Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:27]=[C:28]3[NH:34][CH2:33][C:32]4([CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:29]3=[N:30][CH:31]=2)[CH2:22][CH2:21]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([N:34]1[C:28]3[C:29](=[N:30][CH:31]=[C:26]([N:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)[CH:27]=3)[C:32]3([CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:33]1)=[C:3]([CH3:19])[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[N:5]2
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Cl
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y by stirring 4-chloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (29.7 mg, 0.11 mmol), 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (30 mg, 0.11 mmol), XPhos precatalyst (7 mg, 0.01 mmol) and sodium tert butoxide (20.9 mg, 0.22 mmol) in toluene (3 mL) at 90° C. for 2 h. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 1′-(5-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. 1H NMR (500 MHz, chloroform-d) δ ppm 8.65-8.84 (1H, m), 8.02-8.07 (1H, m), 7.86-7.96 (2H, m), 7.64 (1H, td, J=8.1, 5.4 Hz), 7.56 (1H, d, J=2.2 Hz), 7.42 (1H, ddd, J=6.8, 4.9, 2.0 Hz), 7.14-7.21 (1H, m), 5.77 (1H, d, J=2.2 Hz), 4.08-4.18 (2H, m), 3.91-4.02 (2H, m), 3.70-3.80 (4H, m), 3.51-3.63 (2H, m), 2.95-3.05 (4H, m), 2.42-2.45 (3H, s), 2.35-2.40 (1H, m), 2.28 (1H, ddd, J=13.7, 11.5, 4.4 Hz), 1.85 (1H, ddd, J=13.6, 1.5, 1.3 Hz), 1.70-1.76 (1H, m). Mass Spectrum (ESI) m/e=512.0 (M+1).
Reaction SMILES: C([O:8][C:9]1[C:10]([F:22])=[C:11]([CH2:18][C:19](=[O:21])[CH3:20])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)C1C=CC=CC=1.[Cl-].[NH+]1C=CC=CC=1>Cl.C(OCC)(=O)C>[F:22][C:10]1[C:9]([OH:8])=[CH:14][CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[C:11]=1[CH2:18][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Agent: Cl
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(O)c1F
Temperature: 180 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
Method R-2: A mixture of 1-(3-benzyloxy-2-fluoro-6-nitrophenyl)-propan-2-one (65.0 g, 0.214 mol) and pyridinium chloride (60.74 g, 0.526 mol) was stirred at 180° C. for 1 hr. The reaction mixture was cooled to room temperature, diluted with 3N HCl (100 mL) and ethyl acetate (500 mL) and filtered. The aqueous layer was extracted with ethyl acetate (2×) and the combined organic layers were washed with brine, dried (MgSO4),s filtered through a pad of silica gel and concentrated in vacuo. The residue was decolorized with charcoal in methanol, filtered and concentrated in vacuo to afford 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (37 g, 81%) as a brown solid. LC/MS; (M+H)+=213.2
Reaction SMILES: [Br:1][C:2]1[CH:18]=[C:17]([CH2:19][CH2:20][C:21](=[O:37])[C:22]2[S:23][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]([CH3:14])([CH3:13])[C:6]([O:8]C(C)(C)C)=[O:7].FC(F)(F)C(O)=O>>[Br:1][C:2]1[CH:18]=[C:17]([CH2:19][CH2:20][C:21](=[O:37])[C:22]2[S:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]([CH3:13])([CH3:14])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1Br
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1Br)C(=O)O

Procedure:
2-(2-Bromo-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)-2-methylpropanoic acid is prepared from tert-butyl 2-(2-bromo-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate according to general procedure E using 17 equivalents of trifluoroacetic acid.
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][S:9]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[C:22]([C:32]([NH2:34])=[O:33])[CH:23]=[C:24]([C:27]4[CH:31]=[CH:30][S:29][CH:28]=4)[CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1)(=[O:11])=[O:10].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>>[N:35]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[C:22]([C:32]([NH2:34])=[O:33])[CH:23]=[C:24]([C:27]5[CH:31]=[CH:30][S:29][CH:28]=5)[CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: C1CCNC1
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCl)CC3)c[nH]c12
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Product: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCN4CCCC4)CC3)c[nH]c12
Yield: 28.3 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(2-chloroethyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indole-7-carboxamide (0.09 mmol) and pyrrolidine (0.03 mL, 0.45 mmol) were allowed to react in the presence of K2CO3 (44 mg, 0.45 mmol) and NaI (Cat. 5 mg). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (12.4 mg, 28%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.[N:39]1([CH2:45][CH2:46][O:47][C:48]2[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=2)[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:54][C:51]1[CH:52]=[CH:53][C:48]([O:47][CH2:46][CH2:45][N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)=[CH:49][CH:50]=1)=[N:6]2
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Solvent: CCO
Product: Cc1nc(-c2ccccc2)n2nc(Nc3ccc(OCCN4CCOCC4)cc3)ncc12
Yield: 39.6 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), (4-{[2-(4-morpholinyl)ethyl]oxy}phenyl)amine (38.5 mg, 0.17 mmol) and ethanol (2.5 mL) to afford 5-methyl-N-(4-{[2-(4-morpholinyl)ethyl]oxy}phenyl)-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (29 mg) as a yellow solid. MS m/z 431 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1.[H][H]>[Pt]=O.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:18]=[CH:17][C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=C(O)C=Cc1ccc(-c2ccccc2Cl)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: O=C(O)CCc1ccc(-c2ccccc2Cl)cc1

Procedure:
A suspension of 100 g of p-(2-chlorophenyl)cinnamic acid in 1 l. of 95% ethanol is hydrogenated at atmospheric pressure using platinum oxide catalyst (1 g). The uptake of hydrogen ceases when approximately 9-10 l. of hydrogen is consumed. The catalyst is then filtered off and the reaction evaporated to dryness to give β-(2'-chloro-4-biphenylyl)propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:20][C:21]=2[O:23][CH:24]([CH3:26])[CH3:25])[N:16]=[CH:15][N:14]=1.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)#[CH:38].C(NC(C)C)(C)C>[Cu]I.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([C:38]#[C:37][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:20][C:21]=2[O:23][CH:24]([CH3:26])[CH3:25])[N:16]=[CH:15][N:14]=1
Reactant: C#Cc1ccccn1
Reactant: CC(C)Oc1cc(OCCCN2CCOCC2)cc2ncnc(Nc3c(Cl)cc(I)c4c3OCO4)c12
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CC(C)Oc1cc(OCCCN2CCOCC2)cc2ncnc(Nc3c(Cl)cc(C#Cc4ccccn4)c4c3OCO4)c12
Temperature: -10 °C

Procedure:
N-(5-chloro-7-iodo-1,3-benzodioxol-4-yl)-5-isopropoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine (0.162 g), 2-ethynyl pyridine (0.03 ml), palladium(II) bis-triphenylphosphine dichloride (0.020 g) and copper (I) iodide (0.006 g) was taken up into ethyl acetate (5 ml) and cooled to −10° C. This was set to stir rapidly, then diisopropylamine (0.047 ml) was added and the reaction was stirred cold for 30 minutes before being warmed to room temperature and left to stir for 18 hours. The reaction mixture was then filtered through Celite under suction (washing the Celite with a further portion of ethyl acetate) then the combined filtrate solutions were evaporated under reduced pressure to give a brown gum. This was then purified by column chromatography on silica using increasingly polar mixtures of methanol in dichloromethane as eluent. There was thus obtained the title compound (0.090 g) as a pale brown foam; NMR Spectrum: (CDCl3) 1.54 (d, 6H), 2.04 (quin, 2H), 2.50 (m, 4H), 2.56 (t, 2H), 3.74 (t, 4H), 4.16 (t, 2H), 4.83 (sept, 1H), 6.14 (s, 2H), 6.50 (d, 1H), 6.84 (d, 1H), 7.19 (s, 1H), 7.25 (m, 1H), 7.54 (d, 1H), 7.68 (td, 1H), 8.53 (s, 1H), 8.63 (dd, 1H), 9.46 (s, 1H); Mass Spectrum: M+H+ 602/604.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][CH:7]([CH:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:8].S(=O)(=O)(O)O.[OH-].[Na+]>>[CH3:8][CH:7]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]2[CH2:4][CH2:5][N:1]=[C:2]2[NH:6]1
Reactant: CC(NC1=NCCN1)C(O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC1NC2=NCCN2C1c1ccccc1

Procedure:
A solution of 12 parts of the oily α-[1-(2-imidazolin-2-ylamino)ethyl]benzyl alcohol in 40 parts of sulfuric acid solution 80% is stirred for 3 hours at room temperature. The reaction mixture is poured onto crushed ice. The whole is alkalized with sodium hydroxide solution and the product is extracted with toluene. The extract is dried, filtered and evaporated. The residue is washed with acetone and dried, yielding 2,3,5,6-tetrahydro-2-methyl-3-phenyl-1H-imidazo[1,2-a]imidazole; m.p. 179.4°C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]=1.[CH2:17]([C:23](=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:24]=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O1CCCC1>[CH2:17]([C:23](=[CH:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH:24]([OH:25])[CH2:9][C:10]1[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCC(C=O)=Cc1ccccc1
Reactant: Cc1nccnc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCC(=Cc1ccccc1)C(O)Cc1nccnc1C
Temperature: 25 °C

Procedure:
To a solution of lithium diisopropylamide (1.5 Molar, 73.3 mL, 0.11 mole) in 150 mL of tetrahydrofuran at -78° C. is added slowly to a solution of 2,3-dimethylpyrazine (10.8 g, 0.1 mole) in 100 mL of tetrahydrofuran. The mixture is allowed to warm to room temperature and then cooled to -78° C. A solution of α-hexylcinnamaldehyde (23.7 g, 0.11 mole) in 100 mL of tetrahydrofuran is added dropwise over 15 minutes. The reaction product mixture is then worked up according to the procedures of Example I to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH2:13]([O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][NH:22][CH2:23][C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[CH2:14][CH3:15].C(N(CC)CC)C>C(Cl)Cl.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:22]([CH2:21][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:13][CH2:14][CH3:15])=[CH:30][CH:29]=2)[CH2:23][C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCOc1ccc(CNCc2ccco2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCOc1ccc(CN(Cc2ccco2)S(=O)(=O)c2ccc(C#N)cc2)cc1
Reaction time: 2 h
Yield: 42 %

Procedure:
4-cyanobenzene-1-sulfonyl chloride (600 mg, 2.9 mmol) was added to a stirring solution of N-(4-propoxybenzyl)-1-(furan-2-yl)methanamine (Example 5-8b) (685 mg, 2.9 mmol) and triethylamine (455 mg, 4.5 mmol) in DCM (100 mL) and the reaction was stirred for 2 hours. The reaction was diluted with H2O (200 mL) and extracted with DCM (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated on the rotovap. The residue was purified by silica gel chromatography (10% ethyl acetate in hexanes) to afford 4-cyano-N-(4-propoxybenzyl)-N-(furan-2-ylmethyl)benzenesulfonamide (500 mg, 50%) as an off white solid. NMR (DMSO-d6, 400 MHz): δ 0.95 (t, J=7.2 Hz, 3H), 1.70 (m, J=6.4 Hz, 2H), 3.88 (t, J=6.4 Hz, 2H), 4.25 (s, 2H), 4.28 (s, 2H), 6.15 (d, J=3.2 Hz, 1H), 6.27 (m, 1H), 6.84 (d, J=6.8 Hz, 2H), 7.11 (d, J=8.8 Hz, 2H), 7.39 (m, 1H), 7.93 (d, J=6.4 Hz, 2H), 8.01 (d, J=6.4 Hz, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C@:8]([CH2:26][O:27][P:28]([O:35]C(C)(C)C)([O:30]C(C)(C)C)=[O:29])([CH3:25])[CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:13]([Cl:24])[CH:12]=1)(C)(C)C>C(O)(=O)C.Cl>[NH2:7][C@:8]([CH3:25])([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:13]([Cl:24])[CH:12]=1)[CH2:26][O:27][P:28](=[O:29])([OH:35])[OH:30]
Reactant: CCCCCOc1c(Cl)cc(CC[C@](C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)NC(=O)OC(C)(C)C)cc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCOc1c(Cl)cc(CC[C@@](C)(N)COP(=O)(O)O)cc1Cl
Reaction time: 4 h

Procedure:
A solution of [(R)-1-(Di-tert-butoxy-phosphoryloxymethyl)-3-(3,5-dichloro-4-pentyloxy-phenyl)-1-methyl-propyl]-carbamic acid tert-butyl ester (43 mg, 0.07 mmol) in acetic acid (0.4 ml) and conc. HCl (0.042 ml) is left standing at RT for 4 h. After evaporation of the solvent, the oily residue is treated with Et2O to yield the title compound as a white precipitate which is filtered off. MS (ESI−): m/z =413/415 (M−H−).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:15]=2[Cl:22])=[CH:9][C:8]=1[CH3:23])[CH3:2].C(OC(=O)CO[C:31]1[C:40]2CCCCC=2C(S)=C[CH:32]=1)C.ClC1C=C(C=CC=1Cl)C=O>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[C:8]2[CH2:23][CH2:40][CH2:31][CH2:32][C:9]=2[C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:15]=2[Cl:22])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2ccc(C=O)cc2Cl)cc1C
Reactant: CCOC(=O)COc1ccc(S)c2c1CCCC2
Agent: O=Cc1ccc(Cl)c(Cl)c1
Product: CCOC(=O)COc1ccc(Sc2ccc(C=O)cc2Cl)c2c1CCCC2

Procedure:
The title compound was prepared according to the method described for preparing compound 10.4, using compound 22.3 and 3,4-dichlorobenzaldehyde as the starting materials. 1H NMR (300 MHz) (CDCl3) δ 9.84 (1H, s); 7.82 (1H, d, J=1.8 Hz); 7.49 (1H, dd, J=1.8, 8.4 Hz); 7.40 (1H, d, J=8.4 Hz); 6.63 (1H, d, J=8.4 Hz); 6.59 (1H, d, J=8.0 Hz); 4.70 (2H, s); 4.30 (2H, q, J=7.0 Hz); 2.82-2.70 (4H, m); 1.77-1.70 (4H, m); 1.32 (3H, t, J=7.0 Hz).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH3:7])=[CH:3]\[CH2:4][OH:5].[CH3:8][C:9]([CH2:13]CC=CCCC=CC)=[CH:10]CO>>[CH3:1]/[C:2](/[CH2:6]/[CH:7]=[CH:10]/[C:9]([CH3:13])=[CH2:8])=[CH:3]\[CH2:4][OH:5]
Reactant: CC=CCCC=CCCC(C)=CCO
Reactant: CC/C(C)=C/CO
Product: C=C(C)/C=C/C/C(C)=C/CO

Procedure:
(2E, 6E, 10E)-3-methyl-2,6,10-dodecatrien-1-ol;
Reaction SMILES: [CH3:1][C@H:2]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16](Br)[N:17]=2)[N:12]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:11]=1)=[O:9])[C:3]([CH3:6])([CH3:5])[CH3:4].[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH3:38])[N:33]=[C:32]2[Sn](CCCC)(CCCC)CCCC>CN(C=O)C.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.[Cu]I>[CH3:1][C@H:2]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:32]3[C:31]4[C:35](=[CH:36][CH:37]=[C:29]([Cl:28])[CH:30]=4)[N:34]([CH3:38])[N:33]=3)[N:17]=2)[N:12]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:11]=1)=[O:9])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(Cl)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(Cl)cc34)nc12)C(C)(C)C
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 81 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1,2,2-trimethyl-propyl)-amide (94 mg, 0.21 mmol) and 5-chloro-1-methyl-3-tributylstannyl-1H-indazole (367 mg, 0.40 mmol) were dissolved in DMF (1.9 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol) and copper(I) iodide (8 mg, 0.042 mmol) were added. The reaction mixture was stirred at 90° C. in an oil bath for 3.5 h then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-40% EtOAc) to afford 92 mg (82%) of 2-(5-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1,2,2-trimethyl-propyl)-amide as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[CH3:12][N:13]1[C:17]2=[N:18][C:19]([S:22][CH3:23])=[N:20][CH:21]=[C:16]2[C:15](=[O:24])[NH:14]1.N.C(=O)([O-])O.[Na+]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl.CN(C)C=O.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:14]1[C:15](=[O:24])[C:16]2[C:17](=[N:18][C:19]([S:22][CH3:23])=[N:20][CH:21]=2)[N:13]1[CH3:12]
Reactant: COc1ccccc1B(O)O
Reactant: CSc1ncc2c(=O)[nH]n(C)c2n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccccc1-n1c(=O)c2cnc(SC)nc2n1C
Temperature: 25 °C
Yield: 49 %

Procedure:
280 mg of o-methoxyphenylboronic acid, 320 mg of copper(II) acetate and 0.15 mL of pyridine were added to a chloroform/N,N-dimethylformamide (1/1) solution of 90 mg of 1-methyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, and stirred at room temperature. Aqueous 28% ammonia solution and saturated sodium hydrogencarbonate solution were added to the reaction liquid, and extracted with chloroform. The crude product was purified through a silica gel column (hexane/ethyl acetate) to obtain 68 mg of 2-(2-methoxyphenyl)-1-methyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:21]=[C:20]([CH:22]5[CH2:25][C:24](=[O:26])[CH2:23]5)[N:19]([CH3:27])[C:18]=4[CH:28]=3)[C:10](=[O:29])[CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:21]=[C:20]([CH:22]5[CH2:25][CH:24]([OH:26])[CH2:23]5)[N:19]([CH3:27])[C:18]=4[CH:28]=3)[C:10](=[O:29])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(C2CC(=O)C2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(C2CC(O)C2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
To a stirred solution of 4-((4-fluorobenzyl)oxy)-1-(1-methyl-2-(3-oxocyclobutyl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one (80 mg) in a mixture of THF (10 ml) and MeOH (3 ml) was added NaBH4 (15 mg) at 0° C. The mixture was then allowed to warm to room temperature, and stirred for 3 h. The reaction mixture was then quenched with saturated NH4Cl (5 ml), and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (50 mg) as an off-white solid.
Reaction SMILES: NC1SC(C2C(F)=CC=CC=2F)=NC=1C(NC1C=NN(C)C=1N1CCC[C@H](NCCO)CC1)=O.[OH:35][CH2:36][CH2:37][N:38]([CH2:76][CH2:77][OH:78])[C@@H:39]1[CH2:45][CH2:44][CH2:43][N:42]([C:46]2[N:50]([CH3:51])[N:49]=[CH:48][C:47]=2[NH:52][C:53]([C:55]2[N:56]=[C:57]([C:68]3[C:73]([F:74])=[CH:72][CH:71]=[CH:70][C:69]=3[F:75])[S:58][C:59]=2[NH:60]C(=O)OC(C)(C)C)=[O:54])[CH2:41][CH2:40]1>>[NH2:60][C:59]1[S:58][C:57]([C:68]2[C:69]([F:75])=[CH:70][CH:71]=[CH:72][C:73]=2[F:74])=[N:56][C:55]=1[C:53]([NH:52][C:47]1[CH:48]=[N:49][N:50]([CH3:51])[C:46]=1[N:42]1[CH2:43][CH2:44][CH2:45][C@H:39]([N:38]([CH2:37][CH2:36][OH:35])[CH2:76][CH2:77][OH:78])[CH2:40][CH2:41]1)=[O:54]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](N(CCO)CCO)CC1
Agent: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC[C@H](NCCO)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC[C@H](N(CCO)CCO)CC1
Yield: 71 %

Procedure:
In the preparation of 335, tert-butyl N-[4-[[5-[(4R)-4-[bis(2-hydroxyethyl)amino]azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]-2-(2,6-difluorophenyl)thiazol-5-yl]carbamate was deprotected following the procedure in Example 334 to give 336 (6 mg, 71%). 1H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 8.24 (s, 1H), 7.56 (s, 1H), 7.55-7.41 (m, 3H), 7.27 (t, J=8.7 Hz, 2H), 3.65 (s, 3H), 3.19-3.02 (m, 7H), 2.85-2.71 (m, 2H), 2.46 (t, J=6.2 Hz, 4H), 1.92-1.75 (m, 3H), 1.67-1.50 (m, 3H). LCMS (ES+) m/z 536 (M+1)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([NH:17][CH:18]=[N:19]2)=[C:15]([NH:22][CH2:23][CH2:24][NH2:25])[N:14]=1>CO>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:25][CH2:24][CH2:23][NH:22][C:15]1[N:14]=[C:13]([NH2:12])[N:21]=[C:20]2[C:16]=1[NH:17][CH:18]=[N:19]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCNc1nc(N)nc2nc[nH]c12
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CO
Product: Nc1nc(NCCNCC(O)COc2ccccc2)c2[nH]cnc2n1
Reaction time: 24 h

Procedure:
3.5 g. Phenyl glycidyl ether and 8.7 g. 2-amino-6-(2-aminoethylamino)-purine are dissolved in 50 ml. methanol and left to stand for 24 hours at ambient temperature. The methanol is then removed in a vacuum and the residue is dissolved in methylene chloride and purified on a silica gel column using, as elution agent, methylene chloride-methanol (7:3 v/v). The residue obtained by evaporation of the pure fractions is triturated with ethanol and then recrystallized from this solvent. There are obtained 2.0 g. (25% of theory) of the desired product in the form of colorless crystals; m.p. 169°-171° C.