Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[N+](=[C:10]1[CH:19]=[CH:18][C:17]2[C:16](S(Cl)(=O)=O)=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]1=O)=[N-]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:12]12[CH2:11][CH:15]([CH2:14][CH2:13]1)[CH:16]1[CH:17]2[CH2:18][CH2:19][CH2:10]1
Reactant: [N-]=[N+]=C1C=Cc2c(cccc2S(=O)(=O)Cl)C1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C1CC2C3CCC(C3)C2C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.5 %

Procedure:
To a solution of 1.86 g 4,8-Bis(hydroxyeth-1'-yl)tricyclo [5.2.1.02,6 ] decane, 0.93 g of 4-di-methylamino-pyridine, 4.7 ml of triethylamine and 30 ml of CH2Cl2 at 0° C. was added a solution of 7.8 g of 6-diazo-5,6-dihydro-5-oxo-1-naphthalene sulfonyl chloride and 80 ml of methylene chloride over 0.5 hr. The mixture was stirred 1/2 hour at 9° C. and 6 hours at 25° C. and then diluted with 100 ml of methylene chloride. The mixture was then filtered and the methylene chloride phase washed with 100 ml of 10% sodium bicarbonate solution, 100 ml of water, 100 ml of 2 N sulfuric acid solution 50 ml of 5% sodium bicarbonate solution and 50 ml of water. The solution was then dried over sodium sulfate and the solvent removed at reduced pressure to give 3.5 g of product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:30](Cl)(=[O:37])[O:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34]>ClCCl.[NH4+].[Cl-]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:30]([O:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:37])[CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)nc1
Reactant: CC(C)(C)COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)COC(=O)N1CCC([C@H]2C[C@H]2CCOc2ccc(S(C)(=O)=O)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-(methylsulfonyl)-2-(2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethoxy)pyridine (Step B, Example GJM10; 0.10 g, 0.32 mmol) in dichloromethane (3 mL) under a nitrogen atmosphere was added triethylamine (0.13 mL, 0.89 mmol) and neopentyl carbonochloridate (0.08 mL, 0.57 mmol). The resulting solution was stirred for 2 h at ambient temperature. The solution was diluted with saturated NH4Cl(aq.) (20 mL). The resulting layers were separated and the aqueous phase extracted with dichloromethane (3×15 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the obtained residue by CombiFlash chromatography (12 g silica gel, 0 to 50% EtOAc in hexanes) provided the title compound as an off white semi-solid: 1H NMR (300 MHz, CDCl3) δ 8.72 (m, 1 h), 8.03 (m, 1H), 6.84 (m, 1H), 4.49 (m, 2H), 4.14 (m, 2H), 3.77 (s, 2H), 3.07 (s, 3H), 2.75 (m, 2H), 2.11 (m, 1H), 1.82-1.71 (m, 2H) 1.59-1.47 (m, 1H), 1.39-1.25 (m, 2H), 1.04-0.85 (m, 11H), 0.73-0.54 (m, 2H), −0.11 (q, J=4.8 Hz, 1H); MS (ESI) m/z 439 [M+H]+. GPR119 Human EC50: 2 nM
Reaction SMILES: [CH:1]([S:4][C:5]1[S:6][CH:7]=[C:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[N:9]=1)([CH3:3])[CH3:2].S(Cl)([Cl:18])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH:1]([S:4][C:5]1[S:6][C:7]([Cl:18])=[C:8]([O:10][S:11]([CH3:14])(=[O:12])=[O:13])[N:9]=1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)Sc1nc(OS(C)(=O)=O)cs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Sc1nc(OS(C)(=O)=O)c(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
3.5 g of 2-isopropylthio-4-methylsulfonyloxy-1,3-thiazole (No. 171) was dissolved in 50 ml of methylene chloride. 2 g of sulfuryl chloride was added dropwise to the solution keeping the temperature below 0° C., followed by stirring at room temperature for 2 hours. Then, 20% aqueous solution of sodium carbonate was added to the reaction mixture to cease the reaction, and the methylene chloride layer was separated and washed with water, followed by drying over anhydrous sodium sulfate. The oil obtained by concentration was purified by silica-gel column chromatography to 2 g of the objective compound as a pale yellow oil (yield; 50.4%).
Reaction SMILES: [Br:1][C:2]1[C:10]([C:11](O)=[O:12])=[CH:9][C:8]([Br:14])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.[CH3:44][NH:45][O:46][CH3:47]>C(Cl)Cl>[Br:1][C:2]1[C:10]([C:11]([N:45]([O:46][CH3:47])[CH3:44])=[O:12])=[CH:9][C:8]([Br:14])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2
Reactant: CNOC
Reactant: O=C(O)c1cc(Br)c2c(c1Br)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Br)c2c(c1Br)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.9 %

Procedure:
To a solution of acid 4 (4.8 g, 15.0 mmol) in CH2Cl2 (80 mL) were added EDCI (3.83 g, 20 mmol), HOBT (2.70 g, 20 mmol), NMM (8.8 mL, 80 mmol) and N,O-dimethylhydroxylamine-HCl (1.95 g, 20 mmol) at rt. The mixture was stirred at rt overnight. The reaction mixture was quenched with water (50 mL) and extracted with DCM (100 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the compound 9 (0.27 g, 0.73 mmol, 7%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[O:18][C:17]([CH3:20])([CH3:19])[N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:15]3[CH2:28][F:29])=[CH:10][CH:9]=2)[O:5][N:4]=1.[S:30](Cl)([CH3:33])(=[O:32])=[O:31].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:29][CH2:28][C@@H:15]1[C@@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:6]3[O:5][N:4]=[C:3]([CH2:2][NH:1][S:30]([CH3:33])(=[O:32])=[O:31])[CH:7]=3)=[CH:13][CH:12]=2)[O:18][C:17]([CH3:19])([CH3:20])[N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CN)no3)cc2)OC1(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CNS(C)(=O)=O)no3)cc2)OC1(C)C
Temperature: 0 °C
Yield: 97.1 %

Procedure:
To a methylene chloride (10 ml) solution of (4S,5R)-tert-butyl 5-(4-(3-(aminomethyl)isoxazol-5-yl)phenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidine-3-carboxylate (270 mg, 0.66 mmol) that had been cooled to 0° C. is added mesyl chloride (83 mg, 0.73 mmol) and diisopropylethylamine (94 mg, 0.73 mmol) sequentially. The reaction is stirred at 0° C. for thirty minutes then quenched with water (2 ml). The quenched reaction is stirred for thirty minutes at room temperature. The organic phase is dried over sodium sulfate and concentrated to give the title compound (310 mg): m/z (CI) 484 ([M+H]+.
Reaction SMILES: CN([CH:4]=[CH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7])C.[C:18]1(=[O:25])[CH:23]=[CH:22][C:21](=[O:24])[CH:20]=[CH:19]1>C(O)(=O)C>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:6]([C:5]2[C:20]3[CH:19]=[C:18]([OH:25])[CH:23]=[CH:22][C:21]=3[O:24][CH:4]=2)=[O:7])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: O=C1C=CC(=O)C=C1
Reactant: COc1ccc(C(=O)C=CN(C)C)cc1OC
Solvent: CC(=O)O
Product: COc1ccc(C(=O)c2coc3ccc(O)cc23)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.7 %

Procedure:
A suspension of enaminone 12 (2 g, 8.43 mmol) and compound benzoquinone Q-4 (910 mg, 8.43 mmol) in acetic acid was stirred at room temperature under an atmosphere of N2 for 5 h. The precipitate that formed was filtered, washed with water, and dried under high vacuum to afford compound 13 (1.2 g, 47%) as an off-white solid. TLC Rf=0.5 (petroleum ether-EtOAc, 7:3); 1H NMR (DMSO-d6) δ 9.43 (s, 1H), 8.59 (s, 1H), 7.57-7.43 (band, 4H), 7.12 (d, J=8.3 Hz, 1H), 6.86 (dd, J=9.0 Hz, 2.6 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H); MS (ES) m/z 299 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH:18]1([C:21]([NH2:23])=[O:22])[CH2:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:23][C:21]([CH:18]3[CH2:20][CH2:19]3)=[O:22])[CH:7]=2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: NC(=O)C1CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1)C1CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 46.2 %

Procedure:
Mix 4-chloro-6-(4-nitrophenoxyl)pyrimidine (10.6 g, 39.68 mmol), cyclopropanecarboxamide (8.7 g, 99.2 mmol) and 1,4-dioxane (150 mL). Then under N2, add tris(dibenzylideneacetone)dipalladium [Pd2(dba)3, 1.8 g, 1.98 mmol], (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP, 2.5 g, 3.97 mmol), Cs2CO3 (32 g, 99.5 mmol), and stir at 100° C. for 12 hrs. Cool to room temperature, filter, concentration and purification by chromatography (silica gel, DCM:EtOAc=1:5) afford the title compound (5.5 g, 43.6%). MS: (M+1): 301.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[CH:19][C:18]4=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[C:26]([CH2:30]O)[CH:27]=[CH:28][CH:29]=5)[N:17]4[N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[CH3:49][NH:50][S:51]([CH3:54])(=[O:53])=[O:52].[H-].[Na+]>CN(C)C=O>[CH3:49][N:50]([CH2:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C:23]2[N:17]3[C:18]([CH:19]=[N:20][C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[CH:13][CH:12]=4)=[N:16]3)=[CH:21][CH:22]=2)[CH:25]=1)[S:51]([CH3:54])(=[O:53])=[O:52]
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccc(CO)c5)n4n3)cc2)CC1
Reactant: CNS(C)(=O)=O
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccc(CN(C)S(C)(=O)=O)c5)n4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 54.6 %

Procedure:
(3-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-methanol (63.0 mg, 0.152 mmol) was dissolved in N,N-dimethylformamide (3.00 mL) and triethylamine (27.5 μL, 0.198 mmol). Methanesulfonyl chloride (14.1 μL, 0.182 mmol) was added and the reaction was stirred at room temperature for 40 minutes. LCMS analysis showed complete conversion to the mesylate. In a clean round bottomed flask was added N-methyl-methanesulfonamide (332 mg, 3.04 mmol) in N,N-dimethylformamide (5.00 mL). Sodium hydride (29.2 mg, 1.22 mmol) was added and the reaction was stirred at room temperature for 5 minutes. The mesylate solution was then added and the reaction was stirred at room temperature for 2 hours. The reaction was partitioned between EtOAc (25 mL) and water (25 mL). The organic layer was washed twice with water (15 mL) and dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by prep-HPLC using a gradient of 10-55% AcN/water both containing 0.1% TFA as the eluting solvent. The product was then free based to obtain the title compound as a yellow solid (42 mg, 55%). m.p.=229-230° C.; LCMS (m/e) 506 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.69 (s, 1H), 8.15-8.08 (m, 2H), 7.56-7.46 (m, 3H), 7.38 (d, 1H, J=7.6 Hz), 7.00 (d, 1H, J=4.7 Hz), 6.93 (d, 2H, J=9.0 Hz), 6.82 (d, 1H, J=4.8 Hz), 6.68 (s, 1H), 4.40 (s, 2H), 3.22-3.15 (m, 4H), 2.86 (s, 3H), 2.79 (s, 3H), 2.63-2.56 (m, 4H), 2.37 (s, 3H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:10][C@H:9]([NH2:11])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](N1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[N:17]=[CH:16]1)([O-])=O>>[N+:20]([C:18]1[N:17]=[CH:16][N:11]([C@H:9]2[CH2:8][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:10]2)[CH:19]=1)([O-:22])=[O:21]
Reactant: N[C@H]1C[C@@H](c2ccccc2)C1
Reactant: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Product: O=[N+]([O-])c1cn([C@H]2C[C@@H](c3ccccc3)C2)cn1
Yield: 46 %

Procedure:
This reaction was carried out using the procedure for Preparation 1 with cis-3-phenylcyclobutylamine (J. Med. Pharm. Chem 1960, 2, 687-691; ACIEE 1981, 20, 879-880) and 1,4-dinitroimidazole to afford 46 mg (46% yield) of 4-nitro-1-(cis-3-phenyl-cyclobutyl)-1H-imidazole; 1H NMR (300 MHz, CDCl3) δ7.9 (s, 1H), 7.55 (s, 1H), 7.4-7.2 (m, 5H), 4.73 (m, 1H), 3.48 (m, 1H), 3.12 (m, 2H), 2.54 (m, 2H); MS (AP/Cl): 244 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[OH:13][C:14]1[CH:18]=[C:17]([N:19]2[C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[N:21]=[CH:20]2)[S:16][C:15]=1[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:19]1([C:17]2[S:16][C:15]([C:28]([O:30][CH3:31])=[O:29])=[C:14]([O:13][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=3)[CH:18]=2)[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[N:21]=[CH:20]1
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1O
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1cccc(C(F)(F)F)c1

Procedure:
In a similar manner as described for example B14, 102.8 mg of 3-(trifluoromethyl)benzyl bromide, 100 mg of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate, 59.7 mg of potassium carbonate in 3 ml anhydrous DMF yield the title compound.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:25])([CH2:7][CH2:8][CH2:9][N:10]1[CH2:19][C@@H:18]2[CH2:20][O:21][CH2:22][CH2:23][N:17]2[C:16]2[N:15]=[C:14](Cl)[N:13]=[CH:12][C:11]1=2)[CH3:6])(=[O:3])[CH3:2].[NH:26]1[C:34]2[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[C:29]=2[CH:28]=[CH:27]1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([O:4][C:5]([CH3:25])([CH2:7][CH2:8][CH2:9][N:10]1[CH2:19][C@@H:18]2[CH2:20][O:21][CH2:22][CH2:23][N:17]2[C:16]2[N:15]=[C:14]([C:30]3[CH:31]=[CH:32][CH:33]=[C:34]4[C:29]=3[CH:28]=[CH:27][NH:26]4)[N:13]=[CH:12][C:11]1=2)[CH3:6])(=[O:3])[CH3:2]
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: CC(=O)OC(C)(C)CCCN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CC(=O)OC(C)(C)CCCN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21
Temperature: 120 °C
Yield: 26.6 %

Procedure:
To a 2 mL microwave vial were added (R)-5-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylpentan-2-yl acetate (PREPARATION x81, 148 mg, 0.401 mmol), indole-4-boronic acid (64.6 mg, 0.401 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (16.50 mg, 0.020 mmol). The vial was evacuated and filled with nitrogen. After sealing the vial, dioxane (1600 μL) and saturated NaHCO3 (400 μL) were added. The mixture was then heated in a microwave to 120° C. for 45 minutes. After the mixture was cooled to room temperature, ACN (4 mL) was added and the mixture was filtered by syringe filter. The crude product was purified by preparatory HPLC using a gradient of 20-40% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The collected fractions were pooled, neutralized with NaHCO3, concentrated, and extracted with EtOAc. The combined organics were dried over MgSO4, filtered, and concentrated to give the title compound (48 mg, 27%). ESI-MS m/z [M+H]+ calc'd for C25H31N5O3, 450.25. found 450.3.
Reaction SMILES: CCCCC.C([Li])(C)(C)C.O1CCCC1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[C:27]([C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[N:26]=[C:25]([C:36]3[CH:37]=[C:38]([CH3:42])[CH:39]=[CH:40][CH:41]=3)[N:24]=2)=[CH:19][CH:18]=1.Br[C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:52][CH:51]=2)=[CH:46][N:45]=1>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>[C:56]([C:53]1[CH:54]=[CH:55][C:50]([C:47]2[CH:48]=[CH:49][C:44]([C:17]3[CH:18]=[CH:19][C:20]([C:23]4[N:24]=[C:25]([C:36]5[CH:37]=[C:38]([CH3:42])[CH:39]=[CH:40][CH:41]=5)[N:26]=[C:27]([C:29]5[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=5)[N:28]=4)=[CH:21][CH:22]=3)=[N:45][CH:46]=2)=[CH:51][CH:52]=1)([CH3:59])([CH3:58])[CH3:57]
Reactant: Cc1cccc(-c2nc(-c3ccc(Br)cc3)nc(-c3cccc(C)c3)n2)c1
Reactant: CC(C)(C)c1ccc(-c2ccc(Br)nc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1cccc(-c2nc(-c3ccc(-c4ccc(-c5ccc(C(C)(C)C)cc5)cn4)cc3)nc(-c3cccc(C)c3)n2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Under a stream of argon, 5.3 ml of a pentane solution containing 7.8 mmol of tert-butyl lithium was slowly added to 25 ml of tetrahydrofuran cooled to −78° C., and 15 ml of tetrahydrofuran in which 1.13 g of 2-bromo-5-(4-tert-butylphenyl)pyridine had been dissolved was further added dropwise to this solution. After stirring at −78° C. for 30 minutes, 2.47 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 50 ml portion of tetrahydrofuran prepared by dissolving 1.25 g of 2-(4-bromophenyl)-4,6-di-m-tolyl-1,3,5-triazine synthesized by the method of Reference Example 2 and 0.17 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 3 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (eluting solution hexane:dichloromethane=3:2 to 4:3) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 2-{4-[5-(4-tert-butylphenyl)pyridin-2-yl]phenyl}-4,6-di-m-tolyl-1,3,5-triazine (1.55 g, yield 94%). Its melting point is shown in Table 4. In this case, a distinct point of glass transition was not observed.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:22]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:21][C@@:20]2([CH3:29])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C@H:13]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[C@@H:14]2[O:30]C(=O)C)[CH2:6]1)(=[O:3])[CH3:2]>CO>[C:1]([O:4][C@@H:5]1[C@@H:22]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH2:21][C@@:20]2([CH3:29])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C@H:13]([N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[C@@H:14]2[OH:30])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@@H]2CC[C@@H]3[C@H](CC[C@@]4(C)[C@H]3C[C@H](N3CCCC3)[C@@H]4OC(C)=O)[C@@]2(C)C[C@@H]1N1CCOCC1
Solvent: CO
Product: CC(=O)O[C@H]1C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](O)[C@@H](N5CCCC5)C[C@@H]34)[C@@]2(C)C[C@@H]1N1CCOCC1
Yield: 85.1 %

Procedure:
A solution of (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1pyrrolidinyl)-androstane-3,17-diol diacetate (6.0 g) in methanol (70 ml) was set aside at room temperature for 20 h., during which time the product partially crystallised. Water (150 ml) was added to precipitate the product as a yellow solid, which was filtered off and dried. The crude solid was recrystallised from ethanol (110 ml) to give (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1pyrrolidinyl)-androstane-3,17-diol 3-acetate (4.70 g), m.p. 112°-118° C.; [α]D20 =+33.1° (c 0.97 in CHCl3)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.C1(B(O)O)C=CC=CC=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=4)[CH2:19][CH2:18]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:35])([F:33])[F:34]
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Agent: OB(O)c1ccccc1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccccc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using phenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=497, obsd.=497).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]3[CH2:12][CH2:13][CH:7]([CH2:8][CH2:9]3)[C:6]=2[C:5]([NH:14][NH2:15])=[N:4][N:3]=1.[CH:16](O)=O>>[Cl:1][C:2]1[C:11]2[CH:10]3[CH2:9][CH2:8][CH:7]([CH2:13][CH2:12]3)[C:6]=2[C:5]2=[N:14][N:15]=[CH:16][N:4]2[N:3]=1
Reactant: NNc1nnc(Cl)c2c1C1CCC2CC1
Reactant: O=CO
Product: Clc1nn2cnnc2c2c1C1CCC2CC1
Yield: 88 %

Procedure:
1-Chloro-4-hydrazino-5,6,7,8-tetrahydro-5,8-ethanophthalazine (2.5 grams, 0.111 mol) was mixed with 150 milliliters of formic acid. The mixture was heated at the boiling temperature under reflux for 2 hours, then evaporated to dryness. The residue was triturated with saturated aqueous sodium bicarbonate. The resulting white solid was collected, washed with water and air dried to yield 23.0 grams (88% yield) of 6-chloro-7,8,9,10-tetrahydro-7,10-ethano(1,2,4)triazolo[3,4-a]phthalazine, melting at 137°-140° C. After recrystallization from a mixture of benzene and hexane the purified product melted at 140.5°-141° C. Infrared spectroscopy and elemental analysis confirmed the designated structure.
Reaction SMILES: [Br:1][C:2]1[C:28]([Br:29])=[CH:27][C:5]2[N:6]([C:19](=[O:26])[CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[NH:12][N:13]=3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:32](Cl)[CH2:33][CH3:34]>CN(C)C=O.C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[C:28]([Br:29])=[CH:27][C:5]2[N:6]([C:19](=[O:26])[CH2:20][N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[N:12]([CH2:32][CH2:33][CH3:34])[N:13]=3)[C:4]=2[CH:3]=1
Reactant: CCN(CC)CC(=O)N1c2cc(Br)c(Br)cc2-n2c(n[nH]c2=O)-c2cccnc21
Reactant: CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: CCCn1nc2n(c1=O)-c1cc(Br)c(Br)cc1N(C(=O)CN(CC)CC)c1ncccc1-2
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 6,7-dibromo -9-[(diethylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo-[4,3-a][1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling propyl chloride in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in exanmple 25 to give 6,7-dibromo-2,9-dihydro-2-propyl-9-[(diethylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]-benzodiazepin-3-one.