Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].O1CCCC1.CC(C)([O-])C.[K+:20].[C:21](=[S:23])=[S:22]>CCOCC>[O:1]([CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[C:21]([S-:23])=[S:22].[K+:20]
Reactant: O=C1CCCN1CCO
Reactant: S=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CCCN1CCOC(=S)[S-]
Reaction time: 1 h

Procedure:
To a stirred solution of 5.16 g. of N-(2-hydroxyethyl)-2-oxo-pyrrolidine in 200 ml. of anhydrous tetrahydrofuran at room temperature was added 4.48 g. of potassium t-butoxide. A gummy precipitate formed. The mixture was stirred for 1 hour, and then 3.6 ml. of carbon disulfide was added. The mixture was stirred for 2 hours, and then 100 ml. of anhydrous ether was added, causing the formation of a gummy precipitate. The solvent was decanted from the gummy precipitate, and the gummy precipitate was dried under high vacuum to give a foam (5.0 g.) of the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[N:15]([CH3:28])[C:16](=[O:27])[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[CH:18][C:9]2=1)=[O:5].[CH2:29]([O:31][CH2:32][C:33](O)=[O:34])[CH3:30].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH4+].[Cl-]>C(Cl)Cl>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:17]1[C:16](=[O:27])[N:15]([CH3:28])[C:10]2[NH:11][C:12]3[C:8]([C:9]=2[CH:18]=1)=[CH:7][C:6]([C:4](=[O:5])[CH2:3][NH:2][C:33](=[O:34])[CH2:32][O:31][CH2:29][CH3:30])=[CH:14][CH:13]=3
Reactant: CCOCC(=O)O
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(=O)CN)ccc3[nH]c21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCC(=O)NCC(=O)c1ccc2[nH]c3c(cc(-c4ccc(Cl)cc4Cl)c(=O)n3C)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
756 mg (1.73 mmol) of compound 6-(aminoacetyl)-3-(2,4-dichlorophenyl)-1-methyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one hydrochloride from Example 5A above, 180 μl (1.90 mmol) of ethoxyacetic acid, 991 mg (1.90 mmol) of PyBOP and 905 μl (5.2 mmol) of diisopropylethylamine are dissolved in 9 ml of CH2Cl2. The mixture is stirred at ambient temperature for 16 h. A saturated solution of NH4Cl is added and the mixture is extracted with CH2Cl2, dried over MgSO4, filtered and concentrated under vacuum. The product is purified by chromatography on a silica column, elution being carried out with EtOAc and then EtOAc/3% MeOH.
Reaction SMILES: [N+:1]([CH2:4][C@@:5]1([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[C@@H:6]1[CH:7]=[C:8]([CH:12]([CH3:14])[CH3:13])[CH2:9]2)([O-])=O.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:1][CH2:4][C@@:5]1([CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:11][C@H:10]2[C@@H:6]1[CH:7]=[C:8]([CH:12]([CH3:14])[CH3:13])[CH2:9]2
Reactant: CC(C)C1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)C1=C[C@H]2[C@@H](C1)C[C@@]2(CN)CC(=O)OC(C)(C)C
Reaction time: 4.5 h

Procedure:
Tert-butyl(±)-[(1S,5R,6R)-6-(nitromethyl)-3-isopropylbicyclo[3.2.0]hept-3-en-6-yl]acetate (3.00 g, 9.70 mmol) was dissolved in ethanol (60 mL). To the solution, iron powder (4.47 g, 80.05 mmol) and then an aqueous ammonium chloride (0.54 g, 10.00 mmol) solution (20 mL) were added, and the mixture was stirred for 4.5 hours under heating to reflux. The mixture was allowed to cool and then filtered through Celite to remove insoluble matter. The solution was concentrated, and the residue was diluted with ethyl acetate. The dilution was washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (2.50 g, 92%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1.[CH3:22][O:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:25]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:22][O:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)[CH:27]=1)=[O:25]
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(-c2ccnc3c(C(F)(F)F)cccc23)c2ccccc12
Temperature: 100 °C
Reaction time: 20 h
Yield: 84.6 %

Procedure:
1.04 g (7.5 mmol) of potassium carbonate and 0.695 g (3 mmol) of 4-chloro-8-(trifluoromethyl)quinoline are added to 0.525 g (3 mmol) of 3-methoxycarbonyl-1H-indole in 10 cm3 of dimethylformamide under an argon atmosphere. After stirring at a temperature in the region of 100° C. for 20 hours, the reaction mixture is cooled and diluted with 100 cm3 of ethyl acetate and 100 cm3 of water. The organic phase is separated off by settling and washed with twice 100 cm3 of water and 100 cm3 of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa), resulting in an orange-coloured oil. This oil is triturated in 20 cm3 of isopropyl ether and the resulting precipitate is filtered off, giving 0.94 g of 3-methoxycarbonyl-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a yellow powder. Mass spectrum (EI): m/e 370 (M+•), m/e 339.
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: CC(=O)Nc1ccc2c(c1)OC[C@H]1[C@H](CO[Si](C)(C)C(C)(C)C)OC(=O)N21
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
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: [OH:1][C@:2]1([CH3:20])[CH2:6][CH2:5][C@@H:4]([NH:7]C(=O)OCC2C=CC=CC=2)[C:3]1([CH3:19])[CH3:18]>[Pd].CO>[NH2:7][C@@H:4]1[CH2:5][CH2:6][C@@:2]([CH3:20])([OH:1])[C:3]1([CH3:19])[CH3:18]
Reactant: CC1(C)[C@H](NC(=O)OCc2ccccc2)CC[C@@]1(C)O
Agent: [Pd]
Solvent: CO
Product: CC1(C)[C@H](N)CC[C@@]1(C)O
Reaction time: 2 h
Yield: 97 %

Procedure:
A mixture of benzyl (1R,3R)-3-hydroxy-2,2,3-trimethylcyclopentylcarbamate (900 mg, 3.24 mmol, from Step 1) and 10% palladium on carbon (173 mg) in methanol (15 mL) was stirred under hydrogen at 20 psi for 2 h. The mixture was filtered to remove the catalyst. The filtrate was concentrated to give (1R,3R)-3-amino-1,2,2-trimethylcyclopentanol (450 mg, 97% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 3.11-3.52 (1 H, m), 1.98-2.43 (1 H, m), 1.75-1.93 (1 H, m), 1.56-1.71 (1 H, m), 1.27-1.48 (1 H, m), 1.16 (3 H, s), 0.93 (3 H, s), 0.72 (3 H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][C:27]([CH3:33])([CH3:32])[C:28]([O:30][CH3:31])=[O:29].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:24][CH2:25][CH2:26][C:27]([CH3:33])([CH3:32])[C:28]([O:30][CH3:31])=[O:29])=[CH:11][CH:10]=2)=[O:16])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: COC(=O)C(C)(C)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)CCCOc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reaction time: 3 h

Procedure:
116 g (0.5 mole) of 4'-chloro-4-hydroxybenzophenone, 84 g (0.6 mole) of potassium carbonate and 500 cm3 of DMF are placed in a 1 liter flask. The mixture is brought to reflux and 90 g (0.5 mole) of methyl 5-chloro-2,2-dimethylpentanoate in 200 cm3 of DMF are then added from a dropping funnel. Reflux is continued for 3 hours. The mixture is then cooled and poured into 1 liter of water, so that the desired product precipitates. The precipitate is extracted with diethyl ether, washed with aqueous soda, then with water, dried and decolourised, and the solvent is evaporated under vacuum. 160 g of a white solid are obtained, which are recrystallised from diisopropyl ether. 130 g of the desired product are obtained, m.pt. 64° C.
Reaction SMILES: [CH:1]([Si:4]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[O:5][CH2:6][C@H:7]([OH:9])[CH3:8])([CH3:3])[CH3:2].O[C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:28]([O:27][C:25]1[CH:24]=[C:19]([CH:18]=[C:17]([O:9][C@@H:7]([CH3:8])[CH2:6][O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[CH:13]([CH3:15])[CH3:14])[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)[Si](OC[C@@H](C)O)(C(C)C)C(C)C
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
(2R)-1-[(Triisopropylsilyl)oxy]propan-2-ol (56.1 g, 242 mmol) was added to a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (50 g, 194 mmol) and triphenylphosphine (63.5 g, 242 mmol) in dry THF (500 mL), at to 0° C., followed by addition of DIAD (47.6 mL, 242 mmol) over 45 minutes under an argon atmosphere. The reaction was stirred at 0° C. for 1 hour and allowed to warm up to RT over an hour then stirred at RT for 1 hour. The THF was evaporated and a mixture of ethyl acetate (80 mL) and hexane (120 mL) was added. This mixture stirred for 2 hours and filtered. The precipitate was washed with a mixture of ethyl acetate (20 mL) and hexane (180 mL) and the filtrate evaporated. The residue was purified by column chromatography, eluting with 1:20 to 1:10 ethyl acetate:hexanes, to afford the title compound (65.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]([CH:32]([CH2:35][CH3:36])[CH2:33]O)[CH3:31].Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH2:30]([CH:32]([CH2:35][CH3:36])[CH2:33][O:24][C:23]([C:18]1([C:20]([O:22][CH2:8][CH:4]([CH2:5][CH3:6])[CH2:3][CH3:2])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25])[CH3:31]
Reactant: CCC(CC)CO
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCC(CC)COC(=O)C1(C(=O)OCC(CC)CC)Oc2ccc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)cc2O1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-ethylbutanol according to the procedure of Example 1 as an off-white gum (HCl salt); 1H NMR (CDCl3) δ 0.80-0.95 (m, 12H), 1.25-1.45 (m, 10H), 1.50-1.65 (m, 3H), 2.75-2.85 (m, 1H), 3.10-3.40 (m, 1H), 3.47-3.49 (m, 2H), 4.25 (d, 5H), 5.50 (d, 1H), 6.70-6.80 (m, 1H), 6.80-6.90 (m, 2H), 7.20-7.45 (m, 3H), 7.46 (s, 1H), 8.74 (bs, 1 H), 10.06 (bs, 1H); IR (KBr): 2964 cm-1 (--OH), 1766 cm-1 (C=O); MS (ES) m/z 590.4 (MH+); [α]D25 -21° (c, 1.0, CHCl3). Anal. Calcd. for C32H44ClNO7 ·HCl: C, 61.34; H, 7.08; N, 2.24; Cl, 11.32. Found: C, 61.09; H, 7.46; N, 2.12; Cl, 10.77.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[C:12]([CH3:20])=[N:11]2)=[CH:7][CH:6]=1>CO>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([CH3:20])=[N:11]2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cn2cc(C(=O)O)c(C)n2)cc1
Temperature: 50 °C
Yield: 87.9 %

Procedure:
According to Scheme 2, Step 1: A solution of NaOH 3 M (108 mmol, 35.8 mL) was added slowly, at 0° C., to a solution of ethyl 1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-carboxylate (43 mmol, 11.8 g) in MeOH (108 mL) and the reaction mixture was heated at 50° C. for 2 hours. After evaporation of the solvent, the residue was partitioned between a NaOH 1M solution and Et2O. The organic layer was washed with a NaOH 1M solution. The aqueous layer was acidified to pH=1-2 with a HCl 1M solution and the aqueous phase was extracted with DCM. The organic phase was dried over Na2SO4, was filtered and was concentrated under reduced pressure to yield 1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-carboxylic acid (37.8 mmol, 9.30 g, 88%) as a beige solid. The crude product was used without any purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>CN(C1C=CN=CC=1)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([S:20]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc2cccnc12
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Product: COc1cccc(S(=O)(=O)Nc2cccc3cccnc23)c1
Yield: 61.2 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (200 mg, 1.38 mmol), 3-methoxybenzenesulfonyl chloride (260 mg, 1.3 mmol) and DMAP (cat.) gave the title compound (250 mg, 56%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[S:11]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[S:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][N:22]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:19][CH:20]=1)(=[O:14])(=[O:13])[NH2:12]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=Cc2ccc(Cl)cc2)cc1

Procedure:
A solution of 4-chlorobenzaldehyde (5 mmol) and 4-sulfamylphenylhydrazine hydrochloride is subjected to the General Procedure. The title compound is isolated as described in the general procedure.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([O:18]C)=[O:17])=[CH:12][C:11]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:10]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:16]([C:13]1[C:14](=[O:15])[N:9]([CH2:8][CH:7]=[CH:6][C:5]2[CH:28]=[CH:29][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:10]=[C:11]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH:12]=1)([OH:18])=[O:17]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2cc(C(=O)O)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)cc1
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a suspension of 2-(4-chlorocinnamyl)-4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one (1.35 g, 3.29 mmol) in methanol (50 ml), a 4N aqueous solution of sodium hydroxide (20 ml) was added at room temperature, followed by stirring at the same temperature for 30 minutes. The methanol was distilled off under reduced pressure, and water (100 ml) was added to the residue. The mixture was acidified with hydrochloric acid under ice-water cooling, followed by extraction with chloroform. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was distilled off, whereby the title compound (1.30 g, 99.7%) was obtained as yellow crystals.
Reaction SMILES: Br.C(OC(=O)[NH:11][C:12]([C:15](=[O:37])[NH:16][C:17]1[S:18][C:19]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[N:21]=1)([CH3:14])[CH3:13])C1C=CC=CC=1>C(O)(=O)C>[NH2:11][C:12]([CH3:14])([CH3:13])[C:15]([NH:16][C:17]1[S:18][C:19]([O:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[N:21]=1)=[O:37]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1nc(-c2ccc(F)cc2)c(Oc2ccc(F)cc2)s1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)(N)C(=O)Nc1nc(-c2ccc(F)cc2)c(Oc2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
33% HBr (100 mL) was added to a solution of {1-[5-(4-Fluoro-phenoxy)-4-(4-fluoro-phenyl)-thiazol-2-ylcarbamoyl]-1-methyl-ethyl}-carbamic acid benzyl ester (12 g, 23 mmol) in acetic acid (50 mL). The mixture was stirred at room temperature for 18 h. Most of acetic acid was removed by evaporation under vacuum. The mixture was basified with 1M NaOH, and the product was extracted with dichloromethane. The dichloromethane extract was washed with brine, dried over Na2SO4 and concentrated. The residue was chromatographed to give the title compound. m/z 390.9 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:14]([C:16]2[CH:36]=[CH:35][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:34])[CH2:32][OH:33])[CH:29]=3)[C:24](O)=[O:25])=[C:18]([F:37])[CH:17]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1.[CH3:38][N:39]1[CH:43]=[CH:42][C:41]([NH2:44])=[N:40]1>CN(C=O)C>[N:10]1([C:14]([C:16]2[CH:36]=[CH:35][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:34])[CH2:32][OH:33])[CH:29]=3)[C:24]([NH:44][C:41]3[CH:42]=[CH:43][N:39]([CH3:38])[N:40]=3)=[O:25])=[C:18]([F:37])[CH:17]=2)=[O:15])[CH2:11][CH2:12][CH2:13]1
Reactant: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)O)c1
Reactant: Cn1ccc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.4 %

Procedure:
DIPEA (93 mg, 0.72 mmol; 4.0 equivalents) was added to a suspension of 3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]benzoic acid (70 mg), HATU-(144 mmol; 2.1 equivalents) and 1-methyl-1-H-pyrazole-3-amine (26 mg, 0.27 mmol, 1.5 equivalents) in DMF (2 mL). The resulting mixture was stirred at ambient temperature for 16 hours. The DMF was removed in vacuo, water was added and the mixture extracted with ethyl acetate. The extracts were combined, washed with brine, dried (MgSO4), filtered, and evaporated in vacuo to give the crude product which was chromatographed, eluting with 0-100% ethyl acetate in isohexane, to give desired compound (45 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[CH3:32])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:41])[N:13]2[C:33]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:40].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[CH3:32])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:41])[N:13]2[C:33]1[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CNCCN1Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methyl}-3-methylpiperazine-1-carboxylate (186 mg, 0.30 mmol) in methylene chloride (1 mL) at 0° C. was added trifluoroacetic acid (0.92 mL) dropwise. Then the reaction was stirred at rt for 1 h. Removal of the solvent and subsequent purification by preparative thin layer chromatography using 8% of 2N ammonium in methanol/methylene chloride as eluent provided the 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-[(2-methylpiperazin-1-yl)methyl]-3,4-dihydroquinazolin-2(1H)-one compound. 1H NMR (CDCl3, 500 MHz): δ 0.98 (m, 3H), 2.06 (m, 2H), 2.32 (s, 1H), 2.48 (m, 1H), 2.63 (m, 1H), 2.72 (t, 1H, J=10.2 Hz), 2.84 (m, 2H), 3.15 (dd, 1H, J1=14.0 Hz, J2=6.0 Hz), 3.86 (t, 1H, J=13.2 Hz), 4.34 (abq, 2H, J=14.2 Hz), 5.23 (s, 1H), 6.15 (d, 1H, J=9.4 Hz), 6.88 (s, 1H), 7.20-7.60 (m, 7H). MS (API-ES+): 517 (M+H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:15]([C:16]([NH2:18])=[O:17])[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C@@H:8]([OH:19])[CH2:7][C:5]=2[CH:6]=1.CN(C1C=CC=CN=1)C.[C:29](OC(=O)C)(=[O:31])[CH3:30].Cl>O.ClCCl.C(N(CC)CC)C>[CH3:30][C:29]([O:19][C@@H:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[N:15]([C:16]([NH2:18])=[O:17])[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[CH2:7]1)=[O:31]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)N1c2ccccc2C[C@H](O)c2ccccc21
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 22.5 °C
Reaction time: 3 h

Procedure:
To a solution of eslicarbazepine (30 gm), triethylamine (19.7 gm), dimethylaminopyridine (0.15 gm), and dichloromethane (150 mL), acetic anhydride (14.5 mL in 14.5 mL dichloromethane) was added and solution was stirred at about 20-25° C. for about 3 hrs. The resulting solution was cooled to about 10-15° C. To the resulting solution water (90 mL) was added followed by addition of HCl till pH of the resulting solution was 1-2. Organic layer was separated and washed with water. Water was added to organic layer followed by cooling to about 10-15° C. The pH of the resulting solution was adjusted to 9-10 by adding NaOH (10% w/v) solution. Organic layer was separated and solvent was distilled out completely to obtain the title compound.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[Cl-].[NH4+].[CH2:15]([OH:17])[CH3:16]>>[CH2:15]([O:17][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1)[CH3:16]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Product: CCOc1ccc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 6-chloronicotinamide (1.50 g) in ethanol (30 ml) was added sodium hydride (1.88 g, 60% mineral oil), and the mixture was stirred at room temperature for 24 hours. Another portion of sodium hydride (940 mg, 60% mineral oil) was added to the mixture, and the resulting mixture was stirred at room temperature for 24 hours followed by refluxing for 4.5 hours. Then, the reaction mixture was cooled, a saturated aqueous ammonium chloride solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was triturated with diethyl ether to obtain 6-ethoxynicotinamide (1.05 g) as colorless powder.