Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])=[O:4].[NH2:17][C:18]1[N:23]=[C:22]([CH:24]2[CH2:26][CH2:25]2)[N:21]=[C:20]([O:27][CH3:28])[N:19]=1>C(Cl)Cl>[CH:24]1([C:22]2[N:21]=[C:20]([O:27][CH3:28])[N:19]=[C:18]([NH:17][C:15]([NH:14][S:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:3]([O:2][CH3:1])=[O:4])(=[O:12])=[O:13])=[O:16])[N:23]=2)[CH2:26][CH2:25]1
Reactant: COc1nc(N)nc(C2CC2)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(C2CC2)n1
Temperature: 25 °C

Procedure:
2.1 g of 2-methoxycarbonylbenzenesulfonylisocyanate are added with stirring, under a nitrogen atmosphere, to a solution of 1.3 g of 2-amino-4-cyclopropyl-6-methoxy-1,3,5-triazine in 10 ml of CH2Cl2. A slight exothermic reaction occurs, which soon however subsides. Stirring is maintained for 14 hours at room temperature, and the solution is then caused to crystallise by the addition of ether. The precipitate is filtered off and dried. The yield is 2.3 g of the above urea, which melts at 166°-168° C.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Cl-].[C:8]([CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[F:33][C:34]1[CH:48]=[CH:47][C:37]([C:38]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=O)=[CH:36][CH:35]=1>O1CCCC1>[F:33][C:34]1[CH:48]=[CH:47][C:37]([C:38]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[CH:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])=[CH:36][CH:35]=1
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(O)CCC=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 69.4 %

Procedure:
The reaction was performed as in Example 87 using sodium hydride (56% dispersion in oil; 9.5 g) dimethylsulfoxide (100 mL), (3-carboxypropyl)triphenylphosphonium chloride (35 g), 4,4'-difluorobenzophenone (23.8 g) and tetrahydrofuran (100 mL). After the usual work up, the crude product was crystallized from ether-hexane to furnish 18.2 g of 5,5-bis(4-fluorophenyl)-4-pentenoic acid, mp 100°-100° C. Anal. Calculated for C17H14F2O2 : C, 70.82; H, 4.89. Found: C, 70.77; H, 5.00.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH2:14]([N:26]=[C:27]=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CCOCC>[CH2:14]([NH:26][C:27]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]([CH3:12])[CH2:11][C:2]1([CH3:13])[CH3:1])=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC1CC(C)(C)Nc2ccccc21
Reactant: CCCCCCCCCCCCN=C=O
Solvent: CCOCC
Product: CCCCCCCCCCCCNC(=O)N1c2ccccc2C(C)CC1(C)C
Temperature: -70 °C
Reaction time: 168 h
Yield: 66 %

Procedure:
0.1 mole of 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline is dissolved in 50 ml of ether and the solution is mixed with 0.1 mole of n-dodecyl isocyanate. A spatula tip of diazadicyclooctane is then added, the mixture is left to stand for 7 days at 20° to 25° C. and cooled at -70° C. and the precipitate which has separated out is filtered off. N-n-Dodecylaminocarbonyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline with a melting point of 48°-50° C. is obtained. Yield: 66% of theory.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.[Cl:22][CH2:23][CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[Cl:22][CH2:23][CH2:24][CH2:25][S:26]([NH:2][C@@H:3]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])(=[O:28])=[O:27]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)CCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](NS(=O)(=O)CCCCl)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-Butyl 2-amino-4-methylpentanoate hydrochloride (0.516 g, 2.306 mmol) were dissolved in dichloromethane (15 mL) and triethylamine (1.061 mL, 7.61 mmol) was added. 3-Chloropropane-1-sulfonyl chloride (0.337 mL, 2.77 mmol) was added dropwise, and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the crude material was taken up in ether, filtered, and concentrated to give (S)-tert-butyl 2-(3-chloropropylsulfonamido)-4-methylpentanoate: 1H NMR (300 MHz, CDCl3) δ ppm 4.70 (d, J=9.7, 1H), 4.02-3.91 (m, 1H), 3.77-3.60 (m, 2H), 3.25-2.96 (m, 3H), 2.31 (tdd, J=2.2, 6.6, 9.2, 2H), 1.83 (dq, J=6.5, 13.0, 1H), 1.58-1.53 (m, 8H), 1.38 (t, J=7.3, 1H), 0.96 (dd, J=2.1, 6.6, 6H); MS (ESI+) m/z 345 (M+NH4)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([O:15]C(=O)CCl)=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:20])[NH:10]2)=[O:4]>Cl>[Cl:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:20])[NH:10]2)=[O:4]
Reactant: O=C(CCl)Oc1ccc(C(=O)CCl)c2ccc(=O)[nH]c12
Agent: Cl
Product: O=C(CCl)c1ccc(O)c2[nH]c(=O)ccc12
Reaction time: 2 h
Yield: 85.5 %

Procedure:
1.7 g of the 5-chloroacetyl-8-chloroacetoxycarbostyril (VI) obtained in Example 5 was added to 50 ml of 10% aqueous hydrochloric acid followed by stirring at 95° to 100° C. for 2 hours. After cooling, the precipitated crystals were filtered, washed with water and then recrystallized from methanol to obtain 1.1 g of 5-chloroacetyl-8-hydroxycarbostyril (IV) having a melting point of 285°-286° C. (with decomposition) as pale yellow crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1.C(N(CC)CC)C>CC#N.O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:13]2[CH2:14][CH2:15][N:10]([C:4]3[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:3]=3[Cl:2])[CH2:11][CH2:12]2)=[CH:19][CH:18]=1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Clc1cccc(N2CCN(Cc3ccc(Br)cc3)CC2)c1Cl
Yield: 55 %

Procedure:
A mixture of intermediate 41 (294 mg, 1.1 mmol), 1-bromo-4-(bromomethyl)benzene (250 mg, 1.0 mmol) and anhydrous triethylamine (253 mg, 2.5 mmol) was dissolved in CH3CN and the solution was heated to reflux for 4 h. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=8:1) to give 1-(4-bromobenzyl)-4-(2,3-dichlorophenyl)piperazine (intermediate 54) (220 mg, 74%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:30][CH2:31][CH3:32])=[N:25][C:26]([CH3:29])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:44])[C:35](=[O:43])[CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:40]3[CH2:39][CH2:38][N:37]([CH2:36][C:35]([N:34]([CH3:44])[CH3:33])=[O:43])[CH2:42][CH2:41]3)=[O:21])[C:10]([C:23]3[C:24]([O:30][CH2:31][CH3:32])=[N:25][C:26]([CH3:29])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1nc(C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN(C)C(=O)CN1CCNCC1
Solvent: CC(=O)N(C)C
Product: CCOc1nc(C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 16) was reacted with N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C31H36N7O3Cl2 [(M+H)+] 624.2251, observed 624.2253.
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]([C:19](=[O:33])[NH:20][C:21]3[CH:22]=[N:23][N:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=4)[CH:25]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:34]([OH:36])=[O:35].C[O-].[Na+:39]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:33])[NH:20][C:21]3[CH:22]=[N:23][N:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=4)[CH:25]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:34]([O-:36])=[O:35].[Na+:39]
Reactant: O=C(Nc1cnn(-c2cccc(Cl)c2)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1cnn(-c2cccc(Cl)c2)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
6-chloro-7-(4-(1-(3-chlorophenyl)-1H-pyrazol-4-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (250 mg, 0.48 mmol) was dissolved in methanol (5 ml) and treated with 0.5 N sodium methoxide in methanol (0.954 ml, 0.48 mmol) at ambient temperature. After 30 minutes, the reaction was concentrated in vacuo, triturated with ethyl acetate and hexanes, and dried under high vacuum to provide the title compound (240 mg, 92%) as a white solid. MS (apci)=526.0 (M-Na+2H)
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH3:13])[C:6]([CH3:12])=[C:7]([CH3:11])[CH:8]=2)[C:3]1=O.[BH4-].[Na+]>>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[C:5]([CH3:13])[C:6]([CH3:12])=[C:7]([CH3:11])[CH:8]=2
Reactant: Cc1cc2c(c(C)c1C)C(=O)C(C)C2
Agent: [BH4-]
Agent: [Na+]
Product: CC1=Cc2c(cc(C)c(C)c2C)C1
Yield: 63.9 %

Procedure:
Analogously to Example D, 1.50 g (8 mmol) of 2,5,6,7-tetramethyl-1-indanone (9) were reduced with 0.45 g (12 mmol) of NaBH4. The alcohol, which was not purified further, was then further reacted in the presence of 0.1 g of p-toluenesulfonic acid in 100 ml of toluene. Chromatography on 100 g of silica gel (hexane/methylene chloride 9:1) gave 0.88 g (65%) of 2,4,5,6-tetramethylindene (10).
Reaction SMILES: [C:1]([N:4]([C@H:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C@@H:18]([CH3:36])[CH2:17]1)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13](O)=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C([N:40](C1C2C(=CC=CC=2)N(C(=O)C2C=CC(OC)=CC=2)C(C)C1)C1C=CC(CCC(O)=O)=CC=1)(=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].CCN(C(C)C)C(C)C>CN(C)C=O>[C:1]([N:4]([C@H:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([C:26](=[O:35])[C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C@@H:18]([CH3:36])[CH2:17]1)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([NH2:40])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C(=O)N2c3ccccc3C(N(C(C)=O)c3ccc(CCC(=O)O)cc3)CC2C)cc1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(CCC(=O)O)cc3)C[C@@H]2C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(CCC(N)=O)cc3)C[C@@H]2C)cc1
Yield: 82 %

Procedure:
(2S,4R)-3-(4-{Acetyl-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-amino}-phenyl)-propionamide was prepared from (2S,4R)-3-(4-{Acetyl-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-amino}-phenyl)-propionic acid. To a solution of 3-(4-{acetyl-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-amino}-phenyl)-propionic acid (21 mg, 0.042 mmol) in dimethylformamide (200 μl) was added HATU (24 mg, 0.063 mmol), HOBt (8.5 mg, 0.063 mmol), NH4Cl (4.5 mg, 0.084 mmol) and DIPEA (29 μl, 0.168 mmol). Upon consumption of the starting unit (2.5 hours), the mixture was diluted with EtOAc (10 ml) and washed with sat. NaHCO3 (4X 10 ml). The EtOAc layer was collected, dried over Na2SO4, filtered, and concentrated to afford the title compound (17.2 mg, 82%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1.CS(Cl)(=O)=O.[N+:14]([C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[CH:22][NH:23]2)=[CH:19][CH:18]=1)([O-:16])=[O:15].N1C2C(=CC=CC=2)C=C1.[H-].[Na+].S([O-])(=O)(=O)C>C(Cl)Cl.CN(C=O)C>[N+:14]([C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[CH:22][N:23]2[CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[N:7][CH:8]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: OCc1cncnc1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2ccn(Cc3cncnc3)c2c1
Temperature: -40 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
5-(Hydroxymethyl)pyrimidine (16.2 g, 147 mmol) was dissolved in 500 mL of CH2Cl2 and cooled to −40° C. MsCl (16.0 g, 140 mmol) was added at 40° C. The mixture was stirred for 1 hour allowing to reach −20° C. The solution was used as such. 6-Nitroindole-1H-indole (35.6 g, 220 mmol) was dissolved in 750 mL of DMF and NaH (50%, 12 g, 250 mmol) was added in portions and the mixture was stirred for 1 hour. The mixture was cooled to −40° C. and the solution of the mesylate was added dropwise. The mixture was allowed to reach room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate (2×). The combined organic layers were washed with water (2×) and brine and dried over Na2SO4. After concentration in vacuo the material was purified by means of column chromatography (silica, heptane/ethyl acetate (1:1)→(1:4)) affording compound the title compound as a yellow solid (14 g, 55 mmol, 39%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11](Cl)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([NH:15][CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:21]3)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2nc(Cl)oc12
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: CC#N
Product: CCOC(=O)N1CCC(Nc2nc3cccc(C(=O)OC)c3o2)CC1
Yield: 95.5 %

Procedure:
To a solution of 2-chloro-benzooxazole-7-carboxylic acid methyl ester (0.43 g, 2.05 mmol, 1.0 equiv) in acetonitrile (30 mL) was added ethyl 4-amino-1-piperidine carboxylate (0.64 g, 3.08 mmol, 1.5 equiv) and the reaction mixture heated to reflux for 30 min. The solvent was removed under reduced pressure and the crude material purified with column chromatography on silica eluting with dichloromethane/methanol (4:1) to afforded 0.68 g (95%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.19 (t, J=7.0 Hz, 3H), 1.38-1.51 (m, 2H), 1.95-2.00 (m, 2H), 2.96-3.03 (m, 2H), 3.78-3.81 (m, 1H), 3.89 (s, 3H), 3.82-3.96 (m, 2H), 4.04 (q, J=7.0 Hz, 2H), 7.23 (t, J=7.9 Hz, 1H), 7.50 (dd, J=7.9 Hz, J=1.9 Hz, 2H), 8.34 (d, J=7.3 Hz, 2H). 13C NMR (75 MHz, DMSO): δ 14.54, 31.01, 42.04, 49.71, 52.05, 60.63, 112.36, 119.98, 121.27, 123.51, 144.77, 147.00, 154.57, 162.13, 164.17. MS (ISP): 347.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C@H:23]3[CH2:28][CH2:27][C@H:26]([C:29]4[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=4)[CH2:25][CH2:24]3)[N:21]=[CH:22][C:15]=12.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C@H:23]3[CH2:28][CH2:27][C@H:26]([C:29]4[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=4)[CH2:25][CH2:24]3)[N:21]=[CH:22][C:15]=12
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Reactant: CC(C)c1noc([C@H]2CC[C@H](n3ncc4c(Cl)ncnc43)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1noc([C@H]2CC[C@H](n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5F)ncnc43)CC2)n1
Temperature: 180 °C

Procedure:
A mixture of 2-fluoro-4-methanesulfonyl-phenol (Intermediate 1; 93 mg, 0.49 mmol), 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-trans-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 26; 170 mg, 0.49 mmol) and potassium carbonate (81 mg, 0.59 mmol) in anhydrous DMF (5 mL) was heated in a microwave at 180° C. for 10 min. The mixture was filtered. The filtrate was concentrated and purified using a Supelco 23 g column, eluting with 0-3% methanol/dichloromethane to give 4-(2-fluoro-4-methanesulfonyl-phenoxy)-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-trans-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (153 mg, 62%).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][Cl:12].C1COCC1>O>[Cl:12][CH2:11][CH2:10][CH2:9][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCBr
Reactant: Sc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: ClCCCSc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 112.5 %

Procedure:
A mixture of benzenethiol (0.550 9, 5.00 mmol), 1-bromo-3-chloropropane (106 mg, 5.50 mmol), TEA (1.01 g, 10.0 mmol) and THF (10.0 mL) was stirred for 12 h at 25° C. The resulting crude mixture was diluted with water (40 mL), the aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using hexane:EtOAc (10:1) to give the desired product [(3-chloropropyl)sulfanyl]benzene (1.05 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH2:25])[CH2:11][CH2:10]1.N[C:28](N)=[O:29].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:18](=[O:26])[C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:25][C:28]2=[O:29])[CH2:11][CH2:10]1
Reactant: NC(N)=O
Reactant: COc1ccccc1N1CCN(CCNC(=O)c2ccccc2N)CC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)CC1
Yield: 92.1 %

Procedure:
1-(2-Methoxyphenyl)-4-[2-(2-aminobenzoyl)aminoethyl]piperazine (3.54 g) and urea (1.2 g) were dissolved in dimethylformamide (20 ml) and the resulting solution was heated at an external temperature of 140° to 180° C. for 5 to 8 hours. After completion of the reaction, water (200 ml) was added to the reaction mixture and the resulting crystal was filtered off. Upon recrystallization from dioxane, 3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]2,4-(1H,3H)-quinazolinedione (3.5 g) was obtained as needles. Its physicochemical data was the same as that of the product obtained in (a).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([C:24]2[C:33]([OH:34])=[C:32]3[C:27]([CH:28]=[CH:29][CH:30]=[N:31]3)=[C:26]([Cl:35])[CH:25]=2)[NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1)=[O:4].[CH3:36][NH:37][CH3:38]>>[Cl:35][C:26]1[CH:25]=[C:24]([CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:37]([CH3:38])[CH3:36])[CH:11]=[CH:10][CH:9]=2)[C:33]([OH:34])=[C:32]2[C:27]=1[CH:28]=[CH:29][CH:30]=[N:31]2
Reactant: CNC
Reactant: O=C(CCl)Nc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Product: CN(C)CC(=O)Nc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Yield: 46 %

Procedure:
A solution of 2-chloro-N-(3-{(5-chloro-8-hydroxyquinolin-7-yl)[(phenoxyacetyl)amino]methyl}phenyl)acetamide (100 mg, 0.20 mmol) and dimethylamine (2M/THF, 10 eq.) was heated at 45 C for 18 h. The solvent was removed in vacuo, the residue was dissolved in methylene chloride and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 48 mg (46%) of N-(3-{(5-chloro-8-hydroxyquinolin-7-yl)[(phenoxyacetyl)amino]methyl}phenyl)-N2,N2-dimethylglycinamide as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][CH2:25][N:13]3[C:14](=[O:24])[C:15]=2[O:16]CC2C=CC=CC=2)=[O:9])=[C:4]([N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[CH:3]=1.FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][CH2:25][N:13]3[C:14](=[O:24])[C:15]=2[OH:16])=[O:9])=[C:4]([N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[CH:3]=1
Reactant: CC1(C)CCCn2c1nc(C(=O)NCc1ccc(F)cc1-n1cncn1)c(OCc1ccccc1)c2=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCCn2c1nc(C(=O)NCc1ccc(F)cc1-n1cncn1)c(O)c2=O

Procedure:
Intermediate 13, N-(4-fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide was treated with trifluoroacetic acid, according to Method D to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm: 11.66 (1H, br), 8.88 (1H, t, J=6.2 Hz), 8.44 (1H, s), 8.18 (1H, s), 7.67 (1H, dd, J=8.4, 5.9 Hz), 7.18 (1H, dt, J=8.2, 2.6 Hz), 7.09 (1H, dd, J=8.4, 2.6 Hz), 4.43 (2H, d, J=7.0 Hz), 3.95 (2H, t, J=6.4 Hz), 1.88–2.00 (2H, m), 1.69–1.76 (2H, m), 1.37 (6H, s); HRMS (ESI) calcd for C20H22FN6O3 (M+H) 413.1737, found 413.1719.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[N:27]1[S:28][N:29]=[C:30]2[CH:35]=[C:34]([CH2:36][N:37]3[CH2:41][CH2:40][N:39]([C:42]4[S:43][C:44]([C:48]([OH:50])=O)=[C:45]([CH3:47])[N:46]=4)[C:38]3=[O:51])[CH:33]=[CH:32][C:31]=12.[NH2:52][CH2:53][C:54]1[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=1>>[N:27]1[S:28][N:29]=[C:30]2[CH:35]=[C:34]([CH2:36][N:37]3[CH2:41][CH2:40][N:39]([C:42]4[S:43][C:44]([C:48]([NH:52][CH2:53][C:54]5[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=5)=[O:50])=[C:45]([CH3:47])[N:46]=4)[C:38]3=[O:51])[CH:33]=[CH:32][C:31]=12
Reactant: Cc1nc(N2CCN(Cc3ccc4nsnc4c3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc4nsnc4c3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 44 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(benzo[c][1,2,5]thiadiazol-5-ylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 44% yield: mp 105-107° C. (dichloromethane/hexanes): 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.50-8.48 (m, 1H), 7.96-7.93 (m, 1H), 7.71-7.68 (m, 1H), 7.57-7.55 (m, 2H), 7.29-7.24 (m, 1H), 6.18 (br s, 1H), 4.96 (s, 2H), 4.57 (d, J=5.8 Hz, 2H), 4.09-4.04 (m, 2H), 3.68-3.62 (m, 2H), 2.58 (s, 3H); MS (ES+) m/z 466.2 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:20]3[CH:19]=[CH:18][C:17]([C:21]4[NH:25][C:24](=[O:26])[O:23][N:22]=4)=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:3][CH2:2]1.C(O)([C:29]([F:32])([F:31])[F:30])=O.N1CCC(N2C3C=CC(C4NN=NN=4)=CC=3OC3C2=CC=CC=3)CC1.[CH:59]1[CH:64]=[C:63]([CH:65]=O)[N:62]=[CH:61][CH:60]=1.N1C=CN=C1C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>>[N:62]1[CH:61]=[CH:60][CH:59]=[CH:64][C:63]=1[CH2:65][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:20]3[CH:19]=[CH:18][C:17]([C:21]4[NH:25][C:24](=[O:26])[O:23][N:22]=4)=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:5][CH2:6]1.[C:24]([OH:23])([C:29]([F:32])([F:31])[F:30])=[O:26]
Reactant: O=c1[nH]c(-c2ccc3c(c2)Oc2ccccc2N3C2CCNCC2)no1
Reactant: O=Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Agent: O=Cc1ncc[nH]1
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(-c2ccc3c(c2)Oc2ccccc2N3C2CCN(Cc3ccccn3)CC2)no1

Procedure:
Using an adaptation of the method described in Procedure 7, substituting the TFA salt of 3-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-4H-[1,2,4]oxadiazol-5-one, 2b for the TFA salt of 10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a, 2-pyridylcarboxaldehyde for 1H-imidazole-2-carboxaldehyde and sodium triacetoxyborohydride for tetramethylammonium triacetoxyborohydride, the title compound 3-[10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4]oxadiazol-5-one, 6b was obtained as a TFA salt after purification via reverse phase HPLC (eluent: CH3CN in H2O containing 0.1% TFA). MS m/z (MH+) 441.9.