Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].C1CCN2C(=NCCC2)CC1.[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=1>C(Cl)Cl>[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:8]2[S:7](=[O:13])(=[O:12])[N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=3[O:2][CH3:1])[C:10](=[O:11])[CH2:9]2)=[CH:35][CH:34]=1
Reactant: BrCc1ccc(CBr)cc1
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(CBr)cc3)S2(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the title B compound in Example 9, 2,4-dimethoxybenzyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2.0 g, 6.98 mmol) in CH2Cl2 (100 mL) is treated with DBU (1.06 g, 6.98 mmol). α, α′-Dibromo-p-xylene (9.2 g, 34.9 mmol) is added and the mixture is stirred at RT for 16 h. The mixture is filtered and the filtrate is concentrated to 20 mL. The mixture is chromatographed on silica gel using CH2Cl2 as the eluent. The residual α, α′-dibromo-p-xylene is removed from the product by triturating with Et2O to afford 5-(4-bromomethyl-benzyl)-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a white solid: [M+H]+=469.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>CO.C(Cl)Cl>[O:11]=[C:10]1[C:4]2[CH:3]=[C:2]([NH:1][C:21](=[O:22])[O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:13]=[CH:12][C:5]=2[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: Nc1ccc2c(c1)C(=O)CCCC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)C(=O)CCCC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of Example 128A (1.63 g, 9.30 mmol) and K2CO3 (2.57 g, 18.60 mmol) in MeOH (10 ml) under nitrogen atmosphere was cooled to 0° C. The mixture was treated with benzyl chloroformate (1.726 ml, 12.09 mmol), raised to room temperature and stirred for 16 hours. The mixture was diluted with CH2Cl2, washed with water, dried and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 15% EtOAc/hexanes to provide the title product. 1H NMR (CDCl3) δ 1.75-1.90 (m, 4H), 2.67-2.75 (m, 2H), 2.84-2.92 (m, 2H), 4.70 (d, J=5.76 Hz, 2H), 6.72 (s, 1H), 7.16 (d, J=8.14 Hz, 1H), 7.36-7.39 (m, 5H), 7.49 (d, J=2.71 Hz, 1H), 7.70 (d, J=7.12 Hz, 1H). MS (M+NH4)+ m/z 327.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[N:34][O:35][CH3:36])[C:9]([NH:11][CH:12]2[C:32](=[O:33])[N:14]3[C:15]([C:19]([O:21]CC4C=CC([N+]([O-])=O)=CC=4)=[O:20])=[CH:16][CH2:17][S:18][C@H:13]23)=[O:10])[N:3]=1>[Pd].O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[N:34][O:35][CH3:36])[C:9]([NH:11][CH:12]2[C:32](=[O:33])[N:14]3[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]23)=[O:10])[N:3]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1nccc(N)n1
Agent: [Pd]
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
A mixture of 4-nitrobenzyl 7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) (3.0 g) and 10% palladium on carbon (1.5 g) in 50% aqueous tetrahydrofuran (90 ml) was stirred under hydrogen atmosphere for 3 hours at ambient temperature. The catalyst was removed by filtration and the filtrate was concentrated to half of the original volume. The remaining aqueous solution was diluted with water (100 ml), washed with ethyl acetate, adjusted to pH 3 with 10% hydrochloric acid and subjected to column chromatography over nonionic adsorption resin, "Diaion HP20". The column was washed with water and eluted with 10% methanol. The eluent containing a desired compound was evaporated to remove the methanol in vacuo and then lyophilized to give 7-[2-(4-amino-pyrimidin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) (750 mg), mp 191°-197° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Si](C)(C)C)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=2)[N:7]=1.[C:22]1(=[O:26])[CH2:25][CH2:24][CH2:23]1>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.C1C=CC([Sn-](F)(F)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:3]([C:22]2([OH:26])[CH2:25][CH2:24][CH2:23]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=2)[N:7]=1
Reactant: C[Si](C)(C)c1cc2nnc(-c3ccccc3F)n2nc1Cl
Reactant: O=C1CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: OC1(c2cc3nnc(-c4ccccc4F)n3nc2Cl)CCC1
Temperature: 25 °C
Reaction time: 5.75 h
Yield: 25.5 %

Procedure:
To a stirred solution of 6-chloro-3-(2-fluorophenyl)-7-(trimethylsilyl)-1,2,4-triazolo[4,3-b]pyridazine (1.04 g, 3.24 mmol) in anhydrous THF (15 ml) under nitrogen was added cyclobutanone (1.21 ml, 16.2 mmol), followed by solid tetrabutylammonium difluorotriphenylstannate (0.410 g, 0.650 mmol). The flask was evaporated and refilled with nitrogen four times, then stirred at room temperature for 5.75 h. More tetrabutylammonium difluorotriphenylstannate (0.403 g, 0.639 mmol) was added and the mixture was stirred for a further 36 h. The mixture was then partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was extracted further with dichloromethane (2×50 ml), and the combined organic extracts were dried (Na2SO4) and evaporated in, vacuo. The residue was purified by flash chromatography (silica gel. 70-100% EtOAc/hexane) to give 0.2634 g (26%) of the title compound as a cream solid; 1H NMR (360 MHz, CDCl3) δ1.81 (1H, m), 2.27 (1H, m), 2.52 (2H, m), 2.72 (2H, m), 2.87 (1H, s), 7.30 (1H, t, J=9.3 Hz), 7.36 (1H, t, J=7.5 Hz), 7.58 (1H, m), 7.88 (1H, td, J=7.3 and 1.8 Hz), 8.12 (1H, s); MS (ES+) m/e 319/321 [MH]+, 249.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][CH:12]=1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[S:13]1[CH:14]=[CH:15][C:11]([CH2:10][NH:9][C:16](=[O:18])[CH3:17])=[CH:12]1
Reactant: CC(=O)Cl
Reactant: NCc1ccsc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccsc1
Temperature: -5 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
Triethylamine (0.46 g, 4.4 mmol) was added dropwise to a stirred suspension of 3-(aminomethyl)thiophene hydrochloride (0.6 g, 4 mmol) in dry dichloromethane (20 ml) maintained under nitrogen at -5° C. After 15 minutes acetyl chloride (0.31 g, 4 mmol) was added dropwise to the solution which was then stirred for 3 hours at -5° C. After this time the reaction mixture was washed sequentially with dilute HCl (50 ml, 0.5M) and dilute NaOH (50 ml, 0.5 m). The organic layer was separated, dried with magnesium sulphate, and the solvent removed in vacuo to yield the crude product which was recrystallised from hexane to give N-(3-thienylmethyl)acetamide (0.52 g, 85%) M.p. 46°-47° C. (Found: C, 53.5; H, 6.2; N. 8.7, S, 20.4. Calculated for C7H9NOS: C, 54.2; H, 5.8, N, 9.0; S, 20.7 (%); IR (Nujol): 3250, 1650 cm-1 ; EI m/e Intensity (%): 155 (37, M+), 112 (55, C4H3S.CH2NH+), 97 (29, C4H3S.CH2+). 83 (12, C4H3S); δH(CDCl3) 7.00-7.29 (3H, m), 6.26 (1H, br,s), 4.41 (2H, d), 1.93 (3H, s); δC(CDCl3): 23.1, 38.7, 122.2, 126.3, 127.3, 139.8, 170.0 ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][O:46][C:47]1[CH:48]=[C:49]([CH:52]=[C:53]([O:55][CH3:56])[CH:54]=1)[CH2:50][NH2:51]>CN(C=O)C>[CH3:56][O:55][C:53]1[CH:52]=[C:49]([CH:48]=[C:47]([O:46][CH3:45])[CH:54]=1)[CH2:50][NH:51][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:22]
Reactant: COc1cc(CN)cc(OC)c1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc(OC)c1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 3,5-dimethoxybenzylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-(3,5-dimethoxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide. LCMS; retention time 3.32 min, MH+ 444.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15]/[C:16](/[CH3:20])=[CH:17]/[CH2:18][OH:19].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:19][CH2:18]/[CH:17]=[C:16](\[CH3:20])/[CH2:15][CH2:14][C:4]1[C:5]([CH3:13])=[C:6]([O:11][CH3:12])[C:7]([CH3:10])=[C:8]([CH3:9])[C:3]=1[O:2][CH3:1])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(C)c(C)c(OC)c(CC/C(C)=C/CO)c1C
Solvent: c1ccncc1
Product: COc1c(C)c(C)c(OC)c(CC/C(C)=C/COC(C)=O)c1C
Temperature: 0 °C

Procedure:
A solution of 4.17 g (15 mmol) of (E)-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-methyl-2-penten-1-ol in pyridine (10 ml) and acetic anhydride (2 ml) was stirred at room temperature for 5 hours and thereafter poured into ice-cold 2N hydrochloric acid solution. The mixture was extracted with ether. The combined extracts were washed with water, dried and freed from solvent; the residue obtained was purified on silica gel with hexane/ethyl acetate (95:5), yielding 3.8 g of (E)-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenyl acetate as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[N:14]([C:15]([O:17]C3C=CC([N+]([O-])=O)=CC=3)=O)[C:13](=[O:27])[NH:12][C:11]([CH2:28][O:29][CH3:30])=[C:10]2[C:31]([O:33][CH3:34])=[O:32])[CH:5]=[CH:6][C:7]=1[F:8].[N+:35]([C:38]1[CH:39]=[C:40]([C:44]2[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][CH2:52][NH2:53])[CH2:48][CH:49]=2)[CH:41]=[CH:42][CH:43]=1)([O-])=O.C([O-])([O-])=O.[K+].[K+].CO>ClCCl>[NH2:35][C:38]1[CH:39]=[C:40]([CH:44]2[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][CH2:52][NH:53][C:15]([N:14]3[C@@H:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[C:10]([C:31]([O:33][CH3:34])=[O:32])=[C:11]([CH2:28][O:29][CH3:30])[NH:12][C:13]3=[O:27])=[O:17])[CH2:48][CH2:49]2)[CH:41]=[CH:42][CH:43]=1
Reactant: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Reactant: NCCCN1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)NCCCN2CCC(c3cccc(N)c3)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
A mixture of 3.02 g (6.33 mmol) 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5 (2H)-pyrimidinedicarboxylate, 1.50 g (5.80 mmol) of 3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)-1-propanamine, 7.94 g (75.5 mmol) of K2CO3 and 1.00 mL of methanol in 200 mL dichloromethane (under argon) was stirred at room temperature for 1 hour. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in 100 mL of ethyl acetate and washed 3×50 mL of 5% aqueous NaOH solution, the organic layer was dried (MgSO4) and concentrated in vacuo. The residue was dissolved in 100 mL of anhydrous ethanol containing 0.50 g 10% Pd/c and the reaction mixture was stirred under a hydrogen balloon for 24 hours. The reaction mixture was passed through a column of Celite 545 filtering agent, washed with ethanol, the filtrate was dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica, 9.5:0.5, dichloromethane:methanol+1% isopropyl amine) to afford 1.65 g (52.0% yield) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.22–7.02 (m, 2H), 6.95 (t, J=8.70 Hz, 1H), 6.63–6.44 (m, 4H), 4.56 (Abq, 2H), 3.62 (s, 3H) 3.33 (s, 3H), 3.32-3.20 (m, 4H), 2.96 (br s, 2H), 2.33 (t, J=7.50 Hz, 2H), 2.11–1.94 (m, 3H), 1.81–1.64 (m, 4H); ESMS m/e: 572.3 (M+H)+;
Reaction SMILES: [CH2:1]([O:3][CH:4]1[C:13]2[C:8](=[C:9]([CH3:18])[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[C:12]=2[CH3:14])[S:7][CH2:6][CH2:5]1)[CH3:2].C(O)(=[O:21])C.OO>O>[CH2:1]([O:3][CH:4]1[C:13]2[C:8](=[C:9]([CH3:18])[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[C:12]=2[CH3:14])[S:7](=[O:21])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC1CCSc2c(C)cc(C(=O)O)c(C)c21
Agent: OO
Solvent: O
Product: CCOC1CCS(=O)c2c(C)cc(C(=O)O)c(C)c21

Procedure:
A 50-ml egg-plant type Flask was charged with 2.9 g (0.011 mol) of 4-ethoxy-5,8-dimethylthiochroman-6-carboxylic acid, 10 ml of acetic acid and 1.3 g (0.011 mol) of a 30% hydrogen peroxide aqueous solution, and the mixture was allowed to react at room temperature for 12 hours. Then, the reaction mixture was poured into 100 ml of water. The precipitated oil was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2.5 g of 4-ethoxy-5,8-dimethylthiochroman-6-carboxylic acid-1-oxide (Compound 31) shown in Table 2.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:23])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:9]=2)=[O:4].[NH2:24][CH2:25][C:26]([O-:28])=[O:27].[Na+]>COCCO>[CH:17]1([O:16][C:10]2[CH:9]=[C:8]3[C:13]([C:14]([OH:15])=[C:5]([C:3]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:4])[C:6](=[O:23])[O:7]3)=[CH:12][CH:11]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2ccc(OC3CCCCC3)cc2oc1=O
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CNC(=O)c1c(O)c2ccc(OC3CCCCC3)cc2oc1=O
Yield: 81 %

Procedure:
To a mixture of 7-cyclohexyloxy-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (90 mg, 0.28 mmol) and sodium glycinate (275 mg, 2.83 mmol) in 2-methoxyethanol was microwaved at 150° C. for 1 h and then concentrated. Residue was dissolved in water (60 mL) and extracted with (1/1) EtOAc/hexanes which was discarded. The aqueous layer was acidified using 1 N HCl to pH=3-4 and extracted with EtOAc (2×). Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound (82 mg). MS ESI(−) m/e: 360.06 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6](Cl)[N:5]=[C:4]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.Cl.[F:25][C:26]([F:31])([F:30])[C@@H:27]([NH2:29])[CH3:28].C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:5]=[C:6]([NH:29][C@@H:27]([CH3:28])[C:26]([F:31])([F:30])[F:25])[C:7]=1[C:8]1[C:9]([F:16])=[CH:10][C:11]([F:15])=[CH:12][C:13]=1[F:14]
Reactant: Fc1cc(F)c(-c2c(Cl)nc(-c3cnccn3)nc2Cl)c(F)c1
Reactant: C[C@H](N)C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(-c2cnccn2)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Temperature: 90 °C
Reaction time: 18 h
Yield: 44.9 %

Procedure:
A mixture of 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluorophenyl)pyrimidine (205 mg, 0.57 mmol), (1S)-2,2,2-trifluoro-1-methylethylamine hydrogen chloride (298 mg, 2 mmol), and N,N-diisopropylethylamine (258 mg, 2 mmol) in 5 mL of N,N-dimethylformamide is stirred at 90° C. in a sealed tube for 18 h. The reaction mixture is partitioned between ethyl acetate and saturated sodium chloride. The organic layer is washed with saturated sodium chloride (×3), dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of 20% ethyl acetate in hexanes to 50% ethyl acetate in hexanes. Concentration provides 6-chloro-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine as a light yellow solid (111 mg). MS: m/z 434.1 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][C:10]3[C:17]4([CH3:20])[CH2:18][CH2:19][CH:14]([CH:15]([CH3:21])[O:16]4)[C:11]=3[N+:12]=2[O-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCCCC=1>[Pd].C(O)C>[C:1]1([C:7]2[N:8]=[N:9][C:10]3[C:17]4([CH3:20])[CH2:18][CH2:19][CH:14]([CH:15]([CH3:21])[O:16]4)[C:11]=3[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1OC2(C)CCC1c1c2nnc(-c2ccccc2)[n+]1[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC1OC2(C)CCC1c1nc(-c3ccccc3)nnc12

Procedure:
To a solution of 1.66 g. (0.006 mole) 3-phenyl-5,8-dihydro-6,8-dimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazine-4-oxide and 1.50 g. (0.018 mole) cyclohexene in 30 ml. absolute ethanol there is added 60 mg. 10% palladium on charcoal. The resulting mixture is refluxed under a nitrogen atmosphere for 18 hours. The catalyst is then removed by filtration and the filtrate evaporated to give 3-phenyl-5,8-dihydro-6,8-dimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazine.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.C(N(CC)CC)C.[C:20](=O)([O:26]C(C)(C)C)[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>ClCCl>[C:22]([O:21][C:20]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)=[O:26])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)Cc1csc(N)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
Ethyl 2-amino-4-thiazole-acetate (5.0 g, 26.8 mmol) and triethylamine (3.8 ml, 26.8 mmol) were dissolved in a dichloromethane (20 ml). Di-t-butyl carbonate (7.0 g, 32.2 mmol) was added to the solution under cooling with ice water. The mixture was stirred overnight at room temperature. After 18 hours, additional di-t-butyl carbonate (1.4 g, 13.4 mmol) was added, and the resultant mixture was stirred at room temperature for 6 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resultant residue was dissolved in ethyl acetate, washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain 3.1 g of ethyl 2-t-butoxycarbonylamino-4-thiazole-acetate. A part (2.0 g, 7.0 mmol) of this compound was dissolved in a mixed solvent of ethanoltetrahydrofuran (3:2, 50 ml). Lithium chloride (592 mg, 14.0 mmol) and sodium borohydride (528 mg, 14.0 mmol) were added to the solution at room temperature, and the mixture was stirred at room temperature for 6 hours. After 6 hours, sodium borohydride (530 mg, 14.1 mmol) and lithium chloride (592 mg, 14.0 mmol) were additionally added, and the resultant mixture was stirred further for 3 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on silica gel (hexane:ethyl acetate=1:1 to 2:3) to obtain 959 mg of the title compound (oil).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20]([Cl:23])[N:21]=[CH:22][C:15]=2[N:14]([CH3:24])[C:13]1=[O:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=1>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:39]([C:38]3[CH:41]=[CH:42][C:35]([Cl:34])=[CH:36][CH:37]=3)[OH:40])=[C:20]([Cl:23])[N:21]=[CH:22][C:15]=2[N:14]([CH3:24])[C:13]1=[O:25])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2cc(Cl)ncc21
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Cl)ncc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloro-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (383 mg, 1 mmol) in THF (4 mL) at −78° C. was added LDA (1.8N in THF, 2.7 mL, 4.86 mmol) dropwise. The reaction was stirred at −78° C. for 30 min then 4-chlorobenzaldehyde (280 mg, 2 mmol) in THF (1 mL) was added dropwise. After stirring for 20 min the reaction was quenched with aq. NH4Cl (2 mL) then diluted with EA (5 mL) and water (2 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (2:1) to give 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloro-5-((4-chlorophenyl)(hydroxy)methyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (155 mg, 30% yield) as a white solid. LCMS: (M+-OH—H) 506 and TR=2.357 min.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][CH2:40][CH2:41][NH:42][C:43](=[O:51])[CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][C:43]([NH:42][CH2:41][CH2:40][O:39][CH3:38])=[O:51])[CH2:50][CH2:49]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCNC(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NCCOC)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with N-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide (Enamine) to give the title compound. HR-MS (ES, m/z) calculated for C38H49Cl2N6O4 [(M+H)+] 723.3187, observed 723.3191.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].O=S(Cl)Cl.[CH3:16]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccc1Br
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)c(C)c1
Reaction time: 2 h

Procedure:
Into a 10,000-mL 4-necked round-bottom flask was placed a solution of 4-bromo-3-methylbenzoic acid (500 g, 2.33 mol, 1.00 equiv) in methanol (5000 mL). This was followed by the addition of SOCl2 (556 g, 4.67 mol, 2.00 equiv) dropwise with stirring at <10° C. over 120 min. The resulting solution was heated to reflux for 5 h in an oil bath. The resulting mixture was cooled and concentrated under vacuum. This resulted in 535 g (crude) of methyl 4-bromo-3-methylbenzoate as a dark red solid.