Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C@H:3]1[NH2:12].O.[C:14](=S)=[S:15]>C(O)C>[NH:1]1[C@@H:2]2[C:11]3[C:6]([CH2:5][CH2:4][C@H:3]2[NH:12][C:14]1=[S:15])=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: S=C=S
Reactant: N[C@@H]1CCc2ccccc2[C@H]1N
Solvent: CCO
Solvent: O
Product: S=C1N[C@@H]2c3ccccc3CC[C@H]2N1
Temperature: 25 °C
Yield: 60 %

Procedure:
Trans-1,2-diamino-1,2,3,4-tetrahydronaphthalene (461 mg, 2.84 m mol) was dissolved in ethanol (8 ml), water (4 ml) was added to the solution, then carbon disulfide (190 μl, 3.17 m mol) was added thereto under stirring at room temperature. The mixture was heated under reflux for 4 hours and cooled in an ice-water bath. The crystals precipitating out were separated by filtration, washed with ether and dried in vacuum to give trans-3a,4,5,9b-tetrahydronaphth[1,2-d]imidazoline-2-thione (350 mg, 1.71 m mol) in 60% yield. The data spectroscopy and elemental analysis were as follows:
Reaction SMILES: [O:1]1[CH2:6][C:5](=S)[NH:4][C:3](=[O:8])[NH:2]1.[CH2:9]([NH2:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:9]([NH:27][C:5]1[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=1)[CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Reactant: O=C1NOCC(=S)N1
Product: CCCCCCCCCCCCCC=CCCCNC1=NC(=O)NOC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 16.4 %

Procedure:
To 0.66 g (0.005 mole) of 6H-1,2,4-oxadiazin-3(2H)-one-5(4H)-thione dissolved in 10 ml of freshly distilled dry dioxane is added 1.33 g (0.0051 mole) of oleylamine. The reaction mixture is stirred for 17 hours at room temperature and the crystalline material filtered, washed with additional dry dioxane and chloroform, and dried to give 0.3 g (16 percent) of 5-(4-octadecenylamino)-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][NH:48][C@H:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH3:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:48]([CH3:47])[C@H:49]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH3:50])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CN[C@@H](C)c1ccccc1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)[C@@H](C)c2ccccc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with N-methyl-N-((S)-1-phenyl-ethyl)amine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C45H54Cl2N5O3 [(M+H)+] 782.3598, observed 782.3596.
Reaction SMILES: [NH:1]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:5](=[O:6])[NH:4][C:2]1=[O:3].FC(F)(F)C(O[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=O>N1C=CC=CC=1>[OH:3][C:2]1[N:4]=[C:5]([OH:6])[C:7]([C:9]([O:11][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[O:10])=[CH:8][N:1]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: O=C(O)c1c[nH]c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cnc(O)nc1O
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
Uracil-5-carboxylic acid (1.0 g) is dissolved in dry pyridine (20 ml) under heating. p-Nitrophenyl trifluroacetate (1.8 g) is added to the solution which is subsequently stirred at 45° C for 30 minutes. Then, the solution is concentrated to dryness under reduced pressure, and the cyrstals thus obtained are washed with chloroform and then acetone to give the active ester, i.e. p-nitrophenyl 2,4-dihydroxypyrimidine-5-carboxylate (1.16 g). M.P. 298°-299° C (decomp.).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1.CC1(C)C(C)(C)[O:15][B:14](B2OC(C)(C)C(C)(C)O2)[O:13]1.C([O-])(=O)C.[K+].C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[ClH])(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:9]1[C:5]2[CH:4]=[CH:3][C:2]([B:14]([OH:15])[OH:13])=[CH:10][C:6]=2[N:7]=[CH:8]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Clc1ccc2ocnc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Product: OB(O)c1ccc2ocnc2c1
Temperature: 80 °C

Procedure:
A mixture of 5-chlorobenzoxazole (0.129 g, 0.84 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (0.4956 g, 1.95 mmol), potassium acetate (0.41 g, 4.2 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene hydrochloride (43 mg, 0.10 mmol) and palladium acetate (11 mg, 0.05 mmol) was degassed, treated with tetrahydrofuran (10 mL) and the resulting mixture heated at 80° C. overnight. The mixture was diluted with water (100 mL), acidified to pH 6 and extracted with EtOAc (3×40 mL). The extracts were washed with water, dried and concentrated in vacuo. The residue so obtained was purified by chromatography over silica gel eluting with DCM to 10% MeCN/DCM to afford 1,3-benzoxazole-5-boronic acid, pinacol ester. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37-1.39 (m, 12 H) 7.59 (d, J=8.34 Hz, 1 H) 7.86 (dd, J=8.08, 1.01 Hz, 1 H) 8.10 (s, 1 H) 8.26 (s, 1 H); MS (ES+): m/z 246.23 [MH+].
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[NH2:16])(=[O:4])[CH3:3].[C:17]([O:20][CH:21]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C:22](O)=[O:23])(=[O:19])[CH3:18].C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.O1CCOCC1>[C:2]([NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[NH:16][C:22](=[O:23])[CH:21]([O:20][C:17](=[O:19])[CH3:18])[CH2:25][O:26][C:27](=[O:29])[CH3:28])(=[O:4])[CH3:3]
Reactant: COC(=O)c1ccc(NC(C)=O)c(N)c1
Reactant: CC(=O)OCC(OC(C)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(C)=O)c(NC(=O)C(COC(C)=O)OC(C)=O)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
Compound 16 (0.12 g, 0.57 mmol) was dissolved in a mixture of DMF (2 mL) and dioxane (3 mL) and cooled to 0° C. A solution of 2,3-diacetoxypropionic acid (0.220 g, 1.15 mmol) in dioxane (3 mL) was added followed by the addition of dicyclohexylcarbodiimide (0.195 mL, 0.183 g, 0,870 mmol). The resulting reaction mixture was stirred for 3 hours, initially at 0° C. with slow warming to room temperature. The solid dicyclohexylurea which separated was filtered and the filtrate was concentrated to dryness on a rotary evaporator. The solid residue was filtered and washed on the filter with 5% HCl (5 mL), water (5 mL), 5% NaHCO3 (5 mL), and again with water (2×10 mL). This was dried under vacuum to give 18 (200 mg, 91.3%) as a white solid: mp 130°-134° C.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[CH2:41][NH2:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[CH2:41][NH:42][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:30])([F:29])[F:31])[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: NCc1nc2ccccc2[nH]1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCc1nc2ccccc2[nH]1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 50 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), (1H-benzo[d]imidazol-2-yl)methanamine (10.24 mg, 0.070 mmol), HATU (22.92 mg, 0.060 mmol), and 4-methylmorpholine (18.76 mg, 0.185 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-N-((1H-benzo[d]imidazol-2-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (12.8 mg, 0.023 mmol, 49.3% yield): LCMS=561.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.19 (2 H, d, J=8.58 Hz), 7.51-7.79 (10 H, m), 7.34 (2 H, dd, J=6.05, 3.19 Hz), 5.27 (1 H, s), 4.76-4.94 (2 H, m); HPLC peak RT=2.6 min (Method E).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[S:13][C:14]4[CH2:15][NH:16][CH2:17][CH2:18][C:19]=4[N:20]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>ClCCl>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([O:11][C:12]3[S:13][C:14]4[CH2:15][N:16]([C:28](=[O:31])[CH2:29][CH3:30])[CH2:17][CH2:18][C:19]=4[N:20]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: C1CC(N2CCC(Oc3nc4c(s3)CNCC4)CC2)C1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCc2nc(OC3CCN(C4CCC4)CC3)sc2C1
Yield: 71.5 %

Procedure:
A solution of 2-(1-Cyclobutyl-piperidin-4-yloxy)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine (1.3 grams, 4 mmol, obtained in above step) and triethylamine (1.9 mL, 13 mmol) in dichloromethane (30 mL) was cooled to 0° C. Propionylchloride (0.4 mL, 5 mmol) in dichloromethane (5 mL) was added drop wise over a period of 15 minutes and stirred the reaction for 30 minutes. Reaction mass was poured onto ice cold water and the product was extracted with ethyl acetate (3×50 mL). Combined organics were washed with water followed by brine and dried over anhydrous sodium sulphate. Organic volatiles were evaporated under vacuum. The residue was purified by flash chromatography (methanol/chloroform, 2/98) to obtain the title compound (1.0 gram).
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]([C:24]([OH:26])=[O:25])[C:11](=[CH:15][C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(OC(C)=O)=O>[NH:17]([C:16]1[CH:15]=[C:11]2[C:12](=[O:14])[O:26][C:24](=[O:25])[C:10]2=[CH:9][C:8]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc(Nc2ccccc2)c(Nc2ccccc2)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc21

Procedure:
A solution of 2 g of 4,5-dianilino-phthalic acid (Example 1'b)) in acetanhydride is heated to 60° C. for 30 min, resulting in a strong yellow colouring of the reaction mixture. After evaporation, yellow crystals of the crude title compound remain which are recrystallized from acetone/diethyl ether; the title compound has a m.p. of 196°-197° C. C20H14N2O3 : molecular weight calculated 330, found 330 (FD-MS).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([OH:17])=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:18][C@H:19]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20]1>>[C:26]1([CH2:25][CH2:24][N:21]2[CH2:22][CH2:23][C@H:19]([NH:18][C:15]([CH:13]3[C:14]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:6][C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)=[O:17])[CH2:20]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=C(O)C1c2ccccc2Sc2ccccc21
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C1c2ccccc2Sc2ccccc21

Procedure:
9-Thioxanthenylcarboxylic acid and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-9-thioxanthenylcarboxamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](F)[N:17]=2)=[CH:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[NH2:23][CH2:24][C@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1>CS(C)=O>[NH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([NH:8][C:5]2[CH:4]=[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:23][CH2:24][C@H:25]4[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]4)[N:17]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CN)C1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cccc(F)n3)c(Cl)cn2)CC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](CNc2cccc(-c3cc(N[C@H]4CC[C@H](N)CC4)ncc3Cl)n2)C1
Temperature: 102.5 °C
Reaction time: 40 h

Procedure:
A mixture of trans-N1-(5′-chloro-6-fluoro-2,4′-bipyridin-2′-yl)cyclohexane-1,4-diamine (Example 1a, step 2) (50 mg, 0.156 mmol), DMSO (0.75 ml), (R)-tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (167 mg, 0.779 mmol) and TEA (0.033 ml, 0.234 mmol) was stirred at 100-105° C. for 40 hours and the reaction progress was followed by LCMS. The reaction mixture was let cool, added 0.75 ml of DMSO, filtered and purified by prep LC, and lyapholized to yield 36 mg of titled compound as a TFA salt. LCMS (m/z): 515.4 (MH+), retention time=0.64 min.;
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:29]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:28]=[CH:27][C:26]([S:23]([N:22]2[CH2:21][CH2:20][S:19][CH:18]2[C:16]([NH:15][CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:17])(=[O:24])=[O:25])=[CH:31][CH:30]=1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Product: O=C(NC(CCN1CCCCC1)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method A as outlined in Example 16, starting from 3-({[3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and piperidine, the title compound was obtained in 99.5% purity by HPLC.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:22][CH2:23][N:24]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:25][CH2:26]4)=[CH:19][CH:20]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)s1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)n2)s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.7 %

Procedure:
A mixture of [4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-piperazin-1-yl-phenyl)-amine (86 mg, 0.23 mmol) in anhydrous CH2Cl2 (2 mL) was added Et3N (39 μL, 0.28 mmol). After cooling to 0° C., methanesulfonyl chloride (22 μL, 0.28 mmol) was added dropwise. After 15 min stirring, the reaction mixture was warmed to room temperature and stirring was continued for 18 h. After evaporation, the residue was purified by SiO2 chromatography (98:2 to 95:5 EtOAc/2 M NH3 in MeOH) to afford the title compound (61 mg) as a yellow solid. 1H-NMR (CDCl3) δ: 2.69 (s, 3H, CH3), 2.71 (s, 3H, CH3), 2.84 (s, 3H, CH3), 3.26 (t, 4H, J=5.1 Hz, CH2), 3.41 (t, 4H, J=5.1 Hz, CH2), 6.91 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 6.98 (d, 2H, J=8.8 Hz, Ph-H), 7.10 (br. s, 1H, NH), 7.56 (d, 2H, J=8.8 Hz, Ph-H), 8.30 (d, 1H, J=5.1 Hz, pyrimidinyl-H). MS (ESI+) m/z 446 (C20H24N6O2S2 requires 444.6).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[CH3:24][O:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28](=[O:31])[CH2:29]Br>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:29]=1[C:28](=[O:31])[C:27]1[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=1[O:25][CH3:24]
Reactant: COc1ccccc1C(=O)CBr
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2ccccc2OC)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-methoxyphenacyl bromide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[N:13]=[C:14]=[O:15].[CH3:16][N:17]([CH2:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]2[CH:32]=[C:31]([NH:33][CH3:34])[N:30]=[CH:29][N:28]=2)[CH:23]=[CH:24][CH:25]=1)[CH3:18].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=[O:15])[N:33]([C:31]1[CH:32]=[C:27]([NH:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][N:17]([CH3:16])[CH3:18])[CH:21]=2)[N:28]=[CH:29][N:30]=1)[CH3:34]
Reactant: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Reactant: CNc1cc(Nc2cccc(CN(C)C)c2)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3cccc(CN(C)C)c3)ncn2)c1Cl
Temperature: 70 °C
Reaction time: 18 h

Procedure:
2,6-dichloro-3,5-dimethoxyphenylisocyanate (1.25 eq.) is added to a solution of N-(3-dimethylaminomethyl-phenyl)-N′-methyl-pyrimidine-4,6-diamine (93 mg, 0.36 mmol, 1 eq.) in toluene (3 ml), at 70° C. and under an argon atmosphere. The resulting mixture is stirred at 70° C. for 18 h, allowed to cool to RT, and diluted with DCM and a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the crude product by silica gel column chromatography (DCM/MeOH+1% NH3aq, 9:1) affords 121 mg of the title compound as a white solid: ESI-MS: 504.9/506.9 [MH]+; tR=3.64 min (purity: 100%, gradient J); TLC: Rf=0.12 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4=[CH:23][S:24][CH:25]=[C:19]4[NH:18][C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:29]([N:18]1[C:19]2=[CH:25][S:24][CH:23]=[C:20]2[C:21](=[O:22])[N:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)[CH2:9][CH2:10]2)[C:17]1=[O:26])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3cscc3c2=O)CC1
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)c3cscc3n(C(=O)c3ccccc3)c2=O)CC1

Procedure:
The title compound was prepared by the procedure of Example 11 using 2.0 g (5 mmol) of 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]thieno[3,4-d]pyrimidine-2,4-dione and benzoyl chloride (840 mg, 6 mmol). The named compound (481 mg, 19% yield) was obtained after recrystallization from CH2Cl2 /hexane, mp 153.5°-155° C.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][O:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]1([C:7]2[CH2:8][O:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([CH:23]=[CH:24][C:25]([NH:37][S:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:36])=[O:35])=[O:26])=[CH:21][CH:22]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)COc3ccccc32)cc1
Product: O=C(C=Cc1ccc(C2=C(c3ccccc3)COc3ccccc32)cc1)NS(=O)(=O)c1ccccc1

Procedure:
Prepared by coupling 3d and benzene sulfonamide in accordance with Procedure 1, Method A described hereinabove. Yield (46%); ESI m/z: 492 (M−H−, 100%).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[NH:13][N:12]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[O:21]=[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([CH2:10][NH:9][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:12][NH:13]1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1n[nH]c(=O)c2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1n[nH]c(=O)c2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
Triethylamine (5.9 ml, 42 mmol) was added dropwise to a stirred suspension of 4-aminomethyl-2H-phthalazin-1-one hydrochloride (Geterotsikl. Soedin, 1972, (9), 15) (3.00 g, 14.2 mmol) in DMF (150 ml) at room temperature under nitrogen. The mixture was stirred for 1.5 h before the addition of benzoyl chloride (2.5 ml, 22 mmol) and then stirred at room temperature overnight. The reaction mixture was filtered and water added to the filtrate to form a solid. The mixture was cooled and the solid collected by filtration, washed successively with diethyl ether and isohexane, and dried in vacuo to give the title-compound (3.18 g, 80%), 1H NMR (360 MHZ, d6-DMSO) δ 4.81 (2H, d, J=5.6 Hz, CH2), 7.43-7.53 (3H, m, 3 of Ar—H), 7.83-7.96 (4H, m, 4 of Ar—H), 8.08 (1H, d, J=7.9 Hz, Ar—H), 8.28 (1H, dd, J=7.8 and 1.2 Hz, Ar—H), 8.98 (1H, br s, NH), 12.62 (1H, s NH).
Reaction SMILES: ON1C2N=CC=CC=2N=N1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=2)[CH:19]=[CH:18]1.O>CN(C=O)C>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:27])[CH:24]=2)[CH:19]=[CH:18]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Reaction time: 16 h

Procedure:
1-Hydroxy-7-azabenzotriazole (0.844 g, 6.21 mmol, 0.05 eq), EDCxHCl (26.09 g, 136.64 mmol, 1.1 eq) and morpholine (12.9 g, 149.06 mmol, 1.2 eq) were added to a stirred solution of 1H-indole-6-carboxylic acid (20.0 g, 124.22 mmol, 1.0 eq) in DMF (150 mL). Stirring was continued for 16 h at room temperature and water (200 mL) was then poured into the reaction mixture. The mixture was extracted with dichloromethane (2×150 mL) and the combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulphate and evaporated. White solid. Yield: 16.0 g (56% of theory).