Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]([C:29](O)=[O:30])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34][CH2:33]1.Cl.C(N=C=NCCCN(C)C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:27])[CH3:28])[C:21]([C:29]([N:32]2[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34][CH2:33]2)=[O:30])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S1(=O)CCNCC1
Reactant: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid, thiomorpholine 1,1-dioxide and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as an off-white solid (85%).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:19][C:20]1([CH3:36])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[CH:25]=[C:24]([CH2:32][C:33](Cl)=[O:34])[CH:23]=[CH:22][C:21]1=2>>[OH:1][C:2]1[CH:17]=[C:16]([O:18][C:33](=[O:34])[CH2:32][C:24]2[CH:23]=[CH:22][C:21]3[C:20]([CH3:19])([CH3:36])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]=3[CH:25]=2)[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: CC1(C)CCC(C)(C)c2cc(CC(=O)Cl)ccc21
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1O
Product: CC1(C)CCC(C)(C)c2cc(CC(=O)Oc3ccc(C(=O)OCc4ccccc4)c(O)c3)ccc21

Procedure:
In a manner similar to Example 1(d), by reaction of 2.44 g (10 mmol) of benzyl 2,4-dihydroxybenzoate with 2.6 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthylacetyl chloride, 3.9 g (83% ) of the expected ester are obtained in the form of a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:19])[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1)[CH3:2].[N+:20]([O-])([OH:22])=[O:21]>O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:19])[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:8][C:9]=1[N+:20]([O-:22])=[O:21])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1ccc(C(=O)C(=O)c2ccccc2)cc1
Solvent: O
Product: CCOc1ccc(C(=O)C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
To 0.5 gram of 1-(4-ethoxyphenyl)-2-phenylethane-1,2-dione prepared in Step 1, was add 10 milliliters of concentrated nitric acid and the resulting mixture was heated to 110° C. for 2 hours. The reaction mixture was cooled and poured into 20 milliliters of water. The precipitate was recrystallized from ethanol to give 1-(4-ethoxy-3-nitrophenyl)-2-phenylethane-1,2-dione. The synthesis is summarized by the equation:
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].C(C(CC)(C([O-])=O)C([O-])=O)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]=[CH:25][C:26](=[O:28])[CH3:27]>C(O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]1[CH2:1][C:2](=[O:3])[CH2:27][C:26](=[O:28])[CH2:25]1
Reactant: CC[O-]
Reactant: COc1ccccc1C=CC(C)=O
Agent: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1C1CC(=O)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of NaOEt (21% in EtOH) (9.8 ml, 26.5 mmol) under nitrogen was added diethylmalonate (3.7 ml, 24.3 mmol). The reaction mixture was stirred at ambient temperature for 20 min. 4-(2-methoxy-phenyl)-but-3-en-2-one (3.89 g, 22.1 mmol), Stage 1, was dissolved in ethanol (20 ml) and added to the reaction mixture, which was stirred at reflux and monitored by LC-MS until 4-(2-methoxy-phenyl)-but-3-en-2-one was consumed. The reaction mixture was cooled to ambient temperature. An aqueous solution of sodium hydroxide (2M, 10 ml) was added to the reaction mixture, which was heated at 80° C. for 1.5 h. Excess ethanol was removed by evaporation and the aqueous phase was washed with toluene (20 ml). The aqueous phase was acidified with conc. HCl (5 ml) and the reaction mixture was refluxed for 1 h and left to cool to ambient temperature. The compound was extracted with ethyl acetate (2×30 ml), dried with MgSO4 and filtered. The solvent was removed under reduced pressure. The title compound was purified by column chromatography eluting with ethyl acetate/heptane (1/1) to give a beige solid.
Reaction SMILES: [NH:1]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][NH:37][C:38]([NH2:40])=[O:39])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.OO.CC[O:52]CC.CN(C=O)C>C(O)(=O)C>[NH:1]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][NH:37][C:38]([NH2:40])=[O:39])=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])=[O:20])[CH2:15][CH2:16][S:17]([CH3:18])=[O:52])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Reactant: CCOCC
Agent: OO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CS(=O)CC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Reaction time: 0.17 h

Procedure:
In 5 ml of acetic acid is dissolved 900 mg of BOC-Tyr-(D)-Met-Gly-Phe-NHNHCONH2 followed by addition of 0.24 ml of 30% aqueous H2O2. The solution is stirred for 10 minutes, treated with 100 ml of ether and filtered to obtain a powder. Yield 760 mg; m.p. 114°-121° C.; [α]D21.5 -2.6° (c=0.89, DMF); Rf2 0.38.
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:12][C:13]1[N:18]=[C:17]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C:2]2([CH3:1])[C:8]([O:10][CH3:11])=[O:9])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1
Reactant: COC(=O)C1(C)COCCN1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(C)COCCN1c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
Methyl 3-methylmorpholine-3-carboxylate (4.21 g, 26.4 mmol) was dissolved in THF (60 ml) to form a clear solution. 2,4-Dichloro-5-nitropyrimidine (5.13 g, 26.4 mmol) was added and the solution was cooled to −10° C. Diisopropylethylamine (6.93 ml, 39.7 mmol) was added while the temperature was maintained at −8 to −10° C. The reaction was stirred for 4 hours at 0° C. and for 16 hours at room temperature. The solvent was removed under reduced pressure. EtOAc (120 ml) was added and the mixture was washed with water (3×30 ml). The organic solution was concentrated to afford 8.4 g of crude methyl 4-(2-chloro-5-nitropyrimidin-4-yl)-3-methylmorpholine-3-carboxylate as an oil. The crude material was used in the next step without further purification. MS [M+H] calculated for C11H13ClN4O5, 317. found, 317
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].Cl>O>[CH3:33][S:34]([O:19][CH2:18][CH2:17][CH:16]([C:10]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
500 ml MDC was added in the residue of 3-(2-(benzyloxy)-5-bromophenyl)-3-phenylpropan-1-ol of formula (C) followed by the addition of 50.1 g triethyl amine at 25° C. to 35° C. Reaction mass was cooled to 20° C. to 25° C. followed by the addition of 48.96 g methane sulphonyl chloride. Temperature was raised to 25° C. to 30° C. and maintained for 30 minutes. Further, 300 ml water was added and reaction mass was cooled to 0° C. to 5° C. and pH adjusted to 2 to 3 using 20% hydrochloric acid solution. The reaction temperature was raised to 25° C. to 35° C. and stirred for 30 minutes. The layers were separated and to the MDC layer added 5 g of activated charcoal and stirred for 30 minutes. MDC was distilled out under vacuum below 50° C. and co-distil by 2×50 ml methanol. The residue was treated with 300 ml methanol and heated up to 60° C. to 65° C. and maintained for 1 hour. Further, reaction mass was cooled to 25° C. to 35° C. and further cooled to 0° C. to 5° C. Finally the product was washed with 2×50 ml chilled methanol and dried in hot air oven at 55° C. to 60° C. to afford the title compound 3-(2-(benzyloxy)-5-bromophenyl)-3-phenylpropyl methanesulfonate of formula (D).
Reaction SMILES: C(OC(C[NH:9][C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11]([OH:13])=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[Cl:46][C:47]([Cl:74])([Cl:73])[CH2:48][O:49][C:50](=[O:72])[NH:51][CH2:52][CH2:53][CH2:54][CH2:55][C@@H:56]([C:69](=[O:71])[NH2:70])[NH:57][C:58](=[O:68])[C@H:59]([NH:66][CH3:67])[CH2:60][C:61]1[S:62][CH:63]=[CH:64][CH:65]=1>C(Cl)Cl>[Cl:74][C:47]([Cl:46])([Cl:73])[CH2:48][O:49][C:50](=[O:72])[NH:51][CH2:52][CH2:53][CH2:54][CH2:55][C@H:56]([NH:57][C:58](=[O:68])[C@H:59]([NH:66][CH2:67][C:11](=[O:13])[C@H:10]([NH2:9])[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[CH2:60][C:61]1[S:62][CH:63]=[CH:64][CH:65]=1)[C:69](=[O:71])[NH2:70]
Reactant: CC(C)(C)OC(=O)CN[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CN[C@H](Cc1cccs1)C(=O)N[C@@H](CCCCNC(=O)OCC(Cl)(Cl)Cl)C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: NC(=O)[C@H](CCCCNC(=O)OCC(Cl)(Cl)Cl)NC(=O)[C@@H](Cc1cccs1)NCC(=O)[C@H](N)Cc1ccc2ccccc2c1
Reaction time: 8 h
Yield: 63.4 %

Procedure:
(2R)-2-(tert-Butoxycarbonylmethylamino)-3-(2-napthyl)propionic acid (5.00 g; 15.8 mmole), HOAt (2.35 g; 17 mmole) and EDAC (3.03 g; 15.8 mmole) were added to methylene chloride (200 ml) and stirred for 15 min. [(5S)-5-carbamoyl-5-((2R)-2-methylamino-3-(2-thienyl)propionylamino)pentyl]carbamic acid 2,2,2-trichloroethyl ester (7.01 g; 14.5 mmole) was added and the mixture was stirred overnight. Methylene chloride (200 ml) was added and the organic phase was washed with water (200 ml), an aqueous solution of sodium hydrogensulphate (200 ml), an aqueous solution of sodium hydrogencarbonate (200 ml) and water (200 ml). The organic phase was dried (magnesium sulphate) and the solvent was removed in vacuo. The residue was dissolved in a mixture of trifluoroacetic acid (30 ml) and methylene chloride (70 ml) and stirred for 15 min. Water (150 ml) and sodium hydrogencarbonate were added to neutral pH, the phases were separated and the aqueous phase was extracted with methylene chloride (2×100 ml) and the phases were separated. The combined organic phase were dried (magnesium sulphate) and the solvent was removed in vacuo and the residue was chromatographed on silica using a mixture of aqueous ammonia in water (25%), ethanol and methylene chloride (0.7:9.3:90) as eluent to afford 6.3 g of ((5S)-5-{(2R)-2-[((2R)-2-amino-3-(2-naphthyl)propionyl)methylamino]-3-(2-thienyl)propionylamino}-5-carbamoylpentyl)carbamic acid 2,2,2-trichloroethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([C:14]3[C:15](=[O:21])[CH2:16][CH2:17][C:18]=3[O:19][CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[O:30]1[CH2:35][CH2:34][CH:33]([CH:36]=[O:37])[CH2:32][CH2:31]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([C:14]3[C:15](=[O:21])[CH:16]([CH:36]([OH:37])[CH:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)[CH2:17][C:18]=3[O:19][CH3:20])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=CC1CCOCC1
Reactant: COC1=C(c2cc(-c3ccc(Cl)cc3)sc2C)C(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=C(c2cc(-c3ccc(Cl)cc3)sc2C)C(=O)C(C(O)C2CCOCC2)C1
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-3-methoxy-cyclopent-2-enone (255 mg, 0.8 mmol) in anhydrous tetrahydrofuran (6 ml) at −78° C. under an atmosphere of nitrogen was added lithium diisopropylamide (1.8M in THF/heptanes/ethylbenzene; 0.49 ml, 0.89 mmol) dropwise over a period of 5 minutes and the reaction allowed to stir at 78° C. for 30 minutes. A solution of tetrahydro-pyran-4-carbaldehyde (102 mg, 0.89 mmol) in anhydrous tetrahydrofuran (1 ml) was then added dropwise over a period of 5 minutes before the reaction was allowed to warm to room temperature and stirred for a further 30 minutes. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (50 ml) and extracted with ethyl acetate (50 ml) and the organic later separated, dry loaded onto silica and purified by flash chromatography to give 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-5-[hydroxy-(tetrahydro-pyran-4-yl)-methyl]-3-methoxy-cyclopent-2-enone (292 mg).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[CH3:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+].COCCOC>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>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:32]3[CH:33]=[CH:34][C:29]([C:27]([O:26][CH3:25])=[O:28])=[CH:30][CH:31]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: COC(=O)c1ccc(B(O)O)cc1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a flask charged with 6-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 2) (1000 mg, 2.60 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (561 mg, 3.11 mmol), tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.260 mmol) and potassium carbonate (1076 mg, 7.79 mmol) was added DME (20 mL) and water (4.0 mL). The resulting mixture was stirred at 100° C. under nitrogen for 1 h, then cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc and water and the layers were separated. The organic phase was dried (MgSO4), concentrated in vacuo and the residue was purified by chromatography (10 g column, MeOH/DCM gradient) to give methyl 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (1002 mg, 2.275 mmol, 88% yield) as an orange foam. LCMS (HpH, 2 min), Rt=1.09 min, MH+=441.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([F:27])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:28]#[N:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:44]([NH:43][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:45])=[C:22]([F:27])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:28]#[N:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OCc1ccccc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccccc4)c(F)c3)ccnc2cc1OCc1ccccc1

Procedure:
After adding 1.90 g of the 7-benzyloxy-6-cyano-4-(3-fluoro-4-aminophenoxy)quinoline obtained in Production Example 8 to 60 ml of toluene and 30 ml of acetonitrile, the mixture was heated to reflux. Next, 0.76 ml of phenyl isocyanate was added and the mixture was further heated to reflux for 1 hour. After cooling, the precipitated solid was filtered out and dried under reduced pressure to obtain 1.65 g of the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([OH:11])[C:8]([OH:10])=O)=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[C:30]([C:32]1[CH:33]=[CH:34][C:35]2[O:40][C:39]([CH3:42])([CH3:41])[CH2:38][CH:37]([NH:43]C(NC3C=CC=CC=3)=O)[C:36]=2[CH:53]=1)#[N:31].CN(C)CCCCCN=C=N.Cl>>[C:30]([C:32]1[CH:33]=[CH:34][C:35]2[O:40][C:39]([CH3:42])([CH3:41])[CH2:38][CH:37]([NH:43][C:8](=[O:10])[CH:7]([OH:11])[C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)[C:36]=2[CH:53]=1)#[N:31]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: CC1(C)CC(NC(=O)Nc2ccccc2)c2cc(C#N)ccc2O1
Agent: CN(C)CCCCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: CC1(C)CC(NC(=O)C(O)c2ccccc2)c2cc(C#N)ccc2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 110.4 %

Procedure:
To a solution of R-(-)-mandelic acid (22.1 g, 0.14 mole) and 1-hydroxybenzotriazole hydrate (19.6 g, 0.14 mole) cooled to 0° C. was added successively N-methylmorpholine (16.2 g, 0.16 mole), 4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (29.4 g, 0.14 mole, Example 8, part D) and 1-(3-dimethylaminopropyl)-2-ethylcarbodiimide.HCl (27.9 g, 0.14 mole). The reaction mixture was stirred 0.5 hours at 0° C. and two hours at room temperature. The solvent was recovered under vacuum and the residue was partitioned between 5% aqueous HCl and ethyl acetate. The organic fraction was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo to obtain 52 g of yellow gum. The crude diastereomer mixture was chromatographed on silica eluting with 1:1 hexane/ethyl acetate to obtain 23.2 g (47.7%) of Isomer A. m.p.=120-121° C., [α]D25 =-39.5°. 1H NMR (CDCl3) δ 7.43-7.34 (m, 7H), 6.81 (d, J=8.20 Hz, 2H), 5.23 (m, 1H), 5.13 (d, J=3.52 Hz, 1H), 4.27 (m, 1H), 2.08 (dd, J=5.86 and 13.78 Hz, 1H), 1.71 (d, J=12.31 Hz, 1H), 1.42 (s, 3H), 1.36 (s, 3H). 13C NMR (CDCl3) δ 173.26, 158.09, 139.60, 133.30, 132.46, 129.27, 129.18, 126.88, 123.39, 119.62, 118.99, 103.64, 77.00, 74.50, 42.33, 39.59, 29.77, 25.05. MS: (M+H)+ @337.
Reaction SMILES: [NH2:1][NH2:2].[CH2:3]([C:8]12[CH2:15][CH2:14][C:11]([C:16]([O:18]C)=O)([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)[CH2:4][CH2:5][CH2:6][CH3:7].O>C(O)CO>[CH2:3]([C:8]12[CH2:15][CH2:14][C:11]([C:16]([NH:1][NH2:2])=[O:18])([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC12CCC(C(=O)OC)(CC1)CC2
Reactant: NN
Solvent: O
Solvent: OCCO
Product: CCCCCC12CCC(C(=O)NN)(CC1)CC2
Temperature: 25 °C

Procedure:
Hydrazine (anhydrous, 103 mL, 88.7 mmol) was added to a solution of methyl 4-pentylbicyclo[2.2.2]octane-1-carboxylate (2-B) in ethylene glycol (180 mL) and the mixture was stirred under reflux for 17 h. After cooling to room temperature, the mixture was poured into water (1500 mL) and extracted with methylene chloride (3×600 mL). The combined extracts were washed twice with water, brine, dried (MgSO4) and concentrated in vacuo to provide 4-pentylbicyclo[2.2.2]octane-1-carbohydrazide (2-C). 1H NMR (500 MHz, CDCl3): δ 0.90 (t, 3H); 1.21 (m, 8H); 1.43 (m, 6H); 1.74 (m, 6H); 3.85 (broad s, 2H); 6.81 (broad s, 1H) ppm.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[C:16](F)[CH:17]=1>CN1C(=O)CCC1>[CH2:1]([O:8][C:16]1[CH:15]=[C:14]([CH2:19][C:20]([OH:22])=[O:21])[CH:13]=[C:12]([F:11])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: OCc1ccccc1
Solvent: CN1CCCC1=O
Product: O=C(O)Cc1cc(F)cc(OCc2ccccc2)c1
Reaction time: 0.33 h

Procedure:
To benzyl alcohol (1.4 g, 12.8 mmol) in NMP (30 mL) was added sodium hydride (60% in mineral oil; 0.5 g, 12.8 mmol), and the mixture was stirred for 20 minutes. 3,5-Difluorophenylacetic acid (1.0 g, 5.8 mmol) was added, and the reaction was stirred at 100° C. for 2 hours, and then 60° C. overnight. The mixture was worked-up to give the title compound, plus ˜30% of benzyl alcohol impurity.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28]1>C(Cl)Cl>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:31][CH2:30][CH:29]([NH:32][C:2]2[C:7]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:28]1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cccnc1Cl
Reactant: NC1CCN(c2ccccn2)C1
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccnc1NC1CCN(c2ccccn2)C1
Temperature: 130 °C

Procedure:
A mixture of (2-chloro(3-pyridyl))-N-(3-trifluoromethylphenyl)carboxamide and 1-(2-pyridyl) pyrrolidine-3-ylamine (Step A) was heated at 130° C. neat for 3 h. The reaction was cooled and diluted with CH2Cl2 and washed with H2O twice followed by brine. The organic layer was dried with Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography with EtOAc and further mixed with MeOH and 1 N HCl/Et2O (2 ml). The solution was evaporated to furnish the titled compound. MS (ES+): 428 (M+H); (ES−): 426 (M−H). Calc'd. for C22H20F3N5O−427.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC1=NC(=O)C2=CC=NC2=N1
Reactant: O=C(Cl)c1ccccc1
Product: O=C1N=C(NC(=O)c2ccccc2)N=C2N=CC=C12

Procedure:
Using 2-aminopyrrolo(2,3-d)pyrimidin-4-one and benzoyl chloride, the above-identified compound is produced by the same procedure as Reference Example 2.