Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][CH2:29][O:30][C:23]=3[CH:22]=2)=S)[CH2:10][CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][N:17]=[C:18]=[N:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][CH2:29][O:30][C:23]=3[CH:22]=2)[CH2:12][CH2:13]1
Reactant: S=C(NCCCN1CCN(c2ccccc2Cl)CC1)Nc1ccc2c(c1)OCCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1ccccc1N1CCN(CCCN=C=Nc2ccc3c(c2)OCCO3)CC1
Temperature: 400 °C
Yield: 56.5 %

Procedure:
A mixture of N-3-[4-(2-chlorophenyl)piperazin-1-yl]propyl-N '-(3,4-ethylenedioxyphenyl)thiourea of Example 11 (1.35 g; 3 mmol), triphenylphosphin (1.02 g; 3.9 mmol), carbon tetrachloride (0.56 ml), triethylamine (0.3 g; 3 mmol) and methylene chloride (15 ml) Was stirred at reflux for 3 h and at 400° C. for 16 h. The reaction mixture was concentrated in vacuo and then taken up in petroleum ether. The solution was filtered and concentrated in vacuo to give 0.7 g N-3-[4-(2-chlorophenyl)piperazin-1-yl]propyl-N'-(3,4-ethylenedioxyphenyl)carbodiimide as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13](=O)[NH:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)=O)[N:10]([C:26](=[O:36])[CH:27]([NH:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]([CH3:30])[CH3:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:41]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:41]=2)[N:10]([C:26](=[O:36])[CH:27]([NH:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]([CH3:30])[CH3:29])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 0.75 h
Yield: 62.4 %

Procedure:
4-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-3-(2-methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-1-carboxylic acid tert-butyl ester (723 mg) was dissolved in m-xylenes (6.0 mL) and heated at 135° C. Solid ammonium acetate (500 mg, 6.48 mmol) was added and the reaction was stirred at 135° C. After 45 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc w 10% MeOH/hexanes) to yield the product 4-(4-Bromo-phenyl)-3′-(2-methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-1′-carboxylic acid tert-butyl ester (436 mg): LCMS-ESI+: calc'd for C24H32BrN5O5: 550.4 (M+). Found: 551.2/553.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([C:23](OCC)=[O:24])[CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].C(=O)(O)[O-].[Na+]>C1COCC1>[OH:24][CH2:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[S:15][C:16]=2[CH:22]=1
Reactant: CCOC(=O)c1ccc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)sc2c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc3ccc(CO)cc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
The ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzo[d]thiazole-6-carboxylate (1.1 g) was dissolved in dry THF (50 mL) and lithium borohydride (67 mg) was added. The resulting mixture was stirred overnight at room temperature, then heated to reflux for 24 hours. Saturated aqueous sodium bicarbonate was added and the resulting mixture was extracted with ethyl acetate. The resulting solution was concentrated to yield tert-butyl 4-(6-(hydroxymethyl)benzo[d]thiazol-2-yl)piperazine-1-carboxylate as a white solid (1.0 g). MS: 350.3 (M+H).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:17]([O:19][CH3:20])=[O:18])=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[OH:8][C:9]1[C:10]([C:17]([O:19][CH3:20])=[O:18])=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1
Reactant: COC(=O)c1nc(OC)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1nc(OC)ccc1O
Yield: 74.6 %

Procedure:
10% palladium-carbon (48 mg) was added to 480 mg of methyl 3-benzyloxy-6-methoxy-picolinate. After the replacement of the atmosphere by nitrogen, 25 ml of methanol was added thereto. Further, after the replacement of the atmosphere by hydrogen, the mixture was vigorously stirred to allow a reaction to proceed. One hr after the initiation of the reaction, the reaction mixture was filtered, followed by purification by chromatography on silica gel (chloroform-methanol) to give 240 mg (yield 76%) of the title compound.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Br:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[CH:16]=[C:17]([C:27]([NH2:29])=[O:28])[N:18]3[C:23]([S:24][CH3:25])=[CH:22][C:21]([CH3:26])=[N:20][C:19]=23)=[C:10]([CH3:30])[CH:9]=1>O.C(O)C>[Br:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[CH:16]=[C:17]([C:27]([NH2:29])=[O:28])[N:18]3[C:23]([S:24]([CH3:25])=[O:1])=[CH:22][C:21]([CH3:26])=[N:20][C:19]=23)=[C:10]([CH3:30])[CH:9]=1
Reactant: O=S([O-])OO
Reactant: CSc1cc(C)nc2c(-c3c(C)cc(Br)cc3C)cc(C(N)=O)n12
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cc(S(C)=O)n2c(C(N)=O)cc(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 0 °C
Yield: 2180.4 %

Procedure:
To a solution of Oxone (9.12 g) in water (50 mL) was added a solution of 8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-methylsulfanyl-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid amide (3.00 g) in ethanol (50 mL) in an ice-cooling bath. The reaction mixture was stirred under ice-cooling for 30 minutes, poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: ethyl acetate) to give 8-(4-bromo-2,6-dimethyl-phenyl)-4-methanesulfinyl-2-methyl-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid amide (1:68 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([OH:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].COC1C=C(C2C=CC(N)=C(OC)C=2)C=CC=1N.I.[CH3:36][Si:37]([CH3:40])([CH3:39])Cl>O1CCCC1.C(N(CC)CC)C>[CH3:36][Si:37]([CH3:40])([CH3:39])[O:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][Si:37]([CH3:40])([CH3:39])[CH3:36])=[C:11]([O:16][Si:37]([CH3:40])([CH3:39])[CH3:36])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH:8][Si:37]([CH3:40])([CH3:39])[CH3:36]
Reactant: Nc1ccc(-c2ccc(N)c(O)c2)cc1O
Reactant: C[Si](C)(C)Cl
Agent: COc1cc(-c2ccc(N)c(OC)c2)ccc1N
Agent: I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)Nc1ccc(-c2ccc(N[Si](C)(C)C)c(O[Si](C)(C)C)c2)cc1O[Si](C)(C)C

Procedure:
0.540 g 3,3'-dihydroxy-4,4'-diaminobiphenyl (synthesized from 3,3'-dimethoxy-4,4'-diaminobiphenyl using hydrogen iodide by the known method) and 1.52 g triethylamine were dissolved in 16 mL dry tetrahydrofuran. 1.63 g trimethylchlorosilane was then added dropwise followed by heating under reflux for 72 hours. Operating in an argon atmosphere, the salt was filtered off and the solvent, etc., was removed under reduced pressure to yield 3,3'-bis(trimethylsiloxy)-4,4'-bis(trimethylsilylamino)biphenyl. This monomer was prepared immediately prior to each of the polymerization reactions described below.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31]>>[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: Fc1cccc(Cl)c1CBr
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(Cc3c(F)cccc3Cl)CC1)O2

Procedure:
Compound 129 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-(bromomethyl)-1-chloro-3-fluorobenzene and conditions outlined in procedure V. M.p.=90-92° C.; 300 MHz 1H NMR (CDCl3) δ 8.08-8.02 (m, 1H), 7.76-7.72 (m, 1H), 7.69-7.62 (m, 1H), 7.52-7.44 (m, 1H), 7.28-7.2 (m, 2H), 7.06-6.97 (m, 1H), 3.78 (d, J=2.1 Hz, 2H), 2.91 (s, 2H), 2.9-2.8 (m, 2H), 2.7-2.58 (m, 2H), 2.16-2.04 (m, 2H), 1.92-1.78 (m, 2H); LCMS: 444 [M+H].
Reaction SMILES: CO[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1.ClC1N=CN=C(N[C:36]2[CH:37]=[C:38](CS(N)(=O)=O)[CH:39]=[CH:40][CH:41]=2)N=1.C1(CCC2CCCN2)C=CC=CC=1>>[C:36]1([CH2:8][CH2:9][CH:4]2[CH2:3][CH2:7][CH2:6][N:5]2[C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[N:11]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Agent: c1ccc(CCC2CCCN2)cc1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCC3CCc3ccccc3)n2)c1

Procedure:
B27 was prepared following the procedure reported for B4 using A1 and rac-2-(2-phenylethyl)pyrrolidine and obtained as a white crystalline solid; yield: 140 mg (35%). MS (ES) C22H26N6O2S requires: 438. found: 439 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([F:14])([CH3:13])[CH:7]([OH:12])[C:8]([O:10][CH3:11])=[O:9].[H-].[Na+].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21](S(C)(=O)=O)[N:20]=1.O>CN(C)C=O.C(O)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([F:14])([CH3:13])[CH:7]([O:12][C:21]1[N:22]=[C:23]([O:25][CH3:26])[CH:24]=[C:19]([O:18][CH3:17])[N:20]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)C(O)C(C)(F)c1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(F)c1cccs1
Reaction time: 1 h

Procedure:
2.2 g (10 mmol) of methyl 3-(2-thienyl)-3-fluoro-2-hydroxybutyrate (Compound 1.1) are dissolved in 40 ml of dimethylformamide, and 0.3 g (12 mmol) of sodium hydride is added. The mixture is stirred for 1 hour, and 2.2 g (10 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine are then added. After the mixture has been stirred at room temperature for 24 hours, it is hydrolyzed using 10 ml of water, the pH is brought to 5 using acetic acid, and the solvent is distilled off under a high vacuum. The residue is taken up in ethyl acetate, washed with water and dried over sodium sulfate, and the solvent is distilled off. The residue is treated with 10 ml of methyl t-butyl ether and the precipitate formed filtered off with suction. After drying, 1.8 g of a white powder remain.
Reaction SMILES: Cl.[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:12]1[CH:34]=[CH:33][C:15]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:14][CH:13]=1)C(=O)C)([CH3:4])[CH3:3].C(Cl)(=O)C>>[CH:2]([O:5][CH2:6][CH2:7][NH:8][C:12]1[CH:34]=[CH:33][C:15]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH2:22][CH2:23]2)=[O:17])=[CH:14][CH:13]=1)([CH3:4])[CH3:3]
Reactant: CC(=O)N(CCOC(C)C)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Agent: Cl
Solvent: CC(=O)Cl
Product: CC(C)OCCNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
In a manner analogous to that described in Example 23, 1-{4-[N-(2-isopropyloxyethyl)-N-acetylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine hydrochloride having a melting point of 142°-144° is obtained from 3 g of 1-{4-[N-(2-isopropyloxyethyl)amino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine by reaction with acetyl chloride.
Reaction SMILES: [NH:1]([CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH:1]([CH:8]1[CH2:12][CH2:11][N:10]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(NC2CCNC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(CCN2CCC(Nc3ccccc3)C2)cc1
Yield: 71.6 %

Procedure:
3-Anilinopyrrolidine (0.67 g) and 2-(4-fluorophenyl)ethyl p-toluenesulfonate (1.2 g) were dissolved in acetonitrile (20 ml), and potassium carbonate (2 g) was added. The mixture was refluxed for 3 hours, and after the completion of the reaction, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed with an aqueous potassium carbonate solution, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform:methanol=20:1). The obtained eluate was concentrated to give 3-anilino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine (0.83 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][C:6]=2[CH:13]=1.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].N1C=CN=C1>CN(C=O)C>[Si:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][C:6]=2[CH:13]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(=O)c1cc2cc(O)ccc2o1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)c1cc2cc(O[Si](C)(C)C(C)(C)C)ccc2o1
Yield: 92.8 %

Procedure:
Using 1-(5-hydroxy-1-benzofuran-2-yl)ethanone (1.15 g, 6.53 mmol), DMF (10 mL), tert-butyldimethylchlorosilane (1.07 g, 7.18 mmol) and imidazole (666 mg, 9.80 mmol), an operation in the same manner as in Reference Example 16 was performed to give the title compound (1.76 g, yield 98%).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[OH:22])[CH:17]=[O:18])[CH3:12]>CN(C=O)C>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH2:2][CH2:3][OH:4])[CH:17]=[O:18])[CH3:12]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1OCCO
Temperature: 120 °C

Procedure:
2.76 ml of 2-bromoethanol and 5.40 g of potassium carbonate were added to a solution of 5 g of 3-ethoxy-4-hydroxybenzaldehyde in 150 ml of DMF. The reaction mixture was heated to 70° C. overnight and subsequently to 120° C. for a further 4 hrs. Then, the mixture was left to cool to room temperature, filtered and concentrated in a high vacuum. The crude product was isolated by extraction and purified by chromatography on silica gel. There were obtained 6.09 g of 3-ethoxy-4-(2-hydroxy-ethoxy)-benzaldehyde as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25]CC)=O)=[C:11]([CH:21]=O)[N:12]2[CH:17]([CH3:18])[CH2:16][N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:29][NH2:30]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:10]2[C:23](=[O:25])[NH:30][N:29]=[CH:21][C:11]=2[N:12]2[CH:17]([CH3:18])[CH2:16][N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C=O)C(C)CN(C)C2=O
Solvent: O
Solvent: CC(=O)O
Product: CC1CN(C)C(=O)c2c(OCc3ccccc3)c3c(=O)[nH]ncc3n21

Procedure:
A solution of ethyl 8-(benzyloxy)-2,4-dimethyl-1-oxo-6-formyl-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (0.29 g, 0.79 mmol), and hydrazine monohydrate (0.20 mL, 3.96 mmol) in glacial acetic acid (2 mL) was heated in a microwave oven at 100° C. for 5 minutes. The reaction mixture was concentrated under vacuum and the residue partitioned between dichloromethane and aqueous sodium bicarbonate. The organic extract was dried over MgSO4, filtered, and concentrated to provide the titled dione.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[C:9]([O:11]C)=[O:10])=O.C(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1)[C:9]([OH:11])=[O:10])[CH3:2]
Reactant: COC(=O)c1cc(NC(=O)C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNc1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methyl 3-amino-5-(trifluoromethyl)benzoate (cf. procedures (116a) and (80a); 177 mg, 0.81 mmol) was dissolved in MeOH (12 mL) and the resulting solution was charged successively with acetaldehyde (0.045 mL, 0.81 mmol) and sodium cyanoborohydride (64 mg, 1.01 mmol). The reaction was stirred at RT for 12 h, concentrated in vacuo, and diluted with EtOAc. The organic phase was washed with sat. NaHCO3, water (2×), and brine before being dried (Na2SO4), filtered, and concentrated in vacuo. This product was dissolved in 3:1 THF/MeOH (12 mL) and the resultant solution was charged with lithium hydroxide (3 mL of a 1N solution). The reaction was stirred for 14 h, acidified with 1N, and extracted with EtOAc (2×). The organic extracts were combined, washed with water, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide 3-ethylamino-5-(trifluoromethyl)benzoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([OH:29])[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2].[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]O)=[CH:35][CH:34]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:37][C:36]3[CH:39]=[CH:40][C:33]([F:32])=[CH:34][CH:35]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2]
Reactant: OCc1ccc(F)cc1
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#CCN3CCOCC3)c2)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCc3ccc(F)cc3)c2)cc1C
Reaction time: 1 h

Procedure:
{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.45 mmol), 4-fluorobenzylalcohol (85.7 mg; 0.68 mmol), tributylphosphine (0.27 mL; 1.36 mmol) and 1,1′-(azodicarbonyl)dipiperidine (0.34 g; 1.36 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. After stirring for 1 h the reaction mixture was purified by prep. HPLC (method A). Yield: 200 mg. HPLC-MS: m/z: 550.3 (M+H); Rt: 2.00 min.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)#[N:2].[C:13]([C:16]1[C:17](=[O:25])[N:18]([CH3:24])[C:19]([CH3:23])=[CH:20][C:21]=1[OH:22])(=[O:15])[CH3:14]>C(O)C>[OH:22][C:21]1[CH:20]=[C:19]([CH3:23])[N:18]([CH3:24])[C:17](=[O:25])[C:16]=1[C:13](=[O:15])[CH:14]=[CH:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([CH2:4][CH2:3][C:1]#[N:2])[CH:6]=1
Reactant: CC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: N#CCCc1cccc(C=O)c1
Solvent: CCO
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(CCC#N)c2)c(=O)n1C
Yield: 46.7 %

Procedure:
According to the same manner as that of Example a-1 except that 0.74 g of 3-(2-cyanoethyl)benzaldehyde was used in place of 3-[(methoxycarbonyl)methoxy]benzaldehyde, 0.93 g of 3-acetyl-4-hydroxy-1,6-dimethyl-2(1H)-pyridinone was used in place of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone, and 8 ml of ethanol was used in place of pyridine, 0.70 g of 4-hydroxy-3-[3-[3-(2-cyanoethyl)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (106a)] was obtained as a yellow crystal.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:23])[CH:17]=1)[CH3:15]>CCO.Cl>[CH2:11]([O:10][C:8](=[O:9])[C:7]1[C:2]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:14][CH3:15])=[CH:17][C:18]=2[F:23])=[CH:3][C:4]([Cl:13])=[N:5][CH:6]=1)[CH3:12]
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: CCc1ccc(N)c(F)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(CC)cc1F
Yield: 100 %

Procedure:
Ethyl 4,6-dichloronicotinate (31.62 g, 144.0 mmol) and 4-Ethyl-2-fluoro-phenylamine (20.0 g, 144.0 mmol) were dissolved in EtOH (200 mL), to which was added conc. HCl (6 drops) as for Example 1, alternate Step A to give 6-Chloro-4-(4-ethyl-2-fluoro-phenylamino)-nicotinic acid ethyl ester (46.50 g, 99%). (APCI+) calcd for C16H18ClFIN2O2 322.76 (M−1), found 321.0.
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[C:14]([OH:16])=[O:15])([OH:4])(=[O:3])=[O:2].[OH-].[Ca+2:18].[OH-]>>[S:1]([C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([O-:10])=[O:9])[C:6]=1[C:14]([O-:16])=[O:15])([OH:4])(=[O:3])=[O:2].[Ca+2:18]
Reactant: O=C(O)c1cccc(S(=O)(=O)O)c1C(=O)O
Agent: [Ca+2]
Agent: [OH-]
Product: O=C([O-])c1cccc(S(=O)(=O)O)c1C(=O)[O-]

Procedure:
To 1000 g of 10% sulfophthalic acid aqueous solution stirred at room temperature, 30 g of calcium hydroxide was added. The stirring was continued while measuring the pH value. At the time when the pH value reached 6, approximately, filtration was done by using a 0.4 μm glass filter to remove the insoluble components, so as to obtain a calcium sulfophthalate aqueous solution.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]=[C:7]([C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH:8]=[CH:9]2
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc2ccccc2cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2ccc(C(=O)C(C)C)cc2cc1OC

Procedure:
The solution of 2,3-dimethoxynaphthalene (16.5 g ), isobutyroylchloride (12.5 g) and aluminum chloride (15.7 g) in methylene chloride (200 ml) was stirred at ambient temperature overnight. The solution was then washed with saturated sodium bicarbonate and water, dried with sodium sulfate and evaporated. Finally the crude product was triturated with ether. Yield: 13.5 g, melting point 103-105° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH:31]([NH2:34])([CH3:33])[CH3:32]>>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:34][CH:31]([CH3:33])[CH3:32])[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: CC(C)N
Product: CC(C)NCC1Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1

Procedure:
The title compound was prepared (0.065 g, 66%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.14 g, 0.3 mmol) and isopropylamine (0.18 g, 3.0 mmol). mp 134-135° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=O)=[CH:4][CH:3]=1.[Br:12]CCC1C=CC=CC=1F>>[Br:12][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Fc1ccccc1CCBr
Reactant: O=C(O)Cc1ccc(F)cc1
Product: Fc1ccc(CCBr)cc1

Procedure:
1-(2-Bromoethyl)-4-fluorobenzene was prepared from 4-fluorophenylacetic acid as described above for 1-(2-bromoethyl)-2-fluorobenzene.