Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:65]1([CH2:71][C:72]([NH2:74])=[O:73])[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10][C@H:9]2[C:28]([N:68]2[CH2:69][CH2:70][N:65]([CH2:71][C:72]([NH2:74])=[O:73])[CH2:66][CH2:67]2)=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CN1CCNCC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N2CCN(CC(N)=O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.138 mmol) in methylene chloride (5 mL), HATU (Aldrich, 79 mg, 0.21 mmol) was added followed by the addition of DIPEA (0.145 mL, 0.83 mmol) and 2-piperazin-1-yl-acetamide (Chembridge, 45 mg, 0.21 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a ISCO machine (12 g column, eluent, 20% EtOAc/methylene chloride) to give a white solid. 87 mg.
Reaction SMILES: [C:1]([C:5]1[NH:10][C:9]2[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:12]=[N:13][C:8]=2[C:7](=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)[Cl:37]>>[C:1]([C:5]1[N:6]=[C:7]([Cl:37])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cn2nnc3c(=O)nc(C(C)(C)C)[nH]c32)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: COc1ccc(Cn2nnc3c(Cl)nc(C(C)(C)C)nc32)cc1

Procedure:
A mixture of 5-tert-butyl-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(4H)-one (50.0 mg, 160 μmol) and N,N-diethylaniline (50.8 μL, 319 μmol) in POCl3 (1000 μL, 10.9 mmol) was refluxed for 4 h under N2 atmosphere. The reaction mixture was concentrated in vacuo, diluted with EtOAc, washed with cold H2O and brine, dried over Na2SO4 and concentrated in vacuo to afford crude 5-tert-butyl-7-chloro-3-(4-methoxy benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine. The residue was used for the next reaction without further purification.
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([CH:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([N:23]2[CH2:24][CH2:25][CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22]2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ncoc1-c1ccccc1)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
5-Phenyl-1,3-oxazole-4-carboxylic acid (40 mg, 0.211 mmol), 3-Phenyl-pyrrolidine (31.6 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.0 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C20H18N2O2: 318.1368, found 318.1377.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]C([O-])=O)=O)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[NH:17]1[CH2:32][C@H:30]([OH:31])[CH2:29][C@H:18]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C1COCC1.C(OCC)(=O)C>[N:17]1([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:8])[CH2:32][C@H:30]([OH:31])[CH2:29][C@H:18]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H](O)CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
t-Butyldicarbonate (1.1 g) and then sat. sodium bicarbonate (20 ml) were added to a suspension of trans-Hyp-OBn (1.1 g) in THF (25 ml) and the mixture stirred for 30 min. The mixture was diluted with ethyl acetate and washed with water, dried (MgSO4) and evaporated. Flash chromatography (SiO2 DCM then ether) gave Boc-Hyp-OBn 1.18 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12](F)=[CH:13][C:14]=3[O:19][CH2:20][CH2:21][O:22][CH:23]([CH3:25])[CH3:24])[N:9]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1.[CH3:28][O-:29].[Na+]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:29][CH3:28])=[CH:13][C:14]=3[O:19][CH2:20][CH2:21][O:22][CH:23]([CH3:25])[CH3:24])[N:9]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1
Reactant: C[O-]
Reactant: Cc1cc(-c2nc3cc(F)cc(OCCOC(C)C)c3c(=O)[nH]2)cc(C)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OCCOC(C)C)c2c(=O)[nH]c(-c3cc(C)nc(C)c3)nc2c1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
2-(2,6-Dimethyl-pyridin-4-yl)-7-fluoro-5-(2-isopropoxy-ethoxy)-3H-quinazolin-4-one (22) (960 mg, 2.58 mmol) was taken up in anhydrous DMF (10 mL). Sodium methoxide (25% solution in methanol, 12.9 mmol) was added. After the addition, the reaction mixture was stirred at 60° C. for 72 hours. The reaction mixture was cooled to room temperature, and quenched with saturated solution of NH4Cl. The product was extracted with ethyl acetate (3×200 mL). The combined organic layer was washed with water, brine, dried over Na2SO4, and evaporated to give crude product. The crude compound was purified by preparative HPLC, to give the title compound 23 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:43]=[CH:42][C:18]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)=[O:28])[CH:21]=2)=[CH:17][CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][C:12](=[S:13])[NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([N:29]4[CH2:30][CH2:31][CH:32]([N:35]5[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]5)[CH2:33][CH2:34]4)=[O:28])[CH:21]=3)=[CH:42][CH:43]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)CC1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4)ccn3)CC2)CC1
Reaction time: 3 h
Yield: 40 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.25 M, 3.0 ml) to a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (149 mg) and (+)-10-camphorsulfonic acid (152 mg) in ethanol (4.0 ml) at room temperature, the mixture was stirred for 3 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. The solvent was then distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=98:2 to 97:3) to provide the title compound (88.2 mg, 40%) as white powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:17]([N:24]1[C@@H:29]([CH3:30])[CH2:28][C:27](=O)[CH2:26][C@H:25]1[CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl>[CH2:17]([N:24]1[C@@H:29]([CH3:30])[CH2:28][CH:27]([NH:1][C:2]2[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:26][C@H:25]1[CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Reactant: C[C@@H]1CC(=O)C[C@H](C)N1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C(F)(F)F)cc(NC2C[C@@H](C)N(Cc3ccccc3)[C@@H](C)C2)c1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 34.2 %

Procedure:
To a stirred mixture of MS3A (1.0 g), methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate (350 mg, 1.50 mmol) and (2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-one (359 mg, 1.65 mmol) in chloroform (10 mL) was added acetic acid (500 uL) at 0° C. and stirred at r.t. for 7 hours. To the reaction mixture was added sodium triacetoxyborohydride (670 mg, 3.00 mmol) at 0° C. The reaction mixture was stirred at 23° C. for 1.5 hours. Then the reaction mixture was quenched with aq. NaHCO3 until pH8-9. The MS 3 Å was removed by Celite filtration and the content was extracted with ethylacetate, dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane/ethylacetate=5/1 to 3/1). Target fractions were collected and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=5/1) to give the titled compound as a light yellow oil (223 mg, 62% yield.). For major isomer; 1H-NMR (400 MHz, CDCl3) δppm; 7.40-7.21 (m, 6H), 6.85 (s, 1H), 4.00-3.95 (m, 1H), 3.91 (s, 3H), 3.88 (d, 2H), 3.84-3.76 (m, 1H), 2.83-2.73 (m, 2H), 2.25 (s, 3H), 1.83-1.69 (m, 4H), 1.13 (d, J=6.4 Hz, 6H).
Reaction SMILES: [NH2:1][NH2:2].C(N(CC)CC)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:21](F)=[O:22])[CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1>C(#N)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:21]([NH:1][NH2:2])=[O:22])[CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1
Reactant: O=C(F)C1(c2ccc(Cl)cc2)CCC1
Reactant: NN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NNC(=O)C1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C

Procedure:
Anhydrous hydrazine (2.02 mL, 1.4 eq) was dissolved in acetonitrile (100 μL) and cooled to 0° C. Triethylamine (12.8 mL, 2.0 eq.) was added followed by 1-(4-chlorophenyl)cyclobutanecarbonyl fluoride (10 g, 1.0 eq) in acetonitrile (25 mL). After stirring at room temperature for one hour the acetonitrile was removed by evaporation. Product was obtained after silica gel chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][CH2:8][C@H:9]([OH:21])[CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].CC(O)=O.[O:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.[BH3-]C#N.[Na+]>CO>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[CH2:10][C@@H:9]([OH:21])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:22]=[CH:23][CH:24]=[C:2]([NH:1][CH:32]2[CH2:33][CH2:34][O:29][CH2:30][CH2:31]2)[CH:3]=1
Reactant: Nc1cccc(C(=O)NC[C@H](O)CN2CCc3ccccc3C2)c1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cccc(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To a solution of (S)-3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxylpropyl)benzamide (400 mg, 1.23 mmol) in MeOH (8 mL) was added AcOH (0.05 mL) and dihydro-2H-pyran-4(3H)-one (123 mg, 1.23 mmol). The mixture was stirred at 25° C. for 2 h. NaBH3CN (387 mg, 6.15 mmol) was added and the resulting mixture was stirred at 25° C. for 2 h. The reaction solution was concentrated, and the residue was washed with water and extracted with EA. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (160 mg, Yield 31.8%). 1H NMR (CD3OD, 400 MHz): δ 7.94-7.76 (m, 2H), 7.63-7.56 (m, 1H), 7.56-7.49 (m, 1H), 7.32-7.24 (m, 3H), 7.21-7.15 (m, 1H), 4.71-4.55 (m, 1H), 4.52-4.28 (m, 2H), 4.05-3.95 (m, 2H), 3.92-3.70 (m, 2H), 3.62-3.46 (m, 3H), 3.46-3.33 (m, 4H), 3.28-3.02 (m, 2H), 1.99-1.85 (m, 2H), 1.82-1.66 (m, 2H). LCMS (m/z): 410.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[N:47]([C:50]1[CH:58]=[CH:57][CH:56]=[C:55]2[C:51]=1[CH:52]=[CH:53][N:54]2[CH3:59])=[C:48]=[O:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:48]([NH:47][C:50]2[CH:58]=[CH:57][CH:56]=[C:55]3[C:51]=2[CH:52]=[CH:53][N:54]3[CH3:59])=[O:49])[CH2:42][CH2:41]1)=[O:39]
Reactant: Cn1ccc2c(N=C=O)cccc21
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc2c(NC(=O)N3CCC(C(=O)Nc4ccc5cc4CCc4cccc(c4)Nc4ncc(Cl)c(n4)N5)CC3)cccc21
Yield: 34 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 4-isocyanato-1-methyl-1H-indole as starting materials in 34% yield. LCMS for C34H34ClN8O2 (M+H)+: m/z=621.2.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][CH2:14][CH2:13][CH2:12][C:5]=2[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:1][C:2]1[S:3][C:4]2[CH2:15][CH2:14][CH2:13][CH2:12][C:5]=2[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:18])[CH3:17]
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)c1c(NC(C)=O)sc2c1CCCC2
Temperature: 25 °C
Yield: 80.9 %

Procedure:
Ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (100 g, 444 mmol) and acetic anhydride (227 g, 2.2 mol) were heated at reflux for ˜15 minutes and then allowed to cool to room temperature overnight. The reaction mixture containing white solid was filtered. The solid was rinsed with water (2 L) and dried in a vacuum oven for several hours at ˜45° C. to yield a white crystalline solid (96 g, 81%). 1H NMR (DMSO-d6) δ 4.26 (q, 2H), 2.69 (t, 2H), 2.57 (t, 2H), 2.20 (s, 3H), 1.70 (m, 4H), 1.30 (t, 3H), LCMS RT=3.48 min, [M+H]+=268.0.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[N:21][C:22]([N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:34]([O:36][CH3:37])=[O:35])[CH:32]=3)[C:27]([S:38][CH3:39])=[CH:26]2)=[N:23][CH:24]=1>ClCCl>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[N:21][C:22]([N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:34]([O:36][CH3:37])=[O:35])[CH:32]=3)[C:27]([S:38]([CH3:39])=[O:6])=[CH:26]2)=[N:23][CH:24]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4ccccc4F)cn3)c2c1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4ccccc4F)cn3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
m-Chloroperoxybenzoic acid (77%, 0.98 g, 4.38 mmol) in dichloromethane (5 mL) was added dropwise to an ice-cooled solution of 51c) (2.3 g, 5.85 mmol) in dichloromethane (25 mL). The resulting mixture was stirred at room temperature for 2 h, then diluted with dichloromethane (50 mL), and successively washed with saturated sodium hydrogen carbonate solution (2×50 mL) and brine (1×50 mL). The organic phase was dried over sodium sulfate and evaporated to obtain the crude product that was purified by column chromatography [100-200 mesh silica; 2% methanol in dichloromethane]. White solid. Yield: 2.2 g (92% of theory). HPLC-MS (method 5): Rt=3.38 min; m/z [M+H]+=410
Reaction SMILES: [S:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=[O:14])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>CCOCC>[S:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[CH2:13][OH:14])([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CO)cc1
Yield: 53.1 %

Procedure:
A solution of 1-tosyl-L-proline (17.8 g) prepared in Reference Example 38 in anhydrous ether (80 ml) was dropwise added to a suspension of lithium aluminum hydride (3.76 g) in anhydrous ether (80 ml) over 30 minutes with ice-cooling. After stirring the reaction liquid at room temperature for one hour, 100 ml of ethyl acetate was added thereto and the resulting mixture was stirred for additional 16 hours. The insolubles formed was filtered off through a Celite layer, the organic phase obtained was washed with water and dried over anhydrous magnesium sulfate. The organic phase was concentrated, then the resulting residue was subjected to silica gel column chromatography and eluted with chloroform/ethyl acetate (98/2) to give 8.96 g (yield 53.1%) of the title compound.
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.Cl.[C:11]([NH2:14])(=[NH:13])[CH3:12].[O-]CC.[Na+].C(O)(=O)C>C(O)C>[CH3:12][CH:11]1[NH:14][C:1](=[O:7])[CH2:2][C:3]([CH3:5])=[N:13]1
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1=NC(C)NC(=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
To a solution of ethyl acetoacetate (0.8 g, 6.14 mmol) in ethanol (8 mL) was added acetamidine hydrochloride (0.6 g, 6.3 mmol) and stirred at r.t. for 10 min. A solution of sodium ethoxide [prepared from sodium (0.28 g, 12.3 mmol) and ethanol (3 mL)] was added dropwise and the whole mixture refluxed for 6 h. The reaction mass was cooled, acidified with acetic acid and concentrated under reduced pressure to give a residue which was washed twice with ethyl acetate to afford 2,6-dimethyl-2,5-dihydro-3H-pyrimidin-4-one (460 mg, 60%) as a solid.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Cl.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][Cl:17]>C(O)C>[ClH:17].[C:1]1([S:7][CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: c1ccc(SCc2ccccn2)cc1
Yield: 5.9 %

Procedure:
Thiophenol (21 ml) was added to a solution of sodium (4.6 g) in ethanol (100 ml). To the resulting solution was added 2-picolyl chloride, hydrochloride (15 g) and the mixture was heated at reflux for 2 hours. Precipitated sodium chloride was removed by filtration and the solution was acidified with ethereal HCl. The solvent was removed by evaporation and the residue induced to crystallise by trituration with ether. Recrystallisation from ethanol-ether gave 2-((phenylthio)-methyl)pyridine, hydrochloride (5.0 g) mp 142°-4° C. (Found: C,60.6; H,5.25; N,5.5, C12H11NS,HCl requires C,60.6: H,5.1: N,5.9%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]([NH:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][NH:20][C:19]3=[O:23])[N:8]=2)=[CH:4][CH:3]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>ClCCl.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>[O:23]=[C:19]1[NH:20][CH2:21][CH2:22][N:18]1[CH2:17][CH2:16][NH:15][C:9]1[N:8]=[C:7]([C:5]2[S:6][C:2]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)=[CH:3][CH:4]=2)[C:12]([C:13]#[N:14])=[CH:11][N:10]=1
Reactant: N#Cc1cnc(NCCN2CCNC2=O)nc1-c1ccc(Br)s1
Reactant: OB(O)c1cccs1
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: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1cnc(NCCN2CCNC2=O)nc1-c1ccc(-c2cccs2)s1
Temperature: 130 °C

Procedure:
4-(5-Bromothiophen-2-yl)-2-(2-(2-oxoimidazolidin-1-yl)ethylamino)pyrimidine-5-carbonitrile (0.08 g, 0.2 mmol), thiophen-2-ylboronic acid (0.052 g, 04 mmol), sodium carbonate (1.5 mL of 2 M solution, 1 mmol) were added to a microwave tube containing ethanol (1.5 mL). The tube was flushed with nitrogen and tetrakis(triphenylphosphine)palladium (0.06 g, 0.054 mmol) was added. The tube was capped and heated to 130° C. for 30 min in a Personal Chemistry microwave. The reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, reduced in vacuo and purified by flash chromatography on silica gel using a gradient of 0 to 10% methanol in dichloromethane to afford a yellow solid which recrystallized from ethyl acetate. Yield=0.066 g. MS (M+H)+ 397.
Reaction SMILES: [CH3:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([NH2:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[CH3:21][S:22](Cl)(=[O:24])=[O:23].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([NH:19][S:22]([CH3:21])(=[O:24])=[O:23])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20]
Reactant: Cn1nc(-c2ccc(Cl)c(N)c2)c2ccccc2c1=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1nc(-c2ccc(Cl)c(NS(C)(=O)=O)c2)c2ccccc2c1=O
Reaction time: 8 h
Yield: 78 %

Procedure:
To a mixture of 2-methyl-4-(3-amino-4-chlorophenyl)-1-(2H)-phthalazinone (38.72 g, 0,136 mol), CH2Cl2 (380 mL) and pyridine (75 mL) at 0° C. was added methanesulfonyl chloride (15.75 mL) in CH2Cl2 (75 mL). The reaction mixture was stirred overnight, poured into 1N HCl (400 mL) and stirred for 45 minutes. The mixture was filtered and the filtrate layers were separated. The solid thus obtained was treated with saturated NaHCO3, filtered, stirred with hexane, then filtered, stirred with hot methanol, then filtered and finally stirred with hot ethyl acetate and filtered to afford 38.8 g (78%) of 2-methyl-4-(3-methylsulfonylamino-4-chlorophenyl)-1-(2H)-phthalazinone, m.p. 234°-236° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:4][CH:3]=1.[CH:15](=O)[CH2:16][CH2:17][CH3:18]>>[CH2:15]([NH:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCC=O
Reactant: Nc1cccc(-c2ccc(Cl)cc2)c1
Product: CCCCNc1cccc(-c2ccc(Cl)cc2)c1
Yield: 82.5 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 4′-chlorobiphenyl-3-amine (ChemBridge, 285 mg, 1.40 mmol) and butyraldehyde (125 μL, 1.40 mmol) were converted to the title compound (300 mg, 74%). 1H NMR (CDCl3) δ 7.73-7.62 (m, 2H), 7.57-7.44 (m, 3H), 7.43-7.34 (m, 2H), 7.29-7.19 (m, 1H), 3.04-2.96 (m, 2H), 1.67-1.59 (m, 2H), 1.47 (dd, J=15.1, 7.4 Hz, 2H), 0.99 (t, J=7.3 Hz, 3H); MS (ESI+) m/z 260.2 (M+H)+.