Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C@@H:7]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:8]([F:11])([F:10])[F:9])(=O)=O.[NH:21]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1.CCOCC.CCCCCC.C(OCC)(=O)C>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([C@@H:7]([N:21]2[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22]2)[C:8]([F:11])([F:10])[F:9])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=S(=O)(O[C@@H](c1ccc(Cl)nc1)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(Cl)nc2)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (79.8 g, 232 mmol), (S)-tert-butyl pyrrolidin-3-ylcarbamate (51.9 g, 279 mmol), and K2CO3 (44.9 g, 325 mmol) in THF (500 mL) was stirred at 56° C. for 18 hours. After cooling to ambient temperature, water (200 mL) and ethyl acetate (200 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (4:1 hexane/ethyl acetate) to give a thick oil. The oil was dissolved in ether (200 mL) and hexane (500 mL) was added. The solution was concentrated to about 200 mL and stirred at ambient temperature for 1 hour. Hexane (300 mL) was added, and the resulting solid was collected by filtration to give tert-butyl (S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (68.2 g, 77.3%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes/10% (1:1 MeOH/EtOH) at 1.0 mL/min, >99% d.e. (R,S)-diastereomer).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:4]=2[N:3]=1.Cl.[CH3:15]O>>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:15])=[O:12])=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1nc2cc(C(=O)O)ccc2[nH]1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2[nH]c(C)nc2c1

Procedure:
46.6 g (0.202 mol) of 18a are reacted with methanol and gaseous hydrogen chloride in analogy to Example 14b.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH2:26]([C:31]([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=O)[CH2:27][CH:28]([CH3:30])[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[ClH:1].[CH2:19]([O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][C@H:3]([NH:2][CH:31]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:33][CH2:34][CH:35]([CH3:36])[CH3:37])[C:4]([NH:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:5])=[CH:17][CH:16]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)CCC(=O)CCC(C)C
Reactant: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(C)CCC(CCC(C)C)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
(S)-2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide monohydrochloride (1.04 g. 2.87 mmol, Example 2, Step A) and diisoamyl ketone (0.490 g, 2.87 mmol Aldrich, Milwaukee. Wis.) were mixed in CH2Cl2 (25 mL). After stirring at ambient temperature under a nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.910 g, 4.30 mmol). The resulting reaction mixture was stirred for 30 minutes at 0° C., followed by an additional 12 hours at ambient temperature. Saturated aqueous NaHCO3 solution (25 mL) was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (25% EtOAc in hexanes). The free amine was dissolved in 10 mL of ethyl ether and treated with ethereal HCl to afford 0.45 g (30%) of the pure titled compound as a white solid; mp 114-115° C.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C:7]1[C:17](=[O:18])[NH:16][C:10]2[N:11]=[C:12]([CH3:15])[N:13]=[CH:14][C:9]=2[C:8]=1[NH2:19])=[O:6])[CH3:3].CN(C)C=O.[CH2:25](I)[CH3:26]>O>[CH2:2]([O:4][C:5]([C:7]1[C:17](=[O:18])[N:16]([CH2:25][CH3:26])[C:10]2[N:11]=[C:12]([CH3:15])[N:13]=[CH:14][C:9]=2[C:8]=1[NH2:19])=[O:6])[CH3:3]
Reactant: CCI
Reactant: CCOC(=O)c1c(N)c2cnc(C)nc2[nH]c1=O
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(N)c2cnc(C)nc2n(CC)c1=O
Reaction time: 72 h

Procedure:
To a solution containing 5.4 g. (0.02 mole) of the sodium salt of 5-amino-7,8-dihydro-2-methyl-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester in 50 ml. of dimethylformamide was added 9.35 g. (0.06 mole) of ethyl iodide. The reaction mixture was heated to 50° for 4 hours; cooled in ice and then poured into one liter of water. The reaction mixture was kept in a cold room for 3 days and was then filtered. The product amounted to 3.4 g. (m.p. 230°-231°). The analytical sample was obtained by recrystallization from ethanol.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:5]=1[C:6]#[N:7])[CH3:2]>C(O)C(F)(F)F.FC(F)(F)C(O)C(F)(F)F>[NH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([NH:3][CH2:1][CH3:2])[C:5]=1[C:6]#[N:7]
Reactant: CCNc1cccc([N+](=O)[O-])c1C#N
Solvent: OCC(F)(F)F
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: CCNc1cccc(N)c1C#N
Yield: 81 %

Procedure:
Prepared as in Example 254b from 2-(ethylamino)-6-nitrobenzonitrile (Example 259c) using Trifluoroethanol/Hexafluoroisopropanol (2:1) as solvent, in 81% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.14 (t, J=7.2 Hz, 3H), 3.15-3.22 (m, 2H), 5.41 (bt, J=5.2 Hz, NH), 5.64 (s, NH2), 5.82 (d, J=8.0 Hz, 1H), 5.96 (d, J=8.0 Hz, 1H), 7.00 (t, J=8.4 Hz, 1H). MS 162 (MH+).
Reaction SMILES: [CH2:1]([S:3][C@@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2].[OH:20]O.O>CO>[CH2:1]([S:3]([C@@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:20])[CH3:2]
Reactant: OO
Reactant: CCS[C@@H]1NC(=O)[C@H]1NC(=O)COc1ccccc1
Solvent: CO
Solvent: O
Product: CCS(=O)[C@@H]1NC(=O)[C@H]1NC(=O)COc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.224 g of (3R,4S)-4-ethylthio-3-phenoxyacetamido-2-oxoazetidine in 3 ml of methanol is added 0.16 ml of 30% aqueous hydrogen peroxide and the mixture is stirred at room temperature for 4 hours. Then, 0.1 ml of 30% aqueous hydrogen peroxide is added, and the mixture is further stirred for 4 hours, followed by addition of 10 ml of water. Extraction is carried out with ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 0.20 g of (3R,4S)-4-ethylsulfinyl-3-phenoxyacetamido-2-oxoazetidine.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=2)[CH2:11][CH:10]([C:22]([O:24]CC)=[O:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>CO.C1COCC1.O>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([F:19])([F:20])[F:21])=[CH:15][CH:16]=2)[CH2:11][CH:10]([C:22]([OH:24])=[O:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1Cc2cc(C(F)(F)F)ccc2N(Cc2ccccc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1Cc2cc(C(F)(F)F)ccc2N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a solution of 149C (825 mg, 2.27 mmol) in a mixed solvent of MeOH-THF-H2O (20 mL at ratio of 2:2:1) was added lithium hydroxide monohydrate (400 mg, 11.35 mmol). The mixture was stirred at RT for 2 h, then extracted with ether (20 mL). The aqueous layer was acidified to pH 4-5 using 3N aqueous HCl, then extracted with CH2Cl2 (3×). The combined CH2Cl2 extracts were washed with water, brine, dried Na2SO4), and concentrated in vacuo to afford compound 149D as light yellow foam (735 mg, 97%).
Reaction SMILES: [CH3:1][C:2]12[O:12][CH:11]1[CH2:10][CH2:9][C:4]1([CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:3]2[C:13]([O:15][CH3:16])=[O:14].[Na].Cl>CO>[OH:12][CH:11]1[CH2:10][CH2:9][C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[C:3]([C:13]([O:15][CH3:16])=[O:14])=[C:2]1[CH3:1]
Reactant: COC(=O)C1C2(CCCC2)CCC2OC21C
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)C1=C(C)C(O)CCC12CCCC2

Procedure:
The crude methyl 1-methyl-7-oxaspiro[bicyclo[4.1.0]heptane-3,1′-cyclopentane]-2-carboxylate obtained (13 g) was added to a solution of sodium (1.5 g, 64 mmol) in methanol (100 ml) and the resulting mixture was refluxed for 10 h, poured into cold 2N aqueous HCl (100 ml), and extracted twice with MTBE (100 ml). The combined organic phases were washed with water (100 ml), twice with a saturated aqueous solution of NaCl (100 ml), dried (MgSO4), concentrated, and gave crude gave methyl 8-hydroxy-7-methylspiro[4.5]dec-6-ene-6-carboxylate (5.65 g) which was dissolved in dichloromethane (80 ml) and treated at −30° C. with triethylsilane (14.4 ml, 0.1 mol) and with BF3.OEt2 (4.7 ml, 37.8 mmol). The resulting mixture was stirred for 3 h while allowing the temperature to reach 20° C., poured into cold 2N aqueous NaOH (80 ml), and extracted twice with MTBE (100 ml). The combined organic phases were washed with water (100 ml), with a saturated aqueous solution of NaCl (100 ml), dried (MgSO4), and concentrated. FC (90 g SiO2, hexane/MTBE 95:5) of the crude product (2.05 g) gave methyl 7-methylspiro[4.5]dec-6-ene-6-carboxylate (1.16 g, 42% three-step overall yield). Boiling point: 105° C. (0.08 mbar).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:13])(=[O:12])[NH:18][CH:15]2[CH2:17][CH2:16]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: NC1CC1
Solvent: ClCCl
Product: O=C(O)c1cc(S(=O)(=O)NC2CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a solution of 2-chloro-5-(chlorosulfonyl)benzoic acid (4.0 g, 15.68 mmol) in DCM (60 mL) was added cyclopropyl amine (1.8 g, 31.57 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mass was concentrated and the residue was diluted with ice cold water and acidified with dilute HCl. The crude solid was filtered off, washed with water and dried to afford 3.0 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 0.37 (s, 2H), 0.49 (d, J=5.4 Hz, 2H), 2.12-2.13 (m, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 8.13 (s, 1H), 8.18 (s, 1H), 13.92 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([S:33]([CH:32]=[CH2:31])(=[O:35])=[O:34])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCNCC3)cc2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N1CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)c4ccccc43)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2 g of 4-(4-(piperazin-1-yl)phenyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are placed in a 250 ml round-bottomed flask under an inert atmosphere. 72 ml of anhydrous dichloromethane are added and then, at 0° C., 1.22 ml of chloroethylsulphonyl chloride are added, followed by 3.67 ml of triethylamine. The reaction mixture is allowed to return gently to ambient temperature. The reaction mixture is stirred at ambient temperature for 3 h before being diluted with dichloromethane. The organic phase is washed with a saturated aqueous sodium hydrogencarbonate solution and the aqueous phase is extracted with dichloromethane. The organic phases are combined and washed with water, then dried over sodium sulphate, filtered through a sintered glass filter and concentrated under reduced pressure. 1.01 g of 4-[4-(4-(ethenesulphonyl)piperazin-1-yl)phenyl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are obtained in the form of a white solid, after purification on a silica column, elution being carried out with a heptane/ethyl acetate gradient varying from 95/5 to 40/60.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[S:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=1.I[CH3:24]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:24])[C:6]([CH3:11])=[C:5]2[S:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1[nH]c2ccc(Cl)cc2c1Sc1cccc(CC(=O)O)c1
Reactant: CI
Product: Cc1c(Sc2cccc(CC(=O)O)c2)c2cc(Cl)ccc2n1C

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: [3-(5-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid and iodomethane
Reaction SMILES: [Cl:1][C:2]1[N+:3]([O-])=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]=12.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:4]1[CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]2=[C:2]([Cl:1])[N:3]=1
Reactant: [O-][n+]1ccc2ccsc2c1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc2ccsc2c(Cl)n1
Temperature: 115 °C
Reaction time: 7 h
Yield: 70 %

Procedure:
A mixture of 7-chlorothieno[2,3-c]pyridine 6-oxide (2.58 g, 13.8 mmol) and POCl3 (20 mL) was stirred at 115° C. under N2 for 7 h. After that time, the excess POCl3 was removed in vacuo, and the residue was poured into ice/water (100 mL), basified by addition of 8 N NaOH followed by saturated NaHCO3, and extracted with DCM (3×50 mL). The combined extracts were washed with saturated NaHCO3 (50 mL), water (50 mL) and brine (50 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by ISCO chromatography (0 to 40% EtOAc:heptane) to afford 1.97 g (70%) of the title compound as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 7.82 (d, J=5.6 Hz, 1 H), 7.68 (s, 1 H), 7.37 (d, J=5.6 Hz, 1 H); MS (ESI): 203.94, 205.94 [M+H]+; HPLC tR=1.55 min (TOF: polar—3 min).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[N:41]=[C:42]([CH2:45][CH3:46])[S:43][CH:44]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[N:41]=[C:42]([CH2:45][CH3:46])[S:43][CH:44]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CCc1nc(CCl)cs1
Agent: Cl
Product: CCc1nc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)cs1
Yield: 72.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 4-chloromethyl-2-ethylthiazole (0.49 g) as starting materials, 5-benzyloxy-N-({1-[(2-ethylthiazol-4-yl}methyl]pyrazol-4-yl)methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=O.Cl.[NH2:19][OH:20]>C(O)(C)C.O>[Br:1][C:2]1[C:3]([S:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=[N:19][OH:20]
Reactant: CC(C)(C)Sc1c(Br)cc([N+](=O)[O-])cc1C=O
Reactant: NO
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)Sc1c(Br)cc([N+](=O)[O-])cc1C=NO
Yield: 150.1 %

Procedure:
A solution of 3-bromo-2-tert-butylsulfanyl-5-nitro-benzaldehyde (1.2 g, 3.8 mmol) and hydroxylamine hydrochloride (1.2 g, 7.7 mmol) in isopropanol (36 mL) and water (8 mL) was heated to 90° C. for 16 h. The reaction mixture was cooled and concentrated to remove isopropanol. Water was added to the residue, followed by saturated sodium bicarbonate solution until the pH was ˜8.0. The residue was extracted with dichloromethane (2×30 mL). The combined organic fractions were dried with sodium sulfate, filtered, and concentrated to afford 1.9 g of the crude title compound which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][NH:20][C:19](=[O:23])[N:18]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].Cl.Cl[CH2:30][C:31]1[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][N:20]([CH2:30][C:31]4[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=4)[C:19](=[O:23])[N:18]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:24]([F:25])([F:27])[F:26]
Reactant: O=c1nc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Reactant: Cn1cc(CCl)cn1
Agent: Cl
Product: Cn1cc(Cn2ccc(OCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 4-{[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]oxy}-2(1H)-pyrimidinone and 4-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride. LC-MS (ESI): m/z 491 [M+H]+; 3.49 min (ret time).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([N:31](CC5C=CC(OC)=CC=5)[CH3:32])[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN(C)c2cc(Oc3ccc4c(c3)CC(C(=O)Nc3cccc(C(C)(C)C)c3)CC4)ccn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cccc(C(C)(C)C)c2)CC3)ccn1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
A solution of N-(3-tert-butylphenyl)-7-({2-[(4-methoxybenzyl)(methyl)amino]-pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxamide (454 mg, 0.83 mmol) in DCM (4 mL) and TFA (4 mL) was heated at 50° C. for 18 h. The reaction mixture was allowed to cool to rt and the solvents were evaporated. The residue was purified by column chromatography to give N-(3-tert-butylphenyl)-7-{[2-(methylamino)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide (337 mg, 94.9%). LCMS: (FA) ES+ 430.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=3)[C:12]([C:22]([F:25])([F:24])[F:23])=[CH:11][N:10]=2)[C:5]([CH3:26])=[CH:4][C:3]=1[CH:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O)(=O)C.C([BH3-])#N.[Na+]>>[CH3:26][C:5]1[CH:4]=[C:3]([C@H:27]2[CH2:32][CH2:31][C@@H:30]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:29][CH2:28]2)[C:2]([CH3:1])=[CH:7][C:6]=1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[C:12]([C:22]([F:23])([F:24])[F:25])=[CH:11][N:10]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCC(=O)CC4)cc3C)ncc2C(F)(F)F)n[nH]1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c([C@H]4CC[C@@H](N5CCOCC5)CC4)cc3C)ncc2C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(2,5-dimethyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone (40 mg, 0.087 mmol), morpholine (15 μL, 0.174 mmol) and acetic acid (75 μL, 0.13 mmol) was stirred at room temperature for 1 h. Sodium cyanoborohydride (8.2 mg, 0.13 mmol) was added to the reaction and the reaction mixture was stirred overnight. The mixture was concentrated and purified by silica chromatography (MeOH/DCM 8:92) to afford N2-(2,5-dimethyl-4-(cis-4-morpholinocyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine; Rf: 0.50 (Silica; MeOH/DCM 8:92); ESMS m/z 530.3 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:19])([F:18])[CH2:13][O:14][CH2:15][CH2:16][OH:17]>>[F:11][C:12]([F:19])([F:18])[CH2:13][O:14][CH2:15][CH2:16][O:17][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: OCCOCC(F)(F)F
Reactant: CC(=O)c1ccc(Cl)nc1
Product: CC(=O)c1ccc(OCCOCC(F)(F)F)nc1
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield (1.67 g, colorless oil) from 1-(6-chloropyridin-3-yl)ethanone (2.0 g, 12.9 mmol) and 2-(2,2,2-trifluoroethoxy)ethanol instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:20]=[C:19]([C:21]3[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32](=[O:35])[CH:33]=O)[CH3:30].N1C=CC=CC=1C.B.C(=O)([O-])O.[Na+]>C(O)(=O)C.CN(C)C=O>[CH2:29]([O:31][C:32](=[O:35])[CH2:33][NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[O:18][N:17]=[C:16]([CH2:15][C:12]3[CH:13]=[N:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][CH:11]=3)[CH:20]=2)=[C:22]([NH2:28])[N:23]=1)[CH3:30]
Reactant: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)c(N)n1
Reactant: CCOC(=O)C=O
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: Cc1ccccn1
Product: CCOC(=O)CNc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)c(N)n1
Reaction time: 8 h
Yield: 8 %

Procedure:
To a mixture of 3-(3-(6-benzyloxy-pyridin-3-ylmethyl)-isoxazol-5-yl)-pyridin-2,6-diamine (40 mg, 0.11 mmol) described in Example 25 and N,N-dimethylformamide (0.5 mL) were added glyoxylic acid ethyl ester polymer foam (16 mg, 0.16 mmol), α-picoline-borane (14 mg, 0.13 mmol), and acetic acid (40 mL), which was stirred overnight at the same temperature. A saturated sodium hydrogencarbonate aqueous solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, after which the organic layer was concentrated under a reduced pressure. The residue thus obtained was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (4.9 mg, 8%) as a trifluoroacetic acid salt.
Reaction SMILES: O=[CH:2][C:3](=C)[CH3:4].C(O)C.C(O[CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])C>C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>[CH2:17]([O:16][CH:12]([O:13][CH2:14][CH3:15])[C:3](=[CH2:2])[CH3:4])[CH3:18]
Reactant: C=C(C)C=O
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: C=C(C)C(OCC)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 404.5 %

Procedure:
p-Toluenesulfonic acid (1.14 g, 0.006 mol) was added to a mixture of methacrolein (42.35 g, 0.06 mol), ethanol (141.9 mL), CH2Cl2 (120 mL) and triethylorthoformate (130.6 mL, 0.785 mol). The mixture was stirred at room temperature for 3 days and then K2CO3 (2 g) was added. The mixture was stirred for 10 minutes, filtered, and then the filtrate was concentrated in vacuo. The residue was purified by distillation through a Vigreaux column at 130° C. to afford 35 g of methacrolein diethylacetal.