCCC2)CCCCC1.C([O:19][CH:20]1[CH2:24][CH2:23][N:22]([CH2:25][C:26](O)=[O:27])[C:21]1=[O:29])(=O)C.ON1C(=O)CCC1=O>C(Cl)(Cl)Cl>[OH:19][CH:20]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([NH2:7])=[O:27])[C:21]1=[O:29]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(=O)OC1CCN(CC(=O)O)C1=O
Agent: O=C1CCC(=O)N1O
Solvent: ClC(Cl)Cl
Product: NC(=O)CN1CCC(O)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.64 g of dicyclohexylcarbodiimide dissolved in 20 ml of chloroform are added at room temperature to 1.5 g of (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetic acid, 40 ml of chloroform and 0.86 g of N-hydroxysuccinimide. After 4 hours, the solid is filtered, whereupon the filtrate is concentrated and again filtered. The filtrate is evaporated. The residue is treated at room temperature with 40 ml of a saturated solution of ammonia in methanol. The mixture is stirred at room temperature for 5 minutes, 10 ml of ion-free water are then added thereto and the mixture is stirred at room temperature for an additional minutes. The precipitated solid is filtered. The filtrate is evaporated, the residue is stirred in 30 ml of acetonitrile and the crystallized-out product is recrystallized two more times from acetonitrile. There is obtained (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide of melting point 162°-164°.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C1(C)C(C)=CC=CC=1.[C:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](Cl)[CH:24]=1)(=[O:20])[CH3:19]>C1(C)C=CC=CC=1>[C:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:24]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OCc1cccc(Cl)c1
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: CC(=O)OCc1cccc(Oc2ccccc2)c1
Yield: 73 %

Procedure:
18.07 g. (0.192 mole) of phenol, 8.42 g. (0.15 mole) of potassium hydroxide and 20 cm3 of xylene are weighed together. The water is azeotropically distilled with stirring and boiling then the xylene is also distilled. To the reaction mixture 1.0 g. of copper(I) chloride and 1.0 g. of activated copper are added and in oil bath of 160° C. 18.07 g. (0.1 mole) of 3-chlorobenzyl acetate are dropped during 70 minutes then stirred at the same temperature for four hours. After cooling 25 cm3. of toluene are added to the reaction mixture, then the reaction mixture is filtered off and washed with 25 cm3. of toluene. The filtrate is washed with a mixture of 30 cm3. 15% sodium chloride solution and 2 cm3. 40% sodium hydroxide solution. The organic phase is evaporated and the residue is distilled in vacuo. 17.68 g. of 3-phenoxybenzyl acetate are obtained. Boiling point 138°-144° C./40 Pa, nD20 : 1.562, yield 73%.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][O:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[Br:18][C:19]([CH3:24])([CH3:23])[C:20](Br)=[O:21]>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][O:5][CH2:6][CH2:7][O:8][C:20](=[O:21])[C:19]([Br:18])([CH3:24])[CH3:23]
Reactant: CC(C)(Br)C(=O)Br
Reactant: COC(COCCO)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(COCCOC(=O)C(C)(C)Br)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(2,2-dimethoxy-ethoxy)-ethanol (2.20 g, 14.6 mmol) from Example 9 in dry triethylamine (3.0 mL, 21 mmol) and dry methylene chloride (30 mL) was stirred at 0° C. 2-bromo-2-methylpropionyl bromide (1.7 mL, 14 mmol) methylene chloride (10 mL) was then added to the alcohol over a 15 minute period. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was filtered, the filtrate was washed with saturated sodium bicarbonate, and dried with magnesium sulfate. The solvent was removed and the yellow oil purified by column chromatography. 1H NMR (300 MHz, CDCl3): δ=1.78 (s, 6H), 3.31 (s, 6H), 3.49 (d, 2H), 3.68 (t, 2H), 4.25 (t, 2H), 4.46 (t, 1H) 13C NMR (300 MHz, CDCl3): δ=31.23, 55.85, 56.15, 65.58, 69.55, 71.44, 103.09, 172.07.
Reaction SMILES: [NH2:1][CH:2]([C:5]([OH:7])=O)[CH2:3][OH:4].[OH-].[Na+].[CH2:10]([N:14]=[C:15]=[O:16])[CH2:11][CH2:12][CH3:13]>O>[CH2:10]([N:14]1[C:5](=[O:7])[CH:2]([CH2:3][OH:4])[NH:1][C:15]1=[O:16])[CH2:11][CH2:12][CH3:13]
Reactant: NC(CO)C(=O)O
Reactant: CCCCN=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCN1C(=O)NC(CO)C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
DL-Serine (5.0 g) was dissolved in water (25 ml) containing sodium hydroxide (23.8 ml, 2N) and the mixture cooled to 0° C., stirred and n-butyl isocyanate (9.4 g) added. The mixture was stirred at 0° C. for 2 hours then allowed to rise to room temperature overnight, filtered and the filtrate acidified with concentrated hydrochloric acid (50 ml) and heated on a steam-bath for 2 hours. The mixture was cooled and extracted with ether (3×100 ml). Removal of the ether gave an oil which rapidly crystallised and the title product recrystallised from carbon tetrachloride as small cubes, m.p. 93° C. Yield 5.1 g=57%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH:16]1([CH2:19]Cl)[CH2:18][CH2:17]1>CN(C)C=O>[CH:16]1([CH2:19][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:18][CH2:17]1
Reactant: ClCC1CC1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.7 %

Procedure:
3-Hydroxybenzaldehyde (3 g, 24.6 mmol) and potassium carbonate (10.2 g, 73.8 mmol) were suspended in N,N-dimethylformamide (60 mL). Cyclopropyl methyl chloride (2.86 mL, 29.5 mmol) was added to this suspension, and stirred for 19 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (4.32 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:21][C:22]([C:25]1[CH:26]=[CH:27][C:28]([O:33][C:34]([F:37])([F:36])[F:35])=[C:29]([CH:32]=1)[CH:30]=O)([F:24])[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>C(Cl)Cl>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:30][C:29]2[CH:32]=[C:25]([C:22]([F:24])([F:21])[CH3:23])[CH:26]=[CH:27][C:28]=2[O:33][C:34]([F:35])([F:37])[F:36])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(F)(F)c1ccc(OC(F)(F)F)c(C=O)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(C(C)(F)F)ccc2OC(F)(F)F)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 156.8 %

Procedure:
To a stirred solution of Compound 12 (500 mg, 1.81 mmol) and Compound 25 (552 mg, 2.17 mmol) in dry CH2Cl2 (10 ml) was added sodium triacetoxyborohydride (1.15 g, 5.43 mmol) portionwise at room temperature. Then to this was added acetic acid (109 mg, 1.81 mmol) at same temperature. The reaction mixture was stirred at room temperature for 66 h. The reaction mixture was basified to pH10-11 with 10% NaOH aq. with ice-cooling. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with brine, dried (MgSO4), and concentrated in vacuo to give crude product (1.46g) as a pale yellow oil. This was employed for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6]([C:12]#[N:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C1C=C(O[C:21](OC2N=CC=CC=2)=[S:22])N=CC=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:12]([C:6]1[C:5]2[C:9](=[C:10]([CH3:11])[C:2]([N:1]=[C:21]=[S:22])=[CH:3][CH:4]=2)[NH:8][CH:7]=1)#[N:13]
Reactant: Cc1c(N)ccc2c(C#N)c[nH]c12
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2c(C#N)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of 6-amino-3-cyano-7-methylindole (0.155 g, 0.905 mmol) in methylene chloride (10 mL) is added di-2-pyridyl thionocarbonate (0.210 g, 0.905 mmol) followed by 4-dimethylaminopyridine (0.010 g, 0.0905 mmol). The resulting solution is stirred at room temperature for one hour followed by removal of the methylene chloride by rotary evaporation. The crude material is purified via silica gel column chromatography using 20% ethyl acetate/hexane as the eluting solvent. The product containing fractions are combined and the solvents removed by rotary evaporation to yield 0.154 g of 3-cyano-6-isothiocyanato-7-methylindole as a yellow solid (80% yield).
Reaction SMILES: [C:1]([O:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([OH:17])([CH2:10]3)[CH2:8]1)[CH2:14]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].CC1(C)[O:24][C:23](=O)[CH:22]=[C:21]([CH3:26])[O:20]1.C>C1(C)C=CC=CC=1.COP(OC1C=CC(C#N)=CC=1)(OC)=S>[C:1]([O:6][C:7]12[CH2:14][CH:13]3[CH2:12][CH:11]([CH2:10][C:9]([O:17][C:23](=[O:24])[CH2:22][C:21]([CH3:26])=[O:20])([CH2:15]3)[CH2:8]1)[CH2:16]2)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC12CC3CC(CC(O)(C3)C1)C2
Reactant: CC1=CC(=O)OC(C)(C)O1
Agent: COP(=S)(OC)Oc1ccc(C#N)cc1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC12CC3CC(CC(OC(=O)CC(C)=O)(C3)C1)C2
Temperature: 110 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
3-(Acetoacetyloxy)adamantyl methacrylate (AAHAMA) was prepared according to the following procedure. 65.6 g of 3-hydroxyadamantan-1-yl methacrylate (HAMA) (277.6 mmol) and 42.1 g of 95% pure 2,2,6-trimethyl-4H-1,3-dioxin-4-one (277.6 mmol) were mixed with 0.2 g of CYANOX® 1790 inhibitor in 400 ml of toluene. After refluxing (110° C.) for 4 hours, the reaction was cooled, 10 g of activated charcoal and 400 ml of toluene were added, and the mixture stirred overnight. After filtration, another 10 g of activated charcoal was added, and the mixture stirred for an additional 12 h., then filtered. The filtrate was concentrated and run through a silica gel flash column with ethyl acetate as eluant. The solvent was then removed to yield 80 g (90%) of 3-acetoacetoxyadamantan-1-yl methacrylate was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH2:4][CH2:3]1.CCN(CC)CC.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH2:27]([O:26][C:24]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2([CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[CH2:8]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN1CCC2(CC1)CNc1ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCC2(CC1)CN(C(=O)OCc1ccccc1)c1ccccc12
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of 99 g (489 mmol) of 1'-methylspiro(indoline-3,4'-piperidine) (prepared according to Ong, H. H. et al, J. Med. Chem., 1983, 26, 981-986) in 1 L of CH2Cl2 and 82 mL (539 mmol) of Et3N was cooled to 0-5° C. with an ice bath and 77 mL (539 mmol) of benzyl chloroformate was added over 30 min keeping the reaction temperature below 10° C. After stirring for 2 h 19 mL (136 mmol) of Et3N and 15 mL (105 mmol) of benzyl chloroformate were added since the reaction was incomplete and stirred for 2 h. At this time, additional 19 mL (136 mmol) of Et3N and 15 mL (105 mmol) of benzyl chloroformate were added. After 1 h, when a TLC indicated a complete reaction, the solution was concentrated in vacuo and the residue was partitioned between ether and saturated NaHCO3. The layers were separated, the organic layer was washed with saturated NaHCO3 and brine, and dried over MgSO4. The filtrate was concentrated and the residue was chromatographed on 2 kg of silica gel using 1-5% MeOH/CH2Cl2 to obtain 117 g (71%) of 1-benzyloxycarbonyl-1'-methylspiro(indoline-3,4'-piperidine) as a yellow oil.
Reaction SMILES: O1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([CH3:28])([CH3:27])[CH2:11][C:12](=[O:26])[C:13](NC3C=CC=C4C=3C=CC=N4)=[O:14])[C:4]=2OC1.CC(C1C=CC=CC=1)(C)CC(=O)C(N)=[O:34]>>[CH3:27][C:10]([C:9]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([CH3:28])[CH2:11][C:12](=[O:26])[C:13]([OH:14])=[O:34]
Reactant: CC(C)(CC(=O)C(N)=O)c1ccccc1
Reactant: CC(C)(CC(=O)C(=O)Nc1cccc2ncccc12)c1cccc2c1OCO2
Product: CC(C)(CC(=O)C(=O)O)c1ccccc1

Procedure:
According to the instructions for 4-(1,3-benzodioxol-4-yl)-N-(quinolin-5-yl)-4-methyl-2-oxopentanamide (Example 12) after chromatography on silica gel, 370 mg of N-(quinolin-5-yl)-)-4-methyl-2-oxo-4-phenylpentanamide is obtained from 515 mg of 4-methyl-2-oxo-4-phenylpentanoic acid (WO98/54159). Flash point: 98-99° C.