Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([O:25][C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[CH:31]([CH:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1)([CH3:33])[CH3:32]>>[CH:31]([CH:34]1[CH2:39][CH2:38][CH:37]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([O:25][C:26]([F:28])([F:27])[F:29])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:11]2)[CH2:36][CH2:35]1)([CH3:33])[CH3:32]
Reactant: O=C(CNc1noc2ccc(OC(F)(F)F)cc12)NC1CNC1
Reactant: CC(C)C1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1CCC(N2CC(NC(=O)CNc3noc4ccc(OC(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethoxy-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-isopropyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: C[OH:2].[Cl:3][C:4]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:5]=1[C:6](=O)[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[BH4-].[Na+]>>[OH:2][CH:7]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[CH2:6][C:5]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:4]=1[Cl:3]
Reactant: CO
Reactant: O=C(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Product: OC(Cc1ccc(Cl)cc1Cl)n1ccnc1
Reaction time: 0.5 h

Procedure:
A 150 ml solution of methanol containing 15.6 g (0.061 mole) of 1-(2,4-dichlorophenacyl) imidazole cooled to 0°-5° C. was treated with 1.38 g (0.037 mole) of sodium borohydride in portions. The reaction was stirred 1/2 hour and the methanol removed at reflux while adding 100 ml of H2O. The refluxing aqueous mixture was treated with 16 ml of conc. HCl, cooled, and treated with 50 ml of conc. NH4OH. The mixture was extracted with methylene chloride, dried over MgSO4, and concentrated to give 11.3 g of a white solid product (66.8%), m.p. 139°-141° C. (from ethanol).
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[C:13]#[N:14])([O-])=O.[H][H]>ClCCCl.[Pd]>[NH2:1][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[C:13]#[N:14]
Reactant: N#Cc1c([N+](=O)[O-])sc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCCl
Product: N#Cc1c(N)sc2ccccc12
Reaction time: 8 h
Yield: 73 %

Procedure:
Combine in a 500 mL schlenk flask, 2-nitro-benzo[b]thiophene-3-carbonitrile (5.8 g, 28.4 mmol) and Pd/C (3.0 g, 10% w/w, 2.84 mmol) in 1,2-dichloroethane (120 ml), the reaction mixture is charged with a balloon of hydrogen. After overnight stirring, release the hydrogen, remove the catalyst by filtration, and wash the catalyst by 1,2-dichloroethane several times. Concentrate down to a residue, which purified by flash chromatography on silica gel, gradient (100% hexane to 100% of Hexane:CH2Cl2:EtOAc=50:50:2.5), afford brownish solid 3.6 g of title compound (yield 73%). Mass spectrum: ES(+)(m/e): 175 (M+1); 1H NMR (300MHz, DMSO-d6, ppm): δ 7.81 (br, 2H), 7.65–7.62 (m, 1H), 7.28–7.24 (m, 2H), 7.11–7.01 (m, 1 H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=O)[CH:4]=1.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][N:6]=[C:5](/[CH:9]=[N:19]/[S@@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])[CH:4]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cc(C(F)(F)F)ccn1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a solution of 4-trifluoromethyl-pyridine-2-carbaldehyde (287 mg, 1.64 mmol) and (R)-2-methylpropane-2-sulfinamide (209 mg, 1.72 mmol) in CH2Cl2 (10 mL) was added anhydrous copper (II) sulfate (576 mg, 3.61 mmol). The reaction mixture was stirred at room temperature overnight then filtered over a Buchner funnel, rinsing with CH2Cl2. The filtrate was concentrated and the residue was absorbed on SiO2 and purified by chromatography with 20% to 40% EtOAc/hexanes to give 340 mg (75%) of (R)-2-methyl-propane-2-sulfinic acid 1-(4-trifluoromethyl-pyridin-2-yl)-meth-(E)-ylideneamide as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[CH2:11]([O:15][NH2:16])[CH:12]([CH3:14])[CH3:13]>>[CH2:11]([O:15][N:16]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CON
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Product: CC(C)CON=Cc1ccc(F)cc1

Procedure:
Reaction of 4-fluorobenzaldehyde with O-isobutyl-hydroxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil after chromatography on silica gel (elution toluene-ethyl acetate 95:5), (77% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 0.98 (6H, d, J=6.5 Hz, CH3), 2.07 (1H, m, CH), 3.95 (2H, d, J=7.18 Hz, OCH2), 7.08 (2H, m, aromatics), 7.59 (2H, m, aromatics), 8.08 (1H, s, CH). Anal. calcd for C11H14FNO: C, 67.67; H, 7.22; N, 7.17. Found: C, 67.71; H, 7.32; N, 7.38.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].C=O.[C:35](O)(=O)C.[BH3-]C#N.[Na+]>CO.C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:35])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCC(NC(=O)c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2Br)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol), formaldehyde (30% in water) (0.1 mL, 0.16 mmol) and acetic acid (0.01 mL) in MeOH (5.0 mL) was stirred at ambient temperature for 30 min. After that NaBH3CN (0.01 g, 0.16 mmol) was added at 0° C. and the reaction was stirred for 8 h at ambient temperature. The solvent was removed under reduced pressure to obtain residue which was diluted with ethyl acetate and washed with saturated aq. NaHCO3 solution and brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue, which was triturated with diethyl ether/pentane to afford the title compound as a pale yellow gummy material (0.06 g, 59%).
Reaction SMILES: [NH2:1][C:2]1[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:14]([C:21]1[CH:22]=[C:23]([CH2:27][C:28](Cl)=[O:29])[CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1.C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[N:12][C:2]([NH:1][C:28](=[O:29])[CH2:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:22]=2)=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(Cl)cnc1N
Reactant: O=C(Cl)Cc1cccc(Oc2ccccc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(Cl)cnc1NC(=O)Cc1cccc(Oc2ccccc2)c1
Temperature: 130 °C

Procedure:
To a mixture of ethyl 2-amino-5-chloronicotinate (143, Example 18) (344.9 mg, 1.719 mmol) in pyridine (2.0 mL, distilled) in a 10 mL round-bottom flask with stirring was added a solution of 3-phenoxyphenylacetyl chloride (812.5 mg, 3.293 mmol) in dry CH2Cl2 (2.0 mL). The mixture was gradually heated to reflux (130° C., oil bath), over which time the CH2Cl2 was allowed to evaporate. The resulting solution was refluxed for 3.5 h, then cooled to room temperature. The reaction mixture was quenched with water (10 mL) and extracted with chloroform (3×15 mL). The combined organic extracts were washed with water (3×10 mL), dried (MgSO4), and rota-evaporated to dryness, leaving a dark green liquid. This liquid was chromatographed on silica gel (24 g, Mallinckrodt, grade 62, mesh 60-200) and eluted with hexanes-EtOAc (1:4, 250 mL). The desired fractions were collected (Rf =0.83) and rota-evaporated to dryness, leaving a green oil. This oil eventually precipitated out as a wet green mass. Crystallization from ethanol afforded the title compound as a light brown flakes, 114 mg (16.1%), mp 103°-4° C.; 1H NMR (CDCl3): δ1.39 (t, J=7.2, 3, CH3CH2), 3.88 (s, 2, benzylic), 4.35 (q, J=7.2, 2, CH3CH2O), 7.10 (m, 9, phenyl), 8.24 (d, J=2.4, 1, py), 8.52 (d, J=2.4, 1, py), 10.70 (d, J=2.4, 1, NH); IR (KBr): 3434, 3155, 2925, 1722, 1659, 1401, 1252, 1205, 1102, 775, 700; HPLC: 99%; LRMS: 410 (M+, 40), 211 (35), 210 (100), 200 (35), 183 (30), 181 (40), 128 (15), 89 (50), 77 (20), 51 (15); HRMS Calcd: 410. 1033. Found: 410.1026.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16]([O:26][CH3:27])([O:24][CH3:25])[CH2:15][CH2:14]1)(=[O:12])=[O:11].C[Si](C)(C)[O:30][CH2:31][C:32](CO[Si](C)(C)C)(CO[Si](C)(C)C)[CH2:33][O:34][Si](C)(C)C.O>ClCCl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:14][CH2:15][C:16]2([O:24][CH2:25][C:32]([CH2:33][OH:34])([CH2:31][OH:30])[CH2:27][O:26]2)[CH:17]=[C:18]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:11])=[O:12]
Reactant: C[Si](C)(C)OCC(CO[Si](C)(C)C)(CO[Si](C)(C)C)CO[Si](C)(C)C
Reactant: CCOC(=O)C1=CC(OC)(OC)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)OCC(CO)(CO)CO2
Yield: 86.8 %

Procedure:
500 mg (1.19 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-carboxylate obtained in Example (16a) and 1.0 g (2.38 mmol) of 1,3-bis[(trimethylsilyl)oxy]-2,2-bis[(trimethylsilyl)oxy]methylpropane were dissolved in 10 ml dichloromethane and 10 μl (0.06 mmol) of trimethylsilyl trifluoromethanesulfonate was added thereto with stirring under ice-cooling, followed by stirring for 2 hours at the same temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate alone) to give 510 mg of the title compound as an amorphous substance (yield: 87%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH:23]1[CH2:28][CH2:27][CH2:26][CH:25]=[CH:24]1>>[CH:28]1([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)[CH2:27][CH2:26][CH2:25][CH:24]=[CH:23]1
Reactant: BrC1C=CCCC1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C3C=CCCC3)CC1)O2

Procedure:
Compound 135 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-bromocyclohexene and conditions outlined in procedure V. LCMS: 382 [M+H]; Rt=0.94 min.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([CH3:30])=[CH:28][S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[C:29]([CH3:30])=[CH:28][S:27][C:17]=2[N:18]=1
Reactant: Cc1csc2nc(-c3ccccn3)nc(Cl)c12
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1csc2nc(-c3ccccn3)nc(NCCc3ccc4c(c3)OCCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:21])[NH:14][C:13]([CH3:22])=[C:12]2[C:23]([O:25][CH3:26])=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN(C)C=O.[C:32]1([CH2:38][CH2:39][CH2:40]Br)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:12]([C:23]([O:25][CH3:26])=[O:24])=[C:13]([CH3:22])[N:14]([CH2:40][CH2:39][CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:15]([CH3:21])=[C:16]2[C:17]([O:19][CH3:20])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: BrCCCc1ccccc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccc(OC)c(OC)c1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C1=C(C)N(CCCc2ccccc2)C(C)=C(C(=O)OC)C1c1ccc(OC)c(OC)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
60% Sodium hydride (0.26 g) was washed with several milliliters of anhydrous n-hexane in an argon gas atmosphere, and 10 ml dimethylformamide was added. To the resulting mixture, was added dropwise 20 ml of a dimethylformamide solution containing 2 g (5.5 mmol) dimethyl 1,4-dihydro-4-(3,4-dimethoxyphenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate with stirring. The mixture was heated at 90° C. for one hour, 20 ml of a dimethylformamide solution of 3-phenylpropyl bromide was then added, and heating at 90° C. was continued for one hour. After cooling the mixture to room temperature, 20 ml diethyl ether was added, the resulting mixture was washed with water, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by column chromatography (SiO2 /n-hexane-ethyl acetate 2:1), affording 0.8 g (30%) of the pure product. M.P.: 97°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25].Cl>C(OCC)(=O)C>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)CCCN
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)CCCNc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12

Procedure:
7-Chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (1 g) and 3-dimethylaminopropylamine (30 ml) were heated together in a similar manner to that described for Example 10 to give the crude product, which was suspended in a mixture of 1:1 ethyl acetate and 1N HCl and filtered. The aqueous phase was basified to pH14 with sodium hydroxide and then extracted into ethyl acetate. The organic layer was dried (MgSO4) and the solvent was removed to give the title compound (0.090 g); mp 177°-179° C. (diethyl ether). Found: C, 67.27; H, 6.22; N, 11.61. C20H22ClN3O requires C, 67.50; H, 6.23; N, 11.81%; δ (360 MHz, DMSO-d6) 1.38 (2H, m, NCH2CH2CH2N(CH3)2), 1.98 (2H, m, NCH2CH2CH2N(CH3)2), 2.04 (6H, s, N(CH3)2), 2.58 (2H, m, NCH2CH2CH2N(CH3)2), 6.58 (1H, m, NHCH2CH2CH2N), 7.19-7.94 (8H, m, aromatics), 11.15 (1H, br s, NHCO); m/z (CI-) 355 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[CH3:19])[CH2:6][CH:7](C(OC)=O)[C:8]([O:10]C)=[O:9].[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: COC(=O)C(Cc1ccc(C)c(OC)c1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(CCC(=O)O)ccc1C
Yield: 123 %

Procedure:
A solution of 25.84 g (0.1072 mol) of dimethyl 2-(3-methoxy-4-methylbenzyl)malonate in 150 mL of MeOH was treated with a solution of 20 g (0.5 mol) of NaOH in 100 mL of H2O and heated at reflux overnight. The solution was concentrated under reduced pressure and the residue taken up in H2O and washed with Et2O. The solution was acidified to Congo Red end point with dilute HCl and the solution extracted with Et2O. The Et2O was washed with saturated NaCl and dried over MgSO4. Removal of the solvent under reduced pressure gave 25.6 g of an oil. This was taken up in 125 mL of dioxane and heated at reflux overnight. Removal of the solvent under reduced pressure gave 20.5 g of the crude product. Chromatography on silica gel, eluting with CHCl3 /MeOH (98/2) gave 8.65 g (41.6% yield) of the product as a white solid, mp 80-82° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 195 (M+H+).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH:19]1(Br)[CH2:23][CH2:22][CH2:21][CH2:20]1.Cl>CN(C)C=O.O>[CH:19]1([S:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=2[O:11][CH3:12])[C:5]([OH:7])=[O:6])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1ccc(C(=O)O)cc1S
Reactant: BrC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)O)cc1SC1CCCC1
Temperature: 50 °C
Yield: 13.2 %

Procedure:
A solution of 3-mercapto-4-methoxybenzoic acid (that is prepared as described in Reference Example 45 from 58 g of 3-chlorosulfonyl-4-methoxybenzoic acid) in dimethylformamide (400 mL) is treated with potassium carbonate (120 g) and cyclopentyl bromide (60 g). The solution is heated at 50° C. for 3 hours, and then it is cooled and poured into water (3 L) containing concentrated hydrochloric acid (250 mL). The resulting solid is filtered off and dried, to give 3-cyclopentylthio-4-methoxybenzoic acid (10.5 g), in the form of a white crude solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][O:17][CH2:18][C:19](Cl)=O>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:19]([CH2:18][O:17][CH3:16])=[N:15][N:14]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(-c2cccc(F)c2)nn1
Reactant: COCC(=O)Cl
Product: COCc1nnc2ccc(-c3cccc(F)c3)nn12

Procedure:
As for Example 4, 6-(3-fluorophenyl)-3-hydrazinopyridazine (prepared in a manner similar to that described in Example 1) is reacted with methoxyacetyl chloride to give the product of the Example.
Reaction SMILES: [N:1]1[NH:2][C:3](=[S:15])[N:4]2[CH:10]=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][C:5]=12.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[O-].[Na+]>>[CH2:16]([S:15][C:3]1[N:4]2[C:5]([CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10]2)=[N:1][N:2]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: S=c1[nH]nc2n1C=Cc1ccccc1C2
Reactant: BrCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: C1=Cn2c(nnc2SCc2ccccc2)Cc2ccccc21

Procedure:
The reaction of 2,11-dihydro-3H-s-triazolo[3,4-b][3]benzazepine-3-thione with benzyl bromide in the presence of sodium methoxide gave 3-benzylthio-11H-s-triazolo[3,4-b][3]benzazepine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](Cl)=[O:22]>>[O:11]([CH2:10][C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:21](=[O:22])[N:20]([CH3:19])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(COc1ccccc1)Nc1ccc(O)cc1
Product: CN(C(=O)Oc1ccc(NC(=O)COc2ccccc2)cc1)c1ccccc1

Procedure:
The title product was prepared from N-(4-hydroxy-phenyl)-2-phenoxy-acetamide and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (54%, oil). HPLC-MS: m/z=277.2 (M+1); Rt: 4.19 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][OH:29])[CH:24]=[CH:25][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:19][C:5]1[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:7][C:2]([NH:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][OH:29])[CH:24]=[CH:25][CH:26]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CCO)c1
Reactant: COc1cccc(CCNc2nc(Cl)ncc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(CCNc2nc(Nc3cccc(CCO)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 94.4 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(3-methoxyphenyl)ethyl]pyrimidin-4-amine (0.50 g, 1.7 mmol) (prepared according to Example 8, step A) and 2-(3-aminophenyl)ethanol (0.31 g, 2.3 mmol) (prepared according to Example 22, Step B) in 1,4-dioxane (14.3 mL) was added p-toluenesulfonic acid monohydrate (0.12 g, 0.61 mmol). The mixture was heated at 100° C. for 16 h and the reaction was complete. To the mixture was added NaHCO3 (saturated aqueous solution). The organic solvent was removed under vacuum and water/EtOAc was added. After layer separation, the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as a light brown powder (0.64 g, 96%). LCMS for C21H24ClN4O2 (M+H)+: m/z=399.1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1>>[NH2:31][C:32]1[N:33]=[CH:34][C:35]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:36][CH:37]=1
Reactant: CC(C)(C(N)=O)N1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: Nc1ccc(B(O)O)cn1
Product: CC(C)(C(N)=O)N1CCN(Cc2ccc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(4-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide from Example 121 (115 mg) was reacted with 2-aminopyridine-5-boronic acid, pinacol ester via General Procedure A to yield 8.5 mg 124 following reverse phase HPLC purification. MS (Q1) 492.3 (M)+
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: NC(=O)CC[C@H](N)C(=O)O
Reactant: CCN
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.