Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([O:13][C:14]1[CH:23]=[C:22]([CH:24]2[CH2:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:28]Br>ClCCl>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]([CH:24]2[CH2:27][CH2:26][CH2:25]2)[C:21]([Br:28])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc(C2CCC2)cc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(C2CCC2)cc1OCc1ccccc1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
Sodium bicarbonate (7.51 g) was added to a mixture of methyl 2-(benzyloxy)-4-cyclobutylbenzoate (14 g) and dichloromethane, then a dichloromethane (25 mL) solution of bromine (3.17 mL) was slowly added thereto at 10° C., and the mixture was stirred at the same temperature as above for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bisulfite and saturated saline and then dried over anhydrous sodium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (12.2 g).
Reaction SMILES: [CH2:1]([N:8]([CH3:23])[C:9](=[O:22])[C:10](=O)[NH:11][N:12]=[C:13](OCC)[CH2:14][CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[CH:34][CH:33]=1)#[N:25]>C(O)C>[CH2:1]([N:8]([CH3:23])[C:9]([C:10]1[N:39]([CH2:38][C:35]2[CH:34]=[CH:33][C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:24]#[N:25])=[CH:37][CH:36]=2)[C:13]([CH2:14][CH2:15][CH2:16][CH3:17])=[N:12][N:11]=1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(=NNC(=O)C(=O)N(C)Cc1ccccc1)OCC
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Solvent: CCO
Product: CCCCc1nnc(C(=O)N(C)Cc2ccccc2)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
A mixture of 319 mg (1 mmole) of ethyl valerate 5-benzyl-5-methylsemioxamazone (from Step C), 312 mg (1.5 mmole) of [(2'-cyanobiphenyl-4-yl)methyl]amine (from Step D), and 3 ml of dry ethanol was stirred under N2 in an oil bath at 50° C. for 2 hours and then at 70° C. for an additional 22 hours. The solution was concentrated in vacuo, and a solution of the residue in 30 ml of ethyl acetate was washed with 2×25 ml of 2 N HCl followed by 25 ml of saturated NaHCO3. The dried (MgSO4) ethyl acetate phase was filtered and concentrated. Column chromatography of the residue on silica gel (gradient elution using 0.25-5% isopropanol in CH2Cl2 gave 353 mg (76%) of the title compound as a hard glass, mp >40° C. (gradual), homogeneous by TLC in 19:1 CH2Cl 2 --MeOH; mass spectrum (FAB) m/e 464 (M+i)+. NMR indicated approximately a 1:1 ratio of amide rotamers.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=[O:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[CH3:13][O:14][NH2:15]>C(O)C.ClCCl>[CH3:13][O:14][N:15]=[C:2]([CH2:8][C:9](=[O:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(CC(C)=O)=NOC
Yield: 143.3 %

Procedure:
A mixture of ethyl 2,4-dioxopentanoate (10.9 g, 68.7 mmol) and N-methoxyamine hydrochloride (4.01 g, 48.1 mmol) in ethanol (40 ml) was left to stand over molecular sieves 3A (25 g) for 18 h and diluted with dichloromethane (25 ml) The sieves was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography eluting with 5% ethyl acetate/n-hexane to give the title compound (12.9 g, 34%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:43])[C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]([O:41][CH3:42])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:43])[C:33]1[CH:34]=[C:35]([O:41][CH3:42])[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)cc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc(OC)cc(C(=O)N2CC[C@H](NCc3ccnc4ccccc34)C[C@H]2Cc2ccccc2)c1

Procedure:
250 mg (0.423 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 64 mg (1.69 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR31## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.23, DCI-MS: (M+H)+ =496.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:6]([F:9])([F:8])[F:7])[OH:5].O.[NH2:12][NH2:13]>C(O)CCC>[F:7][C:6]([F:9])([F:8])[CH:4]([OH:5])[C:3]([NH:12][NH2:13])=[O:2]
Reactant: NN
Reactant: COC(=O)C(O)C(F)(F)F
Solvent: O
Solvent: CCCCO
Product: NNC(=O)C(O)C(F)(F)F

Procedure:
As described for example 112a, methyl-3,3,3-trifluoro-DL-lactate in butanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 16 h. The mixture was concentrated and the title compound was obtained as a light yellow oil (yield: 81%). MS: m/e=158.0 [M]+.
Reaction SMILES: [C:1]([Cl:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]([O:32][C:33](=[O:50])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][OH:49])[CH3:31])=[O:28]>C(Cl)(Cl)Cl>[Cl:10][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]([O:32][C:33](=[O:50])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:49][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([Cl:10])=[O:9])[CH3:31])=[O:28])=[O:7])=[O:9]
Reactant: CC(OC(=O)CCCCCCCCCCCCCCCO)OC(=O)CCCCCCCCCCCCCCCO
Reactant: O=C(Cl)CCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CC(OC(=O)CCCCCCCCCCCCCCCOC(=O)CCCCC(=O)Cl)OC(=O)CCCCCCCCCCCCCCCOC(=O)CCCCC(=O)Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 103.2 %

Procedure:
In a three-necked round bottomed flask equipped with a reflux condenser, a glass gas inlet tube and a pressure equalizing dropping funnel was placed freshly distilled adipoyl chloride (2.60 ml, 17.50 mmol) dissolved in absolute chloroform (15 ml). The temperature was raised to ca. 50° C. and under a gentle stream of nitrogen through the solution, a solution of ethylidene bis(16-hydroxyhexadecanoate) (1.0 g, 1.75 mmol) in absolute chloroform (30 ml) was added dropwise and left at this temperature a further 3 hours after addition. The mixture was then cooled to room temperature and quickly transferred into a 50 ml round bottomed flask equipped for distillation under reduced pressure. Chloroform was first distilled off at normal pressure, then oil-pump vacuum was established and excess adipoyl chloride distilled off at ca. 75° C., 5 mbar pressure, leaving the residual title compound (1.56 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22].O>CN(C=O)C>[CH2:21]([O:20][CH:19]([O:23][CH2:24][CH3:25])[CH2:18][O:16][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][OH:7])[CH:15]=[CH:14][CH:13]=1)[CH3:22]
Reactant: OCCc1cccc(O)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(COc1cccc(CCO)c1)OCC
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Caesium carbonate (8.84 g) was added to a solution of 3-(2-hydroxyethyl)phenol (2.5 g) and 2-bromo-1,1-diethoxyethane (3.74 g) in DMF (50 mL), and the resulting mixture was stirred at 90° C. overnight, then allowed to cool. The mixture was poured into water and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, then dried over anhydrous sodium sulphate and purified by flash chromatography on silica eluted with a gradient of diethyl ether in isohexane to afford the subtitled compound as a pale yellow oil. Yield 3.0 g.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[O:7][C:8]3[C:13]([C:14](=[O:16])[CH:15]=2)=[CH:12][CH:11]=[CH:10][C:9]=3[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1.Cl[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:20]([O:19][C:17]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[O:7][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=3)=[CH:23][CH:22]=1)=[CH:15][C:14]2=[O:16])=[O:18])[CH3:21]
Reactant: CCOC(=O)c1cccc2c(=O)cc(-c3ccc(O)cc3)oc12
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2c(=O)cc(-c3ccc(OCc4ccc5ccccc5n4)cc3)oc12
Temperature: 100 °C
Yield: 64 %

Procedure:
4'-Hydroxy-8-ethoxycarbonylflavone (1 eq.) and 2-chloromethylquinoline (1.1 eq.) were dissolved in DMF, followed by the addition of potassium carbonate (1.2 eq.). The resulting mixture was stirred at 100° C. and, subsequent to the completion of the reaction, was charged into water. The water layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from DMF-ethanol, whereby the title compound represented by the following formula was obtained (yield: 64%). ##STR21##
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:14][C:15]([CH3:22])([CH3:21])[C:16](=O)[CH2:17][C:18]#[N:19]>>[C:15]([C:16]1[CH:17]=[C:18]([NH2:19])[N:12]([C:9]2[CH:8]=[CH:7][C:6]([C:2]([CH3:5])([CH3:3])[CH3:4])=[CH:11][CH:10]=2)[N:13]=1)([CH3:22])([CH3:21])[CH3:14]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CC(C)(C)c1ccc(NN)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Yield: 73.7 %

Procedure:
Using the procedure in Example 161A Step 3, 4-tert-butylphenyl-hydrazine monohydrochloride (1.00 g, 4.98 mmol) and 4,4-dimethyl-3-oxopentanenitrile (625 mg, 4.98 mmol) were reacted to give 3-tert-butyl-1-(4-tert-butylphenyl)-1H-pyrazol-5-amine (996 mg, 3.67 mmol, 51%). 1H NMR (300 MHz, DMSO-d6) δ 7.46 (br s, 4H), 5.35 (s, 1H), 5.15 (br s, 2H), 1.30 (s, 9H), 1.20 (s, 9H); LC-MS (ESI) m/z 272 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2[N:10]=[CH:11][N:12]=[C:13](O)[C:8]=2[CH:7]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:13]1[C:8]2[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:15][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc2c(O)ncnc2[nH]1
Product: CCOC(=O)c1cc2c(Cl)ncnc2[nH]1
Temperature: 120 °C

Procedure:
Under a N2 atmosphere, 32.0 g (154 mmol) of 6-ethoxycarbonyl-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine are suspended at RT in 308 ml (338 mmol) of POCl3 and, with stirring, heated at 120° C., during which the solid dissolves. After 3 hours' stirring at 120° C., the excess POCl3 is distilled off (65° C. external temperature; 15 mbar). The residue is suspended in 50 ml of ice-cold toluene, filtered and washed with toluene to yield the title compound; m.p. 219-221° C.; 1H-NMR (DMSO-d6) 8.77 and 7.24 (2s, 2H), 4.39 (q, J=7, 2H), 1.36 (t, J=7, 3H). Further product can be obtained from the filtrate by concentrating by evaporation and then stirring in ethyl acetate/water.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][NH:6][C:7]([C:9]1[C:14]([OH:15])=[C:13]([CH3:16])[N:12]=[C:11]([CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([CH2:36][OH:37])=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[N:10]=1)=[O:8])C.[OH-].[Na+]>CO.O1CCCC1>[OH:15][C:14]1[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:38])=[O:3])=[O:8])=[N:10][C:11]([CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH:35]=[CH:34][C:33]([CH2:36][OH:37])=[CH:32][CH:31]=4)=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)=[N:12][C:13]=1[CH3:16]
Reactant: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(-c4ccc(CO)cc4)cc3)CC2)nc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(CC2CCN(c3ccc(-c4ccc(CO)cc4)cc3)CC2)nc(C(=O)NCC(=O)O)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
Ethyl({[5-hydroxy-2-({1-[4′-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.22 g, 0.42 mmol) was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL), and an aqueous sodium hydroxide solution (1 M, 5.0 mL) was added, followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and hydrochloric acid (1 M, 5.0 mL) was added to the resulting residue, whereby a solid was deposited. The resulting solid was collected by filtration, and dried under reduced pressure to afford the title compound (0.17 g, 0.35 mmol) as a pale yellowish white solid (yield 82%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[Cl:21])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.CCOCC>[ClH:21].[Cl:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(F)c2Cl)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Fc1cccc(C2CCNCC2)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 148.8 %

Procedure:
To a solution of tert-butyl 4-(2-chloro-3-fluorophenyl) piperidine-1-carboxylate (13, 0.520 g, 1.66 mmol) in CH2Cl2 (10 mL) under an atmosphere of N2 was added HCl (2 N in Et2O, 10 mL) solution was stirred at ambient temperature for 18 h. The reaction mixture was diluted with Et2O (20 mL). The resulting precipitate was collected by filtration and washed with Et2O to provide 4-(2-chloro-3-fluorophenyl)piperidine hydrochloride (14) as a white solid (309 mg, 74%): 1H NMR (300 MHz, DMSO-d6) δ 8.81-8.55 (m, 2H), 7.47-7.37 (m, 1H), 7.36-7.27 (m, 1H), 7.21-7.13 (m, 1H), 3.43-3.20, (m, 3H), 3.17-2.97 (m, 2H), 2.00-1.73 (m, 4H).
Reaction SMILES: [CH2:1]([C@H:4]1[C:8]2=[N:9][CH:10]=[C:11]([N:14]([CH2:25][CH:26]=[CH2:27])[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[C:12](=[O:13])[N:7]2[C@H:6]([C:28]([OH:30])=[O:29])[CH2:5]1)[CH:2]=[CH2:3].[CH2:31](N(C1C(=O)N2[C@H](C(N(C(OC(C)(C)C)=O)C3C=CC=CC=3)=O)CC(CC=C)(CC=C)C2=NC=1)C(=O)OCC1C=CC=CC=1)[CH:32]=[CH2:33]>>[CH2:1]([C:4]1([CH2:33][CH:32]=[CH2:31])[C:8]2=[N:9][CH:10]=[C:11]([N:14]([CH2:25][CH:26]=[CH2:27])[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[C:12](=[O:13])[N:7]2[C@H:6]([C:28]([OH:30])=[O:29])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)N(C(=O)OC(C)(C)C)c1ccccc1)CC2(CC=C)CC=C
Reactant: C=CC[C@@H]1C[C@@H](C(=O)O)n2c1ncc(N(CC=C)C(=O)OCc1ccccc1)c2=O
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)O)CC2(CC=C)CC=C
Yield: 76 %

Procedure:
According to the procedure for the preparation of 28d, 29c (372 mg, 0.595 mmol) afforded 202 mg (76%) of 29d. MS (ESI) 450.4 (M+H+), 448.2 (M−H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH2:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([CH3:20])[N:14]=1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:17]2[CH:16]=[C:15]([CH3:20])[N:14]=[C:13]([NH2:12])[N:18]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1CCN(c2cc(C)nc(N)n2)CC1

Procedure:
A solution of 4-piperidinecarboxylic acid ethyl ester (6.6 g), 2-amino-4-chloro-6-methylpyrimidine (5.0 g) and triethylamine (4.2 g) in ethanol (50 ml) is stirred at 90° C. for 3 hours. Ethanol is evaporated under reduced pressure, and the residue is dissolved in chloroform, and washed with water. The organic layer is concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]3[N:17]4[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:16]4[N:15]=[CH:14][C:13]=3[C:24]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[O:25])[C:4]=2[O:3]1.[CH2:39]([S:41]([NH2:44])(=[O:43])=[O:42])[CH3:40]>>[CH3:38][C:2]1([CH3:1])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]3[N:17]4[N:18]=[CH:19][C:20]([C:21]([NH:44][S:41]([CH2:39][CH3:40])(=[O:43])=[O:42])=[O:22])=[C:16]4[N:15]=[CH:14][C:13]=3[C:24]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[O:25])[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(Nc3c(C(=O)N4CCC(c5ccccc5)CC4)cnc4c(C(=O)O)cnn34)c2O1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc4c3OC(C)(C)C4)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 44.8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,2-dimethyl-2,3-dihydrobenzofuran-7-ylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.063 g, 0.58 mmol), the title compound (0.027 g, 44%) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N: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.[CH2:17]=[C:18]1[O:22][C:20](=[O:21])[CH2:19]1>>[C:20]([O:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)(=[O:21])[CH2:19][C:18]([CH3:17])=[O:22]
Reactant: C=C1CC(=O)O1
Reactant: OCCN1CCN(Cc2ccccc2)CC1
Product: CC(=O)CC(=O)OCCN1CCN(Cc2ccccc2)CC1
Yield: 90.2 %

Procedure:
4-Benzyl-1-piperazineethanol was reacted with diketene in the same manner as Reference Example 1-(2) to give 2-(4-benzyl-1-piperazinyl)ethyl acetoacetate as an oil. Yield 90.2%. NMR(CDCl3)δ: 2.26(3H, s), 2.47(8H, s), 2.61(2H, t, J=6), 3.41(2H, s), 3.47(2H, s), 4.22(2H, t, J=6), 7.21(5H, s).
Reaction SMILES: [CH2:1]([C@@H:8]([NH:16][C:17]([CH2:19][CH2:20][CH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])=[O:18])[C@H:9]([C:11]([O:13]CC)=[O:12])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CC(O)=O>[CH2:1]([C@@H:8]([NH:16][C:17]([CH2:19][CH2:20][CH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])=[O:18])[C@H:9]([C:11]([OH:13])=[O:12])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1)NC(=O)CCCc1ccccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(CCCc1ccccc1C(=O)O)N[C@H](Cc1ccccc1)[C@@H](O)C(=O)O
Reaction time: 4 h
Yield: 95 %

Procedure:
Two thirds of the crude 2-[3-((1R,2R)-1-benzyl-2-ethoxycarbonyl-2-hydroxy-ethylcarbamoyl)-propyl]-benzoic acid for the previous example, was combined with THF (8 mL) and 10 M aqueous NaOH (134 μL, 4.0 eq.). The reaction was stirred for 4 hours. Upon completion of the reaction was completed, AcOH (1.5 mL) was added and the product was purified by preparative HPLC to yield the title compound (50 mg, 95% purity). MS m/z [M+H]+ calc'd for C21H23NO6, 386.15. found 386.2.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:30])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15]C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:7].[ClH:31].O1CCOC[CH2:33]1>>[ClH:31].[CH3:1][N:2]([CH3:33])[C:3](=[O:30])[C@H:4]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7]
Reactant: C1COCCO1
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CC[C@H](CNC(=O)OC(C)(C)C)CC1
Agent: Cl
Product: CN(C)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CC[C@H](CN)CC1
Reaction time: 0.5 h

Procedure:
To the compound (III) (34.30 g) was added 4N hydrogen chloride/1,4-dioxane solution (400 ml) under room temperature, and the mixture was stirred for 30 minutes. The mixture was concentrated under a reduced pressure, and the residue was washed with diethyl ether, followed by filtration to give N-(trans-4-aminomethyl-cyclohexylcarbonyl)-L-phenylalanine dimethylamide hydrochloride (28.50 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:30]3([CH3:35])[CH2:32][C:31]3([F:34])[F:33])=[N:9][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:4]=2[CH:3]=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C@H:43]([NH:45][C:46]([NH2:48])=[O:47])[CH3:44])=[CH:39][CH:38]=1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50]>>[F:52][C:51]([F:54])([F:53])[C:49]([OH:55])=[O:50].[F:34][C:31]1([F:33])[CH2:32][C:30]1([C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH:48][C:46]([NH:45][C@@H:43]([C:40]3[CH:39]=[CH:38][C:37]([F:36])=[CH:42][CH:41]=3)[CH3:44])=[O:47])=[CH:3][C:4]=2[NH:10][N:9]=1)[CH3:35]
Reactant: C[C@@H](NC(N)=O)c1ccc(F)cc1
Reactant: CC1(c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)CC1(F)F
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(C3(C)CC3(F)F)c2cn1)c1ccc(F)cc1

Procedure:
In a manner similar to that described in Scheme 6 and Example 30, 6-chloro-3-(2,2-difluoro-1-methylcyclopropyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine was reacted with (R)-1-(1-(4-fluorophenyl)ethyl)urea (Xantphos, Pd(OAc)2, Cs2CO3, dioxane, 80° C., overnight) and then deprotected with TFA to provide (R)-1-(3-(2,2-difluoro-1-methylcyclopropyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-(4-fluorophenyl)ethyl)urea 2,2,2-trifluoroacetate. MS ESI calc'd. for C19H18F3N5O[M+1]+ 390, found 390.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:23])=[CH:4][C:3]=1[C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccccc1C(=O)c1ccccc1
Solvent: ClCCl
Product: Nc1ccc(Br)cc1C(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a solution of (2-Amino-phenyl)-phenyl-methanone (5 g, 25 mmol) in DCM (100 mL) is cooled to −10° C., then NBS (4.512 g, 25 mmol) is added in 30 minutes. After the addition the mixture is stirred at −10° C. for 2 h. The mixture is diluted with DCM, washed with salt NaHCO3 (2×100 mL), salt NaCl (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to give product (6.3 g), which is used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[OH-].[K+].[CH3:11]I>CS(C)=O>[CH3:11][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: CI
Reactant: Cc1ccc(O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Hydroxy-2-methylpyridine (16.4 g, 150.3 mmol) was added to a suspension of KOH (34.6 g, 616 mmol) in DMSO (250 ml) and stirred for 1 h at r.t. followed by the dropwise addition of methyl iodide (10.3 ml, 165 mmol). The reaction mixture was stirred for a further 16 h, poored onto ice-cold water (500 ml) and extracted with diethyl ether (4×350 ml). The combined ether extracts were washed with water (50 ml), brine (50 ml) and dried (MgSO4). Filtration and concentration of the filtrate under reduced pressure gave a crude oil which was purified over silica gel (ethyl acetate/n-heptane 1:2 to 1:1): light brown oil 10.5 g (54%);