Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13](Cl)=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.CCN(CC)CC.[CH2:29]([N:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH2:32])[CH3:30]>C(Cl)Cl>[CH2:29]([N:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH:32][C:13]([C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[O:2][CH3:1])=[O:14])[CH3:30]
Reactant: COc1c(-c2ccccc2)nc2ccccc2c1C(=O)Cl
Reactant: CCN(N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(NC(=O)c1c(OC)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
The 3-methyloxy-2-phenyl-4-quinolinecarbonyl chloride obtained in Step 1 was dissolved in CH2Cl2 (2 mL) and added dropwise to a solution of Et3N (104 μL, 0.76 mmol) and 1-ethyl-1-phenylhydrazine (102 mg, 0.76 mmol) [Synthesis 1983, 157-158] in CH2Cl2 (3 mL) at 0° C. After stirring at 0° C. for 2 h the cooling bath was removed and the solution stirred at room temperature for 18 h. The solvent was evaporated and the residue taken up in ethyl acetate (20 mL). The organic phase was washed with H2O (2×10 mL), 1N NaOH (20 mL) and brine (20 mL). The organic phase was separated, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with isohexane:ethyl acetate (2:1). The fractions containing the desired product were combined, evaporated and triturated with diethyl ether. The title compound (159 mg, 53%) was isolated as a colourless solid. 1H NMR (CDCl3, 400 MHz), δ 8.09 (1H, d, J=7.6 Hz), 7.96-7.93 (2H, m), 7.70 (1H, d, J=7.6 Hz), 7.63 (1H, dt, J=7.0 and 1.4 Hz), 7.51-7.45 (6H, m), 7.42-7.28 (4H, m), 5.36-5.35 (1H, broad s), 4.21-4.19 (1H, m), 3.48 (3H, s). MS (ES+) C26H25N3O2 requires: 411, found: 412 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:13]=2[C:14]([O:16]C)=[O:15])[N:4]=1.[OH-].[Na+].O>C(O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:13]=2[C:14]([OH:16])=[O:15])[N:6]=1
Reactant: COC(=O)c1c(F)cccc1Oc1nc(OC)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)nc(Oc2cccc(F)c2C(=O)O)n1

Procedure:
To a solution in ethanol (10 ml) of methyl 2-(4,6-dimethoxypyrimidin-2-yl)oxy-6-fluorobenzoate (3.0 g), an equimolar amount of an aqueous sodium hydroxide solution (30 ml) was added, and the mixture was reacted at room temperature for 12 hours under stirring. The reaction mixture was poured into water, and extracted with ethyl ether, and non-reacted starting materials were removed. Then, the aqueous phase was acidified with a 10% hydrochloric acid aqueous solution. The aqueous solution was then extracted with ethyl ether. The extract was washed with water and dried, and then the solvent was distilled off under reduced pressure to obtain the above identified compound as a white crystal (1.5 g). (Melting point: 133°-134° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:14]([OH:38])[C@@H:15]([N:23](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[OH-].[OH-].[Pd+2].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:14]([OH:38])[C@@H:15]([NH2:23])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1[C@@H](O)[C@@H](N)Cc1ccccc1

Procedure:
Add 2-(R)-(2-(S)-dibenzylamino-1-(S)-hydroxy-3-phenylpropyl)-piperidine-1-carboxylic acid tert-butyl ester (0.107 g, 0.21 mmol), 20% palladium hydroxide on carbon (60 mg) and methanol (5 mL) and stir 18 h under 1 atmosphere of hydrogen gas. Add filter agent, filter and concentrate to give the title compound as a foam.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[C:11]1[C:12]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[Cl:29])(=[O:21])=[O:20])=[N:13][CH:14]=[C:15]([CH3:17])[N:16]=1>>[Cl:29][C:23]1[C:24]([Cl:28])=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:18][C:12]1[C:11]([O:9][CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:16][C:15]([CH3:17])=[CH:14][N:13]=1)(=[O:20])=[O:21]
Reactant: Cc1cccnc1CO
Reactant: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(Br)n1
Product: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2ncccc2C)n1

Procedure:
Prepared by the method of Example 20 using 3-methylpyridine-2-methanol (0.05 g) and N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (0.1 g). Yield 0.021 g.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C@@H:5]1[CH2:10][C@@H:9]([NH:11][S:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:14])=[O:13])[C@H:8]([OH:23])[CH2:7][CH2:6]1)=[O:4].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.CN1C=CN=C1>ClCCl>[CH3:35][C:25]1[CH:30]=[CH:29][C:28]([S:31]([O:23][C@@H:8]2[CH2:7][CH2:6][C@H:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:24])[CH2:10][C@H:9]2[NH:11][S:12](=[O:13])(=[O:14])[NH:15][C:16]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:22])(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: CN(C)C(=O)[C@H]1CC[C@@H](O)[C@H](NS(=O)(=O)NC(=O)OC(C)(C)C)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cn1ccnc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CC[C@H](C(=O)N(C)C)C[C@H]2NS(=O)(=O)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.6 %

Procedure:
t-Butyl {[(1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl]sulfamoyl}carbamate (200 mg) was dissolved in dichloromethane (2.0 mL), and p-toluenesulfonyl chloride (136 mg) and N-methylimidazole (87.0 mL) were then added to the obtained solution. The obtained mixture was stirred at room temperature for approximately 20 hours. Thereafter, the reaction mixture was purified by silica gel column chromatography to obtain the title compound (107 mg, yield: 38%) in the form of powder.
Reaction SMILES: C(OC(=O)[C:5](=[O:22])[C:6]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)=[CH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)C.[NH2:24][NH2:25]>C(O)C>[Cl:21][C:16]1[CH:15]=[C:14]([CH:6]2[CH:7]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)[NH:25][NH:24][C:5]2=[O:22])[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: NN
Reactant: CCOC(=O)C(=O)C(=Cc1ccncc1)c1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: O=C1NNC(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C

Procedure:
To a solution of 3-(3,4-Dichloro-phenyl)-2-oxo-4-pyridin-4-yl-but-3-enoic acid ethyl ester 11.4 g in ethyl alcohol 50 mL was added hydrazine 1.68 mL. The reaction was heated to 50° C. for 15 hours. All solvent was removed after under reduced pressure to afford the title compound 10.8 g as light yellow solid. MS (ES+): 308 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.CC(C)([O-])C.[Na+]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: Cc1ccc(N2CCOCC2)cc1
Yield: 97.9 %

Procedure:
According to the general procedure B, 4-methylchlorobenzene (71 mg, 0.56 mmol) reacted with morpholine (46 mg, 0.53 mmol) using 1 mol % of catalyst and sodium tert-butoxide (60 mg, 1.03 mmol) at 70° C. for 27 h to give the title compound (92 mg, 98%) as a solid: 1H-NMR (300 MHz, CDCl3): δ 7.12 (d, 2H, J=8.7 Hz), 6.87 (d, 2H, J=8.7 Hz), 3.89 (t, 4H, J=4.8 Hz), 3.14 (t, 4H, J=4.8 Hz), 2.31 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 149.09, 129.64, 129.51, 115.97, 66.90, 49.86, 20.38. GC/MS(EI): m/z 177 (M+).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH:7]([C:11](O)=O)[CH2:6]2)OCC1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:29]1([C:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[C:29]1([C:35]2[CH2:40][CH2:39][N:38]([CH2:11][CH:7]3[CH2:8][CH2:9][CH2:10][C:5](=[O:1])[CH2:6]3)[CH2:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=C(O)C1CCCC2(C1)OCCO2
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCC(CN2CC=C(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
A solution of 1,4-dioxaspiro[4.5]decane-7-carboxylic acid (Step A) (99.3 g) and triethylamine (80.8 g) in 1000 mL of dichloromethane is cooled in an ice bath, and treated dropwise with isobutyl chloroformate (80.1 g), dropwise, under nitrogen. After 30 minutes, a solution of 4-phenyl-1,2,3,6-tetrahydropyridine (84.7 g) in 500 mL of dichloromethane is added dropwise over a 2-hour period. The mixture is stirred at room temperature for 2 additional hours. The solvent is removed in vacuo. The residue is suspended in 1000 mL of ethyl acetate, cooled to 0° C., and sequentially washed with ice-cold 1N aqueous hydrochloric acid solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The crude product is purified by flash chromatography (silica; hexane:ethyl acetate, 3:1) to give 107.1 g of the title compound as a yellow oil (silica; Rf =0.4; 1% methanol, 99% chloroform); Mass Spectrum (Electron Ionization) (MS (EI)) 327 (M, 26.1%), 141 (100%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH2:23][CH2:22][C@@H:21]([NH:24][C:25]([C:27]4[NH:28][C:29]([CH3:34])=[C:30]([Cl:33])[C:31]=4[Cl:32])=[O:26])[C@@H:20]([O:35][CH2:36][CH3:37])[CH2:19]3)[S:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:6][CH:7]=1.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(N(CC)C(C)C)(C)C>CN1CCCC1>[Cl:32][C:31]1[C:30]([Cl:33])=[C:29]([CH3:34])[NH:28][C:27]=1[C:25]([NH:24][C@@H:21]1[CH2:22][CH2:23][N:18]([C:10]2[S:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([C:5]3[CH:4]=[N:3][C:2]([N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:7][N:6]=3)[N:9]=2)[CH2:19][C@@H:20]1[O:35][CH2:36][CH3:37])=[O:26]
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OCC)C2)nc1-c1cnc(Cl)cn1
Agent: CN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OCC)C2)nc1-c1cnc(N2CCCCC2)cn1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
To a stirred solution of ethyl 4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate (Example 66, 120 mg, 0.204 mmol) and piperidine (87 mg 1.023 mmol) in N-methyl pyrrolidine was added N,N-diisopropyl ethylamine; the reaction mixture was then stirred over night at 80° C. The reaction mixture was cooled to room temperature and poured on to ice cold water. The precipitated product was collected by filtration and dried to afford 120 mg (92%) of ethyl 2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-[5-(piperidin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3=[CH:13][C:14]([C:16]([NH2:18])=O)=[N:15][N:6]3[C:5](=[O:19])[C:4]=2[CH:3]=1.S(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3=[CH:13][C:14]([C:16]#[N:18])=[N:15][N:6]3[C:5](=[O:19])[C:4]=2[CH:3]=1
Reactant: Cn1c2ccc(Cl)cc2c(=O)n2nc(C(N)=O)cc12
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cn1c2ccc(Cl)cc2c(=O)n2nc(C#N)cc12
Temperature: 56 °C

Procedure:
A mixture of 3.0 g of 7-chloro-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide, 1.6 ml of thionyl chloride and 35 ml of dimethylformamide is stirred and heated at 56° C. for 18 hrs, then evaporated at reduced pressure. The residue is stirred with 600 ml of water for 1 hour and the resulting solid 7-chloro-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]-quinazoline-2-carbonitrile is collected by filtration, washed with water and dried; mp 350° C., after crystallization from dimethylformamide/ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16](I)[CH:17]=[CH:18][C:19]=1[F:20].C(=O)([O-])[O-].[K+].[K+]>[Cu]Br.CN1CCCC1=O>[F:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[F:20])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: Fc1ccc(I)cc1F
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(O)CCc1ccc(Oc2ccc(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a 50-mL RB-flask was added 3-(4-hydroxyphenyl)propionic acid (1.66 g, 10.0 mmol), 3,4-difluoroiodobenzene (2.40 g, 10.0 mmol), copper(I) bromide (0.100 g), potassium carbonate (2.76 g, 20.0 mmol), and n-methyl-2-pyrrolidone (20 mL) as solvent. The mixture was stirred for 5 min at room temperature and then heated to 140° C. (oil bath). After being stirred for 12 hours at 140° C., the reaction mixture was cooled to room temperature and diluted with EtOAC (100 mL). The diluted mixture was washed with citric acid (aq, 30 mL), water (3×50 mL, brine and dried over MgSO4. The removal of solvent in vacuo afforded crude which was purified by chromatography (0.901 g, 32%): 1H NMR (400 MHz, CDCl3) δ 11.44-11.06 (br, 1H), 7.24-7.14 (m, 2H), 7.14-7.00 (m, 1H), 7.00-6.86 (m, 2H), 6.86-6.75 (m, 1H), 6.75-6.61 (m, 1H), 2.94 (t, 2H, J=7.6 Hz), 2.68 (t, 2H, J=7.6 Hz); ESMS m/e: 277.2 (M−H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:3]1=2.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:24]=2[C:25]([NH:27][CH2:28][CH3:29])=[O:26])[C:19]([Cl:35])=[CH:18][N:17]=1>>[Cl:35][C:19]1[C:20]([NH:22][C:23]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:24]=2[C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[N:21][C:16]([NH:13][C:9]2[C:4]3[O:5][CH2:6][CH2:7][CH2:8][C:2]([CH3:14])([CH3:1])[C:3]=3[CH:12]=[CH:11][CH:10]=2)=[N:17][CH:18]=1
Reactant: CC1(C)CCCOc2c(N)cccc21
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2cccc3c2OCCCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared from 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide in an analogous manner to Example 179. Product isolated as a tan solid (30 mg, 30%). LCMS (m/e) 484 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.08 (s, 1H), 7.92 (d, 1H, J=8 Hz), 7.78 (s, 1H), 7.33 (m, 3H), 6.84 (d, 1H, J=7.8 Hz), 6.74 (t, 1H, J=8, 7.8 Hz), 6.05 (m, 1H), 3.96 (m, 2H), 3.38 (m, 2H), 2.04 (m, 2H), 1.66 (m, 2H) 1.34 (s, 6H), 1.11 (t, 3H, J=7.3 Hz).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH2:23][C:24]1[N:29]=[C:28]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:27]([F:35])=[CH:26][N:25]=1>C(Cl)(Cl)Cl>[C:31]([NH:30][C:28]1[C:27]([F:35])=[CH:26][N:25]=[C:24]([N:23]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[Cl:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[N:29]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: CC(C)(C)Nc1nc(N)ncc1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2ncc(F)c(NC(C)(C)C)n2)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To 3 ml of chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 210 mg of ethyl 3-chloro-2,4,5-trifluorobenzbylacetate by normal process was added 340 mg of 2-amino-4-(t-butylamino)-5-fluoropyrimidine. The solution was concentrated under reduced pressure. To the residue were added 550 mg of anhydrous potassium carbonate and 2 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 1 hour and 10 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (silica gel, 16 g; eluent: chloroform:methanol, 200:1), and the corresponding fractions were collected and concentrated under reduced pressure. To the residue was added 0.5 ml of ethanol, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 98 mg of the title compound as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[N:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C([Sn](CCCC)(CCCC)[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)CCC>O1CCCC1.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>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[N:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)cc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)cc1-c1cccnc1
Temperature: 80 °C
Yield: 43.3 %

Procedure:
7-(3-Bromo-4-methylphenyl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (28 mg, 78 μmol) was dissolved in tetrahydrofuran (3 ml) under nitrogen and degassed for 10 min before 3-(tributylstannyl)pyridine (37 mg, 100 μmol) and tetrakis(triphenylphosphine)palladium(0) (10 mg, 9 μmol) were added. The stirred mixture was heated at 80° C. for 48 h. Solvent was removed in vacuo and the residue purified by chromatography (silica gel, 50% EtOAc/isohexane) to give 12 mg of the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 2.37 (3H, s), 7.40–7.44 (1H, m), 7.50 (1H, d, J 8.2), 7.71–7.75 (1H, m), 7.98 (1H, d, J 1.9), 8.03 (1H, dd, J 1.9, 8.0), 8.62 (1H, s), 8.65–8.68 (2H, m), 8.79 (1H, s); MS (ES+) m/z 356 [M+H]+.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[C:6]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[NH:8])[NH2:7].[C:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(=[NH:17])[NH2:16].[C:24](O[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>O1CCCC1.O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[C:6]([N:9]1[CH2:14][CH2:13][N:12]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:11][CH2:10]1)(=[NH:7])[NH2:8].[C:15]([N:18]1[CH2:23][CH2:22][N:21]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:20][CH2:19]1)(=[NH:16])[NH2:17]
Reactant: N=C(N)N1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=N)N)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 63.4 %

Procedure:
2.50 g of 1-amidinopiperazine hemisulfate were dissolved in 60 ml of a 1:1 by volume mixture of tetrahydrofuran and water, and a solution of 3.40 g of di-t-butyl dicarbonate in 10 ml of tetrahydrofuran was added to the resulting solution, after which the mixture was stirred at room temperature for 2.5 hours. At the end of this time, the tetrahydrofuran was removed from the reaction mixture by distillation under reduced pressure, the insolubles were filtered off and the filtrate was evaporated to dryness under reduced pressure. The resulting residue was extracted with ethanol (twice, each time with 50 ml) and methanol (twice, each time with 50 ml). The extract was evaporated to dryness to obtain 2.48 g of the title compound, as crystals, melting at 278° C. (with decomposition).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:39])[N:10]([C@H:19]([C:21]2[N:30](COCC[Si](C)(C)C)[C:24]3=[N:25][CH:26]=[C:27](Br)[CH:28]=[C:23]3[N:22]=2)[CH3:20])COCC[Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:40]([C@@H:42]1[CH2:51][C:50]2[N:49]=[C:48]([CH3:52])[N:47]=[C:46]([N:53]3[CH2:59][C:58]4[CH:60]=[C:61](B(O)O)[CH:62]=[CH:63][C:57]=4[O:56][CH2:55][CH2:54]3)[C:45]=2[CH2:44][CH2:43]1)[CH3:41]>>[C:1]1([CH2:7][O:8][C:9](=[O:39])[NH:10][C@H:19]([C:21]2[NH:22][C:23]3[C:24]([N:30]=2)=[N:25][CH:26]=[C:27]([C:61]2[CH:62]=[CH:63][C:57]4[O:56][CH2:55][CH2:54][N:53]([C:46]5[C:45]6[CH2:44][CH2:43][C@H:42]([CH2:40][CH3:41])[CH2:51][C:50]=6[N:49]=[C:48]([CH3:52])[N:47]=5)[CH2:59][C:58]=4[CH:60]=2)[CH:28]=3)[CH3:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H](c1nc2cc(Br)cnc2n1COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)OCc1ccccc1
Reactant: CC[C@H]1CCc2c(nc(C)nc2N2CCOc3ccc(B(O)O)cc3C2)C1
Product: CC[C@H]1CCc2c(nc(C)nc2N2CCOc3ccc(-c4cnc5nc([C@H](C)NC(=O)OCc6ccccc6)[nH]c5c4)cc3C2)C1

Procedure:
Prepared according to the method of example 5 by using phenylmethyl{(1S)-1-[6-bromo-3-({[2-(trimethylsilyl)ethyl]oxy}methyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethyl}({[2-(trimethylsilyl)ethyl]oxy}methyl)carbamate (reagent preparation 19) and {4-[(7S)-7-ethyl-2-methyl-5,6,7,8-tetrahydroquinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.54 (br, 1H), 8.05 (br, 1H), 7.61 (s, 1H), 7.48 (d, 1H), 7.41 to 7.29 (m, 5H), 7.09 (d, 1H), 4.77 (d, 2H), 4.61 (d, 2H), 4.43 (m, 1H), 4.20 (m, 1H), 4.04 (m, 1H), 3.95 (m, 1H), 3.88 (s, 3H), 3.29 (m, 1H), 2.87 (m, 1H), 2.78 (m, 1H), 2.60 (m, 1H), 2.35 (s, 3H), 2.29 (m, 1H), 1.96 (m, 1H), 1.69 (m, 1H), 1.63 (d, 3H), 1.41 (m, 2H), 1.16 (m, 1H), 0.99 (t, 3H); MS (EI) for C36H39N7O3: 618 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:23][C@@H:22]3[C:24]([NH:26][CH2:27][CH2:28][F:29])=[O:25])=[CH:17][CH:16]=2)=[N:6][CH:7]=1.[H-].[Na+].I[CH3:33].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:23][C@@H:22]3[C:24]([N:26]([CH2:27][CH2:28][F:29])[CH3:33])=[O:25])=[CH:17][CH:16]=2)=[N:6][CH:7]=1
Reactant: Cn1cnc(-c2ccc([C@H]3C[C@@H]3C(=O)NCCF)cc2)c1Sc1ccc(Cl)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCF)C(=O)[C@H]1C[C@@H]1c1ccc(-c2ncn(C)c2Sc2ccc(Cl)cn2)cc1

Procedure:
To a solution of Example 10 (10 mg, 0.023 mmol) in DMF (1 Ml) was added sodium hydride (60% in mineral oil), (6 mg, 0.139 mmol) and iodomethane (0.009 Ml, 0.139 mmol). The reaction mixture was stirred at rt for 30 min Water was added and the mixture was extracted with ethyl acetate. The organics were dried (MgSO4), concentrated, and purified on 4 g of silica gel eluting a gradient of 0-5% triethylamine in ethyl acetate to give rise to the title compound. 1H NMR (500 MHz), [CD3OD]: 8.34 (s, 1H), 8.04 (s, 1H), 7.73 (m, 2H), 7.63 (d, 1H), 7.14 (m, 2H), 6.92 (d, 1H), 4.58 (m, 1H), 4.48 (m, 1H), 3.66 (s, 3H), 3.19 (s, 3H), 3.00 (br, 2H), 2.37 (m, 1H), 2.18 (m, 1H), 1.53 (m, 1H), 1.31 (m, 1H). LCMS: [M+1]+=445. Human FAAH lysate assay: IC50=3.0 nM.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:26])[CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18]C(OC(C)(C)C)=O)[CH:13]=2)=[CH:6][CH:5]=1>[OH-].[Na+]>[NH2:18][C:14]1[CH:13]=[C:12]([CH2:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)=[O:26])[CH:17]=[CH:16][N:15]=1
Reactant: COc1ccc(C(=O)Cc2ccnc(NC(=O)OC(C)(C)C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=O)Cc2ccnc(N)c2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
2N-hydrochloric acid (30 mL) was added to 1-(4-methoxyphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone (6.1 g, 18 mmol) and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature and, thereafter, 8N-aqueous sodium hydroxide (10 mL) was added. The resulting crude crystals were filtered and washed with water. The crude crystals were recrystallized from tetrahydrofuran-hexane to obtain 4.0 g of the title compound (16 mmol, yield 92%).