Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:11]=1)[C:7]([NH:9][NH2:10])=[O:8].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[N:10][NH:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NNC(=O)c1cc(N)ccc1Oc1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: Nc1ccc(Oc2ccccc2)c(C(=O)NN=Cc2cccc(C(F)(F)F)c2)c1

Procedure:
A mixture of phenol (5.64 g, 60 mmol) and potassium t-butoxide (6.74 g, 60 mmol) in 50 mL 1,4-dioxane was stirred at room temperature for 0.5 h. To the mixture was added 2-chloro-5-nitro-benzoic acid methyl ester (10.78 g, 50 mmol) and the mixture was refluxed overnight. The solvent was evaporated and the residue was purified by chromatography with EtOAc:hexanes, 1:4, as eluant, yielding (11.739 g, 86%) 5-nitro-2-phenoxy-benzoic acid methyl ester. A mixture of 5-nitro-2-phenoxy-benzoic acid methyl ester (2.0 g, 7.32 mmol) in 30 mL ethanol and Pd/C (200 mg) were hydrogenated at 40 psi overnight to yield 5-amino-2-phenoxy-benzoic acid methyl ester (1.672 g, 94%). A mixture of 5-amino-2-phenoxy-benzoic acid methyl ester (0.95 g, 3.9 mmol) and hydrazine (4 mL, 80%) was refluxed for 4 h to yield 5-amino-2-phenoxy-benzoic acid hydrazide (0.722 g, 76%). The title compound was prepared from 5-amino-2-phenoxy-benzoic acid hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (CDCl3): 10.81 (s, 1H), 8.15 (s, 1H), 8.0 (s, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.66 (s, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.40 (m, 2H), 7.19 (t, J=7.5 Hz, 1H), 7.07 (d, J=7.8, 2H), 6.80 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([Br:15])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:19][O:20][CH2:21]Cl.Cl.C(OCC)C>CN(C=O)C>[Br:15][C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=1[O:16][CH2:19][O:20][CH3:21]
Reactant: COCCl
Reactant: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCOc1c(Br)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 7.5 °C
Reaction time: 0.5 h

Procedure:
40.00 g (140.2 mmol) of 2,4-di-tert-butyl-6-bromophenol and 400 ml of DMF are introduced into a one liter three-necked flask. The solution obtained is cooled to 5-10° C., 4.70 g of sodium hydride are added and the mixture is stirred at 10° C. for 30 minutes. 11.7 ml (154.0 mmol) of chloromethyl methyl ether are then added dropwise and the reaction mixture is stirred for one hour at room temperature. The reaction mixture is poured into a 1N HCl/ethyl ether mixture and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. 46.00 g (130%) of the expected compound are collected in the form of an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][O:14][S:23]([CH3:22])(=[O:25])=[O:24])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CC(c2ccc(Br)cn2)=NO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CC(c2ccc(Br)cn2)=NO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
[3-(5-Bromo-pyridin-2-yl)-4,5-dihydro-isoxazol-5-yl]-methanol (38.8 g, 150.5 mmol) was added to anhydrous dichloromethane (200 ml) followed by addition of triethylamine (29.2 ml, 210.7 mmol). The solution was cooled to 0° C. followed by dropwise addition of methane sulfonyl chloride (12.3 ml, 180.6 mmol). The reaction was stirred for 2 hours at 0° C. and then aqueous sodium bicarbonate (100 ml) was added. After further extraction with dichloromethane (2×100 ml), the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the desired product (30.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:48]=[CH:47][C:46]([O:49]CC4C=CC=CC=4)=[CH:45][C:19]=3[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:24]([CH2:36][O:37][Si](C(C)(C)C)(C)C)[CH:23]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[OH2:57]>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][C:19]=3[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:24]([CH2:36][OH:37])[CH:23]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:11][CH2:12][O:57][CH2:13][CH2:14]1
Reactant: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)c(CO[Si](C)(C)C(C)(C)C)c3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Reactant: O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)c(CO)c3)sc3cc(O)ccc23)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
The (30.8 mg, 0.0381 mmol) 6-benzyloxy-2-[3-t-butyldimethylsilyloxymethyl-4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 3-methoxy-4-(1-pyrrolidinylmethyl)phenyl ketone (Part C) was dissolved in 0.5 mL of 1N tetrabutylammonium fluoride in THF. The solution was stirred at room temperature for 1 h. To the reaction mixture was added 1.0 mL of water and diluted with 15 mL of EtOAc. The layers were separated and the aqueous layer was extracted (1×10 mL) with EtOAc. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 80:17:3 THF-Hexanes-Et3N) afforded 5.7 mg (0.0082 mmol, 22%) of a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30])([CH3:23])[CH3:22].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1ccccc1O
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccccc2C(C)C)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (example 284, Step 2) and 2-isopropyl-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (example 285, Step 1), to produce a colorless oil. MS (ES) for C22H28O5 [M+NH4]+: 390.4.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C>[Si:21]([O:1][CH2:2][CH:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCNC(CO)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCNC(CO[Si](C)(C)C(C)(C)C)C1
Reaction time: 20 h

Procedure:
To a solution of racemic tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.5 g, 6.9 mmol, AstaTech) and 1H-imidazole (1.4 g, 21 mmol) in DMF (20 mL) cooled to 0° C. was added tert-butyldimethylsilyl chloride (2.1 g, 14 mmol). The mixture was then allowed to reach RT and stir for 20 h. The mixture was quenched by the addition of saturated ammonium chloride. The product was extracted with two portions of ethyl acetate. The organic extract was washed with water, brine, dried over sodium sulfate and concentrated to afford a clear oil. Flash chromatography on a 120 g silica gel cartridge, eluting with a slow gradient from 0-6% MeOH in DCM afforded purified product (1.15 g, 50%). 1H NMR (400 MHz, CDCl3): δ 4.00-1.63 (m, 9H), 1.45 (s, 9H), 0.89 (s, 9H), 0.05 (s, 6H); LCMS (M+H)+: 331.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:17][OH:18].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:17][OH:18]
Reactant: [H][H]
Reactant: COC(=O)CCCC#CCN1C(=O)CCCC1CO
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCCN1C(=O)CCCC1CO
Reaction time: 23 h
Yield: 101.2 %

Procedure:
Palladium on carbon (10 wt.%, 20 mg) was added to a solution of 7-(2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (180 mg, 0.67 mmol) in MeOH (6.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 23 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo to afford 184 mg (quant.) of 7-(2-hydroxymethyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=1.[Br:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][N:32]=1>C1COCC1>[Br:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=2)=[O:36])=[CH:33][N:32]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(O)c1ccc(Br)nc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)c2ccc(Br)nc2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.7 %

Procedure:
2-Chloro-1-methylpyridinium iodide (2.2 g, 9.8 mmol) and DIPEA (1 ml) were added to a mixture of 5-fluoropyridin-2-amine 1 (554 mg, 4.9 mmol) and 6-bromonicotinic acid 2 (1 g, 4.9 mmol) in THF. The reaction mixture was stirred at rt for 2 days. At the conclusion of the reaction, the reaction mixture was concentrated to ⅓ of its volume and the precipitated product was filtered off. The filtrate was concentrated, diluted with chloroform (100 ml), washed with water and brine and then dried over Na2SO4. Evaporation of the solvent gave a crude yellow product, which crystallized in EtOAc to give 6-bromo-N-(5-fluoropyridin-2-yl)nicotinamide 3 (1.05 g, 71%) as a white solid. Mp. 173-174° C.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH3:23])([CH3:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([C:20]#[CH:21])[CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(NC(C)C)(C)C.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.[Cu]I>[C:1]1([S:7]([C:10]([CH3:23])([CH3:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([C:20]#[C:21][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:15]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CC1CCCN(CCCC(C)(C)S(=O)(=O)c2ccccc2)C1
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: CC(C)(CCCN1CCCC(C#Cc2ccccc2)C1)S(=O)(=O)c1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-benzenesulfonyl-4-methylpentyl)-3-ethynylpiperidine (0.33 g, 1.0 mmol), iodobenzene (80 μL, 0.7 mmol), dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05 mmol) and copper(I) iodide (6 mg, 0.03 mmol) in diisopropylamine (5 ml) was stirred at 70° C. for 2 hours. The reaction mixture was filtered through Celite, washing with dichloromethane (50 ml). The filtrate was concentrated in vacuo and the residue purified by flash column chromatography on silica gel, eluting with 2% methanol/dichloromethane, followed by an SCX cartridge and finally preparative thin layer chromatography, eluting with 7% methanol/dichloromethane, to give the title compound. The hydrochloride salt (63 mg, 14%) was obtained by treatment with ethereal hydrogen chloride and crystallisation from ethanol/diethyl ether.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:31]([C:40]([F:43])([F:42])[F:41])[CH:30]=1>CN(C=O)C>[CH:35]1([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][O:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]3[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[CH:5]4)=[CH:30][C:31]=2[C:40]([F:41])([F:42])[F:43])[CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(O)ccc12
Reactant: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 75 °C
Yield: 73.2 %

Procedure:
To a mixture of ethyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (107 mg, 0.391 mmol) and cesium carbonate (191 mg, 0.587 mmol) in DMF (2 mL)was added 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (123 mg, 0.47 mmol). The reaction was heated at 75° C. for 5 h and cooled down. The solid was filtered and washed with ethyl acetate. The combined solvent was evaporated, and the residue was purified by silica gel column chromatography to give the title compound (143 mg). LCMS m/z=500.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (t, J=7.1 Hz, 3H), 1.52-1.67 (m, 3H), 1.68-1.80 (m, 2H), 1.80-1.92 (m, 2H), 2.00-2.24 (m, 5H), 2.55 (dd, J=15.6 and 8.7 Hz, 1H), 2.95 (dd, J=15.6 and 5.4 Hz, 1H), 3.35-3.45 (m, 1H), 3.45-3.55 (m, 1H), 3.83-3.92 (m, 1H), 4.10-4.18 (m, 1H), 4.23 (q, J=7.1 Hz, 2H), 5.10 (s, 2H), 6.19 (s, 1H), 6.90 (dd, J=8.8 and 2.4 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.60 (dd, J=8.1 and 1.3 Hz, 1H), 7.71 (d, J=1.4 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH3:26][C:27]1[N:32]=[C:31]2[NH:33][CH:34]=[C:35]([CH:36]=O)[C:30]2=[CH:29][CH:28]=1>CO.N1CCCCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:36]/[C:35]3[C:30]4[C:31](=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=4)[NH:33][CH:34]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: Cc1ccc2c(C=O)c[nH]c2n1
Solvent: C1CCNCC1
Solvent: CO
Product: Cc1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c2n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.020 g, 0.058 mmol) obtained in Example A16, Step 1 in methanol (2.0 mL) was added with 6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.010 g, 0.063 mmol). Then, the mixture was added with 5 drops of piperidine, and then the mixture was stirred at 50° C. for 2 hours. The solid formed was collected by filtration, and washed with methanol to obtain tert-butyl (Z)-4-({6-hydroxy-2-[(6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.023 g, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]([CH3:27])([CH3:26])[CH2:10][O:11][C:12]2[N:13]=[CH:14][C:15]([NH:18]C(=O)OC(C)(C)C)=[N:16][CH:17]=2)=[CH:5][CH:4]=1.O.NN.[OH-].[K+].C(O)CO>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([CH3:27])([CH3:26])[CH2:10][O:11][C:12]2[N:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(COC(C)(C)COc2cnc(NC(=O)OC(C)(C)C)cn2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COc1ccc(COC(C)(C)COc2cnc(N)cn2)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A mixture of tert-butyl (5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazin-2-yl)carbamate (330 mg), hydrazine monohydrate (198 μL), potassium hydroxide (1.15 g), and ethylene glycol (9.9 mL) was stirred at 120° C. for 3 hours. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50) to obtain 5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazin-2-amine (220 mg) as a yellow oily substance.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22]([NH2:24])[CH:21]=[N:20]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:18][N:19]1[CH:23]=[C:22]([NH:24][C:2]2[N:7]=[C:6]([NH:8][CH:9]3[CH:13]4[O:14][CH2:15][CH:16]([OH:17])[CH:12]4[O:11][CH2:10]3)[CH:5]=[CH:4][N:3]=2)[CH:21]=[N:20]1
Reactant: OC1COC2C(Nc3ccnc(Cl)n3)COC12
Reactant: Cn1cc(N)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cn1cc(Nc2nccc(NC3COC4C(O)COC34)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a suspension of 6-((2-chloropyrimidin-4-yl)amino)hexahydrofuro[3,2-b]furan-3-ol (354 mg, 1.37 mmol) in n-BuOH (3 mL) were added 1-methyl-1H-pyrazol-4-amine (220 mg, 1.65 mmol) and DIPEA (531 mg, 4.11 mmol). Then the mixture was stirred under nitrogen atmosphere at 150° C. overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to give the title compound as a yellow solid (120 mg, 22%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:18])=[O:17]
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.1 %

Procedure:
To a solution of 40.0 g (0.42 mol, 1 eq.) of phenol in 250 mL of dichloromethane at 0° C. was added 250 mL (1.8 mol, 4.2 eq.) of triethylamine. After 5 min, 49.3 mL (0.64 mol, 1.5 eq.) of methanesulfonyl chloride was added dropwise over 20 min. The resulting cloudy yellow solution was warmed to RT and stirred for 14 h. The reaction was partitioned between ether (250 mL) and water (100 mL) and the resulting organic layer was washed with cold 6N hydrochloric acid (2×200 mL). The combined aqueous layers were extracted with ether (2×50 mL) and the combined organic layers were washed with water (100 mL), saturated sodium bicarbonate (200 mL), brine (200 mL), dried (MgSO4) and concentrated. Recrystallization of the orange solid from isopropanol afforded 44.94 g (61%) of the title compound as light yellow crystals, mp 58.0°-58.5° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)=[O:5])C.O1CCCC1.[OH-].[Li+]>O>[Cl:36][C:32]1[CH:31]=[C:30]([C:7]2[N:8]=[C:9]([N:11]3[C:15]4[CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)[CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[S:10][C:6]=2[C:4]([OH:5])=[O:3])[CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1sc(-n2cnc3ccc(CCCCN4CCOCC4)cc32)nc1-c1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1sc(-n2cnc3ccc(CCCCN4CCOCC4)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a mixture of 0.078 g (0.15 mmole) of 4-(3-chloro-phenyl)-2-[6-(4-morpholin-4-yl-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid ethyl ester (I.41f), 2 mL of tetrahydrofuran and 2 mL of water was added 0.034 g (1.49 mmole) of lithium hydroxide. The mixture was stirred at ambient temperature for 2 hours, then concentrated under reduced pressure and diluted with 5 mL of water. The pH was adjusted to ca. 6-7 by addition of 3M hydrochloric acid. The precipitate was collected by filtration to give 0.054 g of 4-(3-chloro-phenyl)-2-[6-(4-morpholin-4-yl-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid (I.41 g) as a white solid.
Reaction SMILES: O.[NH2:2][NH2:3].[OH:4][CH:5]([C:7](=[CH2:13])[C:8](OCC)=[O:9])[CH3:6]>C(O)C>[OH:4][CH:5]([CH:7]1[CH2:13][NH:3][NH:2][C:8]1=[O:9])[CH3:6]
Reactant: NN
Reactant: C=C(C(=O)OCC)C(C)O
Solvent: O
Solvent: CCO
Product: CC(O)C1CNNC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To hydrazine hydrate (38.6 g) was added dropwise a solution of ethyl 2-(1-hydroxyethyl)acrylate (106 g) in ethanol (20 ml) at 0° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 4 hours at the same temperature. The resulting reaction mixture was chromatographed on silica gel (2.2 l) eluting in turn with chloroform and a mixture of chloroform and methanol (8:1→2:1→1:1, V/V) to give 4-(1-hydroxyethyl)-3-pyrazolidinone (68 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:20]([OH:22])=[O:21])=[CH:6][N:7]2[CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][CH2:32][NH2:33].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:33][CH2:32][CH2:31][NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:20]([OH:22])=[O:21])=[CH:6][N:7]2[CH:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: NCCNc1ccccn1
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CCOCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1c(F)c(NCCNc2ccccn2)cc2c1c(=O)c(C(=O)O)cn2C1CCOCC1
Temperature: 120 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of 5-amino-6,7-difluoro-1,4-dihydro-4-oxo-1-(tetrahydropyran-4-yl)-3-quinolinecarboxylic acid (45.0 mg, 0.139 mmol), 2-(2-pyridylamino)ethylamine (29.0 mg, 0.211 mmol), and triethylamine (0.029 mL, 0.209 mmol) in DMSO (1.0 mL) was stirred at 120° C. for 3 h. After dilution of the reaction mixture with 10% MeOH in CHCl3, the whole mixture washed with water, and the washing was extracted with 10% MeOH in CHCl3 two times. The combined the organic layer and the extracts washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography of the residue (10% MeOH in CHCl3) gave 5-Amino-6-fluoro-1,4-dihydro-4-oxo-1-(tetrahydropyran-4-yl)-7-[2-(2-pyridylamino)ethylamino]-3-quinolinecarboxylic Acid (54.0 mg, 88%) as a white powder.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])[CH3:6].Cl[C:17]1[CH:18]=[CH:19][C:20]2[C:30]3[C:25](=[CH:26][N:27]=[CH:28][CH:29]=3)[CH:24]([C:31]([F:34])([F:33])[F:32])[O:23][C:21]=2[CH:22]=1>>[CH3:6][CH:5]([CH3:7])[CH2:4][C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:2][O:1][C:17]1[CH:18]=[CH:19][C:20]2[C:30]3[C:25](=[CH:26][N:27]=[CH:28][CH:29]=3)[CH:24]([C:31]([F:33])([F:34])[F:32])[O:23][C:21]=2[CH:22]=1
Reactant: FC(F)(F)C1Oc2cc(Cl)ccc2-c2ccncc21
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Product: CC(C)C[C@@H](COc1ccc2c(c1)OC(C(F)(F)F)c1cnccc1-2)NC(=O)OC(C)(C)C
Yield: 49 %

Procedure:
Prepared as described in Example 8, Part C using (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate and 8-chloro-5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridine to afford tert-butyl ((2S)-4-methyl-1-((5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridin-8-yl)oxy)pentan-2-yl)carbamate (0.28 g, 0.516 mmol, 49% yield) as a yellow solid. LCMS (ESI) m/e 467.2 [(M+H)+, calcd for C24H30F3N2O4 467.2]; LC/MS retention time (Method C): tR=2.19 min.