Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[C:9]([N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([OH:29])=O)[CH2:22][CH2:21]2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:6].[CH3:33][N:34]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[C:9]([N:20]2[CH2:21][CH2:22][CH:23]([CH2:26][C:27]([N:37]3[CH2:38][CH2:39][CH2:40][N:34]([CH3:33])[CH2:35][CH2:36]3)=[O:29])[CH2:24][CH2:25]2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:6]
Reactant: CN1CCCNCC1
Reactant: O=C(O)CC1CCN(c2ncc(-c3ccccc3)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCCN(C(=O)CC2CCN(c3ncc(-c4ccccc4)cc3NC(=O)c3cccc(Cl)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A mixture of 0.035 g (0.078 mmol) of [3′-(3-chloro-benzoylamino)-5′-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid, 0.044 g (0.39 mmol) of 1-methyl homopiperazine, 0.032 g (0.10 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and 0.032 mL (0.23 mmol) of triethylamine in N,N-dimethylformamide (2 mL) are stirred overnight at room temperature. The mixture is concentrated under reduced pressure and the residue is diluted with water which causes a solid to precipitate from solution. The colorless solid is collected by filtration, washed with water and dried to provide 0.032 g (75%) of 3-chloro-N-(2-{4-[2-(4-methyl-1,4-diazepan-1-yl)-2-oxoethyl]piperidin-1-yl}-5-phenylpyridin-3-yl)benzamide (124) as a colorless solid. [M+H]+=546.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4](=[CH:9][C:10]1[C:11]([CH:16]2[CH2:18][CH2:17]2)=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:5][C:6]([OH:8])=O.[C:20]([O-])(=[O:22])[CH3:21].[Na+]>CC(O)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:10]2[C:15]([CH:14]=[CH:13][N:12]=[C:11]2[CH:16]2[CH2:18][CH2:17]2)=[C:6]([O:8][C:20](=[O:22])[CH3:21])[CH:5]=1)=[O:19]
Reactant: COC(=O)C(=Cc1cccnc1C1CC1)CC(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC(C)=O)c2ccnc(C3CC3)c2c1
Temperature: 155 °C

Procedure:
2-[1-(2-Cyclopropyl-pyridin-3-yl)-methylidene]-succinic acid 1-methyl ester (18.9 g, 72.4 mmol), sodium acetate (5.94 g, 72.4 mmol) was suspended in AcOH (150 ml) and heated at 155° C. for 6 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc=10/0 to 6/4) to obtain the intended compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:17]2[CH2:16][CH2:15][C:14]3[C:10](=[CH:11][N:12](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:13]=3)[C:9]=2[N:8]([CH3:37])[C:7]=1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:5])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:17]2[C:9](=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)[N:8]([CH3:37])[C:7]=1[C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c2c(n(C)c1C(=O)OC(C)(C)C)-c1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C(=O)OC(C)(C)C)n(C)c2c1ccc1[nH]ncc12
Temperature: 100 °C
Yield: 66 %

Procedure:
To a solution of 1-methyl-7-trityl-1,4,5,7-tetrahydro-1,6,7-triaza-as -indacene-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester VI (1.05 mmol) in 20 mL of dry dioxane under argon, DDQ (1.26 mmol) was added. The dark solution was heated at 100° C. for 4 h then the solvent was evaporated. The residue was dissolved in DCM, washed with water and with 20% aq sodium carbonate. The organic layers were dried (Na2SO4) and evaporated to dryness. The residue was purified by chromatography on silica gel (eluant: hexane/AcOEt 7:3) affording the title compound in 66% yield. ESI (+) MS: m/z 344 (MH+). 1H NMR: 1.34 (t, J=7.09, 3H), 1.59 (s, 9H), 4.12 (s, 3H), 4.33 (q, J=7.09, 2H), 7.44 (d, J=9.02, 1H), 7.90 (d, J=9.02, 1H), 8.47 (s, 1H), 13.43 (bs, 1H).
Reaction SMILES: [C:1]1(=[O:14])[C:9]2[C:8]3[CH:10]=[CH:11][CH2:12][O:13][C:7]=3[CH:6]=[CH:5][C:4]=2[CH2:3][NH:2]1.[N:15]([O-:17])=[O:16].[Na+].II>CN1CCCC1.O>[N+:15]([C:11]1[CH2:12][O:13][C:7]2[CH:6]=[CH:5][C:4]3[CH2:3][NH:2][C:1](=[O:14])[C:9]=3[C:8]=2[CH:10]=1)([O-:17])=[O:16]
Reactant: O=N[O-]
Reactant: O=C1NCc2ccc3c(c21)C=CCO3
Agent: CN1CCCC1
Agent: II
Agent: [Na+]
Solvent: O
Product: O=C1NCc2ccc3c(c21)C=C([N+](=O)[O-])CO3
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
To a mixture of 2,3-dihydropyrano[3,2-e]isoindol-1(7H)-one ((71) 2.3 g, 12.3 mmol) in N-methylpyrrolidine (150 ml) and H2O (3 ml) was added NaNO2 (3.4 g, 49.2 mmol) in portions. To the mixture cooled at 0° C. was added iodine (9.4 g, 36.9 mmol). The reaction mixture was stirred for 3 hr, then quenched with 58% NaHSO3 (12 ml), H2O (12 ml), followed by addition of another 30 ml of 58% NaHSO3 solution. The solid was participated, filtered, and washed with H2O. The desired compound was air-dried under vacuum to give the title compound (2.41 g, 84%) as a yellow solid. MS (ES) m/z 233.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:18]=3[N:19]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3cc(C#N)ccc3o2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2oc(NC3CCNCC3)nc2c1
Yield: 93.1 %

Procedure:
To a solution of 4-(5-cyano-benzooxazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (6.62 g, 19.33 mmol, 1.0 equiv) in dichloromethane (100 mL) was added trifluoro-acetic acid (7.4 mL, 11.03 g, 96.7 mmol, 5.0 equiv). After stirring under Ar at rt for 18 h excess trifluoro-acetic acid was removed under reduced pressure and the crude solid taken up in dichloromethane (100 mL) and water (100 mL). The pH was adjusted to 10 by addition of a conc. solution of K2CO3 and the solution extracted with dichloromethane/2-propanol (4:1, 3×50 mL). The combined organic phases were dried over MgSO4, the organic solvent evaporated under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with a gradient of dichloromethane/methanol (100:0→95:5) containing 33% of NH4OH to yield 4.36 g (93%) of the title compound. MS (ESI): 243.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7].Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[F:31][C:28]([F:29])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH2:13][CH:12]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:23][CH2:24]1)=[O:7]
Reactant: ClCCN1CCOCC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCC2c1ccccc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCN1CCOCC1)CC2c1ccccc1

Procedure:
The title compound, MS: m/e=584.1 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one and 4-(2-chloroethyl)-morpholine.
Reaction SMILES: Br[CH:2]([CH3:6])[C:3](=O)[CH3:4].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1>C(OCC)(=O)C>[CH3:4][C:3]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]2[C:2]=1[CH3:6]
Reactant: CC(=O)C(C)Br
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: CCOC(C)=O
Product: Cc1nc2ccc([N+](=O)[O-])cn2c1C

Procedure:
Operations similar to Production Example 1-(2) were conducted using 3-bromo-2-butanone and 2-amino-5-nitropyridine. The solid whereupon obtained was suspended in ethyl acetate, and washed with saturated aqueous sodium hydrogencarbonate. After concentration under reduced pressure, the residue was recrystallized from ethanol to provide the title compound as yellow crystals.
Reaction SMILES: C([O:9][C@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[N+:39]([O-:41])=[O:40])(=O)C1C=CC=CC=1.C[O-].[Na+]>>[C@@H:11]1([N:34]2[CH:38]=[CH:37][N:36]=[C:35]2[N+:39]([O-:41])=[O:40])[O:12][C@H:13]([CH2:24][OH:25])[C@@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: O=C(OC[C@H]1O[C@@H](n2ccnc2[N+](=O)[O-])[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1nccn1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
1-(2',3',5'-tri-O-benzoyl-β-D-arabinofuranosyl)-2-nitroimidazole (150 mg, 0.27 mmol) was added to 2.5 ml of 0.025 M methanolic sodium methoxide. The mixture was stirred at 0° C. for three hours and then purified by preparative TLC using chloroform:methanol (6:1) to give 36 mg (54.6%) of the title product as white needles, mp 172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:13][CH2:14][C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])=[N:9][C:10]=2[C:11]#[N:12])[CH:7]=1.[NH2:22][Al]CCl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:13][CH2:14][C:15]([F:20])([F:21])[C:16]([F:19])([F:18])[F:17])=[N:9][C:10]=2[C:11](=[NH:22])[NH2:12])[CH:7]=1
Reactant: N#Cc1nc(CCC(F)(F)C(F)(F)F)n2cc(Cl)ccc12
Reactant: N[Al]CCl
Solvent: Cc1ccccc1
Product: N=C(N)c1nc(CCC(F)(F)C(F)(F)F)n2cc(Cl)ccc12
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Trimethyl aluminum (2.0 M toluene, 10 mL, 20 mmol) was added to ammonium chloride (1.07 g, 20 mmol) suspended in toluene (30 mL) at 0° C. The solution was then stirred at room temperature for 2 hours to give a 0.5 M amino(chloro)methylaluminum solution in toluene. To the intermediate from Step I (2 g, 6.33 mmol) in toluene (1 mL) was added amino(chloro)methylaluminum (40 mL of 0.5 M solution in toluene, 20 mmol). The resulting mixture was left stirring at 100° C. for 18 hours. The reaction mixture was cooled to room temperature and quenched with silica-gel and 1:1 methanol-chloroform (50 mL). The resulting slurry was stirred vigorously for 30 minutes. The reaction mixture was filtered through a silca gel pad (1″) and washed with methanol. The filtrate was concentrated. The residue was suspended in water and extracted with 30% IPA/CHCl3 (3×). The organic layer was concentrated in vacuo to yield a brown solid. m/z=340.8 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([N+:11]([O-:13])=[O:12])[C:3]=1N.C(ON=O)(C)(C)C.[ClH:21]>C(#N)C>[Cl:21][C:3]1[C:2]([Cl:1])=[C:8]([F:9])[C:7]([F:10])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1c([N+](=O)[O-])cc(F)c(F)c1Cl
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)c(F)c(Cl)c1Cl
Reaction time: 0.22 h

Procedure:
To a mixture of anhydrous cupric chloride (2.2 g) and 2-chloro-3,4-difluoro-6-nitroaniline (2.63 g) in anhydrous acetonitrile (20 ml) was added t-butylnitrite (2.0 g) dropwise at 46° to 55° C. during 9 minutes. After stirring for 13 minutes at the same temperature, the reaction mixture was poured into chilled 10 diluted hydrochloric acid (20 ml) and extracted with benzene. The organic layer was washed with diluted hydrochloric acid and with water successivly, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel chromatography eluting with dichloromethane-n-hexane (1:5) to give the title compound (2.47 g), as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:42][CH2:43][C:44]1([OH:47])[CH2:46][CH2:45]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:42][CH2:43][C:44]3([OH:47])[CH2:46][CH2:45]3)=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: CS(=O)(=O)OCCC1(O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCC5(O)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Reaction time: 24 h
Yield: 31.2 %

Procedure:
To a mixture of N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (735.7 mg, 1.52 mmol) and 2-(1-hydroxycyclopropyl)ethyl methanesulfonate (3.04 mmol) in 8 mL of N,N-dimethylacetamide was added cesium carbonate (4.955 g, 15.2 mmol). After stirring at 40° C. for 1 day, the reaction was quenched with water (5 mL) and extracted with CH2Cl2 (20 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on a silica gel column (CH2Cl2/CH3OH (v/v)=45:1) to afford the title compound as a white solid (270 mg, 15.6%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH:3]=1.[F:19][C:20]([F:28])([F:27])[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([NH:8][C:4]3[CH:3]=[C:2]([N:24]4[CH2:25][CH2:26][CH:21]([C:20]([F:28])([F:27])[F:19])[CH2:22][CH2:23]4)[N:7]=[CH:6][N:5]=3)[CH:18]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: Clc1cc(Nc2ccc3cccnc3c2)ncn1
Reactant: FC(F)(F)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)C1CCN(c2cc(Nc3ccc4cccnc4c3)ncn2)CC1

Procedure:
This compound could be prepared from (6-chloro-pyrimidin-4-yl)-quinolin-7-yl-amine and 4-trifluoromethyl-piperidine in the presence of K2CO3 and DMF.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.CO.[NH3:36]>>[NH2:36][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: C[C@@H](c1ccc(-c2ccnc(Cl)n2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Solvent: CO
Product: C[C@@H](c1ccc(-c2ccnc(N)n2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 90 °C
Yield: 90 %

Procedure:
(R)-3-((S)-1-(4-(2-chloropyrimidin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (300 mg, 0.6 mmol) was dissolved in MeOH/NH3 (10 mL). The resulting mixture was heated to 90° C. for 24 h. The mixture was concentrated to give the crude product, which was purified by preparative TLC to give (R)-3-((S)-1-(4-(2-aminopyrimidin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (270 mg, 90%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6]CC)=O.[C:9]1([Mg][Cl:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[ClH:16].[C:9]1([C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:6])[CH2:3][NH2:2])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)CN
Reactant: Cl[Mg]c1ccccc1
Agent: Cl
Product: NCC(O)(c1ccccc1)c1ccccc1

Procedure:
Treatment of ethyl glycinate hydrochloride (4.5 g) with phenylmagnesium chloride (from 0.39 mole each of bromobenzene and magnesium), as discussed by A. McKenzie and G. O. Wills J. Chem. Soc. 1925, 127, 283 (and references cited therein), affords the title compound (mp 191°-193° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.[CH:15]1([CH2:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[CH:15]1([CH2:21][NH:22][C:12]([C:5]2[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=2)=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Reactant: NCC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CCCCC1)c1cnc(Cl)nc1C(F)(F)F

Procedure:
To a solution of 2-chloro-4-trifluoromethyl-pyrimidin-5-carbonyl chloride (750 mg, ex Maybridge) in dichloromethane (15 ml) at −400 was added dropwise over 30 minutes a solution of cyclohexanemethanamine (0.35 ml, ex Lancaster) and triethylamine (0.41 ml) in dichloromethane (15 ml). Dichloromethane was removed under reduced pressure and ethyl acetate (20 ml) added. The solution was washed sequentially with water, 5% sodium bicarbonate solution and water, dried (MgSO4), evaporated and triturated with ether:hexane to afford 2-chloro-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (666 mg).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([NH:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH:5]=1.C[Si](C)(C)[O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(N(CC)CC)C>[C:11]([C:10]1[CH:9]=[CH:8][C:7]([N:6]([N:4]2[CH:3]=[N:2][N:1]=[CH:5]2)[C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([OH:17])=[CH:19][CH:20]=2)=[CH:14][CH:13]=1)#[N:12]
Reactant: C[Si](C)(C)Oc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N(C(=O)c2ccc(O)cc2)n2cnnc2)cc1
Yield: 36.1 %

Procedure:
A mixture composed of 10.43 g of 4-[N-(1,2,4-triazol-4-yl)amino]benzonitrile, 7.9 ml of triethylamine, and 56 ml of methylene chloride was stirred under cooling with ice, and a mixture composed of 23.7 g of 4-(trimethylsilyloxy)benzoyl chloride and 28 ml of methylene chloride was added dropwise thereto, followed by stirring at room temperature for 1 hour. Dilute hydrochloric acid was added to the reaction mixture, followed by stirring at room temperature overnight. After the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, the product was extracted with tetrahydrofuran-diethyl ether (1:1). After the extract was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (using a 4:1 mixture of chloroform and acetone as the eluent) to obtain 6.2 g of N-(4-cyanophenyl)-4-hydroxy-N-(1,2,4-triazol-4-yl)benzamide.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH3:29])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(Br)c1ccccc1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(C(C)c3ccccc3)C2=O)CC1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and (1-bromoethyl)benzene, to give the desired product as a white foam (67%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][CH2:11]O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:24]1C=CC=C[CH:25]=1>>[CH3:25][NH:24][CH2:11][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: c1ccncc1
Reactant: OCCc1cc2ccccc2o1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CNCCc1cc2ccccc2o1
Yield: 59 %

Procedure:
A solution of 5.03 g of 3-benzofuranethanol and 8 g of p-toluenesulfonyl chloride in 20 ml of pyridine was kept in a refrigerator for one week. Most of the pyridine was removed under vacuum, and the residue dissolved in ether and washed successively with 5% hydrochloric acid, water, and 5% sodium bicarbonate solution and dried. Removal of the solvent left 5.93 g of crude 3-benzofuranethanol, p-toluenesulfonate which was heated with 8 g of methylamine in 25 ml of tetrahydrofuran to 100° for 4 hours. The mixture was concentrated, made basic with aqueous sodium hydroxide, and extracted with methylene chloride. The crude amine so obtained was short-path distilled (bath 120°, 0.5 micron) to give 3.17 g (59% yield) of N-methyl 3-benzofuranethylamine. NMR spectrum (in CDCl3): τ2.4-3.0 (m, 5); 7.2 (s, 4); 7.6 (s, 3) and 9.0 (s, 1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([C:2]2[N:3]=[C:4]3[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]3[C:6](=[O:8])[CH:7]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: C1COCCN1
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reaction time: 1 h

Procedure:
A mixture of 1 g of (8S)-2-chloro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one and of 15 mL of morpholine is heated to 80° C. After one hour and a half of heating and after monitoring with LC/MS, the reaction is completed. After cooling, the reaction mixture is concentrated under reduced pressure. On the obtained residue, 10 mL of cold water and 100 mL of ethyl acetate are added. The resulting organic phase is separated and then dried on magnesium sulfate, filtered and concentrated under reduced pressure in order to obtain 1.2 g of (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one including the following characteristics:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-])=O.Br[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:12]1([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrC1CCCC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(OC2CCCC2)cc1
Temperature: 80 °C

Procedure:
A mixture of 4-nitrophenol (63.7 g), bromocyclopentane (68.2 g), potassium carbonate (63.3 g) and DMF (300 ml) was heated at 80° C. for 24 hours. After cooling, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was hydrogenated by method B. This resulted in the product with the molecular weight of 177.25 (C11H15NO); MS (ESI): 178 (M+H+).