Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]([CH3:16])[CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[N:20]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:13]([CH3:16])[CH2:14][NH:15][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([C:21]4[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=4)[CH:25]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(CN)c1nc(-c2ccc(F)cc2)cs1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
2-(4-(4-Fluorophenyl)thiazol-2-yl)propan-1-amine (50 mg, 0.21 mmol), 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (54.62 mg, 0.21 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (81.12 mg, 0.42 mmol), and 1-hydroxybenzotriazole (HOBt) (45.74 mg, 0.39 mmol) were dissolved in dichloromethane (3 mL) at room temperature. Diisopropylethylamine (DIEA) (0.147 mL, 0.85 mmol) was then introduced at room temperature and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (1×20 mL) and brine (1×20 mL). The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified on a Teledyne ISCO automated column chromatography system (0-30% EtOAc/Hexanes) to give N-(2-(4-(4-fluorophenyl)thiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide (36 mg, 36% yield). 1H NMR (CDCl3) δ 8.50 (1h, s), 8.23 (1H, d, J=8 Hz), 8.03 (1H, 1H, d, J=8 Hz), 7.85-7.81 (3H, m), 7.58 (1H, t), 7.35 (1H, s), 7.03 (2H, m), 4.05 (1H, m), 3.65 (1H, m), 1.54 (3H, d, J=8 Hz). MS (ESI) m/z: Calculated for C22H16F4N4O2S: 476.09. found: 477.1 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=O)[CH:8]=[C:9]([F:11])[CH:10]=1)=O)C.C([O-])(=O)C.[NH4+:26].O>C(O)(=O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[NH:26][C:4](=[O:3])[C:6]3[N:7]([CH:8]=[C:9]([F:11])[CH:10]=3)[CH:12]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(F)cn1CC(=O)c1ccc(Br)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(Br)cc2)cn2cc(F)cc12
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A suspension of 27.4 g (77.3 mmol) 1-[2-(4-bromo-phenyl)-2-oxo-ethyl]-4-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester and 140 g (1.82 mol) ammonium acetate in 150 ml acetic acid is heated to 110° C. and the resulting solution is stirred for 18 hours at 110° C. The reaction mixture is allowed to cool to room temperature and added to 1.5 I water under stirring. The resulting precipitate is filtered off, washed with water and dried under vacuum. It is taken up in isopropyl acetate, heated to reflux and filtered while hot. The residue is washed with isopropyl acetate and dried under vacuum to afford 3-(4-bromo-phenyl)-7-fluoro-2H-pyrrolo[1,2-a]pyrazin-1-one as grey crystals; HPLC/MS 1.83 min (A), [M+H] 307/309;
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:9]([C:12]1[CH:13]=[C:14]([CH2:23][C:24]([NH2:26])=[O:25])[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH:20]1[O:22][CH2:21]1)[CH:10]=[CH2:11].[OH-].[Na+]>>[CH2:9]([C:12]1[CH:13]=[C:14]([CH2:23][C:24](=[O:25])[NH2:26])[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH:20]([OH:22])[CH2:21][NH:1][CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:10]=[CH2:11]
Reactant: CCOC(=O)CCN
Reactant: C=CCc1cc(CC(N)=O)ccc1OCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: C=CCc1cc(CC(N)=O)ccc1OCC(O)CNCCC(=O)OCC

Procedure:
This compound was prepared in accordance with Example 1 using 10.8 g of thehydrochloride of ethyl 3-aminopropanoate, 11.6 g of 3-allyl-4-(2,3-epoxypropoxy)phenylacetamide, and 2.84 g NaOH. The crude product was crystallized from ethyl acetate. Yield 1.7 g. Melting point 98° C. (base). The structure was determined using NMR and equivalent weight.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][C:4]=1[CH3:9].[C:10]([N:13]1[CH2:17][C:16](=O)[N:15]=[CH:14]1)(=[O:12])[CH3:11]>>[C:10]([N:13]1[CH2:17][CH2:16][N:15]=[C:14]1[NH:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][C:4]=1[CH3:9])(=[O:12])[CH3:11]
Reactant: Cc1cnn(C)c1N
Reactant: CC(=O)N1C=NC(=O)C1
Agent: Cl
Product: CC(=O)N1CCN=C1Nc1c(C)cnn1C

Procedure:
5-amino-1,4-dimethyl pyrazole hydrochloride (Z. Chem. 388, 1970) (5.72 g.) and 1-acetyl-2-imidazolinone (5.54 g.) were reacted as described in Example I to give 4.723 g. product mp 199°-202° (crystallized from CH3CN)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:19][CH:18]=3)[C:12](=[O:31])[C:11]=2[N:10]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)[N:9]=1)=[O:7])[CH3:4].[CH3:39]I>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([C:17]3[CH:18]=[CH:19][C:20]([N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH3:39])=[CH:21][CH:22]=3)[C:12](=[O:31])[C:11]=2[N:10]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)[N:9]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1nn(-c2cccc(Cl)c2)c2c1CCN(c1ccc(NC(=O)OC(C)(C)C)cc1)C2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2cccc(Cl)c2)c2c1CCN(c1ccc(N(C)C(=O)OC(C)(C)C)cc1)C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
Part D. In a 200 mL of flask was placed 60% sodium hydride (0.23 g, 5.69 mmol) and DMF (10 mL). After being cooled to 0° C., a solution of 6-(4-tert-butoxycarbonylamino-phenyl)-1-(3-chloro-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (1.45 g, 2.84 mmol) in DMF (5 mL) was then added. The reaction was stirred for 30 min and then treated with methyl iodide (0.86 g, 5.69 mmol). The reaction was allowed to stir at rt overnight. After quenching with water, the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried with sodium sulfate, and concentrated to give 6-[4-(tert-butoxycarbonyl-methyl-amino)-phenyl]-1-(3-chloro-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (1.12 g). APCI MS m/z 525 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([CH:16]=1)[C:13](O)=[O:14])=[O:6].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(C(C)C)CC)(C)C.[CH3:67][C:68]1[CH:74]=[C:73]([C:75]([F:84])([C:80]([F:83])([F:82])[F:81])[C:76]([F:79])([F:78])[F:77])[CH:72]=[C:71]([CH3:85])[C:69]=1[NH2:70]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:12]([CH:16]=1)[C:13]([NH:70][C:69]1[C:71]([CH3:85])=[CH:72][C:73]([C:75]([F:84])([C:76]([F:77])([F:78])[F:79])[C:80]([F:81])([F:82])[F:83])=[CH:74][C:68]=1[CH3:67])=[O:14])=[O:6]
Reactant: O=C(Nc1ccc(Oc2ccccc2)c(C(=O)O)c1)c1cccc(Cl)c1
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(NC(=O)c2cccc(Cl)c2)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
5-(3-Chloro-benzoylamino)-2-phenoxy-benzoic acid (200 mg, 0.54 mmol) (see Example I2) was suspended in dichloromethane (2 ml), followed by the addition of bis(2-oxo-3-oxazolidinyl)phosphonic chloride “BOP-Cl” (208 mg, 0.81 mmol), diisopropyl-ethylamine “Hunigs base” (280 μl, 1.63 mmol) and 2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-aniline (158 mg, 0.54 mmol) (=4-heptafluoroisopropyl-2,6-dimethylaniline, prepared according to US 2002/198399). The reaction mixture was stirred for 18 hours at ambient temperature, followed by extraction with aqueous sodium bicarbonate (1N) and dichloromethane. The organic phase was washed successively with aqueous hydrochloric acid (2N) and aqueous sodium bicarbonate (1N), dried over sodium sulfate and concentrated. The residue was purified by preparative reverse phase chromatography to yield Compound No. A1 of Table A below (113 mg, 32% yield over three steps).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH:35]([C:34]1[CH:37]=[CH:38][C:31]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])=[CH:32][CH:33]=1)=[O:36]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cccc(COc2ccc(C=O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of 3-(Hydroxymethyl)benzonitrile (1.1 equiv), triphenylphosphine (1.1 equiv), and 4-Hydroxybenzaldehyde (1 equiv) in dry THF was added dropwise Diethyl azodicarboxilate (DEAD) (1.4 equiv). The reaction mixture stirred at room temperature overnight. The reaction was monitored by TLC. The solvent was removed under vacuum. It was purified by silica gel chromatography using Hexane:Ethyl acetate (3:1) to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[C:15]2[C:10](=[N+:11]([O-])[CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[C:17]([O:19][CH3:20])=[O:18])[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:23]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[C:15]2[C:10](=[N:11][C:12]([OH:23])=[CH:13][CH:14]=2)[S:9][C:8]=1[C:17]([O:19][CH3:20])=[O:18])[CH3:2]
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1ccc[n+]2[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(C(=O)OC)sc2nc(O)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of methyl 3-(2-ethoxy-2-oxoethoxy)thieno[2,3-b]pyridine-2-carboxylate 7-oxide (500 mg) and DMF (8 mL) was added TFAA (2.233 mL) at 0° C. The mixture was stirred at room temperature for 4 h. After evaporation of TFAA, the residue was added to water at 0° C., and the resulting precipitate was collected by filtration, washed with hexane to give the title compound (418.5 mg).
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][N:15]=3)[S:13][C:6]=12.[CH3:29][NH:30][CH3:31].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][C:17]([CH2:18][N:30]([CH3:31])[CH3:29])=[CH:20][CH:21]=3)[S:13][C:6]=12
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.1 %

Procedure:
A mixture of 400 (360 mg, 0.91 mmol) and dimethylamine (2M THF solution, 550 μL, 1.09 mmol) in DCM (10 mL) was stirred at room temperature for 10 min. It was then treated with NaBH(OAc)3 (270 mg, 1.27 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with DCM (30 mL) and washed with saturated NaHCO3 solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography using the gradient 10-30% MeOH in DCM as an eluent, to provide title compound 402 (321 mg, 83% yield). MS (m/z): (M+1) 425.1 (100%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[C:5]2[CH:14]=[C:15]([C:18]#[C:19][Si](C)(C)C)[CH:16]=[CH:17][C:4]=2[N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:18]([C:15]1[CH:16]=[CH:17][C:4]2[N:3]=[C:2]([CH3:1])[N:6]([C:7]3[N:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=3)[C:5]=2[CH:14]=1)#[CH:19]
Reactant: Cc1nc2ccc(C#C[Si](C)(C)C)cc2n1-c1ncnc(N)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc2nc(C)n(-c3ncnc(N)n3)c2c1
Reaction time: 1 h

Procedure:
To a solution of 4-{2-methyl-6-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazol-1-yl}-1,3,5-triazin-2-amine (90 mg, 0.279 mmol) in THF (1 mL) was added 1M TBAF in THF (0.33 mL, 0.33 mmol). The mixture was allowed to stand at RT for 1 hr, the mixture was concentrated in vacuo and purified by column chromatography (Biotage 5-8% MeOH/DCM) to give the title compound; LC-MS: m/z+250.95 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][S:5][C:4](=[C:7]([N:21]2[CH:24](SC)[CH2:23][C:22]2=[O:27])[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:9])[S:3]1.[Br:28]Br>O1CCCC1.C(Cl)(Cl)(Cl)Cl>[Br:28][CH:24]1[N:21]([C:7](=[C:4]2[S:3][CH:2]([OH:1])[CH2:6][S:5]2)[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:9])[C:22](=[O:27])[CH2:23]1
Reactant: BrBr
Reactant: CSC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=C1SCC(O)S1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C(=C1SCC(O)S1)N1C(=O)CC1Br
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
p-Nitrobenzyl 2-(4-hydroxy-1,3-dithiolan-2-ylidene)-2-(4-methylthio-2-azetidinon-1-yl)acetate (121 mg) was dissolved in tetrahydrofuran (1 ml). A solution of bromine (45.2 mg) in carbon tetrachloride was added dropwise to the resulting solution, with ice cooling. The mixture was stirred at that temperature for 10 minutes and then the solvent was distilled off under reduced pressure and the resulting residue was purified by column chromatography (eluent: a 1:1 by volume mixture of benzene and ethyl acetate), to give 130 mg of the desired product.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[O:6]=[C:7]([CH2:13][C:14](=[O:16])[CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(Cl)Cl>[Cl:4][CH:13]([C:14](=[O:16])[CH3:15])[C:7](=[O:6])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(=O)C(Cl)C(C)=O
Reaction time: 3 h
Yield: 101.8 %

Procedure:
A solution of sulfuryl chloride (7.08 g, 52 mmol) in 15 mL of CH2Cl2 was added dropwise to a solution of ethyl 2,4-dioxovalerate (7.91 g, 40 mmol) in 125 ml of CH2Cl2 at room temperature. After three hours TLC analysis indicated that all of the starting material had been consumed. The reaction mixture was washed with H2O (2×100 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 7.84 g (81% yield) of the desired product as and orange oil: 1H NMR (CDCl3) 67 14.4 (bs, 1H), 5.4 (s, 1H), 4.4-4.3 (m, 4H), 2.5 (s, 3H), 2.4 (s, 3H), 1.4-1.35 (s, 6H) for a 1:1 mixture of tautomers.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[OH-].[Li+].S(=O)(=O)(O)[OH:16]>O>[F:8][C:7]1[C:6]([F:9])=[CH:5][CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:16]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(F)c1O
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
1.77 g (10 mol) of 2,3,4-trifluoronitrobenzene are added to 2.5 l of water, and the mixture is warmed to 40° C. and vigorously stirred. 1320 g (22 mol) of 40% strength lithium hydroxide solution are then added dropwise in such a way that the temperature rises from 40° to 55° C. within 2.5 h. After this time, GC checking no longer shows any starting compound. The reaction mixture is brought to pH 2 with 70% strength sulfuric acid. It is then worked up, as described in Examples 1 and 2. 1.48 kg of 2,3-difluoro-6-nitrophenol having a purity >99.9% (GC) are obtained after drying (melting point 63.5° C.), which corresponds to a yield of 85% of theory.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]1[C:18]3[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:17]=3[O:16][N:15]=1)[CH:8]=[CH:7]2.O>C(O)(=O)C>[Br:1][C:5]1[C:4]([OH:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([C:14]1[C:18]3[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:17]=3[O:16][N:15]=1)=[CH:10]2
Reactant: Oc1ccc2cc(-c3noc4cc(O)ccc34)ccc2c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc2c(-c3ccc4c(Br)c(O)ccc4c3)noc2c1
Reaction time: 0.5 h
Yield: 53 %

Procedure:
Bromine (0.11 mL, 2.17 mmol) in acetic acid (3 mL) was added dropwise into cold (5° C.) mixture of 3-(6-hydroxy-2-naphthyl)-1,2-benzisoxazol-6-ol (0.6 g, 2.17 mmol) and acetic acid (10 mL). The mixture was stirred for 30 min, poured into water and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/EtOAc 1/1) gave an off-white solid (0.41 g, 53% yield, m.p. 275-277° C.); MS m/e 354 (M−H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=1[NH:12][CH:13]1[CH2:15][CH2:14]1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:29]([C@@H:25]([NH:24][C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH3:26])=[N:11][C:6]=2[CH:7]=[CH:8][C:9]=1[F:10])=[O:16]
Reactant: COC(=O)c1c(F)ccc(N)c1NC1CC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: COC(=O)c1c(F)ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(C3CC3)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A mixture of 3-amino-2-cyclopropylamino-6-fluorobenzoic acid methyl ester (756 mg, 3.37 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (702 mg, 3.71 mmol), HOAt (505 mg, 3.71 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (711 mg, 3.71 mmol) in DCM (20 mL) was stirred at 0° C. for 1 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was dried and concentrated in vacuo. The resulting residue was taken up in AcOH (20 mL) and heated at 70° C. for 21 h. After cooling to RT, the volatiles were evaporated in vacuo and the residue partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with EtOAc and the combined organic fractions washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in DCM) to afford the title compound (700 mg, 55% over 2 steps). LCMS (Method C): RT 3.27 min [M+H]+ 378.18
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[CH2:12][C:13]1[O:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: ClCc1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(OCc2ccco2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
20 mL of DMF was blended with 2.0 g (14.4 mmol) of 3-nitrophenol, 3.57 g (30.6 mmol) of 2-(chloromethyl)furan, and 2.0 g (14.4 mmol) of potassium carbonate, and the mixture was stirred at 80° C. for 3 hours. After cooling the reaction solution to room temperature, the reaction solution was extracted with ethyl acetate, and resultant solid material was washed with water 3 times and with a saturated sodium chloride solution, and dried over magnesium sulfate. Thereafter, filtration was conducted and the filtrate was condensed. The resulting crude product was separated and purified using silica gel column chromatography to give 2-[(3-nitrophenoxy)methyl]furan (yield: 91%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([OH:14])[C:11]2[C:6](=[C:7](C)[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[Cl:18]C1C(OC)=CC=CC=1N>>[Cl:18][C:7]1[C:8]([O:15][CH3:16])=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=[C:12]2[OH:14]
Reactant: CCOc1cc(O)c2ccc(OC)c(C)c2n1
Reactant: COc1cccc(N)c1Cl
Product: CCOc1cc(O)c2ccc(OC)c(Cl)c2n1

Procedure:
8-Chloro-2-ethoxy-7-methoxy-quinolin-4-ol was synthesized according to the method presented in the synthesis of 2-Ethoxy-7-methoxy-8-methyl-quinolin-4-ol in Example 132 with the exception of utilizing 2-Chloro-3-methoxy-aniline.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][C:35]=1[C:41]([F:44])([F:43])[F:42].O>CS(C)=O.[Cl-].[Na+].O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:38][C:37]3[CH:39]=[CH:40][C:34]([F:33])=[C:35]([C:41]([F:44])([F:42])[F:43])[CH:36]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3ccc(F)c(C(F)(F)F)c3)c1)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 9.3 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (54 mg, 0.20 mmol) and 1,1′-Carbonyldiimidazole (36 mg, 0.22 mmol) in 3.0 mL DMSO was stirred at rt for 5 minutes, and then heated at 60° C. for 25 minutes. Then 4-fluoro-3-(trifluoromethyl)aniline (0.051 mL, 0.40 mmol) was added, and the reaction heated at 80° C. for 46 hours. Next, an additional 2 small drops of 4-fluoro-3-(trifluoromethyl)aniline was added and the reaction heated at 160° C. for 1.5 hours. Upon cooling to rt, the reaction mixture was added to a solution of 35 mL H2O plus 5 mL brine, and the resulting precipitate filtered and rinsed with H2O and hexane/EtOAc. The precipitate was chromatographed using CHCl3/MeOH, and the resulting solid chromatographed again using EtOAc/MeOH to give the title compound as a yellow solid (8 mg, 9%). 1H NMR (Acetone-d6) δ: 9.77 (br. s., 1H), 8.31 (dd, J=6.4, 2.6 Hz, 1H), 8.10-8.17 (m, 2H), 7.62-7.64 (m, 1H), 7.35-7.44 (m, 3H), 7.24-7.28 (m, 1H), 5.79 (br. s., 2H), 4.35 (s, 2H), 3.70 (t, J=5.9 Hz, 2H), 2.80-2.86 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2.O[Li].O>C1COCC1.O>[CH3:25][O:24][C:23]1[CH:22]=[CH:21][NH:20][C:19]=1/[CH:18]=[C:10]1\[C:11](=[O:17])[NH:12][C:13]2[C:9]\1=[C:8]([C:7]#[C:6][CH2:5][CH2:4][C:3]([OH:26])=[O:2])[CH:16]=[CH:15][CH:14]=2
Reactant: COC(=O)CCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCC(=O)O)c21

Procedure:
Using Method F above, (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester (50 mg, 0.14 mmol) (from Example 8 above) was hydrolyzed with LiOH•H2O (118 mg, 2.8 mmol) in THF (3 mL) and water (3 mL) for 22 h. (Yield 40 mg, 85%).