Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([F:10])[CH:3]=1.Cl.[CH3:12][C:13](=O)CC(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]2[N:9]=[C:12]([CH3:13])[NH:8][C:6]=2[CH:7]=1
Reactant: Nc1cc(Br)cc(F)c1N
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2c(F)cc(Br)cc2[nH]1
Reaction time: 3 h
Yield: 82 %

Procedure:
A round bottomed flask was charged with 5-bromo-3-fluorobenzene-1.2 diamine (400 mg, 2 mmol) and 30 mL ethanol. 5 N hydrochloric acid (8 mL, 40 mmol) was then added. This mixture was heated to reflux and 2,4-pentanedione was added. The reaction mixture turned deep purple in color then slowly turned back to tan. Reaction was allowed to proceed for 3 hours and then cooled and neutralized with saturated sodium bicarbonate solution. The reaction mixture was then extracted three times with dichloromethane. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The crude mixture was triturated in diethyl ether then filtered to give 6-bromo-4-fluoro-2-methyl-1H-benzo[d]imidazole (375 mg, 82%) as a tan solid, 1H NMR (400 MHz, CDCl3) δ ppm 7.44 (br. s., 1H), 7.10 (d, J=11.22 Hz, 1H), 2.63 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[C:29]1([NH2:36])[C:30]([NH2:35])=[CH:31][CH:32]=[CH:33][CH:34]=1.[C:37](O)(=O)[CH:38]([CH3:40])[OH:39]>>[OH:39][C@H:38]([C:40]1[N:36]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:15][CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]=1)[CH3:37]
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(O)C(=O)O
Reactant: Nc1ccccc1N
Product: C[C@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following the procedures for 157 and General Procedure J, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (1.21 g, 2.96 mmol) and benzene-1,2-diamine were reacted followed by condensation with lactic acid to give a racemic mixture. The enantiomers were separated by SFC to give 199. LCMS m/z: 535.3 (MH+)
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:16]/[CH2:17][O:18][C:19]2[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:21]([CH3:31])[CH:20]=2)=[CH:11][CH:10]=1.[CH2:38]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[C:39]#[CH:40]>O1CCCC1.[Cu]I.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>[CH3:31][C:21]1[CH:20]=[C:19]([O:18][CH2:17]/[CH:16]=[C:15](/[C:12]2[CH:13]=[CH:14][C:9]([C:40]#[C:39][CH2:38][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[CH:10][CH:11]=2)\[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][C:22]=1[O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: C#CCN1CCOCC1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccccc2)c2ccc(Br)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccccc2)c2ccc(C#CCN3CCOCC3)cc2)cc1C
Temperature: 50 °C

Procedure:
Dry triethylamine (8 mL), copper(I) iodide (29 mg, 0.152 mmol) and tetrakis(triphenylphosphine)palladium (68 mg, 0.059 mmol) were added to a degassed solution of the above ester (448 mg, 0.931 mmol) and N-propargylmorpholine (291 mg, 2.32 mmol) in dry tetrahydrofuran (18 mL). In atmosphere of argon, the resulting mixture was heated at 50° C. for 10 h, cooled down and subsequently evaporated in vacuo. The residue was dissolved in dichloromethane (20 mL); the solution was washed with water (3×10 mL), dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 4:1-1:1) yielding methyl (E)-[2-methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-phenylallyloxy]phenoxy]acetate as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
A solution of (2S)-2-(tert-butoxycarbonylamino)-3-phenyl-1-propanol (3.0 g, 11.9 mmol) in anhydrous CH2Cl2 (120 mL) at 0° C. under a dry N2 atmosphere was treated with triethylamine (3.5 mL, 25.1 mmol) followed by dropwise addition of methanesulfonyl chloride (1.0 mL, 13.1 mmol). After stirring for 2 hours at 0° C., the solution was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to a reduced volume (20 mL). The mixture was diluted with hexanes (100 mL) and allowed to stand at ambient temperature overnight. Colorless crystals were collected by filtration and dried under reduced pressure to provide the title compound (3.60 g, 92%). Rf=0.26 (hexanes:ethyl acetate, 2:1); 1H NMR (CDCl3) δ 7.36-7.18 (m, 5H), 4.71 (br s, 1H), 4.28-4.05 (m, 3H), 2.99-2.81 (m, 2H), 1.40 (s, 9H); MS (APCI+) m/z 254 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH:22]C(=O)C)([CH2:20][OH:21])[CH2:18][OH:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O.[OH-].[Li+]>O1CCCC1>[NH2:22][C:17]([CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)([CH2:20][OH:21])[CH2:18][OH:19]
Reactant: CC(=O)NC(CO)(CO)CCc1ccc(OCc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: NC(CO)(CO)CCc1ccc(OCc2ccccc2)cc1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
To a solution of crude N-[3-(4-benzyloxy-phenyl)-1,1-bis-hydroxymethyl-propyl]-acetamide in a mixture of tetrahydrofuran, methanol, water (1/2/2) (450 ml/900 ml/900 ml) is added at room temperature lithium hydroxide (32.7 g, 1.36 mol, 8.0 eq). The reaction mixture is stirred at 55° C. for 5 hours, then extracted with ethyl acetate (500 ml) and washed with brine (2×300 ml), the combined organic layers are then dried with Na2SO4, filtered and concentrated under vacuum. 2-Amino-2-[2-(4-benzyloxy-phenyl)-ethyl]-propane-1,3-diol is isolated after crystallization using ethyl acetate (28.8 g, 97%).
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([NH:21][C:22]3[N:27]=[C:26]([N:28]([CH:38]4[CH2:40][CH2:39]4)[CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[C:25]4=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:24]4[N:23]=3)[C:14]=2[Cl:46])[CH2:8]1)(=O)=O.[CH3:47][O:48][C:49]1[CH:56]=[CH:55][C:52]([CH2:53][NH2:54])=[CH:51][CH:50]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C(OCC)(=O)C>[Cl:46][C:14]1[C:13]([N:9]2[CH2:10][CH2:11][O:12][CH:7]([CH2:6][NH:54][CH2:53][C:52]3[CH:55]=[CH:56][C:49]([O:48][CH3:47])=[CH:50][CH:51]=3)[CH2:8]2)=[CH:18][C:17]([C:19]#[N:20])=[CH:16][C:15]=1[NH:21][C:22]1[N:27]=[C:26]([N:28]([CH:38]2[CH2:40][CH2:39]2)[CH2:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[C:25]2=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:24]2[N:23]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCOC(COS(C)(=O)=O)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COc1ccc(CNCC2CN(c3cc(C#N)cc(Nc4nc(N(Cc5ccc(OC)cc5)C5CC5)c5ncc(C#N)n5n4)c3Cl)CCO2)cc1
Temperature: 80 °C
Yield: 64.9 %

Procedure:
A vial was charged with (+/−)-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)morpholin-2-yl)methyl methanesulfonate (56.5 mg, 0.085 mmol) and 4-methoxybenzylamine (33.3 μl, 0.255 mmol) in acetonitrile (904 μl). Potassium carbonate (58.7 mg, 0.425 mmol) was added and the vial was capped and heated at 80° C. ON. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. (+/−)-2-((2-Chloro-5-cyano-3-(2-(((4-methoxybenzyl)amino)methyl)morpholino)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (38.9 mg) was isolated as a white solid and used as is in subsequent chemistry.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:18]([CH3:20])[CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.O>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:18]([CH3:20])[CH3:19])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)c1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)c1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A cooled (−78° C.) solution of 1-iodo-3-isopropyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (379 mg; 0.673 mmol) in anhydrous THF (6 ml) was treated dropwise with a 1.6N butyllithium solution in hexanes (1.05 ml; 1.680 mmol). The resulting mixture was additionally stirred at −78° C., under nitrogen, for 15 min. Water (0.2 ml) was then added and the reaction mixture was allowed to warm-up to rt. The resulting solution was diluted with ether (30 ml), the organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) gave the pure product 3-isopropyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (229 mg; 78%). LC-MS: tR=0.92 min.; [M+H]+=438.43 g/mol.
Reaction SMILES: C(OC(=O)NC(C(=O)N(CCN)CC(=O)NCC(C)(C1C=CC=CC=1)C)CC1NC=NC=1)C1C=CC=CC=1.[C:39]([O:43][C:44](=[O:49])[NH:45][CH2:46][CH2:47][NH2:48])([CH3:42])([CH3:41])[CH3:40].Br[CH2:51][C:52]([O:54][CH3:55])=[O:53].C(N(CC)CC)C.C(Cl)[Cl:64]>>[ClH:64].[CH3:55][O:54][C:52](=[O:53])[CH2:51][NH:48][CH2:47][CH2:46][NH:45][C:44]([O:43][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:49]
Reactant: ClCCl
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CC(C)(CNC(=O)CN(CCN)C(=O)C(Cc1cnc[nH]1)NC(=O)OCc1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CNCCNC(=O)OC(C)(C)C
Product: Cl

Procedure:
Scheme 3 shows a method by which the compounds of the present invention can be prepared, by illustrating the synthesis of Example 6, [1-{(2-Amino-ethyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester. Reaction of (2-aminoethyl) carbamic acid tert-butyl ester with methyl bromoacetate was carried out in methylene chloride in the presence of triethylamine as the base to give (2-tert-butoxycarbonylamino-ethylamino)-acetic acid methyl ester hydrochloride which was then coupled to Cbz-His(trityl) in methylene chloride/dimethylformamide with HATU and HOAt as coupling agents, and diisopropylethylamine as the base. The resulting product was saponified using sodium hydroxide, followed by coupling with β,β-dimethylphenethylamine in methylene chloride, with PyBOP as coupling agent, and diisopropylethylamine as the base. The trityl and Boc groups were removed by treatment with 95% aqueous TFA.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][OH:11])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[C:19](C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.IC>C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.[Ag+]>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][CH3:19])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4]
Reactant: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Reactant: COC(=O)C1CC(CO)CN1C(=O)OC(C)(C)C
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CI
Product: COCC1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.07 h
Yield: 52.8 %

Procedure:
4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (861 mg, 3.32 mmol) was dissolved in DCM (6.6 mL) then 2,6-di-tert-butyl-4-methylpyridine (1.023 g, 4.98 mmol) and AgOTf (938 mg, 3.65 mmol) were added. The reaction mixture was cooled to 0° C. and iodomethane (0.25 mL, 3.98 mmol) was added. After 4 min, the reaction mixture was diluted with DCM and it was filtered over elite. The filtrate was concentrated to a residue which was dissolved in diethyl ether. The organic solution was washed with 10% HCl and brine, then dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (20% to 80% EtOAc/Hex) to afford the title compound (479 mg, 53%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([CH2:11][CH2:12][C:13]([OH:15])=O)[C:3]1=2.[C:16](N1C=CN=C1)([N:18]1C=CN=[CH:19]1)=O.CNC>ClCCl.O1CCCC1>[CH3:16][N:18]([CH3:19])[C:13](=[O:15])[CH2:12][CH2:11][C:4]1[C:3]2[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=2[NH:6][CH:5]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CCc1c[nH]c2c1C(=O)CCC2
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)CCc1c[nH]c2c1C(=O)CCC2
Reaction time: 1 h
Yield: 56.9 %

Procedure:
3-(4-Oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (12 g, 0.06 mol) was suspended in 80 ml of dichloromethane and carbonyldiimidazole (11.3 g, 0.07 mol) was added with stirring. After 30 minutes 58 ml of 2.0 M dimethylamine in tetrahydrofuran was added. After one hour the solvent was rotary evaporated. The residue was redissolved in dichloromethane, washed with 1 N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and rotary evaporated. The solid residue was washed with ethyl acetate and dried under vacuum to give N, N-dimethyl-3-(4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionamide (8 g, 60% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40][C:41](=[O:47])OC(Cl)(Cl)Cl)Cl.[F:49][C:50]([F:61])([F:60])[C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=1)[CH2:54]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:40][CH2:38][CH2:54][C:53]2[CH:57]=[CH:58][CH:59]=[C:51]([C:50]([F:49])([F:60])[F:61])[CH:52]=2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCc1cccc(C(F)(F)F)c1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCc4cccc(C(F)(F)F)c4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 48 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (82 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (125 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-trifluoromethylphenethyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (68 mg, yield 45%).
Reaction SMILES: [C:1]([CH:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH2:2][CH3:3].O.[NH2:17][NH2:18]>C(O)(=O)C.C(OCC)C>[CH2:9]([O:8][C:6]([C:5]1[C:1]([CH2:2][CH3:3])=[N:17][NH:18][C:11]=1[OH:13])=[O:7])[CH3:10]
Reactant: NN
Reactant: CCOC(=O)C(C(=O)CC)C(=O)OCC
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)c1c(CC)n[nH]c1O
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To diethyl propionylmalonate (3.63 g, 16.8 mmol) in glacial acetic acid (8 ml) at RT, is added hydrazine hydrate (55% hydrazine, 1.4 ml, 25.2 mmol). The reaction mixture is heated at 100° C. for 2 hrs and allowed to cool to ambient temperature whereupon crystallization occurs. The mixture is diluted with diethyl ether (approx. 25 ml) and stirred for 20 minutes and filtered to obtain the title compound as a white solid. This is washed with diethyl ether and dried in vacuo. A second crop of product is obtained by cooling the filtrate liquor, the precipitated solid is washed with diethyl ether and dried in vacuo. 1H NMR (400 MHz, DMSO-d6) δ 12.0 (1H, br s), 9.8 (1H, br s), 4.16 (2H, q, J 7.1), 2.73 (2H, q, J 7.5), 1.24 (3H, t, J 7.1), 1.14 (3H, t, J 7.5).
Reaction SMILES: C(C1N(CC2C=CC=CC=2Cl)C(/C(/C)=C(\C2C=CN=CC=2)/[C:12]([OH:14])=[O:13])=CN=1)CCC.[CH2:30]([C:34]1[N:35]([CH2:41][C:42]2[CH:47]=[CH:46][C:45](C(OC)=O)=[CH:44][CH:43]=2)[C:36]([CH:39]=O)=[CH:37][N:38]=1)[CH2:31][CH2:32][CH3:33].C(C1N(CC2C=CC(C(OCC)=O)=CC=2Cl)C(C=O)=CN=1)CCC.[S:76]1[CH:80]=[CH:79][CH:78]=[C:77]1[CH2:81][CH2:82][C:83]([O:85]C)=[O:84]>>[CH2:30]([C:34]1[N:35]([CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[C:46]([C:12]([OH:14])=[O:13])[CH:47]=2)[C:36](/[CH:39]=[C:82](\[CH2:81][C:77]2[S:76][CH:80]=[CH:79][CH:78]=2)/[C:83]([OH:85])=[O:84])=[CH:37][N:38]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1
Reactant: CCCCc1ncc(/C(C)=C(/C(=O)O)c2ccncc2)n1Cc1ccccc1Cl
Reactant: COC(=O)CCc1cccs1
Agent: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OCC)cc1Cl
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1cccc(C(=O)O)c1

Procedure:
The title compound was prepared by the procedure of Example 1 (iv, Method B) using 2-n-butyl-1-[(4-carbomethoxyphenyl)methyl]imidazole-5-aldehyde (prepared by the method described for the preparation of 2-n-butyl-1-[(4-carboethoxy-2-chlorophenyl)methyl]imidazole-5-aldehyde in Example 42) and methyl 3-(2-thienyl)propanoate; mp 243°-244° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N12CCCN=C1CCCC[CH2:14]2.IC>C(#N)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:14])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1ccc2[nH]ccc2c1

Procedure:
To a solution of 1H-indole-5-carboxylic acid (1 g, 6.2 mmol, 1.0 equiv) in acetonitrile (40 mL) were added 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.1 mL, 7.4 mmol, 1.2 equiv) and iodomethane (2.3 mL, 37.2 mmol, 6 equiv). The solution was stirred under reflux overnight. The reaction mixture was concentrated in vacuo. The residue was dissolved in AcOEt, washed with a 0.5 N HCl aqueous solution, a saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated in vacuo. The obtained oil was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:43][C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[CH:43]=[CH:44][C:45]([C:47]([F:50])([F:49])[F:48])=[CH:46][C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1F
Product: Cn1ncc(NC(=O)c2nc(-c3ccc(C(F)(F)F)cc3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-4-(trifluoromethyl)phenyl)boronic acid gave 259. 1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.31 (q, J=9.1, 8.5 Hz, 1H), 7.93-7.84 (m, 1H), 7.83-7.71 (m, 2H), 7.61 (s, 2H), 5.17-4.82 (m, 2H), 4.31-4.14 (m, 1H), 4.08-3.93 (m, 1H), 3.77 (s, 3H), 3.51-3.37 (m, 1H), 2.19-2.05 (m, 1H), 1.98-1.81 (m, 2H), 1.75-1.67 (m, 1H). LCMS (ES+) m/z 517 (M+1).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[Br:9][CH2:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:9][CH2:10][CH2:11][CH2:12][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Oc1ccc(OCCCBr)cc1

Procedure:
A mixture of 88.0 g. (0.80 m.) of hydroquinone, 161.6 g. (0.80 m.) of 1,3-dibromopropane and 55.2 g. (0.40 m.) of potassium carbonate in 2 liters of 2-butanone was heated at reflux for 24 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo. The solid and liquid phases of the residue were separated, and the liquid fraction was chromatographed on silica gel using chloroform-acetonitrile (95:5) as the eluant. There was thus obtained 37.2 g. of 4-(3-bromopropyloxy)phenol as a light brown oil which was used directly in the next reaction.
Reaction SMILES: P(Cl)(Cl)Cl.[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:38][O:39][CH3:40])[C:12]([NH:14][CH:15]2[C:36](=[O:37])[N:17]3[C:18]([C:24]([O:26][CH2:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:25])=[C:19]([Cl:23])[CH2:20][S:21](=O)[C@H:16]23)=[O:13])[N:10]=1.[Cl-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:38][O:39][CH3:40])[C:12]([NH:14][CH:15]2[C:36](=[O:37])[N:17]3[C:18]([C:24]([O:26][CH2:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:25])=[C:19]([Cl:23])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: CCCCCC(=O)OCOC(=O)C1=C(Cl)CS(=O)[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: CCCCCC(=O)OCOC(=O)C1=C(Cl)CS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12
Reaction time: 0.83 h
Yield: 27.1 %

Procedure:
Phosphorus trichloride (210 mg.) was added to a solution of n-hexanoyloxymethyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate-1-oxide (syn-isomer: 570 mg.) in dry dimethylformamide (10 ml.) at -30° C., and stirred at -20° to -30° C. for 50 minutes. 10% Aqueous solution (50 ml.) of sodium chloride was added to the resultant solution, adjusted to pH 8.0 with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue (560 mg.) was purified with column chromatography on silica gel (20 g.) (eluent:ethyl acetate), and the resultant residue (180 mg.) was pulverized with n-hexane (10 ml.) and diethyl ether (5 ml.) to give n-hexanoyloxymethyl 7-[2-(2-amino-4-thiazolyl)- 2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn-isomer: 150 mg.) over magnesium sulfate and then concentrated under reduced pressure. The residue was pulverized with diisopropyl ether to give 7-[2-{2-(2,2,2-trifluoroacetamido)-4-thiazolyl}-2-methoxyiminoacetamido]-2,3-dimethyl-3-cephem-4-carboxylic acid (syn isomer, 0.9 g.).