Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:46])[CH2:7][N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:26][C:27]2[N:28]=[N:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:31][CH:32]=2)[NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[N:10]=1)(C)(C)C.[ClH:47].O1CCOCC1>C(Cl)Cl>[ClH:47].[C:33]1([C:30]2[N:29]=[N:28][C:27]([CH2:26][CH:15]([NH:16][S:17]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)(=[O:19])=[O:18])[C:11]3[N:10]=[C:9]([NH:8][CH2:7][C:6]([OH:46])=[O:5])[CH:14]=[CH:13][CH:12]=3)=[CH:32][CH:31]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-c3ccccc3)nn2)NS(=O)(=O)c2cccnc2)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)CNc1cccc(C(Cc2ccc(-c3ccccc3)nn2)NS(=O)(=O)c2cccnc2)n1
Reaction time: 23 h

Procedure:
To a solution of tert-butyl(tert-butoxycarbonyl{6-[(6-phenylpyridazin-3-ylmethyl)(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetate (150 mg, 0.232 mmol) obtained in Example 1-(b) in methylene chloride (9.2 ml) was added a 4N hydrogen chloride/1,4-dioxane solution (2.3 ml), and the mixture was left at room temperature for 23 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to afford the title compound (144 mg) substantially quantitatively as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([O:10][C:11](=[O:25])[CH:12]([CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13](=O)[CH3:14])[CH3:9].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.CCOCC>[CH2:8]([O:10][C:11]([C:12]1[CH:16]=[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[C:13]=1[CH3:14])=[O:25])[CH3:9]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: Nc1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccnc2)c1C

Procedure:
3-Aminopyridine (5 mmol, 0.5 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g) and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was resuspended in ether, then washed with water and brine. The organic layer was dried over MgSO4, then the solids were separated and the solvents were removed under vacuum. The named product was purified over silica gel and analyzed by 1H-NMR (CDCl3, ppm): 1.35 t (3H), 2.40 s (3H), 4.3 q (2H), 6.78 s (1H), 7.03-7.39 m (7H), 8.4 sd (1H), and about 8.6 dd (1H).
Reaction SMILES: [C:1]([S:9][C@@H:10]1[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[O:12][C@H:11]1[N:18]1[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]1=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>N1C=CC=CC=1>[Si:31]([O:17][CH2:16][C@H:13]1[O:12][C@@H:11]([N:18]2[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@H:10]([S:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@@H:14]1[OH:15])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(S[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O)c1ccccc1
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](SC(=O)c2ccccc2)[C@@H]1O

Procedure:
2'-Deoxy-2'-(benzoylthio)uridine (2.75 mmole) was dried by co-evaporation with dry pyridine (2×20 ml) and dissolved in dry pyridine (50 ml) containing imidazole (5 mmole); tert-butyldimethylsilyl chloride (5 mmole) was added with stirring. The reaction mixture was stirred at room temperature for 16 hr. Solvent was removed under vacuo and the residue was dissolved in CH2Cl2 (100 ml), washed with 5% sodium bicarbonate solution (2×50 ml) and dried over anhydrous sodium sulfate. Removal of solvent gave crude product 5'-O-(tert-butyldimethylsilyl)-2'-deoxy-2'-(benzoylthio) uridine which was purified on silica gel column chromatography.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][S:37]([NH:40][CH3:41])(=[O:39])=[O:38])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([C@H:30]2[CH2:31][CH2:32][C@H:33]([CH2:36][S:37]([NH:40][CH3:41])(=[O:38])=[O:39])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: CNS(=O)(=O)C[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reactant: C[C@@H](O)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: CNS(=O)(=O)C[C@H]1CC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (25.8 mg, 0.290 mmol) and triethyloxonium tetrafluoroborate (51.9 mg, 0.273 mmol) in tetrahydrofuran (0.40 mL) was stirred at room temperature for 1 h. After evaporated to dry under reduced pressure, the clear oil was mixed with ethanol (0.20 mL, 3.4 mmol) and added to a solution of 1-{trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}-N-methylmethanesulfonamide (32 mg, 0.090 mmol) in ethanol (0.60 mL) in a microwave vial. The mixture was then heated at 80° C. for 1 h. The mixture was concentrated under reduced pressure. The resultant residue was purified using prep-LCMS (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 (9.8 mg, 26%). LCMS calculated for C18H25N4O3S2 (M+H)+: m/z=409.1. Found: 409.1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]([F:22])=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:23][O:24][NH:25][CH3:26]>>[F:22][C:15]1[CH:16]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:11]2[O:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:25]([O:24][CH3:23])[CH3:26])=[CH:4][CH:5]=3)=[N:13][C:12]=2[CH:14]=1
Reactant: CNOC
Reactant: COC(=O)c1cc(F)cc2nc(-c3ccc(CBr)cc3)oc12
Product: COC(=O)c1cc(F)cc2nc(-c3ccc(CN(C)OC)cc3)oc12
Yield: 84 %

Procedure:
Following the experimental procedure as described in Example 144 C, and replacing methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-4-carboxylate with methyl 2-(4-(bromomethyl)phenyl)-5-fluorobenzo[d]oxazole-7-carboxylate and substituting dimethylamine with methoxy(methyl)amine, methyl 5-fluoro-2-(4-((methoxy(methyl)amino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (Yield: 84%. LC-MS (ESI) m/z: 345 (M+1)+) was made.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH:29][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][CH:13]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)c1cccc(C(=O)Cl)c1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2cccc(S(C)(=O)=O)c2)sc1C(=O)NCc1ccccc1
Yield: 15 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3-methanesulfonylbenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 15% yield; m.p. 111-113° C.; 1H NMR (CD3OD, 300 MHz) δ 8.55 (t, J=5.8 Hz, 1H), 8.09 (dd, J=1.2, 7.6 Hz, 1H), 7.36-7.19 (m, 2H), 7.68 (dd, J=1.2, 7.6 Hz, 1H), 7.27 (m, 5H), 4.50 (d, J=1.9 Hz, 2H), 3.33 (s, 3H), 2.52 (s, 3H); MS (ES+) m/z 430.1 (M+1).
Reaction SMILES: [SH:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=1.C[O-].[Na+].Cl[CH2:15][C:16]#[N:17]>CO>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][C:4]([CH3:10])=[CH:5][CH:6]=2)[S:1][C:15]=1[C:16]#[N:17]
Reactant: N#CCCl
Reactant: Cc1ccc(C#N)c(S)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2c(N)c(C#N)sc2n1

Procedure:
To a solution of 7.5 g. (0.05 mole) of 2-mercapto-3-cyano-6-methylpyridine in 200 ml. of MeOH was added 5.4 g. (0.1 M) sodium methoxide. Stirring was continued until all dissolved. 8.0 g. (0.1 M) of chloroacetonitrile in 20 ml. methanol was then added and the mixture was refluxed for 6 hours. After removal of the solvent, the residue was diluted with water and filtered. The crude product was crystallized from methanol, m.p. 241°-242° C. (Offin No. 2,241,717 in 3/4/74 reported m.p. 241°-243°).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH3:18]O>>[CH3:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([O:10][CH3:18])=[O:9]
Reactant: CO
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])ccc1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To methanol (150 ml) at 0° C. under nitrogen was added dropwise thionyl chloride (4.0 ml, 54.8 mmol) over 2 min. The mixture was stirred at 0° C. for 15 min, before adding a solution of 2-methyl-5-nitrobenzoic acid (4.99 g, 27.5 mmol) in methanol (50 ml) by cannula over 5 min. The mixture was then allowed to warm to room temperature before heating at 50° C. for 18 h under nitrogen. The solvents were evaporated in vacuo and the residue stirred with water (100 ml) and dichloromethane (100 ml). The aqueous layer was basified with potassium carbonate, separated and reextracted with more dichloromethane (100 ml). The two organic extracts were combined, dried (MgSO4), and evaporated in vacuo to leave the title compound (5.24 g, 98%) as a white solid. 1H NMR (360 MHz, CDCl3) δ 2.72 (3H, s), 3.96 (3H, s), 7.44 (1H, d, J=8.3 Hz), 8.24 (1H, dd, J=8.4 and 2.6 Hz), 8.78 (1H, d, J=2.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:19][CH3:20])[C:12]2([C:15]([O:17]C)=[O:16])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.O[Li].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:19][CH3:20])[C:12]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCN(C1(C(=O)OC)CC1)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Compound 14B (750 mg, 2.36 mmol) dissolved in THF (10 ml) and water (5 ml) was added with LiOH.H2O (3 equiv., 297 mg) and the reaction was stirred at rt 3 hours. The reaction was concentrated under vacuum. Water was added and 10% HCl till precipitation of the acid. The acid was extracted with ethyl acetate and the organic phase was washed with Brine, dried over sodium sulfate and concentrated under vacuum to give 650 mg of 15B as a white solid. Yield=90%. 1HNMR (DMSO, 200 MHz) δ 1.06 (3H, t, J=7.2 Hz), 1.38 (2H, m), 1.35 (2H, bs), 3.33 (2H, m), 7.43 (2H, m), 7.77 (2H, m), 12.46 (1H, bs)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[C:25]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:32]3[CH:33]=[CH:34][C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:30][CH:31]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(C(C)(C)C)cc3)c1)N2
Temperature: 120 °C
Yield: 49.2 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.50 g, 1.29 mmol), 4-tert-butylbenzeneboronic acid (0.46 g, 2.58 mmol), bis(triphenylphosphine)palladium (II) chloride (91 mg, 0.13 mmol) and 2 M sodium carbonate (1.3 mL, 2.6 mmol) in dioxane (5 mL) was heated for 3 hours at 120° C. After cooling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(10% ethyl acetate/hexanes) to afford 2-(4′-tert-butyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.28 g, 49%) as a white solid: LC/MS m/e calcd for C30H35NO2 (M+H)+: 442.6, observed: 442.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:18][C:19]1[N:20]=[C:21]([N:13]2[CH2:12][CH2:11][N:10]([C:7]3[C:6]4[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:9][N:8]=3)[CH2:15][CH2:14]2)[N:22]=[CH:23][CH:24]=1
Reactant: COc1ccc2c(N3CCNCC3)noc2c1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(N3CCN(c4nccc(Cl)n4)CC3)noc2c1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
A stirred solution of 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole (1.0 g), 4,6-dichloropyrimidine (0.64 g) and sodium bicarbonate (1.08 g) were refluxed in absolute ethanol under N2 for 90 minutes. TLC (silica gel 2/1 acetone/heptane) showed no presence of starting material. The reaction was allowed to cool to room temperature, partitioned between CH2Cl2 and water, extracted with CH2Cl2, dried over MgSO4 and concentrated in vacuo to afford 1.44 g of material. The material was further purified through recrystallization from CH2Cl2 /pet. ether to yield the product 1.1 g, m.p. 203°-204° C.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[CH3:22][O:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[CH:31]([NH2:33])[CH2:30][CH2:29]2>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[CH:31]([NH:33][C:20]1[O:8][CH2:9][C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=3[N:19]=1)[CH2:30][CH2:29]2
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: COc1cccc2c1C(N)CC2
Product: COc1cccc2c1C(NC1=Nc3ccc([N+](=O)[O-])cc3CO1)CC2
Yield: 73.4 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (3.89 g, 12.0 mmol; HPLC: 4.446 min) and the above described rac-7-methoxy-indan-1-ylamine (1.96 g, 12.0 mmol; HPLC 0.4 min) according to the procedure described for Example 1. Obtained the title compound as a yellow solid (2.99 g, 73%; HPLC 1.683 min), MS (ISP) m/e=340.1 [(M+H)+].
Reaction SMILES: O[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][N:4]1[C:9]2=[N:10][C:11]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:12][C:13](=[O:14])[N:8]2[CH2:7][C:6]([CH3:22])([CH3:21])[CH2:5]1.[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:22][C:6]1([CH3:21])[CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[N:10]=[C:9]2[N:4]([CH2:3][CH:2]([N:33]2[C:29](=[O:39])[C:30]3[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:32]2=[O:34])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:5]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC1(C)CN(CC(O)c2ccccc2)c2nc(-c3ccncc3)cc(=O)n2C1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CC1(C)CN(CC(c2ccccc2)N2C(=O)c3ccccc3C2=O)c2nc(-c3ccncc3)cc(=O)n2C1
Reaction time: 18 h

Procedure:
To a solution of 0.2 g (0.531 mmol) of 9-(2-Hydroxy-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, 0.080 g (0.584 mmol) of phthalimide and 0.195 g (0.742 mmol) in 30 ml of anhydrous tetrahydrofuran at 0° C. was added 0.142 ml (0.903 mmol) of diethyl azodicarboxylate and the reaction mixture stirred for 18 h.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:21])([CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10])[C:4]([F:7])([F:6])[F:5].Br[C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1>>[F:5][C:4]([F:7])([F:6])[C:3]([CH2:2][NH:1][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)([OH:21])[CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CN)C(F)(F)F
Reactant: Cc1cc(Br)c2cnn(-c3ccc(F)cc3)c2c1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F

Procedure:
Prepared similarly to Example 25 from 2-(aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol (Intermediate 18) and 4-bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole (Intermediate 28). Purification was conducted by silica gel chromatography using the Flashmaster II (20 g cartridge) eluting with a 100:0 to 50:50 cyclohexane:ethyl acetate gradient over 40 minutes to give the title compound (26.7 mg)
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[NH2:16][NH2:17]>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([NH:16][NH:17][C:14]([NH:13][C:7]2([N:6]=[N:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:15])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NN
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Solvent: CCCCC
Product: CC(C)(C)N=NC1(NC(=O)NNC(=O)NC2(N=NC(C)(C)C)CCCCC2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 9.27 grams (0.044 moles) of 1-t-butylazo-1-isocyanatocyclohexane stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 0.74 grams (0.022 moles) of 97% hydrazine. The reaction mixture rapidly became a solid and pentane was added to slurry the mixture. The slurry was then stirred for 60 minutes at room temperature and filtered. The filter cake was dried leaving 9.5 grams (95% crude yield) of a white powder. The product melted at 195°-197° C. with decomposition. The infrared spectrum of the product contained a strong carbonyl band at 1665 cm-1 and a broad NH band at 3350 cm-1 and a weaker band at 3080 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][N:6]=1)=[O:4].C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C.O.[NH2:33][NH2:34]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:33][NH2:34])=[O:13])=[CH:7][N:6]=1)=[O:4]
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)O)cn1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NN)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.3 %

Procedure:
A mixture of 2-methoxycarbonylpyridine-5-carboxylic acid (Chem. Abstr., 68, 68840 h (1968)) (0.40 g, 2.2 mmol) and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (0.60 g, 2.4 mmol) in dichloromethane (10 mL) was stirred at room temperature under nitrogen for 0.75 hour. Hydrazine hydrate (0.110 mL, 2.2 mmol) was then added and after a further 5 minutes the precipitate formed was collected by filtration, washed with dichloromethane and dried to give the title compound (0.349 g, 81%) as white solid, mp 177-180° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]([C:10]1([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9].[N:28]1([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]([C:10]1([CH2:23][CH2:24][CH2:25][CH2:26][N:31]2[CH2:32][CH2:33][N:28]([C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)[CH2:29][CH2:30]2)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9]
Reactant: O=C(NCc1cccs1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: O=C(NCc1cccs1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(thiophen-2-ylmethyl)-amide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1[CH2:27][CH2:26][CH2:25][CH2:24]1.ICCCC>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH2:24]([NH:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)c1cnn(C)c1N
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCI
Product: CCCCNc1c(C(=O)OCC)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To ethyl 5-amino-1-methylpyrazole-4-carboxylate (3.4476 g, 20.38 mmol) in dimethylformamide (60 mL) at 0° C. was added a solution of 1.0M sodium bis(trimethylsilyl)amide in tetrahydrofuran (20.5 mL, 20.5 mmol). After 1 hour, 1-iodobutane (2.50 mL, 22.0 mmol) was added and the reaction was stirred at ambient temperature for 20 hours. The mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (6×). The combined organic extracts were then washed with water (2×) and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. Chromatography of the residue on silica gel eluting with 20% ethyl acetate in hexane afforded 3.8754 g (84%) of the desired product as a oil. TLC (20% ethyl acetate/80% hexane) Rf =0.12. 1H NMR (CDCl3, 300 MHz) d 0.94 (t, 3H), 1.33 (t, 3H), 1.35-1.50 (m, 2 H), 1.53-1.65 (m, 2H), 3.25 (t, 2H), 3.77 (s, 3H), 4.25 (q, 2H), 5.60-5.80 (br, 1H), 7.62 (s, 1H). MS (DCl/NH3)m/e 226 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[F:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([OH:3])=[O:34])[CH:11]=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=3)[CH:13]=2)=[CH:38][CH:37]=1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1ccc(F)cc1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-fluoro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.88-0.99 (m, 6H), 1.57 (ddd, J=13.33, 6.85, 6.72 Hz, 1H), 1.77 (ddd, J=13.88, 7.21, 7.03 Hz, 1H), 2.02-2.11 (m, 1H), 3.80 (t, J=7.70 Hz, 1H), 7.11-7.20 (m, 3H), 7.51-7.65 (m, 4H), 7.68-7.73 (m, 4H); Calcd for C25H22F4O2 (M+Na) 453.16, Found 453.
Reaction SMILES: [CH3:1][Si:2]([CH3:23])([CH3:22])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:12][CH:11]=2)=[N:8][CH:9]=1.C>[Pd].C(OCC)(=O)C>[CH3:23][Si:2]([CH3:1])([CH3:22])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:12][CH:11]=2)=[N:8][CH:9]=1
Reactant: C[Si](C)(C)Oc1ccc(-c2ccc(C=CCCCO)cc2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[Si](C)(C)Oc1ccc(-c2ccc(CCCCCO)cc2)nc1
Yield: 93.9 %

Procedure:
5.4 g of 5-trimethylsilyloxy-2-(4-[5-hydroxy-1-pentenyl]phenyl)pyridine, 1 g of palladium on active charcoal (10 w/w %) and 50 ml of ethyl acetate were reacted in an analogous manner to Example 1(c) to give 5.1 g of 5-trimethylsilyloxy-2-(4-[5-hydroxy-1-pentyl]phenyl)pyridine.