Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 90 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 2.47 (s, 3H), 3.07-3.17 (m, 4H), 3.77-3.87 (m, 4H), 4.13 (s, 3H), 6.87-8.01 (m, 8H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:27]([O:31][C:32]([O:34][C:35]1[C:47]([C:48]([F:51])([F:50])[F:49])=[CH:46][CH:45]=[C:44]([CH3:52])[C:36]=1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:52][C:44]1[C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[C:35]([O:34][C:32]([O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:33])[C:47]([C:48]([F:49])([F:50])[F:51])=[CH:46][CH:45]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c1C(=O)OC(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Yield: 51.6 %

Procedure:
N-Bromosuccinimide (9.70 g, 54.5 mmol) and benzoyl peroxide (0.7 g) were added to a solution of tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-methyl-3-(trifluoromethyl)benzoate (18.6 g, 49.6 mmol) obtained in Example (28-4) in carbon tetrachloride (400 ml), and the mixture was heated under reflux for 5 hours. The temperature of the reaction mixture was returned to room temperature and the solvent was removed under reduced pressure. After n-hexane was added to the obtained residue and the mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: toluene) to give tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (11.66 g, yield: 52%).
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([NH2:26])[CH:20]=1>>[O:13]=[C:11]1[NH:10][C:9](=[O:14])[C:8](=[CH:7][C:6]2[CH:15]=[CH:16][C:3]([C:1]3[NH:26][C:21]4[CH:20]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:24]=[CH:23][C:22]=4[N:25]=3)=[CH:4][CH:5]=2)[S:12]1
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Product: O=C1NC(=O)C(=Cc2ccc(-c3nc4ccc(C(F)(F)F)cc4[nH]3)cc2)S1

Procedure:
2-[4-[(2,4-Dioxothiazolidin-5-ylidene)methyl]phenyl]-5-trifluoromethylbenzimidazole was prepared from 5-(4-formylbenzylidene)-2,4-thiazolidinedione and 4-trifluoromethyl-1,2-phenylenediamine by following General Procedure 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=3[N:14]2[CH2:13][CH:12]([OH:28])[CH2:11][CH2:10]1.C(#N)C>O.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=3[N:14]2[CH2:13][C:12](=[O:28])[CH2:11][CH2:10]1
Reactant: CCN(CC)c1cccc2nc3n(c12)CC(O)CCN3c1ccc(Cl)cc1Cl
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CC#N
Solvent: O
Product: CCN(CC)c1cccc2nc3n(c12)CC(=O)CCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
A mixture of 1-(2,4-dichlorophenyl)-7-(diethylamino)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-4-ol (Example 70; 60.0 mg, 0.143 mmol), tetra-n-propylammonium perruthenate (5.0 mg, 0.014 mmol), 4-methylmorphorine N-oxide (41.9 mg, 0.358 mmol), molecular sieves 4A (60 mg) and acetonitrile (1.5 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, filtered and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound as a solid (26.5 mg, 0.0635 mmol, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
The mixture of 6-bromonicotinic acid (700 mg, 3.5 mmol), morpholine (391 mg, 4.5 mmol), HATU (220 mg, 0.59 mmol) and DIPEA (0.3 mL) in 10 mL of dry THF was stirred at room temperature for 14 hours. The reaction solution was evaporated to dryness. To the residue was added 20 mL of 0.5N hydrochloride, and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was dried over sodium sulfate and concentrated to give (6-bromopyridin-3-yl)(morpholino)methanone (750 mg, 79%). LC-MS: 271, 273 [M+H]+, tR=1.290 min.
Reaction SMILES: [CH3:1][C:2](=[CH2:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:11]([CH:13]=[CH2:14])=[O:12].C1(C=CC(O)=CC=1)O>>[CH:11]([C@@H:13]1[C@H:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=[C:2]([CH3:1])[CH2:10][CH2:14]1)=[O:12]
Reactant: C=C(C)/C=C/C(=O)OCC
Reactant: C=CC=O
Agent: Oc1ccc(O)cc1
Product: CCOC(=O)[C@@H]1C=C(C)CC[C@@H]1C=O
Temperature: 97.5 °C

Procedure:
A mixture of ethyl(2E)-4-methylpenta-2,4-dienoate (8.5 g, 60.6 mmol), acrolein (5.1 g, 91 mmol) and hydroquinone (67 mg, 0.6 mmol) was heated to 95-100° C. for 24 h. The mainly cis-ethyl 6-formyl-3-methylcyclohex-2-ene-1-carboxylate was isolated by distillation (60-80° C./0.5 mm Hg) and then equilibrated with freshly activated basic alumina (−2 grams of basic alumina per gram of cis-ethyl 6-formyl-3-methylcyclohex-2-ene-1-carboxylate) in benzene as solvent (−6 mL benzene per gram of cis-ethyl 6-formyl-3-methylcyclohex-2-ene-1-carboxylate). After stirring at room temperature for 6 days, the equilibration mixture was filtered through Celite™ and the filter cake was washed with ethyl acetate. (1R/S,6R/S)-Ethyl 6-formyl-3-methylcyclohex-2-ene-1-carboxylate was then purified by distillation (65° C./15 mm Hg) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:3]1.[CH:25]([Mg]Cl)([CH3:27])[CH3:26]>C1COCC1>[OH:1][C:2]1([CH:25]([CH3:27])[CH3:26])[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:3]1
Reactant: N#Cc1ccc(-c2ccc(OCCCN3CCC(=O)C3)cc2)cc1
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)C1(O)CCN(CCCOc2ccc(-c3ccc(C#N)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
The product from Example 154 (147 mg, 0.46 mmol) in dry THF (10 mL) under an atmosphere of nitrogen at 0° C. was treated with a 2.0M solution of isopropylmagnesium chloride (0.92 mmol). After warming to ambient temperature and stirring for 1 hour, the mixture was quenched with 5 mL of cold saturated ammonium chloride solution and then the solution was partitioned between water (50 mL) and dichloromethane (50 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue purified by chromatography (CHCl3:MeOH:NH4OH, 9:1:0.1) to provide the title compound (75% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:6]=1[CH2:18]Br)[CH3:2].[NH:21]([S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:6]=1[CH2:18][N:21]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[S:27]([C:30]1[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=1)(=[O:29])=[O:28])[CH3:2]
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)c1ccc(Oc2ccccn2)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Oc2ccccn2)cc1CN(CC(=O)OC)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A mixture of 2-bromomethyl-4-(pyridin-2-yloxy)-benzoic acid ethyl ester (855 mg, crude from previous step), Ts-Gly-OMe (502 mg), potassium carbonate (425 mg) and KI (32 mg) in DMF (10 mL) was stirred at rt overnight. Then the reaction mixture was diluted with EtOAc, washed with water, diluted NaCl sol and dried over anhydrous sodium sulfate, filtered, concentrated and the residue was column purified to give product (745 mg). LC MS ESI+: 499 (M+1)+.
Reaction SMILES: FC(F)(F)C([O-])=O.[N:8]1([C:12]2[NH+:17]=[C:16]([CH2:18][N:19]3[C@@H:23]([CH3:24])[C@@H:22]([C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=4)[O:21][C:20]3=[O:39])[C:15]([C:40]3[CH:45]=[C:44]([CH2:46][C:47]#[N:48])[CH:43]=[CH:42][C:41]=3[O:49][CH3:50])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1.Cl.C(N(CC)CC)C.[N-:59]=[N+:60]=[N-:61].[Na+].O>CN1C(=O)CCC1>[N:8]1([C:12]2[N:17]=[C:16]([CH2:18][N:19]3[C@@H:23]([CH3:24])[C@@H:22]([C:25]4[CH:26]=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=4)[O:21][C:20]3=[O:39])[C:15]([C:40]3[CH:45]=[C:44]([CH2:46][C:47]4[N:59]=[N:60][NH:61][N:48]=4)[CH:43]=[CH:42][C:41]=3[O:49][CH3:50])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CC#N)cc1-c1ccc(N2CCC2)[nH+]c1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1ccc(Cc2nn[nH]n2)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 150 °C
Reaction time: 72 h

Procedure:
A mixture of 6-azetidin-1-yl-2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-3-[5-(cyanomethyl)-2-methoxyphenyl]pyridinium trifluoroacetate (EXAMPLE 256) (15 mg, 0.021 mmol), triethylamine hydrochloride (15 mg, 0.109 mmol), and sodium azide (30 mg, 0.461 mmol) in NMP (2 ml) was stirred at 150° C. under nitrogen for 3 days. Water was added and the mixture extracted 2 times with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by RP HPLC to afford the title compound. Mass spectrum (ESI) 648.3 (M+1). 1H NMR (500 MHz, CD3OD): δ 7.97 (s, 1H); 7.88 (s, 2H); 7.30 (d, J=8.4 Hz, 1H); 7.26 (m, 1H); 7.08 (s, 1H); 7.01 (d, J=8.5 Hz, 1H); 6.34 (d, J=8.4 Hz, 1H); 5.70 (m, 1H); 4.62 (d, J=14.3 Hz, 1H); 4.25 (s, 2H); 4.20 (s, 1H); 4.04 (t, J=7.4 Hz, 4H); 3.86 (br s, 1H); 3.77 (s, 3H); 2.43-2.36 (m, 2H); 0.59 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:3]=1.[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([NH:28][CH2:29][CH2:30][NH2:31])=[N:26][CH:27]=1)([O-:21])=[O:20]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:4]1[N:3]=[C:2]([NH:31][CH2:30][CH2:29][NH:28][C:25]2[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:27][N:26]=2)[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=1
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Product: O=[N+]([O-])c1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)nc1

Procedure:
In analogy to the procedure for preparing Example 7A, the product is obtained as a solid by reacting 5-chloro-7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidine (Example 6A) with N-(5-nitropyridin-2-yl)ethane-1,2-diamine.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:9])=O)([CH3:3])[CH3:2].O=P(Cl)(Cl)Cl>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]#[N:9])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(N)=O)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1cccc(C#N)c1
Yield: 80.4 %

Procedure:
A solution of the above amide (4.20 g, 25.7 mmol) in POCl3 (36.0 g, 236 mmol) was stirred at 80° C. for 18 h. The solution was concentrated and the residue was poured into water (100 mL). The mixture was exacted with EtOAc. The organic layers were combined, washed by brine, dried over Na2SO4 and concentrated to give 3-isopropyl-benzonitrile (3.00 g, 80%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([OH:10])=[CH:4][C:3]=2[O:2]1.[H-].[Na+].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.Cl>CS(C)=O>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([O:10][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=3)=[CH:4][C:3]=2[O:2]1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc2c(c1)OCO2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2ccc3c(c2)OCO3)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 67.7 %

Procedure:
A solution of 3,4-methylenedioxy phenol (7.0 g, 50.7 mmol) in anhydrous DMSO was added dropwise over 30 minutes to a stirred suspension of 60% oil dispersion NaH (2.02 g, 50 mmol) in anhydrous DMSO (40 mL) under nitrogen. Following the addition, a solution of p-fluorobenzaldehyde (6.2 g, 0.05 mol) in DMSO (10 mL) was added, and the temperature was slowly raised to 150° C. The temperature was maintained between 130°-160° C. for 1 hour and then allowed to cool to ambient temperature. After 12 hours at ambient temperature, the reaction mixture was poured onto crushed ice-water and made barely acidic with concentrated HCl and extracted with ether. The combined ether extracts were washed successively with cold dilute aqueous sodium hydroxide solution, cold dilute HCl solution, cold water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated to give a red liquid which solidified. The solid was triturated with boiling n-pentane, filtered and washed with boiling pentane to give 8.2 g (67%) of the title compound. m.p. 67°-70° C. 1H NMR (CDCl3, 300 MHz) δ6.0 (s, 2H), 6.6 (m, 2H), 6.8 (d, 1H), 7.04 (m, 2H), 7.84 (m, 2H), 9.92 (s, 1H). MS (DCl/NH3) m/e 243 (M+H)+.
Reaction SMILES: [O:1]([CH:8]([CH2:12][CH2:13][CH3:14])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][NH2:25])[N+:20]([O-:22])=[O:21].C(OC(C)C)(C)C>>[O:19]([CH2:23][CH2:24][NH:25][C:9](=[O:11])[CH:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:12][CH2:13][CH3:14])[N+:20]([O-:22])=[O:21]
Reactant: CCCC(Oc1ccccc1)C(=O)O
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: CCCC(Oc1ccccc1)C(=O)NCCO[N+](=O)[O-]
Yield: 54.9 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.69 g of 2-phenoxyvaleric acid and 0.60 g of 2-nitroxyethylamine nitrate, 0.55 g of the title compound was obtained as colorless acicular prisms (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].I[CH2:18][CH3:19].[BH4-].[Na+]>C(O)C>[CH2:18]([N:14]1[CH2:15][CH:16]=[C:11]([C:10]2[C:2]([F:1])=[C:3]([CH:7]=[CH:8][CH:9]=2)[C:4]([NH2:6])=[O:5])[CH2:12][CH2:13]1)[CH3:19]
Reactant: NC(=O)c1cccc(-c2ccncc2)c1F
Reactant: CCI
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN1CC=C(c2cccc(C(N)=O)c2F)CC1

Procedure:
Preparation according to preparation 6: 2-fluoro-3-pyridin-4-ylbenzamide (0.94 g, 4.34 mmol), 1-iodoethane (3 ml), ethanol (40 ml), sodium borohydride (1.25 g, 34.8 mmol). Yield: 0.75 g. MS m/z (rel. intensity, 70 eV) 248 (M+, bp), 247 (37), 233 (99), 146 (22), 110 (41).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[C:19]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:18][CH:17]=[CH:16][N:15]=1>C(#N)C>[O:2]=[C:1]1[NH:13][C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[N:20]1[CH:21]1[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2N)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reaction time: 8 h
Yield: 87.1 %

Procedure:
Carbonyldiimidazole (0.70 g, 4.33 mmol) was added to a solution of 2-amino-3-[(1-t-butoxycarbonylpiperidin-4-yl)amino]pyridine (1.15 g, 3.93 mmol) in acetonitrile (150 mL) at room temperature. After several hours, an additional amount of carbonyldiimidazole was added (0.81 g), and the reaction stirred overnight. The acetonitrile was evaporated in vacuo, the residue partitioned between water and chloroform, and the organic phase washed with saturated brine and dried over magnesium sulfate. The crude product was purified by chromatography (silica gel, 1.2 to 2.5% methanol in methylene chloride gradient elution), which gave the title compound (1.09 g). 1H NMR (500 MHz, CDCl3) δ 9.39 (br s, 1H), 8.04 (dd, J=1, 5 Hz, 1H), 7.33 (dd, J=1, 8 Hz, 1H), 6.99 (dd, J=5, 8 Hz, 1H), 4.50 (m, 1H), 4.32 (br s, 2H), 2.86 (br s, 2H), 2.20 (m, 2H), 1.86 (d, J=12 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:3]([CH3:15])[C:4](=[O:14])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[N:7]=1.Cl.[CH3:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C@@H:29]3[O:34][CH2:33][CH2:32][NH:31][CH2:30]3)=[CH:25][CH:24]=2)[O:20][N:19]=1.C(N(CC)CC)C>>[CH3:15][N:3]1[C:4](=[O:14])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[N:7]=[C:2]1[N:31]1[CH2:32][CH2:33][O:34][C@@H:29]([C:26]2[CH:27]=[CH:28][C:23]([C:21]3[O:20][N:19]=[C:18]([CH3:17])[N:22]=3)=[CH:24][CH:25]=2)[CH2:30]1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: Cc1noc(-c2ccc([C@H]3CNCCO3)cc2)n1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccc([C@H]3CN(c4nc(-c5ccncn5)cc(=O)n4C)CCO3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (intermediate 1, 12.6 g, 56.6 mmol) and (2S)-2-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)morpholine hydrochloride (intermediate 19, 16.7 g, 59.3 mmol) was added triethylamine (17.2 g, 170 mmol) at room temperature and the mixture was stirred at room temperature for 8 hours. The organic solvent was removed under reduced pressure, and the resulting crude product was washed with ethyl acetate and water and dried under reduced pressure to afford 3-methyl-2-((2S)-2-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)morpholino)-6-(pyrimidin-4-yl)pyrimidin-4(3H)-one (compound of the present invention, 23.7 g, 97%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]([CH3:17])=[N:12]3)=[N:5][NH:4][C:3]1=[S:18].Br[CH2:20][CH2:21][CH2:22][Cl:23].[H-].[Na+]>C(O)C>[Cl:23][CH2:22][CH2:21][CH2:20][S:18][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]([CH3:17])=[N:12]3)=[N:5][N:4]=1
Reactant: Cc1ccc2c(-c3n[nH]c(=S)n3C)cccc2n1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1

Procedure:
To 4-methyl-5-(2-methyl-5-quinolinyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (3.6 g, prepared in analogy to the method described in WO200240471) in ethanol (60 mL) containing 1-bromo-3-chloropropane (2.0 mL) was carefully added with stirring sodium hydride (0.60 g, 60% in petrolium). The mixture was heated at reflux for 45 min. Volatiles were evaporated in vacuo and the residue submitted to column chromatography (EtOAc -acetone gradient). The material thus obtained was precipitated from hot EtOAc (20 mL) by adding petroleum ether (40-60, 50 mL), cooled and collected by filtration to provide the title compound as colourless crystals (2.1 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO.O>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:23][CH:24]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester prepared in Step C of Preparation 20, (0.497 g, 2.09 mmol) in MeOH (8 mL) was added 4-tert-butylbenzaldehyde (0.33 mL, 1.97 mmol), and the mixture was stirred at room temperature for 2 h. The solution was cooled to 0° C. and sodium borohydride (0.119 g, 3.15 mmol) was added in one portion. The mixture was stirred for 10 min, and a 1:1 solution of water:aqueous saturated sodium bicarbonate was added to the solution. The product was extracted into CH2Cl2 (3×) and the combined organic solutions were dried (MgSO4) and concentrated in vacuo. The product was purified via silica gel chromatography (EtOAc followed by 5% MeOH in CH2Cl2) to give the title compound of Step A (0.691 g) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.30-7.38 (m, 2H), 7.19-7.28 (m, 3H), 6.87-6.96 (m, 2H), 6.77 (d, 1H), 4.50 (s, 2H), 3.77 (s, 2H), 3.75 (s, 2H), 1.46 (s, 9H), 1.30 (s, 9H); MS 384 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2([CH2:21][C:22]([O-:24])=O)[N:18]=[C:19]=[S:20].[CH3:25][NH2:26]>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]3([CH2:21][C:22](=[O:24])[N:26]([CH3:25])[C:19](=[S:20])[NH:18]3)[CH2:6][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:8][C:9]2=[CH:10][CH:11]=1
Reactant: CN
Reactant: O=C([O-])CC1(N=C=S)CC(c2ccccc2)Oc2ccc(Br)cc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1C(=O)CC2(CC(c3ccccc3)Oc3ccc(Br)cc32)NC1=S
Reaction time: 1 h

Procedure:
To a solution of 2-(6-bromo-4-isothiocyanato-2-phenylchroman-4-yl)acetate (192 mg, 0.46 mmol) in DCM (5 mL) is added a solution of 2 M MeNH2 in THF (1.3 mL), and stirred for 1 h. The solvent is removed under reduced pressure and the residue is dissolved in DCM (2 mL) and hexane (2 mL) and evaporated to afford 6-bromo-1′-methyl-2-phenyl-2′-thioxo-2′,3′-dihydro-1′H-spiro[chroman-4,4′-pyrimidin]-6′(5′H)-one as a white foam (209 mg), which is used for the next step without further purification. MS ESI+ve m/z 417 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:6]=1.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[S:37](Cl)(=[O:39])=[O:38]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[S:37]([C:28]2[CH:29]=[CH:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)(=[O:39])=[O:38])[CH:6]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc2ccccc2c1

Procedure:
Prepared according to the procedure described in Example 22, Step 1, using the following starting materials: [3-(2-ethylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and 2-naphthalenesulfonyl chloride.