Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.[F:26][C:27]1[CH:28]=[C:29](/[C:43](/[NH:46]O)=[N:44]/[H])[CH:30]=[C:31]2[C:35]=1[NH:34][C:33]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:32]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(Cl)CCl>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:44]=[C:43]([C:29]3[CH:30]=[C:31]4[C:35](=[C:27]([F:26])[CH:28]=3)[NH:34][C:33]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:32]4)[N:46]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: [H]/N=C(\NO)c1cc(F)c2[nH]c(CCC(=O)OCC)cc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cc(F)c2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
To a solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (150 mg) in tetrahydrofuran (30 mL) stirred at room temperature was added EDC (280 mg) and HOBT (223 mg). The reaction mixture was stirred at room temperature for 0.5 h. Then ethyl 3-{7-fluoro-5-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-2-yl}propanoate (D163) (214 mg) was added. The reaction mixture was stirred at room temperature for an hour, and then TBAF (763 mg) was added. The reaction mixture was sealed and heated in Biotage Initiator using initial high to 120° C. for 2 hrs. After cooling the reaction, the solvent was removed. The residue was diluted with EtOAc (30 mL). The organic phase was washed with water (25 mL×4) and dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give ethyl 3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-7-fluoro-1H-indol-2-yl]propanoate (D165) (180 mg) as a white solid. MS (ES): C25H23FN4O4 requires 462; found 463.2 (M+H+).
Reaction SMILES: [CH2:1]([S:3][C:4]([CH3:14])([CH3:13])[C:5]([CH2:7][C:8]([O:10]CC)=O)=[O:6])[CH3:2].[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:45])[CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=2[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])=[CH:19][C:17]=1[NH2:18]>C1(C)C(C)=CC=CC=1>[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:45])[CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=2[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])=[CH:19][C:17]=1[NH:18][C:8](=[O:10])[CH2:7][C:5](=[O:6])[C:4]([S:3][CH2:1][CH3:2])([CH3:13])[CH3:14]
Reactant: CCOC(=O)CC(=O)C(C)(C)SCC
Reactant: CCC(C)(C)c1ccc(OCCCC(=O)Nc2ccc(Cl)c(N)c2)c(C(C)(C)CC)c1
Solvent: Cc1ccccc1C
Product: CCSC(C)(C)C(=O)CC(=O)Nc1cc(NC(=O)CCCOc2ccc(C(C)(C)CC)cc2C(C)(C)CC)ccc1Cl
Yield: 87 %

Procedure:
A mixture of 21.8 g of ethyl (2-ethylthio-2-methylpropionyl)-acetate obtained in Step 1 of Synthesis Example 1, 44.5 g of 2-chloro-5-[4-(2,4-di-tert-amylphenoxy)butyramido]aniline and 500 ml of xylene was refluxed for ten hours. Xylene was distilled off from the reaction mixture, and the residue was recrystallized from acetonitrile to obtain 53 g (yield 87%) of Coupler (2) having a melting point of 121° to 122° C.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[C:14](Cl)(Cl)=[O:15].C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:7][C:5]([N:6]=[C:14]=[O:15])=[C:4]([F:13])[CH:3]=1
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)Oc1cc(N=C=O)c(F)cc1Cl

Procedure:
A solution of 4-chloro-2-fluoro-5-isopropoxyaniline (30 g) in toluene (100 ml) was added to a 1 mol/l phosgene/toluene solution (500 ml) at room temperature (ca. 20° C.), followed by heating under reflux for 2 hours. The mixture was concentrated under reduced pressure and the residue was distilled to give 26 g of 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate as pale yellow crystals. M.P., 36°-37° C. B.P., 90°-91° C./3 mmHg.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][C:4]=1[CH3:13]>C1COCC1>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:1])(=[O:11])=[O:10])=[CH:5][C:4]=1[CH3:13]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Reactant: N
Solvent: C1CCOC1
Product: Cc1cc(S(N)(=O)=O)ccc1Br
Temperature: 0 °C
Reaction time: 6.5 h
Yield: 54 %

Procedure:
A 28% aqueous NH3 solution (2.0 ml) was added to a solution of 4-bromo-3-methyl-benzenesulfonyl chloride (250 mg, 0.927 mmol) in THF (2.0 ml) at 0° C. The mixture was stirred at 0° C. for 6.5 hours. The reaction mixture was quenched with 1 N HCl and extracted with CH2Cl2. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (CH2Cl2—AcOEt) to give 4-bromo-3-methyl-benzenesulfonamide as a white powder (126 mg, 54%).
Reaction SMILES: [SH2:1].[Cl:2][C:3]1[C:8]2[C:9](=[O:20])[N:10]([CH3:19])[CH2:11][C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]#[N:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1>N1C=CC=CC=1.C(N(CC)CC)C>[Cl:2][C:3]1[C:8]2[C:9](=[O:20])[N:10]([CH3:19])[CH2:11][C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17](=[S:1])[NH2:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CN1Cc2c(C#N)ncn2-c2cccc(Cl)c2C1=O
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CN1Cc2c(C(N)=S)ncn2-c2cccc(Cl)c2C1=O
Reaction time: 64 h
Yield: 87 %

Procedure:
A stream of hydrogen sulphide was conducted for 1 hr. through a solution of 9.64 g (0.354 mol) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile in 210 ml of pyridine and 2.1 ml of triethylamine. The green solution was left to stand for 64 hrs., then de-gassed with a stream of nitrogen and subsequently completely freed from the solvents. The solid residue was partitioned between dichloromethane and water and the suspension obtained was suction filtered. There were obtained 9.41 g (87%) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-thiocarboxamide as yellow crystals. An analytical sample was obtained from the organic phase after recrystallization in methanol. Yellow crystals; m.p. 300°-302°.
Reaction SMILES: F[C:2](F)(F)C(O)=O.ClCCl.CS(C1C=[C:17]2[C:21](=[CH:22]C=1)[N:20]([C:24]1N=CN=C(OC3CCN(C(OC(C)(C)C)=O)CC3)[CH:25]=1)[CH2:19][CH2:18]2)(=O)=O>C1COCC1>[CH:21]([N:20]([CH:24]([CH3:25])[CH3:2])[CH2:19][CH3:18])([CH3:17])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2.35 mL) was added at 0° C. to a dichloromethane (9.38 mL) solution of the tert-butyl 4-({6-[5-(methylsulfonyl)indolin-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate (469 mg, 0.988 mmol) produced in Example 1, and the mixture was stirred at room temperature for 1 hour. From the reaction solution, the solvent was then distilled off. To a THF (450 μL) solution of a portion (150 mg) of the obtained residue and diisopropylethylamine (431 μL, 2.48 mmol), a THF (3.0 mL) solution of the preceding produced acid chloride compound was added at 0° C., and the mixture was stirred at room temperature for 3 hours. To the reaction solution, a saturated aqueous solution of ammonium chloride and water were added, followed by extraction with ethyl acetate three times. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin-layer silica gel chromatography (hexane:ethyl acetate=1:2, V/V) to obtain the title compound as white foam (13 mg, yield: 11%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:12])[C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCOCC1>[CH3:12][N:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:11]=[C:3]1[CH2:2][O:1][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CO)nc2ncccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ncccc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 2.5 g of 2-hydroxymethyl-1-methylimidazo[4,5-b]pyridine (prepared as described in Preparation 30), 6.5 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 3.47 ml of tributylphosphine, 3.52 g of 1,1'-(azodicarbonyl)dipiperidine and 250 ml of 1,4-dioxane were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:1 to 0:1 by volume and subsequently mixtures of ethyl acetate and methanol in ratios ranging from 20:1 to 10:1 by volume as the eluent, to give 4.1 g of the title compound.
Reaction SMILES: [CH2:1]([C:8]([CH2:10][CH3:11])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12](Cl)[CH:13]=[CH:14][CH3:15]>>[C:2]1([CH:1]([C:8](=[O:9])[CH2:10][CH3:11])[CH2:12][CH:13]=[CH:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)Cc1ccccc1
Reactant: CC=CCCl
Product: CC=CCC(C(=O)CC)c1ccccc1

Procedure:
Ethyl benzyl ketone is reacted with crotyl chloride according to the foregoing details and there is obtained 5-phenyl-oct-2-en-6-one of boiling point 95° C./3 mmHg; nD20 =1.5102.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1)[C:3]#[N:4].CO.[ClH:20].[O:21]1CCOC[CH2:22]1>C(OCC)C>[ClH:20].[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:14])[F:15])[CH:6]=1)[C:3](=[NH:4])[O:21][CH3:22]
Reactant: N#CC(O)c1cccc(OC(F)(F)C(F)F)c1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=N)C(O)c1cccc(OC(F)(F)C(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 130A (249 mg, 1.0 mmol) in anhydrous diethyl ether (4 mL) at 0° C. was added MeOH (0.4 mL, 10 mmol) and 4.0 N HCl in dioxane (2.0 mL, 8 mmol). The mixture was stirred at 0° C. for 30 min and then at rt for 4.0 h. The solvent was removed to give methyl 2-hydroxy-2-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)acetimidate HCl salt. To this salt in CH2Cl2 (4.0 mL) was added H2O (8.0 mL). The mixture was stirred at rt for 30 min, then extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried and concentrated. The crude product was purified by silica gel chromatography to give 130B (170 mg, 60% yield) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.73 (s, 3H) 5.14 (s, 1H) 5.71-6.08 (m, 1H) 7.17 (d, J=7.03 Hz, 1H) 7.28 (s, 1H) 7.31-7.43 (m, 2H).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:8][C:9]1[CH:10]=[C:11]([Br:16])[CH:12]=[C:13](F)[CH:14]=1>CC(N(C)C)=O>[Br:16][C:11]1[CH:10]=[C:9]([F:8])[CH:14]=[C:13]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=1
Reactant: CC(C)(C)O
Reactant: Fc1cc(F)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)Oc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butanol (28.2 g) is dissolved in dimethyl acetamide (200 ml). NaH (15.6 g, 60% dispersion in oil) is added over 15 minutes. The reaction mixture is stirred at room temperature for 2 hours. 3,5-difluorobromobenzene (50 g) is added drop wise over 30 minutes. The reaction mixture is stirred at room temperature until shown to be complete by HPLC. The reastion mixture is quenched by addition of water (10 ml), washed with water (1×), dried over MgSO4, filtered and the solvent removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 7.00 (ddd, 1H), 6.95 (dd, 1H), 6.68 (ddd, 1H), 1.4 (s, 9H).
Reaction SMILES: [Cl-].[NH4+].O.[CH2:4]([O:10][C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:12]=1[C:13]#[N:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>[Fe].C(O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:11]([O:10][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[C:12]([CH:15]=1)[C:13]#[N:14]
Reactant: CCCCCCOc1ccc([N+](=O)[O-])cc1C#N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCCCCCOc1ccc(N)cc1C#N
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To dimethylformamide solution (91 ml) containing 2-chloro-5-nitrobenzonitrile (18.2 g) and n-hexanol (11.2 g) was added sodium hydride (60% content, 4.8 g) under ice-cooling and the mixture was stirred for 1 h. The reaction mixture was added to water and extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to give 2-n-hexyloxy-5-nitrobenzonitrile (16.2 g). Then, ammonium chloride (0.2 g) and iron powder (1.6 g) were added to a mixed solvent of water (6.3 ml) and ethanol (17 ml), and the mixture was heated to 65° C. Then, the obtained ethanol solution (4 ml) containing 5-nitro-2-n-hexyloxybenzonitrile (16.2 g) was added dropwise thereto, and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated and the solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (6.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N:12]2[C:17](=[O:18])[NH:16][C:15](=[O:19])[N:14]([CH2:20][C:21]#[CH:22])[C:13]2=[O:23])=[CH:10][C:5]([NH:6]C(=O)C)=[C:4]([F:24])[CH:3]=1.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(O)C>[NH2:6][C:5]1[C:4]([F:24])=[CH:3][C:2]([Cl:1])=[C:11]([N:12]2[C:17](=[O:18])[NH:16][C:15](=[O:19])[N:14]([CH2:20][C:21]#[CH:22])[C:13]2=[O:23])[CH:10]=1
Reactant: C#CCn1c(=O)[nH]c(=O)n(-c2cc(NC(C)=O)c(F)cc2Cl)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C#CCn1c(=O)[nH]c(=O)n(-c2cc(N)c(F)cc2Cl)c1=O
Temperature: 25 °C
Yield: 82.2 %

Procedure:
A mixture of 4'-chloro-2'-fluoro-5'-[hexahydro-2,4,6trioxo-3(2-propynyl)-s-triazin-1-yl]acetanilide (3.00 g, 8.5 mmol), and 3N hydrochloric acid (25 mL) in ethanol (50 mL) is refluxed for 3 hours, cooled to room temperature, and poured into ethyl acetate. 3N sodium hydroxide solution (25 mL) is added to the organic solution, and the phases are separated. The organic phase is washed sequentially with saturated sodium hydrogen carbonate solution and brine, and concentrated in vacuo to give the title product as a beige solid (2.17 g, mp 118°-121° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][CH3:11].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH2:21][CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:16][CH:15]=1>CC(N(C)C)=O>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH2:21][CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:16][CH:15]=1)[CH2:10][CH3:11]
Reactant: CCC(=O)c1ccc(O)cc1O
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: CC(=O)N(C)C
Product: CCC(=Nc1ccc(C2=NNC(=O)CC2)cc1)c1ccc(O)cc1O
Temperature: 140 °C

Procedure:
A solution containing 1.0 g (0.006 mol) of 2',4'-dihydroxypropiophenone and 0.57 g (0.003 mol) of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one in 10 ml of DMA was heated for 20 h at 140° C. The solvent was evaporated in vacuo and the residue was crystallized from ethanol. Yield 0.05 g (5%), m.p. 350° C. (decomp).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:43])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38][N:37]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][C:9]2[NH:19][C:26](=[O:43])[CH2:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38][N:37]=4)[CH:31]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)ncn1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (145 mg, 0.5 mmol) and 3-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K41) (187 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (59 mg).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[CH:14]12[O:21][CH:18]([CH2:19][CH2:20]1)[CH2:17][NH:16][CH2:15]2.C(N(CC)CC)C>C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([N:16]1[CH2:15][CH:14]2[O:21][CH:18]([CH2:19][CH2:20]2)[CH2:17]1)=[O:8])(=[O:3])[CH3:2]
Reactant: C1CC2CNCC1O2
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)Oc1ccccc1C(=O)N1CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
o-Acetoxybenzoyl chloride (0.1 mole, 19.85 grams) was slowly added to a mixture of 8-oxa-3-azabicyclo(3.2.1)octane (0.1 mole, 11.13 grams) and triethylamine (0.1 mole) in 60 ml of benzene at 20° C. The reaction mixture was stirred 2.5 hours at 25° C. The salt was filtered off and washed with benzene. After removal of benzene, the product was obtained as a viscous liquid which was purified by column chromatography (alumina). Impurities were eluted with ether and the product with methanol to yield the product represented by formula (IX).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:13][CH:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].I[CH3:23]>>[CH3:23][N:14]([CH:12]1[CH2:13][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1)[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC1CN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: CI
Product: CN(C(=O)OC(C)(C)C)C1CN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
tert-Butyl [1-(4-nitrophenyl)azetidin-3-yl]carbamate was alkylated with iodomethane by method F. This resulted in the product with the molecular weight of 307.35 (C15H21N3O4); MS (ESI): 308 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>ClCCl>[CH3:8][C:3]1[C:2]([NH:1][C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1ncccc1N
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccnc1C
Reaction time: 3 h

Procedure:
Under nitrogen atmosphere, 47.6 g of 2-chloro-3-nitropyridine was dissolved in 500 mL of tetrahydrofuran, and 150 mL of 2M methylzinc chloride in tetrahydrofuran and 6.9 g of tetrakis(triphenylphosphine)palladium(0) were added, and the reaction solution was stirred at 70° C. for 2 hours. The reaction solution was poured into cold water, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to column chromatography (n-hexane:ethyl acetate=3:1) to obtain 35.4 g of 2-methyl-3-nitropyridine as a colorless oil. Then 35.4 g of 2-methyl-3-nitropyridine was dissolved in a mixed solution of 300 mL methanol/5 mL triethylamine, added with 5 g of 10% palladium on carbon, and stirred for 6 hours under hydrogen atmosphere and at normal temperature and pressure. The reaction solution was filtered thorough Celite, the solvent was evaporated, and 33.0 g of crudely produced 2-methyl-3-aminopyridine was obtained as a pale brown oil. Next, to 100 mL of a solution of 65 g of crude 3-amino-2-methylpyridine in dichloromethane were added 60 mL of pyridine and 71 mL of acetic anhydride at room temperature and stirred for 3 hours. The reaction solution was added with about 150 mL of silica gel powder, the solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:3), to afford 74 g of the title compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9]O)=[N:6][CH:7]=1.BrC1C=CC(CC[I:20])=CN=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][I:20])=[N:6][CH:7]=1
Reactant: Brc1ccc(CCI)cn1
Reactant: OCCc1ccc(Br)cn1
Product: Brc1ccc(CCI)nc1
Yield: 77 %

Procedure:
The title compound (3571 mg, 77%) was prepared from 2-(5-bromopyridin-2-yl)ethanol (Compound 6, Preparation 4) (3.0 g, 14.9 mmol) by a procedure analogous to that described for the preparation of 2-bromo-5-(2-iodoethyl)pyridine in Preparation 2, Step 1. MS (LCMS) m/z 312.0 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.24-3.36 (m, 2H) 3.41-3.56 (m, 2H) 7.06 (d, J=8.20 Hz, 1H) 7.74 (dd, J=8.20, 2.34 Hz, 1H) 8.60 (d, J=2.34 Hz, 1H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13])=[CH:7][CH:6]=1)[CH3:4].C[O-].[Na+].[CH2:24](Br)[CH:25]=[CH:26][CH3:27]>O>[CH2:24]([O:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13])=[CH:9][CH:10]=1)[CH3:4])[CH:25]=[CH:26][CH3:27]
Reactant: CC=CCBr
Reactant: CCOC(=O)CNC(=O)Nc1ccc(C(C)=NO)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: CC=CCON=C(C)c1ccc(NC(=O)NCC(=O)OCC)cc1

Procedure:
A solution of the N-[4-(1-hydroxyiminoethyl)phenyl]-N'-ethoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of crotyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield the product N-[4-(1-crotyloxyiminoethyl)phenyl]-N'-ethoxycarbonylmethylurea.