Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Yield: 99.4 %

Procedure:
8.51 g (61.57 mmol) of potassium carbonate are added to a solution of 10.0 g (58.64 mmol) of 4-hydroxy-2-nitrobenzaldehyde in 70 ml of DMF. The solution is briefly stirred, then 10.53 g (61.57 mmol) of benzyl bromide are added and the reaction mixture is stirred at room temperature for 3 h. The resulting solid is then filtered off, 250 ml of water are added to the filtrate and the aqueous phase is extracted 3× with ethyl acetate. The organic phase is washed twice with water, dried over sodium sulphate, concentrated in vacuo and the residue is dried. 15.0 g (99%) of 4-benzyloxy-2-nitrobenzaldehyde are obtained as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[C:26][Si](C)(C)C)=[CH:21][C:20]=3[CH3:31])=[C:16]([F:32])[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.O>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][C:20]=3[CH3:31])=[C:16]([F:32])[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: Cc1cc(C#C[Si](C)(C)C)ccc1Nc1c(C(=O)NOCC2CC2)cc2[nH]cnc2c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(Nc2c(C(=O)NOCC3CC3)cc3[nH]cnc3c2F)c(C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
7-Fluoro-6-(2-methyl-4-trimethylsilanylethynyl-phenylamino)-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11bbb (0.020 g, 0.044 mmol) is dissolved in tetrahydrofuran (0.50 mL) and the reaction solution is cooled to 0° C. TBAF (50 uL, 0.050 mmol, 1 M solution in tetrahydrofuran) is added. The reaction mixture is warmed to room temperature and additional TBAF (25 uL, 0.025 mmol, 1 M solution in tetrahydrofuran) is added. The reaction mixture is stirred at 50° C. for 2 hours under N2. The reaction mixture is cooled to room temperature, a few drops of H2O are added and then it is concentrated under reduced pressure. The residue is purified by FCC (eluting with 20:1 methylene chloride:methanol) to yield 0.011 g (65%) of the pure desired product. MS APCI (−) m/z 377 (M−1) detected; 1H NMR (400 MHz, CDCl3) δ 10.56 (broad s, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.28 (s, 1H), 7.11 (d, 1H), 6.42 (broad, 1H), 3.70 (br s, 2H), 2.96 (d, 1H), 2.37 (s, 3H), 0.85 (m, 1H), 0.50 (m, 2H), 0.22 (m, 2H).
Reaction SMILES: [H-].[Na+].[S:3]1[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[CH2:10](I)[CH3:11]>CN(C=O)C.O>[CH2:10]([N:5]1[C:6](=[O:8])[CH2:7][S:3][C:4]1=[O:9])[CH3:11]
Reactant: O=C1CSC(=O)N1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)CSC1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a 100 ml three necked round bottom flask, sodium hydride (60% in paraffin) (0.188 g, 0.00470 mole) was taken in DMF (2.0 ml). Thiazolidine-2,4-dione (0.5 g, 0.00427 mole) in DMF (3 ml) was slowly added at 0° C. over 15 min under nitrogen atmosphere. After addition was complete, the reaction mixture was stirred for 1 hr at 50° C. The reaction was then cooled to 0° C., followed by drop wise addition of ethyl iodide (0.41 ml, 0.00512 mole) at 0° C. The reaction mixture was warmed up to RT and stirred for 1 hr. After completion of the reaction, the reaction mixture was poured in water and aq. layer was extracted with ethyl acetate. Organic layers were combined and washed with brine solution, dried over Na2SO4, filtered and concentrated to afford crude product which was purified using column purification by eluting the compound with 5% ethyl acetate in hexanes to yield 0.5 g of 3-ethylthiazolidine-2,4-dione.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[N:12]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:13]2[C:18]([N:19]=1)=[C:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[N:16]=[C:15]([C:26]1[C:27]([CH3:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1)[N:14]=2>CS(C)=O>[NH2:32][C:29]1[N:28]=[C:27]([CH3:33])[C:26]([C:15]2[N:14]=[C:13]3[C:18]([N:19]=[C:11]([NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:12]3[CH2:34][CH:35]3[CH2:37][CH2:36]3)=[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:16]=2)=[CH:31][N:30]=1
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Reactant: NCCN1CCOCC1
Solvent: CS(C)=O
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(NCCN3CCOCC3)n(CC3CC3)c2n1
Temperature: 150 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
2-Morpholin-4-yl-ethylamine (162 mg, 1.25 mmol) and dimethyl sulfoxide (700 μl) were added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.25 mmol) and the resulting mixture was stirred at 150° C. for 3 hours. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was concentrated, and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (101 mg, 75%) as a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[C@@H:7]([C:25](=[O:35])[NH:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:6]1.O.[OH-].[Li+].Cl>C1COCC1>[CH2:28]([O:27][NH:26][C:25]([C@@H:7]1[C@@H:8]([C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)=[O:12])[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:36])=[O:2])[CH2:6]1)=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)CC1CC[C@H](C(=O)N2CCN(c3ccccc3)CC2)[C@@H](C(=O)NOCc2ccccc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1CC[C@H](C(=O)N2CCN(c3ccccc3)CC2)[C@@H](C(=O)NOCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.3 %

Procedure:
To a solution of [3-(S)-benyloxycarbamoyl-4-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexyl]-acetic acid methyl ester (213 mg, 0.432 mmol) in THF (5 mL) was added water (3 mL) and lithium hydroxide (40 mg, 0.95 mmol). After stirring at ambient temperature for 4 h, the reaction mixture was acidified with 1 N HCl to a pH of ca. 5. The product was extracted with ethyl acetate (4×5 mL) and the combined organic layers were washed with brine (5 mL), dried (NaSO4), and the volatiles were removed in-vacuo to afford 154 mg (87%) of [3-(S)-benyloxycarbamoyl-4-(S)-(4-phenyl-piperazine-1-carbonyl)-cyclohexyl]-acetic acid as a sticky oil that was used without further purification in the following coupling reaction. MS (ESI): 480 (M+H+).
Reaction SMILES: [C:1]([O:4][C:5]1[C:24]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])=[C:23]([O:30]COC)[CH:22]=[C:21]([O:34]COC)[C:6]=1[C:7](=[O:20])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16]COC)=[CH:12][CH:11]=1)(=[O:3])[CH3:2].Cl.CO.C(=O)([O-])O.[Na+]>>[C:1]([O:4][C:5]1[C:24]([CH2:25][CH:26]=[C:27]([CH3:28])[CH3:29])=[C:23]([OH:30])[CH:22]=[C:21]([OH:34])[C:6]=1[C:7](=[O:20])[CH:8]=[CH:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: COCOc1ccc(C=CC(=O)c2c(OCOC)cc(OCOC)c(CC=C(C)C)c2OC(C)=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)Oc1c(CC=C(C)C)c(O)cc(O)c1C(=O)C=Cc1ccc(O)cc1
Yield: 54.4 %

Procedure:
Then, a liquid mixture of 4.95 g of 2'-acetoxy-4,4',6'-tris(methoxymethoxy)-3'-(3-methyl-2-butenyl)chalcone and 8 ml of a hydrochloric acid/methanol reagent was heated and refluxed for 10 minutes, and the temperature of the reaction mixture was lowered to room temperature and the reaction mixture was neutralized with an aqueous solution of sodium hydrogencarbonate and extracted with 1 l of ethyl acetate. The ethyl layer was washed with water, shaken with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation and the obtained residue was subjected to the silica gel column chromatography (130 g of 230-400 mesh silica gel, n-hexane/ethyl acetate=3/1, 0.3 kg/cm2). Fractions of 100 ml were collected and the 13th to 26th fractions were combined to obtain 2.0 g (yield=54.3%) of 2'-acetoxy-4,4',6'-trihydroxy-3'-(3-methyl-2-butenyl)chalcone in the form of a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:26]2[CH2:27][CH2:28][CH2:29][CH:25]2[CH3:24])=[O:21])=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC1CCCN1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCCC2C)cn1
Yield: 99 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted, using 2-methyl-pyrrolidine instead of 2-aminoethyl isopropylether, to the title compound (240 mg, 99%) which was obtained as a colourless. MS: m/e=378.3 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=O.S(=O)(=O)(O)O.[NH2:15][NH:16][C:17]([NH2:19])=[S:18].N>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:18][C:17]([NH2:19])=[N:16][N:15]=1
Reactant: NNC(N)=S
Reactant: O=C(O)CCCCCBr
Agent: N
Agent: O=S(=O)(O)O
Product: Nc1nnc(CCCCCBr)s1
Yield: 59 %

Procedure:
6-Bromohexanoic acid (5.35 g, 27.4 mmol), concentrated sulphuric acid (15 mL), and thiosemicarbazide (3.0 g, 32.9 mmol) were slowly heated to 80-90° C. for 12 h. After cooling, the content was poured onto crushed ice. The mixture was neutralized with 10% aqueous ammonia and extracted with ethyl acetate (3×100 mL). The organic extracts were washed with 10% Na2CO3 (2×50 mL), water (100 mL), and brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography over silica gel 60 (70-230 mesh) eluted with CH2Cl2:MeOH 19:1 to give the product as a solid, mp 128-130° C., in 59% yield (4.03 g, 16.2 mmol). 1H NMR (300 MHz, CDCl3) δ 1.51-1.60 (m, 2), 1.71-1.79 (m, 2), 1.81-1.92 (m, 2), 2.92 (t, 2, J=7.5 Hz), 3.40 (t, 2, J=6.9 Hz), 5.33 (s, 2); 13C NMR (75 MHz, CDCl3) δ 26.9, 28.1, 29.3, 31.8, 35.0, 158.1, 168.2; HRMS (ESI+, m/z) calculated for C7H13BrN3S 250.0014, observed 250.0005 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16]>>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc([N+](=O)[O-])cc2)C1=O

Procedure:
The title compound is prepared from (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as described in EXAMPLE 1, Part H using 4-nitrobenzyl bromide in place of 7-bromomethyl-1-chloro-isoquinoline. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/CH2Cl2 to 25% EtOAc/CH2Cl2 to afford the title compound as a yellow solid.
Reaction SMILES: CS(Cl)(=O)=O.C([CH:8]1[C:12](O)([C:13]([OH:15])=[O:14])[C:11]2[C:17](=[O:22])[CH2:18][CH:19]([CH3:21])[CH2:20][C:10]=2[O:9]1)C.[CH2:23](N(CC)CC)[CH3:24].[OH-].[Na+]>ClCCl>[O:22]=[C:17]1[C:11]2[C:12]([C:13]([O:15][CH2:23][CH3:24])=[O:14])=[CH:8][O:9][C:10]=2[CH2:20][CH:19]([CH3:21])[CH2:18]1
Reactant: CCC1OC2=C(C(=O)CC(C)C2)C1(O)C(=O)O
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1coc2c1C(=O)CC(C)C2
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A solution of methanesulfonyl chloride (6.1 ml, 78.5 mmol) in dichloromethane (50 mL) was added to a stirring solution of ethyl 3-hydroxy 4-oxo-6-methyl-2,3,4,5,6,7-hexahydrobenzofuran-3-carboxylic acid (18.48 g, 76 mmol) and triethylamine (21.4 mL, 154 mmol) in dichloromethane (150 mL) at 0° C. The mixture was allowed to reach ambient temperature, stirred for 2 hours, then poured into aqueous 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give ethyl 4-oxo-6-methyl-4,5,6,7-tetrahydrobenzofuran-3-carboxylate (16.86 g).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O1CCCC1.B.[Na]>C(O)C>[OH:3][CH:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: B
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)O)cc1
Temperature: 0 °C
Yield: 98.5 %

Procedure:
71.2 g (0.4 mol) of methyl 4-acetylbenzoate, 300 ml tetrahydrofuran and 100 ml of ethanol were supplied into a four-necked flask equipped with a stirrer and a thermometer. Then 7.6 g (0.2 mol) of sodium boron hydride was added at 15°-25° C. over a period of 3 hours. The mixture was maintained at the same temperature for 5 hours and the resulting reaction solution was poured into ice-water and extracted twice with 400 ml of ethyl acetate. The organic layer was concentrated under reduced pressure to obtain 71.0 g of methyl 4-(1-hydroxyethyl)benzoate (IIII-1) in a 98.6% yield.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].[NH2:14]CC1SC=CC=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH2:14])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Reactant: NCc1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-acetoxybenzoic acid (8.1 mg, 0.0450 mmol), 5-aminomethylthiophene 18d (22.3 mg, 0.0473 mmol), 1-hydroxybenzotriazole (HOBt, 4.7 mg, 0.0348 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC, 8.5 mg, 0.0443 mmol) was dissolved in DMF (0.6 ml) and stirred overnight at r.t. Work-up (AcOEt/H2O; brine/Na2SO4), concentration, filtration over a silica gel plug (EtOAc) and evaporation gave the intermediate 3-acetoxybenzamide, which was deacetylated by siring in MeOH (2 ml) and Et3N (0.4 ml) for 1 h at 55° C. Evaporation gave 28.5 mg (103%) of the title 3-hydroxy-benzamide as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=1.Cl[CH2:13][C:14]([OH:16])=[O:15]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][O:9][CH2:13][C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1
Reactant: O=C(O)CCl
Reactant: COc1ccc(CCO)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CCOCC(=O)O)cc1
Yield: 79.1 %

Procedure:
6.08 g of 4-methoxyphenethyl alcohol were reacted with 3.8 g of chloroacetic acid in a manner analogous to that described in Example 4(a) to give 6.64 g (79%) of 2-(4-methoxyphenyl)ethoxyacetic acid of melting point 82°-84° C. (from toluene).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[C:28]([O:30]CC)=[O:29])=[O:21])=[CH:14][C:13]=3[N+:33]([O-:35])=[O:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].CCO.[OH-].[Na+]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[C:28]([OH:30])=[O:29])=[O:21])=[CH:14][C:13]=3[N+:33]([O-:35])=[O:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared by the hydrolysis of the compound of Example 203 under basic conditions (aq. NaOH/EtOH), producing a light yellow solid: mp 165° C.(dec.). 1H NMR (DMSO-d6, 300 MHz) δ 1.15-1.52 (m, 3H), 1.46-1.62 (m, 2H), 2.32 (m, 1H), 2.80 (m, 1H), 3.45(br, ½H), 4.00 (br, ½H), 4.44 (br, ½H), 4.800 (br, ½H), 6.83 (d, J=8.0 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 7.09 (dd, J=2.0, 14.0 Hz, 1H), 7.15 (d, J=2.0 Hz, 1H), 7.20 (d, J=15.5 Hz. 1H), 7.35 (d, J=15.5 Hz, 1H), 7.73 (m, 1H), 8.52 (m, 1H). MS (ESI) m/z 469 (M−H)+, 471 (M+H)+. Anal. calcd. for C23H21N2O7SNa.NaOH.2.7H2O: C, 47.54; H, 4.75; N, 4.82. Found: C, 47.18; H, 4.36; N, 4.89.
Reaction SMILES: [CH3:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:4]2[C:5](OC(=O)[NH:9][C:3]=12)=[O:6].O.[NH3:16]>CN(C=O)C.O>[NH2:9][C:3]1[C:2]([CH3:1])=[C:13]([Cl:14])[CH:12]=[CH:11][C:4]=1[C:5]([NH2:16])=[O:6]
Reactant: N
Reactant: Cc1c(Cl)ccc2c(=O)oc(=O)[nH]c12
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cl)ccc(C(N)=O)c1N
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Using two inlets, at 80° C. a suspension of 4.64 g (0.0219 mol) of 3-methyl-4-chloroisatoic anhydride in 21 ml of DMF and 3.1 g (0.0219 mol) of 25% strength ammonia water in 6 ml of water were added simultaneously with stirring and over a period of 15 min to 8 ml of water. The mixture was stirred at 80° C. for 1 h and then cooled and extracted twice with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure, giving 2.61 g (64.4% of theory) of the title compound as colorless crystals of m.p. 206-208° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:29]=[CH:28][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=4)[C:21]([NH:23][OH:24])=[NH:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:32]1(=O)[O:36][CH2:35][CH2:34][CH2:33]1>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:29]=[CH:28][C:11]3[N:12]=[C:13]([C:18]4[CH:27]=[CH:26][CH:25]=[C:20]([C:21]5[N:22]=[C:32]([CH2:33][CH2:34][CH2:35][OH:36])[O:24][N:23]=5)[CH:19]=4)[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCCO1
Reactant: N=C(NO)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CC(c2cccc(-c3noc(CCCO)n3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 65.7 %

Procedure:
To a stirred suspension of 3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-N-hydroxy-benzamidine (Example 167) (78 mg, 0.2 mmol) in EtOH (3 mL) was added at 23° C. sodium hydride (55% dispersion in oil, 32 mg, 0.8 mmol) and the mixture was stirred at 23° C. for 5 min. Butyrolactone (103 mg, 1.2 mmol) was added and the mixture was heated to 70° C. for 3 h. The reaction mixture was cooled to 23° C. and partitioned between ethyl acetate and H2O. The organic layer was dried over Na2SO4, evaporated in vacuum, and the residue was crystallized from dichloromethane to give the title compound as light yellow solid (60 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:22])[CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][C:12]#[CH:13].N12CCN(CC1)CC2.C(O)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]([OH:22])[C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:11][C:12]#[CH:13]
Reactant: C#CCC(NC(=O)OC(C)(C)C)C(=O)c1cc(F)ccc1F
Agent: C1CN2CCN1CC2
Solvent: O=CO
Solvent: C1CCOC1
Product: C#CC[C@H](NC(=O)OC(C)(C)C)[C@@H](O)c1cc(F)ccc1F
Temperature: 45 °C

Procedure:
To a stirred vessel under nitrogen sweep was charged tert-butyl [1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-yl]carbamate (35.0 kg, 113 mol), 1,4-diazabicyclo[2.2.2]octane (38.0 kg, 339 mol), and THF (465 kg). After dissolution, chloro{[(1R,2R)-(−)-2-amino-1,2-diphenylethyl](pentafluorophenylsulfonyl)amido}-(p-cymene) ruthenium (II) (410 g, 576 mmol) was added. The vessel was vacuum sparged and back-filled with nitrogen three times. Then, formic acid (26.7 kg, 580 mol) was added and the reaction heated to 45° C. overnight.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19](=O)[CH2:20]Br>>[F:14][C:15]([F:26])([F:27])[C:16]1[CH:17]=[C:18]([C:19]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[O:3][CH:20]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(C(N)=O)cc1
Product: COC(=O)c1ccc(-c2nc(-c3cccc(C(F)(F)F)c3)co2)cc1
Yield: 21 %

Procedure:
In the same manner as in Example 1, methyl 4-carbamoylbenzoate was reacted with 3-trifluoromethylphenacyl bromide to obtain methyl 4-[4-(3-trifluoromethylphenyl)-2-oxazolyl]benzoate. The product was recrystallized from ethanol. Yield: 21%. Pale yellow prisms. Melting Point: 134 to 135° C.
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[NH:13][CH:14]=[C:15]([C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1)=[O:11]>FC(F)(F)C(O)=O>[CH3:8][O:9][C:10]([C:12]1[NH:13][CH:14]=[C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1)=[O:11]
Reactant: COC(=O)c1cc(C(=O)c2ccccc2)c[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cc2ccccc2)c[nH]1
Reaction time: 8 h
Yield: 57.5 %

Procedure:
Triethylsilane (0.215 mL, 1.35 mmol) was added to a stirring, room temperature solution of methyl-4-benzoyl-1H-pyrrole-2-carboxylate (0.1118 g, 0.488 mmol) in trifluoroacetic acid (TFA) (1.04 mL, 0.47 M) under N2. After stirring overnight, the reaction was complete by HPLC. The TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 95:5 Hexanes: EtOAc) to obtain pure 25 (0.0604 g, 57.5%): 1H (CDCl3, 400 MHz): δ 9.44 (11H, broad s), 7.34-7.21 (5H, m), 6.78 (1H, s), 6.75 (1H, s), 3.853 (2H, s), 3.846 (3H, s) ppm. 13C (CDCl3, 100 MHz): δ 162.09, 141.68, 128.85, 128.70, 126.25, 125.55, 122.67, 121.86, 115.74, 51.70, 33.41 ppm. HPLC: 9.693 min. (Starting material: 8.611 min.)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH3:12][O-].[Na+]>CO.[Cl-].C1([N+](C)(C)C)C=CC=CC=1.CN(C=O)C>[CH3:12][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: C[O-]
Reactant: Oc1cccc2cnccc12
Agent: C[N+](C)(C)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 5-hydroxyisoquinoline (10 g, 69 mmol) in MeOH (100 ml) was added a solution of sodium methoxide in methanol (30% by weight, 13.8 ml, 72.4 mmol) followed by phenyltrimethylammonium chloride (12.4 g, 72.4 mmol). The reaction mixture was stirred at room temperature for 2 h, after which time it was filtered and the filtrate evaporated under reduced pressure to afford an oil which was dissolved in DMF (50 ml). The reaction mixture was refluxed for 2 h after which time the reaction mixture was evaporated under reduced pressure. The resulting oil was partitioned between CH2Cl2 and 1N aqueous NaOH, the organic layer was washed twice with 1N aqueous NaOH, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified on silica gel eluting with EtOAc/hexane (1/1, v/v) to afford the subtitle compound as a yellow oil (6.11 g, 56%). 1H NMR (CDCl3) δ: 4.05 (3H, s), 7.00 (1H, d), 7.55 (2H, m), 8.02 (1H, d), 8.55 (1H, d), 9.22 (1H, s).