Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][N:6]([C:9]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH:19]([C:24]3[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=3)[C:20]([F:23])([F:22])[F:21])=[CH:13][C:10]=2[C:11]#[N:12])[N:5]=1)([O-])=O.[NH4+].[Cl-]>CO.[Zn]>[NH2:1][C:4]1[N:8]=[CH:7][N:6]([C:9]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH:19]([C:24]3[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=3)[C:20]([F:21])([F:22])[F:23])=[CH:13][C:10]=2[C:11]#[N:12])[N:5]=1
Reactant: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc([N+](=O)[O-])n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a stirred solution of (E)-2-(3-nitro-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile (0.6 g, 1.2 mmol) in MeOH (10 mL), were added Zn dust (0.39 g, 5.98 mmol) and sat. aq NH4Cl solution (5 mL) and the resultant reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction (TLC), the reaction mass was concentrated under reduced pressure. The reaction mass was diluted with CH2Cl2, filtered through a celite bed, and the obtained filtrate concentrated under reduced pressure to afford the title compound as a solid (0.5 g, 89%): mp 72-75° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.26 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.91 (s, 2H), 7.77 (d, J=8.4 Hz, 1H), 6.42 (dd, J=15.6, 9.2 Hz, 1H), 6.83 (d, J=15.6 Hz, 1H), 5.87 (s, 2H), 4.89 (m, 1H); ESIMS m/z 469.95 ([M−H]−).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][C:21]([C:24]([O:26]CC)=[O:25])=[CH:20]2)(=[O:13])=[O:12])(=[O:4])=[O:3].[OH-].[Na+].O1CCCC1>CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20]2)(=[O:12])=[O:13])(=[O:3])=[O:4]
Reactant: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1cccc2cc(C(=O)O)[nH]c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A mixture of ethyl 7-{[2-(methylsulfonyl)phenylsulfonyl]amino}-1H-indole-2-carboxylate (1.84 g), 8N aqueous sodium hydroxide solution (2.50 mL), tetrahydrofuran (5 mL) and methanol (5 mL) was stirred at 60° C. for 2 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (1.67 g, yield 97%) as yellow crystals. melting point>304° C. (decomposition).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:30]1([CH2:36][S:37](O)(=[O:39])=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:18][CH:17]([NH:29][S:37]([CH2:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:39])=[O:38])[CH2:16]2)=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Reactant: O=S(=O)(O)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NS(=O)(=O)Cc3ccccc3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
55 mg (0.12 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 7A) and 21 mg (0.11 mmol, 0.9 eq.) of phenylmethanesulphonic acid were reacted according to General Method 6. Yield: 14 mg (24% of theory)
Reaction SMILES: Br[C:2]1[C:3]([N:7]2[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:4][S:5][CH:6]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[C:2]([C:25]4[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=4)=[CH:6][S:5][CH:4]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: OB(O)c1ccncc1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cscc2Br)CCN(C)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2-c2cscc2-c2ccncc2)CCN(C)C1
Temperature: 95 °C

Procedure:
To a de-aerated solution of 5-(4-bromo-thiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (160 mg, 0.44 mmol), 4-pyridinylboronic acid (81.9 mg, 0.66 mmol) and K3PO4 (235 mg, 1.11 mmol) in DMF-water (4.5:0.5 mL) was added dichlorobis(triphenylphosphine) palladium (II) (15.5 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(4-pyridin-4-yl-thiophen-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (90 mg). 1H NMR (Oxalate salt, CD3OD) δ (ppm): 8.4-8.3 (bs, 2H), 8.19 (s, 1H), 7.8 (s, 1H), 7.35 (s, 1H), 7.05-6.9 (m, 4H), 4.7-4.5 (m, 2H), 3.7-3.5 (m, 2H), 3.1 (s, 3H), 3.05-3.0 (m, 1H), 2.7-2.59 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34](O)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH2:34][N:1]1[CH2:2][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)=[N:6]2)[CH2:4]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Reactant: Cn1ccnc1C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cn1ccnc1CN1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Yield: 25.9 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.06 g, 0.00017 mol), 1-methyl-1H-2-imidazolecarboxylic acid (0.056 g, 0.0005 mol), and acetic acid (0.03 g, 0.0005 mol) in dichloroethane (2.5 mL) was stirred at room temperature under an atmosphere of nitrogen for one and a half hours. Sodium triacetoxyborohydride (0.072 g, 0.00034 mol) was added into the mixture and stirred at ambient temperature under an atmosphere of nitrogen for two hours. The solvent was removed under reduced pressure, and the residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 25 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-{1-[(1-methyl-1H-2-imidazolyl)methyl]-3-azetanyl}-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.020 g, 0.000044 mol).
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:2]([CH3:1])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]1)[N:10]=[C:9]2[N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: C1CCNC1
Product: Cc1cccc(C)c1CNc1cc2c(N3CCCC3)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. for C25H25FN6O2, 460.2
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:8]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[C:17]([O:25][CH3:26])=[C:16]([CH2:27]Br)[C:15]1=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[C:17]([O:25][CH3:26])=[C:16]([CH2:27][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:15]1=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCn1c(=O)c(CBr)c(OC)c2cc(C)ccc21
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCn1c(=O)c(Cn2ccnc2)c(OC)c2cc(C)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of imidazole (0.07 g) in dimethylformamide (1.5 ml) was stirred with 60% sodium hydride (0.04 g) at ice-bath temperature under nitrogen until the reaction was complete. The reaction mixture was then treated with a solution of 1-hexyl-3-bromomethyl-4-methoxy-6-methyl-2(1H)-quinolinone (Example 14, 0.27 g) in dimethylformamide (3 ml) and stirred at room temperature for 2 hours. The solution was then diluted with ethyl acetate and washed several times with water. The organic layer was then dried and evaporated under reduced .pressure. The crude reaction product was chromatographed on silica-gel (44 g). Elution with 2% methanoldichloromethane gave 1 -hexyl-3-(1H-imidazol- 1 -ylmethyl)-4-methoxy-6-methyl-2(1H)-quinolinone which crystallized as a white solid. That the expected product was obtained was confirmed by the spectral data: MS: m/e 353 (M+); NMR (CDCl3): δ3.90 (s, 3H, OCH3), 5.18 (s, 2H, CH2 -Im), 6.99, 7.14, 7.72 (s, 3H, CH=) wherein Im represents imidazole.
Reaction SMILES: [CH2:1]([C:3]1([C:11](Cl)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH3:10])[CH3:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>CCOCC>[CH2:1]([C:3]1([C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH3:10])[CH3:2]
Reactant: C1COCCN1
Reactant: CCC1(C(=O)Cl)CCCCCC1C
Solvent: CCOCC
Product: CCC1(C(=O)N2CCOCC2)CCCCCC1C

Procedure:
1-Ethyl-2-methylcycloheptanecarbonyl chloride (1.5 g, 0.007 mole) in ether (10 ml.) was added slowly to a solution of morpholine (0.02 mole) in ether (10 ml.). The mixture was washed with dilute hydrochloric acid, dilute sodium bicarbonate and then with water. The ether layer was dried and distilled to give N-(1-ethyl-2-methylcycloheptanecarbonyl) morpholine bp. 145°-7°/0.35 mm.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=2)=[N:7][N:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=12)=[O:4].[F-:25].[K+].O>CC(N(C)C)=O>[Br:24][C:20]1[CH:19]=[C:18]([C:6]2[C:5]([C:3](=[O:4])[CH2:2][F:25])=[C:9]3[CH:10]=[CH:11][C:12]([C:14]([F:16])([F:17])[F:15])=[CH:13][N:8]3[N:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: [F-]
Reactant: O=C(CBr)c1c(-c2cccc(Br)c2)nn2cc(C(F)(F)F)ccc12
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(CF)c1c(-c2cccc(Br)c2)nn2cc(C(F)(F)F)ccc12
Yield: 49.9 %

Procedure:
A solution of 2-bromo-1-[2-(3-bromophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (300 mg, 0.65 mmol, obtained from composite batches), KF (190 mg, 3.27 mmol) in DMA (10 mL) was heated for 3 h at 80° C. Water (25 mL) was added and the aqueous layer was extracted with EtOAc (2×50 mL). The organic layers were combined and purified by LC (2-10% EtOAc in hexanes) to yield the desired product (130 mg, 42%) as a pale yellow glass. ESIMS (M+H)+=401.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10]C(=O)OCC2C=CC=CC=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd]>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCCCCN1CCCC1)OCc1ccccc1
Agent: [Pd]
Product: NCCCCN1CCCC1
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of benzyl 4-(pyrrolidin-1-yl)butylcarbamate (196 mg, 0.71 mmol) was added catalytic amount of Pd/C (5%). The reaction was stirred under a hydrogen atmosphere overnight and filtered. The filtrate was concentrated to give 4-(pyrrolidin-1-yl)butan-1-amine (83 mg)
Reaction SMILES: C([N:8]1[CH:15]([CH3:16])[CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:16][CH:15]1[CH2:14][CH:13]2[CH:9]([CH2:10][N:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]2)[NH:8]1
Reactant: CCOC(=O)N1CC2CC(C)N(Cc3ccccc3)C2C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CC2CC(C)NC2C1

Procedure:
32 g (0.11 mol) of ethyl 2-benzyl-3-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate in 560 ml of ethanol are hydrogenated on 4.5 g of palladium/active carbon at 100° C. and 100 bar. The catalyst is filtered off with suction, the filtrate is concentrated, and the residue is distilled.
Reaction SMILES: [C:1]([P:3](=[O:10])([O:7]CC)[O:4][CH2:5][CH3:6])#[N:2].[I-].[CH3:12][S+:13]([CH3:16])([CH3:15])=[O:14].CC(N(C)C)=O.CCOCC>CC(C)=O>[CH2:5]([O:4][P:3]([C:1]#[N:2])(=[O:7])[O-:10])[CH3:6].[CH3:12][S+:13]([CH3:16])([CH3:15])=[O:14]
Reactant: CCOP(=O)(C#N)OCC
Agent: C[S+](C)(C)=O
Agent: [I-]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CCOP(=O)([O-])C#N
Temperature: 80 °C
Yield: 67.6 %

Procedure:
Diethyl cyanophosphonate (0.50 g, 3.06 mmol) and trimethylsulfoxonium iodide (0.673 g, 3.06 mmol) were added to dimethylacetamide (1 mL) which was heated to 80° C. for 1 hour. Then ether (9 mL) containing 1 mL of acetone was added to give 0.47 g (78% yield) of a viscous residue which was crystallized within 15 hours. It was washed by CH2Cl2 and dried under vacuum, and analyzed by NMR and mass spectrometry. 31P NMR (D2O) δ (ppm) -19.7 (t, 3JPH =9.15 Hz); 1H NMR (D2O) δ (ppm) 1.22 (t), 3.78 (s), and 4.05 (qnt); 13C NMR (D2O) δ (ppm) 118.1 (d, 1JCP =178.9 Hz), 63.3 (d, 1JCP =6.3 Hz), 39.5, 15.0 (d, 3JCP =6.87 Hz). Mass spectral analysis (FAB+, DTT:DTE, 1:1) detected a peak at m/z 320.1, corresponding to the complex [[+OS(CH3)3 -O(OC2H5)POCN] [OS(CH3)3 ]+ ], the presence of a cation at m/z 93 ([OS(CH3)3 ]+) and an anionic species (FAB-, DTT:DTE, 1:1) at m/z 134 [NCP(O)(OC2H5)O - ].
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]([N:7]1[CH2:19][C:18]2[S:17][C:16]3[N:15]=[CH:14][N:13]=[C:12]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=4)[C:11]=3[C:10]=2[CH2:9][CH2:8]1)=[O:6].[CH:29]([NH:32][CH3:33])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C.CO.ClCCl>ClCCl.CN(C=O)C.CC#N.O>[Cl:28][C:23]1[CH:22]=[C:21]([NH:20][C:12]2[C:11]3[C:10]4[CH2:9][CH2:8][N:7]([C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:32]([CH:29]([CH3:31])[CH3:30])[CH3:33])[CH2:19][C:18]=4[S:17][C:16]=3[N:15]=[CH:14][N:13]=2)[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: CNC(C)C
Reactant: O=C(C=CCBr)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Solvent: O
Solvent: CC#N
Solvent: CO
Product: CC(C)N(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To an ice-bath cooled solution of 4-Bromo-1-[4-(3-chloro-4-fluoro-phenylamino)-5,8-dihydro-6H-9-thia-1,3,7-triaza-fluoren-7-yl]-but-2-en-1-one (0.14 g, 0.291 mmol) in dichloromethane (4.0 ml) was added isopropylmethylamine (0.121 ml, 1.16 m mol) followed by the addition of DIEA (0.056 ml, 0.32 mmol). The resulting mixture was stirred at RT overnight. TLC (10% MeOH/Dichloromethane) indicates no starting material present. The crude mixture was rotavapped to dryness, dissolved in DMF & subjected to HPLC conditions [H2O (containing 0.1% NH4OH)-MeCN] to give the desired product (26 mg, 19%). 1H-NMR (DMSO-d6) δ 8.46 (m, 1H), 8.39 (s, 1H), 7.88 (m, 1H), 7.62 (m, 1H), 7.42 (t, 1H), 6.67 (m, 1H), 3.94 (m, 2H), 3.87 (m, 4H), 2.75 (m, 2H), 2.11 (s, 3H), 0.96 (d, 6H); LCMS RT=2.53 min, [M+H]+=474.1.
Reaction SMILES: C[C:2]1[N:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[C:4]([C:12]2[CH:13]=[N:14][N:15]([CH3:27])[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:3]=1.[2H]C([NH2:32])([2H])[2H]>>[CH3:27][N:15]1[C:16]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)=[C:12]([C:4]2[N:3]=[CH:2][N:10]3[C:5]=2[C:6]([NH2:32])=[N:7][CH:8]=[N:9]3)[CH:13]=[N:14]1
Reactant: Cc1nc(-c2cnn(C)c2-c2ccc(C(F)(F)F)cc2)c2c(=O)[nH]cnn12
Reactant: [2H]C([2H])([2H])N
Product: Cn1ncc(-c2ncn3ncnc(N)c23)c1-c1ccc(C(F)(F)F)cc1

Procedure:
7-Methyl-5-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazin-4(3H)-one was converted to the product according to the general procedure for the synthesis of 4-(azetidin-1-yl)-7-methyl-5-(1-methyl-1H-pyrazol-4-yl)imidazo[1,5-f][1,2,4]triazine in Example 2, except that methyl-d3-amine was used in place of azetidine hydrochloride. In this case, the reaction was worked up via removal of solvent in vacuo, followed by addition of water and extraction with ethyl acetate. The combined organic layers were concentrated under reduced pressure and purified using silica gel chromatography (Gradient: 0% to 100% [5% methanol/5% triethylamine/90% ethyl acetate] in heptane) to afford the product as a gummy oil. Yield: 20 mg, 0.051 mmol, 42%. LCMS m/z 391.4 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.57 (s, 3H), 3.94 (s, 3H), 7.51 (br d, J=8.1 Hz, 2H), 7.70 (br d, J=8.2 Hz, 2H), 7.75 (s, 1H), 7.79 (s, 1H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:23](COCC[Si](C)(C)C)[N:24]=[C:25]([NH:26][CH:27]3[CH2:32][CH2:31][N:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:29][CH2:28]3)[C:11]=2[N:10]=1.FC1C=CC=C(F)C=1C1C2C=C(C(OC)=O)C=CC=2C2=NN(COCC[Si](C)(C)C)C(NC3CCN(S(C)(=O)=O)CC3)=C2N=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:23][N:24]=[C:25]([NH:26][CH:27]3[CH2:28][CH2:29][N:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:31][CH2:32]3)[C:11]=2[N:10]=1
Reactant: COC(=O)c1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(C)(=O)=O)CC3)nn(COCC[Si](C)(C)C)c12
Agent: COC(=O)c1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(C)(=O)=O)CC3)n(COCC[Si](C)(C)C)nc12
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(C)(=O)=O)CC3)n[nH]c12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A 25 ml round-bottomed flask equipped with a magnetic stirrer is charged with 46 mg of the mixture of methyl 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxylate and methyl 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinoline-7-carboxylate obtained in step 9 in 5 ml of DCM. After cooling to 0° C. using an ice bath, 0.5 ml of TFA are added and the mixture is stirred at RT for 18 h. It is concentrated under RP and the solid obtained is taken up in 20 ml of water and extracted with three times 20 ml of AcOEt. The organic phase is dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with DCM and then with a mixture of DCM/AcOEt (50/50 by vol.), to give 12 mg of methyl 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxylate (yellow solid). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67 (m, 2 H) 2.11 (m, 2 H) 2.88 (s, 3 H) 2.92 (m, 2 H) 3.56 (m, 2 H) 3.80 (m, 1 H) 3.87 (s, 3 H) 6.16 (d, J=7.7 Hz, 1 H) 7.37 (m, 2 H) 7.71 (m, 1 H) 8.23 (broad s, 1 H) 8.42 (broad d, J=8.5 Hz, 1 H) 8.54 (d, J=8.5 Hz, 1 H) 13.01 (s, 1 H). LC-MS-DAD-ELSD: 516 (+)=(M+H)(+).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[N:11][CH3:12])[CH2:7][CH2:6]2)OCC1.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCCCC)CCC>[CH3:12][NH:11][C:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][C:5](=[O:1])[CH2:10][CH2:9]1
Reactant: [Li]c1ccccc1
Reactant: CN=C1CCC2(CC1)OCCO2
Solvent: CCCCOCCCC
Product: CNC1(c2ccccc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(1,4-dioxaspiro[4,5]-decan-8-yliden)-methanamine (43 g, 0.25 mol) was dissolved in dibutyl ether (75 ml) and added at room temperature (15-32° C.) to a solution of phenyllithium in dibutyl ether (1.8 M, 149 ml, 0.27 mol). The batch was stirred at room temperature for 1 h.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.Cl[C:20]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:21]>>[C:24]([CH2:23][CH2:22][C:20]([N:11]1[C:5]2=[N:6][C:7]3[C:2]([C:3](=[O:18])[N:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)=[CH:1][CH:10]=[CH:9][CH:8]=3)=[O:21])([O:26][CH3:27])=[O:25]
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Reactant: COC(=O)CCC(=O)Cl
Product: COC(=O)CCC(=O)n1c2ccccc2n2c(=O)c3ccccc3nc12

Procedure:
6-(3-Carbomethoxypropionyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and methyl 3-(chloroformyl)propionate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:5]=[CH:6][C:7]=1[OH:8].[BH4-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([OH:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCCCCC(=O)CCCCc1ccc(O)c(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC(O)CCCCc1ccc(O)c(O)c1
Reaction time: 0.5 h

Procedure:
In 1.5 ml of methanol was dissolved 150 mg of 1-(3,4-dihydroxyphenyl)-5-decanone and 20 mg of sodium borohydride was added to the solution under ice-cooling followed by stirring for 30 minutes. Then, the solvent was distilled off from the reaction mixture and after adding 10 ml of water to the residue thus formed, the product was extracted with ether. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off to provide white crystals of 1-(3,4-dihydroxyphenyl)-5-decanol, which was collected by filtration with the addition of n-hexane. Yield 117 mg.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:28])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([C:23]([O:25]CC)=[O:24])=[C:15]([C:17](=[O:22])[NH:18][CH:19]([CH3:21])[CH3:20])[N:16]=2)=[CH:8][CH:7]=1)[CH3:2].[OH-].[Li+]>CO>[CH2:1]([NH:3][C:4](=[O:28])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([C:23]([OH:25])=[O:24])=[C:15]([C:17](=[O:22])[NH:18][CH:19]([CH3:21])[CH3:20])[N:16]=2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc(C(=O)NC(C)C)c(C(=O)OCC)s2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=O)Nc1ccc(-c2nc(C(=O)NC(C)C)c(C(=O)O)s2)cn1
Temperature: 50 °C
Yield: 82.8 %

Procedure:
To a stirred solution of ethyl 2-[6-(3-ethyl-ureido)-pyridin-3-yl]-4-isopropylcarbamoyl-thiazole-5-carboxylate (Example 65, 0.195 g, 0.48 mmol) in methanol (7 mL) was added 2 N lithium hydroxide (2 mL). The mixture was heated to 50° C. overnight, then concentrated to dryness water was added and the pH was adjusted to pH 2 with 2N hydrochloric acid. The precipitated solid was filtered and dried under vacuum to afford 0.15 g (76.2%) of the title compound as a solid. NMR: 1.11 (t, 3H), 1.28 (d, 6H), 3.22 (q, 2H), 4.20 (m, 1H), 7.62 (d, 1H), 7.7 (r bs, 1H), δ 8.42 (dd, 1H), 8.57 (d, 1H), δ 9.03 (s, 1H).