Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C@H:14]([C:19]([OH:21])=O)[CH2:15][C:16](=[O:18])[NH2:17])=[O:12].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[OH:54][C@H:55]([C@@H:73]([NH2:81])[CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH2:56][N:57]([CH2:66][CH:67]1[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]1)[NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60]>C1COCC1>[OH:54][C@H:55]([C@@H:73]([NH:81][C:19](=[O:21])[C@H:14]([CH2:15][C:16](=[O:18])[NH2:17])[NH:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12])[CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH2:56][N:57]([CH2:66][CH:67]1[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72]1)[NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:63])[CH3:64])=[O:60]
Reactant: CC(C)(C)OC(=O)NN(CC1CCCCC1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(CC1CCCCC1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
At 5° C., 940 mg (3.27 mmol) of quinoline-2-carbonyl-(L)-asparagine (in the form of the hydrochloride salt) are dissolved in 35 ml of THF, and 736 mg (3.57 mmol) of DCC are added. After 10 min, 482 mg (3.57 mmol) of HOBT, 0.82 ml (7.44 mmol) of NMM and 1.165 g (2.98 mmol) of 1-[2(S)-hydroxy-3(S)-amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[tert-butoxycarbonyl]-hydrazine are added and the mixture is stirred at RT for 18 h. The reaction mixture is filtered and the filtrate is concentrated by evaporation. The residue is partitioned between 3 portions of ethyl acetate, saturated NaHCO3 solution, water and brine, and the organic phases, which have been dried with Na2SO4, are concentrated by evaporation and subjected to column chromatography (SiO2, ethyl acetate) to yield the title compound: TLC Rf (O)=0.16; tRet (V)=16.5 min; FAB-MS (M+H)+ =661.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[CH:19][C:20]([N+:25]([O-:27])=[O:26])=[C:21]([CH:24]=1)[CH:22]=[O:23].O>ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:24]=[C:21]([C:20]([N+:25]([O-:27])=[O:26])=[CH:19][CH:18]=1)[CH:22]=[O:23]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Solvent: O
Solvent: Clc1ccccc1
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])c(C=O)c3)c2cc1OC
Temperature: 25 °C
Yield: 66.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (200 mg) and 5-hydroxy-2-nitrobenzaldehyde (299 mg) were suspended in chlorobenzene (2 ml), and the suspension was heated under reflux for 8 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using ethyl acetate-hexane to give 3-[(6,7-dimethoxy-4-quinolyl)oxy]-6-nitrobenzaldehyde (210 mg, yield 66%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.[CH:40]1([CH2:46][NH2:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.O>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])([C:17]([NH:47][CH2:46][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[O:19])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)OCc2ccccc2)CC1
Reactant: NCC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(=O)NCC2CCCCC2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyloxycarbonyl-4-(t-butoxycarbonylamino)piperidin-4-carboxylic acid (297 mg) in dimethylformamide (2.5 mL) were added 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (226 mg), 4-N,N-dimethylaminopiperidine (144 mg) and cyclohexylmethylamine (0.15 mL) and the solution was stirred at room temperature overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate:methanol=40:1-10:1) to give the title compound having the following physical data.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:26]([CH3:41])[C:27]([O:29][CH2:30][CH2:31][S:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)=[O:28]>C(#N)C>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:26]([CH3:41])[C:27]([O:29][CH2:30][CH2:31][S:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)=[O:28])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(Br)C(=O)OCCSCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)OCCSCc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A mixture consisting of 25.4 g of 4-(4-trifluoromethylphenoxy)phenol, 14.5 g of anhydrous potassium carbonate, 33.8 g of 2-(4-chlorobenzylthio)ethyl 2-bromopropionate and 150 ml of dry acetonitrile was refluxed for 3 hours with vigorous stirring. After cooling the reaction mixture to room temperature, the acetonitrile was removed under reduced pressure. Then, 150 ml of toluene were added to the residue and the resulting mixture was washed successively with 1% strength by weight aqueous sodium hydroxide solution and water, followed by dehydration. Upon distilling off the toluene under reduced pressure, there were obtained 46.4 g of 2-(4-chlorobenzylthio)-ethyl 2-[4-(4-trifluoromethylphenoxy)-phenoxy]-propionate in the form of a colorless oil. nD20 =1.5555.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]=[C:27]=[O:28])=[CH:20][CH:19]=1>>[CH2:25]([NH:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:28])[CH2:24][C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C=NCCc1ccccc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)NCCc4ccccc4)cc23)CC1
Yield: 64.1 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 12.51 mg (0.0852 mMol) 2-phenethyl isocyanate, 15.8 mg (65%) of the title compound were recovered.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3[O:37][C:38]([CH3:54])=[C:39]([CH2:41][CH2:42]OS(C4C=CC(C)=CC=4)(=O)=O)[N:40]=3)[CH:31]=2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:42][CH2:41][C:39]2[N:40]=[C:36]([C:32]3[CH:31]=[C:30]([C:27]4[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=4)[CH:35]=[CH:34][CH:33]=3)[O:37][C:38]=2[CH3:54])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccc(F)cc4)c3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3cccc(-c4ccc(F)cc4)c3)oc2C)cc1)Oc1ccccc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (495 mg, 1.7 mmol) (see Ex. 1, Part C), toluene-4-sulfonic acid 2-[2-(4′-fluorobiphenyl-3-yl)-5-methyloxazol-4-yl]ethyl ester (2.2 mmol) and Cs2CO3 (700 mg, 2.2 mmol) are combined in anhydrous DMF (25 mL) and stirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixture was then cooled and diluted with ethyl acetate (100 mL), and washed with water then brine. The organic layer was dried with Na2SO4 and concentrated in vacuo to a viscous yellow oil. The residue was purified by flash column chromatography (100 g silica, 60×15 mL fractions, gradient elution 0–20% ethyl acetate in hexanes) to provide the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.18–8.17 (m, 1H), 7.96–7.94 (m, 1H), 7.62–7.57 (m, 3H), 7.51–7.47 (m, 1H), 7.23–7.11 (m, 2H), 7.16–7.11 (m, 3H), 6.98–6.94 (m, 1H), 6.84–6.81 (m, 4H), 6.78–6.75 (m, 1H), 4.24 (t, J=6.4 Hz, 2H), 4.20 (q, J=7.2 Hz, 2H), 3.26 (d, J=14.0 Hz, 1H), 3.10 (d, J=14.0 Hz, 1H), 2.99 (t, J=6.4 Hz, 2H), 2.40 (s, 3H), 1.38 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); MS (EI) 580.2 (M+)+.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[Br:12][CH:13]([CH3:17])[C:14](Br)=[O:15]>C(OCC)C>[Br:12][CH:13]([CH3:17])[C:14]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:15]
Reactant: CC(C)CO
Reactant: CC(Br)C(=O)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)COC(=O)C(C)Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of iso-butanol and 1.0 equivalent of pyridine in dry diethyl ether was added dropwise 1.3 equivalents of 2-bromopropionyl bromide at 0° C. After stirring at room temperature for 16 hours, the reaction was diluted with diethyl ether, washed with 1N HCl, water, aqueous NaHCO3, brine and dried over magnesium sulfate or sodium sulfate. Removal of the solvents at reduced pressure gave the title compound as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([OH:28])=[O:27])=[C:24]([CH:29]([OH:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:23]=[C:22]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46]>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][N:40]3[C:44](=[O:45])[CH2:43][CH2:42][C:41]3=[O:46])=[O:27])=[C:24]([CH:29]([OH:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:23]=[C:22]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCc1nc(C(O)C(C)(C)C)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Product: CCCCc1nc(C(O)C(C)(C)C)c(C(=O)ON2C(=O)CCC2=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 93.1 %

Procedure:
Following a procedure similar to that described in Example 52(a), but using 600 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxy-2,2-dimethylpropyl)imidazole-5-carboxylic acid [prepared as described in step (c) above], 172 mg of N-hydroxysuccinimide and 250 mg of N,N-dicyclohexylcarbodiimide, 663 mg of the title compound were obtained as an amorphous solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1.[Br:10]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>N1C=CC=CC=1.ClCCl>[Br:10][C:8]1[CH:9]=[C:4]2[CH2:3][CH2:2][NH:1][C:5]2=[N:6][CH:7]=1
Reactant: BrBr
Reactant: c1cnc2c(c1)CCN2
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Brc1cnc2c(c1)CCN2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38.8 %

Procedure:
2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine (4.40 g, 36.6 mmol) in a mixture of pyridine (4.4 mL) and dichloromethane (20 mL) was gradually added dropwise to bromine (7.00 g, 43.8 mmol) in dichloromethane (20 mL) cooled to 0° C., and the resulting reaction mixture was stirred at 0° C. for 20 minutes, after addition of saturated aqueous sodium thiosulfate, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→0/1 (v/v)) to give the title compound as a brown solid (2.83 g, yield 39%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([N+]([O-])=O)=[N:10][C:9]=3[N:8]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.O(Cl)[Cl:24].O>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([Cl:24])=[N:10][C:9]=3[N:8]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: O=c1c2[nH]c([N+](=O)[O-])nc2n(CC2CC2)c(=O)n1CC1CC1
Reactant: ClOCl
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2[nH]c(Cl)nc2n(CC2CC2)c(=O)n1CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,3-Di-cyclopropylmethyl-8-nitro xanthine (6 g, 0.023 mol) was dissolved in dimethylformamide (20 ml) and reacted with phosporous oxychloride (14 g) for 1 hour at 120° C. The mixture was then treated with water and stirred for 1 hour at room temperature. The precipitate was filtered off, dissolved in ethyl acetate, dried over anhydrous sodium sulphate and the solvent was removed in vacuo, yield 2.5 g (40%), m.pt. 220° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:24][Si:25](Cl)([CH3:27])[CH3:26]>CN(C)C=O>[CH3:24][Si:25]([CH3:27])([CH3:26])[O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)OC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C
Yield: 90 %

Procedure:
The mixture of 4-(4-oxo-Piperidin-1-yl)-nitrobenzene (126 mmol), triethylamine (630 mmol), trimethylsilylchloride (375.0 mmol) in dimethylformamide was heated at 70° C. for 24 h. The solvent was removed under vacuum and to the residual mass was extracted with the ethyl acetate water mixture. The combined organic layer was dried and after removal of the solvent afforded title compound as a solid in 90% yield.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.C(N(CC)CC)C.[CH:27]1([CH2:39][NH2:40])[C:37]2=[C:38]3[C:33](=[CH:34][CH:35]=[CH:36]2)[CH:32]=[CH:31][CH:30]=[C:29]3[CH2:28]1>C(O)C>[CH:27]1([CH2:39][NH:40][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:37]2=[C:38]3[C:33](=[CH:34][CH:35]=[CH:36]2)[CH:32]=[CH:31][CH:30]=[C:29]3[CH2:28]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCC1Cc2cccc3cccc1c23
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4Cc5cccc6cccc4c56)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 85 %

Procedure:
Six chloropurine riboside (1.7 g, 6 mmol), triethyl amine (1.5 g, 15 mmol) and the N-[(1,2-dihydro-1-acenaphthylenyl)methyl]amine, B, as prepared in the following Example B (1.4 g, 6.4 mmol) were stirred at reflux in ethanol (100 ml) overnight. The solution was cooled to room temperature and filtered free of solid. The solution was washed with ethanol (50 ml) and dried at 65° C. in vacuo for four hours, to give 2.2 g (85%) of a white solid, mp 173°-175° C. Anal. (C23H23N5O4); calc: C=63.73, H=5.35, N=16.16; found: C=63.55, H=5.49, N=16.00.
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:14][CH2:15][C:16](Br)=[O:17]>ClCCl>[Br:14][CH2:15][C:16]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]([CH3:9])[CH3:8])=[CH:2][CH:3]=1)=[O:17]
Reactant: CC(C)c1ccccc1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)c1ccc(C(=O)CBr)cc1
Reaction time: 2 h

Procedure:
To a solution of cumene (27.8 mL, 200 mmol) and aluminum chloride (32.0 g, 240 mmol) in dichloromethane (300 mL) was added bromoacetylbromide (19.1 mL, 220 mmol) at −10° C., and the mixture was stirred at the same temperature for 2 hours. The reaction solution was poured into ice-cold water, and an organic layer was separated. The organic layer was washed with a saturated sodium hydrogen carbonate solution and a saturated brine, and then was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 2-bromo-1-(4-isopropylphenyl)ethanone of oily matter. The obtained oily matter was added to a solution of 3,5-dimethylphenol (29.3 g, 240 mmol) and potassium carbonate (33.2 g, 240 mmol) in acetone (500 mL), and the mixture then was stirred under heat and reflux for 12 hours. The reaction solution was ice-cooled and poured into cold water, which was extracted with diethyl ether.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: COc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(OC)ccc1C=O

Procedure:
To a solution of 100 g of 2-hydroxy-4-methoxybenzaldehyde in 2 liters of acetone add 79.5 ml of allyl bromide and then, gradually, 272 g of potassium carbonate. Heat at reflux for 4 hours and then filter; concentrate the filtrate in vacuo, take up the residue in 1 liter of dichloromethane and wash the solution with 1N sodium hydroxide solution and then with saturated sodium chloride solution. Dry over magnesium sulphate and concentrate in vacuo.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Brc1ncccn1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)c3ncccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12h and 2-bromopyrimidine
Reaction SMILES: C(N)C=C.[CH2:5]([N:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[CH3:21])C1=S)[CH:6]=[CH2:7]>ClCCl>[CH2:5]([NH:8][CH2:13][CH2:12][CH2:11][NH:10][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH3:21])[CH:6]=[CH2:7]
Reactant: C=CCN1CCCN(c2cc(Cl)ccc2C)C1=S
Solvent: ClCCl
Solvent: C=CCN
Product: C=CCNCCCNc1cc(Cl)ccc1C
Yield: 41.2 %

Procedure:
A mixture of allylamine (1.0 mL) and the hydrobromide salt of Step B (1.0 g) was heated at 100° C. under nitrogen for 45 minutes. The reaction was cooled and partitioned between dichloromethane and 1 N sodium hydroxide. The aqueous layer was extracted with dichloromethane, the extracts were dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with a solvent gradient (from 98:2 dichloromethane-methanol to 90:10 dichloromethane-methanol containing 0.2% ammonium hydroxide) provided the title compound (0.35 g, 50.5%) as a yellow oil which was used as such in the next step.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:20]([C:22]1([C:28]2[N:33]=[CH:32][C:31]([NH:34][C:35]([C:37]3[CH:38]=[N:39][N:40]([C:43]4[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][N:44]=4)[C:41]=3[CH3:42])=[O:36])=[CH:30][CH:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)#[N:21].C(=O)(O)[O-].[Na+]>ClCCl.O1CCCC1>[C:20]([C:22]1([C:28]2[N:33]=[CH:32][C:31]([NH:34][C:35]([C:37]3[CH:38]=[N:39][N:40]([C:43]4[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][N:44]=4)[C:41]=3[CH3:42])=[O:36])=[CH:30][CH:29]=2)[CH2:23][CH2:24][N:25]([CH:3]2[CH2:2][O:1][CH2:4]2)[CH2:26][CH2:27]1)#[N:21]
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(C3(C#N)CCN(C4COC4)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reaction time: 6 h
Yield: 44.5 %

Procedure:
3-Oxetanone (316 mg) and sodium triacetoxyborohydride (112 mg) were added at room temperature to a solution of N-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (200 mg) described in Reference Example 169 in dichloromethane (20 ml) and tetrahydrofuran (20 ml), and stirred at the same temperature for eight hours. Further 3-oxetanone (316 mg) and sodium triacetoxyborohydride (112 mg) were added at room temperature and stirred at the same temperature for six hours. After completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated and the resulting residue was purified with silica gel column chromatography (chloroform/methanol) to give the titled compound (100 mg) as a white solid.
Reaction SMILES: Cl.[OH:2][C@@H:3]1[CH2:7][NH:6][C@@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.[Cl:12][CH2:13][C:14](Cl)=[O:15].C.C(OC)(C)(C)C>C1C=CC=CC=1>[Cl:12][CH2:13][C:14]([N:6]1[CH2:7][C@@H:3]([OH:2])[CH2:4][C@@H:5]1[C:8]([O:10][CH3:11])=[O:9])=[O:15]
Reactant: COC(=O)[C@H]1C[C@H](O)CN1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: c1ccccc1
Solvent: COC(C)(C)C
Product: COC(=O)[C@H]1C[C@H](O)CN1C(=O)CCl
Reaction time: 0.5 h

Procedure:
To a suspension of Example 17A (100 g, 0.55 mol, 1 equivalent) in benzene (2.5 L), chloroacetyl chloride (62.4 g, 0.50 mol, 1 equivalent) was added dropwise at 20-25° C. The reaction mixture was refluxed for 3 hours. Then charcoal (2 g) was added, and the mixture was hot filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to get a solid. To this crude material, methyl tert-butyl ether (500 mL) was added and stirred for 30 minutes. The solid was collected by filtration, and the wet cake was dried in a vacuum tray dryer for 5 hours at about 50° C. to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.06-2.15 (m, 1H), 2.31-2.39 (m, 1H), 3.64 (d, 1H, J=11.1 Hz), 3.76 (s, 3H), 3.76-3.86 (m, 2H), 4.09 (s, 2H), 4.6-4.65 (m, 2H).