Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:11][C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=2)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)=[O:2].NC1C=C(NC(=O)OC(C)(C)C)C=CC=1[F:33]>>[F:33][C:17]1[CH:16]=[CH:15][C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:13][C:12]=1[NH:11][C:4]1[C:3]([CH:1]=[O:2])=[CH:8][N:7]=[C:6]([S:9][CH3:10])[N:5]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(N)c1
Reactant: CSc1ncc(C=O)c(Nc2cccc(NC(=O)OC(C)(C)C)c2)n1
Product: CSc1ncc(C=O)c(Nc2cc(NC(=O)OC(C)(C)C)ccc2F)n1

Procedure:
The title compound was prepared according to the procedures described for Intermediate 50, starting from tert-butyl (3-amino-4-fluorophenyl)carbamate (58a; prepared according to the reported protocol in Kuramoto, Y. et al. J. Med. Chem. 2003, 46, 1905-1917).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.C1(C)CCC(C(C)C)C(S(O[CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)(=O)=O)C1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[F:43][C:42]([F:44])([F:45])[C:38]1[CH:37]=[C:36]([CH2:35][CH2:34][N:1]2[CH2:2][CH2:3][CH:4]([CH:7]3[C:13]4=[CH:14][CH:15]=[CH:16][N:12]4[CH2:11][C:10]4[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=4[O:8]3)[CH2:5][CH2:6]2)[CH:41]=[CH:40][CH:39]=1
Reactant: CC1CCC(C(C)C)C(S(=O)(=O)OCCc2cccc(C(F)(F)F)c2)C1
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(CCN2CCC(C3Oc4ccccc4Cn4cccc43)CC2)c1
Temperature: 65 °C

Procedure:
A mixture of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (6.15 g, 0.023 mole), 2-(3-trifluoromethylphenyl)ethyl menthanesulfonate (7.27 g, 0.027 mole) and K2CO3 (10.6 g) in 125 ml dimethylformamide was heated at 65° C. for 5 hours.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:29][CH2:28]3)=[C:23]([CH:30]=O)[CH:22]=2)=[C:17]([F:32])[CH:16]=1>COCCOC.C(OCC)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:28][CH2:29]3)=[C:23]([CH:30]=[C:5]3[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]3=[O:7])[CH:22]=2)=[C:17]([F:32])[CH:16]=1
Reactant: O=Cc1cc(-c2ccc(Cl)cc2F)ccc1C1CC1
Reactant: CC1(C)CC(=O)C(C)(C)O1
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CC1(C)OC(C)(C)C(=Cc2cc(-c3ccc(Cl)cc3F)ccc2C2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91920 %

Procedure:
To an ice-cold solution of dihydro-2,2,5,5-tetramethylfuran-3-one (8.40 g, 0.059 mol) in anhydrous 1,2-dimethoxyethane (75 ml) is added sodium methoxide (3.60 g, 0.066 mol) in one portion, and the mixture is stirred at this temperature for 30 minutes. A solution of 4′-chloro-4-cyclopropyl-2′-fluorobiphenyl-3-carbaldehyde (14.80 g, 0.054 mmol) is then added dropwise over 20 minutes, maintaining temperature below 10° C. The reaction mixture is stirred at this temperature for 1 hour, then allowed to warm to room temperature before diluting with diethyl ether and distilled water. The two phases are separated, and the aqueous phase is extracted again with diethyl ether (×2). Organic fractions are combined, washed with brine, then dried over magnesium sulfate. The suspension is filtered and the filtrate concentrated in vacuo to afford 4-[1-(4′-chloro-4-cyclopropyl-2′-fluorobiphenyl-3-yl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (19.80 g) which is of sufficient purity to use directly in the next step.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]3[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]3)[N:8]=2)=[CH:4][CH:3]=1.[Li]CCCC.[CH3:29][N:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]1>C1COCC1>[CH3:29][N:30]1[CH2:35][CH2:34][C:33]([C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]4[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]4)[N:8]=3)=[CH:4][CH:3]=2)([OH:36])[CH2:32][CH2:31]1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)s3)n2)CC(C)(C)N1
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)s2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
[4-(5-Bromo-thiophen-2-yl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (Step C of Example 5, 198 mg, 0.5 mmol) was dissolved in THF (10 ml), cooled to −78° C. and treated with nBuLi (1.6M in hexane, 0.94 ml, 1.5 mmol) for 15 minutes. N-methyl-4-piperidone (231 μl, 2 mmol) in THF (0.2 ml) was added rapidly and the reaction mixture stirred for 15 minutes at −78° C., then poured on water and extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, evaporated to dryness and purified via preparative HPLC to give the title compound as colorless crystals, which crystallized from ether. Yield: 40 mg (19%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[C:16](Cl)(=O)[CH3:17]>C(O)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C(O)CCCCCCCCCCCO
Reactant: CC(=O)Cl
Solvent: CCO
Product: CCOC(=O)CCCCCCCCCCCO
Reaction time: 24 h
Yield: 833.6 %

Procedure:
In a 100 mL two-neck flask with a reflux condenser and magnetic anchor, under a static flux of nitrogen, 12-hydroxy-dodecanoic acid (5.0 g, 23.2 mmol) is weighed, ethanol (20 mL) and acetyl chloride (1.62 mmol, 0.09 ml, 0.1 eq.) are added. The mixture is left stirring in reflux conditions for 24 hours. It is concentrated in the Rotavapor and in the high vacuum pump and the product is purified with column chromatography on silica gel with eluant mixture petroleum ether/ethyl acetate 5/4. 3.30 g of ethyl 12-hydroxydodecanoate are isolated as a light yellowish oil for a yield of 96%.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[ClH:13].[F:14][C:15]1[CH:34]=[C:33]([CH3:35])[C:32]([O:36]C(OC)=O)=[CH:31][C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24](O)=[C:25](OC)[CH:26]=2)[N:21]=[CH:20][N:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:60]1([CH2:65][CH2:66][OH:67])[CH:64]=[N:63][CH:62]=[N:61]1>C(Cl)Cl>[ClH:13].[F:14][C:15]1[CH:34]=[C:33]([CH3:35])[C:32]([OH:36])=[CH:31][C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:67][CH2:66][CH2:65][N:60]3[CH:64]=[N:63][CH:62]=[N:61]3)=[CH:25][CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: OCCn1cncn1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(F)c(Nc2ncnc3cc(OCCn4cncn4)ccc23)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
Diethyl azodicarboxylate (244 mg, 1.4 mmol) was added dropwise to a suspension of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (261 mg, 0.7 mmol), (prepared as described for the starting material in Example 22), triphenylphosphine (367 mg, 1.4 mmol) and 2-(1,2,4-triazol-1-yl)ethanol (95 mg, 0.84 mmol), (Ann. Pharm. Fr. 1977, 35, 503-508), in methylene chloride (5 ml). The mixture was stirred for 1 hour at ambient temperature and further triphenylphosphine (184 mg, 0.7 mmol), 2-(1,2,4-triazol-1-yl)ethanol (63 mg, 0.56 mmol) and diethyl azodicarboxylate (122 mg, 0.7 mmol) were added. The mixture was stirred for a further 2.5 hours and the solvent was removed by evaporation. The residue was dissolved in methanol (5 ml) and 2M aqueous sodium hydroxide solution (2 ml) was added. The mixture was stirred for 20 minutes and the mixture was partitioned between ether and water. The aqueous layer was acidified to pH7 with 2M hydrochloric acid and the resulting precipitate was collected by filtration, washed with water, and dried under vacuum. The resulting solid was dissolved in methylene chloride/methanol and a 5M solution of hydrogen chloride in isopropanol (0.5 ml) was added. The volatiles were removed by evaporation, the solid was resuspended in ether, collected by filtration, washed with ether and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-(1,2,4-triazol-1-yl)ethoxy)quinazoline hydrochloride (180 mg, 56%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5](=[N:7][OH:8])[NH2:6].[Br:13][C:14]1[CH:18]=[CH:17][O:16][C:15]=1[C:19](Cl)=O>N1C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:19]([C:15]3[O:16][CH:17]=[CH:18][C:14]=3[Br:13])[O:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: O=C(Cl)c1occc1Br
Reactant: NC(=NO)c1ccc(Cl)c(N)c1
Solvent: c1ccncc1
Product: Nc1cc(-c2noc(-c3occc3Br)n2)ccc1Cl

Procedure:
The title compound was prepared from 3-amino-4-chloro-benzamidoxime (293 mg, 1.58 mmol) and 3-bromofuran-2-carbonyl chloride (329 mg, 1.57 mmol) in pyridine (2.8 mL) under reflux similar to Example 1b, yielded 289 mg (54%) as a white solid. 1H NMR (CDCl3): 7.66 (d, J=1.64 Hz, 1H), 7.59 (d, J=1.92 Hz, 1H), 7.50 (dd, J1=8.38 Hz, J2=2.07 Hz, 1H), 7.37 (d, J=8.24 Hz, 1H), 6.75 (d, J=1.93 Hz, 1H), 4.22 (s, 2H).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:3]=1.C([OH:23])C.CN(C)C=O>[OH-].[Na+]>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:4]2[NH:3][C:2](=[O:23])[C:11]3[C:6](=[N:7][CH:8]=[CH:9][N:10]=3)[N:5]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(OCc2nc(N)c3nccnc3n2)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2nc3nccnc3c(=O)[nH]2)cc1

Procedure:
Obtained using the procedure described in section b of Example 9, starting with 2.5 g (0.0094 mole) of 4-amino-2-[(4-methylphenoxy)methyl]pteridine in 68.1 ml of 5% aqueous sodium hydroxide. Heating time: 3 hours 15 minutes at 85° C. Yld: 1.3 g (52%), m.p. 232°-233° C. (ethanol/N,N-dimethylformamide).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][CH2:4][CH:5]1[NH:9]C(=O)N[C:6]1=[O:11].[OH-:14].[Na+]>>[F:1][C:2]([F:13])([F:12])[CH2:3][CH2:4][C@@H:5]([C:6]([OH:14])=[O:11])[NH2:9]
Reactant: O=C1NC(=O)C(CCC(F)(F)F)N1
Reactant: [OH-]
Agent: [Na+]
Product: N[C@@H](CCC(F)(F)F)C(=O)O

Procedure:
5-(3,3,3-trifluoropropyl)imidazolidine-2,4-dione (0.9 g, 4.59 mmol) was dissolved in a 10 mL solution of aqueous NaOH (0.734 g in 10 mL H2O, 18.35 mmol). The solution was divided in 2 special vessels for microwave technology. The solution was heated by microwave in sealed vessels for 1 h. Microwave conditions: 15 min at about 100% power, 150° C., 50 psi, then 5 min at rest, 0% power. Repeat sequence twice or until reaction is done. Water and ammonia were removed from the reaction mixture in vacuo and the resulting crude 5,5,5-trifluoronorvaline (1.1 g, 140%) and NaOH mixture was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]3[NH:19][C:18]4[CH:20]=[CH:21][C:22](I)=[CH:23][C:17]=4[S:16](=[O:26])(=[O:25])[N:15]=3)=[C:10]([OH:27])[C:9]3=[CH:28][CH:29]=[CH:30][N:8]23)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:38]1[S:39](=[O:44])(=[O:43])[CH2:40][CH2:41][CH:42]=1)CCC>CN(C)C=O.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:43]=[S:39]1(=[O:44])[CH2:40][CH2:41][CH:42]=[C:38]1[C:22]1[CH:21]=[CH:20][C:18]2[NH:19][C:14]([C:11]3[C:12](=[O:13])[N:7]([CH2:6][C:5]4[CH:31]=[CH:32][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]4[CH:30]=[CH:29][CH:28]=[C:9]4[C:10]=3[OH:27])=[N:15][S:16](=[O:26])(=[O:25])[C:17]=2[CH:23]=1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cccn2n1Cc1ccc(F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCS1(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=c1c(C2=NS(=O)(=O)c3cc(C4=CCCS4(=O)=O)ccc3N2)c(O)c2cccn2n1Cc1ccc(F)cc1
Temperature: 90 °C
Yield: 48.5 %

Procedure:
1-(4-Fluoro-benzyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6 benzo[1,2,4]thiadiazin-3-yl)-pyrrolo[1,2-b]pyridazin-2-one (Example 9b, 0.207 g, 0.371 mmol), tributyl-(1,1-dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-stannane (Example 11a, 0.181 g, 0.442 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.025 g, 0.020 mmol) were dissolved in N,N-dimethylformamide (8 mL) at 25° C. The mixture was heated to 90° C. for 24 h, then was allowed to cool to 25° C. and filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm, 0→7% methanol in dichloromethane) to afford a brown solid. This material was re-chromatographed (Merck silica gel 60, 40-63 μm, 40-100% ethyl acetate in hexanes, followed by 100% ethyl acetate, followed by 0→7% methanol in dichloromethane) to afford the desired product, 3-[7-(1,1-dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-1-(4-fluoro-benzyl)-4-hydroxy-pyrrolo[1,2-b]pyridazin-2-one (0.100 g, 0.180 mmol, 48.6% yield). LC-MS (ESI) calcd for C25H19FN4O6S2 554.07. found 555.00 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:14])[N:6]([CH3:13])[C:7](=[O:12])[N:8]([CH3:11])[C:9]=1[CH3:10])([O-])=O.CO>[Pd].C1(C)C=CC=CC=1>[NH2:1][C:4]1[C:5](=[O:14])[N:6]([CH3:13])[C:7](=[O:12])[N:8]([CH3:11])[C:9]=1[CH3:10]
Reactant: Cc1c([N+](=O)[O-])c(=O)n(C)c(=O)n1C
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1c(N)c(=O)n(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.7 %

Procedure:
To a stirred suspension of 5-nitro-1,3,6-trimethylpyrimidine-2,4(1H,3H)-dione (4.2 g, 20.084 mmol) in 1:1 mixture of methanol and toluene (200 ml) was added 10% Pd—C (1.2 g). The reaction mixture was stirred under hydrogen atmosphere at room temperature overnight. The mixture was then filtered over a celite bed and was thoroughly washed with methanol (200 ml). The filtrate was collected and evaporated to give viscous residue which was then purified by column chromatography to afford 4.1 g of the product as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][OH:8])=[NH:6].CC(C)([O-])C.[K+].C(O[C:21](=O)[CH:22]([CH3:38])[CH2:23][C:24]1[N:28]([CH:29]2[CH2:31][CH2:30]2)[C:27]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[N:26][N:25]=1)C>C(O)CC>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:21]([CH:22]([CH3:38])[CH2:23][C:24]3[N:28]([CH:29]4[CH2:31][CH2:30]4)[C:27]([C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)=[N:26][N:25]=3)[O:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: N=C(NO)c1cccc(Cl)c1
Reactant: CCOC(=O)C(C)Cc1nnc(-c2ccncc2)n1C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCO
Product: CC(Cc1nnc(-c2ccncc2)n1C1CC1)c1nc(-c2cccc(Cl)c2)no1
Temperature: 100 °C
Yield: 59 %

Procedure:
After 3-chloro-N-hydroxy-benzamidine (0.7 g, 4.1 mmol) was mixed with potassium-tert-butoxide (0.373 g, 3.33 mmol) in n-propanol at 80° C. for 10 min, 3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-propionic acid ethyl ester (1.0 g, 3.33 mmol) was added to the reaction mixture and heated at 100° C. for 3 h. The reaction mixture was concentrated, quenched with sat. ammonium chloride and extracted with DCM. The organic layer was dried with MgSO4, purified by column chromatography and triturated with Et2O to give racemic 4-(5-{2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine (0.8g, 59%). The title product (10 mg) was obtained by separation on Chiracel OJ with EtOH:hex. (1:4). 1H-NMR: 8.78(d, 2H), 8.05 (s, 1H), 7.96 (d, 1H), 7.74 (d, 2H), 7.50 (d, 1H), 7.43 (t, 1H), 4.15 (m, 1H), 3.64 (dd, 1H), 3.31 (m, 2H), 1.67 (d, 3H), 1.25 (m, 2H) and 0.78 (m, 2H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]([N:16]([CH2:25][CH2:26][CH3:27])[C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:14][NH:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>CCOCC>[F:28][C:29]([F:39])([F:40])[C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:37]([N:13]2[CH2:14][CH:15]([N:16]([CH2:25][CH2:26][CH3:27])[C:17]([O:19][CH2:20][C:21]([Cl:22])([Cl:24])[Cl:23])=[O:18])[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=3)=[N:12]2)=[O:38])=[CH:34][CH:35]=1
Reactant: CCCOc1ccc(C2=NNCC2N(CCC)C(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CCOCC
Product: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2N(CCC)C(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To an ether solution of 3-(4-propoxyphenyl)-4-(N-propyl-N-(2,2,2-trichloroethoxycarbonyl)amino)-4,5-dihydro-1H-pyrazole (Example 585e) (≤85 mmole) was added 12.7 g (68 mmole) of 4-trifluoromethylphenyl isocyanate. After stirring for 30 minutes, the mixture was concentrated in vacuo and dissolved in 200 ml of 50/50 diethyl ether/hexanes and cooled to -20° C. Crystals of the desired compound formed and were filtered yielding 23 g of the desired compound, mp 162°-163° C.
Reaction SMILES: O.[N:2]1(O)C2C=CC=CC=2N=[N:3]1.Cl.C(N=C=NCCCN(C)C)C.[I:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34](O)=[O:35])[CH:32]=2)[N:27]([S:37]([C:40]2[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH:26]=1.NN>CN(C=O)C>[I:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([NH:2][NH2:3])=[O:35])[CH:32]=2)[N:27]([S:37]([C:40]2[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH:26]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)O)ccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NN)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.471 g, 3.07 mmol) (Aldrich), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.589 g, 3.07 mmol) (Sigma-Aldrich), and 3-iodo-1-tosyl-1H-indole-5-carboxylic acid (1.13 g, 2.56 mmol) were weighed into a 100 mL round bottomed flask and dissolved in DMF (12 mL). The solution was stirred at RT for 30 min. Hydrazine (1.4 mL, 44.6 mmol) (Aldrich) was added, and the reaction was stirred at RT for 1.5 h. The solution was partially concentrated. The concentrate was diluted with H2O and a precipitate formed. The solid was collected by filtration, washed with H2O, and dried to give 3-iodo-1-tosyl-1H-indole-5-carbohydrazide (0.802 g, 1.762 mmol, 68.8%) as a beige solid. MS (ESI, pos. ion) m/z: 455.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.91 (s, 1H), 8.15 (s, 1H), 7.97-8.02 (m, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.82-7.92 (m, 2H), 7.41 (d, J=8.2 Hz, 2H), 4.52 (br. s., 1H), 2.33 (s, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:15][NH:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=3)=[C:11]([CH3:14])[CH:12]=2)[C:7]([CH3:29])([CH3:28])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[OH-].[K+]>C(O)C>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:15][NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=3)=[C:11]([CH3:14])[CH:12]=2)[C:7]([CH3:29])([CH3:28])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(NCc2cc3c(cc2C)N(C(C)C)CCC3(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2c(cc1CNc1ccc(C(=O)O)cc1)C(C)(C)CCN2C(C)C
Temperature: 40 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
Ethyl 4-[(1-isopropyl-4,4,7-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)methylamino]benzoate (Compound 21, 43 mg, 0.11 mmol) was dissolved in ethanol (4.0 mL) and the solution treated with 1.8 M KOH (1.0 mL). The solution was heated to 40° C. and stirred for 24 hours. The solution was cooled and concentrated under reduced pressure. The residue was diluted with water, acidified with 10% HCl, and extracted with ether (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. Purification by recrystallization in ethanol gave the title compound (25 mg, 63%).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH:7]=[CH:8][N:9]=1.[H-].[Na+].Cl[CH2:24][C:25]1[N:26]=[C:27](/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])[O:28][CH:29]=1>>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1/[CH:31]=[CH:30]/[C:27]1[O:28][CH:29]=[C:25]([CH2:24][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][N:6]3[CH:7]=[CH:8][N:9]=[C:5]3[CH2:4][CH2:3][S:2][CH3:1])=[CH:15][CH:16]=2)[N:26]=1
Reactant: CSCCc1nccn1CCCCc1ccc(O)cc1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Agent: [H-]
Agent: [Na+]
Product: CSCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3F)n2)cc1
Yield: 92.6 %

Procedure:
Using 4-[4-[4-[2-[2-(methylsulfanyl)ethyl]-1H-imidazol-1-yl]butyl]phenol (500 mg), 65% sodium hydride (69.8 mg) and 4-chloromethyl-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole (483 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (812 mg) as a colorless amorphous form.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.N#N>COCCOC.C([O-])([O-])=O.[Na+].[Na+]>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][CH:10]=1
Reactant: Brc1cccnc1
Reactant: OB(O)c1ccc(F)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2cccnc2)cc1
Temperature: 80 °C
Yield: 109.6 %

Procedure:
A solution of 3-bromopyridine (2.5 g, 15.8 mmol) and 4-fluorophenylboronic acid (2.8 g, 20.0 mmol) in DME (20 ml) and 2N Na2CO3 (aq, 20 ml) was deoxygenated by evacuation/refill with N2 (×2). PdCl2dppf (600 mg, 0.8 mmol) was added and the mixture was deoxygenated again (×3). The reaction was stirred and heated at 80° C. under N2 for 16 hours. After cooling to RT the mixture was partitioned between EtOAc/H2O. The aqueous layer was extracted with EtOAc (×2).The combined extracts were washed with brine (×1), dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica (10→40% EtOAc/Petrol) to give the title compound (3.0 g, oil). 1H NMR (400 MHz, CDCl3): 8.83 (1H, brs), 8.61 (1H, brs), 7.85 (1H, d), 7.54 (2H, dd), 7.39 (1H, brs), 7.18 (2H, t).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Br:9]Br>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: BrBr
Reactant: COC(=O)CC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CC(=O)CBr
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 150 ml of anhydrous carbon tetrachloride solution containing 116 g of methyl acetoacetate was added dropwise 51 ml of bromine at below 5° C. After the addition was finished the reaction mixture was stirred overnight, then the reaction mixture was poured into ice-water, washed with a diluted sodium carbonate aqueous solution five times, then with a saturated sodium chloride aqueous solution, and dried with anhydrous calcium chloride. The solvent was removed by evaporation to yield 170 g of methyl 4-bromoacetoacetate.
Reaction SMILES: [N:1]1([C:6]#[N:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][O-:9].[Na+]>CO>[N:1]1([C:6](=[NH:7])[O:9][CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[O-]
Reactant: N#CN1CCCC1
Agent: [Na+]
Solvent: CO
Product: COC(=N)N1CCCC1

Procedure:
In the manner given in Example 2, 1-pyrrolidinecarbonitrile is treated with sodium methoxide in methanol to give methyl 1-pyrrolidinecarboximidate.