Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH2:27][C:20]5=[N:19][C:18]=4[CH3:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][NH:40]C(=O)OCC.C(O)(C)C.Cl>CN(C=O)C.O.C(O)(C)C.CC(C)=O>[NH2:40][CH2:39][CH2:38][O:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH2:27][C:20]5=[N:19][C:18]=4[CH3:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)NCCBr
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(O)ccc34)CC1)CCCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(OCCN)ccc34)CC1)CCCC2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 3-(2-(4-(6-hydroxybenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, prepared as described in the previous step, (6.6 g, 0.015 mmol) in DMF (50 mL) and acetone (50 mL) was treated with potassium carbonate (3.0 g, 0.03 mmol) and ethyl (2-bromoethyl)carbamate (2.4 g, 0.015 mmol). After stirring overnight at 60° C., the reaction mixture was poured in water (150 mL), extracted with chloroform (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (elution with dichloromethane/methanol (90/10). The combined fractions were treated with HBr (150 mL, 48%) and heated to reflux for 30 min. The mixture was allowed to cool down to room temperature and made basic with ammonium hydroxide (28% NH3 in H2O) and extracted with chloroform (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (gradient elution with dichloromethane/methanol (90/10 to 50/50) resulting in a solid which was dissolved in isopropanol (50 mL) and treated with isopropanol/HCl. The precipitate was removed by filtration and washed with iPrOH/diisopropyl ether (50/50, 3×20 mL). The precipitate was dried under vacuum to yield the title compound ESI-MS (M+1) 452. 1H NMR (360 MHz, DMSO-d6) δ ppm 1.76-1.85 (m, 1H) 1.87-1.96 (m, 1H) 2.19 (d, J=12.81 Hz, 1H) 2.37-2.48 (m, 4H) 2.98-3.10 (m, 3H) 3.10-3.28 (m, 5H) 3.37-3.46 (m, 3H) 3.72 (d, J=11.34Hz, 3H) 3.79-3.85 (m, 2H) 4.31 (t, J=4.94Hz, 1H) 7.05 (dd, J=8.78, 1.83 Hz, 1H) 7.35-7.39 (m, 1H) 8.08 (d, J=8.78 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1=[C:18]([Cl:24])[C:19]([O:21][C:22]1=[O:23])=[O:20]>C(Cl)CCl>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:19](=[O:20])[C:18]([Cl:24])=[C:17]([Cl:16])[C:22]([OH:23])=[O:21])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Solvent: ClCCCl
Product: O=C(O)C(Cl)=C(Cl)C(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 10.0 g (0.052 mole) of 2-phenylindole, 8.8 g (0.052 mole) of dichloromaleic anhydride and 150 ml of ethylene dichloride was stirred at ambient temperature for approximately 48 hours. The solid that formed was collected by filtration and dried at 60° C. in vacuo to obtain 4-(2-phenyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid (Formula VIII: R=Y=H; R1 =C6H5) as a tan-colored solid which melted over the range 150°-152° C.
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([OH:12])=O)[C:6](=[O:13])[N:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C=O)C.[NH2:27][C:28]1[CH:48]=[CH:47][C:31]([O:32][C:33]2[N:38]=[CH:37][N:36]=[C:35]([NH:39][C:40]([N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)=[O:41])[CH:34]=2)=[C:30]([F:49])[CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.O.ClCCl.CO>[F:49][C:30]1[CH:29]=[C:28]([NH:27][C:10]([C:7]2[C:6](=[O:13])[N:5]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:4]([CH2:3][C:2]([OH:1])([CH3:20])[CH3:21])[C:8]=2[CH3:9])=[O:12])[CH:48]=[CH:47][C:31]=1[O:32][C:33]1[CH:34]=[C:35]([NH:39][C:40]([N:42]2[CH2:43][CH2:44][CH2:45][CH2:46]2)=[O:41])[N:36]=[CH:37][N:38]=1
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCCC3)ncn2)c(F)c1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1c(C(=O)Nc2ccc(Oc3cc(NC(=O)N4CCCC4)ncn3)c(F)c2)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Yield: 70.7 %

Procedure:
1-(2-hydroxy-2-methylpropyl)5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (0.230 g, 0.792 mmol) was dissolved in dichloromethane (10 ml). Then DMF (0.5 ml) was added to the mixture while stirring. Then N-(6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-1-carboxamide (0.277 g, 0.871 mmol), along with TEA (0.33 ml, 2.38 mmol) was added to the mixture and stirred 5 minutes at ambient temperature. Then HATU (0.301 g, 0.792 mmol) was added into the mixture in one portion. The resulting mixture was allowed to stir under inert atmosphere for 3 hours. The reaction was monitored by LC/MS, which confirmed completion. The mixture was diluted with dichloromethane and water and with 4:1 dichloromethane/methanol (3×20 ml). Combined organic layer was dried over sodium sulfate, filtered, and concentrated in-vacuo. The crude was purified by chromatography (Amino-Propyl silica gel column, in a gradient of 1-5% MeOH/dichloromethane to give an oil. The oil was recrystallized from dichloromethane/hexanes to give the desired product N-(3-fluoro-4-(6-(pyrrolidine-1-carboxamido)pyrimidin-4-yloxy)phenyl)-1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (0.330 g, 0.56 mmol, 70% yield) as a white solid. MS (ESI pos. ion) m/z: 590 (MH+). Calc'd exact mass for C30H32FN7O5: 589. 1HNMR (300 MHz, CDCl3): 1.05 (s, 6H), 1.91 (s, 4H), 2.21 (s, 1H), 2.78 (s, 3H), 3.40 (s, 4H), 3.78 (s, 2H), 7.01-7.22 (m, 4H), 7.31-7.48 (m, 2H), 7.59 (s, 1H), 7.79 (dd, J=12.42, 2.19 Hz, 1H), 8.26 (s, 1H), 10.75 (s, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][C@H:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:16][O:17][CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1.[CH2:32]=O>>[ClH:2].[Cl:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][C@H:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:16][O:17][CH2:18][CH2:19][CH:20]3[CH2:21][CH2:22][N:23]([CH3:32])[CH2:24][CH2:25]3)=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: C=O
Reactant: O=C(N[C@@H](COCCC1CCNCC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1
Agent: Cl
Product: CN1CCC(CCOC[C@H](NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2)CC1
Yield: 137.6 %

Procedure:
Using alkylation method B, 3-chloro-N-[(R)-1-phenyl-2-[2-(piperidin-4-yl)ethoxy]ethyl]-1H-indole-6-carboxamide hydrochloride (300 mg, 0.65 mmol) and paraformaldehyde (195 mg, 6.5 mmol) afforded 213 mg (75%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[C:14]2[S:13](=[O:16])(=[O:15])[N:12]=[C:11]([CH2:17][C:18]([OH:20])=O)[NH:10][C:9]=2[S:8][CH:7]=1.C([O:23][C:24]([C@H:26]1[C@@H:31]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C@H:30]2[CH2:41][C@@H:27]1[CH2:28][CH2:29]2)=O)C.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[F:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:32]2[C:18](=[O:20])[C:17]([C:11]3[NH:10][C:9]4[S:8][CH:7]=[C:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])[C:14]=4[S:13](=[O:15])(=[O:16])[N:12]=3)=[C:24]([OH:23])[C@H:26]3[C@@H:31]2[C@H:30]2[CH2:41][C@@H:27]3[CH2:28][CH2:29]2)=[CH:39][CH:38]=1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Reactant: COCOCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCOCc1csc2c1S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 75 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a solution of (7-methoxymethoxymethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-acetic acid (0.38 g, 1.20 mmol) and (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.42 g, 1.44 mmol) in N,N-dimethylformamide (4 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.34 g, 1.80 mmol). The reaction was stirred at 25° C. for 15 min before triethylamine (1 mL, 7.20 mmol) was added. The reaction was then stirred at 75° C. overnight. The reaction was cooled to 25° C. and quenched with 1.0 M aqueous hydrochloric acid solution (5 mL). The resulting mixture was extracted with dichloromethane (3×10 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (Teledyne Isco RediSep column; 0-50% ethyl acetate in hexanes) to afford the desired product, (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-methoxymethoxymethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.44 g, 0.80 mmol, 67%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.18-1.78 (6H, m), 2.55-2.56 (1H, m), 2.82-2.86 (2H, m), 3.45 (3H, s), 4.21 (1H, d, J=15.6 Hz), 4.79 (2H, s), 4.82 (2H, s), 5.15 (1H, d, J=15.2 Hz), 7.00-7.07 (3H, m), 7.20 (2H, dd, J=5.6, 8.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[CH3:10][CH:11]1[CH:16](O)[CH2:15][CH2:14][N:13]([C:18]2[N:19]=[N:20][CH:21]=[CH:22][N:23]=2)[CH2:12]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH:16]1[CH2:15][CH2:14][N:13]([C:18]2[N:19]=[N:20][CH:21]=[CH:22][N:23]=2)[CH2:12][CH:11]1[CH3:10]
Reactant: CC1CN(c2nccnn2)CCC1O
Reactant: Oc1cc(Cl)ccc1Cl
Product: CC1CN(c2nccnn2)CCC1Oc1cc(Cl)ccc1Cl

Procedure:
Compound 38 is prepared from 2,5-dichlorophenol and intermediate 5c according to synthesis method 3 under the operating conditions described for example 8 (37% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1.Cl.N1C=CC=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(F)c3)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc(F)c4)oc23)[C@@H]1CO

Procedure:
Compound of example 75 (0.51 g, 1.23 mmol) was demethylated using pyridine hydrochloride (5.1 g, 44.15 mmol) as described in example 17, gave the title compound.
Reaction SMILES: OC1C=CC(CN[C:8]([C:10]2([CH3:15])[CH2:14][S:13][S:12][CH2:11]2)=[O:9])=CC=1OC.Cl.[NH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][CH3:32])[CH:25]=1>>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][NH:21][C:8]([C:10]2([CH3:15])[CH2:14][S:13][S:12][CH2:11]2)=[O:9])=[CH:25][C:26]=1[O:31][CH3:32]
Reactant: COc1cc(CNC(=O)C2(C)CSSC2)ccc1O
Reactant: COc1cc(CCN)ccc1O
Agent: Cl
Product: COc1cc(CCNC(=O)C2(C)CSSC2)ccc1O
Yield: 64 %

Procedure:
Same method as for Compound 16 with 4-(2-aminoethyl)-2-methoxyphenol hydrochloride. 320 mg of a yellow solid are obtained (yield=64%).
Reaction SMILES: [NH2:1][CH:2]([CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[CH:3]([OH:17])[CH2:4][NH:5][C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=2)[CH2:8][CH2:7]1.[C:27]1(=[O:34])[O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28]1>C(Cl)(Cl)Cl>[F:26][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([F:25])[CH:22]=1)[CH2:18][C@H:2]([NH:1][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C@H:3]([OH:17])[CH2:4][NH:5][C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=2)[CH2:8][CH2:7]1
Reactant: O=C1CCCC(=O)O1
Reactant: CCc1cccc(C2(NCC(O)C(N)Cc3cc(F)cc(F)c3)CC2)c1
Solvent: ClC(Cl)Cl
Product: CCc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)CCCC(=O)O)CC2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3-Amino-4-(3,5-difluoro-phenyl)-1-[1-(3-ethyl-phenyl)-cyclopropylamino]-butan-2-ol (0.500 g, 1.387 mmol) in chloroform (7 ml) was added TEA (0.58 ml, 4.161 mmol) with stirring under nitrogen for 30 min. To this solution was added glutaric anhydride (0.158 g, 1.387 mmol) and reaction was stirred overnight at 50° C. The reaction mixture was concentrated in vacuo, yielding the product. (ES+: 475.2)
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH2:12]([O:21][C:22](=[O:25])[NH:23][OH:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CCOCC>[CH2:12]([O:21][C:22](=[O:25])[NH:23][O:24][C:8](=[O:10])[CH3:9])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCOC(=O)NO
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCOC(=O)NOC(C)=O
Reaction time: 2 h

Procedure:
25 Parts of triethylamine are added over 30 minutes to a stirred solution of 19.6 parts of acetyl chloride and 50.6 parts of nonyl-N-hydroxycarbamate in 500 parts of ether at 0°-5° C. keeping the pH of the mixture in the range pH3 to pH6. The reaction is stirred for a further 2 hours at 0°-5° C. followed by 24 hours at 25° C. and is then filtered to remove amine hydrochloride. The filtrates are washed with water, dried, filtered and evaporated to constant weight at 30° C. under reduced pressure to give 61 parts of nonyl-N-(acetoxy)carbamate as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27](OCC)=[O:28])[C:9]2=[O:32])=[CH:4][CH:3]=1.[NH2:33][CH2:34][CH2:35][OH:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27]([NH:33][CH2:34][CH2:35][OH:36])=[O:28])[C:9]2=[O:32])=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Yield: 87 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (26 mg, 0.0596 mmol) and 2-aminoethanol (0.05 mL), was prepared 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxyethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (24 mg, 87% yield) as a white solid. 1H NMR (CDCl3) δ 10.14 (s, 1 H), 8.50 (s, 1 H), 7.29-7.24 (m, 2 H), 7.20-7.16 (m, 2 H), 7.01-6.90 (m, 5 H), 6.71 (s, 1 H), 3.93 (s, 2 H), 3.76-3.73 (m, 2 H), 3.59-3.73 (m, 2 H); HRMS m/z calcd for C24H20F2N3O4: 452.1422. Found: 452.1424.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[C:15]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCCCC>C(OCC)C>[OH:21][C:15]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCCC1
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: CCOCC
Product: COc1ccc(C2(O)CCCCC2)cn1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 66.9 %

Procedure:
A solution of n-butyllithium (1.6M in hexanes, 150 ml) was added dropwise over 1 hour to a mechanically stirred solution of 5-bromo-2-methoxypyridine (39.3 g) in 800 ml of diethyl ether at -40° C. The resulting slurry was stirred at -40° C. to -45° C. for 45 minutes, and then cyclohexanone (23.5 g) in 50 ml of diethyl ether was added dropwise over 1 hour. The mixture was allowed to warm to 0° C. over about 1 hour, and then the reaction was quenched with saturated ammonium chloride solution. The layers were separated, and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to yield a semi-solid material. Trituration with pentane provided 29.0 g of product as a powder. Recrystallization of 8 g of the product gave 6.2 g of plates, m.p. 74°-75° C.
Reaction SMILES: CS(O[C@H:6]([CH3:16])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH3:15])(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+].O>CN(C=O)C>[N:17]([C@@H:6]([CH3:16])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH3:15])=[N+:18]=[N-:19]
Reactant: Cc1ccc(F)cc1C[C@@H](C)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C[C@H](C)N=[N+]=[N-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A solution of (R)-1-(5-fluoro-2-methylphenyl)propan-2-yl methanesulfonate (6.3 g, 2.56 mmol) in anhydrous DMF (30 mL) was added sodium azide (3.32 g, 5.11 mmol) and the solution was heated to 80° C. and stirred for 2 h. Then, the temperature was cooled to rt and 20 mL of water was added, extracted with EtOAc/hexane (1/1, v/v), dried over anhydrous MgSO4 and evaporated to give crude oil, which was passed through silicagel pad and evaporated under reduced pressure to give (S)-2-(2-azidopropyl)-4-fluoro-1-methylbenzene (F-3), which used as starting material for next reduction without more purification. To the solution of (S)-2-(2-azidopropyl)-4-fluoro-1-methylbenzene in 80 mL of EtOAc was added Pd/C (500 mg, 10% Pd) and the mixture was hydrogenated under Parr Apparatus (30˜40 psi) for 2 h. The catalyst was removed by filtration through Celite pad, then purified by column chromatography as an eluent (EtOAc/MeOH/NH4OH=93/5/2) to give (S)-1-(5-fluoro-2-methylphenyl)propan-2-amine (F) as pale yellow oil (total yield=30% through 4 steps). MS (ESI) m/z 168.0 [M+H]+; 1H NMR (CDCl3, 500 MHz) δ 7.10 (m, 1H), 6.84 (m, 2H), 3.19 (m, 1H), 2.69 (dd, J=13.5, 6.0 Hz, 1H), 2.56 (dd, J=13.5, 8.0 Hz, 1H), 2.28 (s, 3H), 1.68 (bs, 2H), 1.15 (d, J=6.0 Hz, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:32]=4[Cl:39])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:40]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:40])=[O:26])=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:32]=4[Cl:39])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccc(C#N)cc1Cl
Solvent: CO
Product: CC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccc(C#N)cc1Cl
Temperature: 125 °C
Reaction time: 5 h

Procedure:
1.50 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[-1-(2-chloro-4-cyanophenyl)ethoxy]thiophene-2-carboxylate are dissolved in 60 ml of a 7 N solution of ammonia in methanol. The reaction mixture is stirred for 5 hours at 125° C. under microwave radiation.
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH3:8][C:9]1[CH:10]=[C:11]([OH:23])[CH:12]=[C:13]([CH3:22])[C:14]=1[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27]>O>[CH3:24][N:25]([CH3:29])[C:26](=[O:27])[O:23][C:11]1[CH:12]=[C:13]([CH3:22])[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:9]([CH3:8])[CH:10]=1
Reactant: Cc1cc(O)cc(C)c1Sc1ccccn1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OC(=O)N(C)C)cc(C)c1Sc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 240 mg. of sodium hydride in 20 ml. of dry tetrahydrofuran is added a solution of 2.31 g. of 3,5-dimethyl-4-(2-pyridylthio)phenol in 30 ml. of dry tetrahydrofuran. After the effervescence has subsided, a solution of 1.1 g. of N,N-dimethylcarbamoyl chloride in 10 ml. of dry tetrahydrofuran is added dropwise. The reaction mixture is stirred at ambient temperature for 16 hours, and then under reflux for 4 hours. The reaction mixture is cooled to room temperature, and then diluted with an excess of water. The product is extracted into ethyl acetate. The ethyl acetate is washed with water, dried using anhydrous magnesium sulfate, and then evaporated in vacuo to give crude 3,5-dimethyl-4-(2-pyridylthio)phenyl N,N-dimethylcarbamate. The crude product can be purified further by recrystallization.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:14][N:15]([CH3:17])[CH3:16])[N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.Cl[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8](=[N:14][N:15]([CH3:17])[CH3:16])[N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:22][CH:23]=1
Reactant: CN(C)N=C(c1ccccc1O)n1ccnc1
Reactant: ClCOc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)N=C(c1ccccc1OCOc1ccc(Cl)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.7 %

Procedure:
To a solution of the Compound No. 13 (0.20 g, 0.869 mmol) obtained in Example 13 in N,N-dimethylformamide (3 ml) were added α,4-dichloroanisole (0.175 g, 0.989 mmol) and potassium carbonate (0.17 g, 1.23 mmol), and the mixture was stirred at room temperature for 20 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object compound (0.202 g, 0.545 mmol, yield 63%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH:6]1[CH2:9][NH:8][CH2:7]1.[CH3:16][N:17]=[C:18]=[O:19]>C1C=CC=CC=1>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH:6]1[CH2:9][N:8]([C:18]([NH:17][CH3:16])=[O:19])[CH2:7]1
Reactant: CN=C=O
Reactant: FC(F)(F)c1ccccc1OC1CNC1
Solvent: c1ccccc1
Product: CNC(=O)N1CC(Oc2ccccc2C(F)(F)F)C1
Reaction time: 0.5 h

Procedure:
To 4.5 g (0.02 mole) of 3-[2-(trifluoromethyl)phenoxy]azetidine stirring in 50 ml of dry benzene, was added slowly 1.2 g (0.02 mole) of methyl isocyanate at room temperature. Stirring was continued for 30 minutes. A solid formed, and after filtration was recrystallized from benzene to yield 3.5 g (68%), mp 134°-136°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH3:22])=[C:14]([CH:18]=1)[C:15]([OH:17])=O)(=[O:9])[CH3:8].C(N(CC)CC)C.[NH2:30][C:31]1[C:32]([CH2:39][CH3:40])=[N:33][NH:34][C:35]=1[C:36]([NH2:38])=[O:37]>CN(C)C=O.ClCCl>[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH3:22])=[C:14]([CH:18]=1)[C:15]([NH:30][C:31]1[C:35]([C:36]([NH2:38])=[O:37])=[N:34][NH:33][C:32]=1[CH2:39][CH3:40])=[O:17])(=[O:9])[CH3:8]
Reactant: CCCOc1ccc(C(C)=O)cc1C(=O)O
Reactant: CCc1n[nH]c(C(N)=O)c1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCOc1ccc(C(C)=O)cc1C(=O)Nc1c(C(N)=O)n[nH]c1CC
Reaction time: 1 h

Procedure:
Oxalyl chloride (5.45 ml, 46.4 mmol) was added to a solution of 5-acetyl-2-n-propoxy-benzoic acid (WO 9312095) (11.1 g, 30.9 mmol) in N,N-dimethylformamide (0.1 ml) and dichloromethane (200 ml) under nitrogen at room temperature. Once addition was complete the solution was stirred for 1 hour. The solution was concentrated under reduced pressure and azeotroped with toluene, and the intermediate acid chloride was dissolved in dichloromethane (200 ml). Triethylamine (10.4 ml, 46.4 mmol) was added followed by 4-amino-3-ethyl-1H-pyrazole-5-Carboxamide (WO 9849166) (7.7 g, 30.9 mmol) and the reaction was stirred at room temperature for 16 hours. The mixture was washed with 1N hydrochloric acid (2×100 ml), 10% sodium bicarbonate solution (100 ml) and brine (100 ml), dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was recrystallised from acetonitrile to afford the title compound as a crystalline solid, 14.8 g.