Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)[NH2:3].[C:13]([CH2:21][C:22](=O)[C:23]([F:26])([F:25])[F:24])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:14]1([C:13]2[N:2]([C:4]3[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=3)[N:3]=[C:22]([C:23]([F:24])([F:25])[F:26])[CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNc1ccc(CCO)cc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Agent: Cl
Solvent: CCO
Product: OCCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1
Yield: 56.2 %

Procedure:
A mixture of 2-(4-hydrazinophenyl)ethanol hydrochloride (J. Med. Chem., 1999, 42, 2504, 202 mg, 1.07 mmol) and benzoyl-1,1,1-trifluoroacetone (278 mg, 1.28 mmol) in ethanol (13 mL) was heated under reflux overnight. After removal of the solvent, the resulting residue was partitioned between dichloromethane and water. Organic phase was washed with brine and dried (Na2SO4). After removal of the solvent, the crude product was purified by TLC with hexane/ethyl acetate (1:1) to afford 200 mg (56%) of the title compound as yellow solids: MS (ESI) m/z 333 [M+H]+, 1H-NMR (CDCl3) δ 7.36-7.20 (9H, m), 6.74 (1H, s), 3.86 (2H, br.s), 2.89 (2H, t, J=6.6 Hz).
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[C:23]1[CH:33]=[CH:32][C:26]2[O:27][C:28]([F:31])([F:30])[O:29][C:25]=2[CH:24]=1>C1(C)C=CC=CC=1>[F:31][C:28]1([F:30])[O:27][C:26]2[CH:32]=[CH:33][C:23]([N:10]3[CH2:11][CH2:12][C:8]4([CH2:14][CH2:15][C:5]5([O:4][CH2:3][CH2:2][O:1]5)[CH2:6][CH2:7]4)[C:9]3=[O:13])=[CH:24][C:25]=2[O:29]1
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1N(c2ccc3c(c2)OC(F)(F)O3)CCC12CCC1(CC2)OCCO1
Temperature: 110 °C
Yield: 76.8 %

Procedure:
To a mixture of 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (262 mg, 1.24 mmol, obtained in example 133, step 3), potassium carbonate (790 mg, 3.72 mmol) and cuprous iodide (354 mg, 1.86 mmol) was added a solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (588 mg, 2.48 mmol) in 5 ml toluene under argon. The solution was then degassed by bubbling argon through the mixture for 2 mins after which N—N′-dimethylethylenediamine (266 uL, 2.48 mmol) was added. The sealed tube was closed and the mixture was heated to 110° C. overnight. The reaction mixture was then cooled to room temperature and filtered through a short pad of Celite® using ethyl acetate to wash the mixture through. The solution was then concentrated in vacuo to give a residue which was purified by flash column chromatography (3:7 ethyl acetate heptane) to give the title compound as white solid (350 mg, 75%). MS (m/e): 368.0 [MH+].
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Br:15])[CH:13]=2)[CH2:8][CH2:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>CCO>[CH2:1]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Br:15])[CH:13]=2)[CH2:8][CH2:7][NH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=NCCc2ccc(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCC1NCCc2ccc(Br)cc21
Reaction time: 2 h

Procedure:
The imine from Step 2 was dissolved in absolute EtOH (25 mL) and NaBH4 (0.303 g, 8.0 mmol) was added. After 2 h, the solvent was removed and the residue treated with 1N HCL. Conc. NH40H was added to the solution which was then extracted with CH2Cl2 (3×), washed with brine, dried and concentrated to give the title compound as a viscous oil which was used as such.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13]([O:15]CC)=O)[C:9]([CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[C:21]([OH:26])[CH:20]=1>C1(C)C(C)=CC=CC=1>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13](=[O:15])[NH:25][C:24]3[CH:19]=[CH:20][C:21]([OH:26])=[CH:22][CH:23]=3)[C:9]([CH3:18])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1C(=O)N(c2ccccc2)N=C1C
Reactant: Nc1ccc(O)cc1
Solvent: Cc1ccccc1C
Product: CC1=NN(c2ccccc2)C(=O)C1C(=O)Nc1ccc(O)cc1

Procedure:
The solution of 2.2 g of 1-phenyl-3-methyl-4-carbethoxy-2-pyrazolin-5-one and 1.1 g of p-aminophenol in 120 ml xylene is refluxed for one hour, and 15 ml of the solvent are distilled off gradually to remove water. The cooled mixture is filtered and evaporated, the residue crystallized from warm methanol and recrystallized from ethyl acetate, to yield the 1-phenyl-3-methyl-4-(p-hydroxyphenylcarbamoyl)-2-pyrazolin-5-one melting at 135°-140° and remelting at 225°; it contains half a mole of ethyl acetate as solvate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[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.C(N(C(C)C)CC)(C)C.[CH2:50]([CH2:52][NH2:53])[OH:51]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14](=[O:16])[NH:53][CH2:52][CH2:50][OH:51])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)NCCO)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.6 %

Procedure:
(S)-Piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (500 mg, 2.2 mmol), HATU (833 mg, 2.2 mmol) and Di-isopropylethylamine (761 μL, 4.4 mmol) were stirred in dry DCM (10 ml) in an ice bath for 5 min, then at room temperature for 5 min. Ethanolamine (198 μL, 3.28 mmol) was added and the reaction stirred at room temperature for 3 hrs. The reaction was diluted with DCM (40 ml), washed with water (50 ml), the DCM layer separated and dried (MgSO4) and concentrated. The residue was columned on silica (20 g isolute). Eluting: MeOH/DCM 0-5% 5 CV, MeOH/DCM 5%-5% 10 CV, MeOH/DCM 5-10% 5 CV. TLC visualized with KMnO4. This yielded the product as a clear oil (327 mg).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]#[N:10])[CH:4]=1.Br>>[OH:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]#[N:10])[CH:4]=1
Reactant: COc1ccnc(C#N)c1
Agent: Br
Product: N#Cc1cc(O)ccn1
Temperature: 130 °C
Reaction time: 22 h
Yield: 301.8 %

Procedure:
4-Methoxy-2-pyridinecarbonitrile (544 mg, 4.055 mmol) was added with 47% hydrobromic acid (6 ml) and refluxed by heating at 130° C. The reaction solution was stirred for 22 hours, returned to room temperature, and then concentrated under reduced pressure. The residue was subjected to azeotropy with toluene and diethyl ether to remove excessive hydrobromic acid. The resulting white crystals were washed with diethyl ether to obtain 1.47 g of the title compound containing hydrogen bromide without purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:23][CH3:24])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:25][C:26]1[C:27]([O:42][CH3:43])=[N:28][C:29]([O:40][CH3:41])=[C:30]([Cl:39])[C:31]=1[C:32](=O)[C:33]([O:35]CC)=O.CC(O)=O>COCCO>[Cl:39][C:30]1[C:29]([O:40][CH3:41])=[N:28][C:27]([O:42][CH3:43])=[C:26]([Cl:25])[C:31]=1[C:32]1[C:33](=[O:35])[N:23]([CH3:24])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:11][CH:10]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(=O)C(=O)c1c(Cl)c(OC)nc(OC)c1Cl
Reactant: CCN(CC)CCOc1ccc(Nc2ncc(N)c(NC)n2)cc1
Solvent: COCCO
Solvent: CC(=O)O
Product: CCN(CC)CCOc1ccc(Nc2ncc3nc(-c4c(Cl)c(OC)nc(OC)c4Cl)c(=O)n(C)c3n2)cc1
Yield: 51.4 %

Procedure:
A mixture of 0.66 g (2 mmol) of 5-amino-2-[[4-[2-(diethylamino)-ethoxy]phenyl]amino]-4-(methylamino)pyrimidine, 1.23 g (4 mmol) of ethyl 2-(3,5-dichloro-2,6-dimethoxypyridin-4-yl)-2-oxoacetate, and 1 mL of HOAc in 20 mL of 2-methoxyethanol is heated under reflux for 16 hours. Workup as in 6 above gives 0.59 g (51%) of the title compound (Compound 21): mp (EtOH) 239–240° C.
Reaction SMILES: [NH2:1][C:2](=[S:15])[CH2:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10]C)=[O:8].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=O>>[F:27][C:26]([F:28])([F:29])[C:22]1[CH:21]=[C:20]([C:18]2[N:1]=[C:2]([CH2:3][C:4]3[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=3)[C:7]([O:9][CH3:10])=[O:8])[S:15][CH:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cccc(CC(N)=S)c1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1cccc(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)c1
Yield: 99.9 %

Procedure:
By a reaction in the same manner as in Example 178b and using the compound (223 mg, 1.00 mmol) obtained in Example 180b and 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (267 mg, 1.0 mmol), the title compound (377 mg, 96%) was obtained as a yellow oil.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:38][CH:37]4[N:22]([C:23](=[O:43])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40](O)=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C([NH:88][S:89]([CH:92]6[CH2:94][CH2:93]6)(=[O:91])=[O:90])=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:38][CH:37]4[N:22]([C:23](=[O:43])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([NH:88][S:89]([CH:92]6[CH2:94][CH2:93]6)(=[O:91])=[O:90])=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C

Procedure:
The title compound was prepared from 18-[2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (29) following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide 11: m/z=750 (M+H)+. 1H NMR (CDCl3): 0.90-1.00 (m, 1H), 1.1-1.2 (m, 4H), 1.4 (d, J=6.9 Hz, 6H), 1.4-1.6 (m, 4H), 2.15-2.25 (m, 1H), 2.3-2.4 (m, 1H), 2.45-2.55 (m, 2H), 2.65 (s, 3H), 2.6-2.7 (m, 2H), 2.85-2.95 (m, 1H), 3.15-3.5 (m, 7H), 3.95 (d, J=10.8 Hz, 1H), 3.95 (s, 3H), 4.1 (dd, J=11.5 Hz, J=3.8 Hz, 1H), 4.6 (t, J=8 Hz, 1H), 5.0 (t, J=9 Hz, 1H), 5.5 (t, J=3.14 Hz, 1H), 5.7-5.8 (dd, J=18.2 and J=8.2 Hz, 1H), 6.85 (s, 1H), 7.02 (s, 1H), 7.2 (d, J=9.5 Hz, 1H), 7.5 (s, 1H), 7.85 (d, J=9.5 Hz, 1H), 10.5 (br s, 1H).
Reaction SMILES: C(OC(N[C:8]1[CH:12]=[CH:11][S:10][C:9]=1/[C:13](=[CH:15]/[CH:16]([CH3:18])[CH3:17])/[CH3:14])=O)(C)C.[CH:19]([O:22][C:23](NC1C=CSC=1/C(=C\C(C)C)/C)=[O:24])([CH3:21])[CH3:20].C(OC(NC1C=CSC=1C(CC(C)C)=C)=O)(C)C>[C].[Pd].CO>[CH:19]([O:22][C:23]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:13]([CH3:14])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:24])([CH3:21])[CH3:20]
Reactant: C/C(=C\C(C)C)c1sccc1NC(=O)OC(C)C
Reactant: C/C(=C/C(C)C)c1sccc1NC(=O)OC(C)C
Agent: [Pd]
Agent: C=C(CC(C)C)c1sccc1NC(=O)OC(C)C
Solvent: CO
Product: CC(C)CC(C)c1sccc1C(=O)OC(C)C
Reaction time: 9 h
Yield: 70 %

Procedure:
2.06 g (7.72 mmol) of the mixture of 3-isopropoxycarbonylamino-{2-(E)-(4-methyl-2-penten-2-yl)}thiophene, 3-isopropoxycarbonylamino-{2-(Z)-(4-methyl-2-penten-2-yl)}thiophene, and 3-isopropoxycarbonylamino-{2-(4-methyl-1-penten-2-yl) }thiophene obtained in Example 13 and 0.41 g of 5% palladium carbon (Degussa chemical catalyst E106R/W) were charged into 20 ml of methanol, and after nitrogen purge, a hydrogenation reaction was conducted at normal pressure under hydrogen atmosphere for 9 hours. After nitrogen purge, the catalyst was filtrated off, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 1.61 g of the intended compound as a colorless crystal (yield: 70%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30](Br)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:40][N:41](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([C:40]#[N:41])=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C#N)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
A mixture of diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (20.0 mg, 0.0318 mmol), zinc cyanide (3.74 mg, 0.0318 mmol), Pd(PPh3)4 (5.52 mg, 0.00477 mmol) in DMF (0.5 mL) was evacuated and purged with N2 three times. The mixture was irradiated in a microwave reactor at 150° C. for 5 minutes. The crude mixture was passed though a Thiol-SPE cartridge to remove Pd and subsequently purified by MDP. The title compound was obtained as white solid (13.5 mg, 74% yield). 1H NMR (400 MHz, CDCl3) δ=1.29 (t, J=7.1 Hz, 6H), 3.20 (d, J=21.5 Hz, 2H), 3.24 (s, 3H), 4.09 (quin, J=7.3 Hz, 4H), 4.54 (s, 2H), 7.31-7.39 (m, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.56 (br. s., 1H), 7.70 (d, J=8.8 Hz, 1H), 8.44 (s, 1H), 8.70 (d, J=8.3 Hz, 1H), 10.85 (s, 1H). MS (ES+): m/z 575.21 (100) [MH+] HPLC: tR=1.08 min (UPLC, purity).
Reaction SMILES: CS(C)=O.[CH2:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[O:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][N:18]=[C:17]([CH2:23][OH:24])[CH:16]=1.C(N(CC)CC)C>O>[CH2:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:6]1[O:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][N:18]=[C:17]([CH:23]=[O:24])[CH:16]=1
Reactant: COc1cnc(CO)cc1OC1Cc2ccccc2C1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1cnc(C=O)cc1OC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 72.4 %

Procedure:
To a dimethyl sulfoxide solution (20 ml) of 4-(2-indanyloxy)-5-methoxy-2-pyridinemethanol (5h) (2.71 g, 10 mmol) and triethylamine (3.03 g, 30 mmol) was added sulfur trioxide-pyridine complex (4.77 g, 30 mmol), and the mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into cold water to cause precipitation of crude crystals. The crude crystals were collected by filtration, dried, and purified by silica gel column chromatography, to thereby obtain the title compound (1.95 g, yield 72%).
Reaction SMILES: CN1CCCC1=O.Cl[C:9]1[N:10]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([C:24]1[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1)[N:12]=2.[CH3:36][C@H:37]1[CH2:42][NH:41][CH2:40][CH2:39][NH:38]1>C(Cl)Cl.CO>[CH3:36][C@@H:37]1[NH:38][CH2:39][CH2:40][N:41]([C:9]2[N:10]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:11]3[C:16]([N:17]=2)=[C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:14]=[C:13]([C:24]2[CH:29]=[N:28][C:27]([NH2:30])=[N:26][CH:25]=2)[N:12]=3)[CH2:42]1
Reactant: C[C@H]1CNCCN1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC(F)(F)F)c3n2)cn1
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Temperature: 100 °C
Reaction time: 5 h
Yield: 30.8 %

Procedure:
An N-methyl-2-pyrrolidone suspension (10 ml) of 5-[8-chloro-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (1.02 g, 2.46 mmol) and (2S)-2-methylpiperazine (1.23 g, 12.3 mmol) was heated at 120° C. to dissolve and then the resulting mixture was stirred at 100° C. for 5 hours. The resulting mixture was left standing to cool, poured into methylene chloride-methanol (10:1), and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting solid was washed with a small amount of methylene chloride and collected by filtration to give the title compound (362.9 mg). The filtrate was concentrated under reduced pressure and the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=32:1 to 7:1) to give the title compound (623.8 mg). These lots were combined to give the title compound (986.7 mg, 84%) as a pale yellow solid.
Reaction SMILES: C([Li])(C)(C)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][N:8]=1.CN(C)[CH:19]=[O:20].[NH4+].[Cl-]>CCCCC.C(OCC)C>[Cl:6][C:7]1[CH:12]=[C:11]([C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][N:8]=1)[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: COCOc1ccc(Cl)nc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCC
Product: COCOc1cnc(Cl)cc1C=O
Temperature: -76 °C
Reaction time: 0.33 h

Procedure:
tert-Butyllithium in pentane (1.7 M, 19.0 mL) was added dropwise to a solution of 2-chloro-5-(methoxymethoxy)pyridine (4.880 g, 28.11 mmol) in 100 ml of ethyl ether at −76° C. Some precipitate appeared. The mixture was kept at −76° C. for 20 min then N,N-dimethylformamide (2.938 mL, 37.95 mmol) was added dropwise. The mixture was stirred for 10 min at −76° C. and then allowed to warm to at 0° C. for 1 h period. 10% aq NH4Cl was added and the mixture was extracted with ethyl acetate. The organic solution was washed with water, brine and dried over Na2SO4. After concentration in vacuum the yield of the crude 2-chloro-5-(methoxymethoxy)isonicotinaldehyde 5.49 g. MS: 202.0, 172.0. Without further purification was used in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[C:17]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23])#[N:18]>>[C:17]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:23])#[N:18]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cccc(C#N)c3)c2)CC1
Yield: 26.6 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 3-cyanobenzoyl chloride (114 mg, 0.687 mmol), 21.2 mg (27%) of the title compound were recovered.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH:22]2[CH2:35][C:34]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH3:37])[CH:32]=4)[N:27]=[CH:26][C:25]=3[O:24][CH2:23]2)[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[CH3:37][O:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][C:25]1[O:24][CH2:23][CH:22]([CH2:21][N:18]3[CH2:19][CH2:20][CH:15]([NH2:14])[CH2:16][CH2:17]3)[CH2:35][C:34]2=1
Reactant: COc1ccc2ncc3c(c2c1)CC(CN1CCC(NC(=O)OC(C)(C)C)CC1)CO3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2ncc3c(c2c1)CC(CN1CCC(N)CC1)CO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 114.2 %

Procedure:
Trifluoroacetic acid (1.25 mL, 16.10 mmol, 15.0 eq) is added at 0° C. to a stirred solution of [1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-piperidin-4-yl-carbamic acid tert-butyl ester (540 mg, 1.07 mmol, 1.0 eq) in dichloromethane (15 mL). After 2 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×20 mL) and water (20 mL) and the pH is adjusted to 12 by the addition of a 1N sodium hydroxide aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-piperidin-4-ylamine as an orange viscous oil (400 mg, 97% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]([O:10][C:11](=[O:19])[NH:12][C@H:13]1[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]1)([CH3:9])[CH3:8].C(N(CC)CC)C>CC(C)=O.O>[CH3:9][C:7]([O:10][C:11](=[O:19])[NH:12][C@H:13]1[CH2:17][CH2:16][C@@H:15]([O:18][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14]1)([CH3:6])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)C1
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Temperature: 4 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
Methanesulphonyl chloride (0.98 ml, 12.6 mmol) was added to a stirred mixture of (1S-cis)-(3-hydroxycyclopentyl)carbamic acid 1,1-dimethylethyl ester (1.41 g, 7.01 mmol) and triethylamine (1.76 ml, 12.6 mmol) in acetone(55 ml) at 4° C. The resulting mixture, containing a white precipitate, was stirred at 4° C. for one hour, then at 21° C. for a further 2.25 h, after which it was diluted with water(150 ml) and extracted with ethyl acetate (3×100 ml). The total organic solution was washed with water (50 ml), dried (MgSO4) and evaporated to a white solid. This was dissolved in hot diethyl ether (25 ml) and cooled to 4° C. for 2 h, after which time, cyclohexane (25 ml) was added which caused a precipitate to form immediately. The mixture was left to stand at 4° C. for a further 3 h, after which the solid was filtered off, washed with cold cyclohexane/diethyl ether(2:1), then dried to give the title compound (1.202 g) as a white solid, m.p. 88°-89° C., [α]D -11.11° (CHCl3 c=0.54%).
Reaction SMILES: Cl[C:2]1[C:3]([CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>>[CH:17]1([C:3]2[C:2]([NH:25][CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])=[N:7][N:6]3[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Reactant: CN(C)CCN
Product: CN(C)CCNc1nn2c(-c3ccccc3)nnc2cc1C1CCC1

Procedure:
6-Chloro-7-cyclobutyl-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (100 mg, 0.35 mmol) and N,N-dimethylethylenediamine were heated together in a sealed tube at 60° C. for 24 h. The mixture was cooled and the white precipitate was collected by filtration and washed with diethyl ether, then dried to give the title compound. 1H NMR (250 MHz, CDCl3) δ 1.94 (1H, m), 2.12-2.24 (3H, m), 2.29 (6H, s), 2.41-2.50 (2H, m), 2.59-2.64 (2H, m), 3.38-3.49 (3H, m), 5.51 (1H, vbs), 7.41-7.52 (3H, m), 7.62 (1H, m), 8.54-8.62 (2H, m); MS (ES+) m/e 337 [MH]+.