Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13]2=[N:14][C:15]3[N:16]([CH3:23])[CH2:17][N:18]([CH3:22])[C:19](=[O:21])[C:20]=3[N:12]2[C:11]([OH:24])=[CH:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(C)=O>[CH2:33]([C:10]1[C:9](=[O:25])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[N:12]([C:11]=1[OH:24])[C:20]1[C:19](=[O:21])[N:18]([CH3:22])[CH2:17][N:16]([CH3:23])[C:15]=1[N:14]=2)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CN1CN(C)c2nc3n(Cc4ccccc4)c(=O)cc(O)n3c2C1=O
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN1CN(C)c2nc3n(Cc4ccccc4)c(=O)c(Cc4ccccc4)c(O)n3c2C1=O

Procedure:
To a suspension of 7.1 g. (0.021 mole) of 9-benzyl-2,3-dihydro-1,3-dimethyl-6-(hydroxy)pyrimido[2,1-f]purine-4,8(1H,9H)-dione in 200 ml. of acetone, add 2.3 g. (0.023 mole) of triethylamine, and stir the mixture for 5 minutes at room temperature under a nitrogen atmosphere to obtain a clear solution. Add dropwise to the solution 4.7 g. (0.027 mole) of benzyl bromide, and reflux the mixture for 5 hours under a nitrogen atmosphere. Remove the acetone under reduced pressure, and triturate the gummy residue with methanol. Remove the resultant white solid by filtration, pour the filtrate into water, acidify to pH 4-5 with dilute hydrochloric acid, and decant the aqueous supernatant. Dissolve the gummy residue in the chloroform, wash the solution with water, and dry over anhydrous magnesium sulfate. Remove the drying agent by filtration, and evaporate solvent from the filtrate under reduced pressure. Chromatograph the residual oil on silica gel, eluting with chloroform(96)-methanol(4), to obtain the title compound as a solid with m.p. 176°-179° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[N:28]([CH3:36])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)(=O)=O.[CH3:39][NH:40][CH3:41].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][CH2:6][N:40]([CH3:41])[CH3:39])[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[N:28]([CH3:36])[C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=3)[C:11]=12
Reactant: COc1cc(-c2nn(CCOS(C)(=O)=O)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2nn(CCN(C)C)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 70 °C
Yield: 13.3 %

Procedure:
A mixture of 2-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-2-indolyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl methanesulfonate (Intermediate 4) (0.080 g, 0.15 mmol), dimethylamine (2.0 M in THF, 0.07 mL, 0.15 mmol), triethylamine (0.021 mL, 0.15 mmol), and sodium iodide (0.021 g, 0.15 mmol) in DMF (2.5 mL) was heated in a resealable tube at 70° C. for 15 h. Additional dimethylamine solution (0.10 mL) was added and the reaction mixture was heated at 70° C. for 20 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Water (5 mL) was added and the resulting precipitate was collected by filtration and purified by silica gel column chromatography (elution with 20% MeOH:CH2Cl2 to 10:30:60 Et3N:MeOH:CH2Cl2); the appropriate fractions were combined and concentrated to afford N2-(4-{4-amino-1-[2-(dimethylamino)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide as a white solid (0.009 g, 0.02 mmol). RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.52.
Reaction SMILES: [C:1]([C:6]1[CH:18]=[C:17]([C:19]([CH2:22][CH3:23])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:7]=1[O:8][CH:9]([CH2:13][CH3:14])[C:10](Cl)=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].[Cl:24][CH:25]([F:40])[C:26]([F:39])([F:38])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=1[OH:37])=[O:28].N1C2C(=CC=CC=2)C=CC=1.Cl>O1CCOCC1>[Cl:24][CH:25]([F:40])[C:26]([F:38])([F:39])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:10](=[O:11])[CH:9]([O:8][C:7]2[CH:15]=[CH:16][C:17]([C:19]([CH2:22][CH3:23])([CH3:21])[CH3:20])=[CH:18][C:6]=2[C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])[CH2:13][CH3:14])=[CH:32][C:31]=1[OH:37])=[O:28]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Cl
Reactant: Nc1ccc(NC(=O)C(F)(F)C(F)Cl)c(O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccc2ncccc2c1
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(NC(=O)C(F)(F)C(F)Cl)c(O)c1
Reaction time: 1.5 h

Procedure:
A solution of 33.85 g (0.1 mole) of 2-(2,4-di-tert-pentylphenoxy)butyryl chloride in 80 ml of dioxan was added to a solution of 26.85 g (0.1 mole) of 2-(3-chloro-2,2,3-trifluoropropionamido)-5-aminophenol and 23.7 ml (0.2 mole) of quinoline in 500 ml of dioxan at room temperature. The mixture was stirred for 90 minutes and left standing overnight. Next it was poured out in 2 l of icewater and 100 ml of concentrated hydrochloric acid. The sticky residue was extracted with ether, rinsed with water until free from acid, and dried. The solvent was evaporated and the residue recrystallized from hexane.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.[CH:25]1[CH:30]=[C:29]([CH:31]=[O:32])[C:28]([CH:33]=O)=[CH:27][CH:26]=1.C(O)(=O)C>C(#N)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:33][C:28]5[C:29](=[CH:30][CH:25]=[CH:26][CH:27]=5)[C:31]4=[O:32])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: O=Cc1ccccc1C=O
Reactant: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Solvent: CC(=O)O
Solvent: CC#N
Product: O=C1c2ccccc2CN1c1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1

Procedure:
4-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine (338.4 mg, 1.0 mmol) was reacted at reflux for 30 min with o-phthaldialdehyde (147.5 mg, 1.1 mmol) and a catalytic amount of acetic acid (57 μL, 0.1 mmol) in acetonitrile (100 mL) to give the title compound. The product obtained was purified by elution through a flash column (silica gel 40, 230–400 mesh, 100:8:1, CH2Cl:EtOH:NH4OH) to give a yellow crystalline material, yield=245 mg (53.9%). mp 175.9° C. MS (APCI): 455 [M+H]+. 1H-NMR (dmso-d6, δ): 2.59 (m, 2H) 2.66 (m, 4H) 2.77 (m, 2H) 3.43 (m, 4H) 4.98 (s, 2H) 7.30 (d, J=8.79 Hz, 2H) 7.40 (dd, J=8.67, 7.45 Hz, 1H) 7.52 (m, 2H) 7.64 (m, 2H) 7.77 (m, 3H) 8.03 (d, J=9.28 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH2:5][OH:6])[CH2:3][OH:4].[Na].Br[CH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[C:33]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])[CH:34]=1)[C:20]([NH:22][C@@H:23]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH3:24])=[O:21]>CN(C=O)C.C1COCC1>[NH2:1][C:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH2:3][OH:4])[CH2:5][O:6][CH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[C:33]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])[CH:34]=1)[C:20]([NH:22][C@@H:23]([C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)[CH3:24])=[O:21]
Reactant: NC(CO)(CO)Cc1ccccc1
Reactant: C[C@@H](NC(=O)c1cc(CBr)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)c1cc(COCC(N)(CO)Cc2ccccc2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of intermediate I 2-amino-2-benzylpropane-1,3-diol (0.09 g, 0.50 mmol) in 2 mL DMF cooled to 0° C. was added sodium hexamethyldisylazide (0.5 mL, 0.50 mmol, 1 M in THF). The reaction mixture was stirred at 0° C. for 5 min and intermediate A 3-(bromomethyl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (0.1 g, 0.23 mmol) in 1 mL DMF was added dropwise. The reaction mixture was stirred at 0° C. for 0.5 h, quenched with water, extracted with EtOAc, washed with aq LiCl (3×), dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography (40 g silica, 0→8% (10% NH4OH in MeOH)/CH2Cl2) to afford 3-[(2-amino-2-benzyl-3-hydroxypropoxy)methyl]-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide. 1H NMR (400 MHz, d4-MeOH) δ 7.80 (s, 2H), 7.64 (s, 1H), 7.44-7.40 (m, 2H), 7.26-7.20 (m, 5H), 7.07-7.02 (m, 2H), 5.24 (q, J=7.0 Hz, 1H), 4.61 (s, 2H), 3.48 (A of AB, d, J=10.4 Hz, 1H), 3.43 (B of AB, d, J=10.4 Hz, 1H), 3.35 (s, 3H), 2.91 (s, 3H), 2.72 (A of AB, d, J=13.9 Hz, 1H), 2.66 ((B of AB, d, J=13.9 Hz, 1H), 1.57 (d, J=7.0 Hz, 3H). HRMS calculated for C28H34FN3O5S+H: 544.2276, found: 544.2275
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[NH2:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:2]=1[Cl:1]
Reactant: Nc1ncnc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CNc2ncnc(N)c2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 10-mL vial was placed 5,6-dichloropyrimidin-4-amine (250.00 mg; 1.52 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (653.40 mg; 3.05 mmol), and N,N-diisopropylethylamine (1.01 ml; 6.10 mmol) suspended in NMP (2.50 ml). The reaction mixture was run in the microwave at 150° C. for 2 hours. The reaction mixture was allowed to cool to rt. The mixture was purified using Biotage column chromatography eluting from 50-100% EtOAc/Hexanes. Fractions containing the desired product were combined and concentrated under reduced pressure to afford tert-butyl 4-{[(6-amino-5-chloropyrimidin-4-yl)amino]methyl}piperidine-1-carboxylate as a yellow viscous oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][N:20]([CH3:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([N:20]([CH3:30])[CH3:19])[CH:26]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cccc(N(C)C)c3)cccc2c1N
Yield: 85.9 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 3-dimethylaminophenyl boronic acid (160 mg, 0.97 mmol) were reacted to afford the title compound (99 mg, 88.6% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.60 (br, 1H), 7.83 (m, 2H), 7.70 (t, J=7.7 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.03 (d, J=7.9 Hz, 1H), 6.98 (m, 1H), 6.82 (dd, J=8.3 Hz, J′=2.3 Hz, 1H), 3.46 (q, J=6.7 Hz, 2H), 2.99 (s, 6H), 1.67 (m, J=7.2 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H) MS APCI, m/z=350 (M+H) HPLC 1.60 min.
Reaction SMILES: O[CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([CH2:17][C:18]3[C:19]([F:29])=[C:20]4[C:25](=[CH:26][C:27]=3[F:28])[N:24]=[CH:23][CH:22]=[CH:21]4)=[N:15][N:16]=2)[N:13]=1)\[CH3:7].COCCN(S(F)(F)[F:40])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1(C)C=CC=CC=1>[F:40][CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([CH2:17][C:18]3[C:19]([F:29])=[C:20]4[C:25](=[CH:26][C:27]=3[F:28])[N:24]=[CH:23][CH:22]=[CH:21]4)=[N:15][N:16]=2)[N:13]=1)\[CH3:7]
Reactant: C/C(=N\OCCO)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C/C(=N\OCCF)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of (E)-1-(3-((5,7-difluoroquinolin-6-yl)methyl)-[1,2,4]-triazolo[4,3-b]pyridazin-6-yl)ethanone O-2-hydroxyethyl oxime (example 54) (20 mg, 0.05 mmol) in dry DCM (4 mL) was added bis-(2-methoxyethyl)aminosulfur trifluoride (a 3.2 M solution in toluene, 0.13 mL, 0.4 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, and then at 35° C. overnight. LC-MS showed the reaction was complete, and 5 mL of saturated NaHCO3 solution was added. The mixture was extracted with DCM; the organic phase was dried over Na2SO4, filtered, concentrated, and purified by column chromatography to afford 6.8 mg (34%) of the title compound as a white solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.95 (dd, 1H), 8.41 (dd, 1H), 8.00 (d, 1H), 7.81 (d, 1H), 7.66 (d, 1H), 7.46 (dd, 1H), 4.83 (s, 2H), 4.78 (dd, 1H), 4.67 (dd, 1H), 4.56 (dd, 1H), 4.49 (dd, 1H), 2.33 (s, 3H). LCMS (method A): [MH]+=401, tR=5.44 min.
Reaction SMILES: CS(O[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([CH2:39][P:40]([O:45][CH2:46][CH3:47])([O:42][CH2:43][CH3:44])=[O:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:17]3[C:13]=2[CH2:14][N:15]([CH3:51])[C:16]3=[O:50])[CH2:8][CH2:7]1)(=O)=O.[CH3:52][N:53](C=O)C>>[C:52]([C@@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([CH2:39][P:40](=[O:41])([O:42][CH2:43][CH3:44])[O:45][CH2:46][CH3:47])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:17]3[C:13]=2[CH2:14][N:15]([CH3:51])[C:16]3=[O:50])[CH2:8][CH2:7]1)#[N:53]
Reactant: CN(C)C=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](OS(C)(=O)=O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](C#N)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 100 °C

Procedure:
In 25 mL Schlenk tube, trans-4-(7-{[2-({4-[(diethoxyphosphoryl)methyl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexyl methanesulfonate (Compound 283A, 130.0 mg, 0.17 mmol) was dissolved in DMF (13.0 mL, 168 mmol) and was added degassed (3×) with argon. The reaction was heated at 100° C. under an atmosphere of argon for 7 hrs. The reaction was dissolved in EtOAc and washed with water (2×) and brine (1×) respectfully. The organic layer was collected and concentrated in vacuo to a solid and was purified by CombiFlash®Rf 4X Organic Purification System [dried loaded on 12 g silica load cartridge, 40 g RediSep® Normal-phase GOLD Silica Flash Column, elution gradient: 0>4% MeOH in DCM] to afford 37.4 mg (31.7%) of the desired product. 1H NMR (400 MHz, MeOD) δ 8.49 (br. s., 1H), 8.33 (s, 1H), 7.85 (d, J=7.58 Hz, 1H), 7.33 (d, J=8.59 Hz, 1H), 7.03-7.09 (m, 1H), 6.93 (td, J=2.27, 8.08 Hz, 1H), 4.51 (s, 2H), 4.08 (quin, J=7.26 Hz, 4H), 3.90 (s, 3H), 3.33 (s, 1H), 3.27 (s, 1H), 3.17 (s, 4H), 2.68 (d, J=5.56 Hz, 1H), 2.10 (d, J=10.36 Hz, 2H), 1.75-1.93 (m, 6H), 1.28 (t, J=7.07 Hz, 6H). MS (ES+): m/z 687.17/688.20 (100/70) [MH+]. HPLC: tR=1.54 min (Micromass TOF: polar—3 min).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[C:7](OCC)=[O:8].[CH:16]([NH2:18])=O>>[N:1]1[C:2]2[C:3]3[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=3[S:5][C:6]=2[C:7](=[O:8])[NH:18][CH:16]=1
Reactant: CCOC(=O)c1sc2ccccc2c1N
Reactant: NC=O
Product: O=c1[nH]cnc2c1sc1ccccc12
Temperature: 190 °C
Yield: 61.2 %

Procedure:
A 100 mL RBF was charged with ethyl 3-aminobenzo[b]thiophene-2-carboxylate (17.7 g, 80 mmol), treated with formamide (60.6 mL, 1520 mmol) and heated to 190° C. for 2 hrs. Precipitate formed upon cooling. The solid precipitate was collected by filtration and washed with ether, then recrystallized from ethanol/tetrahydrofuran. Benzo[4,5]thieno[3,2-d]pyrimidin-4(3H)-one (9.9 g, 61% yield) was obtained.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.C[N:15](C=O)C.N>ClCCl>[CH:1]1([CH2:6][C:7]([NH2:15])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: O=C(O)CC1CCCC1
Agent: N
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: NC(=O)CC1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
Cyclopentylacetic acid (5.2 g, 41 mmol) and thionyl chloride (10 mL) were combined then DMF (0.2 mL) was added and the solution was stirred 1.5 h at R.T. Dichloromethane (10 mL) was added and the solution cooled in an ice bath whereupon 25% aqueous ammonia (30 mL) was added and the mixture stirred for 0.5 h. The solution was extracted with CH2Cl2 (3×) and the combined extracts washed with 1N HCl, dried over MgSO4, and concentrated to give cyclopentylacetamide (2.699 g, 52%). [1H]-NMR(CDCl3) consistent with structure.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1.[C:19]([O:23][C:24]([N:26]1[CH2:29][CH:28]([C:30](O)=[O:31])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(N(CC)CC)C>[CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:30]([CH:28]3[CH2:29][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27]3)=[O:31])=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:4]=1
Reactant: CSc1nn(-c2ccccc2)c2cc(N)ccc12
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1nn(-c2ccccc2)c2cc(NC(=O)C3CN(C(=O)OC(C)(C)C)C3)ccc12
Temperature: 15 °C
Reaction time: 2 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(methylthio)-1-phenyl-1H-indazol-6-amine (500 mg, 1.96 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), triethylamine (0.5 mL), 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (470 mg, 2.34 mmol, 1.19 equiv), HATU (2.235 g, 5.88 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at 15° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5˜1:3) to yield tert-butyl 3-((3-(methylthio)-1-phenyl-1H-indazol-6-yl)carbamoyl)azetidine-1-carboxylate as a white solid. MS: 439 (MH+).
Reaction SMILES: CO[CH:3](OC)[CH:4]([C:17]#[N:18])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([Cl:14])=[C:8]([O:15][CH3:16])[CH:7]=1.[NH2:21][C:22]([NH2:24])=[NH:23]>>[NH2:23][C:22]1[N:24]=[C:17]([NH2:18])[C:4]([CH2:5][C:6]2[CH:7]=[C:8]([O:15][CH3:16])[C:9]([Cl:14])=[C:10]([O:12][CH3:13])[CH:11]=2)=[CH:3][N:21]=1
Reactant: N=C(N)N
Reactant: COc1cc(CC(C#N)C(OC)OC)cc(OC)c1Cl
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1Cl

Procedure:
21 G. of 4-chloro-3,5-dimethoxy-α-cyano-hydrocinnamaldehyde dimethyl acetal were heated to reflux for 1.5 hours with 140 ml. of a 1N methanolic guanidine solution. The solvent was then removed by distillation on an oil bath at 160° C. and the residue heated for 15-20 minutes at this temperature until completely solidified to a crystalline mass. The mass was slurried with 80-100 ml. of water and removed by filtration under suction, whereby there was obtained 2,4-diamino-5-(4-chloro-3,5-dimethoxybenzyl)-pyrimidine of melting point 218° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:42])[CH2:23][N:24]1[C:33](=[O:34])[C:32]2[N:31]([CH2:35][CH:36]=[C:37]([CH3:39])[CH3:38])[C:30](Cl)=[N:29][C:28]=2[N:27]([CH3:41])[C:25]1=[O:26].C(=O)([O-])[O-].[Na+].[Na+].O>CS(C)=O>[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:42])[CH2:23][N:24]1[C:33](=[O:34])[C:32]2[N:31]([CH2:35][CH:36]=[C:37]([CH3:38])[CH3:39])[C:30]([N:11]3[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]3)=[N:29][C:28]=2[N:27]([CH3:41])[C:25]1=[O:26]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: CC(C)=CCn1c(Cl)nc2c1c(=O)n(CC(=O)c1ccccc1O)c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1O)c(=O)n2C
Temperature: 60 °C
Reaction time: 18 h

Procedure:
1.30 g of 3-tert.-butyloxycarbonylamino-piperidine are added to a mixture of 2.51 g of 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine and 880 mg of sodium carbonate in 8 ml of dimethylsulphoxide. The reaction mixture is stirred for 18 hours at 60° C. For working up it is combined with water and the precipitate formed is suction filtered. The solid crude product is dissolved in ethyl acetate, the solution is dried over magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (10:1 to 1:1) as eluant.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@@H:6]([N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:7]([CH3:11])[CH2:8][CH2:9][OH:10].N1C=CN=C1.[CH3:26][C:27]([Si:30](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:29])[CH3:28]>CN(C=O)C.CCOC(C)=O>[Si:30]([O:10][CH2:9][CH2:8][C@@H:7]([CH3:11])[C@H:6]([N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)([C:27]([CH3:29])([CH3:28])[CH3:26])([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C[C@H](CCO)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of 2.18.1d (1.87 g, 6.60 mmol) in DMF (9.7 mL) at 0° C. was added imidazole (988 mg, 14.52 mmol, 2.2 equiv) and TBDPSCl (2.18 g, 7.92 mmol, 1.2 equiv). After stirring at room temperature for 12 hours, the reaction mixture was diluted with EtOAc (20 mL) and washed sequentially with water (5 mL), aqueous 1.0 M HCl solution, saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/heptane) to give product 2.18.1e (3.55 g, yield 100%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:25])[O:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])=[CH:7][CH:8]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: COC(COc1ccc(O)cc1)OC
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(NC(=O)Oc2ccc(OCC(OC)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-(2,2-Dimethoxyethoxy)phenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. 4-Methoxyphenyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is then stripped of solvent and unreacted isocyanate to yield the desired product O-[4-(2,2-dimethoxyethoxy)phenyl] N-4-methoxyphenylcarbamate as the residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2Cl)=O)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:15]=3[NH:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cnccc1Cl
Reactant: NN
Solvent: O
Solvent: CO
Product: Clc1ccc(-c2n[nH]c3ccncc23)cc1
Reaction time: 3 h
Yield: 33 %

Procedure:
(4-Chlorophenyl)-(4-chloropyridin-3-yl)-methanone (3.88 g, 15.4 mmol) was dissolved in MeOH (20 mL) at room temperature and hydrazine hydrate (20 mL) was added. The reaction mixture was stirred for 3 h. The precipitate was filtered and purified by recrystallisation from PhMe/MeOH (˜4:1, ˜150 mL) to give 3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]pyridine (1.16 g, 33.0%) as a yellow solid.