Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15]C(C)(C)C)=O)[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.F[C:21](F)(F)C(O)=O.C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][N:10]([C:13](=[O:15])[CH3:21])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccnc2F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCC(c2cccnc2F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 3-(2-fluoropyridin-3-yl)pyrrolidine-1-carboxylate (0.25 g, 0.939 mmol) dissolved in DCM (3.1 mL) was added trifluoroacetic acid (1.05 mL, 14.1 mmol). The reaction mixture was stirred at RT for 1 h. The solvent was evaporated in vacuo and to the residue dissolved in DCM (1 mL) was added acetic anhydride (0.44 mL, 4.7 mmol) and sodium bicarbonate (0.4 g, 4.7 mmol). The reaction mixture was stirred at RT under N2 for 3 h. The reaction mixture was partitioned between 1N NaOH and DCM. The aqueous layer was back extracted with DCM (3×) and the combined DCM layer was dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, then 10% MeOH in EtOAc, to provide 1-(3-(2-fluoropyridin-3-yl)pyrrolidin-1-yl)ethanone as tan oil. [M+H]=209.2.
Reaction SMILES: [CH3:1][N:2]([CH:4](OC)OC)[CH3:3].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13]2.O>C1COCC1>[CH3:1][N:2](/[CH:4]=[C:13]1/[C:14](=[O:19])[NH:15][C:16]2[C:12]/1=[CH:11][C:10]([F:9])=[CH:18][CH:17]=2)[CH3:3]
Reactant: COC(OC)N(C)C
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)/C=C1/C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DMF-DMA (3.15 g, 26.4 mmol) was added into a solution of 5-fluoroindolin-2-one LXXXVIII (2.0 g, 13.2 mmol) in dry THF. The reaction mixture was stirred at rt for 4 hr before being poured into water and extracted by EtOAc. The organic layer was separated and dried by Na2SO4, and concentrated to give (E)-3-((dimethylamino)methylene)-5-fluoroindolin-2-one LXXXVIX.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[N:15]=[CH:14][NH:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CO.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[N:15]=[CH:14][NH:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1cc(-c2nc[nH]n2)ccc1[N+](=O)[O-]
Solvent: CO
Solvent: O
Product: Cc1cc(-c2nc[nH]n2)ccc1N
Yield: 82.5 %

Procedure:
A solution of Na2S.8H2O (171.89 g) in methanol (690 ml) and water (173 ml) was added dropwise to a refluxing suspension of 3-(3-methyl-4-nitro-phenyl)-1,2,4-triazole (36.8 g) in methanol (170 ml). After two hours of refluxing, the solution was filtered through charcoal and evaporated to dryness. The residue was dissolved in 10% hydrochloric acid, the solution was washed several times with ethyl acetate and neutralized with NaHCO3 solution. The solid which separated out was filtered off and dried to give 25.9 g of the title compound; M.p. 183°-186° C. 3-(3-Methoxy-4-amino-phenyl)-1,2,4-triazole; M.p. 191°-194° C., was prepared in analogous manner.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.P(OCC)(OCC)OCC.O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.[H-].[Na+]>O.COCCOC>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:8]=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1
Reactant: BrCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CCOP(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Br)c2)CC1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 51.5 %

Procedure:
The mixture of 1-bromo-3-(bromomethyl)benzene (6.2 g, 24.8 mmol) and triethyl phosphite (4.53 g, 27.28 mmol) was heated at 90° C. for 12 hours, cooled to 0° C., added DME (40 ml) and tert-butyl 4-oxopiperidine-1-carboxylate (5.73 g, 28.8 mmol) and sodium hydride (1.19 g, 49.6 mmol) and stirred at RT for 2-3 hours. Diluted with water and extracted with ether to afford 4.5 g (51.5% yield) of the titled product after purification with (60/120 silica gel) column chromatography using 10% ethyl acetate in hexane as eluent. MS: m/z=353.2 (M+1).
Reaction SMILES: [CH2:1]([C:8]1([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:31])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)[NH2:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:16][O:17][C:18](=[O:31])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)[NH:20][C:13]([C:8]1([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:15]
Reactant: O=C(O)C1(Cc2ccccc2)CCCC1
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)C1(Cc2ccccc2)CCCC1
Yield: 71.6 %

Procedure:
A solution of 1-benzylcyclopentane carboxylic acid (0.135 g, 0.66 mmol), 4-nitro-L-phenylalanine methyl ester (0.187 g, 0.72 mmol), and HBTU (0.272 g, 0.72 mmol) in 2 mL of DMF was treated with diisopropylethylamine (0.35 mL, 2 mmol). The mixture was stirred over night, concentrated, diluted with ethyl acetate, washed with water, 1 N HCl, water, saturated NaHCO3 and dried (MgSO4). The residue obtained after evaporation was purified by chromatography over 30 g of silica gel, eluting with 40% ethyl acetate:hexane to give 4-nitro-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (194 mg, 71%). as a white foam.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[Br:8][C:9]1[CH:10]=[N:11][N:12]2[CH:17]=[CH:16][C:15](Cl)=[N:14][C:13]=12.C(N(C(C)C)C(C)C)C.CCOC(C)=O>CN(C=O)C>[Br:8][C:9]1[CH:10]=[N:11][N:12]2[CH:17]=[CH:16][C:15]([NH:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4])=[N:14][C:13]=12
Reactant: CC(C)[C@H](N)CO
Reactant: Clc1ccn2ncc(Br)c2n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](CO)Nc1ccn2ncc(Br)c2n1
Temperature: 100 °C
Yield: 97.2 %

Procedure:
To a solution of (S)-2-amino-3-methylbutan-1-ol (3.3 g, 32 mmol) in DMF was added 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (2.5 g, 11 mmol) and N-ethyl-N-isopropylpropan-2-amine (4.2 g, 32 mmol) and the reaction was heated to 100° C. for 4 hours. The reaction mixture was poured into EtOAc and washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to yield (S)-2-(3-bromopyrazolo[1,5-a]pyrimidin-5-ylamino)-3-methylbutan-1-ol (3.2 g, 99%). LCMS (APCI+) m/z 299, 301 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].C(N(CC)CC)C.[C:16](=S)=[S:17].ClC(OCC)=O.[OH-].[Na+]>ClCCCl.O>[N:8]([CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[C:16]=[S:17]
Reactant: S=C=S
Reactant: NCCc1cccs1
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCCl
Product: S=C=NCCc1cccs1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Thiopene ethylamine (4.60 mL, 39.31 mmol) and triethyl amine (5.00 mL, 39.31 mmol) were dissolved in 1,2-dichloroethane (25 mL), and the resulting mixture was cooled to 0° C. A solution of carbon disulfide (2.36 mL, 39.31 mmol) in 1,2-dichloroethane (50 mL) was added dropwise thereto over 15 min. The reaction mixture was allowed to warm to room temperature and re-cooled to 0° C., to which ethyl chloroformate (4.27 mL, 31.39 mmol) was added dropwise. The reaction mixture was stirred at room temperature for about 1-2 h, and water (150 mL) and aqueous 2N sodium hydroxide (75 mL) were sequentially added thereto. The resulting mixture was extracted with dichloromethane. The extract was washed with water and brine, dried over sodium sulfate, and concentrated, to obtain the yellow title compound in a liquid form (5.37 g, 80.75%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>OS(C(F)(F)F)(=O)=O>[Br:19][C:3]1[C:4]2[CH2:8][O:7][C:6](=[O:9])[C:5]=2[CH:10]=[CH:11][C:2]=1[Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2cc(Br)ccc21
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1OCc2c1ccc(Br)c2Br
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a flask containing a stir bar was added commercially available 5-bromo-2-benzofuran-1(3H)-one (12.0 g, 56.3 mmol) and NBS (15 g, 84 mmol). Triflic acid (50 mL) was added at 0° C. and the resulting mixture was stirred for 2 days. TLC analysis of the reaction mixture showed a complete reaction; the reaction mixture was poured into an ice and the organic layer separated. The organic layer was washed with aq. NaCl, water, dried over Na2SO4, filtered and concentrated to dryness, it was then absorbed onto silica gel and subjected for purification over a silica column to give the title compound.
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C(O)=O.[CH3:10][O:11][C:12]([C:14]1[CH:29]=[CH:28][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=O)=[CH:16][CH:15]=1)=[O:13]>C(Cl)Cl>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:18][C:17]2[CH:28]=[CH:29][C:14]([C:12]([O:11][CH3:10])=[O:13])=[CH:15][CH:16]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a mixture of sodium borohydride (2.27 g) and trifluoroacetic acid (50 ml), which was previously prepared under nitrogen atmosphere, was added a solution of 4-methoxycarbonyl-4'-methoxybenzophenone (2.70 g) and methylene chloride (30 ml) at room temperature. After reacting for 24 hours, the reaction mixture was poured into ice-water, and methylene chloride layer was separated. Water layer was further extracted with methylene chloride (50 ml×2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[C:15](=C)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])=[CH:3][CH:2]=1.[CH2:18]([Br:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:26](#N)C>>[Br-:25].[CH2:18]([N+:1]1[CH:6]=[CH:5][C:4](=[C:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:3][C:2]=1[CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC#N
Reactant: C=C1c2ccccc2C(=O)C1c1ccncc1
Product: CC1=[N+](Cc2ccccc2)C=CC(=C2Cc3ccccc3C2=O)C1
Product: [Br-]

Procedure:
##STR7## 10 g of compound from Example 1 were dissolved in 150 ml of boiling acetonitrile and 7.5 g of benzyl bromide were added hot. The mixture was heated to boiling under reflux for a further 2 h, the product precipitating. It was allowed to cool, and the resulting precipitate was filtered off with suction, washed with acetonitrile and methyl tert-butyl ether in the sequence indicated and dried in air.
Reaction SMILES: [C:1](/[C:3](=[CH:9]\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[N+]([CH:19]([CH3:21])[CH3:20])([O-])=O.[O-]CC.[Na+]>C(O)C>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:19]1([CH3:21])[CH3:20])#[N:2]
Reactant: CC(C)[N+](=O)[O-]
Reactant: CCOC(=O)/C(C#N)=C/c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C#N)C(c2ccccc2)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
A mixture of 534 mg (2.65 mmoles) of cyanoester 1 (produced in accordance with Example I), 0.25 mL (2.78 mmoles) of 2-nitropropane, and 4.0 mL (2.60 mmoles of sodium ethoxide) of an 0.65M solution of sodium ethoxide (prepared from sodium metal and ethyl alcohol) in ethyl alcohol was stirred at room temperature for 10 minutes and subsequently heated at gentle reflux, protected from atmospheric moisture, for 3 hours. The product was isolated by cooling the mixture to room temperature, diluting it with 30 mL of 10% aqueous sodium chloride, and extraction with dichloromethane. The dichloromethane extracts were washed with 10% aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. Removal of the dichloromethane at reduced pressure, followed by evaporative distillation, [bath temperature: 125°-135° C. (0.05 mm)], afforded 620 mg (96% yield) of cyclopropanoid cyanoester 10. The presence of a single sharp peak (δ3.30) for the cyclopropyl H in 10 suggested the presence of only one stereoisomer (neglecting optical isomerism)--the phenyl and cyano substituents being cis, as shown by subsequent decarbalkoxylation results).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([C:35]2[S:36][C:37](Br)=[CH:38][CH:39]=2)(=[O:34])=[O:33])[CH:26]=1>>[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([C:35]2[S:36][C:37]([C:13]#[C:12][C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]5[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=5)=[N:6][C:7]=34)=[CH:38][CH:39]=2)(=[O:33])=[O:34])[CH:26]=1
Reactant: O=S(=O)(Nc1cccnc1)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(Nc1cccnc1)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and commercially available 5-bromo-thiophene-2-sulfonic acid pyridin-3-ylamide [CAS-No. 439934-18-6] (160 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (220 mg, 76%). MS (ISN) 574.1 [(M−H)−]; mp 226° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][C:21]([OH:23])=[O:22].C(N(CC)CC)C>O>[CH2:1]([O:8][C:9]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: NCC(=O)O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 50 ml of water was suspended 2.5 g of N-(benzyloxycarbonyloxy)succinimide, and the suspension was stirred for 1 hour at room temperature. To this suspension was added 20 ml of an aqueous solution of 0.75 g of glycine and 1.4 ml of triethylamine, and the reaction mixture was stirred for 12 hours as it was, but the desired product, benzyloxycarbonylglycine, could not be obtained.
Reaction SMILES: C(Cl)(=[O:3])C.[CH2:5]([O:7][C:8]([C:10]1[CH:28]=[C:13]2[C:14](=[O:27])[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:16][CH2:17][N:12]2[N:11]=1)=O)[CH3:6].C([O-])([O-])=O.[Na+].[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(Cl)(=O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:15]2[CH2:16][CH2:17][N:12]3[N:11]=[C:10]([CH2:8][O:7][C:5](=[O:3])[CH3:6])[CH:28]=[C:13]3[C:14]2=[O:27])=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1cc2n(n1)CCN(Cc1ccc(OC)cc1)C2=O
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN2CCn3nc(COC(C)=O)cc3C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 783.9 %

Procedure:
Acetyl chloride (0.043 mL, 0.055 mmol) was added to a stirred solution of 5-(4-methoxy-benzyl)-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (3.8 g, 11.5 mmol), TEA (0.1 mL, 0.75 mmol) and DMAP (6.1 mL, 0.05 mmol)) in DCM (2.5 mL) at 0° C. The mixture was stirred at room temperature for 2 hours. Then more acetyl chloride (0.01 mL, 0.01 mmol) was added and the mixture was stirred at room temperature for 2 hours more. The mixture was treated with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield acetic acid 5-(4-methoxy-benzyl)-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylmethyl ester (142 mg, 86% yield) as a colourless oil that was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:4]1[C:17]([OH:18])=[C:16]([Cl:19])[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:20])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:21])[C:6]=2[CH:5]=1)[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:37](=[O:40])([O-])[O-:38].[K+].[K+]>O>[Cl:19][C:16]1[C:15]2[O:14][C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([F:20])[C:8]=3[C:7](=[O:21])[C:6]=2[CH:5]=[C:4]2[CH2:1][CH:2]([C:37]([OH:38])=[O:40])[O:18][C:17]=12
Reactant: O=C([O-])[O-]
Reactant: C=CCc1cc2c(=O)c3c(F)cccc3oc2c(Cl)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)C1Cc2cc3c(=O)c4c(F)cccc4oc3c(Cl)c2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.5 %

Procedure:
A mixture of 2-allyl-4-chloro-8-fluoro-3-hydroxy-9-oxo-9H-xanthene (2.8 g), m-chloroperbenzoic acid (4.7 g) and chloroform (100 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (10 g) and water (200 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (500 ml) and, to the stirred solution, a mixture of chromium trioxide (2.8 g), water (16 ml) and concentrated sulfuric acid (4.8 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.0 g of 11-chloro-6-fluoro-2,3-dihydro-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylic acid. m.p. 300° C. This compound showed a mass spectrum having a molecular ion peak at m/e 334.
Reaction SMILES: [O-]CC.[Na+].C1(C)C=CC=CC=1.C([O:14][C:15](=[O:32])[CH2:16][C:17]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1)=[N:18][N:19]1[CH2:23][CH2:22][CH2:21][C:20]1=O)C.Cl>O>[CH3:31][C:27]1[N:26]=[C:25]([C:17]2[C:16]([C:15]([OH:14])=[O:32])=[C:23]3[CH2:22][CH2:21][CH2:20][N:19]3[N:18]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)CC(=NN1CCCC1=O)c1cccc(C)n1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2nn3c(c2C(=O)O)CCC3)n1
Temperature: 100 °C
Yield: 85.8 %

Procedure:
Add sodium ethoxide (90 g, 1.32 mol), toluene (5 L) and 3-(6-methyl-pyridin-2-yl)-3-(2-oxo-pyrrolidin-1-ylimino)-propionic acid ethyl ester (Preparation 1, Part B; 201 g, 0.661 mol) to a 22 L flask equipped with a mechanical stirrer, nitrogen inlet and a reflux condenser. Heat the mixture at 100° C. for 24 h then cool to room temperature. Add water (4 L) and adjust the pH to 4 with concentrated hydrochloric acid. Separate the organic layer and extract the aqueous portion with 10% isopropyl alcohol in chloroform is (3×4.5 L). Combine the organic layers, dry (sodium sulfate), filter, and concentrate in vacuo to yield the subtitled product (138 g, 86% yield) as a yellow solid in 78% purity by HPLC analysis. MS ES+ m/e 244 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([O:24]C(C)C)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.ClB(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([OH:24])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OC(C)C)cc12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(O)cc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 2-(4-fluorophenyl)-5-isopropoxy-N-methyl-6-nitrobenzofuran-3-carboxamide (210.5 mg, 0.565 mmol) in CH2Cl2 (14 mL) at 0° C. under N2 was added trichloroborane (1.70 mL, 1.7 mmol) (1M solution in CH2Cl2). The mixture was then stirred at r.t. for 17 hr. The mixture was evaporated. The reddish orange residue was added 7 ml H2O, and then 3.5 ml 1N HCl, and left standing until the solid turned yellow. The yellow solid product was then filtered and washed with 3×3 ml H2O and dried (182 mg, 93%). 1H NMR (500 MHz, DMSO-d6) δ 10.18 (broad s, 1 H), 8.53 (m, 1 H), 8.31 (s, 1 H), 7.98 (apparent dd, J=8.85, 5.49, 2 H), 7.43 (apparent t, J=8.85, 2 H), 7.28 (s, 1 H,), 2.84 (appeared as d, J=4.58, 3 H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)+=331.21, HPLC Rt=1.442 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21](F)[CH:22]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:21]3[CH:20]=[N:19][CH:18]=[C:17]([F:16])[CH:22]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: Fc1cncc(F)c1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cncc(F)c1

Procedure:
The title compound, MS: m/e=313.1 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3,5-difluoro-pyridine.
Reaction SMILES: [C:1](=[O:31])([O:29][CH3:30])[O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[O:11])[C:6](Br)=[CH:5][C:4]=1[CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.CN(C=O)C.[CH2:37]([OH:40])[C:38]#[CH:39]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[C:1](=[O:31])([O:29][CH3:30])[O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[O:11])[C:6]([C:39]#[C:38][CH2:37][OH:40])=[CH:5][C:4]=1[CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.[CH:24]1([C:4]2[C:3]([OH:2])=[CH:8][C:7]([NH:9][C:10]([C:12]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][CH:13]=3)=[O:11])=[C:6]([C:39]#[C:38][CH2:37][OH:40])[CH:5]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C#CCO
Reactant: COC(=O)Oc1cc(NC(=O)c2c[nH]c3ccccc3c2=O)c(Br)cc1C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Oc1cc(NC(=O)c2c[nH]c3ccccc3c2=O)c(C#CCO)cc1C1CCCC1
Product: O=C(Nc1cc(O)c(C2CCCC2)cc1C#CCO)c1c[nH]c2ccccc2c1=O
Temperature: 80 °C

Procedure:
4-bromo-2-cyclopentyl-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate (50 mg, 0.10 mmol), Pd(PPh3)2Cl2 (4 mg, 0.005 mmol), and cuprous iodide (1 mg, 0.10 μL, 0.003 mmol) were added to a microwave tube which was flushed with N2 and capped. A degassed solution of DMF (1 mL), triethylamine (2 mL), and prop-2-yn-1-ol (57.75 mg, 59.97 μL, 1.030 mmol) was added and the reaction mixture was heated at 80° C. for 16 h. The reaction mixture was filtered and purified by HPLC (20-99% CH3CN/0.05% TFA) to give 2-cyclopentyl-4-(3-hydroxyprop-1-ynyl)-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate/N-(4-cyclopentyl-5-hydroxy-2-(3-hydroxyprop-1-ynyl)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide. These product fractions were combined, concentrated to remove acetonitrile, and treated with 5N NaOH (2 mL). The pH of the solution was adjusted to 7 and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 50% saturated sodium bicarbonate solution (2×20 mL) and brine. The solution was dried over anhydrous Na2SO4, filtered, and dried to obtain N-(4-cyclopentyl-5-hydroxy-2-(3-hydroxyprop-1-ynyl)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide. LC/MS: m/z 403.2 (M+H)+ at 0.92 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).