Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:33][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[NH:28][N:27]=[C:26]5[CH3:32])[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34]>CO>[ClH:34].[ClH:34].[ClH:34].[CH3:32][C:26]1[C:25]2[C:29](=[CH:30][CH:31]=[C:23]([NH:22][C:21]3[C:16]4[CH:15]=[C:14]([C:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=5)[NH:33][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:24]=2)[NH:28][N:27]=1
Reactant: Cc1n[nH]c2ccc(Nc3ncnc4[nH]c(C5=CCN(C(=O)OC(C)(C)C)CC5)cc34)cc12
Agent: Cl
Solvent: CO
Product: Cc1n[nH]c2ccc(Nc3ncnc4[nH]c(C5=CCNCC5)cc34)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-[4-(3-methyl-1H-indazol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (488 mg, 1.10 mmol) in MeOH (10 mL) was added hydrogen chloride (9M in MeOH, 2.15 mL, 19.4 mmol), the mixture was stirred at rt for 3 h and concentrated in vacuo. The residue was triturated with Et2O and dried in vacuo to give the title compound. MS (ES+): m/z 347.12 (10) [MH+]. HPLC: tR(polar—5 mins)=1.52 min (ZQ2000, polar—5 min). A purified sample was made by Gilson HPLC to record the 1H NMR spectrum. 1H NMR (DMSO-d6, 400 MHz): δ=2.34 (s, 3H), 2.47 (brs, 2H), 3.12 (brs, 2H), 3.60 (brs, 2H), 6.29 (s, 1H), 6.92 (s, 1H), 7.07 (s, 1H), 7.19 (s, 1H), 7.25 (d, 1H, J=8.4 Hz), 7.40 (d, 1H, J=8.4 Hz), 7.75 (s, 1H), 8.06 (s, 1H), 9.27 (brs, 1H), 12.73 (brs 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.Br[CH2:16][C:17]#[C:18][CH3:19]>>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][S:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:16][C:17]#[C:18][CH3:19])[CH:3]=1)[CH3:14]
Reactant: CCOC(=O)CSc1cccc(O)c1
Reactant: CC#CCBr
Product: CC#CCOc1cccc(SCC(=O)OCC)c1
Yield: 100 %

Procedure:
Ethyl{[3-(2-butynyloxy)phenyl]sulfanyl}acetate was prepared according to the general method as outlined in example 1 (step 2), starting from ethyl [(3-hydroxyphenyl) sulfanyl]acetate (3.87 g, 18.3 mmol) and 4-bromo-2-butyne (2.66 g, 20 mmol); 5.16 g yellow oil. Yield 100%; MS(EI): 264.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.[C:10]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)(=[O:17])=[O:16])([CH3:13])([CH3:12])[CH3:11]>[Pd]>[F:9][C:4]1[CH:3]=[C:2]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:15](=[O:17])(=[O:16])[NH:14][C:10]([CH3:11])([CH3:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Reactant: Cc1ccc(Br)cc1F
Agent: [Pd]
Product: Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 92 %

Procedure:
The palladium(0)-catalyzed coupling of 4-bromo-2-fluorotoluene with 2-(N-t-butylsulfamoyl)phenylboronic acid was carried out according to the procedure of Example 76, Step F. Purification of the crude product by flash chromatography (elution with hexane-EtOAc) gave a 92% yield of the title compound as an off-white foam (TLC in 4:1 hexane-EtOAc); mass spectrum (FAB) m/e 322 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH3:12][NH2:13]>C(Cl)(Cl)Cl.C(O)C>[Cl:11][C:3]1[C:2]([Cl:1])=[CH:10][C:6]([C:7]([NH:13][CH3:12])=[O:8])=[CH:5][N:4]=1
Reactant: O=C(Cl)c1cnc(Cl)c(Cl)c1
Reactant: CN
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CNC(=O)c1cnc(Cl)c(Cl)c1

Procedure:
A solution of 30 g of crude 5,6-dichloronicotinic acid chloride in 150 ml of chloroform is added dropwise to a solution of 50 g of methylamine in 250 ml of ethanol whilst stirring and cooling at 10°-15° C. The reaction mixture is stirred for a further 2 hours at 20°-30° C. and is then evaporated in vacuo. The evaporation residue is taken up in ethyl acetate and this solution is washed with 2 N sodium carbonate solution, dried over magnesium sulphate and evaporated. The residue is recrystallised from ethanol-ether. 2,3-Dichloro-5-methylaminocarbonyl-pyridine, thus obtained, melts at 134°-138° C.
Reaction SMILES: C1(=O)[N:5]([CH:6]([C:9]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:12][NH:13]3)[CH2:7][CH3:8])C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH:6]([C:9]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N:12][NH:13]2)[CH2:7][CH3:8]
Reactant: CCC(c1c(Cl)ccc2[nH]nc(-c3ccccc3)c12)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CCC(N)c1c(Cl)ccc2[nH]nc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
1-Phthalimidopropyl-3-phenyl-5-chloroindazole (8.3 g) and hydrazine hydrate (2.0 g) were added to ethanol (150 ml) followed by heating under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure and to the residue were added benzene (150 ml) and 10% aqueous sodium hydroxide solution (200 ml) followed by stirring at room temperature for 1 hour. The organic layer was separated from the mixture and it was washed with water, dried over sodium sulfate and concentrated under reduced pressure to obtain 5.5 g of 1-aminopropyl-3-phenyl-5-chloroindazole as an oily product. The product was treated with ether-hydrochloric acid to form its hydrochloride. After recrystallization from ethanol-ether, the product had a melting point between 163°-164° C.
Reaction SMILES: [N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6](O)=[O:7])=[N+:2]=[N-:3].CO.Cl>C1COCC1>[N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3]
Reactant: CC(C)(CC(=O)O)N=[N+]=[N-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CCO)N=[N+]=[N-]
Reaction time: 16 h

Procedure:
Borane dimethylsulfide complex (2 M, 15 mL, 30 mmol) was added over 20 min to 3-azido-3-methylbutanoic acid (4.25 g, 30 mmol) in THF (15 mL) at room temperature. The reaction was stirred for 16 h. The reaction mixture was cooled in an ice bath and methanol (50 mL) was added dropwise to the solution over 15 min. Then 4 M HCl in dioxanes (7.5 mL, 30 mmol) was added to the reaction mixture and stirred for 30 min. The reaction mixture was concentrated on a rotovap to a colorless liquid (3.33 g, 91%). This material was used without further purification. 1H NMR (CDCl3, 400 MHz): δ 1.35 (s, 6H), 1.74-1.78 (t, J=6.4, 2H), 3.75-3.80 (t, J=6.4, 2H). LRMS (ESI+) for C5H11N3O (129.1); Found: did not ionize.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[N:23][CH:22]=[CH:21]2>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc2cnccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2)CC1
Temperature: 80 °C
Yield: 76.4 %

Procedure:
7.49 g of 4-hydroxy-piperidine-1-carboxylic acid-tert-butylester were dissolved in 20 mL of dry dimethyl acetamide. 1.49 g of sodium hydride (60%) were added. Then a solution of 3.65 g of 6-fluoroisoquinoline (3) in dimethyl acetamide was added dropwise. The solution was heated at 80° C. for 2 hours, then the solvent was removed and the residue was taken up in dichloromethane. The organic layer was extracted twice with water and then with brine, dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography to yield 6.22 g of 4-(isoquinolin-6-yloxy)-piperidine-1-carboxylic acid-tert-butylester (7). Rt=1.32 min (Method B). Detected mass: 329.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2=[O:14])=[C:4]([F:15])[CH:3]=1.[Cl:16][C:17]1[S:21][C:20]([C:22]([NH:24][CH2:25][CH:26]2[CH2:28][O:27]2)=[O:23])=[CH:19][CH:18]=1.O>C(O)C>[Cl:16][C:17]1[S:21][C:20]([C:22]([NH:24][CH2:25][CH:26]([OH:27])[CH2:28][NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C:9]3=[O:14])=[C:4]([F:15])[CH:3]=2)=[O:23])=[CH:19][CH:18]=1
Reactant: Nc1ccc(N2CCOCC2=O)c(F)c1
Reactant: O=C(NCC1CO1)c1ccc(Cl)s1
Solvent: CCO
Solvent: O
Product: O=C(NCC(O)CNc1ccc(N2CCOCC2=O)c(F)c1)c1ccc(Cl)s1

Procedure:
800 mg (3.8 mmol) of 4-(4-amino-2-fluorophenyl)-3-morpholinone and 700 mg (3.22 mmol) of 5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide are heated in 15 ml of ethanol and 1 ml of water under reflux for 6 hours. The mixture is evaporated in vacuo, the crystals which have separated out after treatment with ethyl acetate are filtered off with suction, and chromatography of the mother liquor results in 276 mg (17% of theory) of the target compound.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=4)[CH2:14][CH2:13]3)[N:11]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[C:10](=[O:33])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:34](Cl)(=[O:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:20]=[C:21]([NH:25][C:34](=[O:36])[CH3:35])[CH:22]=[CH:23][CH:24]=4)[CH2:14][CH2:13]3)[N:11]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[C:10](=[O:33])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)Nc1cccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2 mL CH2Cl2 suspension of 0.05 g (0.11 mmol) 4-(cyclohexylamino)-8-[3-aminobenzyl]-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one, 0.1 mL (0.11 mmol) acetyl chloride and excess K2CO3 was allowed to stir at rt overnight. The reaction was filtered and concentrated then the remaining oil was dissolved in 1 mL CH2Cl2 and purified on an Isco automated system affixed with a Biotage Flash 25(S) cartridge eluted at 20 mL/min with 0-5% MeOH in CH2Cl2 over 15 min and hold at 5% MeOH for 30 min. The product eluted second, pure by HPLC/MS and NMR.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29]>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29])#[N:7]
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Reactant: CNCCc1cccc(C(=O)OC)c1
Product: COC(=O)c1cccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)c1

Procedure:
Reaction of 1f with 2d produced 3o. MS found M+H=453. The oxalate salt of 3o was recrystallized from ethyl acetate; mp 135-136° C.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:29]=[N:30][N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:32]=3)=[CH:18][CH:17]=2)[CH:6]=[C:5]([CH3:52])[N:4]=1>O1CCOCC1>[ClH:1].[CH3:2][C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[CH:6]=[C:5]([CH3:52])[N:4]=1
Reactant: CCOC(=O)c1c(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)cc(C)nc1C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1c(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)cc(C)nc1C
Reaction time: 3 h

Procedure:
6M Hydrochloric acid (10 ml) was added to a solution of ethyl 2,6-dimethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine-3-carboxylate (A) (600 mg) in dioxane (15 ml) and the mixture was stirred for 3 hours. Volatile material was removed by evaporation and the residue stirred for 30 minutes in a mixture of ethanol and ether (1:3 v/v, 20 ml). The insoluble solid was collected by filtration and recrystallised from a mixture of ethanol and methanol (1:1 v/v) to give ethyl 2,6-dimethyl-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine-3-carboxylate hydrochloride (270 mg), as a white powder, m.p. 205° C.; NMR (d6 -DMSO, d4 -acetic acid): 1.2(t,3H), 2.6(s,3H), 2.7(s,3H), 4.4(q,2H), 5.5(s,2H), 7.2(d,2H), 7.4(d,2H), 7.55-7.65(m,3H), 7.67-7.75(m,2 H); mass spectrum [negative fast atom bombardment (-ve FAB), DMSO/glycerol (GLY)]: 428 (M-H)-, 234, 194; microanalysis, found: C,61.7; H,5.0; N,14.9%; C23H24N5O3.HCl requires: C,61.9; H,5.2; N,15.0%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:3][CH:2]=1.[S:16]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][N:22]=2)=[CH:17]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]([N:29]2[CH2:28][CH2:27][N:26]([C:24]3[S:23][N:22]=[C:21]([C:18]4[CH:19]=[CH:20][S:16][CH:17]=4)[N:25]=3)[CH2:31][CH2:30]2)=[O:15])=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccncc1)OCC(Cl)(Cl)Cl
Reactant: c1cc(-c2nsc(N3CCNCC3)n2)cs1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccncc1)N1CCN(c2nc(-c3ccsc3)ns2)CC1
Yield: 13 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-4-ylcarbamate (235 mg, 0.872 mmol), 1-[3-(3-thienyl)-1,2,4-thiadiazol-5-yl]piperazine (200 mg, 0.793 mmol) and diisopropylethylamine (0.152 ml, 0.872 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 3 hours and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate, followed by methanol:ethyl acetate=1:9) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 38.4 mg (13.0%) of the desired product as a solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[Cl-].[Cl-].[Al+3].[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:21]([C:20]2[CH:24]=[CH:25][C:17]([I:16])=[CH:18][CH:19]=2)=[O:22])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: BrCCCOc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(I)cc1)c1ccc(OCCCBr)cc1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A solution of (3-bromopropoxy)benzene (44.4 g, 206 mmol) in DCM was added dropwise to a suspension of aluminum trichloride (27.5 g 206 mmol) and 4-iodobenzoyl chloride (50.0 g, 188 mmol) in anhydrous DCM (330 ml) at −78° C. ca. Reaction turned yellow and was allowed to warm to r.t. and stir for 4 hs. Upon completion, reaction was brought to 0° C., diluted with DCM, and quenched with 5% HCl. The organic layer was separated, washed additionally with brine, and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure and re-crystallized using EtOAc to afford 60.1 g (71.8% yield) of (4-(3-bromopropoxy)phenyl)(4-iodophenyl)methanone as grey solid.
Reaction SMILES: C([O-])=O.[CH3:4][C:5]1[N:6]=[C:7]([NH3+:20])[NH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.[C:21]([O:25][C:26]([NH:28][CH2:29][C:30]1[CH:31]=[C:32]([C:39](O)=[O:40])[C:33]([CH:36]([F:38])[F:37])=[N:34][CH:35]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.O>[F:38][CH:36]([F:37])[C:33]1[N:34]=[CH:35][C:30]([CH2:29][NH:28][C:26](=[O:27])[O:25][C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:31][C:32]=1[C:39](=[O:40])[NH:20][C:7]1[NH:8][C:9]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=2)=[C:5]([CH3:4])[N:6]=1
Reactant: CC(C)(C)OC(=O)NCc1cnc(C(F)F)c(C(=O)O)c1
Reactant: Cc1nc([NH3+])[nH]c1-c1ccc(C(F)(F)F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nc(NC(=O)c2cc(CNC(=O)OC(C)(C)C)cnc2C(F)F)[nH]c1-c1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
Dissolve [4-methyl-5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]ammonium formate (0.205 g, 0.714 mmol) and 5-[(tert-butoxycarbonylamino)methyl]-2-(difluoromethyl)pyridine-3-carboxylic acid (0.283 g, 0.749 mmol) in DCM (5 mL). Add DIPEA (0.50 mL, 2.855 mmol) followed by BOP (0.350 g, 0.792 mmol). Heat the mixture to 60° C., and stir 16 hours. Add benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.150 g, 0.339 mmol). Stir the mixture for 2 hours. Pour the reaction mixture into water (15 mL). Extract with EtOAc (3×15 mL, and sequentially wash the combined organics with a saturated sodium chloride aqueous solution (4×15 mL) and a saturated sodium bicarbonate aqueous solution (15 mL). Dry the organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Purify the residue by reverse phase flash chromatography (Analogix® 55 g @ 40 mL/min) eluting with a gradient of 5-75% ACN/water over 30 minutes. Concentrate the appropriate fractions under reduced pressure until only water remains and the product is a suspended solid. Add a saturated NaHCO3 aqueous solution (50 mL), and extract with EtOAc (2×30 mL) to give the title compound (0.212 g, 56%) as a white solid. LCMS (m/z) 526 (M+1) 524 (M−1).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:15](=[O:27])[NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][N:21]=[CH:22]3)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.O>CO.C(Cl)Cl>[CH:22]1[C:23]2[C:18](=[C:17]([NH:16][C:15]([C:6]3([C:4]([OH:5])=[O:3])[CH2:7][C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:14]3)=[O:27])[CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][N:21]=1
Reactant: CCOC(=O)C1(C(=O)Nc2cccc3cnccc23)Cc2ccccc2C1
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C1(C(=O)Nc2cccc3cnccc23)Cc2ccccc2C1
Reaction time: 20 h
Yield: 86 %

Procedure:
A 30 mL reaction vial is charged with 2-(isoquinolin-5-ylcarbamoyl)-indan-2-carboxylic acid ethyl ester (320, 354 mg, 0.98 mmol) is charged with 1,4-dioxane (6 mL) and MeOH (6 mL). A stirring bar is added and stirring is initiated. After dissolution, water (3 mL) is added followed by the LiOH monohydrate (104 mg, 252 mmol). After 20 h, tlc analysis (silica, 10% MeOH/DCM) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (1 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 64 h, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate by pumping to constant weight to give 0.29 g of off white solid. This material is triturated with DCM (15 mL). The solids are collected by suction filtration and washed with DCM (20 mL). Suction drying provides off white solid (280 mg, 86%).
Reaction SMILES: [Li+].[Cl-].P([CH2:11][C:12]#[N:13])(OCC)(OCC)=O.C1CCN2C(=NCCC2)CC1.[C:25]([O:29][C:30](=[O:42])[NH:31][C@H:32]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:33]=O)([CH3:28])([CH3:27])[CH3:26]>C(#N)C>[C:25]([O:29][C:30](=[O:42])[NH:31][C@@H:32](/[CH:33]=[CH:11]/[C:12]#[N:13])[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N[C@@H](/C=C/C#N)Cc1ccccc1
Reaction time: 1.5 h
Yield: 77.1 %

Procedure:
To a stirred suspension of LiCl (1.0 g, 24 mmol) in dry ACN (200 mL) under nitrogen at rt, was added (EtO)2POCH2CN (4.2 g, 24 mmol), DBU (3.0 g, 20 mmol) and compound 31d (5.0 g, 20 mmol). Almost all of the salt soon dissolved and the reaction completed in 1.5 h. The reaction was quenched with citric acid, and the mixture was extracted with EA three times. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated and the residue was purified by CC (hexane/EAc=5:1) to give compound 31e (4.2 g, 77% yield).
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[C:9]([NH2:12])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:16]=[C:17]([C:23]#[N:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C1(C)C=CC=CC=1>[C:23]([C:17](=[CH:16][NH:12][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:11][CH:10]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:24]
Reactant: Nc1csc(-c2ccccc2)c1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CNc1csc(-c2ccccc2)c1
Yield: 11.6 %

Procedure:
A mixture of 5-phenyl-3-thienylamine (1.00 g, 5.7 mmol) and ethyl (ethoxymethylene)cyanoacetate (950 mg, 5.7 mmol) in 20 mL of toluene is heated at reflux for 45 minutes. The reaction mixture is filtered while warm and the collected solid is washed with diethyl ether to provide 198 mg of ethyl 2-cyano-3-[(5-phenyl-3-thienyl)amino]-2-propenoate as white crystals, mp 190–193° C.; MS 296.9 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(OCC)(=O)C>C(#N)C.O>[Br:1][C:2]1[N:6]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1
Reactant: COC(=O)CBr
Reactant: FC(F)(F)c1cc(Br)[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)Cn1nc(C(F)(F)F)cc1Br
Temperature: 80 °C
Yield: 31.8 %

Procedure:
To a solution of 5-bromo-3-(trifluoromethyl)-1H-pyrazole (1.0 g, 4.6 mmol) and Cs2CO3 (3.0 g, 9.3 mmol) in acetonitrile (10 mL) was added methyl 2-bromoacetate (865 mg, 5.6 mmol). The reaction was heated at 80° C. for 3 h. After the reaction was cooled to room temperature, the mixture was portioned between ethyl acetate and water. The organic layer was separated and washed with saturated aqueous NH4Cl and brine. The organic layer was then dried over Na2SO4, filtered and concentrated to afford crude product which was purified by silica gel chromatography eluting with dichloromethane/hexanes to afford methyl 2-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (420 mg, 32%) as a clear oil. MS (m/z): 287.1 [M+H]+; HPLC retention time 2.93 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).