Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][OH:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1.CN(C)C=O.Cl>O.C(N(CC)CC)C>[C:1]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][OH:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=NO)c1csc(N)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.25 h

Procedure:
47.6 g of trityl chloride were added in small portions over 30 minutes to a mixture (cooled at -30° C.) of 32.2 g of the anti isomer of ethyl 2-(2-amino-4-thiazolyl)- 2-hydroxyiminoacetate of Step A of Example 1, 90 ml of dry dimethylforamide and 24 ml of triethylamine and the mixture was left to spontaneous heating for 21/2 hours. Then, 150 ml of 2N hydrochloric acid and 600 ml of water were added thereto and the mixture was stirred for 15 minutes, then vacuum filtered. The recovered precipitate was empasted 3 times with ether and was then taken up in a mixture of methanol, water and triethylamine. The mixture was stirred and then vacuum filtered. The recovered product was rinsed with aqueous methanol and dried to obtain 60.2 g of the anti isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-hydroxyiminoacetate. 3.4 g of the said product were recrystallized from a methylene chloride-methanol mixture to obtain 3 g of pure product melting at 260° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]2[C:9](=[O:23])[N:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[N:11]=[C:4]2[CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]3[C:9](=[O:23])[N:10]([CH2:12][C:13]4[CH:14]=[N:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=4)[N:11]=[C:4]3[CH:3]=2)=[CH:27][CH:26]=1
Reactant: Cc1nc(Cl)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccc(Cl)cc2)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Temperature: 100 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a stirred solution of 7-chloro-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (2.0 g, 5.8 mmol), 4-chlorophenylboronic acid (1.2 g, 7.58 mmol), and tetrakis(triphenylphosphine)palladium (0.67 g, 0.58 mmol) in toluene (25 mL) at room temperature under argon was added aqueous Na2CO3 solution (2 M, 5.8 mL, 11.6 mmol). The resulting reaction mixture was stirred at 100° C. under argon overnight, after which time analysis by HPLC/MS indicated that the reaction was complete. After cooling the reaction mixture to room temperature, water (50 mL) was added. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was washed with saturated aqueous NaCl, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by triturating with MeOH (15 mL) to obtain 1.95 g of the title compound as an off-white solid. HPLC/MS: retention time=3.85 min, [M+H]30 =420.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[C:13](OC)(=[O:16])[CH:14]=[CH2:15].C[O-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:11][C:10]2=[O:12])=[CH:5][CH:4]=1
Reactant: C=CC(=O)OC
Reactant: COc1ccc(CC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COc1ccc(C2CCC(=O)CC2=O)cc1

Procedure:
A mixture of 4-methoxyphenylacetone (50 g) and methyl acrylate (26.2 g) was added dropwise to a stirred suspension of sodium methoxide (from 7.5 g sodium in 50 ml methanol) in dry xylene (160 ml) at ambient temperature. The resulting solution was then refluxed for 3 hours. The xylene was evaporated in vacuo and the residue partitioned between water and diethyl ether. The aqueous phase was further extracted with diethyl ether. The aqueous layer was finally acidified with concentrated hydrochloric acid to precipitate 4-(4-methoxyphenyl)cyclohexane-1,3-dione (37 g) as a white solid (after an ether washing) of m.p. 150°-151° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.ClC(Cl)(Cl)C(=N)O[CH2:76][CH:77]=[CH:78][C:79]1[CH:84]=[CH:83][C:82]([O:85][Si:86]([C:89]([CH3:92])([CH3:91])[CH3:90])([CH3:88])[CH3:87])=[CH:81][CH:80]=1>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:76][CH:77]=[CH:78][C:79]3[CH:84]=[CH:83][C:82]([O:85][Si:86]([C:89]([CH3:90])([CH3:92])[CH3:91])([CH3:88])[CH3:87])=[CH:81][CH:80]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=CCOC(=N)C(Cl)(Cl)Cl)cc1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccc(O[Si](C)(C)C(C)(C)C)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (700 mg in 12 ml methylene chloride)4-t-butyldimethylsiloxycinnamyl trichloroacetimidate (550 μl neat) was added and the reagents allowed to mix for 5 minutes. Camphorsulfonic acid (35 mg) was added and the mixture stirred at room temperature. After 5 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×15 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification oof the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (190 mg).
Reaction SMILES: C1(C)C=CC=CC=1.C([O:20][C:21]([C:23]1[CH:24]=[C:25]2C(=O)N(O)C(=O)[C:26]2=[CH:33][CH:34]=1)=[O:22])CCCCCCCCCCC.O=O>>[C:21]([OH:22])(=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:33][CH:34]=1
Reactant: CCCCCCCCCCCCOC(=O)c1ccc2c(c1)C(=O)N(O)C2=O
Agent: O=O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1
Yield: 1440 %

Procedure:
A mixture of 47 mmol of toluene, 0.1 mmol of 4-dodecyloxycarbonyl-N-hydroxyphthalimide and 0.01 mmol of acetylacetonatocobalt(II) was stirred at 100° C. in an atmosphere of oxygen gas (1 atm=0.1 MPa) for 6 hours and thereby yielded 1.44 mmol of benzoic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:32][C:17]3=[CH:18][N:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:31][S:28]([C:25]1[CH:26]=[CH:27][C:22]([C:20]2[CH:21]=[C:16]3[CH2:15][CH:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[O:32][C:17]3=[CH:18][N:19]=2)=[CH:23][CH:24]=1)(=[O:29])=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCNCC2)C3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (190 mg) and trifluoro acetic acid (0.40 mL) in dichloromethane (3 mL) is stirred at room temperature for 2 h. The reaction mixture is diluted with dichloromethane and washed with aqueous Na2CO3 solution. The aqueous phase is extracted dichloromethane and the combined organic phases are washed with water, dried over MgSO4, and concentrated in vacuo. LC (method 5): tR=0.62 min; Mass spectrum (ESI+): m/z=359 [M+H]+.
Reaction SMILES: [PH3:1].[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.P(=O)(O)(O)O.[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br-:2].[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][P+:1]([C:3]2[CH:10]=[CH:9][C:6]([CH3:7])=[CH:5][CH:4]=2)([C:19]2[CH:20]=[CH:21][C:16]([CH3:22])=[CH:17][CH:18]=2)[C:19]2[CH:20]=[CH:21][C:16]([CH3:22])=[CH:17][CH:18]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccccc1
Reactant: BrCc1ccc(Br)cc1
Reactant: P
Agent: O=P(O)(O)O
Product: Cc1ccc([P+](Cc2ccc(Br)cc2)(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Product: [Br-]
Temperature: 30 °C

Procedure:
Into a 50 milliliter glass reactor equipped with a thermometer connected to a temperature controller, a heating mantle, a condenser and a magnetic stirring bar, is charged 5.04 gms (0.0166 mole) of trip-p-toly phosphine and 25 gms of toluene. The slurry is heated to 30° C. then 4.6 gms (0.0184 mole) of 4-bromobenzyl bromide is added. This reaction mass is heated to 100° C. and maintained at that temperature for 3.5 hours, then cooled to 29° C. and the resulting phosphonium salt collected by filtration. The salt is washed with 12 gms of toluene then vacuum dried. There is obtained 7.5 gms of catalyst which has a melting point of >250° C. and a chemical shift of 22.1 ppm (phosphoric acid reference).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4][CH2:3]1.[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2S[C:30]([CH:32]=O)=[CH:29][CH:28]=2)[CH:23]=[CH:24][C:25]=1[Cl:26].NCCC(O)=[O:38].CO.C(Cl)Cl>C(O)(=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2[O:38][C:30]([CH:32]=[C:3]3[C:2](=[O:1])[N:6]([CH:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4]3)=[CH:29][CH:28]=2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: O=Cc1ccc(-c2ccc(Cl)c(Cl)c2)s1
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)CNC1=S
Reactant: NCCC(=O)O
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)C(Cc1ccccc1)N1C(=O)C(=Cc2ccc(-c3ccc(Cl)c(Cl)c3)o2)NC1=S
Temperature: 170 °C

Procedure:
To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.055 g, 0.207 mmol) and 5-(3,4-dichloro-phenyl)thiophene-2-carbaldehyde (0.050 g, 0.207 mmol) in acetic acid 5 mL is added β-alanine (1.8 mg, 0.021 mmol) and heat to 170° C. for 30 min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.060 g, 0.123 mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CDCl3/CD3OD/300 MHz): 7.84 (d, J=2.1 Hz, 1H), 7.60 (dd, J=8.7, 2.4 Hz, 1H), 7.44 (d, J=2.7 Hz, 1H), 7.17 (m, 6H), 6.85 (m, 1H), 6.42 (s, 1H), 5.61 (dd, J=11.1, 5.4 Hz, 1H), 3.66 (m, 1H), 3.53 (m, 1H). MS (ES−, m/z): 585.3 (M−, 100.0).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[S:18][C:17]2[N:16]3[C:19]([CH3:22])=[N:20][N:21]=[C:15]3[CH2:14][N:13]=[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:11]=2[CH:10]=1.C(OCCCCCCCC1SC2N3C(C)=NN=C3CN=C(C3C=CC=CC=3Cl)C=2C=1)(=O)C.CCOCC>C(Cl)Cl>[CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[S:18][C:17]2[N:16]3[C:19]([CH3:22])=[N:20][N:21]=[C:15]3[CH2:14][N:13]=[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:11]=2[CH:10]=1)=[O:1]
Reactant: Cc1nnc2n1-c1sc(CCCCCCCO)cc1C(c1ccccc1Cl)=NC2
Agent: CC(=O)OCCCCCCCc1cc2c(s1)-n1c(C)nnc1CN=C2c1ccccc1Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1nnc2n1-c1sc(CCCCCCC=O)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.1 %

Procedure:
2.1 g (0.005 mol) of 2-(7-hydroxyheptyl)-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a]-[1,4]diazepine (prepared, for example, from the compound of Example 4 by alkaline saponification) dissolved in 5 ml of methylene chloride are added dropwise to 1.5 g (0.0075 mol) of pyridinechlorochromate in 20 ml of methylene chloride, the resulting mixture is stirred for a further 90 minutes at ambient temperature and 50 of ether are added to the solution. The black resinous oil precipitated is thoroughly extracted several times with ether, the ether solutions are combined, suction filtered over Kieselguhr, the filtrate is evaporated down and the residue is chromatrographed on silica gel with methylene chloride/methanol (9:1) as eluant. 0.6 g (yield 29% of theory) of the aldehyde are obtained as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:13]=2)[N:6]=1
Reactant: [N-]=[N+]=NCCNC(=O)C=Cc1ccccc1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)/C=C/c3ccccc3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.106 g, 0.384 mmol) was reacted with N-(2-azidoethyl)cinnamamide (0.083 g, 0.384 mmol) following the general click procedure to give (E)-tert-butyl 2-amino-4-(5-(1-(2-cinnamamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), δ 7.51 (d, 1H), δ 7.28 (m, 6H), δ 6.45 (t, 2H), δ 6.08 (s, 2H), δ 4.47 (s, 2H), δ 3.79 (s, 2H), δ 2.57 (s, 2H), δ 2.23 (s, 2H), δ 1.50 (bs, 13H), δ 1.28 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 166.9, 150.4, 149.5, 148.3, 141.2, 138.9, 134.9, 129.9, 128.9, 128.0, 122.1, 120.8, 106.5, 84.8, 53.7, 49.5, 39.9, 31.1, 29.3, 28.9, 28.3, 28.2, 25.6 ppm; HRMS (ESI) calcd for C26H35N7O3 (M+) 493.2801. found 493.2800, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)cinnamamide hydrochloride (0.097 g, 59% yield). 1H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), δ 7.49 (s, 3H), δ 7.32 (s, 3H), δ 6.30 d, 1H), δ 6.39 (s, 1H), δ 4.66 (s, 2H), δ 3.83 (s, 2H), δ 2.73 (s, 2H), δ 2.40 (s, 2H), δ 1.57 (s, 2H), δ 1.55 (s, 2H), δ 1.36 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 167.8, 160.5, 150.2, 147.3, 141.1, 134.8, 130.7, 129.9, 128.8, 127.8, 127.6, 124.9, 23 9, 120.2, 108.5, 108.3, 53.1, 39.3, 36.5, 30.6, 28.4, 28.1, 27.6, 26.5, 24.2, 24.1, 23.7 ppm; HRMS (ESI) calcd for C21H27N7O (M+) 393.2277. found 393.2273.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[C:16]1([CH:26]=O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.[CH:28]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([OH:35])=[O:34])=O>>[CH2:9]([N:8]1[C:3]2=[N:1][N:2]([CH2:26][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[C:28]([C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=3)[C:33]([OH:35])=[O:34])=[C:4]2[C:5](=[O:15])[N:6]([CH3:14])[C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: O=Cc1cccc2ccccc12
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cccc(C(=O)O)c3)n(Cc3cccc4ccccc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 1-naphthaldehyde, followed by 3-formylbenzoic acid. Mass: 482.72 (M+H).
Reaction SMILES: [CH3:1][C@@:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@H:19]4[CH2:24][CH2:23][C@@H:22]([CH3:25])[CH2:21][CH2:20]4)[CH:14]=3)[CH:9]=2)[CH2:6][O:5]C(=O)[NH:3]1.C(O)C.O.[OH-].[Li+]>O>[NH2:3][C@@:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@H:19]3[CH2:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH2:24]3)[CH:14]=2)[CH:9]=1)([CH3:1])[CH2:6][OH:5]
Reactant: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@@H](C)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@](N)(CO)c1ccc2cc(O[C@H]3CC[C@@H](C)CC3)ccc2c1
Temperature: 80 °C

Procedure:
To a solution of (R)-4-Methyl-4-[6-(cis4-methyl-cyclohexyloxy)-naphthalen-2-yl]-oxazolidin-2-one (0.4420 g, 0.001302 mol) in ethanol (5.00 mL, 0.0856 mol) in a capped 40 mL vial was added 4.2 M Lithium hydroxide, monohydrate in water (2.8 mL). The mixture was heated overnight at 80° C. TLC analysis showed the reaction was complete. The mixture was concentrated to dryness under vacuum. Methylene chloride (5 mL) and water (5 mL) were added and the layers were separated (2×). The organic layer was concentrated under vacuum and purified by HPLC to give 0.0233 g of the title compound (6% yield). MS: m/z=297.29 [M-NH2]+. 1H NMR (400 MHz, MeOD) δ 0.98 (d, J=6.02 Hz, 3 H), 1.40-1.51 (m, 2 H), 1.51-1.60 (m, 3 H), 1.64-1.74 (m, 2 H), 1.79 (s, 3 H), 2.03-2.14 (m, 2 H), 3.83 (d, J=11.55 Hz, 1 H), 3.93 (d, J=11.55 Hz, 1 H), 4.69-4.77 (m, 1 H), 7.23 (dd, J=8.91, 2.38 Hz, 1 H), 7.27 (d, J=2.51 Hz, 1 H), 7.53 (dd, J=8.78, 2.01 Hz, 1 H), 7.79-7.89 (m, 3 H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1C2CCC1CC(C#N)C2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:20][CH2:21]O.[C:23](O)(=O)[CH2:24][C:25]([CH2:30][C:31](O)=O)([C:27]([OH:29])=[O:28])O>O>[C:1]([O:5][C:6]([N:8]1[CH:23]2[CH2:20][CH2:21][CH:31]1[CH2:30][CH:25]([C:27]([OH:29])=[O:28])[CH2:24]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(C#N)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(C(=O)O)C2

Procedure:
To 3-cyano-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (Intermediate 104, 190 mg, 0.81 mmol) was added potassium hydroxide (270 mg, 4.83 mmol), EtOH (3 mL) and water (1 mL). The mixture was heated at 95 C for 4 h, allowed to cool and acidified to pH=2 with a 1 M aq. solution of citric acid. The mixture was then extracted with EtOAc (2×5 mL) and the combined extracts washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. Evaporation gave the crude title compound which was used directly without further purification (190 mg, 94%). Method B HPLC-MS: MH+ requires m/z=255. Found: m/z=200 (MH-tBu), Rt=1.68 min (76%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[N:13]1[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14]1)[OH:4].[NH2:21][C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39]C(OC(C)(C)C)=O)[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=2)[CH:25]=[C:24](Cl)[N:23]=1.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:39][C@@H:35]([CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[CH:25]=[C:24]([O:4][CH:3]([C:5]3[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=3[N:13]3[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14]3)[C:2]([F:19])([F:1])[F:20])[N:23]=[C:22]([NH2:21])[N:27]=2)=[CH:29][CH:30]=1)[C:36]([OH:38])=[O:37]
Reactant: COc1ccc(-n2cc(C)cn2)c(C(O)C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-n2cc(C)cn2)c(C(Oc2cc(-c3ccc(C[C@H](N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)c1
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
2,2,2-Trifluoro-1-[5-methoxy-2-(4-methyl-pyrazol-1-yl)-phenyl]-ethanol (0.090 g, 0.31 mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (0.122 g, 0.31 mmol), 1,4-dioxane (2 ml), Cs2CO3 (0.503 g, 1.55 mmol) were combined in a microwave vial and heated to 180° C. for 45 min. The mixture was filtered and concentrated. To the residue, 5% methanol in DCM (50 ml) was added. The mixture was filtered. The filtrate was concentrated to give crude product which was taken in 20% TFA in DCM (30 ml) and stirred for 30 minutes at room temperature. LCMS indicated the completion of the reaction with desired product. The reaction mixture was concentrated to give crude product, which was dissolved in MeOH and H2O (1:1), and purified by preparative HPLC using MeOH/H2O/TFA as solvent system to give (S)-2-amino-3-[4-(2-amino-6-{2,2,2-trifluoro-1-[5-methoxy-2-(4-methyl-pyrazol-1-yl)-phenyl]-ethoxy]-pyrimidin-4-yl)-phenyl]-propionic acid.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]3)=[N:8][CH:9]=1)=[S:3].Br[CH:31]([CH3:35])[C:32](=O)[CH3:33]>C(O)C>[CH3:35][C:31]1[N:1]=[C:2]([C:4]2[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]4)=[N:8][CH:9]=2)[S:3][C:32]=1[CH3:33]
Reactant: CC(=O)C(C)Br
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cn3)ccc21
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc(C)c(C)s4)cn3)ccc21
Temperature: 80 °C
Yield: 82.8 %

Procedure:
A mixture of ethyl [(1 S)-5-(3-{[5-(aminocarbonothioyl)2-pyridinyl]oxy}propoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 259, 90 mg, 0.22 mmol) and 3-bromo-2-butanone (40 mg, 0.26 mmol) in ethanol (9 mL) was heated under argon at 80° C. for 18 h, and then concentrated under reduced pressure. The product (85 mg, 84%) was isolated after purification by silica gel chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 8.54 (dd, 1H), 8.05 (dd, 1H), 7.02 (d, 1H), 6.83 (d, 1H), 6.78 (d, 1H), 6.69 (dd, 1H), 4.51 (t, 2H), 4.18-4.10 (m, 4H), 3.48 (qt, 1H), 2.92-2.75 (m, 2H), 2.69 (dd, 1H), 2.42-2.30 (m, 8H), 2.29-2.20 (m, 2H), 1.80-1.68 (m, 1H), 1.27 (t, 3H).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[CH:10][CH:11]=2)[O+:6]=[C:5]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:4]=1.[O-:25][CH2:26][CH3:27].[Na+].C(O)C>C(Cl)(Cl)Cl>[Cl-:2].[CH2:26]([O:25][C:3]1[C:12]2[C:7](=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[CH:10][CH:11]=2)[O+:6]=[C:5]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:4]=1)[CH3:27]
Reactant: CC[O-]
Reactant: Clc1cc(N2CCOCC2)[o+]c2c(-c3ccccc3)cccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOc1cc(N2CCOCC2)[o+]c2c(-c3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A vial was charged with a magnetic stirring bar, 4-chloro-2-morpholino-8-phenylchromenylium chloride (78) (50 mg, 138 μmol), chloroform (1.0 mL), and a solution of sodium ethoxide in ethanol (21%, 108 μL, 290 μmol). The mixture was magnetically stirred at room temperature for 1 hour to give 4-ethoxy-2-morpholino-8-phenylchromenylium chloride (80).