Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Li+]>C1COCC1.O>[CH2:22]([NH:21][C:14]1[CH:13]=[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)[CH:17]=[CH:16][C:15]=1[N+:18]([O-:20])=[O:19])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Reaction time: 5 h
Yield: 68.1 %

Procedure:
To stirred solution of ethyl-1-(3-(benzylamino)-4-nitrophenyl)piperidine-4-carboxylate (2 g, 6.2 mmol) in 20 ml THF: H2O (3:1) was added lithium hydroxide (0.740 g, 30.9 mmol) at room temperature. The resulting mixture was stirred for 5 h, solvent was evaporated and residue was dissolved in water washed with dichloromethane. The aqueous layer was then neutralised with 2M HCl to get yellow solid 1-(3-(benzylamino)-4-nitrophenyl)piperidine-4-carboxylic acid (1.5 g), 90% yield: 1H NMR (500 MHz, DMSO): δ 1.46 (m, 2H), 1.80 (m, 2H), 3.03 (m, 2H), 3.82 (m, 2H), 4.59 (d, J=5.7 Hz, 2H), 5.94 (d, J=2.5 Hz, 1H), 6.40 (dd, J=2.5 Hz, 1H), 7.27 (m, 1H), 7.37 (m, 2H) 7.42 (m, 2H), 7.90 (d, J=9.8 Hz, 1H), 8.83 (m, 1H). HRMS (ESI) calculated for C19H21N3NaO4: 378.1424, Found: 378.1417.
Reaction SMILES: [CH:1]([C:3]([OH:10])([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6])=[CH2:2].Br[C:12]1[CH:13]=[C:14]([CH:18]([OH:28])[CH2:19][CH2:20][NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH:15]=[CH:16][CH:17]=1>>[F:24][C:23]([F:25])([F:26])[C:22]([NH:21][CH2:20][CH2:19][CH:18]([OH:28])[C:14]1[CH:15]=[CH:16][CH:17]=[C:12](/[CH:2]=[CH:1]/[C:3]([OH:10])([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6])[CH:13]=1)=[O:27]
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Reactant: C=CC(O)(CCC)CCC
Product: CCCC(O)(/C=C/c1cccc(C(O)CCNC(=O)C(F)(F)F)c1)CCC

Procedure:
Coupling of 4-vinylheptan-4-ol with N-(3-(3-bromophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide following the method in Example 111 except the reaction was done in 1 hour at 90° C. gave (E)-2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-enyl)phenyl)propyl)acetamide as a light color oil. Yield (42 g, 45%): 1H NMR (400 MHz, MeOD) δ 7.39 (s, 1H), 7.26-7.27 (m, 2H), 7.18-7.20 (m, 1H), 6.54 (d, J=16 Hz, 1H), 6.23 (d, J=16 Hz, 1H), 4.67 (t, J=6.4 Hz, 1H), 3.37 (t, J=7.2 Hz, 2H), 1.92-1.97 (m, 2H), 1.55-1.59 (m, 4H), 1.30-1.46 (m, 4H), 0.91 (t, J=7.6 Hz, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O>>[Cl:12][CH2:13][C:14]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[O:8][CH:16]=1
Reactant: O=C(CCl)CCl
Reactant: N#Cc1ccc(C(N)=O)cc1
Product: N#Cc1ccc(-c2nc(CCl)co2)cc1
Yield: 41 %

Procedure:
In substantially the same manner as in Reference Example 31, 4-cyanobenzamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(4-cyanophenyl)oxazole. The yield was 41%. Recrystallization form ethyl acetate-hexane gave colorless prisms, mp 134-135° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[F:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([F:42])[CH:41]=1)[C:36](Cl)=[O:37]>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:36](=[O:37])[C:35]3[CH:34]=[C:33]([F:32])[CH:41]=[C:40]([F:42])[CH:39]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cc(F)cc(F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml) was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 3,5-difluorobenzoyl chloride (0.5 g, 2.8 mmol). The reaction mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was then quenched with MeOH (1 mL) and washed with H2O (40 mL), 1N HCl (40 mL) and brine (40 mL). The organic layer was dried over MgSO4 and concentrated in vacuo, and the resulting mixture was purified by ISCO silica gel flash chromatography (eluent: 3% MeOH in CH2Cl2 for 10 min, then 5% MeOH in CH2Cl2 for 10 min) to afford N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3,5-difluoro-benzamide as a white solid (0.5 g, 54%): mp, 218-220° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.4 min. (99%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.53-2.65 (m, 2H), 2.85-2.93 (m, 1H), 4.96 (d, J=5.8 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.46-7.84 (m, 6H), 9.33 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.96, 30.92, 38.49, 48.86, 106.93, 110.58, 110.69, 110.82, 110.93, 121.99, 127.21, 131.54, 133.20, 134.83, 137.42, 138.62, 160.51, 160.67, 163.78, 163.95, 164.10, 166.92, 167.48, 169.81, 172.73. Anal Calcd for C21H15F2N3O5: C, 59.02; H, 3.54; N, 9.83. Found: C, 58.90; H, 3.15; N, 9.73.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([C:13]([O:15]C)=[O:14])[C:10]([O:17][CH3:18])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]>[OH-].[K+]>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[C:10]([O:17][CH3:18])[C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1cc(OC)c(C(=O)OC)cc1OC
Agent: [K+]
Agent: [OH-]
Product: COC(=O)c1cc(OC)c(C(=O)O)cc1OC
Yield: 45.6 %

Procedure:
A suspension of dimethyl 2,5-dimethoxyterephthalate (4 g, 15.7 mmol), prepared as in Description 9, in methanolic KOH (0.86 g of KOH in 100 ml MeOH) was refluxed for 3 h. The solution was cooled and the solvent removed under vacuum. The residue was treated with dilute HCl and the solid filtered off. The crude mixture was purified by column chromatogrphy using 1:1 ethyl acetate/hexane as a solvent obtaining 1.72 g of the title compound (yield 44.7%), mp=123-124° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[N:10]([CH2:21][CH2:22][OH:23])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][CH:18]=[CH:17]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH2:1]([O:8][C:9]([N:10]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][CH:18]=[CH:17]2)[CH2:21][CH2:22][O:23][S:33]([CH3:32])(=[O:35])=[O:34])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N(CCO)Cc1cccc2cc[nH]c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCN(Cc1cccc2cc[nH]c12)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of (2-hydroxy-ethyl)-(1H-indol-7-ylmethyl)-carbamic acid benzyl ester (2.79 g, 8.61 mmol) in dichloromethane (50 mL) was added triethylamine (1.56 mL, 11.2 mmol). The mixture was cooled to 0° C. and methanesulfonyl chloride (0.74 mL, 9.47 mmol) added in a dropwise manner. The mixture was warmed to room temperature and allowed to stir for 2 hours. The mixture was then quenched with water (30 mL) and 1.0 M sodium hydroxide (10 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (20 mL). The combined extracts were washed with 1.0 M hydrochloric acid (20 mL), water (30 mL), dried over anhydrous sodium sulfate and evaporated to dryness. Methanesulfonic acid 2-[benzyloxycarbonyl-(1H-indol-7-ylmethyl)-amino]-ethyl ester (3.46 g) was obtained as an oil
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:23])[CH2:14][N:15]2[C:19]([Br:20])=[C:18]([Br:21])[N:17]=[C:16]2Br)[CH2:9][CH2:8]1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.O1CCOCC1>[Br:21][C:18]1[N:17]=[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:15]([CH2:14][C:13]([N:10]2[CH2:11][CH2:12][N:7]([C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:8][CH2:9]2)=[O:23])[C:19]=1[Br:20]
Reactant: O=C(Cn1c(Br)nc(Br)c1Br)N1CCN(c2ncccn2)CC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Cn1c(-c2ccccc2)nc(Br)c1Br)N1CCN(c2ncccn2)CC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
1.7 g tetrakis was added to a stirred mixture of 15 g 1-(4-pyrimidin-2-yl-piperazin-1-yl)-2-(2, 4, 5-tribromo-imidazol-1-yl)-ethanone, 3.6 g phenylboronic acid, 9.4 g sodiumcarbonate, 250 mL dioxane and 50 mL water under nitrogen atmosphere. The reaction mixture was stirred 3 h at 85° C. Sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. Diisopropylether was added to the residue and the precipitate was filtered to give 11.8 g desired product. Rt: 0.87 (method B), ESI+: 505
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH3:10])=[CH:4][N:3]=1.[CH3:11][N:12]=[C:13]=[O:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([N:8]([CH2:9][CH3:10])[C:13]([NH:12][CH3:11])=[O:14])=[CH:6][CH:7]=1
Reactant: CCNc1ccc(Cl)nc1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CCN(C(=O)NC)c1ccc(Cl)nc1
Yield: 93.6 %

Procedure:
In 30 ml of toluene was dissolved 2.4 g (0.015 mole) of 2-chloro-5-ethylaminopyridine, followed by addition of 3.4 g of methyl isocyanate. The mixture was refluxed for 15 hours. After cooling, the resulting crystals were collected by filtration, washed with a small amount of Et2O and dried. The procedure gave 3.0 g of N-(6-chloro-3-pyridyl)-N-ethyl-N′-methyl-urea as pale yellow crystals.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:30][CH:31]([F:33])[F:32])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.CO.[OH-].[Li+].O>C(O)(=O)C>[F:33][CH:31]([F:32])[O:30][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:34])=[O:2])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(S(C)(=O)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A mixture of [4-difluoromethoxy-2-ethyl-8-fluoro-3-(4-methanesulfonylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.82 g), methanol (33 mL), 5.0 M aqueous lithium hydroxide solution (0.7 mL) and water (1.4 mL) was stirred at room temperature for 35 minutes. The pH of the mixture was adjusted to 4 by the addition of glacial acetic acid and the solvent removed under reduced pressure. The residue was diluted with water (4.0 mL) and the solid collected by filtration, washed with water and dried to afford to title compound as a pale cream solid, 0.60 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:38]=[CH:39][CH:40]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:18]=1[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=1)[C:32]([OH:34])=O)=[O:15])([CH3:4])([CH3:3])[CH3:2].[F:42][C:43]([F:53])([F:52])[C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH2:47][NH2:48].CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[F:42][C:43]([F:52])([F:53])[C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH2:47][NH:48][C:32]([C:31]1[CH:35]=[CH:36][N:37]=[C:29]([C:18]2[CH:19]=[C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]=[CH:22][C:17]=2[NH:16][C:14]([C:13]2[CH:12]=[C:11]([CH:40]=[CH:39][CH:38]=2)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:41])=[O:15])[CH:30]=1)=[O:34]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)O)ccn2)c1
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50 mL round bottom flask, was placed 2-(2-(3-((3-tert-butoxy-3-oxopropylthio)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinic acid (220 mg, 0.38 mmol, 1.00 equiv), 3-(trifluoromethyl)benzylamine (134 mg, 0.77 mmol, 2.00 equiv), EDC.HCl (124 mg, 0.63 mmol, 1.65 equiv), 4-dimethylaminopyridine (76 mg, 0.62 mmol, 1.63 equiv), and dichloromethane (10 mL). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was washed with 5×30 mL of aqueous NH4Cl. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 360 mg (90%) of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)propanoate as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]#[N:22])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([OH:19])=O)[C:10](=[O:20])[CH:9]=2)[CH:7]=1.[NH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]#[N:22])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[CH:26][CH:25]=3)=[O:19])[C:10](=[O:20])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(CC(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cn(CC(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
159 mg (499 μmol) of [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetic acid, 116 mg (599 μmol) of tert-butyl 4-aminobenzoate, 228 mg (599 μmol) of HATU and 261 μl (1.50 mmol) of N,N-diisopropylethylamine in 8 ml of dimethylformamide were reacted according to General Method 5A. The solvent was removed and the residue was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 54.5 mg (22% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]3[CH2:15][CH2:16][S:17][C:18]4[S:22][C:21]([CH3:23])=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[OH:24]O.O>C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]3[CH2:15][CH2:16][S:17](=[O:24])[C:18]4[S:22][C:21]([CH3:23])=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: OO
Reactant: Cc1cc2c(s1)SCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Solvent: O
Solvent: O=CO
Product: Cc1cc2c(s1)S(=O)CCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Temperature: 5 °C

Procedure:
To a solution of 1.0 g of 2-(4-chlorophenyl)-9-methyl-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one in 50 ml of formic acid is added 0.3 ml of 35% aqueous hydrogen peroxide solution with stirring at 5° C. and the mixture is stirred for 10 minutes at the same temperature. To the mixture is further added 0.3 ml of aqueous hydrogen peroxide solution and the mixture is stirred for 20 minutes. Then, the mixture is poured into water, extracted with chloroform three times and the extract is washed with water and dried over magnesium sulfate. After the chloroform is distilled off under reduced pressure, the resulting crystals are recrystallized from a mixed solvent of chloroform and ethanol to give 1.0 g of 2-(4-chlorophenyl)-9-methyl-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one 7-oxide as white crystals, melting at 174°-175° C. with decomposition.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[CH2:15])[CH2:5][CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl[CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[N:30][C:31]([Cl:37])=[CH:32][CH:33]=2)[N:28]=1.Cl>CN(C)C=O.O>[Cl:37][C:31]1[N:30]=[C:29]2[C:34]([CH:35]=[CH:36][C:27]([N:18]3[C:19](=[O:26])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:17]3[CH:8]([C:7](=[O:14])[CH2:6][CH2:5][C:4]([CH3:3])=[CH2:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:28]2)=[CH:33][CH:32]=1
Reactant: C=C(C)CCC(=O)CC(=O)OCC
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)CCC(=O)C(C(=O)OCC)C1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
1.7 g of an oily suspension (50% by weight) of sodium hydride are added to 100 cm3 of anhydrous dimethylformamide, under an argon atmosphere, at a temperature of about 10° C. 9.8 g of ethyl 6-methyl-3-oxo-6-heptenoate in 25 cm3 of anhydrous dimethylformamide are subsequently added. The suspension is stirred for 30 minutes and the temperature is allowed to return to about 20° C., followed by the addition of 11.6 g of 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone. The reaction mixture is stirred for 4 hours at a temperature of about 20° C. and is then poured into 250 cm3 of water. The aqueous phase, which is acidified by the addition of 25 cm3 of aqueous 1N hydrochloric acid solution, is extracted twice with 200 cm3 of dichloromethane. The organic phases are combined and washed twice with 50 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40° C. The oily residue is purified by chromatography on silica [eluent:ethyl acetate/cyclohexane (30/70 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. After crystallization in diisopropyl ether, 9.4 g of ethyl 2-[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo1-isoindolinyl]-6-methyl-3-oxo-6-heptenoate (mixture of A and B forms) are thus obtained, melting at 125° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH3:11].[C:12](Cl)(Cl)=[S:13]>C1(C)C=CC=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:1]=[C:12]=[S:13])=[C:3]([CH2:10][CH3:11])[CH:4]=1)#[N:7]
Reactant: CCc1cc(C#N)ccc1N
Reactant: S=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1cc(C#N)ccc1N=C=S
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-amino-3-ethylbenzonitrile, (75 g, 0.51 mol) in toluene (1 L) was added thiophosgene, (43 mL, 0.56 mol, 1.1 equiv.) slowly via syringe. Within 5 min. a viscous slurry formed. The reaction mixture was heated to the reflux temp. and the viscosity diminished. The reaction mixture was heated at the reflux temp. for 5 h then allowed to cool to room temp. The resulting mixture was concentrated under reduced pressure and the residue was treated with CH2Cl2 (600 mL) and concentrated under reduced pressure to give 4-cyano-2-ethylphenyl isothiocyanate as a light tan crystalline solid (98 g, 100%): 1H NMR (DMSO-d6) δ1.18 (t, J=7.4 Hz, 3H), 2.69 (q, J=7.4 Hz, 2H), 7.55 (d, J=7.0 Hz, 1H), 7.75 (d, J=7.0 Hz, 2H), 7.84 (s, 1H); MS (CI-MS) m/z 189 ((M+H)+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:35][CH3:36])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([CH:32]=O)[NH:23][C:22]=1[CH3:34])=[O:20])[CH3:13]>>[CH2:35]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([CH:32]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:23][C:22]=1[CH3:34])=[O:20])[CH3:36]
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1-c1ccccc1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1-c1ccccc1
Yield: 9.4 %

Procedure:
5-bromo-1,3-dihydroindol-2-one (0.47 g, 2.2 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (0.75 g) to give 0.11 g (42%) of the title compound as an orange solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OC[C@H]2CC[C@H](C)CC2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CC[C@H](COc2cc(F)c(C(=O)O)cc2C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((trans-4-methyl-cyclohexyl)methoxy)benzoate (5.95 g, 16.41 mmol) in anhydrous dichloromethane (28 mL) was added trifluoroacetic acid (14 mL). The mixture was stirred for 1 hour at ambient temperature, and then concentrated in vacuo. The solid was triturated with methanol to give the title compound (2.42 g, 48%):): 1H NMR (300 MHz, CDCl3) δ 12.8 (br s, 1H), 7.30 (d, J=8.5 Hz, 1H), 6.88 (d, J=13.1 Hz, 1H), 3.89 (d, J=6.1 Hz, 2H), 2.05-1.96 (m, 1H), 1.85-1.68 (m, 5H), 1.39-1.25 (m, 1H), 1.17-0.86 (m, 9H), 0.61-0.56 (m, 2H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].O1CCCC1.[CH3:10][O:11][CH2:12][C:13]1[N:18]2[N:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=[C:17]2[C:16]([CH:26]=[O:27])=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1>[OH:27][CH:26]([C:16]1[C:17]2[N:18]([N:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=2)[C:13]([CH2:12][O:11][CH3:10])=[CH:14][CH:15]=1)[CH2:1][CH3:2]
Reactant: COCc1ccc(C=O)c2cc(C(F)(F)F)nn12
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(COC)n2nc(C(F)(F)F)cc12
Temperature: 25 °C

Procedure:
In an argon atmosphere, a 0.97 mol/L ethyl magnesium bromide-tetrahydrofuran solution (12.0 mL) was added dropwise to a solution of the compound of Example 327 (2.00 g) in tetrahydrofuran (50 mL) at −78° C. The mixture was allowed to gradually warm to room temperature. A saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. The extract was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=7:1→2:1) to afford the title compound as a colorless powder (1.68 g).