Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:18]([F:20])[F:19])[N:6]2[CH:13]([CH3:17])[C:14]([OH:16])=O.[CH3:21][N:22](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:23].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>CN(C=O)C>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:18]([F:20])[F:19])[N:6]2[CH:13]([CH3:17])[C:14]([N:22]([CH3:23])[CH3:21])=[O:16]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C(=O)O)n1c(C(F)F)cc2c(Cl)c(C#N)ccc21
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C(=O)N(C)C)n1c(C(F)F)cc2c(Cl)c(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
To a solution of 2-[4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]propanoic acid (0.010 g, 0.034 mmol) in anhydrous DMF (1.5 mL) was added HATU (0.014 g, 0.037 mmol) and DIEA (0.0048 g, 0.0037 mmol) and stirred at rt. After 10 min, dimethylamine (2M in THF, 0.17 mL, 0.34 mmol) was added and stirred at rt for 45 min. The mixture was partitioned between Et2O and 0.2N HCl. The organic phase was washed with 0.2N HCl, 0.2N NaOH and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-1% MeOH—CH2Cl2 gradient) and the product was crystallized from CH2Cl2-hexanes to afford the title compound as a white solid (0.007 g, 64% yield): MS (ES) m/z 326 (M+1).
Reaction SMILES: ClCCC1N=CC=CN=1.OCCC1N=CC=CN=1.S(Cl)(Cl)=O.[NH2:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.[C:35]([NH:37][C:38](=[N:41][CH3:42])SC)#[N:36]>>[C:35]([NH:37][C:38]([NH:41][CH3:42])=[N:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][C:29]1[N:30]=[CH:31][CH:32]=[CH:33][N:34]=1)#[N:36]
Reactant: NCCSCCc1ncccn1
Reactant: CN=C(NC#N)SC
Agent: ClCCc1ncccn1
Agent: OCCc1ncccn1
Solvent: O=S(Cl)Cl
Product: CNC(=NCCSCCc1ncccn1)NC#N

Procedure:
By the procedure of Example 17 using 2-(2-chloroethyl)pyrimidine, prepared by treating 2-(2-hydroxyethyl)pyrimidine with thionyl chloride, as the starting material, 2-[2-(2-aminoethyl)thioethyl]pyrimidine is prepared, which when treated with N-cyano-N',S-dimethylisothiourea by the procedure of Example 3(a) gives the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[CH3:21][O:22][C:23](=[O:27])[CH:24](Br)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH:24]([CH3:25])[C:23]([O:22][CH3:21])=[O:27])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(S(=O)(=O)Nc2ccc(C)cc2)cc1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(S(=O)(=O)N(c2ccc(C)cc2)C(C)C(=O)OC)cc1
Temperature: 60 °C

Procedure:
The crude N-aryl-benzenesulfonamide building block XIII, e.g. 4-ethoxy-N-(4-methylphenyl)benzenesulfonamide (204 mg, 0.70 mmol, preparation described in example 1, step a)), was dissolved in DMF (5 mL). Methyl-2-bromopropionate (0.117 mL, 1.05 mmol) and potassium carbonate (193 mg, 1.40 mmol) were added. The mixture was heated overnight at 60° C. Solvents were evaporated. The crude residue was suspended in ethyl acetate (10 mL) and was washed with 1N HCl solution (7 mL) and with brine (7 mL). Organic phase was dried over MgSO4, fltrated and evaporated. The desired product, e.g. methyl 2-{[(4-ethoxyphenyl)sulfonyl]-4-methylanilino}propanoate (276 mg, quantitative crude yield) was isolated as a light yellow oil, in 94.3% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C:1]1([CH:9]=[CH:10][C:11](Cl)=[O:12])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]=1.C(N(CC)CC)C.[CH3:21][CH2:22][C:23]([CH2:28][O:29][CH2:30][CH:31]=[CH2:32])([CH2:26][OH:27])[CH2:24][OH:25]>C1(C)C=CC=CC=1>[CH3:21][CH2:22][C:23]([CH2:26][O:27][CH2:4][CH:1]=[CH2:2])([CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[CH2:24][OH:25].[C:1]1([CH:9]=[CH:10][C:11]([OH:12])=[O:25])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]=1
Reactant: O=C(Cl)C=CC1=Cc2ccccc21
Reactant: C=CCOCC(CC)(CO)CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCOCC(CC)(CO)COCC=C
Product: O=C(O)C=CC1=Cc2ccccc21

Procedure:
The procedure of Example 8 was repeated except that the following amounts of materials were used: BCB-AA acid chloride from Example 6 (40.98 g, 212.7 mmol), toluene (200 mL), triethylamine (29.11 g, 287.7 mmol) and trimethylolpropane allyl ether (18.18 g, 104.3 mmol). The product was isolated as a clear orange colored viscous oil. Yield: 36.02 g (71.6%). 1H NMR (500 MHz, Chloroform-d) δ 7.68 (d, J=15.9 Hz, 2H), 7.35 (dd, J=7.6, 1.4 Hz, 2H), 7.24 (s, 2H), 7.06 (d, J=7.6 Hz, 2H), 6.39 (d, J=16.0 Hz, 2H), 5.89 (ddt, J=17.2, 10.7, 5.5 Hz, 1H), 5.37-5.23 (m, 1H), 5.17 (dd, J=10.4, 1.6 Hz, 1H), 4.25 (d, J=2.1 Hz, 4H), 3.98 (d, J=5.5 Hz, 2H), 3.44 (s, 2H), 3.19 (s, 8H), 1.59 (q, J=7.6 Hz, 2H), 0.96 (t, J=7.6 Hz, 3H).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([Cl:12])=[O:11])[CH2:3]2.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:12].[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:10]([CH:4]2[CH:5]3[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]3)[CH2:3]2)=[O:11])=[CH:16][CH:15]=1
Reactant: O=C(Cl)C1CN2CCC1CC2
Reactant: Nc1ccc(Br)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Br)cc1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.00 g (4.76 mmol) of 3-quinuclidinecarbonyl chloride hydrochloride is added at 0° C. to a solution of 900 mg (5.24 mmol) of 4-bromoaniline and 1.85 g (14.28 mmol) of N,N-diisopropylethylamine in about 10 ml of dry DMF. The mixture is stirred at room temperature overnight. Purification by preparative HPLC is followed by chromatography again on silica gel (mobile phase: dichloromethane/methanol/triethylamine 80:20:2). The product is dissolved in methanol and mixed with 1N HCl in methanol. Finally, the solvent is removed. 0.63 g (31% of theory) of the title compound is obtained. The raw material is employed directly in the next synthesis.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=O)[C:11]1=[O:20].Cl.[NH2:22][OH:23]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[N:22][OH:23])[C:11]1=[O:20]
Reactant: NO
Reactant: Cc1ccc(Cl)c(N2C(=O)C(=O)c3ccccc32)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)c(N2C(=O)C(=NO)c3ccccc32)c1Cl
Yield: 81.3 %

Procedure:
A solution of 1-(2,6-dichloro-3-methylphenyl)-1H-indole-2,3-dione (0.3 g) and hydroxylamine hydrochloride (0.07 g) in pyridine (2 ml) is stirred at room temperature for 20 minutes. The reaction mixture is diluted with ethyl acetate (20 ml) and washed with 1 N HCl (2×100 ml). The organic layer is dried (MgSO4) and evaporated. Flash chromatography (silica, CH2Cl2) followed by recrystallization from isopropyl ether affords 1-(2,6-dichloro-3-methylphenyl)-1H-indole-2,3-dione 3-oxime (256 mg, 80%), mp 190°-191° C.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@@H:6]([C:10]([OH:12])=[O:11])[CH2:7][CH2:8][CH3:9].[CH3:13]O>>[CH3:13][O:11][C:10](=[O:12])[C@@H:6]([CH2:7][CH2:8][CH3:9])[NH2:5]
Reactant: CCC[C@@H](N)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCC[C@@H](N)C(=O)OC
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Thionyl chloride (47.7 mL) was added dropwise to methanol (300 mL) under stirring at −5° C. over 2 hours and 15 minutes. D-Norvaline (35.00 g) was added to the resulting light yellow solution under stirring at −4° C. The solution was stirred at room temperature for 18 hours and then methanol was removed under reduced pressure. Diisopropyl ether (90 mL) was added to the precipitated crystals, which were filtered and washed twice with diisopropyl ether (30 mL) to give (R)-norvaline methyl ester (47.74 g, 95% yield) as a white powder.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7].C1(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:29]([CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cc(CO)cc(C(F)(F)F)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1cc(CN=[N+]=[N-])cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A solution of 3-hydroxymethyl-5-trifluoromethyl-benzonitrile (200 mg, 0.994 mmol) in toluene (1 ml) at 0° C. was treated with diphenyl phosphoryl azide (328 mg, 1.19 mmol), followed by DBU (182 mg, 1.19 mmol) and stirred at 0° C. for 2 hours. The ice bath was removed and the reaction was stirred at room temperature for overnight. Reaction was diluted with ethyl acetate and washed with 10% HCl solution, dried over anhydrous magnesium sulphate and concentrated in vacuo. The residue was purified by silica gel chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in hexanes) to yield the title compound (150 mg, 67%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.54 (s, 2H) 7.82 (s, 2H) 7.88 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH:12]=[O:13])[CH2:8][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[C:32]([F:35])([F:34])[F:33].O>CN(C=O)C>[F:33][C:32]([F:34])([F:35])[C:23]1[CH:24]=[C:25]([C:28]([F:31])([F:29])[F:30])[CH:26]=[CH:27][C:22]=1[CH2:21][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH:12]=[O:13])[CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: O=CC1=Cc2ccc(O)cc2OC1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=CC1=Cc2ccc(OCc3ccc(C(F)(F)F)cc3C(F)(F)F)cc2OC1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
7-Hydroxy-2H-chromene-3-carbaldehyde (200 mg) was dissolved in DMF (5 mL), and K2CO3 (235 mg) and 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (0.234 mL) were added thereto, followed by stirring at 80° C. for 30 minutes. The reaction liquid was poured into water, and the resulting powder was collected by filtration and dried under reduced pressure to obtain 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-2H-chromene-3-carbaldehyde (455 mg) as a pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:17][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([C:22]([NH2:24])=[O:23])=[C:8]1[C:18]([NH:20][CH3:21])=[O:19].[CH3:25][C:26]1[O:30][N:29]=[C:28]([C@:31]([OH:35])([C:33]#[CH:34])[CH3:32])[N:27]=1>>[F:16][C:15]1[CH:14]=[C:13]2[C:4]([C:5]3[N:9]([CH:10]4[CH2:17][CH:12]2[CH2:11]4)[C:8]([C:18]([NH:20][CH3:21])=[O:19])=[C:7]([C:22]([NH2:24])=[O:23])[N:6]=3)=[CH:3][C:2]=1[C:34]#[C:33][C@@:31]([OH:35])([C:28]1[N:27]=[C:26]([CH3:25])[O:30][N:29]=1)[CH3:32]
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Product: CNC(=O)c1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(C#C[C@@](C)(O)c3noc(C)n3)cc1-2

Procedure:
9-Bromo-10-fluoro-3-N-methyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-3,4-dicarboxamide (125 mg) was reacted with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol similar to as described in General Procedure G to afford 14.5 mg of 10-fluoro-9-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl]-3-N-methyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-3,4-dicarboxamide following reverse phase hplc purification. MS (Q1) 465 (M)+. 1H NMR (400 MHz, DMSO) δ 10.58 (q, J=4.1 Hz, 1H), 8.86 (d, J=7.5 Hz, 1H), 8.28 (s, 1H), 7.74 (s, 1H), 7.33 (d, J=10.0 Hz, 1H), 6.79 (s, 1H), 6.13-6.05 (m, 1H), 3.74-3.63 (m, 1H), 3.18-3.05 (m, 2H), 2.78 (d, J=4.6 Hz, 2H), 2.62 (s, 3H), 1.87 (s, 3H), 1.68 (d, J=12.3 Hz, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:37][CH3:38])[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20](/[CH:33]=[N:34]/OC)[C:21]4[S:25][C:24]([NH:26][C:27](=[O:31])[NH:28][CH2:29][CH3:30])=[N:23][C:22]=4[CH:32]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH2:39].CC#N>CO.[OH-].[Na+].O>[C:33]([C:20]1[C:21]2[S:25][C:24]([NH:26][C:27](=[O:31])[NH:28][CH2:29][CH3:30])=[N:23][C:22]=2[CH:32]=[C:18]([C:15]2[CH:14]=[N:13][C:12]([N:9]3[CH2:8][CH2:7][C:6]([CH2:37][CH3:38])([C:4]([OH:3])=[O:5])[CH2:11][CH2:10]3)=[N:17][CH:16]=2)[CH:19]=1)(=[O:39])[NH2:34]
Reactant: O
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)nc3)cc(/C=N/OC)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)O)CC4)nc3)cc(C(N)=O)c2s1
Temperature: 65 °C
Yield: 5 %

Procedure:
Ethyl-4-ethyl-1-[5-[2-(ethylcarbamoylamino)-7-[(E)-methoxyiminomethyl]-1,3-benzothiazol-5-yl]pyrimidin-2-yl]piperidine-4-carboxylate (619 mg, 1.147 mmol) 100 was suspended in MeOH (9 mL) and NaOH(aq) (1M, 9 mL), sealed in a microwave vessel, irradiated at 85° C. for 1 h, followed by conventionally heating overnight at 65° C. The reaction was diluted with water (40 mL) and washed with EtOAc (1×50 mL). Acidification of the aqueous phase with HCl(aq) (1M, pH 2) and back extracting with EtOAc (3×60 mL) yielded a waxy solid which was subjected directly to reverse phase chromatography (5-100% H2O/MeCN) yielding 25 mg (5% yield) of the Compound 193 as a by-product to the aldoxime. 1H NMR (DMSO-d6) δ 8.84 (s, 2H), 8.33 (s, 1H), 8.11 (d, J=1.4 Hz, 1H), 8.03 (d, J=1.4 Hz, 1H), 7.71 (s, 1H), 6.87 (t, J=5.4 Hz, 1H), 4.46 (dd, J=9.9, 3.6 Hz, 2H), 3.18 (qd, J=13.2, 4.8 Hz, 4H), 2.06 (d, J=13.4 Hz, 2H), 1.54 (q, J=7.4 Hz, 2H), 1.35 (td, J=13.6, 4.0 Hz, 2H), 1.11 (t, J=7.2 Hz, 3H), 0.81 (t, J=7.5 Hz, 3H). MS: 498.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6](N)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1.C(OCC)(=O)C>[CH2:6]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: NCCCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
3-amino-1-propanol (150 g) was dissolved in tetrahydrofuran (200 mL), followed by the addition of benzylamine(23.8 g). The mixture was stirred at room temperature for 1 hour. Subsequently, the reaction mixture was diluted with ethyl acetate, was sequentially washed with water and a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate. The solvent was removed to obtain 3-(benzylamino)-1-propanol (20.1 g, 61%).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:21][C:22]([F:29])([F:28])[CH2:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[F:21][C:22]([F:29])([F:28])[CH2:23][S:24]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2([CH3:13])[CH:11]3[CH:9]2[CH2:8][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:12]3)[CH:15]=1)(=[O:26])=[O:25]
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: c1ccncc1
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(=O)(=O)CC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 0.10 g, 0.37 mmol) in pyridine (8 ml) cooled at 0° C. was treated with 2,2,2-trifluoroethanesulphonyl chloride (0.08 g, 0.44 mmol). The reaction mixture was allowed to warm to room temperature and then stirred for 16 h. The reaction mixture was concentrated in vacuo and the residue was poured into saturated aqueous sodium hydrogen carbonate solution (100 ml) and extracted with dichloromethane (3×50 ml). The combined organics were dried (Na2SO4) and then concentrated in vacuo. The crude residue was purified by preparative HPLC (condition 7) to give a yellow solid, (15 mg, 10%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([CH:7]=[N:8]O)[C:5]([OH:11])=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(OC(=O)C)(=O)C.O.C(O)C>[C:7]([C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[OH:11])#[N:8]
Reactant: ON=Cc1cc(F)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cc(F)ccc1O
Temperature: 25 °C
Yield: 87.5 %

Procedure:
5-Fluorosalicylaldoxime (20.2 g, 0.13 mol) was dissolved in acetic anhydride (100 ml), followed by refluxing for 5 hours, distilling off acetic anhydride under reduced pressure after completion of the reaction, adding to the remaining oily material, a solution of KOH (20 g) dissolved in water (100 ml) and ethanol (100 ml), heating the mixture at 80° C. for 2 hours, allowing to cool down to room temperature, adding 6N-hydrochloric acid (50 ml) and water (200 ml) to deposit crystals, filtering the crystals, and recrystallizing from methanol (30 ml) to obtain acicular crystals (15.6 g). M.p. 121°~122° C.
Reaction SMILES: [N:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([CH2:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2)=[C:2]=[O:3].[CH3:27][NH:28][CH3:29]>O1CCCC1.O>[CH3:27][N:28]([CH3:29])[C:2](=[O:3])[NH:1][C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([CH2:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2
Reactant: CCc1c(C)c2c(c(N=C=O)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(C)c2c(c(NC(=O)N(C)C)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2

Procedure:
A solution of 0.65 g (1.8 mmol) of methyl (E)-6-(1,3-dihydro-4-isocyanato-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate in 10 ml of tetrahydrofuran is treated with 5 ml of a solution of 40% dimethylamine in water. After 1 hour the reaction is partitioned between water and ethyl acetate. The organic phase is washed with water three times, dried over magnesium sulfate, and concentrated under reduced pressure to give methyl (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[NH:9][C:8](=[O:10])[C:7]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:16]2)=[O:12])=[CH:6][C:5]=1[Cl:25].[H-].[Na+].I[CH3:29].O>CN(C)C=O>[NH2:3][C:4]1[N:9]([CH3:29])[C:8](=[O:10])[C:7]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:16]2)=[O:12])=[CH:6][C:5]=1[Cl:25]
Reactant: CI
Reactant: CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)[nH]c2=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)n(C)c2=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 5.9 %

Procedure:
To a solution of 6-amino-N-[(1-butyl-4-piperidinyl)methyl]-5-chloro-2-oxo-1,2-dihydro-3-pyridinecarboxamide dihydrochloride (step 2 in example 3, 80 mg, 0.19 mmol) in N,N-dimethylformamide (3 ml), sodium hydride (60% dispersion in mineral oil, 39 mg, 0.97 mmol) was added at 0° C. and the mixture was stirred for 15 min at room temperature. The mixture was cooled to 0° C. and iodomethane (1.0 M in N,N-dimethylformamide, 0.19 ml, 0.19 mmol) was added. After stirring for 18 h at room temperature, the mixture was poured into water, extracted with ethyl acetate (50 ml×2), washed with water (50 ml) and brine (50 ml) and dried over magnesium sulfate. Removal of solvent gave pale yellow oil, which was chromatographed on a column of silica gel eluting with 25% ammonium hydroxide/methanol/dichloromethane (0.2:1:12) to give 4 mg (6%) of the title compound as a white solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[NH2:51][CH:52]([C:57]1[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=1)[CH2:53][CH2:54][CH2:55][OH:56].C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:63][C:60]1[CH:59]=[CH:58][C:57]([CH:52]([NH:51][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:34][CH2:35][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:37][CH2:38]2)=[O:50])[CH2:53][CH2:54][CH2:55][OH:56])=[CH:62][CH:61]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: NC(CCCO)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CCCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (166 mg, 0.44 mmol) was added portionwise to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (150 mg, 0.42 mmol), 4-amino-4-(4-chlorophenyl)butan-1-ol (Intermediate 16) (83 mg, 0.42 mmol) and N-ethyldiisopropylamine (0.087 ml, 0.50 mmol) in DMF (2.0 mL) at 20° C. The resulting solution was stirred at 20° C. for 3 hours then quenched in water (10 ml) to give a pale yellow ppt. The precipitate was collected by filtration, washed with water and dried under vacuum to afford tert-butyl 4-(1-(4-chlorophenyl)-4-hydroxybutylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (152 mg, 67.4%) as a cream solid, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6]2=[N:7][NH:8][CH:9]=[C:5]2[CH2:4][CH2:3]1.[CH2:11]=[O:12].C(N(CC)CC)C>CC(C)=O>[CH3:1][C:2]1([CH3:10])[C:6]2=[N:7][N:8]([CH2:11][OH:12])[CH:9]=[C:5]2[CH2:4][CH2:3]1
Reactant: C=O
Reactant: CC1(C)CCc2c[nH]nc21
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC1(C)CCc2cn(CO)nc21
Temperature: 130 °C
Reaction time: 5 h
Yield: 15.1 %

Procedure:
The mixture of 1.68 g of 6,6-dimethyl-2,4,5,6-tetrahydrocyclopenta [c] pyrazole, 0.41 g of paraformaldehyde and 0.2 g of triethylamine was stirred at 130° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The filterate was concentrated under reduced pressure. Hexane was added to the residue, and then crystalline was formed. The crystalline was collected to obtain 0.31 g of {6,6-dimethyl-5,6-dihydrocyclopenta [c] pyrazole-2 (4H)-yl} methanol.
Reaction SMILES: C1COCC1.Cl[C:7]1[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19].C(Cl)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:17]([NH:20][C:7]1[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=1)[CH2:18][CH3:19]
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: CCCN
Solvent: ClC(Cl)Cl
Solvent: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Product: CCCNc1nc(SC)ncc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 40 mL of THF, 4-chloro-5-cyano-2-methylthiopyrimidine [Compound (V)] (1.86 g, 10.0 mmol) obtained in Reference Example 4 was dissolved, then n-propylamine (709 mg, 12.0 mmol) and morpholinomethylpolystyrene (7.0 g) were added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction was confirmed by thin-layer chromatography, chloroform (100 mL) and benzoylchloride polymer bound [about 2.5 mmol/g, 4.6 g, Canadian Journal of Chemistry, Vol. 55, p. 3351 (1977)] were added thereto, followed by further stirring at room temperature for 12 hours. After resins in the reaction mixture were filtered out, the filtrate was concentrated under reduced pressure to give 4-n-propylamino-5-cyano-2-methylthiopyrimidine [Compound (W) in which R1 represents n-propylamino].