Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[CH3:6][C@H:7]1[O:12][C@@H:11]([CH3:13])[CH2:10][NH:9][CH2:8]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:13][C@H:11]1[O:12][C@@H:7]([CH3:6])[CH2:8][N:9]([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:10]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=S(=O)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CN(S(=O)(=O)Cl)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sulfuryl dichloride (0.363 ml, 4.47 mmol) was added at room temperature to a solution of cis-2,6-dimethylmorpholine (0.500 ml, 4.06 mmol) and 4-dimethylaminopyridine (496 mg, 4.06 mmol) in CH2Cl2 (5 ml) and the whole was stirred at room temperature for 24 hours. The reaction mixture was quenched with H2O (10 ml) and extracted with ethyl acetate (20 ml×3). The combined organic layer was washed with brine (10 ml), dried over Na2SO4, filtered and concentrated in vacuo to give cis-2,6-dimethylmorpholine-4-sulfonyl chloride.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=1.C=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[C:21]([NH2:23])=[O:22].[C:29](=O)([O-])[O-].[K+].[K+]>C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][CH2:10][N:11]([CH2:29][NH:23][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=[C:18]([O:17][CH3:16])[CH:19]=2)[CH2:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(OC)cc(C(N)=O)c1
Reactant: C1=C(c2ccccn2)CCNC1
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: COc1cc(OC)cc(C(=O)NCN2CC=C(c3ccccn3)CC2)c1
Temperature: 25 °C
Yield: 53.8 %

Procedure:
A mixture of 1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl hydrochloride (20 mg, 0.10 mmol, Saari, W. S.; et al. J. Med. Chem. 1984, 27, 1182), paraformaldehyde (30 mg, 1 mmol), 3,5-dimethoxybenzamide (91 mg, 0.5 mmol, Aldrich), and 42 mg of potassium carbonate (0.3 mmol) in 2.5 mL absolute ethyl alcohol was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, filtered, and the solvent was removed. The residue was purified by flash column chromatography on silica gel (10% methanol:ethyl acetate) to give 19 mg (55%) pure compound. 1H NMR (500 MHz, DMSO-d6) δ 2.59 (m, 2H), 2.79 (t, J=4 Hz, 2H), 3.30 (m, 2H), 3.79 (s, 3H), 3.80 (s, 3H), 4.25 (d, J=5 Hz, 2H), 6.65 (s, 1H), 6.71 (m, 1H), 7.02 (s, 2H), 7.22 (m, 1H), 7.52 (d, J=6 Hz, 1H), 7.75 (t, J=6 Hz), 8.52 (m, 1H), 8.88 (t, J=5 Hz, 1H); MS (ESI/APCI−) m/e 352 (M−H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:27])=[CH:29][CH:30]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)nc23)CC1
Yield: 75.7 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.011 mL (0.057 mMol) 4-tert-butylbenzoyl chloride, 0.013 gm (76%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: C(OC(=O)NCCCN(C(=O)C1C=CC(C)=CC=1)C(C1NC(=O)C2=CC=CN2N=1)CC)(C)(C)C.[C:35]([O:39][C:40](=[O:76])[NH:41][CH2:42][CH2:43][CH2:44][N:45]([CH:55]([C:58]1[N:63]([CH2:64][C:65]2C=CC(F)=[CH:67][CH:66]=2)[C:62](=[O:72])[C:61]2=[CH:73][CH:74]=[CH:75][N:60]2[N:59]=1)[CH2:56][CH3:57])[C:46](=[O:54])[C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1)([CH3:38])([CH3:37])[CH3:36].BrC1(C)CC1>>[C:35]([O:39][C:40](=[O:76])[NH:41][CH2:42][CH2:43][CH2:44][N:45]([CH:55]([C:58]1[N:63]([CH2:64][CH:65]2[CH2:66][CH2:67]2)[C:62](=[O:72])[C:61]2=[CH:73][CH:74]=[CH:75][N:60]2[N:59]=1)[CH2:56][CH3:57])[C:46](=[O:54])[C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1)([CH3:36])([CH3:37])[CH3:38]
Reactant: CCC(c1nn2cccc2c(=O)n1Cc1ccc(F)cc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Agent: CC1(Br)CC1
Agent: CCC(c1nn2cccc2c(=O)[nH]1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Product: CCC(c1nn2cccc2c(=O)n1CC1CC1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Yield: 17 %

Procedure:
(±)-(3-{(4-Methylbenzoyl)-[1-(4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4] triazin-2-yl)-propyl]amino}propyl)carbamic acid tert-butyl ester (Example 3 A, 42 mg, 0.09 mmol) was converted to the title compound (8 mg, 17%) in a manner similar to the preparation of (±)-{3-[{1-[3-(4-fluorobenzyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl]-propyl}-(4-methylbenzoyl)-amino]-propyl}-carbamic acid tert-butyl ester, except that bromo-methylcyclopropane (15 mg, 0.11 mmol) was used instead of 4-fluorobenzyl bromide: 1H NMR (CDCl3) δ 7.40–7.22 (m, 5H), 7.04 (m, 1H), 6.57 (m, 1H), 6.00 (m, 1H), 4.41 (m, 1H), 3.81 (m, 1H), 3.65 (m, 1H), 3.40–3.05 (m, 3H), 2.69 (m, 2H), 2.38 (s, 3H), 2.27 (m, 1H), 1.97 (m, 1H), 1.61 (m, 2H), 1.39 (s, 9H), 1.27 (m, 2H), 0.80–1.10 (m, 3H), 0.59 (m, 2H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1OC)[C:5]([NH:7]C1C=CC(F)=C(F)C=1)=[O:6].ClS(N=C=O)(=O)=O.C(N(CC)CC)C.CNC.Cl>C(Cl)Cl>[C:5]([NH2:7])(=[O:6])[C:4]1[CH:16]=[CH:17][CH:18]=[CH:2][CH:3]=1
Reactant: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Agent: CNC
Agent: Cl
Agent: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
3-Amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (2.0 g, 7.2 mmol) was dissolved in 50 mL of methylene chloride and cooled to 0° C. Chlorosulfonyl isocyanate (0.85 mL, 9.8 mmol) dissolved in 20 mL of methylene chloride was added dropwise. The mixture was stirred overnight. The resulting solid was collected by filtration and dried under vacuum. The dried solid (1.0 g, 2.4 mmol) was sited in 50 mL of methylene chloride with triethylamine (0.7 mL, 4.8 mmol) for 1 hour. Dimethylamine (1.2 mL of a 2N solution, 2.4 mmol) was added, and the solution stirred for 48 hours. The resulting mixture was washed with water (2×50 mL) and the organic phase dried over magnesium sulfate. The solvents were evaporated under reduced pressure to give a foam. The foam was redissolved in a small amount of fresh methylene chloride and treated with 1N hydrochloric acid (20 mL). Vigorous shaking produced a precipitate, which was collected via filtration. The resulting powder was sequentially triturated with water, methylene chloride, and ether. The triturated solid was dried under vacuum to give 0.64 g of benzamide, N-(3,4-difluorophenyl)-3-[[[[(dimethylamino)sulfonyl]-amino]carbonyl]amino]-4-methoxy-. Microanalysis: C17H18F2N4O5S-0.86 H2O; calculated: C=46.00; H=4.31; N=12.69. found: C=46.00; H=4.31; N=12.69. MS:M++1=349 Da. Mp 253-255° C. 1HNMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 10.25 (s, 1H), 9.26 (s, 1H), 7.94-7.89 (m, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.64 (s, 1H), 7.49-7.39 (m, 2H), 7.27 (d, J=8.4 Hz, 1H), 3.92 (s, 3H), 2.95 (s, 6H).
Reaction SMILES: [CH3:1][S-:2].[Na+].[PH:4](=[O:7])([OH:6])[OH:5].[CH2:8]([C:10]([CH2:38][CH3:39])([CH:12](I)[C:13]1[N:17]=[CH:16][N:15]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]=1)[CH3:11])[CH3:9].O>C(O)C>[PH:4](=[O:5])([OH:7])[OH:6].[CH2:8]([C:10]([CH2:38][CH3:39])([CH:12]([S:2][CH3:1])[C:13]1[N:17]=[CH:16][N:15]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]=1)[CH3:11])[CH3:9]
Reactant: CCC(C)(CC)C(I)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C[S-]
Agent: O=[PH](O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(C)(CC)C(SC)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 5 h
Yield: 68.9 %

Procedure:
Sodium thiomethoxide (0.24 g) was added to a stirred solution of diethyl 3-iodo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 30) in ethanol (10 ml). The mixture was stirred for five hours, allowed to stand overnight, poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant, to give diethyl 3-methylthio-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.60 g, m.p. 97°-98° C.). NMR (CDCl3): δ1.3(6H,dt), 1.7-1.9(2H,m), 1.9(3H,s), 2.2-2.4(2H,m), 3.9(1H,t), 4.05(4H,m), 7.1(6H,m), 7.3(9H,m), 7.9(1H,s). FAB M/S: MH+ 536.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[C:25]([NH:29][C:30]([C:32]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>C(O)C>[C:25]([NH:29][C:30]([C:32]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:37][CH2:36][N:35]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:6]3[C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NC(=O)C1(c2ccccc2)CCNCC1
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)C1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 80 °C
Yield: 71.9 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (19 mg, 0.051 mmol, 1 eq.) in 2 mL of ethanol was added N-tert-butyl-4-phenylpiperidine-4-carboxamide (13.2 mg, 0.051 mmol, 1 eq.) and triethylamine (0.02 mL, 0.15 mmol, 3 eq.). The reaction was heated to 80° C. for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 22 mg (72%) of N-tert-butyl-1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidine-4-carboxamide. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14-1.32 (m, 9 H) 2.17 (s, 2 H) 2.39-2.58 (m, 2 H) 4.07 (s, 2 H) 5.01 (s, 2 H) 7.10-7.44 (m, 12 H) 7.51 (d, J=6.59 Hz, 1 H) 8.37 (s, 1 H), [M+H]+ 599.7.
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[CH3:16][C@@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[C:18]1([C@H:17]([N:24]2[C:11](=[O:12])[C:6]3[C:7](=[C:2]([F:1])[C:3]([F:15])=[C:4]([F:14])[C:5]=3[F:13])[C:8]2=[O:10])[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Solvent: ClC(Cl)Cl
Product: C[C@H](c1ccccc1)N1C(=O)c2c(F)c(F)c(F)c(F)c2C1=O
Temperature: 180 °C
Yield: 65.1 %

Procedure:
220 mg of tetrafluorophthalic anhydride and 121 mg of (R)-α-methylbenzylamine were charged in an egg-plant type flask of 50 ml, followed by stirring under heating at a temperature of 180° C. for 2 hours. After cooled, the reaction product was dissolved in chloroform, purified by silica gel column chromatography (eluent; methylene chloride:methanol=30:1 v/v), recrystallized from a mixed solvent of n-hexane-ethyl acetate, to obtain 210 mg of the desired product as colorless needles. Yield: 65%. m.p. 95.5-96° C.; [α]20D=41.5° (C=0.348 AcOEt); MS(EI+) 323(M)+
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:11]1([CH:14]=[CH:15][C:16]2[S:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=2)[CH2:13][CH2:12]1.F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:22][CH2:21][C:19]2[S:20][C:16]([CH:15]=[CH:14][CH:11]3[CH2:13][CH2:12]3)=[CH:17][CH:18]=2)=[O:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: NCc1ccc(C=CC2CC2)s1
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(C(=O)NCc2ccc(C=CC3CC3)s2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
6-Aminonicotinic acid (35 mg, 0.251 mmol), C-(5-(2-cyclopropylvinyl)thiophen-2-yl)methylamine described in Preparation Example 151 (45 mg, 0.251 mmol), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (133 mg, 0.301 mmol) and triethylamine (0.042 mL, 0.301 mmol) were dissolved in N,N-dimethylformamide (3 mL), and the solution was stirred at room temperature for 3 hours. Water (10 mL) was added to the reaction solution, which was then extracted with ethyl acetate (30 mL). The organic layer was washed, dried over anhydrous magnesium sulfate, then, the solvent was evaporated in vacuo, the obtained residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=3:1), and the title compound (50 mg, 0.167 mmol, 66.6%) was obtained as a white solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:35](=[O:36])[N:6]2[C:7]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])=[C:8]([C:11]3[S:15][C:14]4=[C:16](SC)[N:17]=[C:18]([CH3:19])[N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].O[O:38][S:39]([O-:41])=O.[K+].[C:43](=O)([O-])O.[Na+]>C1COCC1.O>[OH:1][C@@H:2]([C@H:4]1[C:35](=[O:36])[N:6]2[C:7]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:39]([CH3:43])(=[O:41])=[O:38])[N:17]=[C:18]([CH3:19])[N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: O=S([O-])OO
Reactant: O=C([O-])O
Reactant: CSc1nc(C)n2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(S(C)(=O)=O)c2sc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Reaction time: 1.5 h

Procedure:
4-Nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5-methyl-7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (315 mg) was dissolved in 6 ml of THF and 6 ml of water. To the solution was added 368 mg of OXONE (manufactured by Du Pont (E.I.) de Nemours & Co.) under ice cooling. The mixture was stirred at the same temperature for 1.5 hr. An aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with dichloromethane. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1 to 10:1). Of two main components, the fraction, which had been eluted earlier, was concentrated under the reduced pressure to give 145 mg of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-5-methylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH3:17])=[CH:12][CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:30]1([O:36][CH2:37][CH2:38]Br)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[ClH:40]>CCOCC.C(N(CC)CC)C.C1(C)C=CC=CC=1>[ClH:9].[ClH:40].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([CH2:38][CH2:37][O:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:5][CH2:4]2)[CH3:17])=[CH:12][CH:11]=1
Reactant: NCC1CCNCC1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: BrCCOc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(NCC1CCN(CCOc2ccccc2)CC1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-aminomethylpiperidine (5.0 g), 4'-chloroacetophenone (6.77 g), p-toluenesulphonic acid (catalytic amount) and toluene (50 ml) was boiled under reflux for 8 hours while removing the water formed using a Dean and Stark apparatus. The mixture was cooled to ambient temperature and 2-bromoethyl phenyl ether (8.84 g) and triethylamine (6.1 ml) were added. The mixture was boiled under reflux for 2 hours and evaporated to dryness. The residue was dissolved in ethanol (100 ml) and sodium borohydride (3.4 g) was added. The mixture was boiled under reflux for 18 hours and then evaporated to dryness. The residue was dissolved in 2M hydrochloric acid, washed with ethyl acetate, basified with 5M sodium hydroxide solution and the mixture extracted with dichloromethane to give an oil. The oil was dissolved in ether and treated with ethereal hydrogen chloride solution to give a solid which was collected by filtration and recrystallised from absolute ethanol to give 4-[1-(4-chlorophenyl)ethylaminomethyl-]-1-(2-phenoxyethyl)piperidine dihydrochloride, m.p. 220° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:8]1C=[CH:12][CH:11]=[CH:10][C:9]=1CBr)=[N:5][O:6][CH3:7].[C:17]([O-:20])(=O)[CH3:18].[K+].[CH3:22][NH2:23]>C1COCC1.O>[CH3:22][NH:23][C:3](=[O:2])/[C:4](/[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:18]=1[CH2:17][OH:20])=[N:5]/[O:6][CH3:7]
Reactant: CN
Reactant: CON=C(C(=O)OC)c1ccccc1CBr
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)/C(=N/OC)c1ccccc1CO
Temperature: 25 °C
Yield: 67.6 %

Procedure:
Methyl-2-(2-bromomethylphenyl)-2-methoxyiminoacetate (2.00 g) and potassium acetate (1.37 g) were suspended in THF, and the suspension was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, and 30% methanolic methylamine (5.4 g) was added thereto. The resultant mixture was stirred for 10 hours, diluted with water and neutralized, followed by extraction with ethyl acetate. The solvent was dried and distilled off, and the residue was purified by silica gel column chromatography, whereby there was obtained (E)-N-methyl-2-(2-hydroxymethylphenyl)-2-methoxyiminoacetamide (1.05 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([N:15]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]([C:22]3[C:23]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=34)=[N:16]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.CO>[O:14]=[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[N:15]1[C:20](=[O:21])[CH:19]=[CH:18][C:17]([C:22]2[C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=23)=[N:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)C1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCNCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Reaction time: 2 h
Yield: 75.6 %

Procedure:
To a solution of 3-[2-(1-tert-butoxycarbonyl-4-oxopiperidin-3-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (500 mg) in dichloromethane (10 ml) was added trifluoroacetic acid (5 ml) at room temperature, and stirred for 2 hours. Solvent was evaporated and removed by toluene azeotrope to give residue, which was chromatographed on silica gel eluting in turn with 5% and 10% methanol in dichloromethane. Fractions containing desired product were collected and concentrated in vacuo to give residue, which was dissolved in methanol and passed through Amberlite IRA-910 (10 ml) eluting with methanol. Solvent was removed under reduced pressure to give 3-[2-(4-oxopiperidin-3-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.3 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][NH:11][N:10]=2)[CH:8]=1)#[N:2].Cl.Cl[CH2:30][C:31]1[N:35]=[CH:34][N:33]([CH3:36])[N:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][N:11]([CH2:30][C:31]3[N:35]=[CH:34][N:33]([CH3:36])[N:32]=3)[N:10]=2)[CH:8]=1)#[N:2]
Reactant: Cn1cnc(CCl)n1
Reactant: COc1ccc(C#N)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1-c1nn(Cc2ncn(C)n2)cc1NC(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.5 %

Procedure:
N-(3-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.15 g, 0.42 mmol) was dissolved in 10 mL of DMF, then 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (82 mg, 0.63 mmol) and Cs2CO3 (0.41 g, 1.26 mmol) were added. The mixture was stirred at room temperature for 2 hours, then filtered through celite and purified by reverse phase HPLC to give 44.8 mg (23%) of N-(3-(5-cyano-2-methoxyphenyl)-1-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=455.1; 1H NMR (400 MHz, CDCl3) δ: 9.64 (s, 1H), 9.34 (d, 1H), 8.75 (d, 1H), 8.64 (s, 1H), 8.44 (s, 1H), 8.35 (s, 1H), 7.95 (d, 1H), 7.73 (d, 1H), 7.47 (d, 1H), 7.28 (dd, 1H), 5.39 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:26])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[CH:10]=[CH:9][C:8]=2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:3])[CH3:2].[CH3:27][CH:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:29][NH2:30]>>[C:1]([C:4]1[C:5](=[O:26])[NH:6][C:7]2[C:12]([C:13]=1[NH:30][CH2:29][CH:28]([CH3:27])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(CN)c1ccccc1
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)ccc(-c3ccccc3)c2[nH]c1=O
Product: CC(=O)c1c(NCC(C)c2ccccc2)c2cccc(-c3ccccc3)c2[nH]c1=O
Yield: 83 %

Procedure:
3-Acetyl-4-methylsulfoxy-8-phenyl-2-quinolinone (3.25g, 0.01 mol) and β-methylphenethylamine (1.35g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (3.29g, yield: 83%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[N:27]=[C:26]([CH2:28][NH:29][CH2:30][C:31]2[O:35][N:34]=[C:33]([CH:36]([CH3:38])[CH3:37])[N:32]=2)[CH:25]=[CH:24][CH:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([CH2:28][NH:29][CH2:30][C:31]3[O:35][N:34]=[C:33]([CH:36]([CH3:38])[CH3:37])[N:32]=3)[N:27]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(C)c1noc(CNCc2cccc(Br)n2)n1
Product: CC(C)c1noc(CNCc2cccc(Nc3sc(-c4ccc(C(C)(C)O)cc4F)cc3C(N)=O)n2)n1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (116 mg, 0.393 mmol) and 1-(6-bromopyridin-2-yl)-N-[(3-isopropyl-1,2,4-oxadiazol-5-yl)methyl]methanamine (120 mg, 0.39 mmol) as the starting materials.