Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:24]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[C@@H:28]([CH3:39])[CH2:27]3)=[O:25])=[C:16]2[N:15]=1.[ClH:40]>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:24]([N:26]3[CH2:31][CH2:30][NH:29][C@@H:28]([CH3:39])[CH2:27]3)=[O:25])=[C:16]2[N:15]=1.[ClH:40]
Reactant: C[C@H]1CN(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4Cl)nc23)CCN1C(=O)OC(C)(C)C
Agent: Cl
Product: C[C@H]1CN(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4Cl)nc23)CCN1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To (S)-tert-butyl 4-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2-methylpiperazine-1-carboxylate (Example 24; 47 mg, 0.084 mmol), was added 1 mL 4 N HCl (dioxane) solution and stirred at ambient temperature for 10 minutes. The reaction was concentrated, treated with ether, and filtered, giving the final product HCl salt as a fine beige powder. MS (apci) m/z=458.1 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[H-].[Na+].CS(O[CH2:18][CH2:19][C:20]1([CH3:31])[O:24][C:23]2=[N:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][N:22]2[CH2:21]1)(=O)=O>CN(C=O)C>[CH3:31][C:20]1([CH2:19][CH2:18][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:1][C:2]2=[O:10])[O:24][C:23]2=[N:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][N:22]2[CH2:21]1
Reactant: O=c1[nH]c2ccccc2o1
Reactant: CC1(CCOS(C)(=O)=O)Cn2cc([N+](=O)[O-])nc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(CCn2c(=O)oc3ccccc32)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
A mixture of 2-benzoxazolinone (240 mg, 1.8 mmol), sodium hydride (67 mg, 1.95 mmol) and DMF (10 ml) was stirred at room temperature for 30 minutes. To the reaction mixture, 2-(2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-yl)ethyl methanesulfonate prepared in Example 42 (500 mg, 1.7 mmol) was added followed by stirring at 50-60° C. for 4 hours. The reaction mixture was allowed to return to room temperature and poured into ice-water. The precipitates were filtered off and recrystallized from ethanol to afford 3-[2-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)ethyl]-3H-benzoxazol-2-one (320 mg, yield 56%) as a light brown powder.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:13]([NH:14][S:15](=[O:21])(=[O:20])[NH:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=[C:10]([F:22])[C:5]=1[C:6]([O:8]C)=[O:7].C1COCC1>CO>[F:3][C:4]1[C:13]([NH:14][S:15](=[O:20])(=[O:21])[NH:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=[C:10]([F:22])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)OC)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
NaOH (1M, 3.20 mL, 3.20 mmol) was added to methyl 2,6-difluoro-3-(N-propylsulfamoylamino)benzoate (0.24 g, 0.80 mmol) in 2:1 THF:MeOH (3 mL). The solution was stirred at room temperature for 16 hours, and then the solution was stirred at 70° C. for 16 hours. The solution was concentrated under reduced pressure to about half volume and then washed with EtOAc. The pH was adjusted to about 5 and extracted with EtOAc (3×5 mL). The organic layers were dried over sodium sulfate, decanted and concentrated to provide 2,6-difluoro-3-(N-propylsulfamoylamino)benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:5]2[NH:6][C:7]([CH3:22])=[C:8]([C:18]([O:20][CH3:21])=[O:19])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:4]2[N:3]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl>[NH2:1][C:2]1[N:23]=[C:5]2[N:6]=[C:7]([CH3:22])[C:8]([C:18]([O:20][CH3:21])=[O:19])=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:4]2[N:3]=1
Reactant: COC(=O)C1=C(C)Nc2nc(N)nn2C1c1ccc(Cl)cc1Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: COC(=O)c1c(C)nc2nc(N)nn2c1-c1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a stirred solution of crude methyl 2-amino-7-(2,4-dichlorophenyl)-5-methyl-4,7-dihydro-[1,2,4]-triazolo[1,5-a]pyrimidine-6-carboxylate (10.1 mmol) in CH2Cl2 (100 mL) was added DDQ (2.75 g, 12.1 mmol). The reaction was kept at room temperature for 1 h and was quenched by satd aq NaHCO3 solution. The organic layer was washed with satd aq NaHCO3 and brine prior to drying over anhydrous MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography afforded methyl 2-amino-7-(2,4-dichlorophenyl)-5-methyl-[1,2,4]-triazolo[1,5-a]pyrimidine-6-carboxylate (2.0 g, 56%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[CH:4][C:3]=1[F:24].[Cl:25][C:26]1[N:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:27]=1[C:28](Cl)=[O:29]>>[Cl:25][C:26]1[N:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[CH:4][C:3]=1[F:24])=[O:29]
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1F
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1F)c1cc(Cl)cnc1Cl
Yield: 46.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 180 using Compound 185 (50 mg, 0.16 mmol) and 2,5-dichloro-nicotinoyl chloride (36 mg, 0.17 mmol) to provide 186 (37 mg, 48% yield) as a dark solid. LC-MS (M+H=496, obsd.=496).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([O:36]CC)=[O:35])=[CH:30][CH:29]=3)[CH:19]=[CH:20][C:21]=2[O:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[CH:8]=[CH:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([OH:36])=[O:35])=[CH:30][CH:29]=3)[CH:19]=[CH:20][C:21]=2[O:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[CH:8]=[CH:9][C:10]=1[N:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCO)c(-c3ccc(N4CCCC4)c(C(C)(C)C)c3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1cc(-c2cc(-c3ccc(C(=O)O)cc3)ccc2OCCCCO)ccc1N1CCCC1
Yield: 57 %

Procedure:
In a manner similar to that of Example 3, by reacting 100 mg of ethyl 3″-tert-butyl-4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate (0.18 mmol) with 0.3 mL of 1N sodium hydroxide solution. 50 mg of 3″-tert-butyl-4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic acid are obtained (yield=56%) in the form of a white solid (m.p.=206° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](F)[CH:14]=2)=[CH:4][CH:3]=1.[C:31]1([C@@H:37]([NH2:39])[CH3:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:25]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:39][C@H:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:38])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCC(c2nc(-c3ccc(F)cc3)c(-c3ccnc(F)c3)s2)CC1
Reactant: C[C@H](N)c1ccccc1
Product: CCOC(=O)N1CCC(c2nc(-c3ccc(F)cc3)c(-c3ccnc(N[C@@H](C)c4ccccc4)c3)s2)CC1
Yield: 67.3 %

Procedure:
4-(4-Fluorophenyl)-2-(1-ethoxycarbonylpiperidin-4-yl)-5-(2-fluoro-4-pyridinyl)thiazole (2.4 g. 5.5 mmol) and 1-(S)-phenylethylamine (5.5 ml are heated to 195° C. for 5 h. The reaction mixture is evaporated and purified by SiO2 chromatography (ethyl acetate/cyclohexane 20/80 to 30/70) to yield the title compound as a white foam (2.0 g 67.3%)
Reaction SMILES: [F:1][CH2:2][C:3]1[N:12]=[C:11](N(C2C=CC(OC)=CC=2)C)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.FCC1NC(=O)C2C(=CC=CC=2)N=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:47])=O>>[Cl:47][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([CH2:2][F:1])[N:12]=1
Reactant: COc1ccc(N(C)c2nc(CF)nc3ccccc23)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=c1[nH]c(CF)nc2ccccc12
Solvent: CN(C)c1ccccc1
Product: FCc1nc(Cl)c2ccccc2n1

Procedure:
(2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: A suspension of 2-fluoromethyl-quinazolin-4(3H)-one (70 mg, 0.39 mmol) in phosphoryl chloride (2 ml) and N,N-dimethylaniline (0.035 ml, 0.27 mmol) was heated under reflux for 12 hours. The reaction mixture was poured onto ice and the precipitate was collected by filtration, then washed and dried to give 4-chloro-2-fluoromethyl-quinazoline, which was used directly for the next reaction. To a solution of 4-chloro-2-fluoromethyl-quinazoline with (4-methoxy-phenyl)-methylamine (160 mg, 1.2 mmol) in isopropyl alcohol (5 ml) was added concentrated HCl (0.05 ml) and the solution was stirred at room temperature overnight. The solution was neutralized with saturated aqueous NaHCO3, and was extracted by ethyl acetate. The extracts were evaporated, and the residue was purified by column chromatography on silica gel with ethyl acetate and hexane (1:1) as eluent, yielding 11 mg (9.5%) of the title compound. 1H NMR (CDCl3): 7.87-7.84 (m, 1H), 7.60-7.54 (m, 1H), 7.14-7.10 (m, 2H), 7.04-7.01 (m, 2H), 6.95-6.91 (m, 2H), 5.60 (s, 1H), 5.44 (s, 1H), 3.85 (s, 3H), 3.60 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21]C(OCC)=O)[CH2:16][CH2:15]2)[C:7](=[O:27])[C:6]=1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]#[N:42])=[CH:31][C:30]=1[F:43])[CH2:2][CH2:3][CH3:4].C[Mg]Br.Cl>O1CCCC1>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C@H:14]2[CH2:15][CH2:16][C@H:17]([O:20][CH2:21][C:17]([OH:20])([CH3:18])[CH3:16])[CH2:18][CH2:19]2)[C:7](=[O:27])[C:6]=1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:31][C:30]=1[F:43])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Reaction time: 1 h

Procedure:
Ethyl [(trans-4-{7-butyl-6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate (1.24 g) was dissolved in tetrahydrofuran (15 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 6.5 mL) was added at room temperature. The reaction mixture was stirred for 1 hr, 1 N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless oil (0.76 g, 63%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.[CH3:12][C:13]1([CH3:31])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][C:15]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[O:14]1.C(N(CC)CC)C>C(#N)C>[OH:11][CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:28]1[CH2:29][CH2:30][C:15]2([O:14][C:13]([CH3:12])([CH3:31])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)[CH2:26][CH2:27]1
Reactant: OCCc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)OC2(CCNCC2)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(C)(C)OC2(CCN(Cc3cccc(CCO)c3)CC2)C1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
2-(3-(Bromomethyl)phenyl)ethanol (0.416 g) was added portionwise over 1 hour to a solution of tert-butyl 2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (Example 271, step c) (0.55 g) and triethylamine (0.809 mL) in acetonitrile (20 mL). The mixture was stirred for 2 hours at 20° C. The solvent was evaporated under reduced pressure and the residue partitioned between saturated sodium bicarbonate solution and DCM, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with 2% methanol in dichloromethane with 1% triethylamine to afford the subtitled compound. Yield 0.78 g.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([OH:15])=[C:10]([C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=1)[CH:9]=[CH:8]2.F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1.O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([O:15][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[C:10]([C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=1)[CH:9]=[CH:8]2
Reactant: COc1ccc2c(O)c(-c3ccc(SC)cc3)ccc2c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3)c(-c3ccc(SC)cc3)ccc2c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Place sodium hydride (1.05 eq.) in dry dimethylformamide in a 3 neck flask equipped with a mechanical stirrer, addition funnel with nitrogen purge, and a temperature probe under nitrogen. Charge the addition funnel with 6-methoxy-2-(4-methylthiophenyl)naphthalene-1-ol (1 eq.) dissolved in dry dimethylformamide. Add this solution dropwise to the stirred sodium hydride solution at a rate that holds the temperature below 35° C. Stir the reaction mixture for 30 minutes before adding 4-fluoronitrobenzene with additional dry dimethylformamide. Heat the solution to 60° C. Once the reaction is complete, cool the flask and add water slowly to cause precipitation of the product. Filter the crude product and wash with water and then methyl tert-butyl ether. Dry the filter cake in a vacuum oven to give 6-methoxy-2-(4-methylthiophenyl)-1-(4-nitrophenoxy)naphthalene.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][C@@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][OH:44])[CH2:36]1.[OH-].[K+].CS(C)=O>O>[CH3:34][C@@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][O:44][C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]([NH:13][C:14]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:15]=4[C:16]([CH3:33])=[N:17][N:18]5[CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=4)=[O:12])=[CH:9][N:10]=[C:4]3[CH:3]=2)[CH2:36]1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(Cl)ccn34)c12
Reactant: C[C@H]1CN(CCO)CCN1C
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)[C@@H](C)C5)ccn34)c12
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
A flask equipped with a condenser was charged with the 7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (15.0 g, 32.68 mmol), (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol (10.34 g, 65.37 mmol, Example 23), crushed KOH (9.17 g, 163.4 mmol) and 100 mL of DMSO. The mixture was heated to 95° C. for 22 hours. The mixture was allowed to cool to ambient temperature, 350 mL of water were added and the mixture stirred vigorously for 30 minutes. The mixture was extracted with EtOAc, and the combined organic extracts were washed with brine and 10% aqueous potassium carbonate, dried and concentrated. The resulting material was purified by column chromatography (10% MeOH/DCM/0.5% NH4OH to 15% MeOH/DCM/0.5% NH4OH) and then triturated with ether. The resulting solid was collected to give 10 g (53%) of the title compound. MS (APCI), positive scan, m/z=581.1 (M+H). [α]D=+5.6° (c=1.0, CHCl3).
Reaction SMILES: [N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([OH:45])=O)=[O:39])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(Cl)Cl.[NH2:49][CH2:50][C:51]([NH:53][CH2:54][C:55]([NH:57][CH2:58][C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])=[O:56])=[O:52].CC1C=CC(S(O)(=O)=O)=CC=1>CCN(CC)CC>[N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([NH:49][CH2:50][C:51]([NH:53][CH2:54][C:55]([NH:57][CH2:58][C:59]([O:61][CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:60])=[O:56])=[O:52])=[O:45])=[O:39])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: NCC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)NCC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of (C18H37)2NCOCH2OCH2COOH (1.0 g, 1.5 mmol) in CH2Cl2 (30 mL) 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.31 g, 1.6 mmol) was added and the reaction was stirred at room temperature. After 0.5 h Gly-Gly-Gly-OCH2Ph.TsOH (0.66 g, 1.5 mmol) and Et3N (0.6 mL) were added and the mixture was stirred overnight. The reaction mixture was then washed with water (20 mL), 0.5 N HCl (20 mL), water (20 mL), 10% aqueous Na2CO3 (20 mL), brine (20 mL), and then dried over MgSO4. The solvent was evaporated and the residue was crystallized form MeOH to yield (C18H37)2NCOCH2OCH2CO-Gly-Gly-Gly-OCH2Ph as a deliquescent white solid (1.26 g, 89%), mp 41–42° C. 1H-NMR (300 MHz, δ, CDCl3) 0.86 (6H, t, J=6.9 Hz), 1.24 (64H, m), 1.49 (4H, bs), 3.04 (2H, t, J=7.5 Hz), 3.24 (2H, t, J=7.5 Hz), 3.95–4.05 (6H, m), 4.09 (2H, s), 4.29 (2H, s), 5.12 (2H, s), 7.23 (1H, t, J=6.0 Hz), 7.30–7.35 (5H, m), 7.93 (1H, t, J=5.7 Hz), 8.27 (1H, t, J=5.7 Hz). 13C-NMR (75 MHz, δ, CDCl3): 13.9, 22.5, 26.7, 26.9, 27.4, 28.6, 29.2, 29.3, 29.6, 31.8, 41.0, 42.9, 46.3, 46.7, 66.9, 69.6, 71.7, 128.2, 128.4, 128.6, 135.3, 168.6, 169.7, 169.8, 170.0, 171.5. IR (KBr, cm−1): 1749 (CO), 1651 (CO).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[C:23]4=[N:24][C:25]([CH3:29])=[CH:26][C:27]([CH3:28])=[C:22]4[N:21]=[C:20]3[CH2:30][CH3:31])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].C(Cl)(Cl)Cl>C1COCC1>[CH2:30]([C:20]1[N:19]([CH2:18][C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][OH:3])=[CH:10][CH:9]=3)=[CH:13][CH:14]=2)[C:23]2=[N:24][C:25]([CH3:29])=[CH:26][C:27]([CH3:28])=[C:22]2[N:21]=1)[CH3:31]
Reactant: CCOC(=O)c1ccc(Nc2ccc(Cn3c(CC)nc4c(C)cc(C)nc43)cc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(Nc2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
Compound 99 (0.453 mg, 1.06 mmol) was dissolved in THF (10 mL), and a diisobutylaluminum hydride-toluene solution (1 mmol/L, 4.2 mL, 4.2 mmol) was added to the solution, followed by stirring at room temperature for 10 minutes. The reaction mixture was added with an aqueous potassium sodium tartrate solution and chloroform, followed by stirring at room temperature for 4 hours, then the mixture was extracted with chloroform three times. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain Compound 101 (0.384 g, 0.994 mmol, yield 94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5](=[C:9]([F:16])[C:10]([F:15])=[C:11]([F:14])[C:12]=1[F:13])C(O)=O.C(N(CCCCCCCC)CCCCCCCC)CCCCCCC>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:9]([F:16])[C:10]([F:15])=[C:11]([F:14])[C:12]=1[F:13]
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Product: COC(=O)c1cc(F)c(F)c(F)c1F
Temperature: 140 °C
Reaction time: 24 h
Yield: 86.4 %

Procedure:
Into a 100 ml three necked flask, 20 g (0.079 mol) of the 3,4,5,6-tetrafluorophthalic acid-monomethyl ester prepared in Example 14, and 2.8 g (0.0079 mol) of tri-n-octylamine were charged, and the mixture was heated and stirred at 140° C. for 24 hours. After completion of the reaction, the reaction mixture was separated by distillation to obtain 14.2 g of 2,3,4,5-tetrafluorobenzoic acid methyl ester. The yield was 86.3%.
Reaction SMILES: C1C2SC3C(=CC=CC=3)SC=2C=CC=1S(Cl)(=O)=O.[CH:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[S:33](Cl)(=[O:35])=[O:34].C([O:41][C:42](=[O:48])[C@H:43]([CH:45](C)C)[NH2:44])(C)(C)C.C(OC(=O)[C@H](C)N)(C)(C)C>>[CH:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[S:33]([NH:44][C@@H:43]([CH3:45])[C:42]([OH:48])=[O:41])(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1O2
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: C[C@H](N)C(=O)OC(C)(C)C
Agent: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1S2
Product: C[C@H](NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2)C(=O)O

Procedure:
When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (L)-alanine-t-butyl ester, (S)-2-(phenoxathiine-2-sulfonylamino)-propionic acid is obtained as a white solid; mp 75-85° C.
Reaction SMILES: [F:1][CH2:2][S:3](Cl)(=[O:5])=[O:4].S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25]Cl)=[N:23][CH:24]=1>O.C(O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][S:3]([CH2:2][F:1])(=[O:5])=[O:4])=[N:23][CH:24]=1
Reactant: ClCc1ccc(Br)cn1
Reactant: O=S(=O)(Cl)CF
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)(CF)Cc1ccc(Br)cn1
Temperature: 100 °C
Yield: 15.2 %

Procedure:
Commercially available fluoromethanesulfonyl chloride (975 mg, 7.36 mmol) is added dropwise to a solution of sodium sulfite (1.85 g, 14.7 mmol) and sodium bicarbonate (1.24 g, 14.7 mmol) in water (2 mL). The reaction mixture is heated in a microwave reactor to 100° C. for 20 minutes. After cooling to room temperature commercially available 5-bromo-2-(chloromethyl)pyridine (894 mg, 3.68 mmol) in ethanol (2 mL) is added. The mixture is heated in a microwave reactor to 100° C. for 20 minutes. The reaction mixture is cooled to 0° C. and the solid filtered off and discarded. The filtrates are diluted with saturated sodium carbonate (10 mL), extracted with tertiarybutyl methyl ether (50 mL). The organic layer is separated, dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give the title compound (150 mg): m/z 268.9 (M+H)+.