Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C@H:16]([CH3:20])[C:17](O)=[O:18])[C:12]2=[O:21])=[CH:7][CH:6]=1.C(Cl)(=O)C([Cl:29])=O>CN(C)C=O.ClCCl>[F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C@H:16]([CH3:20])[C:17]([Cl:29])=[O:18])[C:12]2=[O:21])=[CH:7][CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@H](C(=O)O)n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](C(=O)Cl)n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2R) -2-[3-[4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-2,3-dihydro-2-oxo-1H-imidazol-1-yl]propanoic acid (1.5 g) and 3.8 ml of oxalyl chloride were added to 30 ml of dichloromethane, to which dimethylformamide (7 drops ) was added dropwise at room temperature. After the reaction solution was stirred at room temperature for 2 hours, the solvent was distilled off under reduced pressure to give 1.5 g of (2R)-2-[3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,3-dihydro-2-oxo-1H-imidazol-1-yl]propanoyl chloride as a pale yellow oil. This product was used for the next step without purification.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[CH3:32][C:33]([CH3:35])=O.CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:33]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)([CH3:35])[CH3:32]
Reactant: C[C@@H](Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Reactant: CC(C)=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)N1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@H](C)c3ccccc3)c2)cc2nccn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture of 100 mg (0.24 mmol)(R)-{4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 5 mL chloroform was treated with 0.2 mL (2.4 mmol) acetone, 45 mg (0.72 mmol) NaBH3(CN) and 1 mL methanol. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, dried over anhydrous Na2SO4. After purification by chromatography, obtained the title compound as a yellow solid. MS (ES+): 454 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[O:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:40]([NH:39][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:41])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C=Nc1ccccc1Oc1ccccc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Oc4ccccc4)cc3)cc2C1=O
Yield: 98 %

Procedure:
The compound of example 47 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 2-phenoxy phenyl isocyanate.
Reaction SMILES: F[C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>C(O)C>[F:22][C:17]1[CH:16]=[C:3]2[C:2](=[C:19]([F:20])[C:18]=1[F:21])[N:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]2=[O:5]
Reactant: COc1ccc(N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccc(OC)cc2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
A mixture of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxyacrylate (0.4 g), p-anisidine (0.15 g) and ethanol (4 ml) is stirred at room temperature for 30 minutes. After the reaction, the solvent is distilled off under reduced pressure. To the resulting residue is added anhydrous dioxane (10 ml) and further added portionwise 60% sodium hydride (60 mg). The mixture is stirred at room temperature for 30 minutes. Thereafter, the reaction mixture is poured into saturated aqueous ammonium chloride and then extracted with dichloromethane to give ethyl 6,7,8-trifluoro-1-(4-methoxyphenyl)- 1,4-dihydro-4-oxoquinoline-3-carboxylate (0.37 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN(C=O)C.[Br:54][C:55]1[CH:61]=[CH:60][C:58]([NH2:59])=[CH:57][CH:56]=1>C1COCC1>[Br:54][C:55]1[CH:61]=[CH:60][C:58]([NH:59][C:24]([C:16]2[C:17]3[O:21][C:20]([CH3:22])([CH3:23])[CH2:19][C:18]=3[C:12]3[NH:11][C:10]([NH:9][C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:14][C:13]=3[CH:15]=2)=[O:26])=[CH:57][CH:56]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(Br)cc3)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Yield: 13.5 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(2,6-dichlorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-6, 0.080 g, 0.204 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.130 g, 0.400 mmol), TEA (1.5 mL), DMF (1.5 mL), THF (7.0 mL) and 4-bromo aniline (0.070 g, 0.400 mmol) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.30-1.45 (m, 3H), 1.46-1.56 (m, 3H), 3.08 (s, 2H), 7.39 (m, 2H), 7.53 (d, J=8.7 Hz, 4H), 7.68 (d, J=8.7 Hz, 2H), 9.78 (s, 1H), 11.50-12.00 (s, 2H); MS [M+H]+: 547.16.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14](=[CH:20][N:21](C)[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[C:7]([F:24])[CH:8]=2)[N:3]=1.[CH:26]1(N)C[CH2:27]1>ClC(Cl)Cl>[Cl:25][C:6]1[C:7]([F:24])=[CH:8][C:9]2[C:4]([CH:5]=1)=[N:3][C:2]1[N:21]([CH:22]3[CH2:27][CH2:26]3)[CH:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12](=[O:13])[C:11]=1[CH:10]=2
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Reactant: NC1CC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C2CC2)c2nc3cc(Cl)c(F)cc3cc2c1=O
Temperature: 78 °C
Yield: 70.8 %

Procedure:
A solution of ethyl 2-(2,7-dichloro-6-fluoro-3-quinolinecarbonyl)-3-(dimethylamino)acrylate (20.6 g) and cyclopropylamine (6 g) in trichloromethane (100 cc) is stirred at a temperature in the region of 20° C. for 24 hours. The reaction mixture is concentrated under reduced pressure (2.7 kPa) at 50° C. The residue is taken up with ethanol (180 Zcc) and DBU (10 g) and the solution obtained heated to a temperature in the region of 78° C. for 4 hours. After cooling to a temperature in the region of 20° C., the precipitate obtained is drained and washed with ethanol (2×60 cc). 8-Chloro-1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-di hydrobenzo[b][1,8]naphthyridine (13.65 g) is obtained in the form of a pale yellow solid, m.p. 256° C., which is used without further purification for the subsequent steps.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cc(Cl)nc(SC)n2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 658.1 %

Procedure:
To a solution of 4,6-dichloro-2-(methyl thio)pyrimidine (75 g, 38.4 mmol, Sigma-Aldrich) in DMF (750 mL) was added p-methoxybenzyl alcohol (58.38 g, 42.1 mmol) and K2CO3 (212.3 g, 1538 mmol). The reaction was stirred at 60° C. for 12 h, then cooled to RT. Water (500 mL) was added to get a white solid and the mixture was filtered. The resulting solid was triturated with hexanes to give 4-chloro-6-((4-methoxybenzyl)oxy)-2-(methylthio)pyrimidine (75 g, 66.4%) as white solid. MS (ESI, pos. ion) m/z: 297 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[N:40]([CH2:43][CH2:44]O)=[N+]=[N-].C(N(CC)CC)C.C(S)(S)CC>C1COCC1.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:44][CH2:43][NH2:40])=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: [N-]=[N+]=NCCO
Agent: CCC(S)S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: NCCOc1ccc(I)cc1
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a magnetically stirred solution of 4-iodophenol (15 grams, 0.068 mol) in 100 mL THF was sequentially added triphenylphosphine (19.67 grams, 0.075 mol), diethyl azodicarboxylate (13.06 grams, 0.073 mol), and 2-azidoethanol (5.93 grams, 0.068 mol). The mixture was stirred overnight, concentrated in vacuo, diluted with 90 mL ethyl acetate and diluted with hexane (400 mL), and the resulting solids filtered away. The filtrate was concentrated in vacuo, diluted with diethyl ether, and extracted with 1N NaOH and water. Pentane was added to induce precipitation of a white solid that was again filtered away. The filtrate was concentrated in vacuo, and dissolved in methanol (60 mL). Triethylamine (27 grams, 0.267 mol) and propanedithiol (23 grams, 0.215 mol) were added and the mixture stirred at room temperature overnight. The solution was diluted with 100 mL water and partitioned between methylene chloride and 1N NaOH. The organic layer was extracted with 2×200 mL 1N HCl and the aqueous layer washed with 100 L methylene chloride, made basic with 2N NaOH and extracted 3×75 mL methylene chloride. The combined organics were dried over sodium carbonate, filtered and concentrated in vacuo to yield 12.97 grams of 2-(4-iodophenoxy)ethyl amine (72%). 1H NMR (CDCl3, dTMS) 7.56 (2H, d, 3JHH =9 Hz, Ar--H), 6.63 (2H, d, 3JHH =9 Hz, Ar--H), 4.03 (2H, t, 3JHH =5 Hz, CH2N3), 3.57 (2H, t, 3JHH =5 Hz, OCH2). 13C NMR (CDCl3) 158.0, 138.2, 116.9, 83.4, 66.9, 49.9. IR (NaCl, cm-1) 2930,2107 (s), 1589, 1483, 1284, 1237, 1058, 819.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([C:18]2[C:19]3[C:20]4[CH:33]=[CH:32][S:31][C:21]=4[C:22](=[O:30])[NH:23][C:24]=3[CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C1C(=O)N([Cl:41])C(=O)C1>>[Cl:41][C:25]1[C:24]2[NH:23][C:22](=[O:30])[C:21]3[S:31][CH:32]=[CH:33][C:20]=3[C:19]=2[C:18]([C:16]2[CH:15]=[CH:14][C:3]([CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[C:2]([F:1])[CH:17]=2)=[C:27]([O:28][CH3:29])[CH:26]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(F)c1
Reactant: O=C1CCC(=O)N1Cl
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(F)c1
Yield: 46.6 %

Procedure:
Following General Procedure H, tert-butyl 2-fluoro-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethylcarbamate (300 mg, 0.64 mmol) was reacted with NCS (94 mg, 0.71 mmol) to afford the desired product (150 mg, 46%) as a yellow solid. ESI MS m/z 503 [C25H21ClFN2O4S+H]+.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[O:9]=C1O[C@H]([C@H](CO)O)C(O)=C1O>>[OH:9][C@@H:6]1[CH2:7][CH2:8][NH:1][C@@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: O=C(O)[C@H]1NCC[C@H]1O
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
The reaction mixture was composed of 100 mM TES buffer (pH 7.0), 5 mM L-proline, 5 mM2-ketoglutaricacid, 1 mM ferrous sulfate, 5 mM L-ascorbic acid and a predetermined amount of the pure enzyme, the total volume being 100 μl. The reaction was initiated by addition of the enzyme and continued for 10 minutes at 35° C. The reaction was stopped by heating the reaction mixture at 100° C. for 2 minutes. The amount of cis-3-hydroxy-L-proline formed in the reaction mixture was determined by the pre-column derivatization method using HPLC. One hundred microliters of 0.3 M boric acid buffer (pH 10.7), 4 μl of an aqueous solution of 10% (v/v) mercaptoethanol and 16 μl of ethanol solution of 5% (w/v) OPA were added to 100 μl of the reaction mixture, and the mixture was allowed to stand at 60° C. for 30 seconds. In addition, 50 μl of ethanol solution of 2% (w/v) NBD was added thereto and the mixture was allowed to stand at 60° C. for 40 minutes. The reaction was stopped by adding 30 μl of 1 N HCl to the reaction mixture, and the precipitates formed were removed therefrom by centrifugation and filtration. The cis-3-hydroxy-L-proline formed by the reaction was quantitatively determined by HPLC analysis.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[N+:20]([O-:22])=[O:21].C=O.C(O)C>Cl.O>[N+:20]([C:5]1[CH:6]=[CH:7][C:8]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17](=[O:19])[CH3:18])[CH2:14][CH2:15]2)=[CH:9][C:4]=1[CH:3]=[O:2])([O-:22])=[O:21]
Reactant: COC(OC)c1cc(N2CCC(NC(C)=O)CC2)ccc1[N+](=O)[O-]
Agent: C=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=O)NC1CCN(c2ccc([N+](=O)[O-])c(C=O)c2)CC1

Procedure:
0.3 Gram of 2-nitro-5-(4-acetylamino-1-piperidyl)benzaldehyde dimethylacetal, 5 ml of formalin, 1 ml of ethanol and 2 drops of concentrated hydrochloric acid were refluxed by heating. After the reaction was completed, the solvent was removed by evaporation to obtain the residue, then water was added to the residue. The crystals formed were collected by filtration to yield 0.22 g of 2-nitro-5-(4-acetylamino-1-piperidyl)benzaldehyde.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[Cl:11][C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(Cl)Cl>[Cl:11][C:12]([O:10][C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(O)c(C)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C)c(OC(=O)Cl)c(C)c1
Temperature: 0 °C

Procedure:
2,4,6-trimethylphenol (272 mg, 2.00 mmol, 1.0 equiv) was dissolved in CH2Cl2 (3.33 mL, 0.3 M) under nitrogen (N2) and cooled to 0° C. Triphosgene (208 mg, 0.700 mmol, 0.35 equiv) was dissolved in CH2Cl2 (3.33 mL) and added dropwise, followed by pyridine (0.162 mL, 2.00 mmol, 1.0 equiv). The mixture was allowed to warm to 25° C. over 18 h, at which point the reaction was quenched with 10 mL 1 normal (N) hydrochloric acid (HCl; aq) and extracted with EtOAc. The organic layer was washed with 1 N HCl (aq), dried over Na2SO4, and concentrated to give mesityl chloroformate as an oil (88% purity by 1H NMR spectroscopy). The chloroformate so prepared was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([OH:20])[CH:11]=2)=[CH:4][N:3]=1.[C:21](O)(=[O:25])/[CH:22]=[CH:23]/[CH3:24].[OH-].[NH4+]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:11]3[C:21](=[O:25])[CH2:22][CH:23]([CH3:24])[O:20][C:12]=3[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][N:3]=1
Reactant: C/C=C/C(=O)O
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(O)c1OC
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc(Cc2cnc(N)nc2N)c2c(c1OC)OC(C)CC2=O
Yield: 29 %

Procedure:
A mixture of 2,4-diamino-5-(3-hydroxy-4,5-dimethoxybenzyl)pyrimidine (2.76 g, 0.01 mole) and crotonic acid (0.87 g, 0.01 mole) in polyphosphoric acid (27 g) was stirred and heated on a steam bath for 4 hr. The reaction mixture was cooled to 50° and poured onto ice (100 g) with stirring. The resulting solution was basified to pH 8.0 with concentrated ammonium hydroxide, giving a suspension which was then extracted with methylene chloride (3×100 mL). The combined extracts were washed with 0.1N sodium hydroxide (2×100 mL), water (100 mL) and then dried over anhydrous magnesium sulfate. Evaporation of solent in vacuo gave the title compound (1.0 g, 29%). This was recrystallised from 95% ethanol to give 2,4-diamino-5-(3,4-dihydro-7,8-dimethoxy-2-methyl-4-oxo-2H-1-benzopyran-5-ylmethyl)pyrimidine as the hemihydrate, mp 128°-132°. Anal. Calcd for C17H20N4O4.1/2H2O: C, 57.78; H, 5.99; N, 15.85. Found: C, 57.79; H, 6.02; N, 15.86.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:26])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]2[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:27][O:28][C:29]([NH:31][C:32](=NC(OC)=O)SC)=[O:30].[CH2:40](O)[CH3:41]>>[CH2:40]([O:26][C:9]1([C:4]2[CH:5]=[CH:6][C:7]3[NH:8][C:32]([NH:31][C:29](=[O:30])[O:28][CH3:27])=[N:1][C:2]=3[CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:41]
Reactant: CCO
Reactant: Nc1ccc(C2(O)c3ccccc3C(=O)N2Cc2ccccc2)cc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Product: CCOC1(c2ccc3[nH]c(NC(=O)OC)nc3c2)c2ccccc2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-(3,4-diaminophenyl)-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one (1.5 g, 4.34 mmol) and 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (1.8 g, 8.68 mmol) in anhydrous ethanol (15 mL) was heated to 95° C. and stirred for 18 h, at which time the reaction mixture was cooled to room temperature. The white precipitate was filtered and the powder was triturated in hot ethanol (50 mL). The white powder was collected by filtration to afford methyl {5-[1-(ethyloxy)-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate (700 mg). 1H NMR (400 MHz, d6-DMSO): 7.82-7.81 (m, 1H), 7.58-7.52 (m, 3H), 7.51 (d, 1H), 7.33-7.16 (m, 6H), 6.90 (d, 1H), 4.75 (d, 1H), 4.75 (d, 1H), 3.79 (d, 1H), 2.74-2.67 (m, 2H), 0.65 (t, 3H); 13C NMR (100 MHz, d6-DMSO): 166.9, 154.5, 147.8, 145.7, 137.6, 132.6, 131.1, 130.7, 130.6, 129.4, 128.3, 127.8, 126.8, 122.9, 122.8, 118.9, 95.3, 57.9, 52.4, 42.5, 14.1; MS (EI) for C26H24N4O4: 457 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:11]([C:12]([F:15])([F:14])[F:13])[CH2:10][C:9](=[O:16])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[N:26]([CH2:35][CH2:36][OH:37])[CH:27]=[C:28]([CH2:30][C:31]([F:34])([F:33])[F:32])[N:29]=2)[CH2:21][CH2:20]1.CN1CCCC1=O.C(N(C(C)C)CC)(C)C>C(=O)(O)[O-].[Na+]>[OH:37][CH2:36][CH2:35][N:26]1[CH:27]=[C:28]([CH2:30][C:31]([F:32])([F:34])[F:33])[N:29]=[C:25]1[CH:22]1[CH2:21][CH2:20][N:19]([C:2]2[C:3]3[C@H:11]([C:12]([F:15])([F:14])[F:13])[CH2:10][C:9](=[O:16])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:24][CH2:23]1
Reactant: OCCn1cc(CC(F)(F)F)nc1C1CCNCC1
Reactant: O=C1C[C@@H](C(F)(F)F)c2c(Cl)ncnc2N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C1C[C@@H](C(F)(F)F)c2c(ncnc2N2CCC(c3nc(CC(F)(F)F)cn3CCO)CC2)N1
Temperature: 150 °C
Yield: 67.9 %

Procedure:
Add (R)-4-chloro-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.70 g, 2.78 mmol), 2-(2-(piperidin-4-yl)-4-(2,2,2-trifluoroethyl)-1H-imidazol-1-yl)ethanol dihydrochloride (1.17 g, 1.2 eq), N-methylpyrrolidinone (10 mL) and diisopropylethylamine (2.20 mL, 5.7 eq) in a microwave tube. Seal with crimp cap. Heat in a microwave reactor at 150° C. for one hour. Dilute the reaction mixture with saturated aqueous sodium bicarbonate and extract with ethyl acetate. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with 5% methanol/dichloromethane to 10% methanol/dichloromethane to 10% 2 M ammonia in methanol/dichloromethane, to give (R)-4-(4-(1-(2-hydroxyethyl)-4-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.93 g, 68%). MS (ES) m/z=493 [M]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:14]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[N:17]=[N:16][N:15]=1>O1CCCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][O:10][C:14]2[N:18]([C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)[N:17]=[N:16][N:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-n2nnnc2OCCCC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Cyclohexylpropyl alcohol (237 mL, 1.56 mol) was added to a suspension of NaH (66.0 g, 1.65 mol) in tetrahydrofuran (1.40 L). A solution of 5-Chloro-1-(4-nitro-phenyl)-1H-tetrazole (320 g, 1.42 mol) in tetrahydrofuran (900 mL) was added dropwise over 1.5 hours. The reaction was allowed to cool to room temperature and stirred overnight. The mixture was concentrated in vacuo to a solid. The solid was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride solution (2×), dried (Na2SO4), and filtered through silica gel (700 g). The red filtrate was concentrated in vacuo until product began to precipitate from solution. Hexane was added and the slurry filtered to provide a tan solid (320 g, 64%). Mp 82-88° C. (dec); 1H NMR (CDCl3, 300 MHz) δ 8.43 (d, 9.2 Hz, 2 H), 8.04 (d, 9.2 Hz, 2 H), 4.70 (t, 7.0 Hz, 2 H), 1.96 (m, 2 H), 1.75-1.64 (m, 5 H), 1.39-1.13 (m, 6 H), 0.97-0.87 (m, 2 H); MS (CI) m/z 332 (MH+); Anal. calcd for C16H21N5O3 : C, 57.99; H, 6.39; N, 21.13. Found: C, 57.80; H, 6.35; N, 21.02; Rf =0.43 (N).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH:7]2[N:9]([CH3:10])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[C:11]1([C:17]2[O:18][C:19]3[C:20](=[C:22]([C:26](O)=[O:27])[CH:23]=[CH:24][CH:25]=3)[N:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:10][N:9]1[CH:7]2[CH2:6][CH2:5][CH:4]1[CH2:3][CH:2]([NH:1][C:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:19]3[O:18][C:17]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:21][C:20]=13)=[O:27])[CH2:8]2
Reactant: CN1C2CCC1CC(N)C2
Reactant: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Product: CN1C2CCC1CC(NC(=O)c1cccc3oc(-c4ccccc4)nc13)C2
Yield: 25 %

Procedure:
N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-phenylbenzoxazole-4-carboxamide was prepared from 3-amino-8-methyl-8-azabicyclo[3.2.1]octane and 2-phenylbenzoxazole-4-carboxylic acid using conditions similar to those described for Step C in Example 1. This compound was obtained in 25% yield as a white solid; mp 149-151° C.; 1H NMR (300 MHz, CDCl3) δ 9.55 (d, J=7.6 Hz, 1H), 8.29 (m, 2H), 8.22 (dd, 1H, J=7.8, 1.0 Hz, 1H), 7.72 (dd, J=8.1, 1.0 Hz, 1H), 7.65-7.55 (m, 3H), 7.47 (t, J=8.0 Hz, 1H), 4.48 (q, 1H, J=7.2 Hz), 3.25 (br s, 2H), 2.43-2.24 (m, 9H), 1.87 (d, J=14.2 Hz, 2H); MS (APCI) m/z 362 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[C:9]([CH2:12]O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:34]>O1CCCC1.CC#N>[Br:34][CH2:12][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:11][CH:10]=1
Reactant: OCc1csc(-c2ccccc2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Product: BrCc1csc(-c2ccccc2)c1
Temperature: 0 °C
Yield: 98.3 %

Procedure:
Prepare a solution of (5-phenylthiophene-3-yl)methanol (394 mg, 2.07 mmol) in tetrahydrofuran (30 mL). Cool to 0° C. under nitrogen. Add PPh3 (723 mg, 2.75 mmol). Add dropwise a solution of carbon tetrabromide (912 mg, 2.75 mmol) in CH3CN (15 mL). Stir the reaction at 0° C. for 2 hours, then warm to room temperature overnight. Concentrate the mixture and flash-chromatograph on silica gel eluting with 7:3 ethyl acetate/hexane to afford 515 mg of 4-bromomethyl-2-phenylthiophene as a white solid. MS: m/e=254 [MH+].