Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:9]([I:10])=[C:8]([CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:12][OH:13]>C(O)C>[F:1][C:2]1[C:9]([I:10])=[C:8]([CH3:11])[CH:7]=[CH:6][C:3]=1/[CH:4]=[N:12]/[OH:13]
Reactant: Cc1ccc(C=O)c(F)c1I
Reactant: NO
Solvent: CCO
Product: Cc1ccc(/C=N/O)c(F)c1I
Reaction time: 3 h

Procedure:
A solution of 2-fluoro-3-iodo-4-methylbenzaldehyde (1.26 g, 4.77 mmol) in ethanol (5 mL) at RT was treated with hydroxylamine (5 mL) (50% wt. in water) and the reaction stirred for 3 h. The volatiles were removed and the residue was treated with water (5 mL), extracted with ethyl acetate (3×15 mL). The combined ethyl acetate layers were dried and concentrated. Purification on a 40 g ISCO column (eluted with 10-50% ethyl acetate in hexanes) provided the title compound as an off-white crystalline solid. MS (ESI, pos. ion) m/z: 280.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[C:16](=[O:21])[NH:17][CH2:18][C:19]#[N:20])=[O:5])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[C:25]([CH3:30])[CH:24]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([S:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][C:25]=2[CH3:30])[CH2:8][C@H:7]1[C:16](=[O:21])[NH:17][CH2:18][C:19]#[N:20])=[O:5])[CH3:2]
Reactant: Cc1cc(Cl)ccc1S
Reactant: CCOC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)NCC#N
Product: CCOC(=O)[C@@H]1C[C@H](Sc2ccc(Cl)cc2C)C[C@H]1C(=O)NCC#N

Procedure:
The reaction of (1R,2R,4S)-2-(cyanomethyl-carbamoyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester with 4-chloro-2-methyl-benzenethiol performed in analogy to example 1, step 5, yielded the title compound as a colorless solid. MS: 381.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=5)=[C:20]5[NH:37][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73]>CN(C=O)C>[OH:52][C:49]1[CH:48]=[CH:47][C:46]([C:14]2[C:12]3[NH:13][C:9]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:73][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH3:60])=[CH:3][CH:4]=4)=[C:28]4[N:29]=[C:25]([C:24]([C:30]5[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=5)=[C:23]5[NH:37][C:20](=[C:19]([C:38]6[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=6)[C:18]6[CH:17]=[CH:16][C:15]=2[N:45]=6)[CH:21]=[CH:22]5)[CH:26]=[CH:27]4)=[CH:10][CH:11]=3)=[CH:51][CH:50]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: Oc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1

Procedure:
5,10,15,20-tetrakis-(4-Hydroxy-phenyl)-porphyrin (170 mg, 0.25 mmol) is dissolved and K2CO3 (0.65 g, mmol) is suspended in DMF (30 mL). To the vigorously stirred reaction mixture a solution of 1-bromotetradecane (0.1 mL, 0.45 mmol) in DMF (10 mL) is added dropwise at 50° C. during 30 mins and the mixture is heated for 1.5 h. After evaporation of solvent, the residue is dissolved in toluene:ethanol (1:1 by vol., ca. 5 mL) and purified by chromatography using a column (5×25 cm) of silica gel (Merck 60) which is washed with toluene. After the elution of the first 3 fractions, elution is continued using toluene:ethyl acetate (2:1 by vol.). The fifth compound eluted is collected, the solvent evaporated and the residue dried under high vacuum to afford product as violet crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=1[Cl:20])[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:41](B(CC)CC)[CH3:42]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:41][CH3:42])=[CH:15][C:14]=1[Cl:20])[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(Br)cc3Cl)cc2OC1C(F)(F)F
Reactant: CCB(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(CC)cc3Cl)cc2OC1C(F)(F)F
Temperature: 110 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
To the mixture of 0.3g (0.59 mmol, 1.0 eqv) of ethyl 6-chloro-7-(2-chloro-4-bromophenoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate, 0.32 g (2.3 mmol) of potassium carbonate, 68 mg (0.059 mmol ) of tetrakistriphenyl-phosphinepalladium (0), and 2.5 mL of anhydrous DMF under nitrogen was added 0.83 mL (0.83 mmol, 1.0 M in THF) of triethylborane. The mixture was heated to 110° C. and shaken for five hrs. LC-MS indicated that the reaction was completed. After cooling to room temperature, the reaction was added to 50 mL of ethyl acetate. The resulting organic phase was washed with brine three times, and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified on silica gel column with 1:9 EtOAc/hexane to afford 0.23 g (84.7%) of a light yellow solid. The product was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1([Cl:22])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:17](=[N:19][OH:20])[CH3:18])=[N:12][N:13]2[CH3:16])=[CH:9][C:8]=1[F:21].[H-].[Na+].[CH3:25][O:26][C:27](=[O:40])[C:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]Br)=[CH:29][O:30][CH3:31].C(O)(=O)C>CN(C)C=O>[CH3:25][O:26][C:27](=[O:40])[C:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][O:20][N:19]=[C:17]([C:11]1[C:10]2[C:14](=[CH:15][C:7]([O:6][CH2:5][CH:3]3[CH2:4][C:2]3([Cl:1])[Cl:22])=[C:8]([F:21])[CH:9]=2)[N:13]([CH3:16])[N:12]=1)[CH3:18])=[CH:29][O:30][CH3:31]
Reactant: CC(=NO)c1nn(C)c2cc(OCC3CC3(Cl)Cl)c(F)cc12
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC=C(C(=O)OC)c1ccccc1CON=C(C)c1nn(C)c2cc(OCC3CC3(Cl)Cl)c(F)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.9 g of 1-[6-(2,2-dichlorocyclopropylmethoxy)-5-fluoro-1-methyl-1H-indazol-3-yl]-ethanone oxime in 10 ml of N,N-dimethylformamide is added dropwise to a suspension of 0.2 g of sodium hydride in 15 ml of N,N-dimethylformamide and the reaction mixture is stirred at room temperature for 15 minutes. Then 1.04 g of 2-(α-bromo-o-tolyl)-3-methoxyacrylic acid methyl ester in 10 ml of N,N-dimethylformamide are added dropwise and the reaction mixture is stirred at room temperature for a further 3 hours. The mixture is then acidified with acetic acid and concentrated by evaporation in vacuo at approx. 50° C. The residue is dissolved in ethyl acetate and the solution is washed twice with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in vacuo. Purification by flash chromatography (silica gel, ethyl acetate/hexane 1:1) yields the title compound having a melting point of 138-140° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:27][C:28]([F:42])([F:41])[C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:32]Br>O1CCCC1.CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:10][O:11][CH2:32][C:31]1[CH:34]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:36]=[C:29]([C:28]([F:27])([F:41])[F:42])[CH:30]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled solution (0° C.) of (S)-2-t-butoxycarbonylamino-3,3-diphenylpropan-1-ol (2.04 g, 6.2 mmol, Example 1 g) in tetrahydrofuran (50 ml) and dimethylformamide (10 ml) was added sodium hydride (0.187 g, 80% suspension in oil) over 15 minutes. After an additional 10 minutes 3,5-bis(trifluoromethyl)benzyl bromide (1.14 ml) was added and the solution stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue partitioned between CH2Cl2 and water. After washing the organic phase with saturated brine and drying (MgSO4), the solvent was removed in vacuo and the residue chromatographed on silica gel in ethyl acetate/hexane (0:100 to 50:50) to give (S)-2-t-butoxycarbonylamino-1-((3.5bis(trifluoromethyl)phenyl)methyloxy)3,3-diphenylpropane, 2.92 g.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Br:21])(=[O:3])[CH3:2].I[CH3:23].[H-].[Na+].O>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH3:23])[CH:9]=[CH:8][C:7]=1[Br:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(Nc2ccc(C#N)cc2)ccc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1cc(N(C)c2ccc(C#N)cc2)ccc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-bromo-5-(4-cyanophenylamino)benzyl acetate (1.0 g, 2.9 mmol) in N,N-dimethylformamide (11 mL) under nitrogen atmosphere was added iodomethane (0.543 mL, 8.7 mmol), and the mixture was stirred in ice-water bath for five minutes. Then sodium hydride (0.174 g, 4.35 mmol) was added, and the reaction was stirred at room temperature for 24 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give crude 2-bromo-5-[N-(4-cyanophenyl)-N-methylamino]benzyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.C([O-])(O)=O.[Na+].CO.[Br:19]Br>O>[Br:19][C:7]1[C:2]([Cl:1])=[N:3][C:4]([O:10][CH3:11])=[N:5][C:6]=1[O:8][CH3:9]
Reactant: COc1cc(Cl)nc(OC)n1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(Cl)c(Br)c(OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
In a 250 mL round bottom flask, 4-chloro-2,6-dimethoxy-pyrimidine (3.25 g, 18.65 mmol) and NaHCO3 (3.6 g, 42.9 mmol) was charged with MeOH and water (1:1 ratio, 160 mL). Bromine (1.44 mL, 27.97 mmol) was added to the mixture dropwise (in 1 hour). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated down. Ethyl acetate was added, followed by washing with brine. The organic layer was concentrated down and purified (silica gel, 0-50% EtOAC/hexane) to give white solid (4.06 g, 86%). LC-MS shows 255.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 4.07 (s, 3H), 3.98 (s, 3H); 13C NMR (300 MHz, CDCl3): δ 168.27; 162.79; 160.38; 97.08; 55.78; 55.70.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:22]=[C:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])C>C(O)C(C)C>[CH2:27]([O:26][C:24](=[O:25])[C:23](=[CH:22][NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:28]
Reactant: CN1CCN(c2ccc3ncnc(N)c3c2)CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CC(C)CO
Product: CCOC(=O)C(=CNc1ncnc2ccc(N3CCN(C)CC3)cc12)C(=O)OCC
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 42.5 %

Procedure:
A mixture of 4-amino-6-(4-methylpiperazinyl)quinazoline (2.19 g) and diethyl ethoxymethylenepropanedioate (2.13 g) in isobutylalcohol (9 ml) was stirred for 2 hours and 25 minutes at 100° C. and then cooled to ambient temperature. The resultant mixture was concentrated under reduced pressure to give a residue, which was recrystallized from ethanol to give crystalline diethyl[{6-(4-methylpiperazinyl)-4-quinazolinylamino}methylene]propanedioate (1.58 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:19]=[C:18]([O:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:17]=[CH:16][N:15]=1)[CH2:9][CH2:8]2)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>C(Cl)Cl>[CH:38]([O:37][C:35]([N:24]1[CH2:25][CH2:26][CH:21]([O:20][C:18]2[CH:19]=[C:14]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH2:8][CH2:9]3)[N:15]=[CH:16][N:17]=2)[CH2:22][CH2:23]1)=[O:36])([CH3:40])[CH3:39]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 4b (0.12 mmol) and triethylamine (0.2 mL, 12 eq) in 1 mL of DCM, was added the isopropyl chloroformate (1.3 eq). The mixture was stirred at room temperature for 22 h and the solvent volume was reduced to 0.7 mL under a stream of nitrogen. The residue was purified by preparative HPLC to afford 4-1, LCMS 461.2 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[CH2:35]([O:38][C:39]1[CH:44]=[C:43]([CH2:45]Cl)[CH:42]=[CH:41][C:40]=1[Cl:47])[CH:36]=[CH2:37]>>[CH2:35]([O:38][C:39]1[CH:44]=[C:43]([CH:42]=[CH:41][C:40]=1[Cl:47])[CH2:45][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)[CH:36]=[CH2:37]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: C=CCOc1cc(CCl)ccc1Cl
Product: C=CCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1Cl

Procedure:
Analogously to Method D, 2.00 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 2-allyloxy-1-chloro-4-chloromethylbenzene are reacted. The title compound is obtained as a colourless oil. Rf=0.18 (1:4 EtOAc-heptane); Rt=6.44.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=C(C)C=C(C)N=1.ClC(OC(C)(C)C(Cl)(Cl)Cl)=O.[NH2:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[CH:48]=[N:47][CH:46]=[CH:45]2.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:10]([C:11]([NH:41][C:42]2[CH:43]=[C:44]3[C:49](=[CH:50][CH:51]=2)[CH:48]=[N:47][CH:46]=[CH:45]3)=[O:13])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:15][CH:16]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: CC(C)(OC(=O)Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)(C)OC(=O)NC[C@@H](C(=O)Nc1ccc2cnccc2c1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To (S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (28) (8.5 g, 28.4 mmol) in DMF cooled to 0° C. was added 2,4,6-trimethylpyridine and 2,2,2-trichloro-1,1-dimethylethyl chloroformate in DMF. Then, 6-aminoisoquinoline in DMF was added and the solution stirred for 2 h at 0° C. The mixture was poured into NaHCO3 (sat) and extracted with EtOAc. The organic layers were washed with H2O, dried (Na2SO4), filtered and evaporated to give crude 29. Column chromatography (30% EtOAc-Hexanes) and recrystallization (EtOAc/Hexanes) gave pure (S)-tert-butyl 2-(4-chlorophenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (29, 7.8 g, 64%, >99% S enantiomer).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][CH2:20][NH2:21])=[CH:16][CH:17]=3)[C:12]3[CH:22]=[C:23]([Cl:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[N:25][C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:18]3[C:13]([C:12]=2[CH:22]=1)=[CH:14][C:15]([CH2:19][CH2:20][NH:21][C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[CH:16][CH:17]=3
Reactant: NCCc1ccc2c(c1)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1ccc2c(c1)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48 %

Procedure:
To a cooled mixture (0° C.) of 16 (65 mg, 0.17 mmol) in CH2Cl2 (3 mL) were added Et3N (100 μL, 4.2 equiv.) and benzoyl chloride (30 μL, 1.5 equiv.). The mixture was stirred for 12 h at room temperature. The resulting mixture was then quenched at 0° C. with NaHCO3. It was extracted with the mixture of EtOAc. The resulting organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried over MgSO4, filtered and solvents were removed under reduced pressure. The crude product was purified by flash chromatography (EtOAc/PE 1:1) to afford 17 in 48% yield as a white solid, 1H NMR (300 MHz, CDCl3): δ 8.48 (d, 1H, J=2.3 Hz), 8.41 (d, 1H, J=8.5 Hz), 8.13-8.11 (m, 3H), 7.77 (bs, 1H), 7.70 (d, 1H, J=7.5 Hz), 7.57-7.41 (m, 7H), 6.19 (bs, 1H), 3.05 (q, 2H, J=6.9 Hz), 3.09 (t, 2H, J=6.9 Hz); MS (ESI) m/z 490 [M+H+]
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH:20]([CH3:22])[CH3:21].O>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CBr
Reactant: O=C1CCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COc1ccc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a mixture of 6-hydroxy-2,3-dihydro-1H-inden-1-one (5.0 g, 33.8 mmol) in DMF (170 mL) was added K2CO3 (9.33 g, 67.5 mmol) and 1-bromo-2-methylpropane (5.50 mL, 50.6 mmol). The resulting orange mixture was stirred at r.t. overnight and was then heated to 60° C. for 2 days. The mixture was cooled to r.t., water was added and the mixture was extracted with EtOAc (×4). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography using 0-20% EtOAc in heptane as eluent afforded 4.98 g (72% yield) of the title compound: 1H NMR (500 MHz, CDCl3) δ ppm 1.03 (d, 6 H), 2.10 (dt, 1 H), 2.69-2.75 (m, 2 H), 3.04-3.11 (m, 2 H), 3.75 (d, 2 H), 7.17-7.22 (m, 2 H), 7.37 (d, 1 H); MS (ES+) m/z 205 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][C@@H:19]([CH3:22])[CH2:20][CH3:21])=[N:10][C:11]=2[NH2:17].F[C:24](F)(F)[C:25](O)=O.C1(OC2NC(N)=C3C(N=2)=NC(OC)=N3)CCCCC1.BrCCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH:19]1[CH2:22][CH2:25][CH2:24][CH2:21][CH2:20]1)=[N:10][C:11]=2[NH2:17]
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Agent: COc1nc2nc(OC3CCCCC3)[nH]c(N)c-2n1
Agent: ClCCCCBr
Product: COc1nc2c(N)nc(OC3CCCCC3)nc2n1CCCCCl

Procedure:
Prepared similarly to Intermediate 44 from 2-(cyclohexyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: [I-].[F:2][C:3]1([F:27])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N:12]3[CH:16]=[C:15]([CH3:17])[S:14]/[C:13]/3=[N:18]\[C:19]([N:21]3[CH:25]=[CH:24][N+](C)=C3)=[O:20])=[CH:11][C:5]=2[O:4]1.[CH:28](N(C(C)C)CC)(C)C.CC(N)C>C(#N)C>[F:2][C:3]1([F:27])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N:12]3[CH:16]=[C:15]([CH3:17])[S:14]/[C:13]/3=[N:18]\[C:19]([NH:21][CH:25]([CH3:28])[CH3:24])=[O:20])=[CH:11][C:5]=2[O:4]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)O3)/c(=N/C(=O)n2cc[n+](C)c2)s1
Agent: [I-]
Solvent: CC(C)N
Solvent: CC#N
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)O3)/c(=N/C(=O)NC(C)C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 20 mL vial, a solution of (Z)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-methylthiazol-2(3H)-ylidenecarbamoyl)-3-methyl-1H-imidazol-3-ium iodide (Example 40B, 48 mg, 0.09 mmol) dissolved in acetonitrile (0.5 mL) was added followed by the addition of diisopropylethylamine (21 μL, 0.12 mmol) dissolved in acetonitrile (0.5 mL). Then, to the solution was added propan-2-amine (5.9 mg, 0.10 mmol) dissolved in acetonitrile (0.5 mL). The vial was capped and shaken overnight at room temperature. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC (acetonitrile/water 0.1% TFA gradient elution method) to supply the titled compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 1.07 (6 H) 2.22 (3 H) 3.65-3.83 (1 H) 6.99 (1 H) 7.32 (1 H) 7.43 (1 H) 7.61 (1 H); MS (ESI) m/z 356 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].[C:24](Cl)(=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:5][C:3]=1[NH:4][C:24](=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1cc(OCCN2CCOCC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(C=Cc1ccccc1)Nc1cc(OCCN2CCOCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
2-chloro-5-(2-morpholinoethoxy)aniline (1.9 g, 7.4 mmol, 1 eq.) was placed in a mixture of acetone (2.5 mL) and water (3.2 mL) in the presence of K2CO3 (2.1 g, 14.4 mmol, 2 eq.). Cinnamoyl chloride (1.2 g, 7.4 mmol, 1 eq.) was then added at 0° C. The reaction mixture was allowed to warm-up to room temperature, stirred for 2 hours and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford N-(2-chloro-5-(2-morpholinoethoxy)phenyl)cinnamamide (1.7 g, 60%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16][CH2:17][C@@H:18]([N:22]1[CH:26]=[C:25]([C:27]([NH2:29])=[O:28])[N:24]=[CH:23]1)[C@@H:19]([OH:21])[CH3:20])C1C=CC=CC=1>CCOC(C)=O.CCO.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16][CH2:17][C@@H:18]([N:22]1[CH:26]=[C:25]([C:27]([NH2:29])=[O:28])[N:24]=[CH:23]1)[C@@H:19]([OH:21])[CH3:20]
Reactant: C[C@H](O)[C@@H](CCc1ccc(F)cc1OCc1ccccc1)n1cnc(C(N)=O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H](O)[C@@H](CCc1ccc(F)cc1O)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.9 %

Procedure:
A mixture of 1-[(2S,3R)-5-(2-benzyloxy-4-fluorophenyl)-2-hydroxy-3-pentyl]imidazole-4-carboxamide (0.16 g) and 10% Pd—C (32 mg) in EtOAc (2 ml) and EtOH (2 ml) was stirred under hydrogen atmosphere at room temperature for 3 hr. Pd—C was removed by filtration and the filtrate was evaporated to give an off-white powder of 1-[(2S,3R)-5-(2-hydroxy-4-fluorophenyl)-2-hydroxy-3-pentyl]imidazole-4-carboxamide (62) (131 mg, 99%).