Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=1)[S:12]([CH3:15])(=[O:14])=[O:13])C.[OH-].[Na+].CO>C(Cl)Cl>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([Cl:25])[CH:22]=1)[O:18][CH2:17][CH2:16][N:11]([S:12]([CH3:15])(=[O:13])=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)CCCCCCN(CCOc1cc(Cl)cc(Cl)c1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)N(CCCCCCC(=O)O)CCOc1cc(Cl)cc(Cl)c1

Procedure:
The title compound was prepared from 7-{[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid ethyl ester using the procedure described in Step B of Example 1 with 2N NaOH. Purification by flash chromatography (1% MeOH in CH2Cl2) provided the title acid. 1HNMR (400 MHz, CDCl3) δ 6.95 (m, 1H), MeOH in CH2Cl2) provided the title acid. 1HNMR (400 MHz, CDCl3) δ 6.95 (m, 1H), 6.75 (m, 2H), 4.07 (t, 2H), 3.56 (t, 2H), 3.23 (t, 2H), 2.86 (s, 3H), 2.33 (t, 2H), 1.61 (m, 4H), 1.33 (m, 4H); MS 411 (M−1).
Reaction SMILES: [C:1]1([C:11]#[C:12][CH2:13][CH2:14][CH2:15][OH:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C>[C:1]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: OCCCC#Cc1cccc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: OCCCCCc1cccc2ccccc12
Yield: 93.3 %

Procedure:
A mixture of 3.5 grams (0.017 mole) of 5-(naphth-1-yl)-4-pentyn-1-ol and 0.5 gram (catalyst) of 10% palladium on carbon in 30 mL of ethanol was shaken in a Parr hydrogenator until the theoretical amount of hydrogen gas was taken up. The reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure, yielding 3.4 grams of 5-(naphth-1-yl)pentanol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br-].[Li+].[BH4-].[Na+].[C:5]([C@H:7]1[C@H:11]([C:12](OCC)=[O:13])[S:10][CH2:9][CH2:8]1)#[N:6].[Cl-].[NH4+]>C(O)C>[C:5]([C@H:7]1[C@H:11]([CH2:12][OH:13])[S:10][CH2:9][CH2:8]1)#[N:6]
Reactant: CCOC(=O)[C@@H]1SCC[C@H]1C#N
Agent: [BH4-]
Agent: [Br-]
Agent: [Cl-]
Solvent: CCO
Product: N#C[C@@H]1CCS[C@H]1CO
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.4 %

Procedure:
Under nitrogen atmosphere, lithium bromide (208 mg) and sodium borohydride (50 mg) were dissolved in ethanol (3 ml) and the mixture was stirred for 45 minutes at room temperature. Under ice-cooling, trans-4-cyano-5-ethoxycarbonyltetrahydrothiophene (122 mg) dissolved in ethanol (2 ml) was added to the solution and the mixture was stirred over night. Aqueous ammonium chloride solution was added to the mixture under ice-cooling and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 90 mg (95%) of trans-4-cyano-5-hydroxymethyltetrahydrothiophene.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[OH-:13].[Na+].O>CS(C)=O>[Cl:9][C:6]1[C:7]([F:8])=[C:2]([OH:13])[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(F)c1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(F)c1O
Reaction time: 20 h
Yield: 35.5 %

Procedure:
10.5 g (0.05 mol) of 2,4-dichloro-3-fluoronitrobenzene was dissolved in 30 ml of dimethyl sulfoxide, and 8 ml of a 10% aqueous solution of sodium hydroxide was added to the mixture, followed by stirring the mixture at a temperature of 60° to 70° C. for 20 hours. After completion of the reaction, 200 ml of water was added thereto and the unreacted starting material was removed by extraction with diethyl ether. The aqueous layer was made acidic with acetic acid and extracted with diethyl ether. The ether extract was dried over sodium sulfate and the ether was distilled off. The resulting residue was purified by silica gel (100 g) column chromatography using chloroform as an eluant to provide 3,4 g (35.5% yield) of 3-chloro-2-fluoro-6-nitrophenol with m.p. 73° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH:16]([CH3:18])[CH3:17])[C:3]=1[C:19]#[N:20].[OH:21]S(O)(=O)=O.[OH-].[Na+]>>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH:16]([CH3:18])[CH3:17])[C:3]=1[C:19]([NH2:20])=[O:21]
Reactant: CC(C)c1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C#N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(N)=O
Yield: 92 %

Procedure:
Part B: Thirty grams (91.0 mmol) of 5-amino-4-cyano-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole was dissolved in 80 mL of con. H2SO4 and stirred 24 h at RT. The solution was added to cold aqueous NaOH, and the resulting precipitate was filtered, washed with water, and dried under vacuum to give 29.1 g (92%) of 5-amino-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide as a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.49(s, 2H); 5.06-5.63(m, 4 H); 3.06(septet, 1H, J=6.8 Hz); 1.39(d, 6H, J=6.9 Hz).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:34]1[N:35]=[C:36]([NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])[S:37][CH:38]=1)[C:5]([NH:7][CH:8]1[C:32](=[O:33])[N:10]2[C:11]([C:19]([O:21]CC3C=CC([N+]([O-])=O)=CC=3)=[O:20])=[C:12]([CH2:15][S:16][CH:17]=[CH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].[H][H].C(O)C.P([O-])([O-])([O-])=O>[Pd].O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:34]1[N:35]=[C:36]([NH:39][C:40](=[O:45])[C:41]([F:43])([F:42])[F:44])[S:37][CH:38]=1)[C:5]([NH:7][CH:8]1[C:32](=[O:33])[N:10]2[C:11]([C:19]([OH:21])=[O:20])=[C:12]([CH2:15][S:16][CH:17]=[CH2:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: [H][H]
Reactant: C=CSCC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Yield: 37.3 %

Procedure:
p-Nitrobenzyl 7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-vinylthiomethyl-3-cephem-4-carboxylate (syn isomer) (100 mg) was hydrogenated in the presence of 5% palladium on carbon under an atmospheric pressure of hydrogen in a mixture of tetrahydrofuran (6 ml), ethanol (0.6 ml) and 0.025M phosphate buffer solution (pH 6.85, 6.4 ml) at ambient temperature for 1.5 hours. The catalyst was filtered off and washed with ethyl acetate and a saturated aqueous solution of sodium bicarbonate successively. The filtrate and washings were combined and adjusted to pH 8 with diluted hydrochloric acid. The aqueous layer was separated, adjusted to pH 6 with diluted hydrochloric acid, washed with ethyl acetate, adjusted to pH 2.4 with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated in vacuo and triturated with diethyl ether to give 7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-vinylthiomethyl-3-cephem-4-carboxylic acid (syn isomer) (30.0 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[C:4]=1B(O)O)#[N:2].C([O-])([O-])=O.[K+].[K+].[CH3:20][O:21][C:22](=[O:50])[C@H:23]([CH2:35][C:36]1[CH:41]=[CH:40][C:39](OS(C(F)(F)F)(=O)=O)=[CH:38][CH:37]=1)[NH:24][C:25](=[O:34])[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33]>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH3:20][O:21][C:22](=[O:50])[C@H:23]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][C:5]=2[C:9]#[N:10])=[CH:40][CH:41]=1)[NH:24][C:25](=[O:34])[C:26]1[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: N#Cc1cccc(C#N)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2c(C#N)cccc2C#N)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 90 °C
Yield: 12.1 %

Procedure:
To a mixture of 2,6-dicyanobenzene boronic acid (0.516 g) and anhydrous K2CO3 (0.2 g) in toluene (10 mL) under N2 was added N-(2,6-dichlorobenzoyl)-O-(trifluoromethanesulfonyl)-L-tyrosine methyl ester (0.5 g). Pd(PPh3)4 (0.1 g) was added and the mixture was heated at 90° C. for 8 h. The mixture was cooled, diluted with EtOAc and washed successively with water and brine. The organic layer was dried (MgSO4) and evaporated, and the residue was purified by column chromatography (silica gel; eluent: EtOAc/hexane 1/1) to yield 58 mg of N-(2,6-dichlorobenzoyl)-4-(2,6-dicyanophenyl)-L-phenylalanine methyl ester.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=1.CN([CH:28]=[O:29])C.Cl>O1CCCC1.O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[C:18]=1[CH:28]=[O:29]
Reactant: Fc1ccc(Br)cc1F
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1c(Br)ccc(F)c1F
Yield: 56.2 %

Procedure:
A solution of 152 mmol of 2,2,6,6-tetramethylpiperidine and 152 mmol of n-butyllithium (1.6 M solution in n-hexane) in 280 ml of dry tetrahydrofuran is admixed with 145 mmol of 1-bromo-3,4-difluorobenzene at −75° C. This temperature is maintained for 4 hours, and then 174 mmol of DMF are added dropwise. The reaction mixture is then slowly thawed, hydrolyzed with water at −20° C., acidified using hydrochloric acid and extracted with tert-butyl methyl ether. The combined organic extracts are washed with saturated sodium chloride solution and dried using sodium sulfate. The solvent is removed under reduced pressure, and the raw product is purified by chromatography over silica gel (eluent: dichloromethane/n-heptane 1:1) and recrystallization from n-heptane, yielding 18 g (56%) of 2-bromo-5,6-difluorobenzaldehyde in the form of slightly yellow crystals.—M.p.: 40-43.5° C.—1H-NMR (400 MHz, CDCl3/TMS): δ=10.31 (dd, 4J(HF)=2 Hz, 5J(HF)=1.5 Hz, 1 H, CHO), 7.45 (ddd, 3J(HH)=9 Hz, 4J(HF)=4 Hz, 5J(HF)=2 Hz, 1 H, Har), 7.28 (ddd, 3J(HH)=9 Hz, 3J(HF)=9 Hz, 4J(HF)=8 Hz, 1 H, Har).—19F-NMR (376.5 MHz, 1H broad-band decoupled, CDCl3/CFCl3): δ=−136.4 (d, 3J=19.2 Hz), −139.2 (d, 3J=19.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N.[H][H]>CO.[Ni]>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: [H][H]
Reactant: N#Cc1ccc(Oc2ccccc2Cl)cc1Cl
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ccc(Oc2ccccc2Cl)cc1Cl

Procedure:
1.2 g (4.54 mmol) of 2-chloro-4-(2-chloro-phenoxy)-benzonitrile were dissolved in 30 mL methanol and 30 ml 7M methanolic ammonia were added, then 150 mg Raney nickel were added to the mixture. It was shaken at 50° C. under 50 psi hydrogen pressure. The catalyst was separated off by suction filtering and the filtrate was evaporated down.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:3]([O:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])[C:15]=2[CH2:14]1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCc2c(n(S(=O)(=O)c3ccccc3)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Powdered sodium hydroxide (1.73 g, 43.3 mmol) and tetra-n-butylammonium hydrogen sulfate (111 mg) were added to a solution of the product from stage 1 (6.61 g, 21.6 mmol) in anhydrous methylene chloride (100 ml) and the mixture was stirred at room temperature for 1 h. Benzenesulfonyl chloride (4.21 g, 3.07 ml, 23.8 mmol) was added to the suspension, while cooling with ice. The mixture was stirred at room temperature for 16 h and water and methylene chloride (50 ml of each) were then added. The organic phase was separated off and washed with sodium chloride solution (40 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The residue was purified by flash chromatography with cyclohexane/ethyl acetate (4:2).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:21][CH:20]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Fc1ccc(CCl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Fc1ccc(CN2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h
Yield: 94 %

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (29.9 g) was dissolved in chloroform (150 ml), triethylamine (32 ml) and p-fluorobenzyl chloride (27.5 ml) were successively added under ice-cooling, and the mixture was stirred overnight. The reaction solution was successively washed with a 20% aqueous solution of sodium hydroxide (150 ml×2) and water (150 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (chloroform:methanol=10:1) to give the title compound (49.4g) as a yellow oily substance. Yield=94%.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1C(O)=O>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([OH:1])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccc2c(O)c(C(=O)O)cnc2c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: COc1ccc2c(O)ccnc2c1
Temperature: 25 °C
Yield: 97 %

Procedure:
A suspension of 4-hydroxy-7-methoxyquinoline-3-carboxylic acid (4.0 g) in Dowtherm A (75 mL) was heated at reflux for 2 hrs. The resulting brown solution was allowed to slowly cool to ambient temperature. The resulting precipitate was isolated by filtration and then dried in a vacuum oven at 80° C. for 2.5 days to provide 3.1 g of 7-methoxyquinolin-4-ol as a light tan solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11](=[C:13]([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[C:14](OCC)=[O:15])[CH3:12]>C(Cl)Cl>[CH:11](=[C:13]([CH2:19][CH2:20][CH:21]=[C:22]([CH3:23])[CH3:24])[CH2:14][OH:15])[CH3:12]
Reactant: CC=C(CCC=C(C)C)C(=O)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC=C(CO)CCC=C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.4 %

Procedure:
Diisobutyl aluminum hydride (22.4 mL of a 1M methylene chloride solution) was added dropwise over a 0.5h period to a cold (-78° C.) solution of ethyl 2-ethylidene-6-methyl-5-heptenoate (2.00g, 0.0102 mol) in methylene chloride (20 mL). The cooling bath was removed and the mixture was stirred at 25° C. for 4h. The reaction mixture was added to a 2:1 mixture of ice and 6N hydrochloric acid (30 mL). The aqueous layer was extracted with methylene chloride (3×15 mL). The extracts were washed sequentially with 2N hydrochloric acid (20 mL), sodium bicarbonate solution (until neutral), brine and dried (sodium sulfate). Evaporation of solvents provided 1.48g of crude product. Chromatography and kugelrohr distillation (bath temp: 90° C., 0.2 mm) provided 1.25g of 2-ethylidene-6-methyl5-hepten-1-ol (GLC purity: 98.5%; the E and Z isomers were not separated). NMR (250 MHz, CDCl3) δ 1.60 and 1.68 (6H,2s), 1.64 (3H, d, J=7Hz), 2.00 (1H, broad s), 2.10 (4H, broad s), 4.01 and 4.14 (2H, 2s, ratio; 85:15; 4.01 peak assigned to E isomer), 5.14 (1H, m), 5.40 and 5.51 (1H, 2q, J=7Hz); IR (film) vmax 3300, 2930, 1440, 1370 cm-1 ; MS m/e 154, 139, 121, 107, 93, 69, 41.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=O)=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[C:65]1([NH2:71])[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C=O)C>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[C:27]([CH2:30][C:31]([NH:71][C:65]5[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=5)=[O:33])[CH:28]=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(CC(=O)O)ccc1OCC2
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(CC(=O)Nc3ccccc3)ccc1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
To a mixture of [2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-yl]acetic acid trifluoroacetic acid salt from Example 120 (100 mg, 0.21 mmol), HATU (96 mg, 0.25 mmol) and NEt3 (63 mg, 0.63 mmol) in DMF (2 mL) was added a solution of phenylamine (23 mg, 0.25 mmol) in DMF (0.2 mL) and the resulting mixture stirred at RT for 16 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-8% MeOH in DCM) affording 119 as a white solid (51 mg, 57%). LCMS: RT 4.09 min [M+H]+ 429.3. 1H NMR (CDCl3, 400 MHz): δ 8.43 (1H, d, J=2.27 Hz), 7.91 (1H, s), 7.72 (1H, s), 7.47 (2H, d, J=8.02 Hz), 7.43 (1H, s), 7.29-7.26 (2H, m), 7.09-7.06 (2H, m), 5.86-5.85 (1H, m), 4.46-4.45 (4H, m), 3.78 (2H, s), 1.55 (6H, d, J=6.61 Hz)
Reaction SMILES: [F-:1].[K+].[N+]([C:6]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9])([O-])=O.C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[F:1][C:6]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9]
Reactant: O=C(CNC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])OCc1ccccc1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])cc1F)OCc1ccccc1

Procedure:
A mixture of spray-dried KF (80 mg, 1.392 mmol), intermediate 1 (100 mg, 0.2785 mmol) and catalytic amount of 18-crown-6 in dry DMSO (2 mL) was irradiated using house hold microwave oven for 1.5 min. Work-up of the reaction mixture as described in example 1 (method A) gave benzyl 2-(2-fluoro-4-nitrobenzamido)acetate as a pale yellow color solid (106 mg, 46%), mp 104-106° C. Which was further reduced as described in example 1 gave compound 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]=[C:10]2[C:15](=[O:16])OC(C)(C)OC2=O)[CH:5]=[N:6][CH:7]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:15](=[O:16])[CH:10]=[CH:9][NH:8]2)=[N:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(=CNc2cncc(F)c2)C(=O)O1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1cc[nH]c2cc(F)cnc12
Temperature: 250 °C
Reaction time: 0.08 h
Yield: 44.7 %

Procedure:
A 500 mL round bottom flask equipped with a reflux condenser was charged with 5-((5-fluoropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.0 g, 30.0 mmol) and diphenyl ether (83.5 mL). This was heated to 250° C. in heating mantle and allowed to stay at this temperature for five minutes. Cooled to room temperature, diluted with hot hexanes, and filtered to afford 7-fluoro-1,5-naphthyridin-4(1H)-one (2.2 g, 45% yield) as a crude brown solid. The title compound was used without further purification. MS [M+H]=165.2, Calc'd for C8H5FN2O=164.14.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:7][C:6](=[O:8])[C:5](=[C:9]([CH3:11])[CH3:10])[C:4](=[O:12])[O:3]1.[C-:14]#[N:15].[K+]>>[CH3:13][C:2]1([CH3:1])[O:3][C:4](=[O:12])[CH:5]([C:9]([CH3:10])([CH3:11])[C:14]#[N:15])[C:6](=[O:8])[O:7]1
Reactant: [C-]#N
Reactant: CC(C)=C1C(=O)OC(C)(C)OC1=O
Agent: [K+]
Product: CC1(C)OC(=O)C(C(C)(C)C#N)C(=O)O1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 2 starting from 2,2-dimethyl-5-(1-methylethylidene)-1,3-dioxane-4,6-dione and potassium cyanide.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:7]([C:12]([OH:14])=O)[C:8]2=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.O>ClCCl>[CH:28]1([NH:34][C:12]([C:7]2[C:8](=[O:11])[C:9]3[C:5]([C:6]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=[C:2]([OH:1])[CH:10]=3)=[O:14])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCCCC1
Reactant: O=C(O)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Temperature: 25 °C
Yield: 19.7 %

Procedure:
6-Hydroxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid (100 mg, 0.38 mmol) obtained in Step 2 was dissolved in dichloromethane, and triethylamine (175 μl, 1.25 mmol) and cyclohexylamine (43 μl, 0.38 mmol) were added thereto at 10° C. Then, bis(2-oxo-3-oxazoline)phosphoryl chloride (100 mg, 0.38 mmol) was further added thereto, stirred for 10˜20 minutes at RT, and then stirred for additional 1 hr in a water bath. After water was added to complete the reaction, the mixture washed with sodium bicarbonate and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4, concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 26 mg of the titled compound (yield: 20.0%) as a red solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([O:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:18]=1.Cl.O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([F:16])=[CH:18][C:19]=3[O:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: Nc1ccc(F)cc1OC1CCOCC1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (8.5 g) and 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (7.4 g) (intermediate XX) in dioxane (100 ml) was added HCl in dioxan (4M; 0.9 ml). The reaction was stirred at 100° C. overnight. The reaction mixture was allowed to warm to room temperature and water (50 ml) was added. The precipitate was isolated by filtration