Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22](O)=[O:23])[CH:18]=[CH:19][CH:20]=1>C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]([NH:1][CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[O:23])[CH:18]=[CH:19][CH:20]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: COc1cccc(CC(=O)O)c1
Solvent: CCOC(C)=O
Product: COc1cccc(CC(=O)NCCc2c[nH]c3ccccc23)c1
Temperature: 200 °C
Yield: 84.8 %

Procedure:
A mixture of 29 g of tryptamine and 30 g of 3-methoxy-phenylacetic acid was heated at 200° C. for one hour and after cooling the mixture to 50° C., the mixture was dissolved in 200 ml of ethyl acetate. The organic phase was washed successively with N hydrochloric acid, with water, with 2 N sodium hydroxide and with water and was dried and evaporated to dryness. The 59 g of red oil were crystallized from ether and the mixture was vacuum filtered. The product was dried to obtain 47.2 g of 3-methoxy-N-[2-(1H-indol-3-yl)-ethyl]-benzeneacetamide in the form of a beige solid melting at 78° C. which was used as is for the next step. A sample recrystallized from ether melted at 82° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:21])[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[O:10]2)=[C:5]([OH:22])[C:4]=1[I:23].[C:24]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O.CO.C(Cl)Cl>C1COCC1>[I:23][C:4]1[C:5]([O:22][CH3:24])=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[O:10][C:9]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)=[CH:8][C:7]2=[O:21]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2cc(=O)c3c(O)c(I)c(OC)cc3o2)cc1
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: COc1ccc(-c2cc(=O)c3c(OC)c(I)c(OC)cc3o2)cc1
Yield: 23.2 %

Procedure:
To a solution of 7 (3.00 g, 7.08 mmol) and K2CO3 (1.47 g, 10.6 mmol) in 150 mL THF was added dimethylsulfate (1.07 g, 8.49 mmol) and the solution heated at reflux overnight. The solvent was evaporated and the residue partitioned between 50 mL each of CHCl3 and H2O. The organic phase was separated and washed with saturated brine, dried over magnesium sulfate, filtered and evaporated to provide a yellow solid. Recrystallization from CHCl3/EtOH (1:2, 150 mL) afforded pale-yellow needles. Column chromatography of the evaporated mother liquor (100 g silica gel, 2% MeOH/CH2Cl2) afforded an additional 720 mg of desired product (total yield 2.21 g, 71.3%); mp 204° C. (lit.13 mp 191-194° C.); 1H NMR (CDCl3) δ 3.89 (s, 3 H), 3.94 (s, 3 H), 4.01 (s, 3 H), 6.62 (s, 1 H), 6.78 (s, 1 H), 7.01 (d, 2 H, J=9.1 Hz), 7.83 (d, 2 H, J=9.1 Hz); EI-MS in/z 438 (M+, 65), 311 (100). Anal. calcd for C18H15IO5: C, 49.34; H, 3.45. Found: C, 48.58; H, 3.21.
Reaction SMILES: [CH3:1][C:2]1([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=2)[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)=[O:12])=[CH:10][C:4]=2[O:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>CC(=O)CC>[CH3:1][C:2]1([C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=2)[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:14]=3)=[O:12])=[CH:10][C:4]=2[O:3]1
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)Cc1ccc(C2(C)Oc3ccc(C(=O)c4c[nH]c5ccccc45)cc3O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc3c(c2)OC(C)(c2ccc(CC(C)C)cc2)O3)c2ccccc21
Yield: 87 %

Procedure:
A mixture of the compound of part (d) (2.88 g), potassium carbonate (3.9 g), ethyl 4-bromobutyrate (1.7 g) and 2-butanone (25 ml) was heated under reflux for 5 hours. The mixture was cooled, filtered and the filtrate evaporated to give a viscous gum which was purified by flash chromatography (silica, 9:1 hexane/ethyl acetate) to provide the title compound as a clear gum (3.2 g).
Reaction SMILES: Cl[C:2]1[C:3]([C:10]([OH:12])=[O:11])=[CH:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[Cl:29])[NH2:25]>O1CCCC1.C(OCC)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[C:3]([C:10]([OH:12])=[O:11])=[CH:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: Cn1cc(C(=O)O)c(Cl)cc1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cn1cc(C(=O)O)c(Nc2ccc(Cl)c(Cl)c2)cc1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
A suspension of 4-chloro-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (161 mg, 0.86 mmol) was treated with lithium diisopropylamide (2.0 M solution in tetrahydrofuran-ethylbenzene-heptane, 0.45 mL, 0.9 mmol). The resultant solution was stirred for 30 min at ambient temperature under nitrogen and was then cooled to −78° C. This is solution A. In a separate flask, a solution of 3,4-dichloroaniline (147 mg, 1.21 mmol) in tetrahydrofuran (3.0 mL) was cooled to −78° C. and treated with lithium diisopropylamide (2.0 M solution in tetrahydrofuran-ethylbenzene-heptane, 1.2 mL, 2.4 mmol). The resultant solution was stirred for 30 min at −78° C. and was transferred to solution A (also at −78° C.) via cannula. The resultant reaction mixture was stirred for 30 min at −78° C. and was then warmed to ambient temperature for 2.5 h. The reaction was diluted with ethyl ether (10 mL) and filtered. The solid was washed with ether (10 mL). The filtrate and washings were discarded. The solid was partitioned between ethyl acetate (60 mL) and 1 N hydrochloric acid (20 mL). The organics were washed with water (2×20 mL) and brine (20 mL). The combined aqueous portion was further extracted with ethyl acetate (20 mL). All organics were combined and dried over magnesium sulfate and concentrated in vacuo to afford a brown-colored solid (234 mg), used in step B without further purification.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][C:15]([NH:19][CH2:20][CH2:21][OH:22])=[N:16][CH:17]=3)[NH:12][N:11]=2)[CH:7]=[CH:6][N:5]=1)=O.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH:28][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][C:15]([NH:19][CH2:20][CH2:21][OH:22])=[N:16][CH:17]=3)[NH:12][N:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: NCc1cccc(Cl)c1
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NCCO)ncc23)n1
Product: OCCNc1ncc2c(-c3ccnc(NCc4cccc(Cl)c4)n3)n[nH]c2n1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
The mixture of 2-[3-(2-methane sulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-ethanol (from Example 21 supra) (1.9 g, crude, 2.31 mmol) and 3-chlorobenzylamine (797 mg, 4.62 mmol) was heated at 130° C. with stirring for 3 hours. The solvent was removed under reduced pressure and the solid was purified by prep-TLC and prep-HPLC. Concentrated HCl was added to the fractions with product and concentrated under reduced pressure to give 2-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-ethanol; hydrochloride. (Yield 28 mg, 3.1% of the 3 steps).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([CH3:29])[CH2:16][C:17]([CH2:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH2:21])([CH3:18])[C:5]1=2)C=C>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[CH2:19][C:17]3([CH3:18])[CH2:16][N:15]([CH3:29])[CH2:14][C:6]4[C:7]5[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][C:12]=5[N:4]([C:5]=43)[CH2:1][CH:21]=2)=[CH:23][CH:24]=1
Reactant: C=CCn1c2c(c3cc(C)ccc31)CN(C)CC2(C)CC(=C)c1ccc(F)cc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c3n2CC=C(c2ccc(F)cc2)CC3(C)CN(C)C1
Temperature: 80 °C
Yield: 96.5 %

Procedure:
5-Allyl-4-[2-(4-fluoro-phenyl)-allyl]-2,4,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.25 mmol) was dissolved in DCM (15 mL) and purged with nitrogen. Hoveyda-Grubbs 2nd generation catalyst (10 mg, 0.015 mmol) was added and the reaction mixture was re-purged with nitrogen. The reaction mixture was heated at 80° C. for 6 h, cooled to RT, concentrated under reduced pressure and the residue purified by column chromatography using silica (100-200 mesh) eluting with 1% MeOH in DCM to obtain 87 mg of 5-(4-fluoro-phenyl)-2,3a,10-trimethyl-1,2,3,3a,4,7-hexahydro-2,7a-diaza-cyclohepta[jk]fluorene. 1H NMR (Oxalate salt, CD3OD) δ (ppm): 7.40 (m, 2H), 7.30 (d, 1H), 7.26 (s, 1H), 7.05 (m, 3H), 6.06 (d, 1H), 5.22 (m, 1H), 4.76 (m, 1H), 4.60-4.40 (m, 2H), 3.60 (m, 2H), 3.18 (s, 3H), 3.05 (m, 1H), 2.70 (m, 1H), 2.40 (s, 3H), 1.66 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9].[F:24]C1C=CC(S(Cl)(=O)=O)=CC=1>>[F:24][C:6]1[CH:5]=[CH:4][C:3]([S:8]([NH:11][C@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:2][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=C(O)[C@@H](Cc1ccc(O)cc1)NS(=O)(=O)c1ccccc1F
Product: O=C(O)[C@@H](Cc1ccc(O)cc1)NS(=O)(=O)c1ccc(F)cc1

Procedure:
Following 17a synthetic method, using 4-fluorobenzenesulfonyl chloride (214.08 mg, 1.1 mmol) instead of 2-fluorobenzenesulfonyl chloride gave the final compound 19a; as a colorless oil; (93.99 mg, 55.4%). [α]D25: +12.8 (c=0.26, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 7.77-7.73 (m, 2H), 7.24-7.21 (m, 7H), 6.92 (d, J=9 Hz, 1H), 4.21-4.14 (m, 1H), 3.15-2.90 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 171.55, 166.28, 162.95, 137.53, 136.53, 129.74, 129.62, 129.39, 128.24, 126.68, 115.93, 115.63, 57.29, 38.49; HRMS (ESI): calcd for: C15H14FNO4S [M+Na]+=346.0520, obsd [M+Na]+=346.0513.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=[O:5].C(N(CC)CC)C.[O:25](S(C(F)(F)F)(=O)=O)[S:26]([C:29]([F:32])([F:31])[F:30])(=O)=[O:27]>ClCCl>[F:30][C:29]([F:32])([F:31])[S:26]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=[O:5])(=[O:27])=[O:25]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(OC2CCCCO2)cc(O)c1C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OC2CCCCO2)cc(OS(=O)(=O)C(F)(F)F)c1C=O
Temperature: -78 °C

Procedure:
Into a 50-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, were placed a solution of 2-hydroxy-6-methyl-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (300 mg, 1.27 mmol, 1.00 equiv) in dichloromethane (20 mL) and triethylamine (510 mg, 5.05 mmol, 3.97 equiv). This was followed by the addition of a solution of Tf2O (720 mg, 2.55 mmol, 2.01 equiv) in dichloromethane (5 mL) dropwise with stirring at −78° C. The resulting solution was stirred for 2 h at −78° C., then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3×30 mL of dichloromethane. The organic layers were combined, washed with 3×10 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10). This resulted in 110 mg (19%) of 2-formyl-3-methyl-5-(tetrahydro-2H-pyran-2-yloxy)phenyl trifluoromethanesulfonate as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[O:39][CH3:40])=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.CO>CO>[CH3:40][O:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:30]1[N:21]2[CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:8]4([NH2:7])[CH2:11][CH2:10][CH2:9]4)=[CH:13][CH:14]=3)=[N:19][C:20]2=[N:32][CH:31]=1
Reactant: COc1ccccc1-c1cnc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cn12
Agent: Cl
Solvent: CO
Product: COc1ccccc1-c1cnc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-7 (55 mg, 0.1 mmol) in 1 mL of MeOH was added 4M HCl/MeOH (2 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 4-8.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[OH:39][C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][C:41]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.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:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:41]5[CH:42]=[C:43]([CH3:46])[CH:44]=[CH:45][C:40]=5[OH:39])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: Cc1ccc(O)c(B(O)O)c1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(C)ccc5O)c4)cn23)CC1
Temperature: 90 °C
Yield: 57.9 %

Procedure:
To a solution of (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate (84 mg, 0.144 mmol, 1 equiv) and (2-hydroxy-5-methylphenyl)boronic acid (33 mg, 0.216 mmol, 1.5 equiv) in DMF (1.4 mL, sparged with nitrogen for 10 min) was added Pd(PPh3)4 (17 mg, 0.014 mmol, 0.1 equiv) and 2 M Na2CO3 (0.144 mL, 0.287 mmol, 2 equiv). The reaction was heated at 90° C. for 3 h. Upon cooling to ambient temperature, the reaction was diluted with EtOAc, washed with water, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (51 mg, 58%) as a yellow foam. 1H NMR (400 MHz, CDCl3) δ 8.13 (br. s., 1H), 8.08-8.01 (m, J=7.0 Hz, 1H), 7.95 (br. s., 1H), 7.62-7.56 (m, 1H), 7.51 (br. s., 1H), 7.14 (s, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.01 (s, 1H), 6.96 (d, J=7.5 Hz, 1H), 6.10-5.94 (m, 2H), 5.40 (d, J=17.1 Hz, 1H), 5.03 (d, J=9.5 Hz, 1H), 3.99 (d, J=5.0 Hz, 2H), 3.90 (br. s., 1H), 3.79-3.75 (m, 1H), 3.71 (s, 3H), 3.08 (br. s., 1H), 2.79-2.70 (m, 1H), 2.56 (br. s., 3H), 2.35 (s, 3H), 2.00 (d, J=13.6 Hz, 2H), 1.88-1.77 (m, 2H), 1.34 (s, 3H), 1.26 (s, 9H); LCMS (ESI, M+1): 612.4.
Reaction SMILES: [C:1]1(=[O:14])[N:5]([CH2:6][C:7]#[N:8])[C:4](=[O:9])[C:3]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:2]12.P([S-])(OCC)(OCC)=[S:16]>Cl.C(OCC)(=O)C>[C:4]1(=[O:9])[N:5]([CH2:6][C:7]([NH2:8])=[S:16])[C:1](=[O:14])[C:2]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:3]12
Reactant: CCOP(=S)([S-])OCC
Reactant: N#CCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=S)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a 20 ml 4N solution of hydrogen chloride in ethyl acetate, 3.07 g of phthalimidoacetonitrile was dissolved. To the resulting solution, 3.17 ml of O,O-diethyl dithiophosphate was added, followed by stirring at room temperature for 6 hours. The precipitate formed was collected by filtration, and washed successively with ethyl acetate and diethyl ether, whereby 2.29 g of phthalimidothioacetamide was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:30][Si](C)(C)C>CC(CC)=O>[ClH:30].[CH3:29][N:2]([CH3:1])[C:3]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccc(F)cc2)CCC(=CC(=O)NCCCc2ccccc2)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-[4-Dimethylamino-4-(4-fluorophenyl)cyclohexylidene]-N-(3-phenylpropyl)acetamide (180 mg, 0.45 mmol) was dissolved in ethyl methyl ketone (10 ml), and chlorotrimethylsilane (0.087 ml, 0.68 mmol) was added. After 1.5 h the hydrochloride was isolated as a colourless solid with an m.p. of 209-212° C. in a yield of 65% (126 mg).
Reaction SMILES: N1CCCCC1.C(NNC1(N=C=S)C=CC=CC1)=O.[CH:20]([NH:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([N:33]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=CC=2)CC2C=CC=CC=2)=[S:32])=[CH:26][CH:25]=1)=[O:21]>>[CH:20]([NH:22][NH:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([N:33]2[CH2:41][CH2:42][CH2:47][CH2:46][CH2:45]2)=[S:32])=[CH:28][CH:29]=1)=[O:21]
Reactant: O=CNNc1ccc(NC(=S)N(Cc2ccccc2)Cc2ccccc2)cc1
Agent: O=CNNC1(N=C=S)C=CC=CC1
Solvent: C1CCNCC1
Product: O=CNNc1ccc(NC(=S)N2CCCCC2)cc1

Procedure:
Piperidine (0.085 g, 0.001 mole) and 1-(2-formylhydrazino)phenyl isothiocyanate (0.19 g, 0.001 mole) were reacted according to the procedure described for NA-11 in Example 3. Yield 0.14 g (50 percent), m.p. 174°-176° C.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[Br:5][C:6]([CH3:12])([CH2:10][CH3:11])[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.C(OCC)C>C(=O)([O-])O.[Na+]>[Br:5][C:6]([CH3:12])([CH2:10][CH3:11])[C:7]([O:9][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:8]
Reactant: C=C(C)C
Reactant: CCC(C)(Br)C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Product: CCC(C)(Br)C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A mixture of about 40 ml of isobutene, 40 g of 2-bromo-2-methylbutyric acid, 1 ml of concentrated sulfuric acid, and 20 ml of dry ethyl ether was reacted in a closed tube overnight at room temperature. After the reaction was over, the reaction mixture was dispersed in a mixture of 150 ml of ice-water and 10 g of sodium hydrogencarbonate and extracted with 200 ml and then 100 ml of ether. The organic layers were collected, washed twice each time with 50 ml of water and then once with 50 ml of a saturated aqueous sodium chloride solution, and after drying with anhydrous magnesium sulfate, ether was distilled off to provide 36.3 g of tert-butyl 2-bromo-2-methylbutyrate.
Reaction SMILES: [CH2:1]([C:4]1([CH2:11][CH2:12][CH3:13])[CH2:9][C:8](=[O:10])[O:7][C:5]1=[O:6])[CH2:2][CH3:3].[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([CH2:25][O:26][C:27]3[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=3)[NH2:30])=[N:22]2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([CH2:25][O:26][C:27]3[CH:28]=[C:29]([NH:30][C:8](=[O:10])[CH2:9][C:4]([CH2:11][CH2:12][CH3:13])([CH2:1][CH2:2][CH3:3])[C:5]([OH:7])=[O:6])[CH:31]=[CH:32][CH:33]=3)=[N:22]2)=[CH:17][CH:16]=1
Reactant: CCCC1(CCC)CC(=O)OC1=O
Reactant: Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1
Product: CCCC(CCC)(CC(=O)Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1)C(=O)O

Procedure:
The title compound is prepared analogously to the compound described in Example 20 from 2,2-dipropylsuccinic acid anhydride and 3-(7-fluoro-2-quinolinylmethoxy)aniline; beige crystals of m.p. 155°-156°.
Reaction SMILES: I.[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1.[OH:24][C@H:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:26][C:27](O)=[O:28].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([C:27](=[O:28])[CH2:26][CH:25]([OH:24])[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)C[C@H](O)c1ccccc1
Reactant: Cc1onc2c1c(=O)n(C1CCCNC1)c1cccc(Cl)c21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCN(C(=O)CC(O)c3ccccc3)C1)c1cccc(Cl)c21
Yield: 67.3 %

Procedure:
To a dry roundbottom flask add 9-chloro-3-methyl-5-piperidin-3-yl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide (50 mg, 0.11 mmol), (S)-3-hydroxy-3-phenylpropanoic acid (22 mg, 0.13 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.13 mmol), 1-hydroxy-7-azabenzotriazole (18 mg, 0.13 mmol), 4-dimethylamino-pyridine (1 mg, 0.01 mmol), and dimethylformamide (3 mL). Stir the reaction under nitrogen, and add triethylamine (30 μL, 0.22 mmol) dropwise. Stir the solution under nitrogen at room temperature overnight. Concentrate the solution and dissolve in 20% isopropanol/chloroform, wash with 1N HCl, 1N sodium thiosulfate, saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–1.5% methanol/chloroform) to give 34.5 mg of the title compound as a white solid, 66% yield. 1H NMR: consistent with structure. MS (ion spray) 466 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:22][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2Cl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccccc1-c1ccc(CBr)cc1
Yield: 61.3 %

Procedure:
A mixture of 4′-methyl-2-chloro-biphenyl (1.08 g, 5.33 mmol), NBS (1.14 g, 6.40 mmol) and AIBN (175 mg, 1.06 mmol) in CCl4 (37 mL) was heated at reflux for 3 h. The reaction mixture was diluted with CH2Cl2 and the organic solution was washed sequentially with aqueous saturated NaHCO3 (2×), water (1×), and brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (hexanes to 5% EtOAc/hexanes) to afford the title compound (920 mg). 1H NMR (CDCl3 400 MHz) δ 7.63-7.25 (m, 8H), 4.56 (s, 2H).
Reaction SMILES: CNCCNC.[C:7]1([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1>[Cu].C1(C)C(C)=CC=CC=1>[CH:17]1[CH:16]=[CH:15][C:14]([N:13]([C:24]2[CH:25]=[CH:26][C:21]([Br:20])=[CH:22][CH:23]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:19][CH:18]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Brc1ccc(I)cc1
Agent: [Cu]
Agent: CNCCNC
Solvent: Cc1ccccc1C
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
N,N′-dimethylethylenediamine 1.76 g was added to diphenylamine 16.9 g, 4-bromoiodobenzene 28.2 g sodium t-butoxide 14.4 g, copper powder 3.81 g and a xylene 100 ml solution, and the mixture was heated and refluxed for 24 hours under argon atmosphere. After cooled down to room temperature, the mixture was filtered to remove an insoluble matter, and the filtrate was concentrated. The residue was refined by silica gel chromatography to obtain 22.7 g of white crystal of 4-bromotriphenylamine.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].[CH:11]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:21]=O)[C:15]=2[CH:14]=[CH:13][N:12]=1>>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH:7][CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:6])[CH3:2]
Reactant: O=Cc1cccc2cnccc12
Reactant: CCOC(OCC)[C@H](C)N
Product: CCOC(OCC)[C@H](C)NCc1cccc2cnccc12
Yield: 93.1 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-6, (S)-1,1-diethoxypropan-2-amine (Compound XVIII-1) (883 mg, 6.0 mmol) was reacted with isoquinoline-5-carbaldehyde (802 mg, 5.1 mmol) to obtain the title compound (1.37 g, 95%).