Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9]([OH:10])=[C:8]([CH3:11])[C:7]([CH3:12])=[C:6]([OH:13])[C:5]=1[CH3:14])(=[O:3])[CH3:2].[CH3:15][O:16][CH:17]([O:21][CH3:22])[C:18](=O)[CH3:19].N1CCCC1>C1(C)C=CC=CC=1>[CH3:15][O:16][CH:17]([O:21][CH3:22])[C:18]1([CH3:19])[CH2:2][C:1](=[O:3])[C:4]2[C:9](=[C:8]([CH3:11])[C:7]([CH3:12])=[C:6]([OH:13])[C:5]=2[CH3:14])[O:10]1
Reactant: CC(=O)c1c(C)c(O)c(C)c(C)c1O
Reactant: COC(OC)C(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: COC(OC)C1(C)CC(=O)c2c(C)c(O)c(C)c(C)c2O1
Yield: 70 %

Procedure:
15.0 g (77 mmoles) of acetyl-trimethylhydroquinone, 10.5 g (89 mmoles) of 1,1-dimethoxy-propan-2-one and 9.30 g (131 mmoles) of pyrrolidine were reacted in toluene solution by a method similar to that of Example 1 to give the above product. Boiling point: 165°-170° C./6.10-5 mbar (bulb tube); yield: 70%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])[N:3]=1.[F:22][C:23]([F:29])([F:28])[CH2:24][N:25]=[C:26]=[S:27].CN(C)C=O>C(#N)C>[F:22][C:23]([F:29])([F:28])[CH2:24][NH:25][C:26](=[S:27])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])[N:3]=1
Reactant: FC(F)(F)CN=C=S
Reactant: Nc1ccnc(SCCN2C(=O)c3ccccc3C2=O)n1
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCSc1nccc(NC(=S)NCC(F)(F)F)n1
Reaction time: 72 h
Yield: 59.5 %

Procedure:
A mixture of 4-amino-2-(2-phthalimidoethylthio)pyrimidine (0.8 g.), 2,2,2-trifluoroethylisothiocyanate (0.56 g.) and dimethyl formamide (2 ml.) was stirred at 70° for 72 hours. The mixture was cooled, diluted with acetonitrile and filtered to give 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(2-phthalimidoethylthio)pyrimidine (0.7 g.), m.p. 238°-241°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:20])=[C:4]([C:13]([NH:15][CH2:16][CH:17]([OH:19])[CH3:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].[C:21](Cl)(=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>CC(N(C)C)=O>[C:21]([NH:1][C:2]1[C:3]([I:20])=[C:4]([C:13]([NH:15][CH2:16][CH:17]([OH:19])[CH3:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8])(=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:1][C:2]1[C:3]([I:20])=[C:4]([C:13]([NH:15][CH2:16][CH:17]([OH:19])[CH3:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8])=[O:27]
Reactant: O=C(Cl)CCCCC(=O)Cl
Reactant: CC(O)CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Product: CC(O)CNC(=O)c1c(I)c(NC(=O)CCCCC(=O)Nc2c(I)c(C(=O)O)c(I)c(C(=O)NCC(C)O)c2I)c(I)c(C(=O)O)c1I

Procedure:
Analogously to Example 10, 5-amino-N-(2-hydroxypropyl)2,4,6-triiodoisophthalamic acid is reacted with hexanedioic acid dichloride in dimethylacetamide and then worked up. The thus-obtained product melts at 284°-285° C., with decomposition.
Reaction SMILES: C(O)(C)C.C[O:6][C:7](=O)[CH2:8][CH2:9][SH:10].[CH2:12]([NH2:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(Cl)Cl>[CH2:12]([NH:20][C:7](=[O:6])[CH2:8][CH2:9][SH:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCN
Reactant: COC(=O)CCS
Solvent: ClCCl
Solvent: CC(C)O
Product: CCCCCCCCNC(=O)CCS
Reaction time: 19.5 h

Procedure:
In a small multi-necked reaction vessel equipped with a magnetic stirrer and gas inlet was placed isopropanol (2 ml), methyl-3-mercaptopropionate (2.0 g, 16.64 mmol), and n-octylamine (2.19 g, 16.94 mmol). The reaction vessel was connected to a trap containing bleach to trap mercaptan vapors, and the reaction was stirred for 19.5 hours while the reaction temperature was held at 30°-35° C. Methylene dichloride was added and the crude product was transferred to a round bottom flask. Evaporation of the solvent under reduced pressure yielded crude N-(n-octyl)-3-mercaptopropionamide as an oily white solid in essentially quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[C:5]#[N:6].C([O-])([O-])=[O:12].[K+].[K+].OO>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[C:5]([NH2:6])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(I)c(F)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 251549.91 %

Procedure:
To a solution of 3-fluoro-4-iodobenzonitrile (2.7 g, 0.010 mmol) in DMSO (6.0 mL), K2CO3 (0.450 g, 0.003 mmol) and 30% H2O2 (2.4 mL) were added at 0-10° C. and the reaction mass was stirred at RT for 2 h. After completion of the reaction, the reaction mass was quenched in ice cold water. The obtained solid product was filtered off to afford 2.0 g of the desired title product. 1H NMR (400 MHz, DMSO d6): δ 7.48-7.51 (m, 2H), 7.66 (br s, 1H), 7.69-7.70 (m, 1H), 8.09 (brs, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:33]=[CH:32][C:8]2[NH:9][C:10]([C:15]3[C:16](=[O:31])[N:17]([NH:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:18]4[C:23]([C:24]=3[OH:25])=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:11][S:12](=[O:14])(=[O:13])[C:7]=2[CH:6]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[CH:28]1([CH2:27][NH:26][N:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]([OH:25])=[C:15]([C:10]3[NH:9][C:8]4[CH:32]=[CH:33][C:5]([O:4][CH2:3][CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:6][C:7]=4[S:12](=[O:14])(=[O:13])[N:11]=3)[C:16]2=[O:31])[CH2:30][CH2:29]1
Reactant: NCCOc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCOc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 120 °C
Yield: 28.5 %

Procedure:
To the product of Example 394 (15 mg, 0.032 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (12 μl, 0.156 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was cooled to 25° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered, and washed with 1:1 hexane:ethyl acetate. The crude product was purified by chromatography on silica gel eluting with 199:1 dichloromethane:methanol to give the title compound (5 mg, 29%). 1H NMR (300 MHz, DMSO-d6) δ 0.14 (d, J=4.04 Hz, 2 H) 0.41 (d, J=7.72 Hz, 2 H) 1.01 (m, 1 H) 2.86 (d, J=5.52 Hz, 2 H) 2.97 (s, 3 H) 3.38 (t, J=5.33 Hz, 2 H) 4.18 (t, J=5.33 Hz, 2 H) 6.44 (s, 1 H) 7.32 (t, J=5.88 Hz, 1 H) 7.41 (m, 3 H) 7.67 (d, J=9.93 Hz, 1 H) 7.89 (t, J=7.91 Hz, 1 H) 8.10 (d, J=8.46 Hz, 1 H) 8.17 (d, J=8.46 Hz, 1 H) 14.08 (s, 1 H) 15.11 (s, 1 H). MS (ESI−) m/z 546 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH:11](O[Si](C)(C)C)[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[C:7]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=1[OH:29])([CH3:4])([CH3:3])[CH3:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CCCCCC>[C:25]([C:7]1[CH:8]=[C:9]([CH:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:6]=1[OH:29])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cc(C(CCc2ccccc2)O[Si](C)(C)C)cc(C(C)(C)C)c1O
Reactant: C1COCCN1
Solvent: CCCCCC
Product: CC(C)(C)c1cc(C(CCc2ccccc2)N2CCOCC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a nitrogen-purged, 250 mL, three-neck, round-bottom flask were added the 148.9 grams of the 2,6-di-t-butyl-4-(1-trimethylsilyloxy-3-phenylpropyl)phenol produced in step (B) of this example, 67 grams of hexane, and 45.8 grams (0.53 mole) of morpholine. The mixture was stirred overnight at ambient temperature. After this time, the solvent was removed and the solids recrystallized from a solution of 5 percent toluene in hexane to give pure 2,6-di-t-butyl-4-(1-morpholino-3-phenylpropyl)phenol as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][N:27]3[CH2:28][CH2:29][N:24]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:25][CH2:26]3)[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccc(-c2cc(CCCN3CCN(Cc4ccccc4)CC3)on2)cc1
Yield: 61.2 %

Procedure:
About 2 min after dissolving 3-[3-(4-chlorophenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-benylpiperazine (7.3, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (27 mg, 0.13 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 2 hr and followed the same processes as in Example 1 to obtain 9.7 mg (58.3%) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:30])[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]1=[O:31])(=[O:14])=[O:13])[CH:6]=[CH:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:43][C:44]#[N:45]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:43][C:44]#[N:45])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:30])[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]1=[O:31])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: N#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](N(CC#N)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: -78 °C
Reaction time: 16 h
Yield: 27.7 %

Procedure:
A solution of 6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide [Example 1] (0.01 g) in THF (2 ml) was cooled to −78° C. under nitrogen, and treated with lithium bis(trimethylsilyl)amide (1.0M solution in THF; 0.026 ml), followed by bromoacetonitrile (0.013 g). The resultant solution was allowed to reach room temperature and stirred for a further 16 h. The mixture was then cooled to −78° C. and further lithium bis(trimethylsilyl)amide (0.026 l) added. After reaching room temperature, the reaction mixture was stirred for a further 18 h and then quenched by the addition of methanol (1 ml). The resultant solution was concentrated under reduced pressure and the residue purified by mass directed preparative h.p.l.c. to give the title compound (0.003 g) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[C:7]([CH3:38])=[C:8]([C:27]2[CH:28]=[N:29][N:30]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH:31]=2)[C:9]([O:25][CH3:26])=[C:10]([CH:12]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]3[C:16]([CH3:24])=[N:15]2)[CH3:13])[CH:11]=1.C(N(C(C)C)CC)(C)C.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([N:35]1[CH2:34][CH2:33][CH:32]([N:30]2[CH:31]=[C:27]([C:8]3[C:9]([O:25][CH3:26])=[C:10]([CH:12]([N:14]4[C:18]5=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]5[C:16]([CH3:24])=[N:15]4)[CH3:13])[CH:11]=[C:6]([Cl:5])[C:7]=3[CH3:38])[CH:28]=[N:29]2)[CH2:37][CH2:36]1)(=[O:3])[CH3:2]
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1cnn(C2CCNCC2)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1cnn(C2CCN(C(C)=O)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.2 %

Procedure:
Acetyl chloride (2.4 μL, 0.033 mmol) was added to a solution of 1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-piperidin-4-yl-1H-pyrazol-4-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (8.0 mg, 0.017 mmol, chiral intermediate from Example 181, Step 2) and N,N-diisopropylethylamine diisopropylethylamine (14 μL, 0.083 mmol) in methylene chloride (0.3 mL) at 0° C. and the reaction was stirred at room temperature for 15 min. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.0 mg, 7.8%). The product was isolated as a single enantiomer. LCMS calculated for C26H32ClN8O2 (M+H)+: m/z=523.2; Found: 523.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([Cl:30])=[CH:32][CH:33]=3)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CN2CCOC2=O)c1
Temperature: 25 °C

Procedure:
{3-[4-Amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.15 g, 0.38 mmol), 4-chlorobenzoyl chloride (0.15 g, 0.86 mmol), and triethylamine (0.27 mL, 1.9 mmol) were combined in CH2Cl2 (10 mL) and stirred at room temperature until no starting material was seen by analytical tlc. The mixture was concentrated to give the title compound, which was used directly in the hydrolysis step.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.[C:12]1([S:18]([NH2:21])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:21][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(O)ccc1C=NS(=O)(=O)c1ccccc1
Temperature: 25 °C

Procedure:
An equimolar mixture of 27.4 g (0.18 mol) 4-hydroxy-2-methoxybenzaldehyde and 28.3 g (0.18 mol) benzenesulfonamide was placed into toluene. 100 mg p-toluenesulfonic acid was added as a catalyst. The mixture was then heated under reflux on a water separator until the theoretically calculated quantity of water had separated. After cooling to room temperature, the precipitated solid was filtered off and dried under vacuum. Yield: 43.0 g (78.9%).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[CH3:31])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CN(C=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[C:25]([CH3:31])[CH:26]=1
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(F)cc3C)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(F)cc3C)c[nH]c12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
90.8 mg (1.40 mmol) of potassium cyanide were added to 294 mg (0.70 mmol) of the compound from Example 62A in 15 ml of DMF. The mixture was stirred at 80° C. for 4 h and then concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 188 mg (77% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:32])=[C:4]([NH:10][C@H:11]([C@@H:29]([OH:31])[CH3:30])[C:12]([NH:14][NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(NP1(N(CC)CC)N(C)CCCN1C)(C)(C)C>C1COCC1>[N:23]1([C:20]2[CH:19]=[CH:18][C:17]([C:16]3[O:13][C:12]([C@H:11]([NH:10][C:4]4[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=4[CH3:32])[C@@H:29]([OH:31])[CH3:30])=[N:14][N:15]=3)=[CH:22][CH:21]=2)[CH:27]=[CH:26][CH:25]=[N:24]1
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(-n3cccn3)cc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN(CC)[PH]1(NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(-n4cccn4)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Yield: 15.3 %

Procedure:
To a solution of N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-(1H-pyrazol-1-yl)benzohydrazide (164 mg, 0.36 mmol) in anhydrous THF (12 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3-dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol base/1) (495 mg, 1.09 mmol) followed by p-TSCl (83 mg, 0.44 mmol) and the mixture was stirred for 70 mm. The mixture was filtered under suction and the residue washed with acetone (2×50 mL) followed by MeOH (2×50 mL). The filtrate was concentrated under reduced pressure to provide a off white solid, which was purified by flash chromatography over silica gel (25-50% EtOAc in hexanes) to provided 4-((1R,2S)-1-(5-(4-(1H-pyrazol-1-yl)phenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-2-chloro-3-methylbenzonitrile as a yellow oil (24 mg, 15%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.46 (d, J=2.5 Hz, 1H), 8.11 (dm, J=9.2 Hz, 2H), 8.06 (dm, J=9.0 Hz, 2H), 7.77 (d. J=1.8 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 6.57 (dd, J=1.8, 2.5 Hz, 1H), 5.70 (d, J=8.6 Hz, 1H), 5.12 (dd, J=3.5, 8.6 Hz, 1H), 4.86 (br s, 1H), 4.69-4.60 (m, 1H), 2.41 (5, 3H), 1.42 (d, J=6.5 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]=2[O:19][CH3:20])[CH:9]=1)=[O:4].O.[OH-].[Li+].CN(C)C=O.Cl>O>[N+:16]([C:12]1[C:11]([O:19][CH3:20])=[C:10]([C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[NH:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=1)([O-:18])=[O:17]
Reactant: COC(=O)c1cc(-c2cccc([N+](=O)[O-])c2OC)cn1S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(-c2c[nH]c(C(=O)O)c2)cccc1[N+](=O)[O-]
Yield: 55.2 %

Procedure:
4-(3-Nitro-2-methoxy-phenyl)-1-(p-tolylsulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 57f (1.04 g, 2.42 mmol) and lithium hydroxide monohydrate (1.01 g, 24.19 mmol) were added to a solvent mixture of 10 mL of N,N-dimethylformamide and 5 mL of water. The reaction mixture was reacted at 100° C. for 30 minutes under microwave. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was adjusted to pH 3 with hydrochloric acid (1 N) to form a lot of precipitates. The mixture was filtered and the filter cake was dried to obtain the title compound 4-(3-nitro-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acid 57g (350 mg, yield 50%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1([CH2:5][CH2:6][OH:7])[CH2:4][CH2:3]1.N1C=CC=CC=1.[Si:14](OS(C(F)(F)F)(=O)=O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl>[Br:1][C:2]1([CH2:5][CH2:6][O:7][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:4][CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: OCCC1(Br)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC1(Br)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the cyclopropyl alcohol (Step A) (1.303 g, 7.95 mmoles) in 30 ml anhydrous DCM was added anhydrous pyridine (1.2 ml, 1.1736 g, 14.8 mmoles), TBSOTf (2.7 ml, 3.1077 g, 11.76 mol) and the solution was stirred at room temperature for 16 h. It was extracted with CHCl3/brine and the organic fraction was dried with MgSO4. The solvent was reduced and the crude product purified using flash-column chromatography (CHCl3/hexanes 1:10, Rf=0.4). Yield: 0.796 g, 36%. 1H-NMR (500 MHz, CDCl3): δ=3.95-3.75 (t, 2H), 1.95-1.85 (t, 2H), 1.15-1.05 (m, 2H), 0.95-0.80 (m, 11H), 0.15-0.05 (s, 6H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH:9]1([CH2:15][N:16]2[CH2:24][C:23]3[C:18](=[C:19]([CH3:32])[CH:20]=[C:21]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:22]=3)[C:17]2=[O:33])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>O>[CH:9]1([CH2:15][N:16]2[CH2:24][C:23]3[C:18](=[C:19]([CH3:32])[CH:20]=[C:21]([CH2:25][CH:26]4[CH2:27][CH2:28][N:29]([CH2:2][C:3]5[N:8]=[CH:7][CH:6]=[CH:5][N:4]=5)[CH2:30][CH2:31]4)[CH:22]=3)[C:17]2=[O:33])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: ClCc1ncccn1
Reactant: Cc1cc(CC2CCNCC2)cc2c1C(=O)N(CC1CCCCC1)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(CC2CCN(Cc3ncccn3)CC2)cc2c1C(=O)N(CC1CCCCC1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a mixture of 2-Chloromethylpyrimidine (32 mg, 0.247 mmol), 2-Cyclohexylmethyl-7-methyl-5-piperidin-4-ylmethyl-2,3-dihydro-isoindol-1-one (56 mg, 0.164 mmol) and cesium carbonate (160 mg, 0.492 mmol) was added acetonitrile (3.0 mL). The mixture was allowed to stir at room temperature overnight. Water (2.0 mL) was added and the product was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Column chromatography provided the title compound as a yellow oil (48 mg, 69%). 1H NMR (300 Adz, CDCl3): δ 8.76-8.72 (d, 2H), 7.18 (t, 1H), 6.99 (s, 1H), 6.95 (s, 1H), 4.30 (s, 2H), 3.78 (s, 2H), 3.40-3.37 (d, 2H), 2.97-2.93 (d, 2H), 2.70 (s, 3H), 2.58-2.56 (d, 2H), 2.10-2.05 (t, 2H), 1.71-1.42 (m, 10H), 1.26-1.13 (m, 4H), 1.09-0.98 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][CH2:13][CH2:14][NH:15][CH3:16])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.Br[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:23][O:22][C:20](=[O:21])[CH2:19][CH2:18][N:15]([CH2:14][CH2:13][NH:12][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:11])[CH3:16]
Reactant: COC(=O)CCBr
Reactant: CNCCNC(=O)c1nc(Cl)c(N)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCN(C)CCNC(=O)c1nc(Cl)c(N)nc1N
Yield: 63.4 %

Procedure:
A mixture of 2.44 g (10.0 mmol) of 3,5-diamino-6-chloro-N-(2-methylaminoethyl)pyrazine-2-carboxamide, 1.67 g (10.0 mmol) of methyl 3-bromopropionate and 1.38 g (10.0 mmol) of potassium carbonate was stirred in 20 ml of DMF for 18 hours at ambient temperature. Water (100 ml) was added and the solid was filtered and air dried. Crystallization from ethanol provided 2.1 g (6.34 mmol, 63%) of N-[2-[[(3,5-diamino-6-chloropyrazinyl)carbonyl]amino]ethyl]-N-methyl-beta-alanine methyl ester as white crystals; mp 136.5°-137° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:28])[CH3:29])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@@H:36]4[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:38][CH2:37]4)=[O:34])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c6) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.