Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:42])([CH2:31][CH2:32][CH2:33][O:34][Si:35]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH2:36][CH3:37])[CH2:3][CH2:4][C:5]1[C:17]2[CH2:16][N:15]3[C:10](=[CH:11][C:12]4[C:22]([CH2:24][CH3:25])([OH:23])[C:21](=[O:26])[O:20][CH2:19][C:13]=4[C:14]3=[O:18])[C:9]=2[N:8]=[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=12.N1C=CC=CC=1.[C:49](Cl)(Cl)=[O:50].[CH2:53]([OH:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:42][Si:2]([CH3:1])([CH2:31][CH2:32][CH2:33][O:34][Si:35]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH2:36][CH3:37])[CH2:3][CH2:4][C:5]1[C:17]2[CH2:16][N:15]3[C:10](=[CH:11][C:12]4[C:22]([O:23][C:49](=[O:50])[O:60][CH2:53][C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=5)([CH2:24][CH3:25])[C:21](=[O:26])[O:20][CH2:19][C:13]=4[C:14]3=[O:18])[C:9]=2[N:8]=[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=12
Reactant: OCc1ccccc1
Reactant: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCO[Si](CC)(CC)CC
Reactant: O=C(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCO[Si](CC)(CC)CC
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
To a solution of Compound 51 (1.21 g, 2 mmol), 4-dimethylaminopyridine (244 mg, 2 mmol) and pyridine (1.62 mL, 20 mmol) in dichloromethane (20 mL) at −10° C. was added phosgene (20% in toluene, 2.10 mL, 4 mmol) dropwise. The resulting mixture was stirred for 15 minutes at −10° C. Benzyl alcohol (0.83 mL, 8 mmol) was added and the resulting mixture was stirred at 21° C. for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution, and aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to afford yellow oil, which was chromatographed to give the desired product (Yield: 47%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[N:16]4[CH:17]=[C:18]([CH:21]([N:26]5[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]5)[C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:39][N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1.C(N(CC)CC)C>CC(O)C.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]>[F:23][C:22]([F:24])([F:25])[CH:21]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]1)[C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([C:43]5[CH:42]=[N:41][N:40]([CH3:39])[CH:44]=5)=[CH:3][CH:4]=4)[N:9]=3)=[N:13][N:14]=2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(c2ccc3nnc(-c4ccc5ccc(Br)cc5n4)n3c2)C(F)(F)F)C1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cn1cc(-c2ccc3ccc(-c4nnc5ccc(C(N6CC[C@H](NC(=O)OC(C)(C)C)C6)C(F)(F)F)cn45)nc3c2)cn1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of tert-butyl (3S)-1-(1-(3-(7-bromo quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (Example 2, Step A; 0.18 g, 0.30 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.127 g, 0.61 mmol), PdCl2(dppf)*dcm (0.0249 g, 0.030 mmol), and triethylamine (0.064 mL, 0.46 mmol) in IPA (3 mL) was heated at 100° C. for 3 hours. After cooling to ambient temperature, the residue was directly purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-90% CH3CN/water gradient; 30 CV) to give tert-butyl (3S)-1-(2,2,2-trifluoro-1-(3-(7-(1-methyl-1H-pyrazol-4-yl)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.15 g, 83.2%) as a solid.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([C:9]2[N:31]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:12]3=[N:13][CH:14]=[C:15]([Cl:30])[C:16]([C:17]4[S:21][C:20]([C:22]5([O:26][CH2:27][O:28][CH3:29])[CH2:25][CH2:24][CH2:23]5)=[N:19][CH:18]=4)=[C:11]3[CH:10]=2)[CH:6]=[N:5]1)C=C.[CH3:42][C:43]([CH3:45])=[O:44].C[N+]1([O-])CC[O:50]CC1>O.O.[O-][Os]([O-])(=O)=O.[K+].[K+].O>[Cl:30][C:15]1[C:16]([C:17]2[S:21][C:20]([C:22]3([O:26][CH2:27][O:28][CH3:29])[CH2:23][CH2:24][CH2:25]3)=[N:19][CH:18]=2)=[C:11]2[CH:10]=[C:9]([C:7]3[CH:6]=[N:5][N:4]([CH2:42][CH:43]([OH:44])[CH2:45][OH:50])[CH:8]=3)[N:31]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:12]2=[N:13][CH:14]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Reactant: C=CCn1cc(-c2cc3c(-c4cnc(C5(OCOC)CCC5)s4)c(Cl)cnc3n2S(=O)(=O)c2ccc(C)cc2)cn1
Agent: O=[Os](=O)([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3cnn(CC(O)CO)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Reaction time: 8 h

Procedure:
To an ambient solution of 5-(2-(1-allyl-1H-pyrazol-4-yl)-5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 14A) (1.5 g, 2.458 mmol) in a solvent mixture of acetone (6.15 mL) and water (2.05 mL) was added potassium osmate (VI) dihydrate (9.06 mg, 0.025 mmol) followed by N-methylmorpholine-N-oxide (0.288 g, 2.458 mmol). The reaction was stirred overnight and was then quenched by the addition of 10% aqueous sodium thiosulfate solution (10 mL) and ethyl acetate (15 mL). The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×15 mL). The combined organics were washed with 10% aqueous sodium thiosulfate solution (10 mL), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 10% methanol in dichloromethane, to give the title compound. MS ESI(+) m/z 642.2 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Br[CH2:16][CH2:17][OH:18].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:9]1([CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH2:16][CH2:17][OH:18])[CH2:3][CH2:4]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCBr
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: OCCNC1CCN(Cc2ccccc2)CC1
Yield: 93.1 %

Procedure:
To a mixture of 4-amino-1-benzylpiperidine (2.13 g, 11.2 mmol) and 2-bromoethanol (0.15 g, 4.08 mmol) in anhydrous CH2Cl2 (20 ml) was added Hunig's base (2.6 ml, 5.7 mmol). The solution was refluxed for 24 hours. After evaporating off CH2Cl2, the crude material was purified by silica flash chromatography to afford 2-[[1-(phenylmethyl)-4-piperidinyl]amino]ethanol (0.88 g, 3.8 mmol) with 92% yield. FAB Mass [M+1]+35Cl 235.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:34](=[O:37])[CH2:35][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f30) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[CH2:10]([N+:17](C)(C)C)[C:11]1C=CC=C[CH:12]=1>C(#N)C=C.CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][C:10]#[N:17])=[CH:4][CH:3]=1
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: Cc1ccc(O)cc1
Agent: [OH-]
Solvent: CO
Solvent: C=CC#N
Product: Cc1ccc(OCCC#N)cc1
Yield: 76 %

Procedure:
A solution of 4-methylphenol, (20.0 g 0.185 moles), in acrylonitrile, (150 ml), was treated with benzyltrimethylammonium hydroxide, 40% in methanol (Triton B), (6 ml) and the reaction refluxed for 10 hours, then cooled, and evaporated in vacuo. The residual oil was partitioned between diethyl ether and water and the organic phase separated and washed with water, dilute sodium hydroxide solution, dilute hydrochloric acid, brine and dried (MgSO4). Evaporation of the solvent in vacuo gave 23.44 g of crude product, which was recrystallized from petroleum ether 60°-80° C./diethyl ether to yield 22.93 g, (76%) of pure product as a white crystalline solid, mp 47°-8° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]1[C:22](=O)[C:21]2[C:20]([C:24]([O:26]C)=O)=[CH:19][CH:18]=[CH:17][C:16]=2[NH:15][CH:14]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:35][NH2:36]>CO>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]1[C:22]2=[N:35][NH:36][C:24](=[O:26])[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([C:21]=32)[NH:15][CH:14]1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1nccn1Cc1ccccc1)C(c1ccccc1)N2
Solvent: O
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1nccn1Cc1ccccc1
Yield: 27 %

Procedure:
Methyl 3-(1-benzyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (3.7 g, 8.46 mmol) in hydrazine monohydrate (25 mL) and methanol (100 mL) was stirred at room temperature for 5 h. The resulting mixture was filtered to give 9-(1-benzyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as a white solid (950 mg, yield 27%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.61-4.64 (d, J=11.2 Hz, 1H), 4.99-5.12 (m, 1H), 6.83-6.89 (m, 4H), 7.14-7.28 (m, 1H), 7.36-7.38 (d, J=7.6 Hz, 1H), 7.54-7.58 (t, J=8.0 Hz, 7H), 12.20 (s, 1H). LC-MS (ESI) m/z: 420 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@:12]([CH3:16])([C:13]([OH:15])=O)[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:53][CH2:54][C:55]([C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[C:59]([C:72]([F:75])([F:74])[F:73])[CH:58]=1)=[O:56]>CCOC(C)=O.CN(C=O)C>[CH3:17][C:9]1([CH3:18])[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@:12]([CH3:16])([C:13](=[O:15])[NH:53][CH2:54][C:55]([C:57]2[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[C:59]([C:72]([F:73])([F:74])[F:75])[CH:58]=2)=[O:56])[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)O
Reactant: CCCCCCCCOc1ccc(C(=O)CN)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C(=O)CNC(=O)[C@@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F
Yield: 40 %

Procedure:
To a solution of protected oxazolidine-4-carboxylic acid 4 (176 mg, 1 equivalents), HATU (310 mg, 1.2 equivalents), and DIEA (1.2 mL, 10 equivalents) in CH2CL2/DMF (1:1, 10 mL) was added amino-acetophenone 3 (250 mg, 1.0 equivalents). The resultant mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (50 mL) and washed with 10% NH4Cl (2×50 mL) and saturated NaCl (1×50 mL). The solvent removed in vacuo and the product was obtained, silica gel column chromatography using the Combi-Flash system (Hex:EtOAc), as a white solid in 40% yield (185 mg). TLC (1:2 EtOAc:Hex), Rf=0.3; MS (ESI, M+Na)=572.99; 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.11 (d, 1H, J=8.4 Hz), 7.05 (d, 1H, J=8.4 Hz), 4.62-4.79 (m, 2H), 4.13 (t, 2H, J=6.4 Hz), 3.28 (br s, 1H), 1.22-1.90 (m, 30H), 0.89 (t, 3H, J=6.4 Hz).
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][C@H:14]([N:18]2[C:24](=[O:25])[CH2:23][CH2:22][NH:21][C@H:20]([CH3:26])[CH2:19]2)[CH2:15][O:16][CH3:17])[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:27][C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1>>[Cl:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]([N:21]2[CH2:22][CH2:23][C:24](=[O:25])[N:18]([C@H:14]([CH2:15][O:16][CH3:17])[CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:7][CH2:6]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:19][C@H:20]2[CH3:26])=[O:36])[CH:31]=[CH:32][CH:33]=1
Reactant: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)NCCC1=O
Reactant: O=C=Nc1cccc(Cl)c1
Agent: Cl
Product: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)N(C(=O)Nc2cccc(Cl)c2)CCC1=O
Yield: 58 %

Procedure:
In analogy to the procedure described for intermediate 58F, (R)-4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-methoxymethyl-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride and 3-chlorophenyl isocyanate gave the title compound in 58% yield as yellow oil. MS: 493.4 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][NH2:19])[CH:13]=[C:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=3[OH:24])[N:9]=[C:5]2[CH:4]=1.[C:29](Cl)(=[O:33])[C:30]([CH3:32])=[CH2:31].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:26]=[CH:25][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][NH:19][C:29](=[O:33])[C:30]([CH3:32])=[CH2:31])[CH:13]=[C:12]([C:20]([CH3:22])([CH3:23])[CH3:21])[C:11]=3[OH:24])[N:9]=[C:5]2[CH:4]=1
Reactant: CC(C)(C)c1cc(CCCN)cc(-n2nc3ccc(C(F)(F)F)cc3n2)c1O
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)NCCCc1cc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c(C(C)(C)C)c1

Procedure:
The title compound is prepared by the reaction of the compound of Example 58 with methacryloyl chloride in the presence of triethylamine in toluene.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1)C(=O)C.[CH3:18][NH:19][CH3:20].C(O)C.C>>[CH3:18][N:19]([CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1
Reactant: CNC
Reactant: CC(=O)N(CCCCCl)c1cc(C)cc(C)n1
Solvent: CCO
Product: Cc1cc(C)nc(NCCCCN(C)C)c1

Procedure:
N-(4-Chlorobutyl)-N-(4,6-dimethyl-2-pyridyl)acetamide (28 g., 0.11 mole) is heated with dimethylamine (25 g., 0.55 mole) in 250 mole of ethanol in the presence of cuprous chloride (0.5 g.) for 6 hours at 100°. On cooling the mixture is treated with charcoal, filtered, and then concentrated under vacuum. The residue is taken up in dilute sodium hydroxide and the mixture extracted with diethyl ether, then methylene chloride. The organic extracts are concentrated after washing with water. The residue, weighing 26 g is then refluxed in 5 N sodium hydroxide (200 ml) overnight. On cooling the mixture is extracted with methylene chloride. The organic extracts are washed with brine, dried over sodium sulfate and concentrated. The residue is distilled to obtain the product oil, b.p. 137-142/1.2 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[Sn](Cl)(Cl)(Cl)Cl.[OH2:18].[ClH:19]>C1C=CC=CC=1>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1[C:8]([CH2:3][CH2:4][CH2:5][Cl:19])=[O:18]
Reactant: COc1cc(OC)cc(OC)c1
Reactant: O
Reactant: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc(OC)c(C(=O)CCCCl)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
To a solution of 67.2 g (0.400 mole) of 1,3,5-trimethoxybenzene and 61 g (0.432 mole) of chloro-4 butyryl chloride in 300 ml of benzene, maintained at +5° C., a solution of 121 g (0.464 mole) of tin tetrachloride in 150 ml of benzene is added over 3 hrs 30 mins. It is agitated for 4 hrs at room temperature and the reaction mixture is rapidly poured onto 500 ml of iced water and 100 ml of 12N hydrochloric acid. The organic phase is decanted, washed with water and dried with anhydrous sodium sulphate. The oily residue is caked by washing with hexane, giving 97.2 g of a light grey powder.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=3C=O)[CH:8]=2)[N:3]=1.[CH2:32]([NH:34][CH2:35][CH2:36][OH:37])[CH3:33].[C:38](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=3[CH2:38][N:34]([CH2:32][CH3:33])[CH2:35][CH2:36][OH:37])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)ccc3C=O)ccc2n1
Reactant: CCNCCO
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCCl
Product: CCN(CCO)Cc1ccc(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
114 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4-fluorobenzaldehyde are dissolved in 2 ml of 1,2-dichloroethane and 2 ml of tetrahydrofuran. 57 μl of 2-(ethylamino)ethanol and 28 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 216 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH3:34])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].C(OC1C(=O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N2CCN(C)C(=O)C=12)C1C=CC=CC=1>>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:25][CH2:26][CH2:27]2)[N:8]2[CH2:2][CH2:3][N:4]([CH3:34])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(CCO)C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN1CCn2c(Cc3ccccc3-c3ccccc3)nc(=O)c(OCc3ccccc3)c2C1=O
Product: CN1CCn2c(CC3(c4ccccc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Yield: 56.7 %

Procedure:
9-Benzyloxy-2-methyl-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (31-01) (300 mg, 56.69%) was synthesized from 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (30-01) (550 mg, 1.193 mmol) as a white solid following the procedure as described for 9-benzyloxy-6-biphenyl-2-ylmethyl-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (11-01).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=O)[CH2:29][CH2:28]1.[Cl:36][C:37]1[CH:62]=[CH:61][C:40]2[N:41]3[C:45]([CH2:46][NH:47][CH2:48][C:39]=2[CH:38]=1)=[N:44][N:43]=[C:42]3[CH:49]1[CH2:54][CH2:53][N:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=2)[CH2:51][CH2:50]1>ClCCl>[NH3:8].[Cl:36][C:37]1[CH:62]=[CH:61][C:40]2[N:41]3[C:45]([CH2:46][N:47]([C:33]([CH:30]4[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]4)=[O:35])[CH2:48][C:39]=2[CH:38]=1)=[N:44][N:43]=[C:42]3[CH:49]1[CH2:50][CH2:51][N:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=2)[CH2:53][CH2:54]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: CN1CCC(C(=O)O)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN1CCC(C(=O)N2Cc3cc(Cl)ccc3-n3c(nnc3C3CCN(c4ccccn4)CC3)C2)CC1
Product: N
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (395 mg, 1.04 mmol) was added to a solution of 1-methylpiperidine-4-carboxylic acid hydrochloride (210 mg, 1.04 mmol) in dichloromethane (10 ml) and the solution stirred for 30 minutes. The amine from example 4 (200 mg, 0.52 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The mixture was washed with aqueous sodium carbonate solution and the organic solution was dried over magnesium sulphate. The solution was evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel using ethyl acetate:methanol:0.88 ammonia (90:10:1) as eluant, to afford the title compound as a white solid (195 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.O>CN1CCCC1=O>[N:10]1([C:2]2[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=2)[C:8]#[N:9])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: C1COCCN1
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccnc(N2CCOCC2)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 71.1 %

Procedure:
2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol) was dissolved in N-methylpyrrolidone (2.0 ml), and morpholine (0.7 ml, 8.0 mmol) was added thereto. The reaction mixture was stirred at 100° C. for 2.5 hrs and combined with water to give precipitates, which were collected by filtration and dried to give the titled compound (0.39 g, 70%).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH:9]1([C:12](O)=[O:13])[CH2:11][CH2:10]1.C(Cl)CCl.CCN(CC)CC>C(Cl)Cl>[CH:9]1([C:12]([O:1][N:2]2[C:6](=[O:7])[CH2:5][CH2:4][C:3]2=[O:8])=[O:13])[CH2:11][CH2:10]1
Reactant: O=C(O)C1CC1
Reactant: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(ON1C(=O)CCC1=O)C1CC1

Procedure:
1-Hydroxypyrrolidine-2,5-dione (1.18 g, 10.3 mmol), cyclopropanecarboxylic acid (1.01 ml, 10 mmol), EDC (2.01 g, 10.5 mmol) and Et3N (2.8 mmol, 20 mmol) in DCM were stirred at rt for 5 h before it was partitioned with saturated NH4Cl solution. The organic layer was washed with brine and dried over Na2SO4. After filtration and concentration, 2,5-dioxopyrrolidin-1-yl cyclopropanecarboxylate 24 was isolated and used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:12][C:13]([F:17])=[C:14]([F:16])[F:15].C1(O)C=CC=CC=1.[OH-].[K+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]([O:11][C:14]([F:16])([F:15])[CH:13]([F:17])[F:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: FC(F)=C(F)F
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: Oc1ccccc1
Product: O=[N+]([O-])c1ccc(OC(F)(F)C(F)F)cc1F
Reaction time: 2 h
Yield: 10.6 %

Procedure:
After dissolving 1.15 g of 3-fluoro-4-nitrophenol in 10 ml of dioxane, the resulting solution was violently stirred at about 60° C. for 15 minutes under the stream of a tetrafluoroethylene gas in large excess of said phenol. After quickly adding 0.04 g of potassium hydroxide, the solution was violently stirred for 2 hours under the same condition. The reaction solution was cooled, and after adding water, extracted with two 100-ml portions of diethyl ether. The ether layers were combined, dried and concentrated to obtain a yellow oily product as a residue. This oily product was subjected to chromatography on silica gel to obtain 0.20 g of 2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)nitrobenzene.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1)[CH3:25]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[N:7][C:2]([N:27]4[C@H:26]([CH2:24][CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Reactant: CC[C@@H]1COC(=O)N1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)nn1
Yield: 31.9 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (152 mg) described in Preparation Example 230 and (R)-4-ethyloxazolidin-2-one (79 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (60 mg) was obtained.