Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38]C)=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])(C)(C)C.[Cl:52][C:53]1[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[C:54]=1[CH2:55]Br.C(=O)([O-])[O-].[K+].[K+].[N:68]([C@@H:71]([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[CH3:72])=C=O>CN(C=O)C.O>[Cl:52][C:53]1[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[C:54]=1[CH2:55][O:51][C:48]1[CH:47]=[CH:46][C:45]([C@H:43]2[CH2:42][O:41][C:13]3=[CH:14][C:15]4[CH2:16][C@@H:17]([C:18]([NH:19][C@@H:20]([CH2:21][C:22]5[CH:23]=[CH:24][C:25]([C:28]6[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=6[CH3:35])=[CH:26][CH:27]=5)[C:36]([OH:38])=[O:37])=[O:40])[N:8]([C:6](=[O:7])[NH:68][C@@H:71]([C:73]5[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=5)[CH3:72])[CH2:9][C:10]=4[CH:11]=[C:12]3[O:44]2)=[CH:50][CH:49]=1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: C[C@@H](N=C=O)c1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(O)cc1)CO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)N[C@H](C)c3ccccc3)O[C@@H](c3ccc(OCc4c(Cl)cccc4Cl)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C

Procedure:
(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethyl-carbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester was dissolved in DMF and 2,6-dichlorobenzyl bromide (2 eq.) and potassium carbonate (3 eq.) was added. The reaction mixture was stirred at room temperature and was poured onto EtOAc and water. The organic layer was dried over sodium sulfate and concentrated. The mixture was purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH). The resulting compound was dissolved in 2 mL DCM and 1 mL 4N HCl (dioxane) was added. The mixture stirred at room temperature for 1.5 hours and was concentrated. The residue was suspended in DCM, TEA (3 eq.) added and the mixture used in the following reaction sequence. ((R)-1-isocyanato-ethyl)-benzene (5 eq.) was added and the reaction was stirred at room temperature for 1 hour. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (5 mg). LCMS (m/z): 886.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH2:13][CH2:14][CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][CH2:21][P:22](=[O:27])([O:25][CH3:26])[O:23][CH3:24].C(N(CC)CC)C.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([CH:21]([P:22](=[O:27])([O:25][CH3:26])[O:23][CH3:24])[NH2:20])=[O:18])[CH2:13][CH2:14][CH3:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COP(=O)(CN)OC
Reactant: CCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC[C@H](NC(=O)OCc1ccccc1)C(=O)C(N)P(=O)(OC)OC
Temperature: -12 °C
Reaction time: 0.25 h
Yield: 75.5 %

Procedure:
(i)(b) 45.4 g (180 mmol) of N-benzyloxycarbonyl-L-norvaline were stirred in 200 ml of methylene chloride while 31.76 g (180 mmol) of dimethyl aminomethylphosphonate hydrochloride were added. The resulting suspension was cooled to -12° C. and 25.3 ml (180 mmol) of dry triethylamine were added dropwise. After completion of the addition, the cold mixture was stirred for 0.25 hour. 56.8 g (230 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline in 100 ml of methylene chloride were then added rapidly. The mixture was stirred in the cold for 2 hours and then at room temperature overnight. The mixture was washed with 100 ml of water and then with four 100 ml portions of 1-N hydrochloric acid. The combined acid washings were back-extracted with two 50 ml portions of methylene chloride. The combined organic solutions were washed with 100 ml of water and finally with three 100 ml portions of 15% potassium bicarbonate solution, then dried over anhydrous sodium sulphate, filtered and evaporated. The residual oil was re-evaporated with benzene to give an oil which was triturated with 200 ml of anhydrous ether. There were obtained 58.2 g of crude product of melting point 77°-80° C. Recrystallization from 200 ml of ethyl acetate gave 50.6 g of dimethyl N-benzyloxycarbonyl-L-norvalyl-aminomethylphosphonate of melting point 82°-84° C.
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(N(CC)CC)C.[CH3:43][N:44]([CH3:50])[S:45]([CH:48]=[CH2:49])(=[O:47])=[O:46]>>[CH3:43][N:44]([CH3:50])[S:45]([CH2:48][CH2:49][N:33]1[CH2:34][CH2:35][CH:30]([C:28]2[CH:27]=[CH:26][C:23]3[C:24]4[N:25]=[C:16]([C:15]5[N:11]([CH:8]([CH3:10])[CH3:9])[N:12]=[CH:13][N:14]=5)[S:17][C:18]=4[CH2:19][CH2:20][O:21][C:22]=3[CH:29]=2)[CH2:31][CH2:32]1)(=[O:47])=[O:46]
Reactant: C=CS(=O)(=O)N(C)C
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(CCS(=O)(=O)N(C)C)CC3)ccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 375 (188 mg, 0.37 mmol) and triethylamine (0.18 mL, 1.3 mmol) in IMS (3 mL) was added ethenesulfonic acid dimethylamide and the reaction mixture stirred at RT for 18 h before being concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 5% MeOH in DCM) to give 499 as a beige solid (145 mg, 74%). LCMS: RT=3.47 min, [M+H]+=531. 1H NMR δ (ppm) (DMSO-d6): 8.23 (1H, d, J=8.19 Hz), 8.05 (1H, s), 7.04 (1H, dd, J=8.26, 1.80 Hz), 6.88 (1H, d, J=1.76 Hz), 5.82-5.72 (1H, m), 4.30 (2H, t, J=5.02 Hz), 3.37 (2H, t, J=5.04 Hz), 3.19 (2H, t, J=7.23 Hz), 2.95 (2H, d, J=10.97 Hz), 2.75 (6H, s), 2.65 (2H, t, J=7.25 Hz), 2.04 (2H, t, J=11.43 Hz), 1.75 (2H, d, J=12.62 Hz), 1.67-1.53 (2H, m), 1.50 (6H, d, J=6.58 Hz). 1H obscured by solvent
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:49][C:50]1[CH:51]=[CH:52][C:53]([C:56](O)=[O:57])=[N:54][CH:55]=1>CN(C=O)C.C(OCC)(=O)C>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:56]([C:53]3[CH:52]=[CH:51][C:50]([Cl:49])=[CH:55][N:54]=3)=[O:57])=[CH:7][CH:6]=2)[CH2:9]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3ccc(Cl)cn3)cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.2 %

Procedure:
To a stirred suspension of (RS)-tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate (200 mg, CAS 908334-28-1) in DMF (10 ml) were added sequentially N-methylmorpholine (0.22 ml), TBTU (490 mg) and 5-chloro-2-pyridine carboxylic acid (180 mg) and the mixture was stirred at room temperature for 90 min. The mixture was then diluted with ethyl acetate and washed sequentially with 1 M aq. hydrochloric acid and with saturated brine. The phases were separated and the organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (RS)-3-{4-[(5-chloro-pyridine-2-carbonyl)-amino]-phenyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (310 mg, quant.) as a white solid. MS (ISP): 421.3 ([M+NH4]+), 419.2 ([M+NH4]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=O)[O:6][CH:5]2O.[NH2:13][NH2:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:6])[NH:14][N:13]=[CH:5]2
Reactant: NN
Reactant: O=C1OC(O)c2cc(Br)ccc21
Product: O=c1[nH]ncc2cc(Br)ccc12

Procedure:
5-Bromo-3-hydroxyphthalide is reacted in alcoholic solution with hydrazine to give 6-bromophthalazin-1(2H)-one which in turn is reacted with the appropriate (dialkylamino)alkylhalide in a polar solvent such as DMSO in the presence of a base such as KOH to give the 2-(dialkylaminoalkyl)-6-bromophthalazin-1(2H)-one. The styryl group is then attached by reacting the 6-bromo-2-substituted-phthalazin-1(2H)-one with styrene or 4-methoxystyrene in solvents such as DMSO or acetonitrile or mixtures thereof, in the presence of the reagents tri(o-tolyl)phosphine and palladium acetate to give the 6-[2-(phenyl or 4-methoxyphenyl)ethenyl]-2-[(dialkylamino)-alkyl]phthalazin-1(2H)-one. Specific methods for preparing the compounds of this invention are disclosed in the examples.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[O:17][C:18]2[C:24]([C:25](OC)=O)=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:29].[NH3:30]>CO>[C:25]([C:24]1[C:18]2[O:17][C:16]([CH:12]3[CH2:13][CH2:14][CH2:15][N:11]3[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[N:20][C:19]=2[CH:21]=[CH:22][CH:23]=1)(=[O:29])[NH2:30]
Reactant: COC(=O)c1cccc2nc(C3CCCN3C(=O)OCc3ccccc3)oc12
Reactant: N
Reactant: O
Solvent: CO
Product: NC(=O)c1cccc2nc(C3CCCN3C(=O)OCc3ccccc3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a stirred solution of methyl 2-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)benzo[d]oxazole-7-carboxylate (150 mg, 0.394 mmol) in methanol (8 mL) was added ammonia water (6 mL) at 0° C. After the addition, the mixture was allowed to stir at room temperature overnight. Methanol was removed in vacuum. The residue was diluted with water (100 mL), extracted with ethyl acetate (50 mL×3). The combined organic layers washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=20:1 to 1:1) to give benzyl 2-(7-carbamoylbenzo[d]oxazol-2-yl)pyrrolidine-1-carboxylate (68 mg, yield 42%). LC-MS (ESI) m/z: 366 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C@H:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][C@H:16]3[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:33]([C@@:41]([C:56]([OH:58])=[O:57])([OH:55])[C@@:42]([C:47](=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([OH:46])[C:43]([OH:45])=[O:44])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(OCC)(=O)C.C(OC(C)C)(C)C>[C:47]([C@:42]([C:43]([OH:45])=[O:44])([OH:46])[C@:41]([C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([OH:55])[C:56]([OH:58])=[O:57])(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C@H:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][C@H:16]3[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Agent: CCOC(=O)C[C@@H]1CN(CC(=O)OCC)CC[C@@H]1N1CCN(c2ccc(C#N)cc2)CC1
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1

Procedure:
6.3 g of (+/-)-cis-diethyl 4-[4-(4-cyanophenyl)-1-piperazinyl]-1,3-piperidinediacetate and 5.4 g of (-)-dibenzoyl-L-tartaric acid were dissolved in 180 ml of a mixed solvent of ethyl acetate/diisopropyl ether (1/1) and subjected to resolving crystallization. The crystals obtained were recrystallized several times from a mixed solvent of ethyl acetate/diisopropyl ether (1/1), whereby was obtained 640 mg of (-)-cis-diethyl 4-[4-(4-cyanophenyl)-1-piperazinyl]-1,3-piperidinediacetate (-)-dibenzoyl-D-tartrate (98.4% e.e.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[O:18])=[N:15][N:16]=2)[N:13]=1.[H-].[Na+].I[CH3:41]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17]([N:19]([CH3:41])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=3)=[O:18])=[N:15][N:16]=2)[N:13]=1
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)c1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C(F)(F)F)cc1)C(=O)c1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66 %

Procedure:
To a solution of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-N-(4-(trifluoromethyl) benzyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide Example 34) (22 mg, 0.041 mmol) in anhydrous DMF at room temperature was added sodium hydride (6.5 mg, 0.164 mmol). The resulting suspension was stirred at room temperature for 5 min, then iodomethane (25 μL, 0.4 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc (30 mL), washed with water, saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (4 g) eluting with a gradient of EtOAc (0-60%) in hexanes to afford 15 mg (66%) of the title compound as a white powder. HPLC/MS (method A): retention time=3.85 min, (M+H)+=556.3
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:32]#[C:31][CH2:30][CH2:29][OH:33])[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: C#CCCO
Product: OCCC#Cc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Yield: 81 %

Procedure:
Following the procedures for 246, 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene and but-3-yn-1-ol were reacted under palladium catalysis to give 4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-but-3-yn-1-ol (Yield: 81%. 1H NMR (DMSO-d6, 400 MHz): δ8.31 (s, 1H), 7.94-7.88 (m, 1H), 7.74-7.68 (m, 1H), 7.43-7.38 (m, 2H), 7.31 (d, J=8.4 Hz, 1H), 6.92 (s, 1H), 4.95 (s, 1H), 4.31 (t, J=4.0 Hz, 2H), 3.62 (m, 2H), 3.12 (t, J=4.4 Hz, 2H), 2.61 (t, J=6.8 Hz, 2H). LC-MS (ESI): m/z=451 [M+H]+), which was hydrogenated to give 245 Yield: 43%. 1H NMR (DMSO-d6, 400 MHz): δ8.27 (s, 1H), 7.90-7.84 (m, 1H), 7.70-7.65 (m, 1H), 7.41-7.39 (m, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.99 (s, 1H), 4.37 (s, 1H), 4.23 (t, J=4.8 Hz, 2H), 3.40 (t, J=6.4 Hz, 2H), 3.09 (t, J=4.8 Hz, 2H), 2.64-2.60 (m, 2H), 1.65-1.59 (m, 1H), 1.44-1.38 (m, 1H). LC-MS (ESI): m/z=455 [M+H]+
Reaction SMILES: [OH:1][CH2:2][CH:3]=[CH:4][CH2:5][N:6]1[C:11]([C:12](=[O:21])[C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[C:10]([CH:22]([CH3:24])[CH3:23])[C:9](=[O:25])[NH:8][C:7]1=[O:26].C(N1[C:36]([C:37](=[O:46])C2C=C(C)C=C(C)C=2)=C(C(C)C)C(=O)NC1=O)C#CC.C1(C#CCN2C(C(=O)C3C=C(C)C=C(C)C=3)=C(C(C)C)C(=O)NC2=O)C=CC=CC=1>>[C:37]([O:1][CH2:2][CH:3]=[CH:4][CH2:5][N:6]1[C:11]([C:12](=[O:21])[C:13]2[CH:14]=[C:15]([CH3:20])[CH:16]=[C:17]([CH3:19])[CH:18]=2)=[C:10]([CH:22]([CH3:23])[CH3:24])[C:9](=[O:25])[NH:8][C:7]1=[O:26])(=[O:46])[CH3:36]
Reactant: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC=CCO)c1
Reactant: CC#CCn1c(C(=O)c2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC#Cc2ccccc2)c1
Product: CC(=O)OCC=CCn1c(C(=O)c2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O

Procedure:
1-(4-hydroxy-2-butenyl)-5-isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione; 1-(2-butynyl)-5-isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione; 1-(3-phenyl-2-propynyl)-5-isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione;
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][NH2:7].[OH-:8].[Na+].O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>CCOCC>[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][NH:7][C:15](=[O:8])[C:14]1[CH:18]=[CH:19][CH:20]=[C:12]([Cl:11])[CH:13]=1)=[O:16]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: [OH-]
Reactant: NCCSCCN
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(NCCSCCNC(=O)c1cccc(Cl)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of bis-(β-aminoethyl)sulfide (2.5 g., 0.021 M) and sodium hydroxide (1.6 g., 0.04 M) in 20 ml. of water and 40 ml. of ether was added a solution of m-chlorobenzoyl chloride (7.0 g., 0.04 M) in 15 ml. of ether at 10°-20° C. A precipitate appeared. The mixture was stirred 45 minutes at room temperature and the solid filtered, washed with water and dried. The product was a white solid. m.p. 150°-152° C. Its structure was confirmed by IR spectroscopy. Yield: 7.0 g. (88%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([C:9]2[N:13](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:12]=[N:11][CH:10]=2)O)=[CH:3][CH:2]=1.[CH3:33][CH:34](O)[CH3:35].[OH-].[Na+]>I.C(Cl)(Cl)Cl>[NH:13]1[C:9]([CH:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH2:33][C:34]2[CH:35]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:10][N:11]=[CH:12]1
Reactant: OC(c1ccncc1)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)O
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: c1ccc(CC(c2ccncc2)c2cnc[nH]2)cc1
Temperature: 160 °C

Procedure:
A mixture of pyridin-4-yl(1-trityl-1H-imidazol-5-yl)methanol, (Intermediate 4) (526 g, 1.03 mmol) in 57% aqueous HI (10 mL) and iPrOH (2 mL) was added red phosphorus (318 mg, 10.3 mmol) in a resealable tube was heated at 160° C. for 16 h. The mixture was then cooled to room temperature and poured into ice-water, which was then basified with NaOH and diluted with CHCl3. The residue was isolated in a typical aqueous workup using CHCl3 and purified by MPLC with 5 to 15% MeOH: CH2Cl2 to give 4-(1-(1H-imidazol-5-yl)-2-phenylethyl)pyridine (AGN214418) as a solid, 36 mg. 1HNMR (CD3OD, 300 MHz) δ 6.98 (s, 1H), 7.20-7.11, (m, 9H), 7.61 (s, 1H), 4.38 (t, J=9 Hz, 1H), 3.43 (dd, J=6 Hz, 12 Hz, 1H), 3.19 (dd, J=9 Hz, 15 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][C:14]2[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[CH:16][N:15]=2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([NH:53][NH2:54])(=[O:52])[CH3:51].CCN(C(C)C)C(C)C>ClCCl>[C:50]([NH:53][NH:54][C:7](=[O:8])[C:6]1[CH:10]=[C:2]([Cl:1])[C:3]([NH:13][C:14]2[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:24])([F:23])[F:25])=[CH:16][N:15]=2)=[CH:4][C:5]=1[O:11][CH3:12])(=[O:52])[CH3:51]
Reactant: CNc1nc(Nc2cc(OC)c(C(=O)O)cc2Cl)ncc1C(F)(F)F
Reactant: CC(=O)NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(Nc2cc(OC)c(C(=O)NNC(C)=O)cc2Cl)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
A suspension of 5-chloro-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzoic acid (144 mg, 50% pure material, 0.19 mmol), HATU (85 mg, 0.22 mmol), acetic hydrazide (16 mg, 0.22 mmol) and DIPEA (81 uL, 0.46 mmol) in dichloromethane (4 mL) was stirred at room temperature for 18 h. The mixture was diluted with dichloromethane (10 mL) and washed with saturated aqueous NaHCO3 solution (10 mL). A solid persisted in the aqueous layer; this was filtered, washed with water and then suspended in methanol. The solid was collected by filtration and dried in a vacuum oven to afford N′-acetoyl-5-chloro-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzohydrazide as a white solid (68 mg, 85%). This was taken through to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8]>O=[Mn]=O.C(Cl)Cl.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CCCCCC
Product: O=Cc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (5,6-dichloro-pyridin-3-yl)-methanol (1.78 g, 10 mmol, TCI-US) and MnO2 (17.39 g, 200 mmol, Aldrich) in 1:1 CH2Cl2/hexane (10 mL) was stirred at room temperature for 1 h. The catalyst was filtered and washed with 50% EtOAc/hexane. The filtrate was evaporated and the residue dried in vacuo to give the title compound product, which was used in the next step without additional purification. MS (ESI, pos. ion) m/z: 176 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2(Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:8][C:7]=1[CH2:18]Br)=[O:5])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)=[N:8][C:7]=1[CH2:18][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc(C2(Br)CCCCC2)nc1CBr
Reactant: C1COCCN1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)c1oc(C2=CCCCC2)nc1CN1CCOCC1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
1.25 g 2-(1-Bromo-cyclohexyl)-4-bromomethyl-oxazole-5-carboxylic acid ethyl ester was dissolved in 15 ml tetrahydrofuran. 1.38 ml morpholine and 0.5 ml DBU were added and the reaction mixture stirred at 65° C. for three hours. The solvent was removed in vacuo and the resulting crude material was purified by reversed phase HPLC. The lyophilisate was dissolved in ethyl acetate and washed with saturated NaHCO3 and 2N NaOH solution the organic layer was dried over MgSO4. The solvent was removed in vacuo to obtain 580 mg 2-Cyclohex-1-enyl-4-morpholin-4-ylmethyl-oxazole-5-carboxylic acid ethyl ester as an oil.
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](O)=[O:20])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1[N:39]=NN(CC(O)=O)N=1)CCCCCCCCC.[F:47][C:48]1[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:49]=1N.C(C1C=CC=C(C(C)C)C=1N)(C)C>>[F:47][C:48]1[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:49]=1[C:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([N:16]1[N:15]=[N:14][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N:17]1)[C:19]([NH2:39])=[O:20]
Reactant: Nc1ccc(F)cc1F
Reactant: CCCCCCCCCCCCc1nnn(C(C(=O)O)c2ccccc2)n1
Reactant: CCCCCCCCCCc1nnn(CC(=O)O)n1
Agent: CC(C)c1cccc(C(C)C)c1N
Product: CCCCCCCCCCCCc1nnn(C(C(N)=O)(c2ccccc2)c2ccc(F)cc2F)n1

Procedure:
When in the general procedure of Example 88 an appropriate amount of (±)-5-dodecyl-α-phenyl-2H-tetrazole-2-acetic acid was substituted for 5-decyl-2H-tetrazole-2-acetic acid and 2,4-difluoroaniline was substituted for 2,6-diisopropylaniline, the title compound was obtained, mp 62°-64° C.