Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.7 %

Procedure:
To a solution of 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (50 mg, 0.19 mmol) and benzoyl chloride (24 μL, 0.21 mmol) in dichloromethane (1 mL) at 0° C. was added diisopropylethylamine (66 μL, 0.38 mmol). The mixture was stirred at room temperature 15 hours, the solvent removed, and the residue purified by flash chromatography (0-30% ethyl acetate-hexanes) to give 18 mg (26% yield) of a yellow solid. 1H-NMR (CDCl3): δ 8.97 (s, 1H), 7.78 (d, 2H), 7.61 (m, 1H), 7.52 (m, 1H), 7.44 (t, 2H), 7.23 (m, 1H), 7.17 (d, 1H), 6.42 (d, 1H), 5.34 (m, 1H), 2.72 (m, 2H), 2.32 (m, 1H), 2.02-1.93 (m, 3H); MS m/z 369 (M−1).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].[Cl:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1F.O>CN(C=O)C.C1CCCCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3](=[O:8])[N:4]([C:17]2[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=2[Cl:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]cccc1Br
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCCCC1
Product: O=c1c(Br)cccn1-c1ccc([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2.00 g (11.5 mmol) of 3-bromopyridin-2(1H)-one (O, S. Tee, M. Pavent, J. Am. Chem. Soc. 1982, 104, 4142-4146) are dissolved in 40 ml of DMF. The mixture is cooled to 0° C., and 2.04 g (17.2 mmol, 95% strength) of potassium tert-butoxide are added. After about 15 min, the ice bath is removed, and after a further 30 min, 2.22 g (12.6 mmol) of 2-chloro-1-fluoro-4-nitrobenzene are added. The mixture is stirred at RT for 4 h. The mixture is then added to water and extracted three times with ethyl acetate. The combined organic phases are shaken with saturated sodium chloride solution and dried over sodium sulphate. The solvent is removed under reduced pressure, and the residue is suspended in pentane and filtered off with suction. The solid obtained is boiled with cyclohexane/ethyl acetate 10:1. The product is filtered off with suction and washed with cyclohexane/ethyl acetate 10:1. This gives 2.54 g (67% of theory) of the desired compound.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[O:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:18]3[N:38]=[CH:39][C:40]([C:41]4[CH:42]=[N:43][C:44]5[C:49]([CH:50]=4)=[CH:48][CH:47]=[CH:46][CH:45]=5)=[C:17]3[N:16]=2)[CH2:11][CH2:10]1>CC#N>[Br:8][C:20]1[C:15]([N:12]2[CH2:11][CH2:10][O:9][CH2:14][CH2:13]2)=[N:16][C:17]2[N:18]([N:38]=[CH:39][C:40]=2[C:41]2[CH:42]=[N:43][C:44]3[C:49]([CH:50]=2)=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:19]=1[N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:36])[CH3:37])[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of NBS (20.6 mg, 0.116 mmoL) in CH3CN (1 mL) was added to a mixture of 5-morpholino-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (70.0 mg, 0.116 mmoL) in CH3CN (6 mL). After stirring at room temperature for 10 min, the reaction mixture was concentrated and purified by column chromatography to afford the desired compound. LCMS tR=2.91 Min (5 min run, UV254nm). Mass calculated for, M+ 684.2, observed LC/MS m/z 685.2 (M+H).
Reaction SMILES: [N:1]([C:4]1[C:5]([N+:17]([O-:19])=[O:18])=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[N:10]=[C:9]([OH:15])[C:8]([OH:16])=[N:7]2)=[N+]=[N-]>C1(C)C(C)=CC=CC=1>[Cl:14][C:13]1[C:4]2[C:5](=[N+:17]([O-:19])[O:18][N:1]=2)[C:6]2[N:7]=[C:8]([OH:16])[C:9]([OH:15])=[N:10][C:11]=2[CH:12]=1
Reactant: [N-]=[N+]=Nc1c(Cl)cc2nc(O)c(O)nc2c1[N+](=O)[O-]
Solvent: Cc1ccccc1C
Product: [O-][n+]1onc2c(Cl)cc3nc(O)c(O)nc3c21
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of 1 g (3,5 mmol) 6-azido-7-chloro-2,3-dihydroxy-5-nitroquinoxaline and 15 ml xylene was refluxed for 3 h. After cooling to 25° C. the precipitate was filtered off and washed with toluene and ether to give 0,86 g (96%) 4-chloro-7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline-1-oxide, m.p.>300° C. NMR (DMSO-d6): 12.6 (lH, broad s), 12.0 (lH, broad s), 7.10 (lH,s).
Reaction SMILES: [C:1]([N:4]1[CH:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[NH:26][C:25](=[O:27])[C:24]4[C:19](=[CH:20][C:21]([F:29])=[CH:22][C:23]=4F)[N:18]=3)=[CH:13][CH:12]=2)[CH2:6][CH:5]1[CH3:30])(=[O:3])[CH3:2].[CH3:31][O-:32].[Na+].CO.O>CN(C=O)C.C(O)(=O)C>[C:1]([N:4]1[CH:5]([CH3:30])[CH2:6][N:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[NH:26][C:25](=[O:27])[C:24]4[C:19](=[CH:20][C:21]([F:29])=[CH:22][C:23]=4[O:32][CH3:31])[N:18]=3)=[CH:15][CH:16]=2)[CH2:8][CH:9]1[CH3:10])(=[O:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(=O)N1C(C)CN(c2ccc(-c3nc4cc(F)cc(F)c4c(=O)[nH]3)cc2)CC1C
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(F)cc2nc(-c3ccc(N4CC(C)N(C(C)=O)C(C)C4)cc3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-phenyl]-5,7-difluoro-3H-quinazolin-4-one (0.66 g, 1.60 mmol) in DMF (10 mL), a solution of sodium methoxide in methanol (25 wt %, 3.5 mL, 16.0 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Water was added, acidified to pH approximately 4-5 with acetic acid, and the precipitated solid was filtered and dried under vacuum to give crude compound, which was further purified by column chromatography (silica gel 230-400 mesh; eluting with 2% methanol solution in dichloromethane) to yield 2-[4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-phenyl]-7-fluoro-5-methoxy-3H-quinazolin-4-one as a light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[F:24][C:25]1[CH:26]=[C:27]([C:35](O)=[O:36])[C:28]2[O:33][CH2:32][O:31][CH2:30][C:29]=2[CH:34]=1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:35]([C:27]3[C:28]4[O:33][CH2:32][O:31][CH2:30][C:29]=4[CH:34]=[C:25]([F:24])[CH:26]=3)=[O:36])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc(F)cc2c1OCOC2
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cc(F)cc4c3OCOC4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 6-fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid. LC-MS (basic): tR=0.89 min; [M+H]+=512.1.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=4)[C:12]=3[CH:27]=2)=[N:6][N:7]=1.C[C:29](C)([O-:31])C.[K+]>CO>[CH3:29][O:31][CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=4)[C:12]=3[CH:27]=2)=[N:6][N:7]=1
Reactant: FC(F)(F)Oc1cccc(-c2coc3ccc(-c4nnc(CCl)o4)cc23)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: COCc1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Temperature: 50 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
A solution of 2-(chloromethyl)-5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole (0.30 g, 0.76 mmol) and potassium tert-butoxide (85%, 0.12 g, 0.91 mmol) in methanol (5 mL) was stirred overnight at room temperature. Potassium tert-butoxide (85%, 0.03 g, 0.23 mmol) was added to the reaction mixture, and the resulting mixture was stirred at 50° C. overnight. The reaction mixture was concentrated under reduced pressure, saturated aqueous ammonium chloride solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) and recrystallized from hexane/ethyl acetate to give the title compound (0.20 g, yield 67%) as colorless crystals.
Reaction SMILES: [C:1]([O:9][CH:10]([CH:15]1[CH:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:18]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:17]([CH2:45][O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:16]1[CH2:54]C1C=CC=CC=1)[CH2:11][CH2:12]CO)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCCCC=1>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:9][CH:10]1[CH:15]2[N:16]([CH:17]([CH2:45][O:46][CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH:18]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:19]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:20]2[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:54][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC(CCCO)C1C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C(COCc2ccccc2)N1Cc1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1=CCCCC1
Product: O=C(OC1CCCN2C(COCc3ccccc3)C(OCc3ccccc3)C(OCc3ccccc3)C(OCc3ccccc3)C12)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
To a solution of Compound (XV) (0.60 g; 0.74 mmoles) and cyclohexene (5 mL) in methanol (30 mL), Pearlman's catalyst (0.2 g) was added under a nitrogen atmosphere. The suspension was stirred at room temperature for 18 hours, then the catalyst was filtered through Celite and washed with methanol (20 mL). The combined organic layer was evaporated under reduced pressure to yield a crude oil, which was purified via flash chromatography (silica gel; 1:1 as a clear colorless oil (0.34 g) and recovered Compound (XV) (0.10 g; 16% recovery). The N-debenzylated alcohol (0.34 g) was dissolved in pyridine (20 mL) and cooled to -10° C., then methanesulfonyl chloride (0.04 mL) was added, and reaction was continued for 96 hours. The solvent was evaporated under reduced pressure and saturated aqueous sodium bicarbonate solution was added to the residue. After extraction with ether (2×60 mL), the combined organic solution was dried over magnesium sulfate and the solvent evaporated under reduced pressure. The crude product was purified via flash chromatorgraphy (silica gel; 1:1 ethyl acetate:hexane) to yield Octahydro-7,8,9-tris (phenylmethoxy)-6-[(phenylmethoxy)methyl]-2H-quinolizin1-ol benzoate (ester) (XVI) (0.16 g; 50%) as a colorless oil. IR (film from CDCl3) 1718 cm-1 (C=0); MS(CI--CH4) 698 (MH+), 576 (MH+ -PhCO2H); 1H nmr (CDCl3) δ 1.2 (m, 1H), 1.6-1.9 (m, 2H), 2.2 (d, 1H), 2.8 (t, 1H), 3.3-3.4 (m, 2H), 3.5-3.7 (m, 3H), 3.8 (m, 1H), 4.1 (t, 1H), 4.3 (d, 1H), 4.4-4.7 (m, 7H), 4.9 (d, 1H), 5.5 (s, 1H), 7.0-7.4 (m, 22H), 7.5 (m, 1H), 8.1 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4=[CH:19][NH:20][CH:21]=[C:15]4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.[NH:23]1[CH:27]=[N:26][N:25]=[N:24]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4=[C:19]([C:27]5[NH:26][N:25]=[N:24][N:23]=5)[NH:20][CH:21]=[C:15]4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: c1nnn[nH]1
Reactant: CC1c2c[nH]cc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Product: CC1c2c[nH]c(-c3nnn[nH]3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 52, (6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-methyl-2,4,6,7-tetrahydro-pyrrolo[3,4-c]pyridin-5-yl)-methanone is reacted with 1H tetrazole to provide the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([S:29][CH3:30])=[N:23][C:24]=2Cl)(=[O:3])[CH3:2].N[N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(N(CC)CC)C>O1CCOCC1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([S:29][CH3:30])=[N:23][C:24]=2[N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)(=[O:3])[CH3:2]
Reactant: NN1CCCCC1
Reactant: CSc1nc(Cl)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSc1nc(N2CCCCC2)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.6 %

Procedure:
The above 9-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-methylthio-9H-purine (1.83 g, 3.9 mmol) was dissolved in dioxan (40 ml) followed by 1-aminopiperidine (0.59 g, 5.85 mmol) and triethyl-amine (1.63 ml, 11.7 mmol). The reaction mixture was stirred at ambient temperature for 18 h, evaporated and purified by flash chromatography on silica gel. Elution initially with dichloromethane, followed by dichloromethane/methanol (100/1) provided 9-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-2-methylthio-6-(1-piperidinyl)-9H-purine (1.24 g, 59%) as a foam. This compound was dissolved in methanolic ammonia (10 ml) and the solution was stirred at room temperature for 18 h, evaporated and purified by flash chromatography on silica gel. Elution initially with dichloromethane, followed by dichloromethane/methanol (19/1) gave 2-methylthio-N-(1-piperidinyl) adenosine (0.67 g, 55%) as a foam, 1H NMR (DMSO-d6) δ 2.51 (3H, s, --SCH3), 3.50-3.56 (1H, m, H-5'a), 3.62-3.68 (1H, m, H-5'b) 3.92 (1H, q, H-4'), 4.15 (1H, q, H-3'), 4.50 (1H, q, H-2'), 5.03 (1H, t, 5'-0H), 5.18, 5.44 (2H, 2d, 2'- and 3'-OH), 5.84 (1H, d, H-1'), 8.24 (1H, s, H-8), 8.84 (1H, s, N--H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=O)=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[Cl:25][C:26]1[CH:33]=[CH:32][C:29](/[CH:30]=[C:19]2\[N:18]=[C:16]([C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[CH:24][CH:23]=3)[O:22][C:20]\2=[O:21])=[CH:28][CH:27]=1
Reactant: COc1ccc(CCOc2ccc(C(=O)NCC(=O)O)cc2)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(CCOc2ccc(C3=N/C(=C\c4ccc(Cl)cc4)C(=O)O3)cc2)cc1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 86.7 %

Procedure:
A mixture of N-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg, 1.00 mmol) prepared in Example 1 (1b), 4-chlorobenzaldehyde (148 mg, 1.05 mmol), sodium acetate (111 mg, 1.35 mmol), and acetic anhydride (467 μL, 5.00 mmol) was stirred at 120° C. for 20 minutes, and then water was added thereto to terminate the reaction. Then, continuously, the mixture was vigorously stirred until the mixture was cooled to room temperature. The deposited precipitate was collected by filtration, washed with water and hexane, and dried by heating under reduced pressure to give 376 mg of the title compound (yellow powder, yield: 87%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH3:33])[CH:18]=[CH:17][C:16]([S:19]([N:22]2[C:26]3[N:27]=[CH:28][CH:29]=[C:30]([C:31]#[N:32])[C:25]=3[CH:24]=[CH:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[I:34]I>O1CCCC1.O>[I:34][C:23]1[N:22]([S:19]([C:16]2[CH:15]=[CH:14][C:13]([CH3:33])=[CH:18][CH:17]=2)(=[O:21])=[O:20])[C:26]2[N:27]=[CH:28][CH:29]=[C:30]([C:31]#[N:32])[C:25]=2[CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C#N)ccnc32)cc1
Reactant: II
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(C#N)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.6 %

Procedure:
A stirred solution of diisopropylamine (0.38 mL) in tetrahydrofuran (7 mL), at −70° C. and under nitrogen, was treated with a solution of n-butyllithium in hexanes (1.06 mL, 2.5M) over 5 minutes, whilst maintaining the temperature below −65° C. After stirring for 20 minutes the mixture was added, at −70° C., to a solution of 1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (0.65 g, Reference Example 63) in tetrahydrofuran (15 mL) and stirred at −70° C. for 45 minutes. A solution of iodine (0.9 g) in tetrahydrofuran (10 mL) was then added at −70° C. The reaction mixture was allowed to warm up to room temperature over 1 hour, and stirred for 18 hours, then treated with water (10 mL). The reaction mixture was evaporated in vacuo and the residue partitioned between ethyl acetate (75 mL) and water (50 mL). The insoluble material was filtered, washed with ether and dried in vacuo to give the title compound (0.45 g) as a white solid. The filtrate was separated and the organics washed sequentially with saturated sodium thiosulphate solution (2×30 mL), water (30 mL) and brine (30 mL), dried over sodium sulphate and evaporated. The residue was triturated with diethyl ether to give the title compound (0.25 g) as a cream solid. TLC RF=0.43 (ethyl acetate/heptane 1:1). MS: 424 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[ClH:10].N1C=CC([C:16]([NH2:18])=[NH:17])=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:10].[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C@@H:2]([NH:1][C:16]([NH2:18])=[NH:17])[CH2:3]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: N=C(N)c1cc[nH]n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(N)N[C@H]1CN2CCC1CC2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a mixture of (R)-3-aminoquinuclidine (5.85 g, 46.4 mmol) and pyrazole carbox-amidine hydrochloride (6.80 g, 46.4 mmol) is added Hunig's base (8.07 ml, 46.4 mmol) and DMF (30 ml). The reaction is heated at 70° C. for 40 hours. The reaction is then cooled to room temperature and quenched by adding 400 ml of diethyl ether and stirring at room temperature for 2 hours. Product separates out as a white solid, which is filtered, washed and dried (8.94 g, 94%).
Reaction SMILES: [CH3:1][CH2:2][O:3][P:4]([O:15][CH2:16][CH3:17])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N+:11]([O-])=[CH:10][CH:9]=1)=[O:5].C[Si]([C:22]#[N:23])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:22]([C:12]1[CH:13]=[C:8]([CH2:7][CH2:6][P:4](=[O:5])([O:15][CH2:16][CH3:17])[O:3][CH2:2][CH3:1])[CH:9]=[CH:10][N:11]=1)#[N:23]
Reactant: CCOP(=O)(CCc1cc[n+]([O-])cc1)OCC
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: CCOP(=O)(CCc1ccnc(C#N)c1)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.6 %

Procedure:
Diethyl 2-(4-pyridyl)ethylphosphonate N-oxide (9.9 g, 38 mmol) was dissolved in nitroethane (200 ml), and trimethylsilyl cyanide (7.5 g, 75 mmol) and N,N-dimethylcarbamoyl chloride (6.1 g, 56 mmol) were added thereto. The mixture was stirred at room temperature for 12 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (15:1) were collected and concentrated to give the titled compound (7.3 g, 71%).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[NH:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=2)=[N:18][N:17]=[N:16]1.C([O-])([O-])=O.[K+].[K+].COCCOCCO.Cl>[OH-].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH:18]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([C:2]3[C:11]([CH3:12])=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=4)[N:3]=3)=[CH:22][CH:21]=2)=[N:15][N:16]=[N:17]1
Reactant: COc1ccc2nc(Cl)c(C)cc2c1
Reactant: OB(O)c1ccc(-c2nnn[nH]2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: COCCOCCO
Solvent: O
Product: COc1ccc2nc(-c3ccc(-c4nnn[nH]4)cc3)c(C)cc2c1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 83.7 %

Procedure:
To a mixture of 2-chloro-6-methoxy-3-methylquinoline (100 mg, 0.482 mmol), 4-(1H-tetrazol-5-yl)phenylboronic acid (91.2 mg, 0.482 mmol), K2CO3 (199 mg, 1.45 mmol), and PdCl2(dppf) (17.6 mg, 0.024 mmol) was added 7 mL of DEGME and 3 mL of H2O under argon. The mixture was stirred at 150° C. in a microwave reactor for 1.5 hours. The crude mixture was diluted with 1N NaOH (10 mL) and slowly acidified to a pH of 4.0 using conc. HCl. The solids were filtered to yield 128 mg (84% yield) of the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[N:5]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1.[OH-].[Na+].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.ClCCl>CN(C=O)C.O>[N:19]1([C:2]2[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[N:5]=[C:4]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:3]=2)[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: c1c[nH]cn1
Reactant: CN(C)c1nc(Cl)nc(N2CCOCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)c1nc(N2CCOCC2)nc(-n2ccnc2)n1
Reaction time: 0.75 h
Yield: 91.3 %

Procedure:
The obtained 2-chloro-4-dimethylamino-6-morpholino-1,3,5-triazine 492mg (2.02 mmol) was dissolved in DMF (20 ml), added with sodium hydroxide (182 mg, 4.55 mmol) and imidazole (308 mg, 4.52 mmol) and stirred at 110° C.-120° C. for 45 minutes. The reaction mixture was evaporated under reduced pressure. The residue obtained was added with dichloromethane and water, and then was shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography, using dichloromethane and methanol (95:5) as eluant, to obtain 508 mg (yield: 91.4%) of the titled compound as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9](=[O:13])[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:7][CH2:6][C:5]=2[N:4]=1.[F:23][C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][CH:29]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:23][C:24]1[CH:29]=[C:28]([CH:27]=[CH:26][CH:25]=1)[O:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9](=[O:13])[N:8]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: Oc1cccc(F)c1
Reactant: COc1ccc(CN2CCc3nc(CO)ccc3C2=O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2CCc3nc(COc4cccc(F)c4)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
2-(Hydroxymethyl)-6-(4-methoxybenzyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (270 mg, 0.9 mmol) from above and 3 equiv of 3-fluorophenol was dissolved in THF (10 mL). To this mixture was added polystyrene bound-PPh3 (3 equiv) and diisopropylazodicarboxylate (3 equiv) in THF (2 mL) dropwise. The mixture was allowed to warm to RT and stirred for 6 h. The residue was loaded directly onto a silica and eluted with EtOAc/hexanes to give the compound (310 mg, 88%). LC-MS (M+H)=393.2.