Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@@H:10]([C:12]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:30])[NH:17]2)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Br[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:53]=[C:54]([S:58]([NH2:61])(=[O:60])=[O:59])[CH:55]=[CH:56][CH:57]=1>C(#N)C.O>[CH2:1]([N:8]([CH2:9][C@@H:10]([C:12]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:30])[NH:17]2)[OH:11])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:53]=[C:54]([S:58]([NH2:61])(=[O:60])=[O:59])[CH:55]=[CH:56][CH:57]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cccc(CCCOCCCCCCCBr)c1
Reactant: O=c1ccc2c([C@@H](O)CNCc3ccccc3)ccc(OCc3ccccc3)c2[nH]1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NS(=O)(=O)c1cccc(CCCOCCCCCCCN(Cc2ccccc2)C[C@H](O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1
Yield: 46.1 %

Procedure:
5-[(1R)-2-(Benzylamino)-1-hydroxyethyl]-8-(benzyloxy)quinolin-2(1H)-one (48 mg) was dissolved in acetonitrile (2 ml). N,N-diisopropylethylamine (0.042 ml), and 3-{3-[(7-bromoheptyl)oxy]propyl}benzenesulfonamide (43 mg) were added to the solution, which was heated at reflux for 72 h under nitrogen. The mixture was diluted with water and extracted with ethyl acetate. The organic extracts were combined, dried (MgSO4) and evaporated in vacuo. The residue was purified on a silica SPE cartridge eluting with ethyl acetate-cyclohexane mixtures to give the title compound (36 mg). LCMS RT=2.76 min
Reaction SMILES: [S:1](=[O:3])=[O:2].[OH-].[Na+:5].[S:6]([O-:9])([O-:8])=[O:7].[Na+].[Na+]>>[S:6]([S:1]([O-:3])=[O:2])([O-:9])(=[O:8])=[O:7].[Na+:5].[Na+:5]
Reactant: O=S([O-])[O-]
Reactant: O=S=O
Agent: [Na+]
Agent: [OH-]
Product: O=S([O-])S(=O)(=O)[O-]

Procedure:
Sulfur dioxide is introduced into a solution of sodium sulfite and sodium bisulfite to form sodium bisulfite in a solution having dissolved sulfur dioxide present with a pH between 3.5 and 4.2. The solution is drawn to a cooling crystallizer where an alkali such as soda ash, caustic soda, sodium sulfite, and mixtures thereof is added to produce additional sodium metabisulfite that increases the yield of sodium metabisulfite crystallizing per pass. The mother liquor is recycled.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37])[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Reactant: N#Cc1cc(N)ccc1N1CCN(CCOCCO)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(CCOCCO)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 65.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (2 g) and 5-amino-2-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}benzonitrile (4.2 g), the title compound (2.8 g) was obtained, melting point: 196° C.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8](OCC)=[O:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[N:1]12[CH2:7][C:4]([CH2:8][OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: CCOC(=O)C12CCN(CC1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC12CCN(CC1)C2

Procedure:
1-Azabicyclo[2.2.1]heptan-4-ylmethanol was prepared by reducing ethyl 1-azabicyclo[2.2.1]heptane-4-carboxylate with lithium aluminum hydride, as described in J. Med. Chem. 35, 2392 (1992).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](O)(=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>Cl>[C:12]1([CH2:11][CH2:10][C:9]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)CCc1ccccc1
Agent: Cl
Product: c1ccc(CCc2nc3ccccc3[nH]2)cc1
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A 100 mL flask fitted with a stir-bar and condenser was charged with 1,2-phenylenediamine (2.88 g, 26.6 mmol), hydrocinnamic acid (4.00 g, 26.6 mmol), and 4M HCl (40 mL). The resultant suspension was heated in a 130° C. bath 48 hr. The mixture was cooled, and the precipitate was filtered. The solid was suspended in H2O (70 mL), and the suspension was brought to pH 11 with 50% aqueous NaOH and stirred overnight. The pH was readjusted from 3 to 11 with 50% NaOH. The solid was filtered, pressed with rubber dam, and rinsed with H2O (2×10 mL). The material was dried to give 4.9 g of 67 as a white solid (83%). 1H NMR (60 MHz, CDCl3): δ 12.3 (s, 1H), 7.6-7.4 (m, 2H), 7.4-6.8 (m, 7H), 3.2 (s, 4H) ppm. HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of greater than 99% with a retention time of 3.2 min.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]([CH3:39])=[C:20]([CH:37]=[O:38])[C:21]4[O:25][C:24]([CH3:27])([CH3:26])[CH:23]([C:28]5[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=5)[C:22]=4[C:35]=3[CH3:36])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.O>C1COCC1>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]([CH3:39])=[C:20]([CH:37]([OH:38])[CH3:1])[C:21]4[O:25][C:24]([CH3:27])([CH3:26])[CH:23]([C:28]5[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=5)[C:22]=4[C:35]=3[CH3:36])[CH2:14][CH2:13]2)=[CH:10][CH:11]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C=O)c4c(c3C)C(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N2CCN(c3c(C)c(C(C)O)c4c(c3C)C(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Reaction time: 0.33 h
Yield: 1.3 %

Procedure:
To a solution of methyl magnesium bromide (THF solution 3.0 M, 1.0 mL, 3.0 mmol) in THF (5 ml) at −30° C. was added 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-7-carbaldehyde (310 mg, 640 mmol) obtained in Example 105. The reaction mixture was stirred for 20 minutes under the same temperature. The resulting mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane-ethyl acetate to obtain 19.5 mg (yield 61%) of the title compound. mp. 149–151° C.
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[CH:29]1[C:34](/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38])=[CH:33][CH:32]=[C:31]([OH:40])[CH:30]=1.C(OC(C)C)(C)C>CO>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:37]([O-:39])(=[O:38])/[CH:36]=[CH:35]/[C:34]1[CH:33]=[CH:32][C:31]([OH:40])=[CH:30][CH:29]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CO
Solvent: CC(C)OC(C)C
Product: O=C([O-])/C=C/c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Sitagliptin free base (2.0 gms) and coumaric acid (0.80 gms) were dissolved in methanol (12 ml) at 60° C. to 65° C. and the solution was cooled to room temperature. Isopropyl ether (240 ml) was added to the resultant clear solution and stirred for 14 hours. Precipitated solids were filtered and dried at 50° C. to 55° C. for 6 hours to obtain the title compound. Yield: 2.05 gms.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][O:3][CH2:2]1.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[CH3:33][C:34]1[C:39]([Pb+3])=[C:38]([CH3:41])[CH:37]=[C:36]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:35]=1.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:33][C:34]1[CH:35]=[C:36]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:37]=[C:38]([CH3:41])[C:39]=1[CH:9]1[C:10](=[O:12])[CH2:11][C:6]2([CH2:5][CH2:4][O:3][CH2:2][CH2:1]2)[CH2:7][C:8]1=[O:13]
Reactant: Cc1cc(-c2ccccc2)cc(C)c1[Pb+3]
Reactant: O=C1CC(=O)CC2(CCOCC2)C1
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)CC2(CCOCC2)CC1=O
Temperature: 25 °C

Procedure:
To a mixture of 3-oxaspiro[5.5]undecane-8,10-dione (0.182 g, 1 mmol) and 4-dimethylamino-pyridine (0.61 g; 5 mmol) is added dry chloroform (4 ml), and the mixture is stirred under an atmosphere of nitrogen at room temperature until the solid dissolves. To this solution is then added dry toluene (2 ml), and then a solution of 3,5-dimethylbiphen-4-yllead triacetate (1.2 mmol) in chloroform is added. The reaction mixture is heated under reflux for 1 hour, then cooled to room temperature, acidified to pH=1 with 2N aqueous hydrochloric acid, filtered and the filtrate is extracted with dichloromethane (2×40 ml). The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo. The residue is purified by column chromatography over silica gel to give 9-(3,5-dimethylbiphenyl-4-yl)-3-oxa-spiro[5.5]undecane-8,10-dione.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].[Cl-].[NH4+]>O1CCCC1>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:17])[C@@H:11]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC[C@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 91.2 %

Procedure:
A solution of 4-(S)-isopropyl-3-(1-oxoheptyl)-2-oxazolidinone (519 mg) in tetrahydrofuran (15 ml) was cooled to -15° C., a 0.58M solution (39 ml) of lithium diisopropylamide in tetrahydrofuran was added thereto under an atmosphere of nitrogen, and the resulting mixture was stirred at -78° C for 10 minutes. A solution of tert-butyl bromoacetate (1.7 ml) in tetrahydrofuran (5 ml) was then added thereto and the temperature was allowed to rise gradually to -55° C. over a period of 5.5 hours with stirring. The reaction mixture was poured into a 5% aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic extract was successively washed with water and a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography through silica gel using a 10:1 mixture of hexane and ethyl acetate as an eluent, to give 697 mg (91.2%) of the desired compound. Recrystallization from aqueous methanol gave rise to crystals having a m.p. of 51°-53° C.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=[O:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:17]([CH2:19][CH2:20][PH:21](=[O:26])[CH2:22][CH2:23][C:24]#[N:25])#[N:18].CN(C)C(=O)C>O>[C:17]([CH2:19][CH2:20][P:21]([CH2:22][CH2:23][C:24]#[N:25])(=[O:26])[O:11][C:9]1[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)#[N:18]
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reactant: N#CCC[PH](=O)CCC#N
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)c1cc(OP(=O)(CCC#N)CCC#N)cc(C(C)(C)C)c1O
Yield: 40.2 %

Procedure:
2,6-Di-tert.-butyl-1,4-benzoquinone (11.0 grams; 0.05 mole) and bis-(2-cyanoethyl)phosphine oxide (8.0 grams; 0.05 mole) are dissolved in 20 mls. of N,N-dimethylacetamide and the solution is heated at reflux for 2 hours. The solution is then cooled to ambient conditions and drowned in water to precipitate a pale yellow oil which is subsequently separated, washed well with water, and extracted with diethyl ether. The ethereal extract is then stripped of diethyl ether and the residue is dried in vacuo at 50° C. to obtain 7.56 grams of a yellow oil which has an infrared absorption spectrum consistent with the desired product.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[C:4]([F:12])[CH:3]=1.[CH:13]1([CH:18]([OH:21])[CH:19]=[CH2:20])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:13]1([C:18](=[O:21])[CH2:19][CH2:20][C:2]2[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[C:4]([F:12])[CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C=CC(O)C1CCCC1
Reactant: N#CCOc1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#CCOc1ccc(CCC(=O)C2CCCC2)cc1F
Temperature: 140 °C
Yield: 90.8 %

Procedure:
A mixture of (4-bromo-2-fluorophenoxy)acetonitrile (2.5 g, 10.8 mmol), 1-Cyclopentyl-2-propen-1-ol (2.0 g, 16.2 mmol), dichlorobis(triphenylphosphine)palladium (II) (151 mg, 0.22 mmol), and sodium bicarbonate (1.08 g, 12.9 mmol) in N-methylpyrrolidinone (20 mL) was heated to 140° C. under N2 for 5 hours. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a black oil. The oil was purified by flash column chromatography (Hexanes to 10% EtOAc in hexanes) to give the desired product (2.7 g, 93%). 1H NMR (CDCl3): δ 1.52-1.83 (m, 8H), 2.75 (m, 2H), 2.85 (m, 3H), 4.80 (s, 2H), 6.92-7.06 (m, 3H).
Reaction SMILES: [O:1]1[C:5]([CH2:6][OH:7])=[CH:4][CH:3]=[C:2]1[CH2:8][OH:9].[H-].[Na+].S(OC)(O[CH3:16])(=O)=O.Cl>O1CCCC1.CN(C)C=O>[CH3:16][O:7][CH2:6][C:5]1[O:1][C:2]([CH2:8][OH:9])=[CH:3][CH:4]=1
Reactant: OCc1ccc(CO)o1
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCc1ccc(CO)o1
Reaction time: 2 h

Procedure:
6.4 g of 2,5-furandimethanol were dissolved at 20° C. in 120 ml of tetrahydrofuran and 2.4 g of sodium hydride were added over 30 minutes. The mixture was stirred for 2 hours and 60 ml of dimethylformamide and 4.7 ml of dimethyl sulfate were added. The mixture was stirred for 16 hours at 20° C., poured into ice-cold water and acidified with hydrochloric acid. The mixture was extracted with isopropyl ether and the extract was washed with water and dried. The solvent was evaporated and the residue was chromatographed on silica (eluent: 5/5 hexane/ethyl acetate) to obtain 2.97 g of the expected product.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:36])[CH:15]=[CH:16][CH:17]2[C:22]([CH3:24])([CH3:23])[C:21]([CH3:25])=[C:20]([C:26]([O:28]C(C)(C)C)=[O:27])[C:19]([CH3:33])=[C:18]2[O:34][CH3:35])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].BrC(C)(C)C(OC(C)(C)C)=O>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14](=[O:36])[CH:15]=[CH:16][CH:17]2[C:22]([CH3:23])([CH3:24])[C:21]([CH3:25])=[C:20]([C:26]([OH:28])=[O:27])[C:19]([CH3:33])=[C:18]2[O:34][CH3:35])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccc(C(=O)C=CC2C(OC)=C(C)C(C(=O)OC(C)(C)C)=C(C)C2(C)C)cc1
Agent: CC(C)(C)OC(=O)C(C)(C)Br
Product: CCCCCCCc1ccc(C(=O)C=CC2C(OC)=C(C)C(C(=O)O)=C(C)C2(C)C)cc1

Procedure:
This compound was synthesized from 1-[4-heptylphenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl]prop-2-en-1-one (compound 38) and tertbutyl bromoisobutyrate according to general method 4 described earlier.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]([OH:9])[C:7]([CH3:10])=[CH:6][C:5](=[O:11])[C:4]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[C:28]1([CH:34](Br)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[OH:1][CH2:2][C:3]1[N:8]([O:9][CH:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:7]([CH3:10])=[CH:6][C:5](=[O:11])[C:4]=1[O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: COc1ccc(COc2c(CO)n(O)c(C)cc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2c(CO)n(OC(c3ccccc3)c3ccccc3)c(C)cc2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 300 mg of 6-hydroxymethyl-5-p-methoxybenzyloxy-2-methyl-1-hydroxy-4-pyridone in 10 ml of dimethylformamide were successively added 213 mg of potassium carbonate and 423 mg of diphenylmethyl bromide. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction liquid was concentrated and the concentrate was added to 20 ml of water and 40 ml of dichloromethane. The organic phase was washed with 20 ml of water.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29]>O1CCCC1.O>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:24])=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29]
Reactant: Cc1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc(F)c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of p-Tolylamine (626 mg, 5.89 mmol), and Hunig's base (2.054 ml, 11.8 mmol) in tetrahydrofuran (20 mL) was added the product from Example 86A (1.20 g, 5.89 mmol) in tetrahydrofuran (10 mL) dropwise over 10 minutes. The solution was stirred at room temperature for 1 hour, the reaction mixture diluted with water and the title compound was collected by filtration (1.77 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32](Cl)=[O:33])[CH2:28][CH2:27]1.C(Cl)(Cl)=O.[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]\[C:42]([OH:44])=[O:43]>C(Cl)(Cl)Cl.ClCCl.CO.O>[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]\[C:42]([OH:44])=[O:43].[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[C:2]([NH:1][C:32]([N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)=[O:33])[CH:7]=1
Reactant: Cc1ccc(N2CCc3ccccc32)c(N)c1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Agent: O=C(Cl)Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(N2CCc3ccccc32)c(NC(=O)N2CCN(C)CC2)c1
Reaction time: 0.25 h

Procedure:
To a stirred solution, under nitrogen of 43.0 g (0.190 mole) of 1-(2-amino-4-methylphenyl)indoline of Example 5b and 105 g (0.76 mole) of milled potassium carbonate in 1000 ml of chloroform was added 56.7 (0.285 mole) of 4-methyl-1-piperazinecarbonyl chloride hydrochloride in portions over 10 minutes. The reaction was refluxed for 7 hours, when an additional charge of 13.1 g (0.095 mole) of potassium carbonate and 18.9 g (0.095 mole) of the carbonyl chloride reagent was added. After refluxing overnight (about 16 hours), the reaction was cooled, treated with 500 ml of water, and stirred vigorously for 15 minutes. The layers were separated and the organic phase was washed thrice with water, dried over NaSO4, and concentrated in vacuo to a semi-solid weighing 77 g. This was dissolved in 200 ml of methanol and treated with a solution of 24.4 g of maleic acid in 100 ml of methanol. This afforded 37.7 g (43% overall yield) of crystalline maleate salt. This salt was reversed back to the free base urea, yielding 18.1 g. This material was dissolved in 50 ml of dichloromethane and absorbed on a tall chromatography column containing 300 g of silica gel packed in dichloromethane. Elution first with dichloromethane, followed by 25% methanol/75% dichloromethane brought forth 16.2 g (24% overall yield) of pure urea. This (0.046 mole) was dissolved in 50 ml of methanol and treated with a solution of 5.92 g (0.051 mole) of maleic acid dissolved in 25 ml of methanol. The resulting maleate salt was recrystallized from methanol to afford 12.6 g of N-[ 5-methyl-2-(2,3-dihydro-1H-indol-1-yl)-phenyl]-4-methyl-1-piperazinecarboxamide maleate, m.p. 173°-175° C. dec.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[S:27])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1.Cl.[NH:39]1[CH2:42][CH2:41][CH2:40]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:39]1([CH:17]2[CH2:18][CH2:19][N:14]([C:12]([NH:11][C:7]3[CH:6]=[C:5]([O:4][C:3]4[CH:21]=[CH:22][C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[S:27])=[CH:24][C:2]=4[F:1])[CH:10]=[CH:9][N:8]=3)=[O:13])[CH2:15][CH2:16]2)[CH2:42][CH2:41][CH2:40]1
Reactant: O=C1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC4)CC3)c2)c(F)c1
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of 4-{2-fluoro-4-[3-(2-phenylacetyl)thioureido]phenoxy}-2-[(4-oxopiperidin-1-yl)carbonylamino]pyridine (38 mg) in dichloromethane (2.0 ml) were added azetidine hydrochloride (17 mg) and sodium triacetoxyborohydride (40 mg) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under a reduced pressure to give a residue, which was dried in vacuum to provide the titled compound (31.9 mg, 78%) as white powder.
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([Br:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:22]([CH3:24])[CH3:23])[CH:16]=1)[CH2:9]O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([Br:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:22]([CH3:24])[CH3:23])[CH:16]=1)[CH2:9][Br:2]
Reactant: CC(C)c1cc(Oc2c(Br)cc(CO)cc2Br)ccc1O
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Br)cc(CBr)cc2Br)ccc1O
Yield: 72.1 %

Procedure:
A solution of PBr3 (125 mg, 0.463 mmol) in 5 ml of CH2Cl2 was added dropwise, under nitrogen, to a stirred solution of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)-benzylalcohol (Example 12) (385 mg, 0.925 mmol) in 20 ml CH2Cl2 at 0° C. The reaction mixture was left to stand at room temperature over night and then diluted with CH2Cl2. The organic phase was washed with water, dried over MgSO4 and concentrated. The residue was purified by column chromathography (silica gel, 75:25 petroleum-ether/EtOAc) to give 160 mg (36%) of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzylbromide.