Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[N:9](CC3C=CC(OC)=CC=3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:22])[C:4](=[O:23])[C:3]=1[CH3:24]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:22])[C:4](=[O:23])[C:3]=1[CH3:24]
Reactant: COc1ccc(Cn2cnc3c(c(Cl)c(C)c(=O)n3C)c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cl)c2c(=O)[nH]cnc2n(C)c1=O
Yield: 171.3 %

Procedure:
5-Chloro-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (8.75 g, 23.9 mmol, compound 8C) was dissolved in trifluoroacetic acid (15 mL) and subjected to microwave irradiation at 150° C. for 1 hour. TFA was evaporated in vacuo and the residue azeotroped with toluene (2×20 mL) then DCM (2×20 mL) to give 9.24 g of the title compound as a crude material which was used without further purification. [M+H] calc'd for C9H8ClN3O2, 226. found, 226.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]=1[OH:19].[CH2:20]=O>O1CCOCC1>[CH3:1][O:2][C:3]1[C:4]2[O:19][CH2:20][N:10]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CNCCc2ccccc2)c1O
Reactant: C=O
Solvent: C1COCCO1
Product: COc1cccc2c1OCN(CCc1ccccc1)C2

Procedure:
To 5 ml. of dioxane are added 0.6 g. of 2-methoxy-6-phenethylaminomethylphenol prepared as above and 1 ml. of 37 % formalin. The mixture is heated on reflux for 3 hours and distilled to remove the solvent. The residue is purified by column chromatography on silica gel with a mixture of acetone and benzene (1:4). The resultant oil is left standing at cool place for 2-3 days to be solidified. Recrystallization from normal hexane yields 8-methoxy-3-phenethyl-3,4-dihydro-2H-1,3-benzoxazine as colorless needles melting at 63°-66° C. Yield: 0.4 g.
Reaction SMILES: [C:1]([C:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[O:17])[CH:12]=3)[C:7]=2[C:6]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:26]2)=[CH:5][CH:4]=1)#[N:2].[OH-:42].[K+].OO.O>CS(C)=O>[C:1]([C:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[O:17])[CH:12]=3)[C:7]=2[C:6]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:26]2)=[CH:5][CH:4]=1)(=[O:42])[NH2:2]
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C#N)ccc(N4CCC[C@@H](NC(=O)OCc5ccccc5)C4)c23)CC1
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(N4CCC[C@@H](NC(=O)OCc5ccccc5)C4)c23)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.9 %

Procedure:
Step 5 A solution of (R)-benzyl 1-(1-cyano-7-(4-methylpiperazine-1-carbonyl)-9H-carbazol-4-yl)piperidin-3-ylcarbamate (108 mg, 0.196 mmol) in DMSO (2 mL) was treated with 22% aqueous potassium hydroxide (0.208 mL, 0.981 mmol), and then dropwise with a solution of 30% aqueous hydrogen peroxide (0.200 mL, 1.961 mmol). The mixture was stirred at rt for 2.5 h. Water was added, the resulting suspension was stirred at rt for 15 min, and the solid was collected by filtration, washed with water and dried to afford (R)-benzyl 1-(1-carbamoyl-7-(4-methylpiperazine-1-carbonyl)-9H-carbazol-4-yl)piperidin-3-ylcarbamate as an off-white solid (89 mg, 80%). 1H NMR (400 MHz, methanol-d4) δ 8.17 (d, J=8.13 Hz, 1H) 7.81 (d, J=8.35 Hz, 1H) 7.66 (s, 1H) 7.30 (d, J=7.91 Hz, 1H) 7.09-7.26 (m, 5H) 6.82 (d, J=8.35 Hz, 1H) 4.90-5.03 (m, 2H) 3.87-3.99 (m, 1H) 3.57-3.68 (m, 1H) 3.27-3.54 (m, 5H) 3.06-3.19 (m, 4H) 2.69-2.82 (m, 1H) 2.47-2.65 (m, 1H) 1.98-2.11 (m, 1H) 1.83-1.97 (m, 2H) 1.32-1.53 (m, 1H). Mass spectrum m/z 569.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C1C(=O)N([Br:16])C(=O)C1>C(#N)C>[Br:16][C:7]1[C:2]([F:1])=[CH:3][C:4]([NH2:8])=[N:5][CH:6]=1
Reactant: Nc1cc(F)ccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1cc(F)c(Br)cn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-fluoropyridin-2-amine (400 mg, 3.57 mmol) in acetonitrile (35. 7 mL) was added NBS (648 mg, 3.64 mmol) in three portions at 0° C. The reaction mixture was stirred at 0° C. for 20 min. LCMS showed the reaction complete. After quenched with sat Na2S2O3 and NaHCO3, stirred for 30 min. The reaction mixture was extracted with EtOAc 3 times. Washed by sat NaHCO3, water and brine. Dried and concentrated. The crude material was triturated with ether and taken to the next step without further purification. LCMS (m/z): 192.9 (MH+), 0.32 min.
Reaction SMILES: C(O)(=O)C.C(OC([NH:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH3:22])[CH:16]=1)=O)(C)(C)C>ClCCl>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([NH:13][NH2:12])=[O:23])=[CH:16][C:17]=1[CH3:22]
Reactant: Cc1cc(C(=O)NNC(=O)OC(C)(C)C)ccc1F
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(C(=O)NN)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
50 mL trifluor acetic acid was added to 13 g N′-(4-fluoro-3-methyl-benzoyl)-hydrazinecarboxylic acid tert-butyl ester in 150 mL dichlormethane. The reaction was stirred for 1 h at RT and the solvent was evaporated. The residue was basicfied with 1 N sodium hydroxide and extracted with saturated sodium chloride solution and tetrahydrofuran. The organic layer was evaporated and the residue crystallized from ethyl acetate to yield 6.8 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[CH3:32][O:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1.CN(C1C=CC=CN=1)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][N:8]([C:38](=[O:39])[C:37]2[CH:41]=[CH:42][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)c3ccc(OC)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.9 %

Procedure:
To a solution of 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (260 mg, 0.77 mmol) in chloroform (7 ml) was added triethylamine (311 mg, 3.08 mmol), 4-methoxybenzoyl chloride (158 mg, 0.92 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 280 mg (75%) of the product as a solid. HR-MS: m/z Calculated for C25H27NO7S 486.1581; Found 486.1576.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:44][S:45]([C:48]1[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=1)(=[O:47])=[O:46]>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:54][C:51]3[CH:50]=[CH:49][C:48]([S:45]([CH3:44])(=[O:47])=[O:46])=[CH:53][CH:52]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(S(C)(=O)=O)cc3)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-methanesulfonyl-phenylamine according to procedure B followed by deprotection yielded the title compound as a white solid. MS (ESI): m/z=433.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[NH2:10])=[CH:5][C:4]=1[CH3:16].[O-:17][C:18]#[N:19].[Na+].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[NH2:19][C:18]([NH:10][N:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:16])[CH:5]=1)=[O:17]
Reactant: COC(=O)CN(N)c1ccc(OC)c(C)c1
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)CN(NC(N)=O)c1ccc(OC)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A mixture of methyl [1-[4-methoxy-3-methylphenyl]hydrazino]acetate (Intermediate 97, 380 mg, 0.0017 mol), sodium cyanate (380 mg, 0.0058 mol) and trifluoroacetic acid (0.4 ml, 0.0052 mol) in dry toluene (10 ml) was stirred under nitrogen and at room temperature for 31/2 hours. It was poured into 8% sodium bicarbonate solution (20 ml) and extracted with ethyl acetate (2×20 ml). The organic extract was dried (MgSO4) and evaporated to give a yellow solid which was triturated with ether and filtered to give the title compound as a yellow solid (237 mg, 52%) m.p. 174°-176° C.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:11][C:12]1[C:16]([CH3:17])=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:14][N:13]=1>C(#N)C>[CH2:8]([O:7][C:5]([CH2:4][C:3]1[NH:11][C:12]2[N:13]([CH:2]=1)[N:14]=[C:15]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:16]=2[CH3:17])=[O:6])[CH3:9]
Reactant: Cc1c(N)n[nH]c1-c1ccccc1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CC#N
Product: CCOC(=O)Cc1cn2nc(-c3ccccc3)c(C)c2[nH]1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
0.78 ml of ethyl 4-chloroacetoacetate was added to a solution of 1.0 g of 3-amino-4-methyl-5-phenyl-1H-pyrazole in 25 ml of acetonitrile, and then the mixture was stirred at room temperature for 4 days. At the end of this time, the crystals which separated were filtered off and the mother liquor was concentrated by evaporation under reduced pressure. The residue was partitioned between ethyl acetate and water, and the organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 80 mg of the title compound in the form of an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][CH3:21])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=3)[C:6]=2[N:7]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[N:30]1[C:34]([CH3:35])=[N:33][CH:32]=[N:31]1)[NH2:26]>C(O)(=O)C.C1COCC1>[F:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[N:3]=[C:4]([NH:20][CH3:21])[C:5]3[CH2:10][CH2:9][CH:8]([C:11]4[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=4)[C:6]=3[N:7]=2)[CH:27]=[CH:28][C:29]=1[N:30]1[C:34]([CH3:35])=[N:33][CH:32]=[N:31]1
Reactant: Cc1ncnn1-c1ccc(N)cc1F
Reactant: CNc1nc(Cl)nc2c1CCC2c1cc(F)c(F)c(F)c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1nc(Nc2ccc(-n3ncnc3C)c(F)c2)nc2c1CCC2c1cc(F)c(F)c(F)c1
Temperature: 80 °C

Procedure:
2-Chloro-N-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (65.3 mg, 0.208 mmol) was added to a solution of 3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline (40 mg, 0.208 mmol) in acetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heated at 80° C. overnight. Partial formation of the desired product was observed. The reaction mixture was heated at 130° C. for 6 h. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, TFA salt (5.3 mg, 8.99 μmol, 4.32% yield). LC-MS (M+H)+=470.0. 1H NMR (500 MHz, CDCl3) δ ppm 12.17 (1H, s), 8.75 (1H, d, J=1.8 Hz), 8.05 (1H, dd, J=13.7, 2.1 Hz), 7.80 (1H, t, J=8.7 Hz), 7.44-7.65 (1H, m), 6.74-6.99 (2H, m), 5.33-5.66 (1H, m), 4.34-4.67 (1H, m), 3.42-3.74 (2H, m), 3.29 (3H, d, J=4.9 Hz), 2.70-2.99 (2H, m), 2.57 (2H, s), 2.14-2.38 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12]>>[CH2:11]([N:13]([CH2:14][CH3:15])[C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:12]
Reactant: CCNCC
Reactant: O=C(Cl)c1ccccc1Cl
Product: CCN(CC)C(=O)c1ccccc1Cl

Procedure:
2-Chlorobenzoyl chloride is reacted with diethylamine using General Method E1 or E2 to produce the title compound.
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][C@H:7]([O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:15]([Si:12]([CH3:14])([CH3:13])[O:11][C@H:9]1[CH2:10][C@H:5]([OH:4])[CH2:6][C@@H:7]([O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:8]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(=O)O[C@@H]1C[C@@H](OC(=O)C(C)(C)C)C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)C(=O)O[C@@H]1C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
A solution of 7.45 g of (1R,3R,5S)-2,2-dimethyl-propionic acid 3-acetoxy-5-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl ester and 2.76 g of potassium carbonate in 52 ml of methanol and 24 ml of water was stirred at 22° for 6 h after which time t.l.c. showed completion of the reaction. The mixture was evaporated and the residue partitioned between dichloromethane and water. The organic layer was dried over MgSO4 and evaporated to give 6.49 g of the pure (t.l.c.) title compound as a white solid, m.p. 39-42°. IR (nujol): 3240m (OH), 1731s (C═O); MS (EI): 273/10 (M-tert-butyl).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[C:10]([F:16])[CH:9]=1)=O.[BH4-].[Na+]>O1CCCC1.CO>[F:16][C:10]1[CH:9]=[C:8]([CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][NH:1]2)[CH:13]=[C:12]([F:14])[C:11]=1[F:15]
Reactant: NCCCCC(=O)c1cc(F)c(F)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Fc1cc(C2CCCCN2)cc(F)c1F
Reaction time: 18 h
Yield: 677.6 %

Procedure:
To 5-amino-1-(3,4,5-trifluorophenyl)pentan-1-one (0.11 g, 0.48 mmol) in tetrahydrofuran/methanol 4:1 (10 mL) was added in portions over 20 minutes solid sodium borohydride (0.20 g, 5.0 mmol) and stirring was continued 18 hours at 25° C. The reaction mixture was concentrated then taken into ethyl acetate (40 mL), washed with saturated sodium chloride/2 N aqueous sodium hydroxide 10:1 (11 mL) then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes, 1:1) to give 2-(3,4,5-trifluorophenyl)piperidine (0.70 g, 68% yield) as an oil. 1H NMR (400 MHz, CDCl3): 7.01 (m, 2H), 3.52 (m, 1H), 3.17 (m, 1H) 2.77 (m, 1H), 2.07 (br s, 1H), 1.88 (m, 1H), 1.74 (m, 1H), 1.64 (m, 1H), 1.55-1.35 (m, 3H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5](O)=[O:6])=[CH2:3].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[CH2:10]([N:17]1[C:5](=[O:6])[CH2:4][CH:2]([C:1]([OH:9])=[O:8])[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: NCc1ccccc1
Solvent: O
Product: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
A mixture of itaconic acid (130 g, 1.00 mol) and benzylamine (107 g, 1.00 mol) were heated to 130° C. After 30 minutes, the reaction mixture was cooled and diluted with water (200 mL). The resulting slurry was filtered, washed with cold water, dissolved in aqueous sodium hydroxide, and treated with active carbon. The slurry was filtered to remove the carbon, and the aqueous solution was acidified with hydrochloric acid to precipitate solids. The solids were recrystallized from ethanol to afford 1-benzyl-5-oxopyrrolidine-3-carboxylic acid that was used without additional purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:18])[NH:13]2.[OH:19][CH:20]([CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1[CH:31]=O)=[O:24].N1CCCCC1>C(O)C>[OH:19][CH:20]([CH2:33][N:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1/[CH:31]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH:17]=[CH:16][CH:15]=2)=[O:24]
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2F)N1
Reactant: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(/C=C2\C(=O)Nc3cccc(-c4ccc(F)cc4F)c32)[nH]1
Yield: 60 %

Procedure:
4-(2,4-Difluoro-phenyl)-1,3-dihydro-indol-2-one (73.5 mg, 0.3 mmol) was condensed with 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide (excess) and piperidine in ethanol to give 75 mg (60%) of the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[CH:6]=[CH:7]/[CH2:8]P(OCC)(OCC)=O)=[O:5].C([Li])CCC.[C:22]([O:25][C@@H:26]1[CH2:48][CH2:47][C@@:46]2([CH3:49])[CH:28]([CH2:29][CH2:30][C@@H:31]3[C@@H:45]2[CH2:44][C@H:43]([O:50][C:51](=[O:53])[CH3:52])[C@@:42]2([CH3:54])[C@H:32]3[CH2:33][CH2:34][C@@H:35]2[C@H:36]([CH3:41])[CH2:37][CH2:38][CH:39]=O)[CH2:27]1)(=[O:24])[CH3:23].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>C(COC)OC.CCCCCC>[CH2:2]([O:3][C:4](=[O:5])/[CH:6]=[CH:7]/[CH:8]=[CH:39]/[CH2:38][CH2:37][CH:36]([C@@H:35]1[C@:42]2([CH3:54])[C@H:32]([C@H:31]3[C@H:45]([CH2:44][C@@H:43]2[O:50][C:51](=[O:53])[CH3:52])[C@:46]2([CH3:49])[C@@H:28]([CH2:27][C@H:26]([O:25][C:22](=[O:24])[CH3:23])[CH2:48][CH2:47]2)[CH2:29][CH2:30]3)[CH2:33][CH2:34]1)[CH3:41])[CH3:1]
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)C(CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC=O)[C@@]4(C)[C@@H](OC(C)=O)C[C@@H]32)C1
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Product: CCOC(=O)/C=C/C=C/CCC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C[C@H](OC(C)=O)[C@]12C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 19.6 g of freshly distilled triethyl 4-phosphonocrotonate in 50 ml of dry glyme was added (at -70° ) 50 ml of a 1.6 M solution of butyl lithium in hexane. After 15 min the temperature was brought to -10° and 30 g of 3α,12α-diacetoxycholan-24-al was dissolved in 200 ml of dry glyme was added dropwise. After stirring for 20 min at this temperature the reaction mixture was allowed to warm to room temperature and stirred for 0.5 hr. The reaction mixture was then poured into 2 liters of a 5% monobasic sodium phosphate solution and the mixture extracted with ether. The ether solution was washed with a saturated aqueous sodium chloride solution and dried (MgSO4). The solvent was removed under reduced pressure and the residue after being dissolved in a minimum amount of benzene was washed through 300 g of silica gel. The column was eluted with 4 liters of benzene and then 4 liters of 0.5% ethyl acetate-benzene solution, and the solids obtained therefrom were combined to give 20.7 g of crude 7-(3α,12α-diacetoxy-5β-pregnane-20-yl)-trans,trans- 2,4-heptadienoic acid ethyl ester. Trituration with petroleum ether afforded 13.1 g of 7-(3α,12α-diacetoxy-5β-pregnane-20-yl)-trans,trans-2,4-heptadienoic acid ethyl ester, mp 129°-131°, plus a second crop of 2.4 g, mp 128°-130°. Crystallization from methanol afforded the analytical sample, mp 130°-132°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]([NH2:10])[CH2:8][S:7][C:6]=2[CH:11]=1.[F:12][C:13]([F:24])([F:23])[C:14]([NH:16][C:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1)=[O:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]([NH:10][C:20]([C:17]3([NH:16][C:14](=[O:15])[C:13]([F:12])([F:23])[F:24])[CH2:18][CH2:19]3)=[O:21])[CH2:8][S:7][C:6]=2[CH:11]=1
Reactant: NC1CSc2cc(Br)ccc21
Reactant: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Product: O=C(NC1(C(=O)NC2CSc3cc(Br)ccc32)CC1)C(F)(F)F

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B] and A-1 [C], (rac)-6-bromo-2,3-dihydro-benzo[b]thiophen-3-ylamine has been coupled with 1-(2,2,2-trifluoroacetamido)cyclopropanecarboxylic acid (intermediate A-1 [A]) to give 1-(2,2,2-trifluoro-acetylamino)-cyclopropanecarboxylic acid ((rac)-6-bromo-2,3-dihydro-benzo[b]thiophen-3-yl)-amide, which was subsequently reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to yield the title compound as yellow oil. MS: 455.4 (M−H−).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Br:21]N1C(=O)CCC1=O>C(Cl)Cl.S(=O)(=O)(O)O>[CH2:19]([O:18][C:16]([C:9]1[C:10]2[C:15](=[CH:14][C:13]([Br:21])=[CH:12][CH:11]=2)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=1)=[O:17])[CH3:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c2ccccc12
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C(=O)OCC)c2cc(Br)ccc12
Reaction time: 8 h

Procedure:
Naphthalene-1,4-dicarboxylic-acid diethyl ester 35.0 g was dissolved in a mixed solvents 280 ml of methylene chloride and concentrated sulfuric acid (weight ratio 3:7), and N-bromo succinimide 22.9 g was added here at a room temperature. After stirring overnight, the reaction mixture was poured into ice, and extracted with ethyl acetate. The extracted solution was washed with diluted alkaline water, subsequently with water, and then dried by magnesium sulfate. The solution was concentrated, and treaded with column processing (silica gel/chloroform), and 28.0 g of a crude product of 6-bromonaphthalene-1,4-dicarboxylic-acid diethyl ester was obtained.
Reaction SMILES: C[N:2]([CH3:14])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1)=O.N[C:16]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=C[NH:18][N:17]=1>C(O)(=O)C>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:18]3[N:17]=[CH:16][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:14]3[N:2]=[CH:3][CH:4]=2)=[N:8][CH:9]=1
Reactant: Cc1ccc(C(=O)C=CN(C)C)nc1
Reactant: CCOC(=O)c1c[nH]nc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3ccc(C)cn3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(5-methyl-2-pyridyl)-2-propen-1-one and 0.01 mole of ethyl 3-aminopyrazole-4-carboxylate in glacial acetic acid is refluxed for 6 hours. The solvent is removed under reduced pressure and the residue worked up as for Example 53 to give the product of the example.