Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:25]1[CH:29]=[C:28]([C:30]2[C:31]3[CH:38]=[CH:37][N:36](COCC[Si](C)(C)C)[C:32]=3[N:33]=[CH:34][N:35]=2)[CH:27]=[N:26]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17](C#N)=[CH:16][C:15]=2[F:22])=[O:13])[CH2:8][CH:7]1[CH2:23]O)#[N:2].[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48].C(N)CN>C(Cl)Cl>[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[F:22][C:15]1[CH:16]=[C:17]([OH:48])[CH:20]=[CH:21][C:14]=1[C:12]([N:9]1[CH2:8][CH2:7][CH2:23][N:6]([CH2:5][CH:4]([N:25]2[CH:29]=[C:28]([C:30]3[C:31]4[CH:38]=[CH:37][NH:36][C:32]=4[N:33]=[CH:34][N:35]=3)[CH:27]=[N:26]2)[CH2:3][C:1]#[N:2])[CH2:11][CH2:10]1)=[O:13]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCN(C(=O)c5ccc(C#N)cc5F)CC4CO)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: N#CCC(CN1CCCN(C(=O)c2ccc(O)cc2F)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
4-{[4-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-(hydroxymethyl)piperazin-1-yl]carbonyl}-3-fluorobenzonitrile (9 mg, 0.01 mmol; peak 1 from Step 5) was stirred in a solution of 1:1 TFA:DCM (2 mL) for 1 h. Solvents were removed in vacuo. The residue was dissolved in methanol (1.0 mL), and ethylenediamine (0.050 mL, 0.75 mmol) was added. After 30 min, the product was purified via preparative HPLC-MS (C18, eluting first with a gradient of H2O/MeCN containing 0.15% NH4OH, then repurified eluting with a gradient of H2O/MeCN containing 0.1% TFA) and lyophilized to afford product as the (2.66×) trifluoroacetate salt (6.3 mg, 60%). 1H NMR (500 MHz, DMSO-d6, 90° C.): δ 12.11 (br s, 1H), 8.77 (s, 1H), 8.74 (s, 1H), 8.38 (s, 1H), 7.84 (d, 1H), 7.71 (d, 1H), 7.63-7.60 (m, 1H), 7.55 (t, 1H), 6.99 (br d, 1H), 4.92-4.85 (m, 1H), 3.85-2.35 (m, 13H); 19F NMR (400 MHz, DMSO-d6): δ −74.94 (s, 8F), −114.23 to −114.96 (m, 1F); LCMS (M+H)+: 514.2.
Reaction SMILES: [CH2:1]([CH:8]([CH2:14][S:15](Cl)(=[O:17])=[O:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:30])[C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1)([CH3:22])([CH3:21])[CH3:20]>C(N(CC)CC)C>[C:19]([O:23][C:24](=[O:30])[C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[S:15]([CH2:14][CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:17])=[O:16])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
In an analogous manner to that described above, by reacting ethyl 2-benzyl-3-chlorosulphonylpropionate with L-proline tert-butyl ester in the presence of triethylamine there is obtained 1-[[(RS)-2-(ethoxycarbonyl)-3-phenylpropyl]sulphonyl]-L-proline tert-butyl ester which is converted into (S)-α-[[[(S)-2-(tert-butyloxycarbonyl)-1-pyrrolidinyl]sulphonyl]methyl]hydrocinnamic acid by enzymatic hydrolysis using α-chymotrypsin.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH2:14][OH:15])([O-:3])=[O:2].[F:16][C:17]([F:44])([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])=[CH:32][CH:31]=1)[O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[F:16][C:17]([F:44])([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])=[CH:32][CH:31]=1)[O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([O:15][CH2:14][CH2:13][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[O:28])=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(CCO)c([N+](=O)[O-])c1
Reactant: O=C(O)/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
2.50 g (11.8 mmol) of 2-(2,4-dinitrophenyl)ethanol, 4.91 g (11.8 mmol) of (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoic acid, 144 mg (1.2 mmol) of 4-dimethylaminopyridine are dissolved in 30 mL of dichloromethane. 2.48 g (13.0 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0° C. The solution is stirred for 1 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature, the reaction mixture is partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Chromatography of the residue on 200 g silica gel using toluene: ethyl acetate 95:5 as eluent and crystallization from ethyl acetate:hexane mixture yielded 5.11 g (71%) of 2-(2,4-dinitrophenyl)ethyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: Cl[CH:2]([CH3:24])[C:3]([N:5]([CH:14]1[CH:21]2[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:23][CH:15]1[CH2:16]3)[CH2:20]2)[NH:6]C(OC(C)(C)C)=O)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH:21]12[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:23]3)[CH:14]1[N:5]1[C:3](=[O:4])[CH:2]([CH3:24])[NH:6]1)[CH2:22]2
Reactant: CC(Cl)C(=O)N(NC(=O)OC(C)(C)C)C1C2CC3CC(C2)CC1C3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1NN(C2C3CC4CC(C3)CC2C4)C1=O
Reaction time: 1 h
Yield: 53.7 %

Procedure:
A solution of t-butyl 2-(2-chloropropanoyl)-2-(adamantan-2-yl)hydrazinecarboxylate (200 mg, 0.560 mmol) in dichloromethane (3 mL) was added with trifluoroacetic acid (3 mL) at room temperature, and the resultant was stirred at the same temperature for 1 hour. The reaction solution was concentrated, and the obtained residue was purified using silica gel chromatography (hexane:ethyl acetate=1:1), 2-(adamantan-2-yl)-4-methyl-1,2-diazetidin-3-one (66.3 mg, 53.7%) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](F)=[C:11]([C:16]#[N:17])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:18]([O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)([CH3:20])[CH3:19].CC([O-])(C)C.[K+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:26][C:25]3[CH:24]=[CH:23][C:22]([O:21][CH:18]([CH3:20])[CH3:19])=[CH:28][CH:27]=3)=[C:11]([C:16]#[N:17])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)ccc1F
Reactant: CC(C)Oc1ccc(N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(Nc2ccc(-c3ccc(Cl)c(Cl)c3)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3′,4′-dichloro-4-fluorobiphenyl-3-carbonitrile (173 mg, 0.650 mmol), 4-isopropoxyaniline (108 mg, 0.715 mmol), and KOtBu (154 mg, 1.375 mmol) in DMSO (4 mL) was stirred at rt for 1.5 h, The mixture was diluted with ethyl acetate, washed with H2O and brine, and then dried over Na2SO4. The solvent was removed and the product was purified by silica gel chromatography (eluting with hexane containing 0 to 8% ethyl acetate) followed by preparative HPLC (100×30 mm Luna C18 column, flow rate 42 ml permin, gradient elution starting with A:B=50:50 and ending with A:B=0:100 [A=10 mM NH4OAc in 5% aqueous acetonitrile; B=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min). This afforded 99 mg of 3′,4′-dichloro-4-(4-isopropoxyphenylamino)-biphenyl-3-carbonitrile which still contained some impurities according to the LC/MS but was used as such for next step. MS (ESI) m/z 397.1 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc([N+](=O)[O-])c(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
Piperazine-1-carboxylic acid benzyl ester (8.00 g; 36.3 mmol), 2-fluoro-4-methyl-1-nitro-benzene (4.70 g; 30.3 mmol) and potassium carbonate (8.5 g; 61.5 mmol) were stirred 3 hours in 50 mL DMSO at 80° C. The reaction mixture was cooled to room temperature and 250 mL Water was added. The mixture was extracted with diethyl ether (2×250 mL). The organic phase was washed with water (100 mL), 1 N HCl (2×100 mL), brine (2×100 mL), dried with MgSO4 and concentrated in vacuo to give 10.5 g (29.5 mmol; 97.6%) 4-(5-methyl-2-nitro-phenyl)-piperazine-1-carboxylic acid benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][N+:3]=1[O-:20]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc(C(F)(F)F)ccc1Cl
Temperature: 60 °C
Reaction time: 30 h
Yield: 11.8 %

Procedure:
2-Chloro-5-trifluoromethylpyridine (5 g) was dissolved in chloroform (150 mL) and m-chloroperbenzoic acid (14.3 g) was added thereto. The mixture was stirred at 60° C. for 30 hr. Aqueous sodium thiosulfate solution and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture, and after stirring, the mixture was extracted with chloroform. The extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and brine, and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give 2-chloro-5-trifluoromethylpyridine 1-oxide (0.64 g).
Reaction SMILES: O.[OH:2][CH2:3][C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[NH:8][CH:9]=1.C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:42]=[CH:41][C:24]([C:25](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([O:2][CH2:3][C:4]2[C:5](=[O:11])[NH:6][C:7](=[O:10])[NH:8][CH:9]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:24]2[CH:41]=[CH:42][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[CH:31][CH:30]=1
Reactant: O=c1[nH]cc(CO)c(=O)[nH]1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(OCc2c[nH]c(=O)[nH]c2=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 6 h

Procedure:
5-(Hydroxymethyl)-uracil hydrate 1 (10.00 gm, 0.070 moles) is co-evaporated three times with 50 ml dry pyridine and dissolved in 200 ml dry pyridine at room temperature. Triethylamine (9.8 ml, 0.070 moles) and 4,4'-dimethoxytrityl chloride (23.7 gm, 0.070 moles) are added and the mixture is stirred for 6 hours under a nitrogen atmosphere. Most of the pyridine is removed under reduced pressure and the residue is partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase is washed twice with saturated sodium chloride, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The oily residue is triturated with ethyl acetate and hexane to give 5-(4,4'-dimethoxytrityloxymethyl)-uracil 2 as an off-white solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C@H:4]([CH2:7][CH3:8])[CH2:5][OH:6].Cl[CH2:10][C:11](Cl)=[O:12].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:7]([C@H:4]1[NH:3][C:11](=[O:12])[CH2:10][O:6][CH2:5]1)[CH3:8]
Reactant: CC[C@@H](N)CO
Reactant: O=C(Cl)CCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC[C@@H]1COCC(=O)N1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 55.3 %

Procedure:
NaH (1.51 g, 37.9 mmol) in dry toluene (10 mL) was cooled to 0° C. under nitrogen, and (2R)-2-amino-1-butanol (1.5 g, 16.8 mmol) in toluene (5 mL) was added dropwise. The mixture was stirred for 20 minutes warming up to room temperature, and chloroacetyl chloride (1.5 mL, 18.9 mmol) in toluene (5 mL) was added dropwise. An exotherm was observed so the mixture was cooled in an ice bath during the addition. After the addition was completed, the reaction mixture was heated to 110° C. overnight. The mixture was cooled to room temperature and 5 g of ammonium chloride were added portionwise. The mixture was stirred for 20 minutes and filtered. The filter cake was washed with toluene and discarded. The filtrate was concentrated to give an orange oil that was dissolved in CH2Cl2 and purified by SiO2 chromatography (gradient: 100% CH2Cl2 to 90:10:1 CH2Cl2/CH3OH/NH4OH) to afford the title compound (1.2 g) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 0.96 (t, J=7.6 Hz, 3H), 1.52-1.63 (m, 2H), 3.40-3.51 (m, 2H), 3.85-3.94 (m, 1H), 4.07-4.20 (m, 2H), 7.55 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[CH:6][C:7]=1Cl>CNCCO>[Cl:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[CH:6][C:7]=1[N:4]([CH2:3][CH2:9][OH:10])[CH3:5]
Reactant: OCc1nccc(Cl)c1Cl
Agent: CNCCO
Product: CN(CCO)c1ccnc(CO)c1Cl

Procedure:
A mixture of 3,4-dichloro-2-hydroxymethylpyridine (J. Med. Chem. 1989, 32, 1970) (2.5 g) in 2-methylaminoethanol (30 ml) is heated at 160° C. for 2.5 h in a steel autoclave, the excess amine is stripped off in a high vacuum and the residue which remains is chromatographed on silica gel (dichloromethane/methanol 95/5). Yield: 2.3 g as a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([NH2:22])[C@H:12]1[OH:13].[C:23]([O:27][C:28]([NH:30][CH:31]([C:40](O)=[O:41])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([NH:22][C:40](=[O:41])[CH:31]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:29])[C@H:12]1[OH:13]
Reactant: CCOC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1N
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1Cl)C(=O)O
Product: CCOC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1NC(=O)C(Cc1ccccc1Cl)NC(=O)OC(C)(C)C
Yield: 56.9 %

Procedure:
Ethyl 1-(6amino-9H-purin-9-yl)-1,3-dideoxy-3-[N-tert-butoxycarbonyl-β-(2-chlorophenyl)-D,L-alanylamino]-β-D-ribofuranuronate (320 mg) was prepared by reacting ethyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronate 294 mg) prepared in Example 63 with N-tert-butoxycarbonyl-β-(2-chlorophenyl)-D,L-alanine (300 mg) according to a similar manner to that of Example 64, mp. 120°-130° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:35][C:36]([C:38]2[CH:39]=[C:40]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH:41]=[CH:42][CH:43]=2)=[O:37])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15](CC3C=CC(OC)=CC=3)[N:16]=[C:17]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[C:10]=12.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[CH:3]=[C:4]([NH:35][C:36]([C:38]2[CH:39]=[C:40]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:41]=[CH:42][CH:43]=2)=[O:37])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][N:16]=[C:17]([NH:18][CH:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)[C:10]=12
Reactant: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(NC(=O)c5cccc(-c6ccccc6)c5)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(Nc2n[nH]c3nccc(Oc4ccc(NC(=O)c5cccc(-c6ccccc6)c5)cc4F)c23)CC1
Temperature: 50 °C
Yield: 27.3 %

Procedure:
To a flask containing N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)biphenyl-3-carboxamide (10 mg, 0.015 mmol) at room temperature under a drying tube was added TFA (1 mL). The solution was warmed to 50° C. for 3 hours. After cooling to ambient temperature, the solution was concentrated, and the residue was redissolved in 5 mL dichloromethane and stirred rapidly with 5 mL 10% sodium carbonate solution to provide the free base. The organic layer was isolated, dried (MgSO4), filtered and concentrated. The crude product was passed through a small gravity silica cartridge with 95/5 dichloromethane/MeOH to provide the desired product as a clear oil (2.2 mg, 27% yield). 1H NMR (400 MHz, CDCl3) δ 9.40 (br s, 1H), 8.20 (d, 1H), 8.11 (m, 1H), 8.01 (m, 1H), 7.92 (m, 1H), 7.85 (m, 1H), 7.82 (m, 1H), 7.65 (m, 2H), 7.60 (m, 1H), 7.50 (m, 2H), 7.41 (m, 2H), 7.30 (m, 1H), 6.10 (d, 1H), 4.54 (m, 1H), 3.73 (br m, 1H), 2.89 (br m, 2H), 2.34 (s, 3H), 2.24 (br m, 3H), 1.68 (br m, 2H). LCMS (APCI+): m/z 537 (M+1) detected.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:17])([F:16])[F:15])[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[F:33][C:34]([F:48])([F:47])[C:35]1[CH:36]=[C:37]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:38]=[CH:39][CH:40]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:15])([F:16])[F:17])[C:3]=1[C:18]([N:44]1[CH2:43][CH2:42][N:41]([C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([C:34]([F:47])([F:48])[F:33])[CH:36]=2)[CH2:46][CH2:45]1)=[O:20]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Nc1onc(-c2ccccc2OC(F)(F)F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccccc2OC(F)(F)F)c1C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 69 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-(trifluoromethyl)phenyl)piperazine (424 mg, 1.84 mmol), a white solid required compound (633 mg, 1.27 mmol, 69%) was obtained.
Reaction SMILES: N[C:2]1[C:3]([CH3:15])=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].S(=O)(=O)(O)[OH:17].N([O-])=O.[Na+]>>[OH:17][C:2]1[C:3]([CH3:15])=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6]
Reactant: Cc1c(N)cccc1C(=O)CCC(=O)O
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1c(O)cccc1C(=O)CCC(=O)O

Procedure:
3-(3-amino-2-methylbenzoyl)propionic acid was diazotised in a solution of sulphuric acid with sodium nitrite, and the diazonium salt solution was added dropwise to boiling aqueous sulphuric acid to give 3-(3-hydroxy-2-methylbenzoyl)proprionic acid.
Reaction SMILES: [C:1]([O:20]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH2:27]>CO>[C:1]([NH:27][CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[CH3:22])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC
Reactant: CN(C)CCCN
Solvent: CO
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCN(C)C
Temperature: 180 °C
Reaction time: 5 h

Procedure:
(a-2) was synthesized by a de-methanol amidation reaction between methyl stearate and N,N-dimethyl-1,3-propanediamine. Specifically, a four-neck flask equipped with a stirrer, a temperature gage and a dewatering pipe was charged with 161 g of N,N-dimethyl-1,3-propanediamine and 448 g of methyl stearate and the mixture was raised to 180° C. The mixture was heated under stirring at this temperature for about 5 hours while distilling generated methanol. The reaction mixture was cooled to 120° C. and unreacted amine was distilled under reduced pressure to obtain 545 g of the target N-stearoylaminopropyl-N,N-dimethylamine (a-2).
Reaction SMILES: [C:1](=[NH:10])([O:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[CH2:12]CO>>[C:2]1([C:1]2[O:8][CH2:9][CH2:12][N:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=N)c1ccccc1
Reactant: NCCO
Product: c1ccc(C2=NCCO2)cc1

Procedure:
The methods (1) to (6) will be described more specifically. For example, as the method (1), potassium hydroxide or acetic anhydride is reacted to 2-chloroethylformamide to provide 2-oxazoline, and the case where 2-bromoethylbenzamide is used provides 2-phenyl-2-oxazoline (see, for example Non-patent Document 1). As the method (2), thionyl chloride is reacted to 2-formamide ethanol to provide 2-oxazoline, and N-(2-hydroxyethyl)benzamide is heated with phosphorous pentoxide to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 2). As the method (3), benzoic acid and 2-aminoethanol are heated with alumina to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 3). As the method (4), benzonitrile and 2-aminoethanol are heated with calcium chloride at 110 to 120° C. to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 4 and Patent Document 1). As the method (5), methyl benzimidate and 2-aminoethanol are heated with alumina to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 5). Vinylbenzamide is simply heated to provide 2-phenyl-2-oxazoline. As the method (6), N-allylbenzamide is heated with sulfuric acid to provide 5-methyl-2-phenyl-2-oxazoline (see, for example, Non-patent Document 6).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.O.O.[NH2:17][NH2:18]>O>[CH3:1][CH:2]([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[N:17][NH2:18]
Reactant: CC(C)C(=O)c1cccc([N+](=O)[O-])c1
Reactant: NN
Solvent: O
Product: CC(C)C(=NN)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a partially dissolved solution of 2-methyl-1-(3-nitrophenyl)-1-propanone (Preparation 55, 1.0 g, 5.2 mmol) in industrial methylated spirits (6 ml) was added dropwise hydrazine hydrate monohydrate (0.5 ml, 10.4 nmuol). The reaction mixture was refluxed for 16 h, before cooling to room temperature and pouring into ice and water (50:50, 15 ml) giving a very fine white precipitate in a yellow solution. The mixture was extracted with diethyl ether (2×50 ml), the combined organic extracts were washed with brine and dried (MgSO4), before concentrating to give an amber oil. The crude product was purified by chromatography on silica gel cluting with dichloromethane:ethyl acetate (19:1) to give the title compound as a mixture of cis and trans hydazones (0.54 g, 50%).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[CH3:5][CH:6]([CH2:8][C:9]([CH3:11])=[O:10])[CH3:7]>>[CH3:5][CH:6]([CH2:8][C:9]([CH2:11][CH:2]([CH3:4])[CH3:1])=[O:10])[CH3:7]
Reactant: CC(C)=O
Reactant: CC(=O)CC(C)C
Product: CC(C)CC(=O)CC(C)C

Procedure:
Pd was found to be the most effective among metals used for the hydrogenation function of catalysts. The 1% wt. n-Pd/n-ZnCr2O4 gave the most active and selective catalyst for direct synthesis of MIBK from acetone. The highest MIBK selectivity of 72.1% was obtained at 77.3 wt % acetone conversion at 350° C. The total MIBK and DIBK selectivity of 85.6% was obtained at these conditions (Table 5, FIG. 2).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13]([O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[CH2:13]([O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[O:11][CH3:12])=[CH:20][CH:19]=1)=[O:17])[CH3:14]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2cc([N+](=O)[O-])ccc2OC)cc1
Yield: 76.8 %

Procedure:
A mixture of 2-bromo-1-methoxy-4-nitro-benzene (1 g), 4-ethoxycarbonyl-phenyl boronic acid (836 mg), cesium carbonate (1.4 g) and tetrakis(triphenylphosphine)palladium0 (catalytic quantity), in 1:2 aqueous DME (45 ml) was heated to reflux for 18 h. The mixture was then cooled and partitioned between water and ethyl acetate. The dried extracts were evaporated and the residue purified on silica gel. Elution with 5-40% ethyl acetate:petrol gave a yellow solid (997 mg).