Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C:12]2(C(OCC3C=CC=CC=3)=O)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].[CH3:38][CH2:39][O:40][C:41](C)=[O:42]>CN(C=O)C.O>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([CH:12]3[CH2:13][CH2:14][N:15]([C:41]([O:40][CH2:39][C:38]4[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=4)=[O:42])[CH2:16][CH2:17]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(NCc1nccnc1Cl)C1(C(=O)OCc2ccccc2)CCNCC1
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(c2ncc3c(Cl)nccn23)CC1
Temperature: 25 °C

Procedure:
To a suspension of benzyl 4-{[(3-chloropyrazin-2-yl)methyl]carbamoyl}piperidine-4-carboxylate (0.100 g, 0.220 mmol) in EtOAc (0.9 mL) and DMF (0.068 mL) at 0° C. was slowly added POCl3 (0.082 mL, 0.88 mmol). After stirring at rt for an hour the mixture was cooled to 0° C. then treated with solid NaHCO3. The mixture was stirred for 20 min at rt, diluted with water and extracted with EtOAc (3×20 mL). The combined extracts were washed with water (2×30 mL) and brine (30 mL), then dried over Na2SO4, and concentrated in vacuo to yield 2.07 g of desired product. 1H NMR (400 MHz, CDCl3): δ 1.98-2.04 (m, 4H), 3.03-3.20 (m, 3H), 4.30-4.33 (m, 2H), 5.16 (s, 2H), 7.33 (d, J=5.2 Hz, 1H), 7.35-7.38 (m, 5H), 7.26 (d, J=4.4 Hz, 1H), 7.79 (s, 1H). MS (ES+): m/z 371.22 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[CH2:20][C:19]2[C:14](=[N:15][C:16]([S:21]([CH3:24])(=[O:23])=[O:22])=[N:17][CH:18]=2)[N:13]([CH3:25])[C:12]1=[O:26].[H][H]>O1CCCC1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([S:21]([CH3:24])(=[O:22])=[O:23])=[N:17][CH:18]=3)[N:13]([CH3:25])[C:12]2=[O:26])[CH:4]=1
Reactant: [H][H]
Reactant: CN1C(=O)N(c2cc([N+](=O)[O-])ccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Solvent: C1CCOC1
Product: CN1C(=O)N(c2cc(N)ccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Yield: 98 %

Procedure:
5.94 g 3-(2-chloro-5-nitro-phenyl)-7-methanesulfonyl-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one were dissolved in 200 mL tetrahydrofuran. Pd(CaCO3)/C was added to the solution which was then treated with hydrogen (1 atm) for 18 h. The solution was then filtrated and the solvent evaporated. The residue was extracted with diethyl ether and the title product obtained in 98% yield.
Reaction SMILES: [N+](C1C=CC(N2CCNCC2)=CC=1)([O-])=O.[N+:16]([C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1)([O-])=O.CS(C1N=CC2=CC=C([C:43]3C=CC=[CH:45][C:44]=3[O:49]C)N2N=1)=O.[Cl:51][C:52]1[CH:53]=[CH:54][C:55]([O:70][CH3:71])=[C:56]([C:58]2[N:66]3[C:61]([CH:62]=[N:63][C:64](S(C)=O)=[N:65]3)=[CH:60][CH:59]=2)[CH:57]=1>>[Cl:51][C:52]1[CH:53]=[CH:54][C:55]([O:70][CH3:71])=[C:56]([C:58]2[N:66]3[C:61]([CH:62]=[N:63][C:64]([NH:16][C:19]4[CH:20]=[C:21]([N:25]5[CH2:30][CH2:29][N:28]([CH2:43][C@@H:44]([OH:49])[CH3:45])[CH2:27][CH2:26]5)[CH:22]=[CH:23][CH:24]=4)=[N:65]3)=[CH:60][CH:59]=2)[CH:57]=1
Reactant: COc1ccc(Cl)cc1-c1ccc2cnc(S(C)=O)nn12
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Agent: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: COc1ccc(Cl)cc1-c1ccc2cnc(Nc3cccc(N4CCN(C[C@H](C)O)CC4)c3)nn12

Procedure:
The compound was prepared in an analogous fashion to Example 69 replacing 1-(4-Nitro-phenyl)-piperazine with 1-(3-Nitro-phenyl)-piperazine and 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine with 7-(5-Chloro-2-methoxy-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine to afford 25.13 mg of (S)-1-(4-{3-[7-(5-Chloro-2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperazin-1-yl)-propan-2-ol as a lyophilized powder. (M+H)=493.11. 1H NMR (400 MHz, DMSO, d6) δ 9.34 (s, 1H), 8.98 (s, 1H), 7.94 (m, 1H), 7.50 (dd, 1H, J=2.68, 6.20 Hz), 7.39 (d, 1H, J=8.20 Hz), 7.23 (d, 1H, J=8.96 Hz), 7.14 (m, 2H), 7.01 (d, 1H, J=4.68 Hz), 6.93 (d, 1H, J=4.64 Hz), 6.59 (dd, 1H, J=1.80, 6.32 Hz), 4.11 (m, 2H), 3.80 (s, 3H), 3.73 (m, 4H), 3.16 (m, 3H), 3.02 (m, 2H), 1.15 (d, 3H, J=6.16 Hz).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7](C#N)=[CH:6][CH:5]=1.Cl.[NH2:15][OH:16].[OH-].[Na+].C[CH2:20][OH:21]>>[F:13][C:2]([F:1])([F:12])[O:3][C:4]1[C:5]([C:4]2[CH:11]=[CH:10][CH:7]=[CH:6][CH:5]=2)=[C:6]([CH:7]=[CH:10][CH:11]=1)[C:20]([NH:15][OH:16])=[O:21]
Reactant: NO
Reactant: CCO
Reactant: N#Cc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(NO)c1cccc(OC(F)(F)F)c1-c1ccccc1

Procedure:
To a solution of 4-Trifluoromethoxybenzonitrile (1.0 g, 5.0 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (0.365 g, 5.0 mmol) and NaOH (0.212 g, 5.0 mmol). The resulting reaction mixture was refluxed for 15 h. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added EtOH and filtered. The filtrate was evaporated in vacuo and used as such for the next step (crude yield 12.0 g, 66%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C(=O)C)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.C([O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)(=O)C>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1.[OH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1
Reactant: CC(=O)Oc1ccc(-c2ccc(OC(C)=O)cc2)cc1
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(O)cc1
Product: Oc1ccc(-c2ccc(O)cc2)cc1

Procedure:
Process according to claim 7, characterized in that 4,4'-diacetoxy-biphenyl, p-acetoxy-benzoic acid and 2,6-acetoxy-naphthoic acid are formed by means of the reaction of acetin anhydride with 4,4'-dihydroxybiphenyl, with p-hydroxy-benzoic acid and with 2,6-hydroxy-naphthoic, acid by heating to about 140° C., prior to the polymerization, within the same polymerization medium.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N+:7]([O-])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]=1[CH3:20].C[Si]([C:30]#[N:31])(C)C.C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][C:11]([C:30]#[N:31])=[CH:12][CH:13]=[C:8]2[N:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]=1[CH3:20]
Reactant: C[Si](C)(C)C#N
Reactant: CCOC(=O)[N+]1([O-])C(C)=C(Cc2ccc(Cl)cc2Cl)c2ncccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCOC(=O)n1c(C)c(Cc2ccc(Cl)cc2Cl)c2nc(C#N)ccc21
Yield: 48.1 %

Procedure:
To a suspension of ethyl 3-(2,4-dichlorobenzyl)-2-methylpyrrolo[3,2-b]pyridine-1-carboxylate N-oxide (414 mg) in anhydrous triethylamine (4 ml) was added trimethylsilylcyanide (704 mg) at room temperature in a nitrogen atmosphere, and the mixture was refluxed with heating overnight. The reaction mixture was cooled and a saturated aqueous sodium hydrogencarbonate solution was added. The mixture was extracted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the residue was subjected to flash silica gel chromatography (silica gel, 80 ml, eluted with hexane-ethyl acetate=5-1) and crystallized from isopropyl ether to give the objective compound (204 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][CH:19]([SH:21])[CH3:20]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:21][CH:19]([CH3:20])[CH3:18])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CC(C)S
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Sc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 96.6 %

Procedure:
4-Bromo-1-fluoro-2-nitrobenzene (1.0 g, 4.5 mmol) [Aldrich] and potassium carbonate (1.6 g, 11 mmol) were stirred in N,N-dimethylformamide (10 mL), and 2-propanethiol (0.42 mL, 4.5 mmol) was added. The mixture was heated to 100° C. for 16 hours. The mixture was cooled to rt, diluted with water (100 mL), and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, and evaporated to give the desired compound (1.2 g, 96%). 1H NMR (300 MHz, CDCl3): δ 8.27 (s, 1H), 7.62 (d, 1H), 7.38 (d, 1H), 3.55 (m, 1H), 1.40 (d, 6H).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[N:22]=[C:21]([CH:23]([NH2:25])[CH3:24])[CH:20]=[N:19][C:18]=1[O:26][CH2:27][C:28]([F:31])([F:30])[F:29]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:25]([CH:23]([C:21]3[CH:20]=[N:19][C:18]([O:26][CH2:27][C:28]([F:30])([F:31])[F:29])=[C:17]([CH3:16])[N:22]=3)[CH3:24])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1nc(C(C)N)cnc1OCC(F)(F)F
Agent: Cl
Product: Cc1nc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Yield: 80 %

Procedure:
The title compound is prepared in 80% yield (300 mg, brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (270 mg, 0.96 mmol, Step-1 of Intermediate-1) and 1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethanamine hydrochloride (260 mg, 0.96 mmol, Amine-55, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([OH:22])[CH2:20][CH2:19][O:18][CH:17]([CH3:21])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]I>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([O:22][CH3:23])[CH2:20][CH2:19][O:18][CH:17]([CH3:21])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CC(O)(c2cccc(OCc3ccccc3)c2)CCO1
Reactant: CI
Product: COC1(c2cccc(OCc3ccccc3)c2)CCOC(C)C1
Yield: 66 %

Procedure:
Using the procedure described in Example 3, (2RS,4SR)-4-(3-benzyloxyphenyl)-4-hydroxy-2-methyltetrahydropyran (1.22 g; obtained as described within Note k. below Table IX in Example 44) was reacted with methyl iodide (0.5 ml), to give (2RS,4SR)-4-(3-benzyloxyphenyl)-4-methoxy-2-methyltetrahydropyran (0.84 g, 66%), as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=N.O[N:45]=[C:46]([NH2:56])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([S:54][CH3:55])=[CH:50][CH:49]=1>ClCCl.O1CCOCC1>[CH3:55][S:54][C:51]1[CH:50]=[CH:49][C:48]([CH2:47][C:46]2[N:45]=[C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)[O:16][N:56]=2)=[CH:53][CH:52]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CSc1ccc(CC(N)=NO)cc1
Agent: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CSc1ccc(Cc2noc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 92 h
Yield: 54.2 %

Procedure:
1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (1.00 g, 4.36 mmol), 1-hydroxybenzotriazole (589 mg, 4.36 mmol) and N-methylmorpholine(0.97 mL, 8.72 mmol) were dissolved in dicloromethane (50 mL), under argon, and (3-dimethylaminopropyl)carbodiimide hydrochloride (921 mg, 8.72 mmol) and N′-hydroxy-2-[4-(methylthio)phenyl]ethanimidamide (855 mg, 4.36 mmol) were added. The mixture was stirred at room temperature for 92 hours. The organics were washed with sodium hydroxide (0.1 N) and citric acid (0.5M), dried (phase separating filter) and the solvent evaporated to give a yellow oil which was redissolved in 1,4-dioxane (100 mL) and heated to reflux for 5 hours, cooled and the solvent evaporated and chromatographed (50 g Silica Isolute, eluent 20% ethyl acetate/isohexane) to give a yellow oil, tert-butyl 4-{3-[4-(methylthio)benzyl]-1,2,4-oxadiazol-5-yl}piperidine-1-carboxylate (920 mg, 54%); NMR (CDCl3): 1.46 (9H, s), 1.71-1.87 (2H, m), 2.03 (2H, m), 2.48 (3H, m), 2.92 (2H, t), 3.05 (1H, m), 4.00 (2H, s), 4.07 (2H, m), 7.24 (4H, m).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([O:4][C:5]([N:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:8]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[N:17]=[N:16][N:15]=2)=[CH:12][C:11](Br)=[CH:10][N:9]=1)=[O:6])[CH3:3].[C:36]([Si:38]([CH3:41])([CH3:40])[CH3:39])#[CH:37]>C(NCC)C.C(Cl)Cl.[Cu]I>[CH3:1][C:2]([CH3:35])([O:4][C:5]([N:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:8]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[N:17]=[N:16][N:15]=2)=[CH:12][C:11]([C:37]#[C:36][Si:38]([CH3:41])([CH3:40])[CH3:39])=[CH:10][N:9]=1)=[O:6])[CH3:3]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)cc1-c1nnnn1-c1cccc(F)c1F
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(C#C[Si](C)(C)C)cc1-c1nnnn1-c1cccc(F)c1F
Temperature: 50 °C
Yield: 29.3 %

Procedure:
In a tube was placed N,N-di(1,1-dimethylethoxycarbonyl)-3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-bromopyridin-2-amine (2.3 g, 4.1 mmol) in diethylamine (10 mL) with ethynyltrimethylsilane (1.5 g, 15.3 mmol) and the reaction was deoxygenated with a stream of nitrogen gas. To the mixture was added copper(I) iodide (554 mg, 2.9 mmol). The reaction vessel was sealed and warmed to 50° C. to achieve dissolution. To the mixture was added PdCl2dppf2.CH2Cl2 (190 mg, 0.06 eq). The reaction vessel was sealed and the mixture sonicated at 50° C. for 10 minutes. The reaction was diluted with methylene chloride, filtered through Celite™, concentrated, and purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give N,N-di(1,1-dimethylethoxycarbonyl)-3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(2-(trimethylsilyl)ethynyl)pyridin-2-amine (713 mg, 1.2 mmol, 30%) as a yellow solid; LC-MS: m/e=471.3 [M-Boc+H].
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])=[C:10]([CH3:21])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:22])=[N:7]2.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:30][CH3:31]>CN(C=O)C.O>[Br:1][C:2]1[C:11]([C@H:12]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[C:13]([O:15][CH2:30][CH3:31])=[O:14])=[C:10]([CH3:21])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:22])=[N:7]2
Reactant: Cc1ccc2c(Br)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetic acid (17 g, 46.6 mmol) in DMF (200 mL) was added Cs2CO3 (30.4 g, 93.2 mmol), followed with the addition of iodoethane (11 g, 69.9 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours, diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product. LCMS-ESI+: calc'd for C19H24BrNO3: 394.1 (M+H+); Found: 394.0 (M+H+).
Reaction SMILES: [F:1]C1C=CC(C)=CC=1C(O)=O.F[C:13]1[CH:14]=[C:15]([C:22]([OH:24])=[O:23])[CH:16]=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19]>>[F:1][C:14]1[CH:13]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[C:22]([OH:24])=[O:23]
Reactant: Cc1ccc(F)c(C(=O)O)c1
Reactant: O=C(O)c1cc(F)cc(C(=O)O)c1
Product: O=C(O)c1ccc(F)c(C(=O)O)c1

Procedure:
The precursor compound was synthesized from 2-fluoro-5-methylbenzoic acid following the procedure described for 5-fluoro-isophthalic acid.
Reaction SMILES: [OH:1][C@H:2]([CH2:28][NH:29][C:30]([CH3:43])([CH3:42])[CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1)[CH2:3][N:4]([CH3:27])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH:21][C:22]([O:24]CC)=[O:23])[CH:15]=1)(=[O:7])=[O:6].O.[OH-].[K+].Cl>O1CCCC1>[OH:1][C@H:2]([CH2:28][NH:29][C:30]([CH3:43])([CH3:42])[CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1)[CH2:3][N:4]([CH3:27])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH:21][C:22]([OH:24])=[O:23])[CH:15]=1)(=[O:7])=[O:6]
Reactant: CCOC(=O)C=Cc1cccc(-c2ccccc2S(=O)(=O)N(C)C[C@H](O)CNC(C)(C)Cc2ccc3ccccc3c2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccccc1-c1cccc(C=CC(=O)O)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Ethyl (R)-3-(2′-(N-(2-hydroxy-3-(2-methyl-1-(naphthalen-2-yl)propan-2-ylamino)propyl)-N-methylsulfamoyl)biphenyl-3-yl)acrylate synthesized from Example 3-1 Step A was dissolved in tetrahydrofuran (4 mL), water (1 mL) and potassium hydroxide (five granules) were added thereto followed by stirring at 50° C. for 1 day. The residue was neutralized with 2N hydrochloric acid, and extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. Thus obtained residue was purified by HPLC to obtain the target compound (3.7 mg).
Reaction SMILES: C(N(CCCC)CCCC)CCC.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][C:20]([NH:22][C@@H:23]1[C:35](=[O:36])[N:25]2[C:26]([C:32]([OH:34])=[O:33])=[C:27]([CH2:30]O)[CH2:28][S:29][C@H:24]12)=[O:21].[SH:37][C:38]1[N:42]([CH3:43])[N:41]=[N:40][N:39]=1.O>C(OCC)(=O)C>[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][C:20]([NH:22][C@@H:23]1[C:35](=[O:36])[N:25]2[C:26]([C:32]([OH:34])=[O:33])=[C:27]([CH2:30][S:37][C:38]3[N:42]([CH3:43])[N:41]=[N:40][N:39]=3)[CH2:28][S:29][C@H:24]12)=[O:21]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: Cn1nnnc1S
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: -20 °C
Yield: 83.9 %

Procedure:
To 10 ml of ethyl acetate were added 0.540 g of 7β-(2-thienylacetamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid tri-n-butylamine salt and 0.175 g of 5-mercapto-1-methyl-1H tetrazole and, under cooling at -20° C. and stirring, a solution of 0.370 g of methyl o-phenylene phosphorochloridate in 5 ml of ethyl acetate was added. The mixture was stirred under ice-cooling for 1.5 hours and 10 ml of water was added. After phase separation, 20 ml of water was added to the organic layer and the mixture was adjusted to pH 9.0. The aqueous layer was taken and washed with 5 ml of ethyl acetate. To the aequous layer was added 20 ml of ethyl acetate and the mixture was adjusted to pH 2.0. After phase separation, the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure and ether was added. The powdery precipitate was collected by filtration to give 0.380 g (yield 84.1%) of 7β-(2-thienylacetamido)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid. The IR and NMR spectra of this product were identical with those of the authentic sample.
Reaction SMILES: O=C1[N:11]2[N:12]=[C:13]([CH:21]=O)[C:14]([C:15]3C=CC=CC=3)=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[BH4-].[Na+].[OH2:25].[CH3:26][OH:27]>>[OH:25][CH2:15][C:14]1[C:13]([C:21]2[CH:6]=[CH:5][CH:4]=[CH:9][CH:8]=2)=[N:12][N:11]2[C:10]=1[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:3][C:26]2=[O:27]
Reactant: O
Reactant: CO
Reactant: O=Cc1nn2c(=O)[nH]c3ccccc3c2c1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=c1[nH]c2ccccc2c2c(CO)c(-c3ccccc3)nn12
Reaction time: 0.25 h

Procedure:
To a suspension of 4.0 g (0.0139 mole) of 5,6-dihydro-5-oxo-1-phenylpyrazolo[1,5-c]quinazolin-2-carboxaldehyde (prepared as in Example 1A) in 300 ml of methanol (at 0°) there is added 2.5 g (0.066 mole) of sodium borohydride. The suspension is stirred at 0° for 15 minutes and then overnight at room temperature. Another 2.5 g of sodium borohydride is added, and, after 6 hours another 2.5 g, and stirring continued overnight. The reaction mixture is treated with 200 ml of water, the methanol stripped, the solid (3.7 g) filtered and dried. This material is suspended in 500 ml of absolute ethanol, the mixture cooled to 0°, treated with 2.5 g of sodium borohydride, and stirred for 5 hours at room temperature, after which reduction is complete. The suspension, is treated with 250 ml of water and stripped to a low volume. The precipitate is filtered, washed with water and dried (wt. 2.5 g). Recrystallization from absolute ethanol containing 2% benzene gives 2.1 g of analytically pure material, which contains 1 mole of water, m.p. 267°-270° (d).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH:6]([CH:10]([CH3:12])[CH3:11])[CH2:7][CH2:8][N:9]=1.[Cl-:13].[NH4+:14]>CO>[ClH:13].[CH3:11][CH:10]([CH:6]1[CH2:7][CH2:8][NH:9][C:3](=[NH:14])[CH2:4][CH2:5]1)[CH3:12]
Reactant: COC1=NCCC(C(C)C)CC1
Reactant: [NH4+]
Reactant: [Cl-]
Solvent: CO
Product: CC(C)C1CCNC(=N)CC1
Product: Cl

Procedure:
The product of EXAMPLE 77 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[C:14]([S:24](Cl)(=[O:26])=[O:25])=[CH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([Cl:23])=[CH:18][CH:17]=2.Cl>O.O1CCOCC1>[Cl:12][C:13]1[C:14]([S:24]([NH:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:26])=[O:25])=[CH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([Cl:23])=[CH:18][CH:17]=2
Reactant: NCC(=O)O
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CNS(=O)(=O)c1cc2ccc(Cl)cc2cc1Cl
Temperature: 25 °C
Yield: 80.8 %

Procedure:
To a solution of potassium carbonate (11.7 g) and glycine (6.4 g) in water (140 ml) were added 3,6-dichloronaphthalen-2-ylsulfonyl chloride (20.8 g) and dioxane (50 ml) at room temperature, and the mixture was stirred under reflux for 2 hours. After cooling to room temperature, the resultant solution was acidified with 2N hydrochloric acid to a pH in the range of 1 to 2, and extracted with ethyl acetate. The organic layer was washed with water, then with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. Ethyl acetate was removed in vacuo to give 19.0 g of the objective compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[C:17]([C:27](=[O:30])[NH:28][CH3:29])[C:16]=3[C:31]=2[F:32])[C:10]=1[CH3:11])[C:5](O)=[O:6].Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[N:36][C:35]=1[C:40]1([NH2:44])[CH2:43][O:42][CH2:41]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[F:32][C:31]1[C:16]2[C:17]([C:27]([NH:28][CH3:29])=[O:30])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[O:19][C:15]=2[CH:14]=[CH:13][C:12]=1[C:9]1[CH:8]=[C:4]([C:5](=[O:6])[NH:44][C:40]2([C:35]3[N:34]=[CH:39][CH:38]=[CH:37][N:36]=3)[CH2:43][O:42][CH2:41]2)[CH:3]=[C:2]([F:1])[C:10]=1[CH3:11]
Reactant: NC1(c2ncccn2)COC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)cc(F)c3C)c(F)c12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncccn5)COC4)cc(F)c3C)c(F)c12
Reaction time: 8 h

Procedure:
To a yellow solution mixture of 3-fluoro-5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (30 mg, 0.068 mmol) and 3-(pyrimidin-2-yl)oxetan-3-amine hydrochloride (12.5 mg, 0.067 mmol) in DMF (1 ml) in a 25 mL round-bottomed flask was added PyBOP (50 mg, 0.096 mmol), followed by TEA (0.1 ml, 0.717 mmol), and the reaction mixture was stirred for overnight. Ice cooled water was added to the reaction mixture, which was then stirred for 10-15 min. at 0° C. Precipitation was observed. The solid was collected by filtration, washed with cold water, and then dissolved in dichloromethane. The organic was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC. Yield (10 mg, 25%).