Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:11]=[CH:10][N:9]([CH3:12])[C:5]2=[C:6](Cl)[N:7]=1.CN(C)[CH:15]=[O:16].[I:18]N1C(=O)CCC1=O.S(=O)(=O)(O)[O-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]([I:18])=[CH:10][N:9]([CH3:12])[C:5]2=[C:6]([O:16][CH3:15])[N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CN(C)C=O
Reactant: Cn1ccc2cc(Br)nc(Cl)c21
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: COc1nc(Br)cc2c(I)cn(C)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of Example 187A (3.24 g, 13.44 mmol) and dimethylformamide (37 mL) was cooled to 0° C. After the addition of 1-iodopyrrolidine-2,5-dione (3.6 g, 16.00 mmol), the reaction mixture was stirred at ambient temperature for 3 hours. The solution was cooled to 0° C. and 60 mL water was added followed by aqueous sodium bisulfate (60 mL, 10%) solution. The mixture was stirred for 1 hour at ambient temperature. Solid was collected by filtration, rinsed with water and was dried under vacuum to provide 4.9 g (99%) of the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:9][C@@H:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.NC1N=CC([C:28]2[CH:29]=[N:30][N:31]([CH:33]3[CH2:38][CH2:37][N:36]([C:39](=O)CO)[CH2:35][CH2:34]3)[CH:32]=2)=CC=1O[C@@H](C1C(Cl)=CC=C(F)C=1Cl)C>>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C@H:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:28]2[CH:29]=[N:30][N:31]([CH:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)[CH:32]=2)[N:3]=1)[CH3:11]
Reactant: C[C@@H](Oc1nc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)CO)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Product: C[C@@H](Oc1nc(-c2cnn(C3CCN(C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to procedure 62 using 5-bromo-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine and 4-(4-bromo-pyrazol-1-yl)-1-methyl-piperidine (prepared according to general procedure 11). 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.49 (m, 1H), 7.36 (t, 1H), 6.46 (q, 1H), 6.15 (s, 2H), 4.02 (m, 1H), 2.84 (m, 2H), 2.19 (s, 3H), 2.00 (m, 4H), 1.85 (m, 3H), 1.75 (d, 3H); LCMS: 465 [M+1]; c-Met Ki: 0.03 μM.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH:6]([N:21]2[CH2:26][C@@H:25]([CH3:27])[NH:24][CH2:23][C@@H:22]2[CH3:28])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:8]=2)=[CH:4][CH:3]=1.[CH2:31](Br)[CH:32]=[CH2:33].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH2:33]([N:24]1[CH2:23][C@@H:22]([CH3:28])[N:21]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][Si:14]([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:16])[CH3:15])[CH:8]=2)[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:30][CH:29]=2)[CH2:26][C@@H:25]1[CH3:27])[CH:32]=[CH2:31]
Reactant: C=CCBr
Reactant: C[C@@H]1CN(C(c2ccc(Br)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)[C@@H](C)CN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN1C[C@@H](C)N(C(c2ccc(Br)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)C[C@@H]1C
Yield: 99.5 %

Procedure:
The purified benzhydrylpiperazine (41.0 g, 83.7 mmol) was dissolved in 500 mL of dry tetrahydrofuran with 7.3 mL (84 mmol) of allyl bromide and 22 g (200 mmol) of sodium carbonate and heated at reflux overnight under nitrogen. The cooled reaction solution was filtered and the solvent removed to give 44.1 g of crude (±)-trans-1-allyl-4-(4-bromo-α-(3-(tert-butyldimethyl -silyloxy)phenyl)benzyl)-2,5-dimethylpiperazine as a brown oil. NMR (200 MHz, CDCl3): δ0.15 (s,6H); 0.95 (m,12H); 1.15 (2 overlapping d,J=6 Hz,3H); 1.8 (m,1H); 2.1 (m,1H); 2.35-2.65 (m,3H); 2.7-2.9 (m,2H); 3.35 (dd,J1 =5 Hz,J2 =12 Hz,1H); 5.0-5.2 (m,3H); 5.85 (m,1H); 6.6-7.5 (m,8H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([F:37])=[C:7]([C:9]2[CH:18]=[C:17]([C:19]3[CH:20]=[C:21]([C:25]4[CH:26]=[N:27][C:28]([N:31]5[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[CH:29][CH:30]=4)[CH:22]=[N:23][CH:24]=3)[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:8]=1.[CH2:38]=O.[OH-].[Na+]>C(O)=O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([F:37])=[C:7]([C:9]2[CH:18]=[C:17]([C:19]3[CH:20]=[C:21]([C:25]4[CH:26]=[N:27][C:28]([N:31]5[CH2:36][CH2:35][N:34]([CH3:38])[CH2:33][CH2:32]5)=[CH:29][CH:30]=4)[CH:22]=[N:23][CH:24]=3)[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:8]=1
Reactant: C=O
Reactant: Fc1ccc(Cl)cc1-c1cc(-c2cncc(-c3ccc(N4CCNCC4)nc3)c2)c2cccnc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN1CCN(c2ccc(-c3cncc(-c4cc(-c5cc(Cl)ccc5F)nc5ncccc45)c3)cn2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 180 mg (0.34 mmol) 2-(5-chloro-2-fluoro-phenyl)-4-(6′-piperazin-1-yl-[3,3′]bipyridinyl-5-yl)-[1,8]naphthyridine hydrochloride in 1.5 ml formic acid was treated with 80 μl (1.01 mmol) 35% aqueous formaldehyde solution and heated to 80° C. The reaction mixture was stirred at this temperature for 2 hours. The volume of the reaction mixture was reduced under vacuum and the residue made strongly alkaline with 2 N NaOH. The resulting precipitate was filtered off, washed with water and dried yielding 2-(5-chloro-2-fluoro-phenyl)-4-[6′-(4-methyl-piperazin-1-yl)-[3,3′]bipyridinyl-5-yl]-[1,8]naphthyridine as gray-green solid; HPLC-MS: 1.55 min, [M+H] 511.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[C:13]([O:16][CH3:17])(=[O:15])[CH3:14].[CH3:18][C:19]([S@@:22]([N:24]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])=[O:23])([CH3:21])[CH3:20]>C1COCC1>[CH3:21][C:19]([CH3:18])([S@@:22]([NH:24][C@:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH2:14][C:13]([O:16][CH3:17])=[O:15])=[O:23])[CH3:20]
Reactant: COC(C)=O
Reactant: CC(=N[S@@](=O)C(C)(C)C)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C[C@@](C)(N[S@@](=O)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
A solution of i-Pr2NH in THF (25 mL) was cooled to −78° C., n-BuLi (2.5M, 2 mL) was added and the solution was stirred for 1 h. Then methyl acetate (4.48 mmol, 278 mg) was added and the mixture was stirred for 30 min. To this solution Ti(Oi-Pr)3Cl (1 M, 9.4 mL) was added. After 0.5 h, (S)-2-methyl-N-(1-phenylethylidene)propane-2-sulfinamide (500 mg, 2.24 mmol) dissolved in THF (1 mL) was added. The mixture was stirred at −78° C. for 3 h. The reaction was quenched with NH4Cl and warmed to rt. The mixture was diluted with water and filtered. The solid was washed with H2O/EtOAc and filtered. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by preparative TLC to afford (R)-methyl 3-((S)-1,1-dimethylethylsulfinamido)-3-phenylbutanoate (305 mg, 46%). 1H NMR (CDCl3): 1.24 (s, 9H), 1.68 (s, 3H), 3.08 (s, 2H), 3.53 (s, 3H), 5.46 (s, 1H), 7.15-7.18 (m, 1H), 7.23-7.30 (m, 2H), 7.30-7.36 (m, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][N:11]=1.BrC1C=CC(Br)=CN=1.O1C2C=CC=CC=2C=C1B(O)O.[S:37]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38]1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:39]2[CH:40]=[CH:41][S:37][CH:38]=2)=[CH:12][N:11]=1
Reactant: OB(O)c1ccsc1
Reactant: Brc1ccc(-c2cc3ccccc3o2)nc1
Agent: Brc1ccc(Br)nc1
Agent: OB(O)c1cc2ccccc2o1
Product: c1ccc2oc(-c3ccc(-c4ccsc4)cn3)cc2c1

Procedure:
It is easy to synthesis the following compound in the same manner as in Example 1 except that 2-(benzofuran-2-yl)-5-bromopyridine was synthesized from 2,5-dibromopyridine (made by Tokyo Kasei Kogyo K.K.) and 2-benzofuranboronic acid (made by Aldrich Co.) and is reacted with 3-thiopheneboronic acid (made by Aldrich Co.) to obtain 2-(benzofuran-2-yl)-5-(thiophene-3-yl)pyridine, which is used instead of 2-(5-trifluoromethylpyridine-2-yl)benzofuran.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6](=[O:18])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[C:9]([N+:15]([O-])=O)[CH:8]=1>[Fe].C(O)(=O)C>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([C:6]([O:5][CH3:4])=[O:18])=[CH:8][C:9]=1[NH2:15])=[O:14]
Reactant: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C=O)c(N)c1
Reaction time: 1 h
Yield: 85 %

Procedure:
To a 1:1 mixture of ethanol and acetic acid was added methyl4-formyl-3-nitrobenzoate (1 eq) and Fe dust (3 eq) was added in portions. The reduction was complete in 1 h. The reaction mixture was filtered and then concentrated and partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate and dried and concentrated to give methyl 4-formyl-3-aminobenzoate in 85% yield. ES/MS m/z 180 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[C:17]2=[N:18][CH:19]=[CH:20][C:21]([I:22])=[C:16]2[C:15]([CH:23]([CH3:25])[CH3:24])=[N:14]1)[C:8]#[N:9])[CH3:3].[OH:26]O.[OH-].[Na+].O>CS(C)=O>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[C:17]2=[N:18][CH:19]=[CH:20][C:21]([I:22])=[C:16]2[C:15]([CH:23]([CH3:25])[CH3:24])=[N:14]1)[C:8]([NH2:9])=[O:26])[CH3:1]
Reactant: OO
Reactant: CC(C)c1nn(-c2ccc(C#N)cc2CN(C)C)c2nccc(I)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1nn(-c2ccc(C(N)=O)cc2CN(C)C)c2nccc(I)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
Compound (125a) (0.500 g), 2-picoline-borane complex (0.166 g), and dimethylamine (0.216 mL) were dissolved in acetic acid (1.0 mL) and methanol (10 mL), followed by stirring at room temperature for 12 hr. The reaction solution was concentrated, and the residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to obtain 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile (0.213 g, 40%). This 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile was dissolved in DMSO (1.6 mL), and a hydrogen peroxide solution (30 wt %) (0.060 mL) and a 4 mol % aqueous sodium hydroxide solution (0.132 mL) were added to the resulting solution, followed by stirring at room temperature for 20 min. Water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (0.144 g, 65%). According to Example 97(2), compound (126) (64%) was prepared as a white solid using 3-{(dimethylamino)methyl}-4-{4-iodo-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide instead of compound (97a) and using 4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole hydrochloride instead of 4-phenyl-1H-imidazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1C1(N)CCCCC1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:20]([C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:23]=1)=O.OOS([O-])=O.[K+]>CN(C=O)C.O>[CH2:8]([O:7][C:5]([C:4]1[CH:10]=[CH:11][C:12]2[N:1]([CH:2]3[CH2:3][CH2:4][CH2:10][CH2:11][CH2:12]3)[C:20]([C:22]3[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:23]=3)=[N:1][C:2]=2[CH:3]=1)=[O:6])[CH3:9]
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Reactant: CCOC(=O)c1ccc(C2(N)CCCCC2)c(N)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(OCC(=O)O)cc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Following the procedure of example 1, ethyl 3-amino-4-(aminocyclohexyl)benzoate (1.077 g, 4.1 mmol) and 4-formylphenoxyacetic acid (0.748 g, 4.15 mmol) were dissolved in a mixture of DMF (8 mL) and water (0.5 mL). Oxone® (0.7 equivalent, 2.87 mmol, 1.764 g) was added and the mixture stirred for 30 min at room temperature (HPLC complete). Water was added to precipitate the product, which was collected by filtration, washed with water and dried (1.130 g, 65% yield, brown solid).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:33])[CH:9]([CH3:32])[C:10]([NH:12][C:13]1[CH:18]=[C:17](B(O)O)[CH:16]=[C:15]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:24])[N:14]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:35]1[N:36]=[C:37](Cl)[C:38]2[N:43]([CH3:44])[N:42]=[C:41]([CH3:45])[C:39]=2[N:40]=1>>[C:1]([O:5][C:6](=[O:7])[N:8]([CH:9]([C:10](=[O:11])[NH:12][C:13]1[CH:18]=[C:17]([C:37]2[C:38]3[N:43]([CH3:44])[N:42]=[C:41]([CH3:45])[C:39]=3[N:40]=[CH:35][N:36]=2)[CH:16]=[C:15]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:24])[N:14]=1)[CH3:32])[CH3:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(C)c2c(Cl)nc(Cl)nc12
Reactant: CC(C(=O)Nc1cc(B(O)O)cc(NC(=O)c2ccc(Cl)cn2)n1)N(C)C(=O)OC(C)(C)C
Product: Cc1nn(C)c2c(-c3cc(NC(=O)c4ccc(Cl)cn4)nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)c3)ncnc12

Procedure:
K63a is prepared analogously from D1 utilizing 5,7-dichloro-1,3-dimethyl-1H-pyrazolo-[4,3-d]pyrimidine:
Reaction SMILES: CCN(C(C)C)C(C)C.C([Si](C)(C)[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:26][O:25]2)=[CH:18][CH:17]=1)(C)(C)C.Cl.[N:30]1[C:35]2[CH:36]=[CH:37][S:38][C:34]=2[C:33]([N:39]2[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]2)=[N:32][CH:31]=1>CC(O)C.CS(C)=O>[OH:25][CH:24]([CH2:26][NH:45][CH:42]1[CH2:43][CH2:44][N:39]([C:33]2[C:34]3[S:38][CH:37]=[CH:36][C:35]=3[N:30]=[CH:31][N:32]=2)[CH2:40][CH2:41]1)[CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Reactant: NC1CCN(c2ncnc3ccsc23)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc(OCC(O)CNC2CCN(c3ncnc4ccsc34)CC2)cc1
Yield: 13 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 1.2 eq. DIEA, 120° C., 48 h), using 200 μmol tert-butyldimethyl(4-(oxiran-2-ylmethoxy)phenoxy)silane and 1-(thieno[3,2-d]pyrimidin-4-yl)piperidin-4-amine HCl-salt to give O-silylated intermediate upon purification by prep. HPLC (reversed phase) and prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 6:4:1) with 13% yield. Product was obtained by deprotection according to SP7 and purification by prep. HPLC (reversed phase) with 37% yield.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[OH-].[K+].S(=O)(=O)(O)[OH:16]>O>[F:8][C:7]1[C:6]([F:9])=[CH:5][CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:16]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(F)c1O
Temperature: 40 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
1.77 kg (10 mol) of 2,3,4-trifluoronitrobenzene are added to 4 l of water. The mixture is then warmed to 40° C. and vigorously stirred. 389.4 g (22 mol) of 31.7% strength potassium hydroxide solution are then added dropwise in such a way that the temperature remains between 40° and 55° C. After about 4 h, the reaction is complete (GC checking). The reaction mixture is brought to pH 3 using 70% strength sulfuric acid at 70° C. Steam is then passed into the solution, the product passing over with it and being isolated after cooling to 10° C. 1.51 kg of 2,3-difluoro-6-nitrophenol having a purity >99.9% (GC) are obtained after drying (melting point 63.5° C.), which corresponds to a yield of 86% of theory.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CO.C(Cl)Cl.[Pd]>[CH2:19]([O:26][C:27]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.1 %

Procedure:
A solution of 1-benzhydryl-3-hydroxyazetidine (10 g, 41.8 mmol) in methanol (300 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium (10 g) on charcoal in a water bath (50° C.) for 3 hours. After checking the completion of the reaction, the reaction mixture was filtered and the residue washed with methanol. The combined filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and distilled water. The organic layer was concentrated under reduced pressure, and the obtained residue dried under reduced pressure. The resulting crude product was dissolved in a mixture of methylene chloride (120 ml) and methanol (120 ml), chloroformic acid benzyl ester (8.95 ml, 62.7 mmol) and triethylamine (8.79 ml, 62,7 mmol) were added thereto, and the mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1)→ethyl acetate as the eluant to afford 1-benzyloxycarbonyl-3-hydroxyazetidine (1.91 g, yield 22%).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:6][C:7](=[S:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>C1COCC1>[C:1]([C:4]1[CH:5]([C:22]2[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=2)[N:6]([C:36](=[O:39])[CH2:37][CH3:38])[C:7](=[S:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC(=O)N1C(=S)N(c2cccc(C(F)(F)F)c2)C(C)=C(C(C)=O)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{5-Acetyl-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-4-pyrimidinyl}benzonitrile (Example 1; 100 mg, 0.24 mmol) is dissolved in 3 ml THF. After addition of pyridine (21 mg, 0.26 mmol) and propanoyl chloride (22 mg, 0.24 mmol), the reaction mixture is stirred at room temperature overnight and is then quenched with 10 ml water. After extraction with ethyl acetate (2×10 ml), the organic layer is dried with sodium sulfate, and the crude product is purified via flash chromatography on silica gel using a gradient of cyclohexane/ethyl acetate.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1.C(Cl)(Cl)Cl.[Cl-].[Na+]>C(O)(=O)C>[C:1]([O:4][CH:5]1[C:13]2[C:8](=[C:9]([N:14]3[CH:17]=[CH:21][CH:20]=[CH:19]3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC1CCC(OC)O1
Reactant: CC(=O)OC1CCc2c(N)cccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)OC1CCc2c1cccc2-n1cccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.2 %

Procedure:
A stirred solution of 10.0 g (0.052 mole) of 4-amino-1-indanyl acetate (prepared as in Example 1, step F) and 7.5 g (0.056 mole) of 2,5-dimethoxytetrahydrofuran in 21.2 mL of acetic acid was heated under reflux for 3.5 hours. The reaction mixture was then allowed to cool to ambient temperature, and was stirred for 16 hours. The reaction mixture was poured into 200 mL of chloroform. An aqueous saturated solution of sodium chloride (200 mL) was added, and the mixture was stirred for 10 minutes. The aqueous layer was separated and washed with 50 mL of chloroform. The combined organic phases were washed with two portions of 50 mL each of an aqueous saturated solution of sodium chloride. The organic layer was dried over potassium carbonate, filtered, and the filtrate concentrated under reduced pressure to give 13.2 g of 4-(1-pyrrolyl)-1-indanyl acetate.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.C(N(CC)C(C)C)(C)C.[C:37](O)(=[O:39])[CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37](=[O:39])[CH3:38])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (Intermediate A) (50 mg, 0.136 mmol) in DMF (1 ml) was added N,N-diisopropylethylamine (62 mg, 0.0831 ml, 0.476 mmol), acetic acid (9.8 mg, 9.33 μl, 0.163 mmol) and TBTU (52.4 mg, 0.163 mmol). The mixture was allowed to stir at room temperature for 4 h and poured into ice/water (0.5 ml). The crude reaction mixture was concentrated in vacuo. The reaction mixture was solved with sat NaHCO3 (1×10 mL). and extracted with dichloromethane (2×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 100 g, 0% to 20% MeOH in dichloromethane) to yield the title compound as an off-white solid (53 mg, 62%), MS (ISP) m/z=374.3 [(M+H)+].
Reaction SMILES: C(OC1CC2C3[C:15](=CC=CC=3)[NH:14][C:13]=2CC1)(=O)C1C=CC=CC=1.[H-].[Na+].ClC1C=CC(CCl)=CC=1.C(O[CH:43]1[CH2:55][C:54]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]([CH2:56][C:57]3[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=3)[C:46]=2[CH2:45][CH2:44]1)(=O)C1C=CC=CC=1>O.CN(C)C=O>[Cl:63][C:60]1[CH:61]=[CH:62][C:57]([CH2:56][N:47]2[C:46]3[CH2:45][CH2:44][CH:43]([N:14]([CH3:15])[CH3:13])[CH2:55][C:54]=3[C:53]3[C:48]2=[CH:49][CH:50]=[CH:51][CH:52]=3)=[CH:58][CH:59]=1
Reactant: O=C(OC1CCc2[nH]c3ccccc3c2C1)c1ccccc1
Reactant: O=C(OC1CCc2c(c3ccccc3n2Cc2ccc(Cl)cc2)C1)c1ccccc1
Agent: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1CCc2c(c3ccccc3n2Cc2ccc(Cl)cc2)C1

Procedure:
A mixture of 29.1 g. of 3-benzoyloxy-1,2,3,4-tetrahydrocarbazole and 4.3 g. of sodium hydride (56% in mineral oil) in 200 ml. of dimethylformamide was heated on a steam ba th and 16.1 g. of p-chlorobenzyl chloride in 30 ml. of dimethylformamide was added dropwise. The reaction mixture was heated two hours, cooled, and diluted with water. The resulting oil was washed with water and crystallized from isopropyl alcohol to give 12.7 g. of 3-benzoyloxy-9-(p-chlorobenzyl)-1,2,3,4-tetrahydrocarbazole, m.p. 150°-152° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:24]=[CH:23][C:22](=[O:25])[NH:21][C:20]1=[O:26])(=[O:3])[CH3:2].[I:27]I.C(OCC)(=O)C.S(=O)(=O)(O)[O-].[Na+]>C(#N)C>[C:1]([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:24]=[C:23]([I:27])[C:22](=[O:25])[NH:21][C:20]1=[O:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: II
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 80 °C

Procedure:
454 mg (1.23 mmol) of the above product 4 as starting material, 420 mg (1.66 mmol, 1.3 eq) of iodine and 700 mg (1.27 mmol, 1 eq) of ceric ammonium nitrate are dissolved in 15 mL of anhydrous acetonitrile and heated to 80° C. After the starting material disappears, 100 mL of ethyl acetate and 30 mL (5%) of sodium bisulfate are added in turns. 30 mL of saturated saline is used to wash. After collection and combination with an organic phase, the solution is concentrated by reduced pressure. After purified by rapid column chromatography (acetone/n-hexane=2:3), a white powder product (1-(2′,3′,5′-Tri-O-acetyl-β-D-arabinofuranosyl)-5-iodopyrimidin-2,4(3H)-dione) 5 is obtained. Its weight and yield are 425 mg and 70% respectively.