Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:7]([Br:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br-:13].[CH2:7]([N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: c1ccncc1
Reactant: CCCCCCBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCC[n+]1ccccc1
Product: [Br-]
Temperature: 75 °C
Reaction time: 9 h

Procedure:
Pyridine (10 mL), hexyl bromide (18 mL), and triethylamine (0.1 mL) were dissolved in 122 mL of toluene, and the solution was stirred at 75° C. for 9 h. The solvent was then removed under reduced pressure. N-Hexylpyridinium bromide thus obtained was washed with hexane four times and dried overnight under vacuum.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]([NH2:13])=[N:11][C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:9]2)[CH:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.O>CN1C(=O)CCC1>[C:15]1([NH:14][C:10]2[N:11]=[C:12]([NH2:13])[N:8]([C:4]3[CH:3]=[C:2]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[N:7]=[CH:6][N:5]=3)[N:9]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1nc(Nc2ccccc2)nn1-c1cc(Cl)ncn1
Reactant: C1CNCCN1
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1nc(Nc2ccccc2)nn1-c1cc(N2CCNCC2)ncn1
Temperature: 220 °C

Procedure:
To a solution of 200 mg of 1-(6-chloro-pyrimidin-4-yl)-N3-phenyl-1H-[1,2,4]triazole-3,5-diamine (0.69 mMol, 1 equiv) in 5 mL of NMP was added 200 mg of piperazine (2.32 mMol, 3.3 equiv). The reaction vessel was sealed and warmed to 220° C. via microwave irradiation for 6 min and allowed to cool. The resulting solution was poured into 50 mL of water and the precipitate was filtered and washed with water (3×20 mL). The resulting waxy solid (150 mg) was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24]>C1COCC1>[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([O:25][C:23]([N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH2:14][CH2:13]2)=[O:24])=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2F)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
1-(2,4-Difluoro-phenyl)-piperazine (3.70 g, 18.9 mmol) and triethylamine (2.8 mL, 19.8 mmol) were dissolved in anhydrous THF (30 mL) under nitrogen and the reaction mixture was cooled to 0° C. 4-Nitrophenyl chloroformate (3.8 g, 18.9 mmol), dissolved in anhydrous THF (25 mL), was added dropwise and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue triturated with water, and then filtered. The yellow solid was recrystallised from a mixture of hexane and toluene(3:7) using charcoal to give 4-(2,4-difluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (4.3 g, 63%) as a yellow crystalline solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[CH:25][N:24]=3)=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:43]([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]([CH3:43])[CH2:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:35][CH:36]=4)=[CH:25][N:24]=3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=C(c1ccc(Oc2ccc(NCc3ccc(C(F)(F)F)cc3)cn2)cc1)N1CCN(Cc2ccccc2)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(Cc1ccc(C(F)(F)F)cc1)c1ccc(Oc2ccc(C(=O)N3CCN(Cc4ccccc4)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4-benzylpiperazin-1-yl){4-[5-(4-trifluoromethylbenzylamino)pyridin-2-yloxy]phenyl}methanone (5.40 g, 9.88 mmol) in methanol (150 mL) were added 37% aqueous formaldehyde (2.8 mL), sodium cyanoborohydride (1.86 g, 29.6 mmol) and acetic acid (1.7 mL) under ice cooling, and the resulting solution was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. Water was added to the residue, and this solution was neutralized with a saturated sodium bicarbonate solution, and extracted with chloroform. The organic layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=60:1). To the resulting product was then added a solution of 4 M hydrogen chloride in ethyl acetate until the resulting solution had a pH of 1. The precipitates were collected by filtration and recrystallized from ethanol (80 mL), to thereby yield 2.5 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:37]=[C:5]2[N:6]([CH2:33][C:34](=O)[CH3:35])[C:7](=[O:32])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Cl.[NH2:39][O:40][CH:41]([CH3:43])[CH3:42].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH3:1][C:2]1[N:37]=[C:5]2[N:6]([CH2:33]/[C:34](=[N:39]\[O:40][CH:41]([CH3:43])[CH3:42])/[CH3:35])[C:7](=[O:32])[C:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:18][CH:19]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(C)=O)c2nc(C)nn12
Reactant: CC(C)ON
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C/C(C)=N\OC(C)C)c2nc(C)nn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 13.2 %

Procedure:
A mixture of 2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.4 g), 2-(aminooxy)propane hydrochloride (1.8 g) and pyridine (10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.059 g, 11%).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6]C(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:45]=[C:46]([C:50]2[CH:55]=[CH:54][C:53]([C:56](O)=[O:57])=[CH:52][CH:51]=2)[CH:47]=[CH:48][CH:49]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)CCCN>C1COCC1>[CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6][C:56]([C:53]1[CH:52]=[CH:51][C:50]([C:46]2[CH:47]=[CH:48][CH:49]=[C:44]([CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:45]=2)=[CH:55][CH:54]=1)=[O:57]
Reactant: O=C(O)c1ccc(-c2cccc(CSCCOc3ccccc3)c2)cc1
Reactant: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1ccc(-c2cccc(CSCCOc3ccccc3)c2)cc1

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-bipheny-4-carboxylic acid (3-dimethylamino-propyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4carboxylic acid (0.80 g, 2.19 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.36 g, 2.23 mmol, 1.02 eq.) and 3-(dimethylamino)propylamine (0.27 g, 2.63 mmol, 1.2 eq.). When complete, the reaction was worked up as described leaving a yellow oil.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28]I>C1COCC1.CCOC(C)=O>[Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([O:15][CH3:28])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CO[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of (3R,5R)-benzyl 3-(tert-butyldimethylsilyloxy)-5-hydroxypiperidine-1-carboxylate (1 eq) in 30 mL of THF was added sodium hydride (1.5 eq) and followed by methyl iodide (5 eq) at 0° C. The reaction mixture was allowed to stir at room temperature for 3 hours. The crude mixture was diluted with 120 mL of EtOAc, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:5) to yield (3R,5R)-benzyl 3-(tert-butyldimethylsilyloxy)-5-methoxypiperidine-1-carboxylate (93%). LC/MS (m/z): 380.2 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]1[CH:33]=[CH:32][CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]2[N:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20]([NH:22][O:23]C3CCCCO3)=[O:21])=[N:16][CH:17]=2)[CH2:7]1.[ClH:35]>CO.CCO>[ClH:35].[ClH:35].[ClH:35].[CH3:34][N:2]([CH3:1])[C:3]1[CH:33]=[CH:32][CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]2[N:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20]([NH:22][OH:23])=[O:21])=[N:16][CH:17]=2)[CH2:7]1
Reactant: CN(C)c1ccccc1CN1CC[C@@H](Nc2cnc(/C=C/C(=O)NOC3CCCCO3)cn2)C1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CN(C)c1ccccc1CN1CC[C@@H](Nc2cnc(/C=C/C(=O)NO)cn2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-[5-({(3R)-1-[2-(dimethylamino)benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (236 mg) in MeOH (3.5 mL) was added 2N—HCl solution in EtOH (1.27 mL), which was stirred at room temperature for 1 hour. To the reaction mixture was dropwised IPE (9.4 mL), which was stirred further more 1 hour. The prepicitate was filtered to give (2E)-3-[5-({(3R)-1-[2-(dimethylamino) benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-hydroxyacrylamide trihydrochloride as a yellow powder (241 mg).
Reaction SMILES: [C:1](=O)([O-])[O-:2].[K+].[K+].[Cl:7][C:8]1[C:9]([O:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])=[CH:10][C:11]2[O:16][C:15](=[O:17])[C:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[C:13]([CH2:28]Br)[C:12]=2[CH:30]=1.CO.O>C1COCC1>[Cl:7][C:8]1[C:9]([O:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])=[CH:10][C:11]2[O:16][C:15](=[O:17])[C:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[C:13]([CH2:28][O:2][CH3:1])[C:12]=2[CH:30]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc([N+](=O)[O-])c3)c(CBr)c2cc1Cl
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2cc(OC(=O)N(C)C)c(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.9 %

Procedure:
Potassium carbonate (279 mg, 2.01 mmol) was added to a solution of dimethylcarbamic acid 6-chloro-4-bromomethyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester (compound 6b-1-3) (500 mg, 1.01 mmol) in THF (7.5 mL)/methanol (5.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled away by concentration under reduced pressure, and the resultant residue was purified by column chromatography to yield the title compound (40 mg, 10%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:17]([CH2:29][CH3:30])=[N:18][C:19]3[C:24]([C:25]=2[C:26]([OH:28])=[O:27])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:10]=1)#[N:2].[CH2:31](I)[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.CC(C)=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[C:17]([CH2:29][CH3:30])=[N:18][C:19]3[C:24]([C:25]=2[C:26]([O:28][CH2:31][CH3:32])=[O:27])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:14]=1)#[N:2]
Reactant: CCI
Reactant: CCc1nc2ccccc2c(C(=O)O)c1Oc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Oc2ccc(-c3ccccc3C#N)cc2)c(CC)nc2ccccc12
Temperature: 25 °C
Reaction time: 9 h
Yield: 93 %

Procedure:
A mixture containing the title C compound of Example 2, 3-[(2'-cyano[1,1'-biphenyl]-4-yl)oxy]-2-ethyl-4-quinolinecarboxylic acid (707 mg, 1.79 mmol), ethyl iodide (559 mg, 3.58 mmol), and cesium carbonate (1.46 g, 4.48 mmol) in dimethylformamide (4 mL) was stirred at room temperature for nine hours, then diluted with a mixture of acetone and ethyl acetate and filtered. The filtrate was concentrated in vacuo and the product extracted into ethyl acetate. The organic extract was rinsed with water and brine, dried (magnesium sulfate), and concentrated in vacuo to afford a crude product (720 mg). Flash chromatography on Merck silica gel (30 g) eluted with 1:1 hexanes:ethyl acetate afforded the title compound (703 mg, 93% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)[C:13](Cl)=[O:14]>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:9]=[C:13]=[O:14])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C(N)=O)cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)N=C=O)cc1

Procedure:
To 4-methoxybenzamide (2.6 mmol) in dichloromethane (10 mL) was added oxalyl chloride 98% (6.61 mmol) dropwise. The mixture was heated to reflux for 20 h. Reaction completion monitored by TLC. The solvent was removed in vacuo (40° C., 760 mmHg) to obtain title compound D11, which was immediately used without purification.
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.CN(CCN(C)C)C.[CH2:20]([NH:22][C:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([F:35])=[CH:27][CH:26]=1)=[O:24])[CH3:21].[CH3:36][Si:37](Cl)([CH3:39])[CH3:38]>C1COCC1>[CH2:20]([NH:22][C:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([F:35])=[CH:27][C:26]=1[Si:37]([CH3:39])([CH3:38])[CH3:36])=[O:24])[CH3:21]
Reactant: CCNC(=O)c1ccc(F)c2ccccc12
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCNC(=O)c1c([Si](C)(C)C)cc(F)c2ccccc12
Temperature: -90 °C
Reaction time: 0.08 h
Yield: 20.4 %

Procedure:
A 1.3 M solution of s-BuLi in cyclohexane (40.7 mL, 52.9 mmol) was added to a liquid nitrogen-cooled solution of TMEDA (8.68 mL, 57.5 mmol) in THF (50 mL), maintaining the reaction temperature at -90° C. throughout the addition. The resulting solution was stirred 5 min, a solution of N-ethyl-4-fluoro-1-naphthalene-carboxamide (5.00 g, 23.0 mmol) in THF (15 mL) was added, and the resulting purple solution was stirred for 10 min at -90° C. TMSCl (8.76 mL, 69.0 mmol) was added, and after 10 min the cold bath was removed. The mixture slowly warmed to RT. The mixture was quenched with 100 mL 25% citric acid and extracted with ether (3×200 mL). The combined extracts were dried (MgSO4) and concentrated to a yellow powder which was purified by chromatography with ethyl acetate/hexanes to give 1.36 g of the desired amide, a 20% yield. m.p. 134-136° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([OH:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:14][C:15]#[CH:16].C1COCC1>O>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:16][C:15]#[CH:14])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)O)c1
Reactant: C#CCBr
Solvent: O
Solvent: C1CCOC1
Product: C#CCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Yield: 53.3 %

Procedure:
93.5 g (0.5 mol) of 3-nitrobenzenesulfinic acid were dissolved in 500 ml of water at pH 6.5 and the solution was added to a solution of 65.5 g of 3-bromo-prop-1-yne and 70 ml of THF. The reaction mixture was heated at 40°-50° C. until the reaction had ended (check by TLC). The reaction product was extracted with about 1.5 l of ethyl acetate, and the organic phase was neutralized and dried over sodium sulfate. The solvent was evaporated off to leave 60 g of 3-nitro-1-(prop-1-yn-3-ylsulfonyl)benzene (melting point 250°-255° C.). ##STR29##
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8][C:7]=1[C:17]([F:20])([F:19])[F:18])=[O:5])C.[OH-].[Na+]>CO.O>[N:16]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:17]([F:19])([F:20])[F:18])[N:8]=1
Reactant: CCOC(=O)c1sc(-c2ncccn2)nc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1sc(-c2ncccn2)nc1C(F)(F)F
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-pyrimidin-2-yl-4-trifluoromethyl-thiazole-5-carboxylic acid ethyl ester (1.6 g) and sodium hydroxide (1.2 g) in MeOH (10 mL) and water (3 mL) is heated at 50° C. with stirring for 30 min, cooled and evaporated. The residue is acidified with citric acid solution and extracted with EtOAc six times. The combined extracts are washed once with brine, dried over Na2SO4 and concentrated to give the title compound as a solid.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:14]([NH2:18])(=[O:17])[CH:15]=[CH2:16].C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[CH2:6]([O:5][C:3]([CH:2]1[CH2:16][CH2:15][C:14](=[O:17])[NH:18][C:1]1=[O:9])=[O:4])[CH3:7]
Reactant: C=CC(N)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCC(=O)NC1=O
Reaction time: 0.17 h

Procedure:
To a solution of diethyl malonate (2.3 ml) in tetrahydrofuran (2.3 ml) cooled at 0° C. is added sodium hydride (400 mg). After stirring for 10 minutes, the mixture is mixed with acrylamide (710 mg) and let react at 0° C. for 70 minutes and at room temperature for 3.5 hours. The mixture is mixed with acetic acid (0.7 ml), stirred for 20 minutes, diluted with ethyl acetate, filtered to remove solid, concentrated, and triturated in n-hexane to afford 2,6-dioxo-piperidine-3-carboxylic acid ethyl ester (1.18 g). m.p. 69°-74° C.
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[C:10]2[C:4]([C:5](=[O:14])[CH2:6][CH2:7][NH:8][S:9]2(=[O:13])=[O:12])=[CH:3]1.Cl[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:31][C:28]1[CH:27]=[CH:26][C:25]([N:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][N:8]3[CH2:7][CH2:6][C:5](=[O:14])[C:4]4=[CH:3][N:2]([CH3:1])[CH:11]=[C:10]4[S:9]3(=[O:13])=[O:12])[CH2:24][CH2:23]2)=[CH:30][CH:29]=1
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Reactant: Cn1cc2c(c1)S(=O)(=O)NCCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cn1cc2c(c1)S(=O)(=O)N(CCCN1CCN(c3ccc(F)cc3)CC1)CCC2=O
Yield: 57.7 %

Procedure:
A suspension of 236 mg (1.1 mmol) of Compound 15, 308 mg (1.2 mmol) of 1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine and 304 mg (2.2 mmol) of potassium carbonate in 15 ml of 2-butanone was refluxed for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: ethyl acetate), whereby 276 mg of the title compound were obtained (yield: 58%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[CH3:12][C:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:28])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:27])[CH2:25][CH3:26])=[CH:14]CO>ClCCl>[Cl:1][CH2:26][CH:25]=[C:24]([CH3:27])[CH2:23][CH2:22][CH:21]=[C:20]([CH3:28])[CH2:19][CH2:18][CH:17]=[C:13]([CH3:14])[CH3:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(C)=CCCC(C)=CCCC(C)=CCO
Solvent: CSC
Solvent: ClCCl
Product: CC(C)=CCCC(C)=CCCC(C)=CCCl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
(Note: all temperatures indicated are for the contents of the reaction flask). To a stirred solution of 299 mg (2.24 mmol) of N-chlorosuccinimide in 15 mL of dichloromethane at -30° C. under argon was added 0.18 mL (2.45 mmol) of distilled dimethyl sulfide over 5 minutes. After 10 minutes at -30° C., the reaction was allowed to warm to 0° C. for 10 minutes, followed by cooling to -40° C. A solution of 441.4 mg (1.99 mmol) of 3,7,11-trimethyl-2,6,10-tridecatrien-1-ol in 5 mL of dichloromethane was added dropwise over 10 minutes. The reaction was allowed to warm gradually to 0° C. over 1 hour, and then maintained at 0° C. for 1 hour. After quenching with cold water, the mixture was extracted with hexane and the hexane extract was washed with cold water and cold brine, dried (MgSO4) and evaporated to afford 483 mg of a crude product. Rapid flash chromatography on 20 g of Merck 9385 silica gel eluted with 3:97 ethyl acetate:petroleum ether provided 406.5 mg (85%) of a colorless liquid. 13C NMR indicated that this material contained a trace (3%) impurity.
Reaction SMILES: [C:1]1([C:7](=[O:17])[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH:20][C:21](=[O:24])[CH:22]=[CH2:23])O>>[C:11]1([C:9](=[O:10])[CH:8]([CH2:18][NH:20][C:21](=[O:24])[CH:22]=[CH2:23])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CC(=O)NCO
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Product: C=CC(=O)NCC(C(=O)c1ccccc1)C(=O)c1ccccc1

Procedure:
1,3-Diphenyl-2-(acrylamidomethyl)-propane-1,3-dione was prepared from 143 g of 1,3-diphenylpropane-1,3-dione and 64.8 g of N-methylolacrylamide similarly to the method described in Synthesis Example I.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:44][O:45][C:46]1[N:51]=[CH:50][C:49]([N:52]2[CH2:67][CH2:66][C:55]3[N:56]=[CH:57][N:58]=[C:59]([O:60][C@H:61]4[CH2:65][CH2:64][NH:63][CH2:62]4)[C:54]=3[CH2:53]2)=[CH:48][C:47]=1[C:68]([F:71])([F:70])[F:69]>CN(C=O)C>[CH3:44][O:45][C:46]1[N:51]=[CH:50][C:49]([N:52]2[CH2:67][CH2:66][C:55]3[N:56]=[CH:57][N:58]=[C:59]([O:60][C@H:61]4[CH2:65][CH2:64][N:63]([C:6]([C:4]5[N:3]=[CH:2][O:1][CH:5]=5)=[O:8])[CH2:62]4)[C:54]=3[CH2:53]2)=[CH:48][C:47]=1[C:68]([F:71])([F:69])[F:70]
Reactant: O=C(O)c1cocn1
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)c5cocn5)C4)c3C2)cc1C(F)(F)F
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
To the oxazole-4-carboxylic acid (27 mg, 0.24 mmol)) and HBTU (89 mg, 0.24 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.08 mL, 0.45 mmol). The mixture was stirred for 20 min and then 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine dihydrochloride (100 mg, 0.214 mmol) and additional N,N-diisopropylethylamine (0.08 mL, 0.45 mmol) were added. The mixture was allowed to stir at room temperature for 30 min. Purified by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions over PL-HCO3 MP to give {(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanone as a yellow solid (38 mg, 36% yield) 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.11-2.39 (m, 2 H) 2.80-3.01 (m, 2 H) 3.22-4.29 (m, 11 H) 5.59-5.80 (m, 1 H) 7.72-7.94 (m, 1 H) 8.10-8.29 (m, 1 H) 8.41-8.55 (m, 1 H) 8.57-8.77 (m, 2 H) LCMS: [M+H]+=491.1, Rt(1)=1.69 min.