Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12].[CH2:15]1COC[CH2:16]1>>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:9])[CH2:15][CH3:16])[CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Nc1ccc(C=O)cc1F
Reactant: C1CCOC1
Product: CCC(O)c1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A cooled solution of N-(2-Fluoro-4-formylphenyl)methansulfonamide (20-3, 0.424 g, 2 mmol) in THF (20 mL) at 0° C. was treated with Grignard reagent (4 mmol) and stirred at 0° C. for 30 min. The reaction mixture was quenched with saturated ammonium chloride solution, diluted with water and extracted with EtOAc several times. The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:1) as eluant to N-[2-fluoro-4-(1-hydroxypropyl)phenyl]methanesulfonamide (20-4, LJO-337).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13](O)[CH3:14].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.S([O-])(O)(=O)=O.[Na+]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
(tert-Butoxycarbonylamino)acetic acid (4.00 g, 22.8 mmol) was dissolved in dichloromethane (8 ml). Ethanol (1.60 ml, 27.40 mmol) and 4-dimethylaminopyridine (0.31 g, 25.1 mmol) were added. The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (4.81 g, 25.11 mmol) was added. The solution was stirred for 16 h, while warming up to room temperature. It was diluted with ethyl acetate (150 ml) and 10% aqueous sodium hydrogen sulfate solution (100 ml). The phases were separated. The aqueous phase was extracted with ethyl acetate (4×50 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (150 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (100 g), using ethyl acetate/heptane (1:4) as eluent, to give 4.25 g of ethyl 2-(tert-butoxycarbonylamino)acetate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.Cl>O>[NH2:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: O
Product: N#Cc1ccc(Nc2cc(Cl)nc(N)n2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
300 mg (1.83 mmol) of 2-amino-4,6-dichloropyrimidine and 216 mg (1.83 mmol) of 4-aminobenzonitrile are suspended in 6 ml of water. 180 μl of concentrated hydrochloric acid are added, and the mixture is stirred at 100° C. overnight. The precipitate is filtered off with suction.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C@H:13]([C:23]([O:25]C)=[O:24])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:11].[OH-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C@H:13]([C:23]([OH:25])=[O:24])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[O:11]
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)c1cc2ccccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)c2cc3ccccc3o2)C(=O)O)cc1
Yield: 79.6 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 51 (3.4 g), 1 mol/L of an aqueous sodium hydroxide solution (15 mL), and methanol (150 mL), to give the captioned compound (2.6 g, 78%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](C(C3C(C)=NC(C)=CC=3)O)[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.N1(C2C=CC(CC3C(Cl)=NC4C(C=3Cl)=CC(Br)=CC=4C)=CC=2)C=CC=N1.[CH3:61][N:62]1[C:66]([C:67]([CH:69]2[CH2:74][CH2:73][O:72][CH2:71][CH2:70]2)=[O:68])=[CH:65][N:64]=[C:63]1[CH3:75].S1C(CC2C(OC)=NC3C(C=2Cl)=CC(C(C2N(C)C=NC=2)(C2C=NC(C(F)(F)F)=CC=2)O)=CC=3)=CC2C=CC=CC1=2>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:67]([C:66]3[N:62]([CH3:61])[C:63]([CH3:75])=[N:64][CH:65]=3)([CH:69]3[CH2:74][CH2:73][O:72][CH2:71][CH2:70]3)[OH:68])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1ncc(C(=O)C2CCOCC2)n1C
Agent: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1cc2ccccc2s1
Agent: Cc1cc(Br)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Product: COc1nc2ccc(C(O)(c3cnc(C)n3C)C3CCOCC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared analogously to the method described in Example 78, using 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (Intermediate 12: step d) in place of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloro-8-methylquinoline (Intermediate 57) and (1,2-dimethyl-1H-imidazol-5-yl)(tetrahydro-2H-pyran-4-yl)methanone (Intermediate 31) in place of 1-(4-(6-(trifluoromethyl)nicotinoyl)piperidin-1-yl)ethanone (Intermediate 56: step d). MS m/e 560.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:20][NH:21][C:22]([C:24]1[C:25]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:26]=2[S:27][C:28]=1[CH2:29][CH3:30])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:20][NH:21][C:22]([C:24]1[C:25]2[CH:34]=[CH:33][C:32]([O:35][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:31][C:26]=2[S:27][C:28]=1[CH2:29][CH3:30])=[O:23]
Reactant: CCc1sc2cc(O)ccc2c1C(=O)NC
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](OC)C5)sc34)ccc2c1C(=O)NC
Yield: 27.4 %

Procedure:
This material was prepared by reacting 7-chloro-2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine 4b (74 mg, 0.25 mmole) with 2-ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic acid methylamide 134d (71 mg, 0.30 mmole) and Cs2CO3 (244 mg, 0.75 mmole) in a manner analogous to that described for example 1 to give a yellow solid (34 mg, 19%). 1H NMR (DMSO-d6, 300 MHz), δ8.59 (1H, d, J=5.31 Hz), 8.33 (1H, q, J=4.46 Hz), 8.06 (1H, s), 7.99 (1H, d, J=2.27 Hz), 7.81 (1H, d, J=8.84 Hz), 7.34 (1H, dd, J=2.27, 8.84 Hz), 6.76 (1H, d, J=5.56 Hz), 4.08-3.83 (3H, m), 3.67-3.48 (2H, m), 3.27, 3.24 (3H, s), 3.00 (2H, t, J=7.49 Hz), 2.83 (3H, d, J=4.55 Hz), 2.16-1.95 (2H, m), 1.28 (3H, t, J=7.58 Hz).
Reaction SMILES: [OH-:1].[K+].[CH2:3]1O[CH:4]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:12][CH2:11]1>>[O:12]1[C:10]2([O:1][CH:11]12)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:4][CH3:3]
Reactant: [OH-]
Reactant: C(CCC1CO1)CC1CO1
Agent: [K+]
Product: CCCCCCC12OC1O2

Procedure:
A 1-liter resin flask was charged with 200 g of PEG-7500 and 0.3 g KOH and vacuum stripped at 100° C. for one-half hour. To this stirred solution under nitrogen were added 5.5 g of 1,2,7,8-diepoxyoctane at 100° C. over 15 minutes. The mixture was maintained at this temperature for an additional one and one-half hours followed by quenching with 250 g of water.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:30])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C@H:13]1[CH2:18][CH2:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1.Cl>C(Cl)Cl.CO>[CH3:3][O:4][C:5](=[O:30])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C@H:13]1[CH2:18][CH2:19][CH:20]([OH:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1
Reactant: COC(=O)COCCCCN1C(=O)CC[C@H]1CCC(=O)Cc1cccc(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)COCCCCN1C(=O)CC[C@H]1CCC(O)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 20.1 %

Procedure:
Sodium borohydride (4.1 mg, 0.11 mmol) was added to a solution of (4{(R)-2-[4-(3-Chlorophenyl)-3-oxo-butyl]-5-oxo-pyrrolidin-1-yl}-butoxy)-acetic acid methyl ester (44 mg, 0.11 mmol) in CH2Cl2 (1 mL) at rt. Methanol (3 drops) was added and the reaction was stirred at rt for 4.5 h. Aqueous HCl (0.5 M, 5 mL) was added and the mixture was extracted with CH2Cl2 (2×8 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (0%→3% MeOH/CH2Cl2) to afford 9.1 mg (21%) of (4-{(R)-2-[4-(3-chlorophenyl)-3-hydroxy-butyl]-5-oxo-pyrrolidin-1-yl}-butoxy)-acetic acid methyl ester.
Reaction SMILES: [CH3:1][S:2]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:32][CH:31]=1)(=[N:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[O:25][CH:26]=[CH:27][C:28]=3[CH3:29])=[O:23])[CH:16]=2)[CH:12]=1)=[O:6])=[O:3].CCN=C=NCCCN(C)C.[CH2:52](O)[CH2:53][OH:54]>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:1][S:2]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([O:40][CH2:52][CH2:53][OH:54])=[O:39])=[CH:32][CH:31]=1)(=[N:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[O:25][CH:26]=[CH:27][C:28]=3[CH3:29])=[O:23])[CH:16]=2)[CH:12]=1)=[O:6])=[O:3]
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)O)cc3)c2)c1
Reactant: OCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)OCCO)cc3)c2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)phenyl]propanoic acid (0.150 g, 0.270 mmol) was dissolved in DMF (2.7 mL) then treated with EDCI (0.062 g, 0.324 mmol) and DMAP (0.003 g, 0.027 mmol) and allowed to stir at 60° C. for 30 min. Ethylene glycol (3 mL) was then added and the reaction was allowed to stir for 4 hours. The reaction mixture was then cooled to room temperature and dissolved in EtOAc (10 mL) and extracted with brine (3×10 mL). The organic layer was dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude mixture was then redisolved in EtOAc (1 mL) and triturated with Hexanes (20 mL) causing the product to precipitate out. The resulting white solid to give the title compound (0.125 g, 77%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30]C)=[O:29])=[CH:23][CH:22]=3)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>C1COCC1.CO>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([O:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:25][CH:26]=3)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCC(Oc1ccc(CC(=O)OC)cc1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCC(Oc1ccc(CC(=O)O)cc1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.3 %

Procedure:
A solution of methyl {4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}acetate (329 mg, 0.72 mmol) in THF (9.5 mL) and methanol (9.5 mL) was treated with aqueous NaOH (2M, 9.5 mL) drop-wise and the resulting solution stirred at rt for 17 hours. The volatile solvents were then removed under vacuum and the resulting aqueous mixture acidified with aqueous HCl (2M, 15 mL), diluted with water (100 mL) and the product extracted with DCM (2×100 mL). The combined organic layers were then washed with brine (100 mL), dried (MgSO4), filtered and then reduced under vacuum to give the title compound as a pale yellow foam (314 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)[C:10]=2[N:11]=1.[C:20](O)(=[O:23])[CH:21]=[CH2:22].Cl.CN(C)CCCN=C=NCC.CCOC(C)=O.C(Cl)Cl>CC(N(C)C)=O.C(Cl)Cl.CCCCCC.CO.C(Cl)Cl.CCOC(C)=O>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:9]2[C:10]3[N:11]=[C:2]([NH:1][C:20](=[O:23])[CH:21]=[CH2:22])[CH:3]=[CH:4][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Reactant: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: CCCCCC
Product: C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Yield: 26 %

Procedure:
To a stirred solution of 6-amino-4-[(3-bromo-phenyl)amino]pyrido[3,2-d]pyrimidine (J Med Chem, 1996;39:1823) (46 mg, 0.15 mmol) and acrylic acid (6 mol eq., 0.91 mmol, 62 μL) in DMA (5.0 mL) under N2 was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl) (4.0 mol eq., 0.61 mmol, 116 mg). The reaction mixture was stirred for 48 hours with additional amounts of acrylic acid and EDCI.HCl (62 μL/116 mg) being added every 12 hours it was then worked up as above to give after chromatography on silica gel eluting with EtOAc:CH2Cl2 (1:1) to MeOH/CH2Cl2/EtOAc (2:48:50), N-[4-[(3-bromophenyl)-amino]pyrido[3,2-d]pyrimidin-6-yl]acrylamide (14 mg, 26%) as a cream powder, mp (CH2Cl2/hexane) 226-228° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([OH:25])[CH2:21][CH:22]([CH3:24])[CH3:23])=[C:16]([CH3:26])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])(O)=O.[Na+].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:29])([F:28])[F:30])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23])=[C:16]([CH3:26])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(O)CC(C)C
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)CC(C)C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 1-{4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-phenyl}-3-methyl-butan-1-ol (i.e. the product of Step 1, 1.20 g) in CH2Cl2 (50 mL) was added Dess-Martin-Periodinan (CAS [87413-09-0], 1.216 g) in small portions. After 30 min at room temperature, saturated aqueous NaHCO3 and Na2S2O4 solutions were added and the mixture was extracted with CH2Cl2. The organic layer was washed with water, dried (Na2SO4) and concentrated in vacuum. The residue was purified by flash chromatography on silica gel to yield the title compound (1.05 g, 88%).
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[C:6]([O:20][CH3:21])[CH:7]=[C:8]([CH2:11][CH2:12][NH:13]C(=O)C(F)(F)F)[CH:9]=2)[NH:4][N:3]=1.[ClH:22].Cl.OC1C2C(=C(OC)C=CC=2CCN)NN=1>C(O)C.C(OCC)C>[ClH:22].[OH:1][C:2]1[C:10]2[C:5](=[C:6]([O:20][CH3:21])[CH:7]=[C:8]([CH2:11][CH2:12][NH2:13])[CH:9]=2)[NH:4][N:3]=1
Reactant: COc1cc(CCNC(=O)C(F)(F)F)cc2c(O)n[nH]c12
Agent: COc1ccc(CCN)c2c(O)n[nH]c12
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: COc1cc(CCN)cc2c(O)n[nH]c12

Procedure:
2.7 g of N-[2-(3-hydroxy-7-methoxy-1H-indazol-5-yl)ethyl]trifluoroacetamide is refluxed with hydrochloric acid as disclosed in the preparation of 2-(3-hydroxy-7-methoxy-1H-indazol-4-yl)ethylamine, hydrochloride, thus obtaining by crystallization from ethanol/diethyl ether 1.5 g of 2-(3-hydroxy-7-methoxy-1H-indazol-5-yl)ethylamine, hydrochloride, decomposition point 266°-268° C.
Reaction SMILES: CCN(CC)CC.[O:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:18])[CH2:9]1.[CH:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)=O>CC(OC(C)=O)=O>[O:18]=[C:10]1[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:8][CH:9]1[CH2:19][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: O=C1COc2ccccc2N1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(CC2Oc3ccccc3NC2=O)cc1
Yield: 13.2 %

Procedure:
Et3N (3.18 ml, 22.8 mmol) was added to a stirring solution of 2-H-1,4-benzoxazin-3-(4H)one (2.50 g, 16.8 mmol) and methyl 4-formylbenzoate (4.59 g, 27.5 mmol) in Ac2O (20 ml). The reaction mixture was refluxed 16 h. After this mixture was cooled for 3 days, the solid was filtered and rinsed with ethyl acetate to afford the title compound 266 (657 mg, 13%) as a yellow solid. LRMS: 295.1 (Calc.). 296.0 (found).
Reaction SMILES: F[C:2]1(F)[C:10]2[C:5](=[C:6]([F:14])[C:7]([F:13])=[C:8]([F:12])[C:9]=2[F:11])[C:4](=[O:15])[O:3]1.C(=O)([O-])[O-:18].[Na+].[Na+]>>[F:11][C:9]1[C:8]([F:12])=[C:7]([F:13])[C:6]([F:14])=[C:5]2[C:4](=[O:15])[O:3][C:2](=[O:18])[C:10]=12
Reactant: O=C1OC(F)(F)c2c(F)c(F)c(F)c(F)c21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 87.5 %

Procedure:
Into a 500 ml glass reactor equipped with a reflux condenser and a stirrer, 100 g (0.413 mol) of the 3,3,4,5,6,7-hexafluoro-1-[3H]-isobenzofuranone separated by distillation from the mixture of Example 2, and 43.8 g (0.413 mol) of sodium carbonate were charged, and the mixture was reacted at 130° C. for 8 hours with vigorous stirring. Then, the reaction mixture was separated by distillation to obtain 79.5 g of tetrafluorophthalic anhydride. The yield was 87.5%.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:24](=[O:35])[NH:23][CH2:22]2)=[C:4]([O:36][CH3:37])[CH:3]=1.[H-].[Na+].[F:40][C:41]([F:55])([F:54])[C:42]1[CH:43]=[C:44]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[CH2:45]Br>CN(C=O)C>[F:40][C:41]([F:54])([F:55])[C:42]1[CH:43]=[C:44]([CH:47]=[C:48]([C:50]([F:53])([F:51])[F:52])[CH:49]=1)[CH2:45][N:23]1[CH2:22][CH:21]([C:12]2[CH:13]=[C:14]([C:17]([F:20])([F:18])[F:19])[CH:15]=[CH:16][C:11]=2[C:5]2[CH:6]=[C:7]([CH:8]([CH3:9])[CH3:10])[C:2]([F:1])=[CH:3][C:4]=2[O:36][CH3:37])[N:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:24]1=[O:35]
Reactant: COc1ccc(CN2C(=O)NCC2c2cc(C(F)(F)F)ccc2-c2cc(C(C)C)c(F)cc2OC)cc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2c2cc(C(F)(F)F)ccc2-c2cc(C(C)C)c(F)cc2OC)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 19 mg of 5-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1-(4-methoxybenzyl)imidazolidin-2-one (INTERMEDIATE 32) in 1 mL of DMF was added 3 mg of NaH (60% dispersion in oil). The solution was stirred for 10 min at 0° C. and then 8 μL of 3,5-bistrifluoromethylbenzyl bromide was added and the mixture was stirred for 3 h at 0° C. The reaction mixture was quenched with a drop of water and then filtered and purified by reverse-phase HPLC [Waters XTerra C8 19×50 mm column, eluting at 20 mL/min with 90% water (0.1% TFA) to 100% acetonitrile (0.1% TFA) over 5.15 min, hold for 1.45 min, then back to 90% water over 0.5 min] to provide the title compound. Mass spectrum (ESI) 743.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[S:27]>C(=O)(O)[O-].[Na+]>[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[NH:25][C:26]([NH:16][CH2:15][C:14]1[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[N:10][CH:11]=[CH:12][CH:13]=1)=[S:27]
Reactant: COc1ccccc1-c1ncccc1CN
Reactant: S=C=Nc1cccc(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccccc1-c1ncccc1CNC(=S)Nc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To an oven-dried, N2-purged, 25-mL, round-bottomed flask containing a magnetic stir bar was added the crude C-[2-(2-methoxy-phenyl)-pyridin-3-yl]-methylamine (430 mg, 2.0 mmol) from above. The flask was sealed with a septum and purged with N2 atmosphere. Anhydrous tetrahydrofuran (10 mL) was added via syringe. Neat 2,3-dichlorophenylisothiocyanate (510 mg, 356 μL, 2.50 mmol) was added via syringe. The pale green solution was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate (10 mL) was added to quench. The mixture was transferred to a separatory funnel and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to give a tan solid. The product was recrystallized from ethyl acetate/hexanes to give a 712 mg (85%) of the title compound as a white powder. MS (LC-MS, ESI+) m/z 417.0 (M+H)+; 1H NMR (DMSO-d6) δ 3.74 (s, 3H), 4.35 (br s, 1H), 4.66 (br s, 1H), 7.03-7.13 (m, 2H), 7.22 (dd, J=7.5, 1.7 Hz, 1H), 7.31-7.60 (m, 6H), 7.74 (dd, J=7.1, 1.0 Hz, 1H), 8.23 (br s, 1H), 8.51 (dd, J=4.9, 1.5 Hz, 1H), 9.46 (br s, 1H).
Reaction SMILES: C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[NH2:16][C:17]1[S:18][C:19]([Cl:48])=[C:20]([C:22](=[N:38][O:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])[C:23]([NH:25][CH:26]2[C:36](=[O:37])[N:28]3[C:29]([C:33]([OH:35])=[O:34])=[CH:30][CH2:31][S:32][C@H:27]23)=[O:24])[N:21]=1>CCOCC>[NH2:16][C:17]1[S:18][C:19]([Cl:48])=[C:20]([C:22](=[N:38][O:39][CH2:40][C:41]([OH:43])=[O:42])[C:23]([NH:25][CH:26]2[C:36](=[O:37])[N:28]3[C:29]([C:33]([OH:35])=[O:34])=[CH:30][CH2:31][S:32][C@H:27]23)=[O:24])[N:21]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nc(N)sc1Cl
Solvent: CCOCC
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c(Cl)s1
Yield: 79.2 %

Procedure:
To a mixture of anisole (2 ml) and trifluoroacetic acid (6 ml) was added 7-[2-(2-amino-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) (1.7 g) at 20° to 25° C. with stirring. The reaction mixture was stirred for an hour at the same temperature. The resultant solution was poured into a mixed solvent of dissopropyl ether (300 ml) and petroleum ether (100 ml). The precipitates were collected by filtration, washed with petroleum ether, and were dissolved in an aqueous solution of sodium bicarbonate at pH 7.5. The aqueous solution was washed with ethyl acetate, adjusted to pH 2.8 with a diluted hydrochloric acid, and extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After removing the solvent in vacuo, diisopropyl ether was added to the residue. The insoluble precipitates were collected by filtration to give 7-[2-(2-amino-5-chlorothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer)(1.2 g), mp 165° to 167° C. (dec.).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][NH:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].Br[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>>[CH3:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([NH:15][CH2:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[C:5]=2[C:3]([OH:2])=[O:4])=[O:24])=[CH:22][CH:21]=1
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)c1[nH]c2ccccc2c1CNC(=O)c1ccc(C)cc1
Product: Cc1ccc(C(=O)NCc2c(C(=O)O)n(Cc3cccc4ccccc34)c3ccccc23)cc1

Procedure:
Using general procedure B, 3-[(4-methyl-benzoylamino)-methyl]-1H-indole-2-carboxylic acid methyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 447.3 ([M−H]−).