Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[C:5]([F:21])[CH:4]=1)[CH3:2].CC1(C)O[C@H](CNO)CO1.[CH3:32][C:33]1([CH3:42])[O:38][C@@H:37]([CH2:39][O:40][NH2:41])[CH2:36]C[O:34]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl>[CH3:42][C:33]1([CH3:32])[O:38][C@@H:37]([CH2:39][O:40][NH:41][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][C:17]([F:20])=[C:18]([F:19])[C:10]=2[NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[F:21])[CH2:36][O:34]1
Reactant: CC1(C)OCC[C@H](CON)O1
Reactant: CCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: CC1(C)OC[C@@H](CNO)O1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(Nc2c(C(=O)NOC[C@H]3COC(C)(C)O3)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring solution of the product of Example 1, Step D, 2-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluorobenzoic acid (0.480 g, 1.626 mmol) in dichloromethane (25 mL) is added to the product of Example 31, Step D, (R)—O-(2,2-dimethyl-[1,3]dioxan-4-ylmethyl)-hydroxylamine (0.38 g, 2.57 mmol), triethylamine (0.54 mL, 3.85 mmol), and benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (1.34 g, 2.57 mmol) and allowed to stir at ambient temperature for 90 minutes. The reaction mixture was concentrated in vacuo and the affording residue was partitioned between ethyl acetate and water. The organic layers were washed twice with saturated sodium carbonate solution and twice with brine. The organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo. N-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-(4-ethyl-2-fluoro-phenylamino)-3,4-difluoro-benzamide was isolated via silica column chromatography in 4:1 hexanes/ethyl acetate, then 3:1 hexanes/ethyl acetate affording a white foam (0.515 g, 56.7%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]2[N:10]=[CH:11][C:12]([CH:13]=[O:14])=[C:4]2[N:3]=1.[BH4-].[Na+].[NH4+].[Cl-]>C(O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]2[N:10]=[CH:11][C:12]([CH2:13][OH:14])=[C:4]2[N:3]=1
Reactant: Cc1c(Cl)nc2c(C=O)cnn2c1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1c(Cl)nc2c(CO)cnn2c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.3 %

Procedure:
To 5,7-dichloro-6-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde (200 mg) in ethanol (20 mL) was added sodium borohydride (70 mg) and the reaction mixture was stirred at room temperature for 15 min. Saturated aqueous NH4Cl (1 mL) was added and the reaction mixture was stirred for a further 10 min then the solvent was removed under reduced pressure. Water and ethyl acetate were added and the product was extracted with ethyl acetate (3×). The combined organic phase was washed (water, saturated aqueous NaCl) and dried (MgSO4) to give the title compound (150 mg); 1H-NMR (400 MHz, CDCl3) d(ppm): 8.22 (1H, s, 2-H), 4.90 (1H, s, CH2OH).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:14]2[C:9]3([CH:18]=[CH:17][CH:16]=[CH:15][C:10]3=[N:11][CH2:12][CH2:13]2)[S:8][CH2:7]1)=[O:5])[CH3:2].[CH2:19]=O>>[CH2:1]([O:3][C:4]([CH:6]1[CH:14]2[C:9]3([CH:18]=[CH:17][CH:16]=[CH:15][C:10]3=[N:11][CH2:12][CH2:13]2)[SH:8]([CH3:19])[CH2:7]1)=[O:5])[CH3:2]
Reactant: C=O
Reactant: CCOC(=O)C1CSC23C=CC=CC2=NCCC13
Product: CCOC(=O)C1C[SH](C)C23C=CC=CC2=NCCC13

Procedure:
1-Methyl-1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester was synthesized by following the same procedure as the synthesis of 1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester in Example 1 except that 19.5 g of acetadehyde was used in place of 10.2 ml of formalin in Example 1.
Reaction SMILES: [CH2:1](N)[CH3:2].[NH2:4][C@H:5]([C:11]([OH:13])=[O:12])[CH2:6][CH2:7][C:8](=[O:10])[NH2:9]>>[NH2:4][C@H:5]([C:11]([OH:13])=[O:12])[CH2:6][CH2:7][C:8]([NH:9][CH2:1][CH3:2])=[O:10]
Reactant: CCN
Reactant: NC(=O)CC[C@H](N)C(=O)O
Product: CCNC(=O)CC[C@H](N)C(=O)O

Procedure:
Ten gram of the prepared cells were used for enzymatic reaction in 0.3M glutamine, and 0.9M ethylamine at 30° C. and pH 10. Forty grams of theanine were obtained from 1 liter after incubating at 30° C. for 24 hours. Theanine was extracted from the reaction mixture by eliminating cells first and fractionated by passing through Dowex50×8 and Dowex 1×2 columns serially. The theanine fraction was crystallized and washed with ethanol.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C@H:3]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31]C(=O)OC(C)(C)C)[CH2:27]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([CH3:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1>C(O)(C(F)(F)F)=O>[F:39][C:2]([F:1])([F:40])[C@H:3]([N:26]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH3:25])=[C:18]([CH3:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1
Reactant: COc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)ccc2cc1C
Yield: 86.2 %

Procedure:
tert-Butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(7-methoxy-6-methylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (154 mg, 0.277 mmol) was stirred in TFA (3 mL) for 1 hour then concentrated. The residue was dissolved in minimum methanol and added dropwise to a 4N HCl in ether solution. The resulting solid was filtered and dried to yield (S)-1-((R)-2,2,2-trifluoro-1-(3-(7-methoxy-6-methylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine (109 mg, 86.3% yield) hydrochloride as a solid. LCMS APCI (+) m/z 457 (M+H).
Reaction SMILES: [CH2:1]([C:9]1[CH:24]=[CH:23][C:12]([CH:13]=[N:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC(O)=O>C1COCC1.CCOCC>[CH2:1]([C:9]1[CH:24]=[CH:23][C:12]([CH2:13][NH:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(C=NNC(=O)OC(C)(C)C)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCc1ccc(CNNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.6 %

Procedure:
To a solution of the product of Step A (0.13 g; 0.391 mmol) in anhydrous THF (1 ml) and glacial AcOH (0.6 ml) NaBH3CN (0.06 g; 0.95 mmol) was added at ˜0° C. (ice bath). The resulting mixture was stirred overnight at room temperature then diluted to 15 ml with Et2O. This was washed with 5% NaHCO3. H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure to give the title compound (0.01 g; 16%) as a colourless syrup, which was used in the next step without further purification. 1H-NMR (CDCl3) 7.23 (d, 2H, J=8 Hz); 7.12 (d, 3H, J=8 Hz); 6.0 (s, 1H); 4.1 (broad s, 2H); 3.94 (s, 2H); 2.57 (t, 3H, J=7.9 Hz); 1.56 (m, 2H); 1.45 (s, 9H); 1.26 (m, 10H); 0.86 (t, 3H, J=7 Hz).
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[CH2:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C1C=CC(C2OC(NC3C=CC=C4C=3CC(=O)CC4)=NC=2)=CC=1>>[CH2:1]([C:8]1[O:12][C:11]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]3)=[N:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCc2cccc(Nc3ncc(Cc4ccccc4)o3)c2C1
Agent: O=C1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: OC1CCc2cccc(Nc3ncc(Cc4ccccc4)o3)c2C1

Procedure:
The title compound was prepared using the procedure as described in Example 2, substituting the product of Example 16D for the product of Example 1I. 1H NMR (DMSO-d6) δ 8.72 (s, 1H), 7.56-7.63 (m, 3H), 7.23-7.37 (m, 3H), 7.02 (t, 1H, J=7.5 Hz), 6.77 (d, 1H, J=7.3 Hz), 6.56 (s, 1H), 4.74 (d, 1H, J=3.7 Hz), 3.93 (s, 2H), 3.81 (m, 1H), 2.70-2.90 (m, 4H), 1.81 (m, 1H), 1.58 (m, 1H); MS (ESI+) m/z 321 (M+H)+.
Reaction SMILES: C([O:8][C:9]([C@H:11]([N:13]1[C:18](=[O:19])[C@@H:17]([OH:20])[C@@H:16]([OH:21])[CH2:15][O:14]1)[CH3:12])=[O:10])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[C:9]([C@H:11]([N:13]1[C:18](=[O:19])[C@@H:17]([OH:20])[C@@H:16]([OH:21])[CH2:15][O:14]1)[CH3:12])([OH:10])=[O:8]
Reactant: C[C@H](C(=O)OCc1ccccc1)N1OC[C@H](O)[C@H](O)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](C(=O)O)N1OC[C@H](O)[C@H](O)C1=O
Reaction time: 1 h
Yield: 97.7 %

Procedure:
A suspension of 5% Pd-C (0.137 g) in EtOAc (10 mL) was stirred for 1 h under H2 atmosphere and a solution of the benzyl ester 8a (0.137 g, 0.464 mmol) in EtOAc (15 ml) was added portionwise. The reaction mixture was stirred for 8 hours under H2 and filtered through a short pad of Silica Gel 60H (for TLC) followed by washing with MeOH (7×5 mL). After evaporation of the filtrate in vacuo, the residue was triturated with dry ether and dried in vacuo to provide 0.093 g (98%) of the product 9a as a white solid. 1H NMR (400 MHz) in CD3CN (J, Hz): δ 1.44 (3H, d, 3J=7.3, α-MeCH), 3.00 (2H, br. s, OH, OH), 3.90 (1H, m, 6-HA), 4.37 (1H, d, 3J=4.4, 4-H), 4.49-4.43 (2H, m, 6-HB, 5-H), 5.01 (1H, q, 3J=7.3, α-CH), 5.31 (1H, br. s, COOH). 13C (100 MHz) in CD3CN: δ 13.55, 54.34, 70.15, 70.64, 78.41, 171.22, 172.85.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:12][OH:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccc2c(Cl)nccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc2c(Cl)nccc12
Yield: 76.9 %

Procedure:
A solution of 1-chloro-5-isoquinolinecarboxaldehyde (308 mg, 1.6 mmol) and sodium borohydride (NaBH4) (68 mg, 1.8 mmol) in MeOH (6 mL) was stirred at room temperature for 2 h. The reaction was quenched with water (2 mL) and concentrated in vacuo. The residue was suspended in CH2Cl2, washed with water, with brine and then dried over MgSO4 and evaporated. The residue was purified by column chromatography upon silica gel using hexanes-EtOAc (80:20 to 50:50) as eluant to give 1-chloro-5-(hydroxymethyl)isoquinoline (240 mg, 1.23 mmol) as a white solid.
Reaction SMILES: C([N:8]1[C:16]2[C:15]([O:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])=[N:14][C:13]([NH:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)=[N:12][C:11]=2[CH:10]=[CH:9]1)C1C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[C:19]1([CH3:26])[CH:20]=[C:21]([CH3:25])[CH:22]=[C:23]([CH3:24])[C:18]=1[O:17][C:15]1[C:16]2[NH:8][CH:9]=[CH:10][C:11]=2[N:12]=[C:13]([NH:27][C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[N:14]=1
Reactant: Cc1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3ccn(Cc4ccccc4)c23)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Cc1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3cc[nH]c23)c(C)c1
Temperature: 160 °C
Yield: 22.8 %

Procedure:
To a suspension of 4-(5-benzyl-4-(mesityloxy)-5H-pyrrolo[3,2-d]pyrimidin-2-ylamino)benzonitrile (150 mg, 0.33 mmol) in 1,2-dichlorobenzene (13 mL) was added AlCl3 (436 mg, 3.27 mmol). The reaction mixture was heated at 160° C. for 1.5 h during which the reaction mixture became dark and homogeneous. Upon completion of the reaction, the reaction mixture was cooled and washed with NH4Cl. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with Hexanes:Ethyl acetate (5:1-1:1) provided the product as a tan solid (27.8 mg, 23%).
Reaction SMILES: [CH3:1][C@@H:2]([NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:3]([O-:5])=[O:4].C(N(CC)CC)C.ClC(OCC)=O.N[CH:28]1[CH:32]([CH3:33])[S:31][S:30][CH:29]1[CH3:34]>O.O1CCCC1>[CH3:34][CH:29]1[CH:28]([N:6]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[C@@H:2]([C:3]([OH:5])=[O:4])[CH3:1])[CH:32]([CH3:33])[S:31][S:30]1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)[O-]
Reactant: CC1SSC(C)C1N
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1SSC(C)C1N(C(=O)OC(C)(C)C)[C@H](C)C(=O)O
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
Under anhydrous conditions, to a mixture of 1.7 g (8.9 mmole) of N-t-Boc-D-alanine obtained in Part A, 1.98 g (19 mmole) triethylamine and 40 ml of tetrahydrofuran, cooled to -10° C. is added dropwise 0.96 g (8.9 mmole) ethyl chloroformate and the resulting mixture is stirred at this temperature for 20 minutes. To this is added 1.1 g (7.5 mmole) of mixed cis- and trans-isomers of 4-amino-3,5-dimethyl-1,2-dithiolane and the resulting mixture is stirred at -10° C. for 10 minutes, then allowed to warm to room temperature. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with sodium bicarbonate solution, dilute hydrochloric acid, water, brine, then dried (Na2SO4) and the solvent is evaporated at reduced pressure to obtain the desired product which is used in the next step.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:16]2[C:15]3[N:11]([CH:12]=[CH:13][N:14]=3)[CH2:10][CH2:9][C:8]=2[NH:7][CH:6]=1)=[O:4].[BrH:17]>>[BrH:17].[N:14]1[CH:13]=[CH:12][N:11]2[C:15]=1[C:16]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][NH:7][C:8]=1[CH2:9][CH2:10]2
Reactant: COC(=O)c1c[nH]c2c1-c1nccn1CC2
Agent: Br
Product: O=C(O)c1c[nH]c2c1-c1nccn1CC2
Temperature: 25 °C

Procedure:
A solution of 5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid methyl ester (516 mg) and 48% hydrobromic acid (5 mL) is heated at 600 for 60 hours. The mixture is cooled to room temperature and concentrated in vacuo. The residue is slurried with diethyl ether and the ether is decanted off. This is repeated until no more color is visible in the ether layer. The remaining solid is dried in vacuo to give 5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid hydrobromide, 350 mg, brown solid: 1H NMR(DMSO-d6) 3.17 (2H, t), 4.40 (2H, t), 7.35 (1H, d), 7.57 (1H, d), 7.63 (1H, s) 12.34 (1H, s), 12.45 (1H, s).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:24])[CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[NH:16]C(=O)OC(C)(C)C)=[CH:6][CH:5]=[CH:4][N:3]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:16][C:15]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH2:9][CH:8]([C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[OH:24]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1CC(O)c1cccnc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccncc1CC(O)c1cccnc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-[2-(2-fluoropyridin-3-yl)-2-hydroxyethyl]pyridin-4-ylcarbamate (2.00 g, 6.00 mmol, Intermediate D-3) was dissolved in methylene chloride (40 mL) and trifluoroacetic acid (40 mL). The solution was stirred at room temperature for one hour. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with NaHCO3/water. The aqueous layer was then saturated with solid NaCl, and extracted with ethyl acetate repeatedly (8 times). The combined extracts were dried over MgSO4, filtered, and concentrated to provide an oil which slowly solidified. The desired product was isolated as an off-white solid and was used directly in the next step without further purification. 1H NMR (DMSO-d6) δ 8.10 (d, 1H), 8.01 (m, 1H), 7.90 (d, 1H), 7.77 (s, 1H), 7.34 (m, 1H), 7.18 (m, 1H), 6.59 (m, 2H), 5.80 (bs, 1H), 5.00 (m, 1H), 2.83 (m, 2H). LC/MS: 234 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([NH:13][CH:14]([CH3:16])[CH3:15])[N:7]=1)=[O:5].[CH2:18]1COCC1>C[Mg]Br.CCOCC>[CH:14]([NH:13][C:8]1[N:7]=[C:6]([C:4](=[O:5])[CH3:18])[CH:11]=[C:10]([CH3:12])[N:9]=1)([CH3:15])[CH3:16]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1cc(C)nc(NC(C)C)n1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(=O)c1cc(C)nc(NC(C)C)n1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid methoxy-methyl-amide (2.39 g, 10.0 mmol) in THF (50 mL), methyl magnesium bromide (7.0 mL of a 3 M solution in ether, 20.1 mmol) is added dropwise at 5° C. The mixture is stirred at 5° C. for 1.5 h. The reaction is quenched by adding NH4Cl. The mixture is diluted with EtOAc (75 mL), washed with sat. aq. NaHCO3, dried over Na2SO4, filtered and concentrated to give 1-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-ethanone (1.71 g) as a yellow solid. LC-MS: tR=0.75 min, [M+H]+=194.01; 1H NMR (CDCl3): δ 1.29 (d, J=6.5 Hz, 6H), 2.41 (s, 3H), 2.62 (s, 3H), 4.22 (m, 1H), 5.02 (m, 1H), 6.97 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7](Br)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1Br
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1N1CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
1-Bromo-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (10 mg, 0.40 mmol) obtained in Example 18 was dissolved in THF (15 mL), and morpholine (175.01 mg, 0.18 mL, 2.01 mmol) was added dropwise thereto. The mixture was stirred for 12 hrs at RT, and the solvent was removed under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 126 mg of the titled compound (yield: 83%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C1C(=O)N([Br:20])C(=O)C1>C(#N)C>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Br:20])=[C:6]([F:8])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc(F)cc1N
Solvent: CC#N
Product: COC(=O)c1nc(Br)c(F)cc1N
Yield: 41 %

Procedure:
To a solution of methyl 3-amino-5-fluoropicolinate (1.0 equiv.) in acetonitrile (0.3 M solution) was added NBS (1.1 equiv.) for 2 minutes at room temperature. After quenched with water, the reaction mixture was extracted with EtOAc. The crude product was purified by silica column chromatography (20% to 50% EtOAc in hexanes) to give methyl 3-amino-6-bromo-5-fluoropicolinate, (41%). LCMS (m/z): 249.1 (MH+); LC Rt=2.80 min.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[C:5]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:8])[CH2:6][OH:7].S(=O)(=O)(O)O>C(Cl)Cl>[C:2]([O:7][CH2:6][C:5]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])([CH3:3])([CH3:1])[CH3:4]
Reactant: C=C(C)C
Reactant: CCCCOC(=O)CO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCCCOC(=O)COC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 500-ml, thick-walled Erlenynmeyer flask equipped with a magnetic stirring bar was cooled to -78° C. (dry iece-acetone bath) and charged with isobutylene (150 ml). Then, n-butyl glycolate (20.0 g, 0.151 mol) and 50 ml of methylene chloride was added along with 1 ml of concentrated sulfuric acid. The cold bath was removed and the mixture stirred for 3 days at room temperature. The reaction was quenched with 50 ml of saturated sodium bicarbonate and the product extracted with ether. The ether layer was dried over sodium sulfate and concentrated. After distillation, the title compound was obtained as a colorless oil: bp 64°-65° C. (0.7 mm).
Reaction SMILES: [Cl-].[CH2:2]([CH:9]([NH3+:28])[CH:10]([OH:27])[CH2:11][N:12]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[O:36]1[CH:40]2[O:41][CH2:42][CH2:43][CH:39]2[CH:38]([O:44][C:45](=O)[O:46]N2C(=O)CCC2=O)[CH2:37]1>>[O:36]1[CH:40]2[O:41][CH2:42][CH2:43][CH:39]2[CH:38]([O:44][C:45](=[O:46])[NH:28][CH:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]([OH:27])[CH2:11][N:12]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:37]1
Reactant: CC(C)CN(CC(O)C([NH3+])Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(OC1COC2OCCC12)ON1C(=O)CCC1=O
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1-benzyl-3-(benzyloxycarbonyl-isobutyl-amino)-2-hydroxy-propyl-ammonium chloride (4) (29.70 g, 72.90 mmol, 1 equiv), triethylamine (22.00 g, 220 mmol, 3 equiv) and carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester hexahydro-furo[2,3-b]furan-3-yl ester (19.80 g, 73.00 mmol, 1 equiv) in 120 mL of dichlomethane were stirred at ambient temperature. Due to the incompleteness of the reaction, carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester hexahydro-furo[2,3-b]furan-3-yl ester (5.00 g, 18.43 mmol) was added to the solution. The solution was stirred at room temperature for 24 h. The solution was washed twice with 300 mL of water and once with 300 mL of saturated NaHCO3 solution. The organic layer was dried on MgSO4, filtered, and evaporated to dryness to obtain the desired product as a white solid. (37.04 g, 70.34 mmol, 96.4%). LRMS (ES+): m/z 527 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16]C(=O)OC(C)(C)C)=[CH:5][C:4]=1[NH:24][C:25]1[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=1)#[N:2].C([O-])([O-])=[O:32].[K+].[K+].OO.O>CS(C)=O.CCOC(C)=O>[NH2:16][C@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:32])=[C:4]([NH:24][C:25]2[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=2)[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)ccc2C#N)cn1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)ccc2C(N)=O)cn1
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(4-cyano-3-(1-methyl-1H-pyrazol-4-ylamino)phenylamino)cyclohexylcarbamate (50 mg, 0.12 mmol) in DMSO (1 mL), K2CO3 (100 mg, 0.724 mmol) and H2O2 (50% aq., 0.800 mL) were added. The mixture was stirred at 100 C for 10 min. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was dissolved in TFA (1 mL). After 10 min of standing, TFA was removed in vacuo. The residue was purified by HPLC to give the titled compound (31 mg). MS 329.4 (M+H); UV 205.3, 258.4, 280.5, 327.9 nm
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[Cl:10].[SH:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=1.C(N(CC)CC)C>C(O)C>[Cl:10][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[CH2:3][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:20])[F:21])[N:13]=1
Reactant: Clc1cnccc1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1cc(C(F)(F)F)nc(SCc2ccncc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a 0° C. mixture of 4-(bromomethyl)-3-chloropyridine hydrobromide (7.2 mmol) and 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (922 mg, 4.7 mmol) in absolute ethanol (40 mL) was added triethylamine (4.0 mL, 28.7 mmol). The mixture was stirred at room temperature overnight. The solid material was removed by filtration. Diethyl ether (2×50 mL) was used to wash the recovered solid. The solid material was removed by filtration. The filtrate was evaporated to dryness and then co-evaporated with ethyl acetate (1×25 mL). The solid residue was treated with water (100 mL). The solid product was recovered by filtration, washed with water (2×30 mL), diethyl ether (1×30 mL), and hexanes (2×30 mL), and was dried in vacuo to afford 2-{[(3-chloropyridin-4-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (822 mg, 54%); 1H NMR (500 MHz, DMSO-d6): δ 4.50 (s, 2H), 6.66 (s, 1H), 7.58 (d, 1H, J=4.9 Hz), 8.47 (d, 1H, J=4.9 Hz), 8.64 (s, 1H); M+ 322.