Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4]CC(=O)CC1C=CC(Cl)=C(Cl)C=1)(=[O:3])[CH3:2].[CH2:17]([O:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH2:36][C:37](=[O:40])[CH2:38]Cl)=[CH:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C(N(CC)CC)C>>[C:1]([O:4][CH2:38][C:37](=[O:40])[CH2:36][C:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]([C:25]([O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])[CH:28]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(CCl)Cc1cn(C(=O)OCc2ccccc2)c2ccccc12
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Cc1cn(C(=O)OCc2ccccc2)c2ccccc12
Yield: 44 %

Procedure:
The procedure described above for the synthesis of 3-(3,4-dichlorophenyl)-2-oxopropyl acetate was followed, reacting 3-[1-(benzyloxycarbonyl)indol-3-yl]-1-chloropropan-2-one (19.28 g, 56.4 mmol) with acetic acid (6.5 mL, 6.8 g, 0.11 mol) and triethylamine (15.7 mL, 11.4 g, 0.113 mol). Flash chromatography over silica gel (25% ethyl acetate in hexanes) gave pure product as an orange oil that solidified under vacuum to a yellow solid (9.06 g, 44% yield): 1H NMR (400 MHz, CDCl3) δ 2.15 (s, 3H) 3.81 (d, J=0.8 Hz, 2H) 4.73 (s, 2H) 5.45 (s, 2H) 7.26-7.30 (m, 1H) 7.32-7.51 (m, 7H) 7.62 (s, 1H) 8.18 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>O>[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([N:15]=[C:1]([CH3:2])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(=O)c1ccccc1
Solvent: O
Product: CC(=Nc1ccc(Cl)cc1)c1ccccc1

Procedure:
A solution of acetophenone (132 ml), p-chloroaniline (128 g) benzene (150 ml) was refluxed in the presence of molecular sieve (40 g) with continuous removal of water. The crude product was crystallized from ethanol to give p-chloro-N-(α-methyl benzylidene) aniline (XVII). It was then hydrogenated using 5% Pd/C as the catalyst and 95% ethanol as the solvent. The crude product was crystallized from ethanol and pet. ether to give p-chloro-N-(α-methyl benzyl) aniline (XVIII). XVIII had a melting point of 62° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](O)[CH2:11][OH:12]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:12][CH2:11][CH2:10][O:6]2)[CH:7]=[CH:8][CH:9]=1
Reactant: OCCO
Reactant: O=Cc1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1cccc(C2OCCO2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
A solution of 3-fluorobenzaldehyde (3.0 g, 24.2 mmol) in toluene (100 ml) was treated with ethylene glycol (1.8 g, 29.0 mmol) and p-toluenesulfonic acid (0.05 g, 0.24 mmol). The resulting solution was stirred at 80° C. for 3 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed (brine), dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified on silica gel using 10% ethyl acetate/hexane to provide the title compound (3.4 g, 85%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH:12]1[C:25]2[CH:24]([CH2:26][C:27](O)=[O:28])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.[C:30]([C:34]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][C:45](=[O:53])[CH2:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)=[CH:37][C:35]=1[NH2:36])([CH3:33])([CH3:32])[CH3:31]>C(OCC)C.N1C=CC=CC=1.C(Cl)Cl>[C:30]([C:34]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][C:45](=[O:53])[CH2:46][CH:47]2[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]2)=[CH:37][C:35]=1[NH:36][C:27](=[O:28])[CH2:26][CH:24]1[C:25]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:33])([CH3:31])[CH3:32]
Reactant: O=C(O)CC1c2ccccc2Oc2ccccc21
Reactant: CC(C)(C)c1ccc(CCCCC(=O)CC2CCCCC2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)c1ccc(CCCCC(=O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
0.66 ml (7.65 mmol) of oxalyl chloride and 30 mg of N,N-dimethylformamide were added, in turn, to 10 ml of a methylene chloride suspension containing 368 mg (1.53 mmol) of 2-(9H-xanthen-9-yl)acetic acid. The suspension was stirred in an ice bath for 30 minutes and then at room temperature for 1 hour. At the end of this time, the solvent and excess reagents were removed by distillation under reduced pressure. The residue was again dissolved in 10 ml of methylene chloride, and the resulting solution was placed in an ice bath. 2 ml of a methylene chloride solution containing 458 mg (1.39 mmol) of 2-t-butyl-5-(6-cyclohexyl-5-oxohexyl)aniline and 0.56 ml of pyridine were then added to the solution, and the mixture was stirred for 10 minutes. The reaction solution was then diluted with diethyl ether, washed with a dilute aqueous solution of sodium hydroxide, with dilute aqueous hydrochloric acid and with water, in that order. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 40 g of silica gel. Elution with a 100:20 by volume mixture of hexane and ethyl acetate afforded 663 mg (yield 86%) of the title compound as crystals, melting at 126°-127° C. (after recrystallization from a mixture of diethyl ether and hexane).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH2:18][N:19]([C:27]2[N:35]=[CH:34][N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][N:31]3C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C(=O)OC(C)(C)C)[O:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:35]1[C:27]([NH:19][CH2:18][C:4]2[O:3][C:2](=[O:1])[C:11]3[C:6]([C:5]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[C:28]2[C:32]([NH:31][CH:30]=[N:29]2)=[N:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N(Cc1oc(=O)c2ccccc2c1-c1ccccc1)c1ncnc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1oc(CNc2ncnc3[nH]cnc23)c(-c2ccccc2)c2ccccc12

Procedure:
tert-Butyl (1-oxo-4-phenyl-1H-isochromen-3-yl)methyl(9-trityl-9H-purin-6-yl)carbamate (80 mg, 0.112 mmol) was dissolved in DCM (0.7 ml) and TFA (1 mL) at RT for 45 min. Solvent was then removed and the crude was straightforward purified by Preparative HPLC (method 1) to the title compound (17 mg, 40.9%).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:21])[C:9]([O:19][CH3:20])=[C:10]([O:17][CH3:18])[C:11]2=[O:16].C(O)(=O)C.[ClH:26]>O>[Cl:26][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:21])[C:9]([O:19][CH3:20])=[C:10]([O:17][CH3:18])[C:11]2=[O:16]
Reactant: Cl
Reactant: COC1=C(OC)C(=O)c2c(N)cccc2C1=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC1=C(OC)C(=O)c2c(Cl)cccc2C1=O
Temperature: -5 °C

Procedure:
A solution of sodium nitrite (0.69 g, 10 mmol) in water (5 ml) was added at 0°-5° C. to a solution of 5-amino-2,3-dimethoxy-1,4-naphthoquinone (1.17 g, 5 mmol) in 5:1 acetic acid:water (25 ml) containing concentrated hydrochloric acid (1.7 ml). A further quantity of sodium nitrite (0.69 g) was then added to the reaction mixture after cooling to -5° C., followed by a solution of cuprous chloride (0.6 g) in concentrated hydrochloric acid (5 ml). The mixture was allowed to warm to 22° C. and solid cuprous chloride was added portionwise until the mixture assumed a green color. Water was then added to the reaction mixture and the precipitated yellow-solid filtered off, washed with water and recrystallized from methanol:water (2:1) giving 1.01 g of 5-chloro-2,3-dimethoxy-1,4-naphthoquinone, mp 120°-121° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([Br:9])[N:6]=[C:5](Br)[C:4]1=[O:11])[CH3:2].[NH3:12]>O1CCOCC1>[CH2:1]([N:3]1[CH:8]=[C:7]([Br:9])[N:6]=[C:5]([NH2:12])[C:4]1=[O:11])[CH3:2]
Reactant: N
Reactant: CCn1cc(Br)nc(Br)c1=O
Solvent: C1COCCO1
Product: CCn1cc(Br)nc(N)c1=O
Reaction time: 15 h

Procedure:
A mixture of 4.6 g of 1-ethyl-3,5-dibromopyrazin-2-one, 9.6 ml of dioxane and 6.4 ml of 30% ammonia is stirred at 20°-25° C. for 15 hours. The product is filtered off and washed with alcohol and ether to give 1.3 g of 1-ethyl-3-amino-5-bromo-pyrazin-2-one with a melting point of 227°-230° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1.O.[Cl-].[Na+].O>[C:11]([O:10][C:9]([NH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:2][CH2:3]1)=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl piperidine-4-ylmethyl-carbamate (2.00 g) is dissolved in tetrahydrofuran (10 ml), and thereto is added triethylamine (1.69 ml), followed by an addition dropwise of ethyl bromoacetate (1.24 mL) in water bath and the mixture is stirred at room temperature for 2 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure, and to the resulting crystalline residue is added isopropylether and the mixture is filtered to give ethyl [4-(tert-butoxy-carbonylamino-methyl)-piperidin-1-yl]-acetate (1.87 g). MS (m/z): 301 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:23]([O:25]CC)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:33])([F:32])[F:31].[Li+].[OH-]>CO.C1COCC1.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:31])([F:32])[F:33]
Reactant: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(c2cc(OCC(F)(F)F)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.6 %

Procedure:
The ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentane carboxylate (80 mg) dissolved in 10 mL of MeOH/THF/H2O (10 mL/10 mL/5 mL) and 57 mg LiOH added. The reaction mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 1-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentane carboxylic acid (45 mg) as a white solid. 1H-NMR (500 MHz, CDCl3): 7.74 (d, 2H), 7.55 (d, 2H), 7.08 (s, 1H), 4.44 (q, 2H), 2.66 (m, 2H), 1.98 (m, 2H), 1.78 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30]([O:32]CC)=[O:31])[CH2:25]2)=[O:23])=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.C(O)C.[OH-].[Na+].O>C(OCC)(=O)C>[CH3:1][C:2]1[C:3]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30]([OH:32])=[O:31])[CH2:25]2)=[O:23])=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)c2cc3c(cc2C)[nH]c(=O)c2cnn(C4CCOCC4)c23)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2[nH]c(=O)c3cnn(C4CCOCC4)c3c2cc1C(=O)N1CCC[C@@H](C(=O)O)C1
Temperature: 70 °C
Reaction time: 9 h
Yield: 79.5 %

Procedure:
To 95 mg of ethyl (3R)-1-{[7-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-8-yl]carbonyl}piperidine-3-carboxylate were added 5 mL of ethanol and 200 μL of a 3 M aqueous sodium hydroxide solution, followed by stirring at 70° C. for 9 hours. The reaction mixture was cooled, and water and ethyl acetate were added thereto, and then the organic layer was separated. The aqueous layer was adjusted to about pH 4 with 1 mL of 1 M hydrochloric acid, then the solution was coevaporated with toluene. After forming a precipitate, f the precipitared powder was collected by filtration. The obtained powder was dried under reduced pressure to obtain 71 mg of (3R)-1-{[7-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-8-yl]carbonyl}piperidine-3-carboxylic acid as white powder.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH2:7].Cl.Cl[CH2:10][C:11]1[N:12]=[C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]2[CH:21]=1>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][CH2:10][C:11]1[N:12]=[C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]2[CH:21]=1
Reactant: NCC1OCCO1
Reactant: N#Cc1ccn2cc(CCl)nc2c1
Agent: Cl
Solvent: ClCCl
Product: N#Cc1ccn2cc(CNCC3OCCO3)nc2c1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
To a DCM solution of 1-(1,3-dioxolan-2-yl)methanamine (799 mg, 7.83 mmol) was added 2-(chloromethyl)imidazo[1,2-a]pyridine-7-carbonitrile hydrochloride (Intermediate 17) (500 mg, 2.61 mmol). After heating to reflux for 1 hr, the reaction mixture was cooled room temperature, concentrated under reduced pressure, chromatographed on silica gel eluting with a gradient solvent mixture (5% MeOH-DCM to 15% MeOH-DCM) to give the title compound as oil (410 mg). LC/MS: m/z 259(M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[CH:13]([CH2:16][C:17]([O:19]C)=[O:18])[CH2:12][C:11]2[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][N:29]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:24][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1NCCCOC1C=CC2CC(CC(OCC)=O)C(=O)NCC=2C=1>>[CH2:1]([N:8]1[C:14](=[O:15])[CH:13]([CH2:16][C:17]([OH:19])=[O:18])[CH2:12][C:11]2[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][N:29]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[CH:24][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC1Cc2ccc(OCCCN(C(=O)OC(C)(C)C)c3ccccn3)cc2CN(Cc2ccccc2)C1=O
Agent: CCOC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CNC1=O
Product: CC(C)(C)OC(=O)N(CCCOc1ccc2c(c1)CN(Cc1ccccc1)C(=O)C(CC(=O)O)C2)c1ccccn1

Procedure:
According to the procedure of Example 1(c), except substituting methyl (±)-2-benzyl-3-oxo-8-[3-[N-(pyridin-2-yl)-N-(tert-butoxycarbonyl)amino]-1-propyloxy]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate for the ethyl (±)-8-[3-(2-pyridylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate, the title compound (0.044 g, quantitative) was prepared: MS (ES) m/e 560.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:33])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][N:22]4C(=O)C5=CC=CC=C5C4=O)=[CH:14][CH:13]=3)[O:11][C:6]=2[C:5]([F:34])=[CH:4][C:3]=1[F:35]>CN(C)C=O.CO.O.NN>[NH2:1][C:2]1[C:7]2[C:8](=[O:33])[CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([NH:18][CH2:19][CH2:20][CH2:21][NH2:22])=[CH:16][CH:17]=3)[O:11][C:6]=2[C:5]([F:34])=[CH:4][C:3]=1[F:35]
Reactant: Nc1c(F)cc(F)c2oc(-c3ccc(NCCCN4C(=O)c5ccccc5C4=O)cc3)cc(=O)c12
Agent: NN
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: NCCCNc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1
Reaction time: 1.5 h

Procedure:
600 mg of Compound 23 was dissolved in 75 ml of a mixed solvent of dimethylformamide and methanol (1:1), 0.613 ml of hydrazine monohydrate was added and the mixture was stirred at 50° to 60° C. for 1.5 hours. Additional 0.307 ml of hydrazine monohydrate was added and the mixture was stirred at 50° to 60° C. for 10 minutes. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform:methanol:aqueous ammonia =9:1:1) to give Compound 24 which was dissolved in ethanol, a 5.5N hydrochloric acid-isopropylalcohol solution was added, and the precipitated crystals were collected by filtration to give 331 mg (69%) of Compound 24.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=2)[S:21][CH2:20][C:19]1([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=1)[CH3:32])(C(C)(C)C)(C)C.[OH-].[Na+].COCCl.O>C(O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=2)[S:21][CH2:20][C:19]1([C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:37][CH:38]=1)[CH3:32]
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COCCl
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2CCCCCCCCCO)cc1
Reaction time: 24 h
Yield: 74.9 %

Procedure:
4-[9-(t-Butyldimethylsilyloxy)-1-nonynyl]-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylthiochroman (1.43 g, 2.27 mmol) was dissolved in ethanol (100 ml) and tetrahydrofuran (10 ml), and 20% palladium hydroxide on carbon (500 mg) which had been washed with ethanol was added thereto. The reaction solution was stirred for 1 day under hydrogen (atmospheric pressure). Ethyl acetate was added to the reaction mixture, which was then filtered and concentrated. The concentrate was dissolved in dichloromethane (50 ml) and 1N-sodium hydroxide (2 ml), and tetra-n-butylammonium chloride (556 mg, 2 mmol) was added thereto at room temperature. To the reaction mixture was added dropwise methoxymethyl chloride (0.22 ml, 3 mmol) at the same temperature, which was then stirred for 2 hours. Water was added, and the resulting solution was extracted with ethyl acetate. Then, the organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (855 mg, yield 75%) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:20](=[O:21])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[N:37]1[CH:42]=[CH:41][CH:40]=[N:39][C:38]=1[N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.[I-].[K+]>CN(C=O)C>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[C:9]2[C:20](=[O:21])[CH:5]([CH2:4][CH2:3][CH2:2][N:46]3[CH2:47][CH2:48][N:43]([C:38]4[N:37]=[CH:42][CH:41]=[CH:40][N:39]=4)[CH2:44][CH2:45]3)[CH2:6][CH2:7][C:8]=2[O:12][N:11]=1
Reactant: O=C1c2c(-c3ccccc3F)noc2CCC1CCCCl
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2c(-c3ccccc3F)noc2CCC1CCCN1CCN(c2ncccn2)CC1
Temperature: 80 °C
Yield: 38.7 %

Procedure:
To a solution consisting of 5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (7.3 g) and DMF (100 ml) was added anhydrous potassium carbonate (1.6 g), diisopropylethyl amine (6.2 ml), 1-(2-pyrimidyl)piperazine (5.8 g) and potassium iodide (0.4 g) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 16 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with water twice, then brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 2% triethylamine/ether) afforded 4.0 g of 6,7-dihydro-3-(2-fluorophenyl)-5-[3-(4-(2-pyrimidyl)-1-piperazinyl)-propyl]-1,2-benzisoxazol-4(5H)-one as an oil which solidified upon standing. Recrystallization with ether gave the product as a solid, m.p. 115°-117° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.CN(C)C=O.F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[N+:35]([O-:37])=[O:36]>O>[N+:35]([C:26]1[CH:27]=[C:28]([C:31]([F:32])([F:33])[F:34])[CH:29]=[CH:30][C:25]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)([O-:37])=[O:36]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: c1ccc2c(c1)CCN2
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
Indoline (402 μl, 3.59 mmol, commercially available product) and N,N-diisopropylethylamine (619 μl, 3.59 mmol) were sequentially added at 0° C. to a N,N-dimethylformamide (DMF; 2 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (498 mg, 2.38 mmol, commercially available product). The resulting mixture was warmed to room temperature and stirred for one hour. The mixture was then heated at 70° C. for 5.5 hours with stirring. The mixture was cooled to room temperature. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=20/1). Thus, 1-(2-nitro-4-(trifluoromethyl)phenyl)indoline (730 mg, 99.4%) was yielded as a deep red oily material.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:14]([C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)#[CH:15]>>[OH:22][C:18]1[CH:17]=[C:16]([C:14]#[C:15][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: C#Cc1cccc(O)c1
Reactant: COC(=O)CCc1ccc(I)cc1
Product: COC(=O)CCc1ccc(C#Cc2cccc(O)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-iodophenyl)propanoate (100 mg, 0.34 mmol) and 3-ethynylphenol (0.025 mL, 0.38 mmol) according to the general procedure IC to give 66 mg (69%) of a light brown solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:6→1:0). Rf=0.24 (EtOAc:PE; 1:2); 1H NMR (CDCl3): δ 7.43 (d, J=8.0 Hz, 2H), 7.20-7.15 (m, 3H), 7.10-7.08 (m, 1H), 7.00-6.99 (m, 1H), 6.84-6.80 (m, 1H), 5.50 (br, 1H), 3.68 (s, 3H), 2.96 (t, J=8.0 Hz, 2H), 2.64 (t, J=8.1 Hz, 2H); 13C NMR (CDCl3): δ 173.7, 155.7, 141.0, 132.0, 129.8, 128.5, 124.7, 124.4, 121.3, 118.4, 115.9, 89.4, 89.0, 52.0, 35.6, 31.0; ESI-MS m/z 303.0 (M+Na+).
Reaction SMILES: C([O:9][CH:10]1[C:14]([F:16])([CH3:15])[CH:13]([N:17]2[CH:22]=[CH:21][C:20]([NH:23]C(=O)C3C=CC=CC=3)=[N:19][C:18]2=[O:32])[O:12][CH:11]1[CH2:33][O:34]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[NH2:23][C:20]1[CH:21]=[CH:22][N:17]([CH:13]2[C:14]([F:16])([CH3:15])[CH:10]([OH:9])[CH:11]([CH2:33][OH:34])[O:12]2)[C:18](=[O:32])[N:19]=1
Reactant: CC1(F)C(OC(=O)c2ccccc2)C(COC(=O)c2ccccc2)OC1n1ccc(NC(=O)c2ccccc2)nc1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1(F)C(O)C(CO)OC1n1ccc(N)nc1=O
Temperature: 50 °C
Yield: 93.9 %

Procedure:
A slurry of 14 (14.7 kg) in MeOH (92.6 kg) is treated with catalytic amounts of methanolic sodium methoxide (0.275 kg). The reaction mixture is heated to ca. 50° C. and aged (ca. 1 h) until the hydrolysis is complete. The reaction mixture is quenched by addition of isobutyric acid (0.115 kg). The resulting solution is concentrated under moderate vacuum and then residual solvents are replaced with IPA (80 kg). The batch is distilled to a volume of ca. 50 L. The resulting slurry is heated to ca. 80° C. and then cooled slowly to ca. 5° C. and aged (ca. 2 h). The precipitated product is isolated by filtration, washed with IPA (16.8 kg) and dried in an oven at 70° C. in vacuo to afford 6.26 kg (88.9%) of 18 which assayed at 99.43% pure