Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([CH2:29][CH2:30][S:31][CH3:32])[NH:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]2[NH:20][C:19](=[O:21])[CH2:18][CH2:17]2)=[O:15])=[CH:9][C:8]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.C1COCC1>[NH:20]1[CH:16]([C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([OH:33])=[O:2])[CH2:29][CH2:30][S:31][CH3:32])=[O:28])=[C:8]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:9]=2)=[O:15])[CH2:17][CH2:18][C:19]1=[O:21]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)C2CCC(=O)N2)cc1-c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)c1ccc(NC(=O)C2CCC(=O)N2)cc1-c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
LiOH monohydrate (29 mg, 0.69 mmol) was dissolved in 1 mL H2O and added to a solution of [4-(2-pyrrolidinone-5-ylcarbonylamino)-2-phenylbenzoyl]methionine methyl ester, prepared as in Example 202A, (108 mg, 0.23 mmol) in 3 mL of THF and the reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was evaporated and 2 mL of 1N HCl was added to the aqueous residue. The resulting precipitate was filtered and dried under vacuum to give [4-(2-pyrrolidinone-5-ylcarbonylamino)-2-phenylbenzoyl]methionine (96 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:23]([N:26]1[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[N:27]1)[CH2:24][CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:20])([F:21])[F:22])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:28]2[CH:29]=[CH:30][N:26]([CH2:23][CH2:24][CH3:25])[N:27]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CCCn1ccc(CN)n1
Product: CCCn1ccc(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CAS Registry No. 1018782-82-5) and 1-propyl-1H-pyrazole-3-methanamine (CAS Registry No. 1006333-47-6) as starting materials, LC-MS (UV peak area/ESI) 96%, 453.29 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:41][CH2:42][CH3:43])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([O:38]C)=[O:37])=[CH:32][CH:31]=2)=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:40])[CH3:2].[OH-].[K+]>CO>[CH2:1]([O:3][CH:4]([O:41][CH2:42][CH3:43])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][CH:31]=2)=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:40])[CH3:2]
Reactant: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C(=O)OC)cc2)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C(=O)O)cc2)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Reaction time: 24 h
Yield: 97.6 %

Procedure:
To a solution of 0.588 g of (RS)-1-(2,2-diethoxyethyl)-3-((4-methoxycarbonylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one in 30 ml of methanol was added 5 ml of an aqueous solution of 0.20 g of potassium hydroxide (85%) at room temperature. The mixture was stirred for 1 day, followed by concentration. The concentrate was diluted with water, and washed with chloroform. The aqueous layer was adjusted to pH 2 with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate 1/1) to give 0.56 g (98%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[S:11][C:12]=2[CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[OH-].[Na+].[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>>[C:26]([O:23][C:20]1[CH:19]=[CH:18][C:17]([C:10]2[S:11][C:12]([CH2:13][C:14]([OH:16])=[O:15])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=2)=[CH:22][CH:21]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)Cc1sc(-c2ccc(O)cc2)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1ccc(-c2nc(-c3ccc(Cl)cc3)c(CC(=O)O)s2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
4-(4-Chlorophenyl)-2-(4-hydroxyphenyl)-thiazole-5-acetic acid (7.0 g, 0.016 moles) was dissolved in 0.1 N sodium hydroxide (493 ml, 0.372 moles) and cooled to 0° C. Acetic anhydride (1.5 ml, 0.016 moles) was added and the mixture left standing at room temperature for 3 hours. To the solution was added dilute hydrochloric acid and the resulting precipitate was filtered off, washed with a little water, dried and recrystallised from methylethylketone to give 2-(4-acetoxyphenyl)-4-(4-chlorophenyl)thiazole-5-acetic acid as a colourless solid (2.4 gm), m.p. 177°-180° C.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][C:13]([CH3:24])([CH3:23])[CH2:14][CH2:15][N:16]3[C:20](=[O:21])[CH2:19][S:18][C:17]3=[O:22])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:25](=O)[CH2:26][CH2:27][CH3:28].N1CCCCC1>C(O)C>[CH:25](=[C:19]1[S:18][C:17](=[O:22])[N:16]([CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:20]1=[O:21])[CH2:26][CH2:27][CH3:28]
Reactant: CC(C)(CCSc1cccc2nccn12)CCN1C(=O)CSC1=O
Reactant: CCCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCC(C)(C)CCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 339 mg (0.93 mmol) of 3-[5-(imidazo[1,2-a]pyridin-5-ylthio)-3,3-dimethylpentyl]thiazolidine-2,4-dione and 90 μl (1.0 mmol) of n-butyraldehyde in 5 ml of ethanol, 10 μl (0.1 mmol) of piperidine was added, followed by refluxing for 1.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=2/1→1/2) to yield 310 mg (74.2%, light yellow oily substance) of the desired product.
Reaction SMILES: [CH:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:18]O>>[CH3:18][O:9][C:8](=[O:10])[CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CO
Reactant: O=C(O)C(c1ccccc1)C1CCCCC1
Agent: Cl
Product: COC(=O)C(c1ccccc1)C1CCCCC1
Yield: 99 %

Procedure:
To a stirring solution of 2-cyclohexyl-2-phenyl-acetic acid (2 g, 0.0091 mole) in methanol (100 mL) was added HCl (2 mL), and the mixture was heated at reflux for 5 hours. Methanol was removed, the residue was dissolved in ethyl acetate, and washed with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give 2.2 g (99% yield) of the title compound as an oil. MS (ESI) 233.2 (M+H+).
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:18][CH:19]([CH2:23][CH3:24])[C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][CH:19]([CH2:23][CH3:24])[C:20]([NH:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][OH:10])=[O:21]
Reactant: CCC(Cl)C(=O)Cl
Reactant: N[C@@H](CO)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(Cl)C(=O)N[C@@H](CO)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-phenylglycinol (2.00 g, 14.6 mmol) and triethylamine (2.03 mL, 14.6 mmol) in CH2Cl2 (100 mL) at 0° C. was slowly added 2-chlorobutyryl chloride (1.66 mL, 14.6 mmol). After 30 min, the reaction mixture was quenched with saturated aqueous NaHCO3 (30 mL) and extracted with CH2Cl2 (2×75 mL). The combined organic extracts were washed with 10% citric acid, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—70:30 to 0:100, to give the title compound. MS: m/z=242 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:14]([O-])=O>COCCOC.C(Cl)(Cl)Cl.[Pd]>[NH2:14][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:1])[C:6]([OH:8])=[O:7]
Reactant: Nc1c([N+](=O)[O-])cc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1N
Reaction time: 15 h
Yield: 113.6 %

Procedure:
To a solution of 4-amino-3,5-dinitrobenzoic acid (10 g, 44 mmol, 1 equiv) in DME (100 ml) and CHCl3 (10 ml) under nitrogen was added 10% palladium on charcoal (50% wet, 1 g, 5% w/w) and the resulting suspension was stirred under an atmosphere of nitrogen (35 psi) for 15 h. 10% Palladium on charcoal (50% wet, 1 g, 5% w/w) was added and the resulting suspension was stirred under an atmosphere of hydrogen (35 psi) for another 15 h. The catalyst was filtered off through a pad of celite and the solution was concentrated in vacuo to give 3,4-diamino-5-nitrobenzoic acid (D244) (9.85 g, 113%) as a red solid which was used in the next step without further purification. [M−H]−=196.1, RT=2.15 min
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([Mg]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(Br)=CC=1)(C)(C)C.[Mg].[B:25](OCCCC)([O:31]CCCC)[O:26]CCCC.S(=O)(=O)(O)O>C(OCC)C.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([B:25]([OH:31])[OH:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: CC(C)(C)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
A solution of para-tert-butylphenyl magnesium bromide prepared from 52 ml of para-tert-butylphenyl bromide and 8.0 g of the magnesium turnings in 250 ml of diethyl ether was added to 81 ml of tri-n-butyl borate in 250 ml of diethyl ether at −80° C. with stirring under argon. The reaction mixture was allowed to warm to ambient temperature, and was poured into 150 ml of 10% sulfuric acid in water. The organic phase was extracted twice by 100 ml of diethyl ether. The solvent and n-butanol were removed under vacuum. The viscous residue was recrystallized from boiling water. Yield of 4-tert-butylphenyl boronic acid was 10% as white crystals with mp. 202-203° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1Br.[Li]CCCC.S(C)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.CCCCCC>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(OC)c1cc(OCc2ccccc2)ccc1Br
Agent: [Li]CCCC
Solvent: CSC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(OC)c1cc(OCc2ccccc2)ccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromo-5-benzyloxy benzaldehyde dimethyl acetal (Tet. Lett., 22, 5027 (1981)) (52.2 g) in THF (600 mL), cooled to -78° C., was added dropwise a solution of n-BuLi (78 ml, 2.1M) in hexane. After 15 min. CuBr.SMe2 (32 g) was added in 3 portions. The reaction mixture was stirred at -78° C. until CuBr.SMe2 was dissolved (approx. 1 hr.), then benzoyl chloride (20 mL) was added dropwise. The cooling bath was removed and the reaction mixture was stirred at room temperature over night and was quenched with a saturated NH4Cl solution. The organic phase was diluted with Et2O, washed with H2O (3×), brine, dried (MgSO4) and evaporated to afford the title compound which was used as such for the next step.
Reaction SMILES: [CH2:1](N)[CH:2]=C.C[N:6]1[CH2:11][CH2:10][O:9]CC1.[Cl:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=O>C(#N)C>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][C:10]([CH:11]([NH2:6])[CH:1]=[CH2:2])=[O:9]
Reactant: C=CCN
Reactant: CN1CCOCC1
Reactant: O=C(Cl)CCCCl
Solvent: CC#N
Product: C=CC(N)C(=O)CCCCCl
Yield: 86.4 %

Procedure:
To a stirred mixture of allyl amine 25 (2.0 g, 27 mmol), NMM (8.9 mL, 81 mmol), and acetonitrile (140 mL), at ambient temperature was added 4-chlorobutyryl chloride (3.4 mL, 27 mmol). After 20 hours the reaction mixture was concentrated. The residue was dissolved in ethyl acetate and then washed with water, 5% KHSO4 and brine, dried (MgSO4), and concentrated to give 26 (4.1 g, 87%) as a yellow oil. TLC Rf=0.17 (40% ethyl acetate/hexanes).
Reaction SMILES: [NH2:1][C:2]1[C:23]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([NH:15][CH:16]2[CH2:18][CH2:17]2)=[O:14])[CH:10]=[CH:9][C:8]=1[CH3:19])=[O:5].[CH3:31]OC(OC)OC>>[CH:16]1([NH:15][C:13](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([CH3:19])=[C:7]([N:6]3[C:4](=[O:5])[C:3]4[C:2](=[C:23]([N:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)[CH:22]=[CH:21][CH:20]=4)[N:1]=[CH:31]3)[CH:12]=2)[CH2:17][CH2:18]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cccc(N2CCN(C)CC2)c1N
Reactant: COC(OC)OC
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(N3CCN(C)CC3)cccc2c1=O

Procedure:
Using an analogous procedure to that described in Example 1, 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3-(4-methylpiperazine-1-yl)benzamide was reacted with trimethylorthoformate. There was thus obtained the title compound; NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.67 (m, 2H), 2.13 (s, 3H), 2.24 (s, 3H), 2.50 (m, 4H), 2.84 (m, 1H), 3.31 (m, 4H), 7.33 (d, 1H), 7.48 (m, 2H), 7.78 (m, 2H), 7.88 (d, 1H), 8.25 (s, 1H), 8.41 (d, 1H); Mass Spectrum: M+H+ 418
Reaction SMILES: [C:1]([OH:32])(=[O:31])[CH2:2][CH2:3][C@H:4]([NH:8][C:9]([C:11]1[CH:30]=[CH:29][C:14]([NH:15][CH2:16][C:17]2[N:28]=[C:27]3[C:20]([N:21]=[C:22]([NH:24][C:25]3=[O:26])[NH2:23])=[N:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[C:5]([OH:7])=[O:6].[CH:33](O)=[O:34]>>[CH:33]([N:15]([CH2:16][C:17]1[N:28]=[C:27]2[C:20]([N:21]=[C:22]([NH:24][C:25]2=[O:26])[NH2:23])=[N:19][CH:18]=1)[C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C@H:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2][C:1]([OH:32])=[O:31])=[CH:30][CH:29]=1)=[O:34]
Reactant: O=CO
Reactant: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)nc2c(=O)[nH]1
Product: Nc1nc2ncc(CN(C=O)c3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)nc2c(=O)[nH]1

Procedure:
5-CHO- and 5-Me-(6R,S)-THF can be prepared in a known manner from folic acid. Formylation with formic acid produces 10-formyl-folic acid (10-CHO-FA). The latter can subsequently be catalytically hydrogenated to 10-formyl-tetrahydrofolic acid (10-CHO-THF). 5,10-Methenyl-tetrahydrofolic acid (I; 5,10-CH-THF; "anhydroleucovorin") can be obtained from the latter by dehydration: ##STR1##
Reaction SMILES: C([O:3][CH:4]([O:19]CC)[C:5]#[C:6][C:7](=[O:18])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)C.CCOCC.O>O1CCOCC1.Br>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10](/[CH:9]=[CH:8]/[C:7](=[O:18])/[CH:6]=[CH:5]/[C:4]([OH:19])=[O:3])=[CH:15][CH:14]=1
Reactant: CCOC(C#CC(=O)/C=C/c1ccc(OC)cc1)OCC
Agent: Br
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: COc1ccc(/C=C/C(=O)/C=C/C(=O)O)cc1

Procedure:
A solution of 1.0 g (3.47 mmol) of (E)-6,6-diethoxy-1-(p-methoxyphenyl)-1-hexen-4-yn-3-one in 4 ml of dioxane and 2 ml of 2.2N aqueous hydrobromic acid was stirred at 30° for 18 hours and subsequently treated with 20 ml of ether and 10 ml of water. The aqueous phase was extracted twice with ethyl acetate. The combined organic fractions were dried over magnesium sulphate, filtered and evaporated. The residue was chromatographed on 80 g of silica gel with acetonitrile/water (1:1). The fractions containing the product were extracted with ethyl acetate. The combined ethyl acetate extracts were dried over magnesium sulphate, filtered and evaporated. The residue was recrystallized from ethyl acetate/hexane, whereby there was obtained (E,E)-6-(p-methoxyphenyl)-4-oxo-2,5-hexadienoic acid of melting point 138°-139°.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([CH2:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.[O:27]1[CH2:32][CH2:31][CH:30]([CH:33]=O)[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]([C:6]2[C:7]([CH2:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:33][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)[CH2:2][CH2:3]1
Reactant: O=CC1CCOCC1
Reactant: CCc1nn2c(-c3c(C)cc(C)cc3OC)cccc2c1NCC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1nn2c(-c3c(C)cc(C)cc3OC)cccc2c1N(CC1CCOCC1)CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
After dissolving N-cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine (255 mg) in tetrahydrofuran (2 mL), tetrahydro-2H-4-pyrancarbaldehyde (173 mg) [CAS No. 50675-18-8] and sodium triacetoxyborohydride (241 mg) were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (134 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a yellow oil.
Reaction SMILES: COB(OC)OC.C1(C(C2C=CC=CC=2)([C@@H]2CCCN2)O)C=CC=CC=1.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35](=[O:37])[CH3:36]>O1CCCC1>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C@H:35]([OH:37])[CH3:36]
Reactant: CC(=O)c1cc(Cl)ccc1Br
Agent: COB(OC)OC
Agent: OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Solvent: C1CCOC1
Product: C[C@@H](O)c1cc(Cl)ccc1Br
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
Trimethylborate (1.74 mL, 15.4 mmol) was added to a stirred solution of (S)-(−)-alpha,alpha-diphenyl-2-pyrrolidinemethanol (3.24 g, 12.8 mol) in tetrahydrofuran (350 mL) at room temperature. After 1.25 h, borane-methyl sulfide complex (70.4 mL of a 2M solution in tetrahydrofuran, 0.141 mol) was added slowly and a gentle effervesence was observed. The resulting soution was cooled to approximately 0° C. and a solution of 1-(2-bromo-5-chlorophenyl)ethanone (˜30.0 g, 0.128 mmol) in tetrahydrofuran (150 mL) was then added uniformly over 1 h. After the addition, the resulting mixture was allowed to warm to ambient temperature and aged overnight. The reaction mixture was concentrated under reduced pressure to approximately one quarter of its original volume, poured into 1N hydrochloric acid and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (9% ethyl acetate/hexanes as eluent) afforded the title compound as a colorless solid (98:2 enantiomer ratio).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([OH:25])=O)[CH:16]=1.C(C1NC=CN=1)([C:29]1[NH:30]C=CN=1)=O.CN>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([NH:30][CH3:29])=[O:25])[CH:16]=1
Reactant: Nc1c(C(=O)c2cccc(OCC(=O)O)c2)cnn1-c1ccc(F)cc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)COc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
To a solution of 5-amino-4-[3-(carboxymethyloxy)benzoyl]-1-(4-fluorophenyl)-pyrazole (0.5 g, 1.43 mmol) in tetrahydrofuran (10 ml) was added carbonyl diimidazole (0.3 g, 1.85 mmol) and the reaction mixture was heated at 60° C. After 1 h, methylamine (10 ml, 5 mmol, 0.5 M solution in tetrahydrofuran) was added and reaction was continued at 60° C. overnight. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was separated and washed with brine and dried over sodium sulfate. The organics were removed in vacuo and the residue was purified by flash chromatography (elution gradient: 20-30% acetone/hexane) to give 5-amino-1-(4-fluorophenyl)-4-[3-(methylaminocarbonylmethyloxy)benzoyl]pyrazole (0.25 g, mpt. 195.6-196.3° C.) as a solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[C:14]12([NH2:24])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.O>N1C=CC=CC=1>[C:14]12([NH:24][C:11]([C:2]3[CH:3]=[N:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[O:12])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: O
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1cnc2ccccc2n1
Reaction time: 0.5 h

Procedure:
2-Quinoxaloyl chloride (0.84 g, 4.4 mmol) was added to a solution of 1-adamantanamine (0.60 g, 4.0 mmol) in pyridine (10 mL). The reaction was then stirred for 30 min. To the stirring reaction mixture was added water (100 mL) which caused the product to precipitate. This precipitate was filtered, washed with water (3×25 mL), and dried under high vacuum for 16 h. This provided 1.00 g (82%) of (91):
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[N:10]([CH3:16])[CH2:9]1)(C)(C)C.Cl.CO>O1CCOCC1>[CH3:16][N:10]1[C:11]([CH3:15])([CH3:14])[CH2:12][CH2:13][C:8]([NH2:7])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1
Reactant: CN1CC(NC(=O)OC(C)(C)C)(c2ccccc2)CCC1(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1CC(N)(c2ccccc2)CCC1(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.2 %

Procedure:
To a solution of 50 mg (0.157 mmol) (1,6,6-Trimethyl-3-phenyl-piperidin-3-yl)-carbamic acid tert-butyl ester in 0.3 ml dioxane was added 0.39 ml (1.57 mmol) of a 4M HCl solution in dioxane at room temperature. After 30 minutes 0.3 ml methanol was added to dissolve the product. The mixture was stirred at room temperature for 5 hours. The solvent was removed in vacuo. The residue was dissolved in water. The aqueous layer was extracted twice with ethyl acetate and then basified with a 2M sodium carbonate solution. The aqueous layer was extracted 3 times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to provide 22 mg (64%) of the title compound as a brown oil. MS (m/e): 219.4 (M+H).