Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([Cl:14])=[O:13])=[CH:7][C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2].[S:17](=[O:20])(=[O:19])=[O:18].O1CCOCC1>ClCCl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([S:17]([OH:20])(=[O:19])=[O:18])[C:12]([Cl:14])=[O:13])=[CH:7][C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2]
Reactant: COc1cc(CC(=O)Cl)ccc1OC(C)=O
Reactant: O=S(=O)=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(C(C(=O)Cl)S(=O)(=O)O)ccc1OC(C)=O
Temperature: 25 °C

Procedure:
A solution of 4-acetoxy-3-methoxyphenylacetyl chloride (2.42 g, 10 mmole) in dichloromethane (20 ml) was treated with a suspension of sulphur trioxide - dioxane complex (15 mmole) dichloroethane at 0° C. This mixture was stirred at room temperature for eighteen hours and evaporated to afford a yellow gum. νmax. (CHCL3) 1800, 1748 cm-1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(OCC)(=O)C.Cl>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:3][CH:4]=1
Reactant: NCCc1ccc(O)cc1
Reactant: Brc1ccc(Br)nc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(CCNc2ccc(Br)cn2)cc1
Yield: 80 %

Procedure:
A mixture of 2,5-dibromo-pyridine (5 g; 21.10 mmol) and tyramine (5.79 g; 42.21 mmol) was heated at 200C for 1 hour. Upon cooling the residue was taken up into ethyl acetate, water and 1N HCl. The phases were separated and the organic phase was washed twice with 1N HCl. The combined aqueous phases were basified to pH-9 with 2N NaOH and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to afford 4-{2-[(5-bromopyridin-2-yl)amino]ethyl}phenol as a beige solid (5 g; 80% yield), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][S:7][C:8]1[N:12]=[CH:11][NH:10][N:9]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.[CH2:20]([N:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])[CH3:21]>O1CCCC1>[CH2:20]([N:22]([CH2:26][CH3:27])[C:23]([N:10]1[CH:11]=[N:12][C:8]([S:7][CH2:6][CH2:5][O:4][CH2:1][CH:2]=[CH2:3])=[N:9]1)=[O:24])[CH3:21]
Reactant: C=CCOCCSc1nc[nH]n1
Reactant: CCN(CC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCOCCSc1ncn(C(=O)N(CC)CC)n1

Procedure:
A solution of 7.4 g. 3-(2-allyloxyethylthio)-1,2,4-triazole, 8ml. triethylamine 6.0 g. diethylcarbamoyl chloride in 40 ml. of tetrahydrofuran was heated under reflux for 15 hours. The cooled reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was evaporated under vacuum to remove the solvent. Further precipitation of amine hydrochloride was filtered off. The filtrate was dissolved in 50 ml. methylene chloride and washed with ice-cold N/10 sodium hydroxide, with N/10 hydrochloric acid and finally with ice-cold water. The solvent was removed by vacuum distillation to give a liquid product, 1-diethylcarbamoyl-3-(2-allyloxyethylthio)-1,2,4-triazole, b.p. 148° - 153°C./0.05 mm. GLC assay showed that the 1-isomer was present to the extent of 98.33%. Elemental analysis was satisfactory.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(O)c(C(F)(F)F)c2)COC(C)(C)OC1
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOc1ccc(CCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 1-1 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and 1-bromohexane (0.201 ml) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (620 mg) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][CH:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cccc(N)c2)CC1
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To 10% palladium-carbon (30 mg), a solution of tert-butyl 4-((3-nitrophenyl)amino)azepane-1-carboxylate (C25, 78 mg) in tetrahydrofuran (2 mL) and methanol (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour under a hydrogen atmosphere. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure to obtain tert-butyl 4-((3-aminophenyl)amino)azepane-1-carboxylate (C26, 64 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([CH3:9])[C:3]=1[OH:10].C([Li])CCC.CCCCCC>O1CCCC1>[Br:8][C:6]1[N:5]=[C:4]([CH3:9])[C:3]([OH:10])=[CH:2][CH:7]=1
Reactant: Cc1nc(Br)cc(Br)c1O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nc(Br)ccc1O
Temperature: -78 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
4,6-Dibromo-2-methyl-pyridin-3-ol (14.32 g, 53.65 mmol) was dissolved in tetrahydrofuran (181 mL). The solution was cooled to −78° C. and n-butyllithium in hexane (45.16 mL of 2.5 M, 112.9 mmol) was added drop-wise keeping the temperature at −78° C. The mixture was stirred for 2 hours before it was quenched with water (45 mL) and neutralized with 1 N HCl. The aqueous mixture was extracted with dichloromethane (3×100 mL). The organic layers were combined and dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield 6-bromo-2-methyl-pyridin-3-ol (9.41 g, 93%). 1H NMR (400 MHz, DMSO) δ 10.10 (s, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 2.29 (s, 3H). ESI-MS m/z calc. 187.0, found 188.3 (M+1)+; Retention time: 0.85 minutes (3 min run).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18]Br.FC(F)(F)C1C=CC(C2(C#N)CCCC2)=CC=1>>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([C:9]2([C:10]#[N:11])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=[CH:7][CH:8]=1
Reactant: BrCCCCBr
Reactant: N#CCc1cccc(C(F)(F)F)c1
Agent: N#CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: N#CC1(c2cccc(C(F)(F)F)c2)CCCC1

Procedure:
1-(3-(Trifluoromethyl)phenyl)cyclopentanecarbonitrile (468) was synthesized from 2-(3-(trifluoromethyl)phenyl)acetonitrile (467) and 1,4-dibromobutane following the procedure described for 1-(4-trifluoromethyl-phenyl)-cyclopentanecarbonitrile (237).
Reaction SMILES: C(O)(=[O:3])C.[CH3:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][O:25][P:26]1([O:32][CH2:31][C@H:30]([CH2:33][N:34]2[C:39](=[O:40])[N:38]=[C:37]([NH2:41])[CH:36]=[CH:35]2)[O:29][CH2:28]1)=[O:27]>[OH-].[Na+]>[CH3:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][O:25][P:26]([OH:32])([CH2:28][O:29][C@H:30]([CH2:31][OH:3])[CH2:33][N:34]1[C:39](=[O:40])[N:38]=[C:37]([NH2:41])[CH:36]=[CH:35]1)=[O:27]
Reactant: CC(=O)O
Reactant: CCCCCCCCCCCCCCCCOCCCOP1(=O)CO[C@@H](Cn2ccc(N)nc2=O)CO1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCOCCCOP(=O)(O)CO[C@H](CO)Cn1ccc(N)nc1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
As described in U.S. Pat. No. 6,716,825, in Step 1 of the scheme above, cidofovir was suspended in N,N-DMF and N,N′-dicyclohexyl-4-morpholine-carboxamide was added. The mixture was stirred overnight to dissolve the cidofovir. The clear solution was then charged to an addition funnel and slowly added (30 min) to a stirred, hot pyridine (60° C.) solution containing 1,3-dicyclohexyl carbodiimide. The resulting reaction mixture was stirred at 100° C. for 16 h, cooled to room temperature and the solvents were removed under reduced pressure. The reaction mixture was adsorbed on silica gel and the product was purified by flash column chromatography using gradient elution (CH2Cl2 and MeOH) followed by 5:5:1 CH2Cl2/MeOH/H2O. The fractions containing the product were combined and concentrated in vacuo. The product, the DCMC salt of cyclic cidofovir was isolated in a 44% yield. In step 2, a solution of cyclic cidofovir DCMC salt in dry N,N-DMF was charged with 1-bromo-3-hexadecyloxypropane and the mixture was stirred and heated at 80° C. for 6 h. The solution was concentrated in vacuo, the residue adsorbed on silica gel and purified by flash column chromatography using gradient elution (CH2Cl2 and ethanol). The product was eluted with 90:10 CH2Cl2/EtOH. The fractions containing pure product were concentrated in vacuo. Hexadecyloxypropyl-cyclic cidofovir was obtained in a 55% yield. In Step 3, hexadecyloxypropyl-cyclic cidofovir was dissolved in 0.5M NaOH and stirred at room temperature for 1.5 h. 50% aqueous acetic acid was then added dropwise to adjust the pH to 9. The precipitated hexadecyloxypropyl-cidofovir was isolated by filtration, rinsed with water, and dried. The product was crystallized from 3:1p-dioxane/water to give hexadecyloxypropyl-cidofovir (HDP-CDV, i.e., CMX001).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1B(O)O.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:33]4[S:32][CH:36]=[CH:35][CH:34]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: OB(O)c1cccs1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, part B), 2-thiophenyl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4-thiophen-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: [CH2:1]1[O:21][C:20]2[C:3](=[CH:4][CH2:5][C:6](OC)([CH:19]=2)[CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:2]1.[BH4-].[Na+].[CH2:26]([OH:28])C>>[CH2:1]1[O:21][C:20]2[C:3](=[CH:4][C:5]([O:28][CH3:26])=[C:6]([CH:19]=2)[CH2:7][CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:2]1
Reactant: CCO
Reactant: CCOC(=O)C(=CC1(OC)C=C2OCOC2=CC1)C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1cc2c(cc1OC)OCO2)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
To a solution of the diethyl 2-(4,5-methylenedioxy-1-methoxybenylidene)-malonate (23.40 g, 0.073 mol) in ethanol (100 mL) was added sodium borohydride (2.80 g, 0.073 mol) and the mixture was stirred at room temperature for 5 h. The reaction was quenched with water and extracted with ethyl acetate (3×200 mL). The combined organic extracts were dried (Na2SO4) and evaporated to afford the title compound as an oil (20.30 g, 86%): 1H NMR (250 MHz, CDCl3) δ 7.45 (d, J=10 Hz, 1H), 7.20 (d, J=15 Hz, 1H), 5.85 (s, 2H), 4.22 (m, 4H), 3.40 (s, 2H), 3.30 (s, 3H), 1.25 (m, 6H).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[F:34]C(F)(F)S([O-])(=O)=O.ClC1C=CC=C(Cl)[N+]=1F>ClCCl.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=4)=[CH:23][C:22]=3[F:34])[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(O)c1cnc(-c2cc(F)c(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazol-5-yl]ethanol (420 mg) in dichloromethane (5 mL) was added 2,6-dichloro-1-fluoropyridinium trifluoromethanesulfonate (410 mg), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give a mixture of the title compound and a positional isomer thereof (35.0 mg). The mixture of the obtained positional isomers was dissolved in hexane-ethanol (850:150, volume ratio, 114 mL), and the solution was subjected to HPLC using TSK GEL SHILICA-60 (20 mmID×250 mL, manufactured by Tosoh Corporation-silica). Using hexane-ethanol (850:150, volume ratio) as a mobile phase, the solution was eluted at flow rate 20 mL/min and at room temperature, and the fraction was separated at retention time 34.5 min, and concentrated. The obtained solid was dissolved in ethyl acetate and the insoluble material was filtered off. The filtration was concentrated to give the title compound (18.1 mg, yield 3%) as a colorless amorphous solid. MS: 505 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:31])[C@@H:19]([N:21]([CH3:30])[C:22](=[O:29])/[CH:23]=[CH:24]/[CH2:25][N:26]([CH3:28])[CH3:27])[CH3:20])=[CH:4][N:3]=1.[Cl:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36].[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(NCC)C>O1CCCC1>[Cl:32][C:33]1[CH:34]=[C:35]([NH:36][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:31])[C@@H:19]([N:21]([CH3:30])[C:22](=[O:29])/[CH:23]=[CH:24]/[CH2:25][N:26]([CH3:28])[CH3:27])[CH3:20])=[CH:4][N:3]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCCNc1nc(Cl)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)/C=C/CN(C)C
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCCNc1nc(Nc2cccc(Cl)c2)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)/C=C/CN(C)C
Temperature: 70 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
To a solution of (S,E)-N-(1-((5-(2-chloro-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)-4-(dimethylamino)-N-methyl-2-butenamide (L4, 20 mg) and 3-chloroaniline (28 mg) in tetrahydrofuran (3 mL), (1S)-(+)-10-camphorsulfonic acid (52 mg) was added at room temperature, and the mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature, and then diethylamine was added until the mixture became basic. The solvent was evaporated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography to obtain (S,E)-N-(1-((5-(2-((3-chlorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)-4-(dimethylamino)-N-methyl-2-butenamide (12-2, 4 mg).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[F:8][C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:20]=[C:21]2[CH:27]=[C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[O:25][C:22]2=[CH:23][N:24]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH:5]([O:4][C:2]([N:31]1[CH2:32][CH2:33][CH:28]([C:26]2[O:25][C:22]3=[CH:23][N:24]=[C:19]([C:10]4[CH:11]=[CH:12][C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:9]=4[F:8])[CH:20]=[C:21]3[CH:27]=2)[CH2:29][CH2:30]1)=[O:3])([CH3:7])[CH3:6]
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2cc3cc(C4CCNCC4)oc3cn2)c(F)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4F)ncc3o2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Isopropyl chloroformate (1 mol/L in toluene; 0.30 mL) is added to a solution of 5-(2-fluoro-4-methanesulfonyl-phenyl)-2-piperidin-4-yl-furo[2,3-c]pyridine (75 mg) and N,N-diisopropyl-ethylamine (0.10 mL) in tetrahydrofuran (1 mL) chilled in an ice bath. The solution is stirred at room temperature for 3 h. The solution is concentrated and the residue is taken up in water and dichloromethane. The resulting mixture is extracted with dichloromethane and the combined extracts are dried (Na2SO4). The solvent is evaporated and the residue is purified by HPLC on reversed phase (methanol/water) to give the title compound. Mass spectrum (ESI+): m/z=461 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.[OH-].[Na+].[C:12]([O:16][C:17](OC([O-])=O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CC(O)(C)C.O>[C:12]([O:16][C:17]([N:5]1[CH2:6][CH2:7][CH2:8][C:2](=[O:1])[CH2:3][CH2:4]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1CCCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a stirred solution of 4-oxohomopiperidine.HCl (1.2 g, 8.05 mmol), NaOH (0.68 g, 16.9 mmol) in t-BuOH/H2O (1:1, 10 mL) was added t-butyldicarbonate (1.93 mL, 8.9 mmol) drop-wise. The reaction was stirred at RT overnight, extracted with EtOAc (2×10 mL) and the organic layer separated. The organic layer was dried over Na2SO4 and concentrated under vacuo. Pure 1-t-butoxycarbonyl-4-oxohomopiperidine (1.42 g, 84%) was isolated via silica gel flash chromatography eluting with 50% EtOAc/hexane. 1H NMR CDCl3 δ: 44 (9H, s), 1.72–1.84 (2H, m), 2.60–2.65 (4H, m), 3.55–3.61 (4H, m).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](Cl)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:33]([NH2:35])=[O:34])[CH2:28][CH2:27]1)[CH:19]=[CH:18]2.N1C=CC=CC=1>ClCCCl>[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([NH:32][C:33]([NH:35][C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[O:12])=[O:34])[CH2:30][CH2:31]1)[CH:19]=[CH:18]2
Reactant: O=C(Cl)c1ccc2ncccc2c1
Reactant: NC(=O)NC1CCN(Cc2ccc3cc(F)ccc3c2)CC1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C(NC(=O)c1ccc2ncccc2c1)NC1CCN(Cc2ccc3cc(F)ccc3c2)CC1

Procedure:
A mixture of 6-quinolinoyl chloride (4.77 g, 22 mmol), N-[[(6-fluoro-2-naphthalenyl)methyl]-4-piperidinyl]urea (6.02 g, 20 mmol), dry pyridine (2.5 ml) and 1,2-dichloroethane (30 ml) is stirred at reflux for 18 hours. The solution is then cooled, washed with aqueous sodium carbonate solution, dried and evaporated. The residue is crystallised from ethanol to give the title compound, mp 200°-201° C. (softens, maleate salt).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=2)[CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[H][H]>CCO.[Pd]>[C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:17][CH2:18]2)[CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A mixture of tert-butyl 4-[5-(isobutyrylamino)-2-methylphenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate (335 mg, 0.93 mmol) and 10% Pd/C (35.0 mg) in EtOH (20.0 mL) was hydrogenated at room temperature overnight using the hydrogen balloon method. The reaction mixture was filtered through Celite and washed with ethanol (3×10 mL). The combined extracts were concentrated in vacuo to afford tert-butyl 4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinecarboxylate (335 mg, 100%): ESMS m/e: 361.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:24]=1[NH2:25]>>[Cl:30][C:27]1[CH:28]=[CH:29][C:23]([O:22][CH3:21])=[C:24]([NH:25][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:15])[CH:26]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: COc1ccc(Cl)cc1N
Product: COc1ccc(Cl)cc1NC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 2-methoxy-5-chloroaniline (61 mg, 0.39 mmol). The title compound was obtained as a yellow solid (110 mg, 69% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.17 (1H, s), 9.00 (2H, s), 8.76 (1H, s), 7.57 (1H, m), 7.27 (1H, m), 7.13 (1H, m), 3.83 (3H, s). MS m/z: 488.02, 490.07 [M+H]+.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:21]=[CH:20][C:19]3[S:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11](=[O:22])[C:10]=3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.S(=O)(=O)(O)[OH:27].OO>O>[C:1]1([S:7]([C:8]2[CH:21]=[CH:20][C:19]3[S:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11](=[O:22])[C:10]=3[CH:9]=2)=[O:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: O=c1c2ccccc2sc2ccc(Sc3ccccc3)cc12
Agent: OO
Solvent: O
Solvent: CC#N
Product: O=c1c2ccccc2sc2ccc(S(=O)c3ccccc3)cc12
Temperature: 40 °C
Reaction time: 14 h
Yield: 83 %

Procedure:
While 11.2 parts of 2-(phenylthio)thioxanthone synthesized in Production Example 1, 215 parts of acetonitrile, and 0.02 parts of sulfuric acid were stirred at 40° C., 4.0 parts of a 30% aqueous hydrogen peroxide solution was dropped thereto slowly and then a reaction was performed at 40 to 45° C. for 14 hours. Subsequently, the reaction solution was cooled to room temperature (about 25° C.) and then was poured into 200 parts of distilled water, so that the product was precipitated. This was filtered and the residue was washed with water until the pH of the filtrate became neutral. Then the residue was dried under reduced pressure, affording a yellow powdery product. The product was purified by column chromatography (eluate: ethyl acetate/toluene=⅓:volume ratio) to afford 2-[(phenyl)sulfinyl]thioxanthone in a yield of 83%. The product was identified by 1H-NMR {d6-dimethyl sulfoxide, δ (ppm) 8.75 (1H, s), 8.45 (1H, d), 8.01 (2H, d), 7.75-7.85 (4H, m), 7.53-7.62 (4H, m)}.