Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].[H-].[Na+].IC.[CH3:36][N:37]([CH:39]=O)[CH3:38]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[C:10]3[C:39]([N:37]([CH3:36])[CH3:38])=[C:3]([C:26](=[O:31])[C:27]([CH3:29])([CH3:28])[CH3:30])[O:4][C:5]3=[N:6][C:7]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:12][CH:13]=1
Reactant: CC(C)(C)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C)c1c(C(=O)C(C)(C)C)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 0.050 g (0.106 mmol) of the product from Example 17 in DMF (1 mL) at 0° C. was treated with sodium hydride (0.010 g; 60% dispersion; 0.232 mmol). After the addition, the reaction mixture was stirred for 20 minutes at 0° C., and then treated with iodomethane (26 μL; 0.424 mmol). The reaction was warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated NaHCO3 solution. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethyl acetate:hexane gradient) gave the title compound. HPLC/MS: 501.0 (M+1), 503.0 (N+3); Rt=5.08 min.
Reaction SMILES: B1([O-])OO1.[OH2:5].O.O.O.[Na+].[N:10]1([C:19]2[CH:47]=[CH:46][C:22]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][S:30][CH2:31][C@H:32]([NH:36][C:37](=[O:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]([OH:35])=[O:34])=[CH:25][CH:24]=3)=[CH:21][CH:20]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>C(O)(=O)C.C(OCC)(=O)C>[N:10]1([C:19]2[CH:20]=[CH:21][C:22]([C:23]3[CH:24]=[CH:25][C:26]([CH2:29][S:30]([CH2:31][C@H:32]([NH:36][C:37](=[O:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]([OH:35])=[O:34])=[O:5])=[CH:27][CH:28]=3)=[CH:46][CH:47]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: O=C(Cc1ccccc1)N[C@@H](CSCc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)O
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(Cc1ccccc1)N[C@@H](CS(=O)Cc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Sodium perborate tetrahydrate (97 mg, 0.63 mmol) was added as a solid to a stirred solution of (2R)-3-(4′-indol-1-ylbiphen-4-ylmethylsulfanyl)-2-phenylacetylamino-propionic acid (300 mg, 0.58 mmol) in acetic acid (10 mL) at 40° C. This solution was stirred at 40° C. for 2 hours (HPLC control) and then diluted with ethyl acetate (50 mL), washed with water, brine (2×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 15% methanol in dichloromethane as eluent, afforded the title compound has an off-white solid (261 mg g, 84%) as a 1:1 mixture of diasereomers; 1H NMR (DMSO-d6, 300 MHz) δ 12.98 (1H, s, COOH), 8.75 and 8.80 (both 0.5H, d, J=8 Hz, NH), 8.40 (1H, d, J=8 Hz, NH), 7.84 (2H, m, Ar—H), 7.60-7.78 (7H, m, Ar—H), 7.44 and 7.39 (both 1H, d, J=8 Hz, Ar—H), 7.12-7.28 (7H, m, Ar—H), 6.72 (1H, d, J=3 Hz, Ar—H), 4.68 and 4.48 (both 0.5H, m, CHN), 4.16 (2H, m, PhCH2CO) 3.52 and 3.32 (both 1H, s, PhCH2S), 3.09 (1H, m, CHHCHN), 2.96 (1H, m, CHHCHN); ESI-LCMS e/z calcd for C32H28N2O4S 536.649, found 537 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[C:24]([CH:28]=1)[C:25](O)=[O:26]>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[C:24]([C:25]([N:14]2[CH2:13][CH:12]3[CH:16]([CH2:17][N:10]([C:4]4[N:5]=[C:6]([CH3:9])[C:7]([CH3:8])=[C:2]([CH3:1])[N:3]=4)[CH2:11]3)[CH2:15]2)=[O:26])[CH:28]=1
Reactant: Cc1nc(N2CC3CNCC3C2)nc(C)c1C
Reactant: COc1ccc(-n2nccn2)c(C(=O)O)c1
Product: COc1ccc(-n2nccn2)c(C(=O)N2CC3CN(c4nc(C)c(C)c(C)n4)CC3C2)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 42 and 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass calculated for C23H27N7O2, 433.22; m/z found 434.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.84 (d, J=9.0, 1H), 7.69 (s, 2H), 7.01 (dd, J=9.0, 2.8, 1H), 6.91 (d, J=2.8, 1H), 3.91-3.74 (m, 5H), 3.70-3.58 (m, 2H), 3.55 (dd, J=11.4, 5.2, 1H), 3.47-3.28 (m, 2H), 3.04-2.82 (m, 3H), 2.41-2.25 (m, 5H), 2.13-2.01 (m, 4H).
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)C[C:19]1=O.C(=O)C1C=CC=CC=1.CN(C)CCN(C)C.C([Li])CCC.IC>O1CCCC1.O>[CH3:19][C:8]1([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1Nc2ccccc2C1Cc1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: O=Cc1ccccc1
Product: CC1(Cc2ccccc2)C(=O)Nc2ccccc21
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
3-Phenylmethyl-1,3-dihydro-2H-indol-2-one (prepared from 1,3-dihydro-2H-indol-2-one (4 g, 18.25 mmol) and benzaldehyde by the method of Daisley and Walker J. Chem. Soc. (C) (1971) page 1373) and tetramethylethylenediamine (4.5 g, 38.7 mmol) was dissolved in freshly distilled tetrahydrofuran under nitrogen and cooled to -75° C. in an acetone/dry ice bath. n-Butyllithium (2.5M, 20 ml, 50 mmol) was added and the mixture was stirred at -75° C. for 30 minutes. Iodomethane (2.84 g, 20 mmol) was added and the mixture was allowed to warm to room temperature. Water (5 ml) was added and the mixture was concentrated under reduced pressure to a yellow oil. Column chromatography on silica gel (eluent ethyl acetate/hexane) gave 3-methyl-3-phenylmethyl-1,3-dihydro-2H-indol-2-one as a yellow oil which solidified on standing.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Cl:25][CH2:26][CH2:27][CH2:28][CH:29]([CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:30]([OH:32])=O.[C:39]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])(=[O:42])[NH:40][NH2:41]>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:25][CH2:26][CH2:27][CH2:28][CH:29]([CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:30]([NH:41][NH:40][C:39]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:32]
Reactant: O=C(O)C(CCCCl)C1CCOCC1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NNC(=O)C(CCCCl)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
IPEA (1.03 ml) and BOPCl (756 mg) were added to a solution of the crude 5-chloro-2-(tetrahydropyran-4-yl)valeric acid (442 mg) and tert-butyl carbazate (357 mg) in methylene chloride (7 ml), and the reaction solution was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was sequentially washed with 1 N hydrochloric acid, water, a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was triturated with ethyl acetate to obtain 250 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:15][C:16](OC)=[O:17])=[O:13])=[CH:7][CH:6]=1)[CH3:4].O(C)[Na]>CO>[CH2:23]([O:22][C:20]([N:14]1[CH2:15][C:16](=[O:17])[N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3](=[N:2][OH:1])[CH3:4])=[CH:6][CH:7]=2)[C:12]1=[O:13])=[O:21])[CH:24]=[CH2:25]
Reactant: C=CCOC(=O)N(CC(=O)OC)C(=O)Nc1ccc(C(C)=NO)cc1
Agent: CO[Na]
Solvent: CO
Product: C=CCOC(=O)N1CC(=O)N(c2ccc(C(C)=NO)cc2)C1=O

Procedure:
0.01 mol of this urea is dissolved in 150 mL of CH3OH. the pH is adjusted to approximately 10.0 using 25% NaOCH3 solution in CH3OH. The solution is heated to reflux for 2.5 hours, after which time the solvent is removed in vacuo. The residue is washed with cold water and dried in vacuo to yield crude 1-allyloxycarbonyl-3-[4-(1-hydroxyiminoethyl)phenyl]hydantoin. The hydantoin is purified by recrystallization from CH3OH: H2O.
Reaction SMILES: C([N:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[CH:6]=[N:5]1)(=O)C.N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O1CCOCC1>[C:19]1([C:18]([N:8]2[C:7](=[O:11])[CH:6]=[N:5][NH:4][C:9]2=[O:10])=[O:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)n1ncc(=O)[nH]c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=C(c1ccccc1)n1c(=O)cn[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To a solution of 2-acetyl-1,2,4-triazine-3,5(2H,4H)-dione (1.05 g, 6.77 mmol) in 1,4-dioxane (11 ml) and pyridine (1.64 ml, 20.31 mmol) was treated dropwise at 5° C. with benzoyl chloride (0.90 ml, 7.78 mmol), then the mixture was stirred at room temperature overnight. The day after, 0.1 eq of benzoyl chloride was added and the mixture was stirred at rt for further 4 hours. The reaction mixture was then filtered to remove the piridinium salt and the filtered was evaporated under vacuum. The residue was dissolved in ethanol (23 ml) and then hydrochloride acid 37% (0.74 ml, 24.19 mmol) was added and the reaction was refluxed for 15 minutes. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica eluting with a gradient of methanol in DCM (from 0 to 4%) to afford the title compound as a white solid (0.35 g, 23.47%).
Reaction SMILES: C[O:2][C:3]1[C:13]([O:14]C)=[CH:12][C:6]2[S:7][C:8]([C:10]#[N:11])=[CH:9][C:5]=2[CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[C:13]([OH:14])=[CH:12][C:6]2[S:7][C:8]([C:10]#[N:11])=[CH:9][C:5]=2[CH:4]=1
Reactant: COc1cc2cc(C#N)sc2cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cc2cc(O)c(O)cc2s1
Temperature: -70 °C
Yield: 95.6 %

Procedure:
5,6-Dimethoxy-benzo[b]thiophene-2-carbonitrile (9.0 g) was dissolved in dichloromethane (135 ml) and the solution was stirred and cooled to -70° C. and treated at a rapid dropwise rate with a cold solution of boron tribromide (19.5 ml) in dichloromethane (60 ml). The resultant suspension was stirred at room temperature for 1 h. then poured into ice-cold water (1000 ml). The light coloured solid was filtered, dried, dissolved in acetone:hexane (1:1) then eluted through coarse silica (0.2-0.5 mm, Merck, 50 g) in acetone:hexane (1:1). The appropriate fractions were combined, evaporated to dryness and crystallised from acetone/n-hexane to give 5,6-dihydroxy-benzo[b]thiophene-2-carbonitrile (7.5 g), m.p. 229°-230° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[H][H]>[Pd].O1CCOCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C(O)C(O)Cc1ccc(O)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 98.9 %

Procedure:
10 g of 3-(4-hydroxyphenyl)pyruvic acid and 50 ml of dioxane were charged to a pressure reactor to form a solution, and 0.5 g of 5% palladium on charcoal was added thereto. The atmosphere was displaced with hydrogen, and the mixture was stirred at 70° C. under a hydrogen pressure of 5 kg/cm2 for 6 hours. After completion of the reaction, the reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure to give 10.0 g of 3-(4-hydroxyphenyl)lactic acid as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][C:22](=[O:26])[CH:23](Br)[CH3:24])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O>[C:17]([O:21][C:22](=[O:26])[CH:23]([O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)[CH3:24])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(C#N)c(F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.1 %

Procedure:
2-Fluoro-4-hydroxybenzonitrile (1 g, 7.29 mmol) was dissolved in N,N-dimethyl-formamide (20 mL) and stirred with potassium carbonate (1.1 g, 8.0 mmol) at rt for 2 h. (±) 2-Bromopropionic acid tert-butyl ester (1.67 g, 8.0 mmol) was added and the reaction was stirred at rt for 72 hours. The reaction was quenched into dilute aqueous hydrochloric acid and extracted 2× with ethyl acetate. The pooled organics were dried (Na2SO4) and adsorbed onto silica gel, followed by purification by flash column chromatography (20% ethyl acetate/hexane) to afford 1.8 g colorless oil (93% yield).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[CH:14]=[CH:13][O:12][N:11]=2)=[CH:8][C:7]([C:15](=[NH:17])[NH2:16])=[N:6]1.[C:22](#[N:26])[CH2:23][C:24]#[N:25]>C(O)C>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[CH:14]=[CH:13][O:12][N:11]=2)=[CH:8][C:7]([C:15]2[N:16]=[C:24]([NH2:25])[CH:23]=[C:22]([NH2:26])[N:17]=2)=[N:6]1
Reactant: N#CCC#N
Reactant: N=C(N)c1cc(-c2ccon2)n(Cc2ccccc2F)n1
Solvent: CCO
Product: Nc1cc(N)nc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)n1
Temperature: 110 °C
Yield: 31.1 %

Procedure:
To a solution of 1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamide (50 mg, 0.18 mmol) in ethanol (2 mL) was added malononitrile (35 mg, 0.53 mmol). After heating the solution to 110° C. for 6 hours, the solvent was removed in vacuo to give the crude product as a red oil. Purification by silica gel chromatography (0-10% methanol in dichloromethane) gave 2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidine-4,6-diamine (I-103, 20 mg, 0.056 mmol, 32% yield) as a pink solid. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, 1H), 7.31 (s, 1H), 7.19-7.14 (m, 1H), 7.01-6.96 (m, 1H), 6.92 (t, 1H), 6.74-6.71 (m, 1H), 6.58 (d, 1H), 5.90 (s, 2H), 5.57 (s, 1H), 5.03 (br s, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([NH:9][NH2:10])=[O:8].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16]>C(O)C>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[N:10][NH:9][C:7]([C:6]2[S:5][C:4]3[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=3[C:2]=2[Cl:1])=[O:8])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: NNC(=O)c1sc2ccccc2c1Cl
Solvent: CCO
Product: O=C(NN=Cc1ccc([N+](=O)[O-])cc1)c1sc2ccccc2c1Cl
Yield: 66.7 %

Procedure:
A solution of 3-chlorobenzo[b]thiophene-carboxylic acid hydrazide (34 mg, 0.15 mmol) and p-nitrobenzaldehyde (23 mg, 0.15 mmol) in ethanol (10 mL) was refluxed for 6 h. The precipitate was collected by filtration and washed with ethanol, dried to give 36 mg (67%) of the title compound. 1H NMR (DMSO-d6): 12.40 (bs, 1H), 8.60−7.60 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[C:10]([NH:12][C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1)#[N:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:18]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]2=[N:12][C:10]#[N:11])=[CH:4][N:3]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: N#CNc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CN=c1ncccn1Cc1ccc(Cl)nc1
Yield: 38.1 %

Procedure:
A mixture of 2-chloro-5-chloromethylpyridine (3.24 g), 2-cyanaminopyrimidine(2.4 g), anhydrous potassium carbonate (3.04 g) and acetonitrile (100 ml) was refluxed for 5 hours under stirring. About 50 ml of the acetonitrile were evaporated under reduced pressure, and the residue was poured into ice water. The precipitated crystals were collected by filtration, and recrystallized from ethanol to give 1-(2-chloro-5-pyridylmethyl)-2-cyanoimino-1,2-dihydropyrimidine (1.87 g) as colorless crystals. mp. 218°-220° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:18]([OH:20])=O)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C.O>[C:38]([O:37][C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:18]([C:12]2([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:20])=[CH:28][CH:27]=1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: O=C(NC1(C(=O)O)CCOCC1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CNC(=O)C2(NC(=O)OCc3ccccc3)CCOCC2)cc1
Reaction time: 0.67 h

Procedure:
850 mg of the compound prepared in step B are dissolved in 15 ml of DMF, and equimolar amounts of 4-aminomethyl-2'-tert-butoxycarbonylbiphenyl, DIPEA and then BOP (10% excess) are added. After 40 minutes, the medium is taken up in 200 ml of ethyl acetate and 200 ml of water. The organic phase is decanted and then washed twice with a saturated solution of sodium bicarbonate, twice with a 5% solution of sodium bisulfate and then once with a saturated solution of sodium chloride. After drying over sodium sulfate, the organic phase is evaporated under vacuum to give 1.8 g of the expected product.
Reaction SMILES: Br[C:2]1[CH:39]=[CH:38][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([C:26]4[S:30](=[O:32])(=[O:31])[N:29]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:28](=[O:37])[CH:27]=4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:40]1([CH2:46][O:47][C:48]2[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[C:33]([N:29]1[C:28](=[O:37])[CH:27]=[C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([N:8]3[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=[C:7]3[CH2:6][C:5]3[CH:4]=[CH:3][C:2]([C:51]4[CH:52]=[CH:53][C:48]([O:47][CH2:46][CH:40]5[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]5)=[CH:49][CH:50]=4)=[CH:39][CH:38]=3)[CH:21]=2)[S:30]1(=[O:32])=[O:31])([CH3:35])([CH3:36])[CH3:34]
Reactant: OB(O)c1ccc(OCC2CCCCC2)cc1
Reactant: CC(C)(C)N1C(=O)C=C(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S1(=O)=O
Product: CC(C)(C)N1C(=O)C=C(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCC5CCCCC5)cc4)cc3)c2)S1(=O)=O

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-2-tert-butyl-isothiazol-3-one-1,1-dioxide (7 mg, 0.01 mmol) was treated as described in general procedure G using 4-(cyclohexylmethoxy)-phenylboronic acid (5 mg, 0.02 mmol, prepared according to general procedure H) to give 2-tert-Butyl-5-{3-[2-(4′-cyclohexylmethoxy-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-isothiazol-3-one-1,1-dioxide.
Reaction SMILES: [OH:1][C:2]1([C:18]2[C:19](=[O:25])[NH:20][C:21](=[O:24])[NH:22][CH:23]=2)[C:8]2[N:9]=[C:10]([CH3:12])[O:11][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:3]1=2.[CH3:26]I>>[CH3:26][N:22]1[CH:23]=[C:18]([C:2]2([OH:1])[C:8]3[N:9]=[C:10]([CH3:12])[O:11][C:7]=3[CH2:6][CH2:5][C:4]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:3]2=3)[C:19](=[O:25])[NH:20][C:21]1=[O:24]
Reactant: Cc1ccc2c(c1)CCc1oc(C)nc1C2(O)c1c[nH]c(=O)[nH]c1=O
Reactant: CI
Product: Cc1ccc2c(c1)CCc1oc(C)nc1C2(O)c1cn(C)c(=O)[nH]c1=O

Procedure:
The subtitle compound was prepared from the product of example 14 step (vi) (1.55 g) and methyl iodide (0.284 ml) according to the method of example 15 step (i). Purification was by flash column chromatography eluting with 5% methanol in ethyl acetate.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(N(CC)CC)C.[C:17]([O:22][CH2:23]Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>CN(C)C=O>[C:17]([O:22][CH2:23][N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(=O)OCCl
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(=O)OCn1cc(F)c(=O)[nH]c1=O
Yield: 86.9 %

Procedure:
In a 300 cc 4-necked flask equipped with a stirrer, a thermometer and a dropping funnel were placed 80 ml of dimethylformamide. Then, 10.41 g (0.08 mol) of 5-fluorouracil was dissolved in the dimethylformamide and 24.29 g (0.24 mol) of triethylamine was added to this solution. To the mixture was added dropwise over 15 minutes 10.93 g (0.08 mol) of butyryloxymethyl chloride. The mixture was reacted together for 5 hours at room temperature and the reaction liquid was filtered to remove the precipitated triethylamine hydrochloride. The solvent was then distilled from the filtrate and the residue was subjected to a treatment using a column packed with silica gel and a mixture (1:1 in mixing ratio) of benzene and ethyl acetate whereby crude 1-butyryloxymethyl-5-fluorouracil was isolated. This crude product was recrystallized from benzene whereby 16.0 g of pure white crystals having a melting point of 96°~98° C. were obtained in a yield of 86.9%.
Reaction SMILES: [C:1]1([C:7]2[O:8]C3C(N=2)=NC=CC=3)C=CC=[CH:3][CH:2]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:24][C:25]2[C:26]([N:32]=1)=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=2.S(=O)(=O)(O)O.C(O)(=O)C>O>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:24][C:25]2[C:26]([N:32]=1)=[N:27][C:28]([CH3:31])=[CH:29][C:30]=2[C:7](=[O:8])[CH2:1][CH2:2][CH3:3]
Reactant: Cc1ccc2oc(-c3ccccc3F)nc2n1
Reactant: c1ccc(-c2nc3ncccc3o2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCCC(=O)c1cc(C)nc2nc(-c3ccccc3F)oc12

Procedure:
Using the procedure described in Example 1, but replacing -phenyloxazolo[4,5-b]pyridine by 2-(2-fluorophenyl)-5-methyloxazolo[4,5-b]pyridine and using 1.5 ml of sulfuric acid, 5 ml of acetic acid (and not 7.5 ml) and 5 ml of water (and not 7.5 ml), and on purification by chromatography on silica gel (40 to 63μ; 70-230 mesh; eluent: ethyl acetate/toluene, 2:8), the product of the title is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:34][CH2:33][C:11]3([CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[C@H:13]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:35][C@H:36]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=2[N:48]2[CH:52]=[CH:51][C:50]([CH3:53])=[N:49]2)[C:37]([F:40])([F:39])[F:38])[N:3]=1>CCOC(C)=O.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:34][CH2:33][C:11]3([CH2:15][NH:14][C@H:13]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:35][C@H:36]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=2[N:48]2[CH:52]=[CH:51][C:50]([CH3:53])=[N:49]2)[C:37]([F:38])([F:40])[F:39])[N:3]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)OC(C)(C)C)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of (S)-2-benzyl 3-tert-butyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (1.35 g, 1.7 mmol) in EtOAc (130 mL) was added 5% (w/w) Pd/C (130 mg). The solution was degassed, charged with 1 atm H2 (balloon), and stirred at RT for 3.5 h. Then the solids were filtered through celite, washed with EtOAc/methanol, and the filtrate was concentrated in vacuo. Purification on a 220 g Isco RediSep silica cartridge (CH2Cl2/MeOH/NH4OH) provided the title compound as an off-white solid.