Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14](O)=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21].P(Cl)(Cl)(Cl)=O>>[CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14]([Cl:21])=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1cc(O)nc2sc(SCc3ccccc3)nn12
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1cc(Cl)nc2sc(SCc3ccccc3)nn12
Reaction time: 0.42 h
Yield: 25 %

Procedure:
A mixture of 31.7 g of the thus obtained 2-benzylthio-7-hydroxy-5H-1,3,4-thiadiazolo[3,2-a]-pyrimidin-5-one, 24.0 g of phosphorus pentachloride and 117 g of phosphorus oxychloride was heated to 70°-80° C. and stirred for 25 minutes. After cooling, the reaction mixture was concentrated under reduced pressure and chloroform and water were added to the residue. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was separated by silica gel column chromatography using an ethyl acetate/hexane mixture as an eluent, and thus 8.5 g of 2-benzylthio-7-chloro-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 138°-140° C. Yield 25%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([CH2:9][CH2:10][CH2:11][CH3:12])[C:4]([O:6]CC)=[O:5].S(=O)(=O)(O)O.[Cl-].[Na+]>>[F:1][C:2]([F:13])([F:14])[CH:3]([CH2:9][CH2:10][CH2:11][CH3:12])[C:4]([OH:6])=[O:5]
Reactant: CCCCC(C(=O)OCC)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: CCCCC(C(=O)O)C(F)(F)F
Yield: 86 %

Procedure:
Ethyl 2-trifluoromethylhexanoate (10.05 g.) was mixed with 50 ml. of concentrated sulfuric acid and warmed to 75° C. for 20 hours. After cooling, the acid was poured onto excess ice. The resulting mixture was saturated with sodium chloride, extracted with ether (3×100 ml.). The combined ether extracts were dried (MgSO4) and evaporated to give a residual oil which yielded 2-trifluoromethylhexanoic acid (7.50 g.) upon distillation, b.p. 80°-85°/2.8 mmHg.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[N+:38]([C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:30][C:28]([C:26]2[N:27]=[C:23]([N:21]3[CH2:22][CH:19]([OH:18])[CH2:20]3)[S:24][CH:25]=2)=[O:29])=[CH:33][CH:34]=1)([O-:40])=[O:39]
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)c1csc(N2CC(O)C2)n1
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)azetidine (93 mg, 0.16 mmol) (obtained as described in Reference Example 2(5)) in anhydrous tetrahydrofuran (4.7 ml) were added acetic acid (0.028 ml, 0.49 mmol) and a solution of 1 M tetrabutylammonium fluoride in tetrahydrofuran (0.48 ml, 0.48 mmol) in an ice bath. The mixture was stirred for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (2:1) as the eluant to afford 1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (42.4 mg, yield 81%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH:33]=[CH:34][NH:35]2>CC(N(C)C)=O>[NH:35]1[C:36]2[C:32](=[C:31]([O:30][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:34]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3cccc4[nH]ccc34)ncnc2cc1OCCCN1CCCCC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 50.9 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (200 mg, 0.595 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (411 mg, 2.98 mmol) and 4-hydroxyindole (103 mg, 0.774 mmol) in DMA (2.0 ml) was stirred at 85° C. for 3 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated to give a solid residue. The residue was purified by silica column chromatography, with gradient elution using dichloromethane with 0%, 2%, 4%, 10% methanolic ammonia to give 4-(indol-4-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (131 mg, 51%).
Reaction SMILES: C[O:2][C:3](=O)[NH:4][N:5]=[C:6]([C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][C:12]=1[I:13])C>ClC1C=CC=CC=1Cl.CO>[C:14]1([C:10]2[N:9]3[C:3](=[O:2])[NH:4][N:5]=[CH:6][C:8]3=[C:12]([I:13])[N:11]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)NN=C(C)c1nc(-c2ccccc2)[nH]c1I
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: O=c1[nH]ncc2c(I)nc(-c3ccccc3)n12
Reaction time: 0.33 h
Yield: 70.4 %

Procedure:
3-[1-(5-Iodo-2-phenyl-4-imidazolyl)ethylidene]-carbazic acid methyl ester (1.01 gm., 0.0027 mole) is dissolved in a mixture of o-dichlorobenzene (150 ml.) and methanol (15 ml.). The solution is heated to the boiling point and boiled for 20 minutes allowing solvent to distill off partially. The reaction mixture is chromatographed over a silica gel column and eluted with a hexane-ethyl acetate (2:1) mixture to yield the title product (0.63 gm., 0.0019 mole). Recrystallization from ethyl acetate-hexane yields the product as yellow needles, m.p. 176°-189° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[C:27](F)[CH:28]=3)[C:23](=[O:32])[N:22]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:21]2=[O:41])=[CH:16][CH:15]=1>>[OH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[C:27]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:28]=3)[C:23](=[O:32])[N:22]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:21]2=[O:41])=[CH:16][CH:15]=1
Reactant: C1CCNC1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccc(O)cc2)c(=O)n1OCc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccc(O)cc2)c(=O)n1OCc1ccccc1
Yield: 22.3 %

Procedure:
Using General Method 4, the reaction of pyrrolidine (0.04 mL, 0.5 mmol), triethylamine (0.07 mL, 0.5 mmol), and 1-(4-hydroxyphenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example J-1, 0.065 g 0. 16 mmol) provided 0.05 g of the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1C=O.[CH:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])OCC>C(O)C.[Cl-].[NH4+]>[CH2:18]([O:17][CH:10]([O:14][CH2:15][CH3:16])[C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Br:1])[CH3:19]
Reactant: O=Cc1ccccc1Br
Reactant: CCOC(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(OCC)c1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A mixture of 2-bromobenzaldehyde (33.2 g), triethyl orthoformate (29 g) and powdered ammonium chloride (0.379 g) in ethanol (30 ml) was stirred for eight hours at room temperature. The resulting suspension was filtered and the filtrate evaporated. The resulting yellow oil was distilled at reduced pressure to give the title compound (31 g). b.p. 63° C. 0.3 mm Hg. T.l.c. (Petrol/diethyl ether, 6:1) Rf=0.6.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[NH2:18][C:13]1[C:12]2=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=[C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[CH2:2][NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[N:17]2[N:16]=[CH:15][N:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Product: CS(=O)(=O)NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Yield: 8 %

Procedure:
Using a procedure similar to that of Example 5 and 7-(3-aminomethyl-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and methanesulfonyl chloride as starting materials, 18 mg (8%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 4.20 (s, 2 H), 2.90 (s, 2 H), 2.80 (s, 3 H); ES-MS m/z 524.3 [M+H]+, HPLC RT (min) 2.84.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:24]=[CH:23][C:10]2[N:11]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:12]([C:14]([F:17])([F:16])[F:15])=[N:13][C:9]=2[C:8]=1[Cl:25])(=O)=O.[CH3:28][N:29](C=O)C>[C-]#N.[Zn+2].[C-]#N>[Cl:25][C:8]1[C:9]2[N:13]=[C:18]([C:19]([F:22])([F:21])[F:20])[N:11]([CH2:12][C:14]([F:16])([F:17])[F:15])[C:10]=2[CH:23]=[CH:24][C:7]=1[C:28]#[N:29]
Reactant: CN(C)C=O
Reactant: O=S(=O)(Oc1ccc2c(nc(C(F)(F)F)n2CC(F)(F)F)c1Cl)C(F)(F)F
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(nc(C(F)(F)F)n2CC(F)(F)F)c1Cl
Temperature: 140 °C

Procedure:
To 4-chloro-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-yl trifluoromethanesulfonate (0.053 g, 118 mmol) in DMF (3 mL) was added zinc cyanide (0.008 g, 0.071 mmol) and palladium tetrakistriphenylphosphine (0.014 g, 0.012 mmol). The resulting mixture was heated over night under N2 atm at 140° C. The cooled reaction mixture was partitioned between EtOAc and water, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification (SiO2, EtOAc/hexanes) afforded the title compound (0.0045 g): MS (ESI) m/z 328 (M+1).
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[C:31]1(CCN)[CH2:36][CH2:35]C[CH2:33][CH:32]=1>>[C:12]1([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:35][CH2:36][CH2:31][CH2:32][CH:33]=1
Reactant: NCCC1=CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCCC1=CCCCC1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(1-cyclohexenyl)ethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 367 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 10.20 (1H, s) 7.94-8.06 (2H, m) 7.76 (1H, d, J=5.37 Hz) 7.44 (1H, d, J=5.37 Hz) 7.30 (1H, dd, J=3.37, 2.49 Hz) 6.77 (1H, d, J=5.37 Hz) 6.43 (1H, dd, J=3.47, 1.90 Hz) 5.37 (1H, br. s.) 3.25-3.37 (2H, m) 2.11 (2H, t, J=7.96 Hz) 1.91 (2H, t, J=5.81 Hz) 1.84 (2H, br. s.) 1.49-1.60 (2H, m) 1.36-1.47 (2H, m)
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8]([CH3:28])([CH3:27])[C@H:9]2[NH:12][C:13]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([N+:24]([O-])=O)=[CH:19][CH:18]=3)=[O:14])=[CH:5][CH:4]=1)#[N:2]>[Pd].C1COCC1.CO>[NH2:24][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:13]([NH:12][C@H:9]1[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:11]=3)[CH2:7][C:8]1([CH3:28])[CH3:27])=[O:14])=[CH:23]2
Reactant: CC1(C)Cc2ccc(C#N)cc2[C@@H]1NC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2ccc(C#N)cc2[C@@H]1NC(=O)c1cc2cc(N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.6 %

Procedure:
A mixture of (R)—N-(6-cyano-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)-5-nitro-1H-indole-2-carboxamide (200 mg, 0.534 mmol) (prepared as described in Example 8) and 10% Pd/C (80 mg) in 1:1 THF/MeOH (24 mL) was stirred at rt under H2, provided a H2 balloon, for 3 hr. The catalyst was removed by suction filtration, and the filtrate was concentrated under vacuum. The residue was diluted with ethyl acetate (50 mL), washed with brine (20 mL), and dried over anhydrous MgSO4. It was concentrated under vacuum, and the residue was applied to ISCO (12 g silica gel, 40-55% ethyl acetate/hexane) to afford the desired title product (106 mg, 58% yield) as a pale yellow solid. LCMS (M+H)=345.38. 1H NMR (500 MHz, DMSO-d6) δ: 11.1 (s, 1H), 8.33 (d, J=9.3 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.59 (s, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 6.98 (s, 1H), 6.68 (s, 1H), 6.61 (d, J=8.8 Hz, 1H), 5.35 (d, J=9.3 Hz), 4.60 (br. s, 2H), 2.86 (dd, J=23.6, 16.5 Hz, 2H), 1.20 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[P:18]([NH:26][NH2:27])(=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>C(Cl)Cl>[CH:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[N:27][NH:26][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(C2CCCCC2)CC1
Reactant: CCOP(=O)(NN)OCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOP(=O)(NN=C1CCC(C2CCCCC2)CC1)OCC
Temperature: 25 °C
Reaction time: 27 h

Procedure:
To a solution of 4-cyclohexylcyclohexanone (27.04 g) and acetic acid (3 ml) in CH2Cl2 (400 ml) was added a solution of diethyl phosphorohydrazidate (28.91 g) in CH2Cl2 (100 ml). The reaction was stirred at room temperature for 27 hours and then was concentrated under reduced pressure. Toluene was added (2×) and removed under reduced pressure in order to aid in the removal of acetic acid by co-distillation. The residual yellow liquid was the product and was used without further purification. TLC Rf=0.52 (20% acetone in CH2Cl2, silica gel).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:37][C:38]([O:40][CH3:41])=[O:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH3:41][O:40][C:38](=[O:39])[CH:37]=[C:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: c1ccccc1
Product: COC(=O)C=C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 60.5 %

Procedure:
A solution of N-benzyloxycarbonyl-4-piperidinone (5.0 g, 21.4 mol) and methyl (triphenylphosphoranylidene)acetate (10.0 g, 30.0 mmol) in benzene (100 mL) was heated at 75° C. for 48 h. The reaction was concentrated, diluted with ether, the precipitate filtered off, and the rinsate concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 20 to 60% ethyl acetate:hexanes to give the title compound (5.25 g). MS: m/z=290.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]3[C:19]4[CH:31]=[CH:30][C:29](=[O:32])[N:28]([C:33]5[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=5[F:40])[C:20]=4[N:21]=[C:22](S(C)(=O)=O)[N:23]=3)[CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:41][C:42]1([CH3:51])[CH2:47][CH:46]([NH2:48])[CH2:45][C:44]([CH3:50])([CH3:49])[NH:43]1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]3[C:19]4[CH:31]=[CH:30][C:29](=[O:32])[N:28]([C:33]5[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=5[F:40])[C:20]=4[N:21]=[C:22]([NH:48][CH:46]4[CH2:47][C:42]([CH3:51])([CH3:41])[NH:43][C:44]([CH3:50])([CH3:49])[CH2:45]4)[N:23]=3)[CH:12]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1-c1nc(NC2CC(C)(C)NC(C)(C)C2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared as described in Example 1d from 6-chloro-N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-3-pyridinecarboxamide and 2,2,6,6-tetramethyl-4-piperidinamine: LC-MS m/z 658 (M+H)+, 1.92 min (ret time).
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.Cl.[NH:24]1[CH2:27][CH:26]([C:28]#[N:29])[CH2:25]1>>[N:15]1[N:14]2[C:18]([N:19]=[C:11]3[CH2:10][CH2:9][NH:8][CH2:22][CH2:21][C:12]3=[C:13]2[N:24]2[CH2:27][CH:26]([C:28]#[N:29])[CH2:25]2)=[CH:17][CH:16]=1
Reactant: N#CC1CNC1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Agent: Cl
Product: N#CC1CN(c2c3c(nc4ccnn24)CCNCC3)C1

Procedure:
The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) azetidine-3-carbonitrile hydrochloride was used as the amine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:19])[CH:3]=1.[H-].[Na+].Br[CH2:23][CH:24]1[CH2:26][CH2:25]1>CN(C)C=O>[CH:24]1([CH2:23][O:1][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=3)[C:4](=[O:19])[CH:3]=2)[CH2:26][CH2:25]1
Reactant: CCOC(=O)c1sc(-n2ccc(O)cc2=O)nc1C
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-n2ccc(OCC3CC3)cc2=O)nc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylate (1.00 g, 3.56 mmol) in N,N-dimethylformamide (10 mL) at 0° C. was added sodium hydride (0.14 g, 5.70 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, then (bromomethyl)cyclopropane (0.58 g, 4.28 mmol) was added. The reaction mixture was stirred at ambient temperature for 16 hours. The solvent was removed at high vacuum and the residue was diluted with dichloromethane (30 mL), washed with brine (25 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with ethyl acetate/hexane (1/1) to afford the title compound as a colorless solid (1.15 g, 97%): mp 180-183° C. (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.68-8.65 (m, 1H), 6.19-6.16 (m, 1H), 5.93 (d, J=2.6 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.81 (d, J=7.1 Hz, 2H), 2.68 (s, 3H), 1.35 (t, J=7.1 Hz, 3H), 1.31-1.19 (m, 1H), 0.70-0.64 (m, 2H), 0.38-0.33 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 167.6, 162.9, 162.2, 156.6, 155.6, 131.3, 119.6, 104.5, 96.7, 60.9, 17.3, 14.3, 9.8, 9.5, 3.3; MS (ES+) m/z 335.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37])[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1cc(N)ccc1N1CCN(CCOCCO)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(CCOCCO)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 65.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (2 g) and 5-amino-2-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}benzonitrile (4.2 g), the title compound (2.8 g) was obtained, melting point: 196° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>CCOCC>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: OCCC1CCN(Cc2ccccc2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Fc1ccc(OCCC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.7 %

Procedure:
To a solution of 1.5 g (6.84 mmol) of 1-benzyl-4-(2-hydroxy-1-ethyl)piperidine (Acros Chemical), 3.8 g (34.2 mmol) of 4-fluorophenol and 3.6 g (13.7 mmol) of triphenylphosphine in 25 mL of ether at 0° C. was slowly added dropwise 2.15 mL (13.7 mmol) of diethylazodicarboxylate (DEAD). The reaction mixture was allowed to warm to rt and was stirred for 12 h. To the reaction mixture was added 70 mL of ether and it was filtered through a thin pad of celite. The filtrate was washed with sat'd Na2CO3 solution and sat's NaCl solution. It was dried over MgSO4, filtered and the filtrate concentrated. The residue was purified by chromatography (silica, hexanes: ethyl acetate, 4:1) to give 0.85 g of the title compound.
Reaction SMILES: O[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:12][CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:25])=O>C1C=CC=CC=1>[Cl:25][CH:2]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:12][CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CCCc1ccc(C(O)Cc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)CCCc1ccc(C(Cl)Cc2ccccc2)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 3.49 g of methyl 4-[4-(1-hydroxy-2-Phenylethyl)phenyl]butyrate in 17 ml of benzene, 1.10 ml of thionyl chloride was added dropwise under ice-cooling, and then stirring was continued at room temperature for 1.5 hours. The reaction solvent was removed under reduced pressure, and the residue was dissolved in ether. The ether layer was washed with water and dried, and then the solvent was removed under reduced pressure to yield 3.30 g of pale yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH2:20][Cl:21])=[N:18][C:17]([C:22](O)=[O:23])=[N:16]1)=[O:8].C(Cl)(Cl)Cl.C(Cl)(=O)OCC.[NH3:35]>C(N(CC)CC)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH2:20][Cl:21])=[N:18][C:17]([C:22]([NH2:35])=[O:23])=[N:16]1)=[O:8]
Reactant: N
Reactant: O=C(O)c1nc(CCl)n(-c2ccccc2C(=O)c2ccccn2)n1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: NC(=O)c1nc(CCl)n(-c2ccccc2C(=O)c2ccccn2)n1
Reaction time: 0.17 h

Procedure:
To a solution of 0.258 g. of 1-[2-(2-pyridinecarbonyl)phenyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxylic acid in 7.5 ml. of chloroform are added 0.14 ml. of triethylamine and then 0.1 ml. of ethyl chlorocarbonate with ice-cooling. After stirring for 10 minutes, to the resulting mixture is added 0.5 ml. of concentrated aqueous ammonia, and the whole mixture is further stirred for 30 minutes. The precipitated crystals are collected by filtration, washed successively with water, ethanol and ether, and then dried to give 1-[2-(2-pyridinecarbonyl)phenyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxamide as crystals. The filtrate is extracted with chloroform and the chloroform layer is washed with water, dried over sodium sulfate, followed by evaporation of the solvent to give additional crystals identical with the abovementioned crystals. Recrystallization of the combined crystals from chloroform-ethanol gives colorless needles, melting at 228° to 229° C. (decomposition).