Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH3:13][O:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[C:30]([Cl:31])=[C:29]([CH3:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:25]3[C:30]([Cl:31])=[C:29]([CH3:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(Cl)c(C)sc3n2)cc1
Reactant: COc1ccc(CN)cc1OC
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(OC)c3)c3c(Cl)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dimethoxy-benzylamine is reacted with 4-(4-chloro-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dimethoxybenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:8]=2[CH:26]=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1.C(OCC)C>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)(=[O:17])=[O:18])[C:8]=2[CH:26]([OH:27])[CH3:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C=O)c(-c3ccccc3)c3ccccc32)cc1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2c(C(C)O)c(-c3ccccc3)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-phenyl-1-(toluene-4-sulfonyl)-1H-indole-2-carbaldehyde (2.11 g, 5.62 mmol) in THF (30 mL) cooled to −78° C. and under a nitrogen atmosphere, was added 3.0M MeMgBr in diethyl ether (2.6 mL). The mixture was stirred at 0° C. for 30 min and then additional 3.0M MeMgBr in diethyl ether (0.3 mL) was added. After 15 min stirring, the reaction mixture was poured into a saturated solution of NH4Cl and extracted with EtOAc (×2). The combined organic layers were washed with water, then dried (Na2SO4) and concentrated in vacuo. The crude material was combined with a second portion of crude reaction mixture obtained following the same method (starting from 140 mg, 3.73 mmol of 3-phenyl-1-(toluene-4-sulfonyl)-1H-indole-2-carbaldehyde) and the combined batches were purified by column chromatography (Si—PCC, gradient 20-100% DCM in pentane) affording the title compound as a gum which then solidified on standing (2.02 g, 86%). 1H NMR (CDCl3, 400 MHz): δ 8.07 (1H, d, J=8.35), 7.80-7.75 (2H, m), 7.51-7.38 (5H, m), 7.33-7.26 (2H, m), 7.20-7.14 (3H, m), 5.25-5.15 (1H, m), 4.06 (1H, d, J=11.01 Hz), 2.31 (3H, s), 1.70 (3H, d, J=6.88 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12](C(=O)C(F)(F)F)[CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][NH:12][CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A mixture of 2-trifluoroacetyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonic acid dimethylamide (prepared according to the method of Example 247, Step A, 337 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol) in a 3:1 mixture of methanol/water (10 mL) was stirred at room temperature for 1 h and concentrated. The remaining aqueous residue was extracted with 10% isopropanol/chloroform (7×) and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give 214 mg (89%) of the title compound of Example 247, Step B as a white solid. 1H NMR (CD3OD, 300 MHz) δ 7.52 (d, 1H), 7.48 (s, 1H), 7.36 (d, 1H), 4.90 (s, 2H), 3.11 (t, 2H), 2.91 (t, 2H), 2.65 (s, 6H); MS (Cl/NH3) 241 (MH+).
Reaction SMILES: [OH-].[Na+].FC(F)(F)C(O)=O.[CH3:10][N:11]1[C:15]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:14][N:13]=[CH:12]1.[ClH:22]>C1COCC1>[ClH:22].[CH3:10][N:11]1[C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][NH:13][CH2:12]1
Reactant: COC(=O)CCc1cncn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CNC=C1CCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
2 ml of an aqueous solution of sodium hydroxide at 30% are added to a solution of 320 mg (1.13 mmol) of methyl 3-(3-methyl-3H-imidazol-4-yl)propionate tri-fluoroacetate in 10 ml of THF. The reaction medium is stirred at ambient temperature for 16 hours and then cooled to 0° C., and concentrated hydrochloric acid is added dropwise until pH 1 is obtained. After filtration, the filtrate is evaporated. 87 mg of 3-(3-methyl-1H-imidazol-4-yl)propionic acid hydrochloride are obtained with a yield of 39%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH3:19][N:20]1[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[N:21]1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:22]3[CH:23]=[CH:24][N:20]([CH3:19])[N:21]=3)=[O:26])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: Cn1ccc(C(=O)O)n1
Product: Cn1ccc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)c2)n1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 1-methyl-1H-pyrazole-3-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=368.1 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[CH:14][N:15]3[CH2:18][CH3:19])=[C:11]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[N:10]=2)[CH2:3]1.N[C@@H]1CCC[C@H](NC2N=C3C(N=CN3CC)=C(NC3C=CC=C([Cl:54])C=3)N=2)C1>>[Cl:54][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[CH2:18][CH3:19])=[C:11]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[N:10]=1.[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH2:8])[CH2:3]1
Reactant: CCn1cnc2c(Nc3cccc(Cl)c3)nc(N[C@H]3CCC[C@H](N)C3)nc21
Reactant: CCn1cnc2c(Nc3cccc(Cl)c3)nc(N[C@H]3CCC[C@@H](N)C3)nc21
Product: CCn1cnc2c(Nc3cccc(Cl)c3)nc(Cl)nc21
Product: NC1CCCC(N)C1

Procedure:
Analogously to Example 1, 2-(trans-3-amino-cyclohexyl-amino)-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine; FAB-MS: (M+H)+=386; HPLC: tret (grad20/2)=9.32 minutes, and 2-(cis-3-amino-cyclohexyl-amino)-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine; FAB-MS: (M+H)+=386; HPLC: tret (grad20/2)=9.19 minutes, are obtained from 308 mg (1.00 mmol) of 2-chloro-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine [described in Stage 1.2] and 3.26 g (28.6 mmol) of 1,3-diamino-cyclohexane (cis/trans mixture) after 13 h at 100° C. and purification by means of column chromatography.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[Cl:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:29]([F:32])([F:31])[F:30])[C:18]([CH2:33][NH2:34])=[CH:17]2.C(N(CC)C(C)C)(C)C.C(O)C>>[Cl:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:29]([F:30])([F:31])[F:32])[C:18]([CH2:33][NH:34][C:2]1[N:10]=[CH:9][N:8]=[C:7]3[C:3]=1[N:4]=[CH:5][NH:6]3)=[CH:17]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1OC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: FC(F)(F)Oc1ccccc1-c1nc2c(Cl)cccc2cc1CNc1ncnc2[nH]cnc12
Temperature: 75 °C
Reaction time: 36 h

Procedure:
A mixture of 6-chloropurine (0.1109 g, 0.7175 mmol), (8-chloro-2-(2-(trifluoro-methoxy)phenyl)quinolin-3-yl)methanamine (0.2531 g, 0.7175 mmol), and N,N-diisopropylethylamine (0.2500 mL, 1.435 mmol) in ethanol (4.221 mL, 0.7175 mmol) was stirred at 75° C. After 36 h, the mixture was removed from the heat and concentrated under reduced pressure. The residue was purified by flash column chromatography on a silica gel column using 50% of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 as eluent to give N-((8-chloro-2-(2-(trifluoromethoxy)phenyl)quinolin-3-yl)methyl)-9H-purin-6-amine as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.94 (1 H, s), 8.38 (1 H, s), 8.03-8.32 (3 H, m), 7.96-8.02 (1 H, m), 7.93 (1 H, dd, J=7.5, 0.9 Hz), 7.51-7.75 (5 H, m), 4.69 (2 H, br. s.); LC-MS (ESI) m/z 471.1 [M+H]+.
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[N:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1.[I:25]I>C1COCC1>[Cl:16][C:17]1[N:18]=[N:19][C:20]([O:23][CH3:24])=[C:21]([I:25])[CH:22]=1
Reactant: COc1ccc(Cl)nn1
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nnc(Cl)cc1I
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flask containing THF (350 mL) at −30° C. under nitrogen was added 26 mL (76.1 mmol. 2.93M n-BuLi in hexanes. 2,2,6,6-tetramethylpiperidine (12.9 mL, 76.1 mmol) was then added dropwise and the resulting solution was allowed to warm to 0° C. over 50 min. The solution was then cooled to −78° C. and there was added dropwise 3-chloro-6-methoxypyridazine (1) (5.0 g, 34.6 mmol) in 50 mL THF and the resulting solution stirred at −78° C. for 30 min. Iodine (9.3 g) was then added in three portions and the solution stirred at −78° C. for 2 hrs. The reaction was quenched by the addition of saturated aqueous sodium thiosulfate solution and allowed to warm to room temperature, then diluted with CH2Cl2 and water, the CH2Cl2 layer separated, the aqueous layer extracted once more with CH7Cl2, and the combined CH2Cl2 layers washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica) eluting with hexane/ethyl acetate to give desired product 2, 5.6 g (60%), ˜95% desired regioisomer.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[S:12]([NH2:22])(=[O:21])([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)=[O:13]>>[S:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])=[CH:16][CH:15]=1)(=[O:13])(=[O:21])[NH2:22]
Reactant: O=C(CCl)Nc1ccccc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(NCC(=O)Nc2ccccc2)cc1

Procedure:
α-Chloracetanilide (17.0 g) and sulfanilamide (34.5 g) were heated together in an autoclave for 8 hours at 120°C. The mixture was triturated with 2N HCl and filtered to yield 27.5 g, m.p. 257°-258°C (acetone).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8](OC)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:25]CCl>C(#N)C.O.N1C=CC=CC=1>[Cl:25][C:10]1[C:2]2[NH:1][C:14](=[O:16])[O:6][C:4](=[O:5])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: ClCCl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(N)c(C(=O)O)c1
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: O=c1[nH]c2c(Cl)cccc2c(=O)o1
Temperature: 50 °C
Yield: 80 %

Procedure:
To a stirred solution of 2-amino-5-methoxy benzoic acid (9 g, 0.054 mmol) in acetonitrile (60 mL, 1 M), was added pyridine (8.7 mL, 0.108 mmol, 2 equiv), and triphosgene (15.9 g, 0.054 mmol, 1 equiv) in dichloromethane (85 mL, 0.7 M). The orange reaction solution was heated at 50° C. for two hours then cooled to room temperature. The solution was diluted with water (50 mL), and the organic and aqueous layers were separated. The aqueous layer was washed with dichloromethane (3×50 mL), and the combined organic layers were washed once with brine (50 mL), and dried over magnesium sulfate. The solvent was removed in vacuo leaving a yellow solid. The solid was titrated with hexanes to yield 8-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (8.3 g, 80%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[C:7]1[NH:8][N:9]=[CH:10][C:6]=1[CH2:5]2.[Li]C1C=CC=CC=1.[Li]C(CC)C.CN([CH:31]=[O:32])C>C1COCC1>[CH3:15][O:14][C:13]1[CH:12]=[C:11]2[C:4]([CH2:5][C:6]3[CH:10]=[N:9][NH:8][C:7]=32)=[CH:3][C:2]=1[CH:31]=[O:32]
Reactant: COc1cc2c(cc1Br)Cc1cn[nH]c1-2
Reactant: CN(C)C=O
Agent: [Li]C(C)CC
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: COc1cc2c(cc1C=O)Cc1cn[nH]c1-2
Temperature: -78 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a suspension of Example 104C (5.49 g, 0.0207 mol) in THF (300 mL) was added PhLi (1.9 M, 21.8 mL, 0.0414 mol) at −78° C. s-BuLi (1.4 M, 29.6 mL, 0.0414 mol) and DMF (12.8 mL, 0.166 mol) were added to the reaction mixture after 30 and 60 minutes, respectively. The mixture was stirred at −78° C. for 1 hour and the cold bath was removed. The reaction was quenched with saturated NH4Cl solution after 1 hour at room temperature. The mixture was extracted with EtOAc, washed with water, brine, dried over MgSO4, filtered, concentrated, and triturated with ether to give 3.62 g (81%) of the desired product. MS (DCI/NH3) m/z: 215.1 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 3.62 (s, 2H) 4.01 (s, 3H) 7.45 (s, 1H), 7.73 (s, 1H) 7.80 (s, 1H) 10.37 (s, 1H) 13.07 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[CH2:15][NH2:16].C(N(C(C)C)CC)(C)C.COC([N:32]1[C:40]2[C:35](=[C:36]([NH:41][C:42](ON3C(=O)CCC3=O)=[O:43])[CH:37]=[CH:38][CH:39]=2)[CH:34]=[N:33]1)=O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:6]=1[CH2:15][NH:16][C:42]([NH:41][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:35]=1[CH:34]=[N:33][NH:32]2)=[O:43]
Reactant: CC(C)(C)CCc1cc(C(F)(F)F)ccc1CN
Reactant: COC(=O)n1ncc2c(NC(=O)ON3C(=O)CCC3=O)cccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)CCc1cc(C(F)(F)F)ccc1CNC(=O)Nc1cccc2[nH]ncc12
Reaction time: 1 h

Procedure:
To the product of Example 1B dissolved in DMF (80 mL) was added diisopropylethylamine (5.6 mL, 32.1 mmol, 1.2 eq), followed by the addition of the product of Example 1C (8.82 g, 26.5 mmol, 1 eq). The mixture was stirred for 1 hour, diluted with ethyl acetate (600 mL) and the resulting solution washed sequentially with H2O (1×250 mL) and saturated aqueous NH4Cl (1×250 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was taked up in 2:1 methanol:THF (90 mL) and 1 N NaOH (30 mL) was added. The solution was stirred 45 minutes, concentrated under reduced pressure to remove the organic solvents. The residue was diluted with ethyl acetate (600 mL), washed sequentially with H2O (2×200 mL), brine (1×200 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude solid was filtered through SiO2 (80 mL) with 4% ethanol in ethyl acetate, stirred over charcoal, filtered and concentrated under reduced pressure, triturated with 4:1 hexane and ethyl ether (150 mL). The solid was recrystallized from methanol and water, filtered and dried under reduced pressure to provide the title compound. 1H-NMR (DMSO-d6) δ 12.99 (brs, 1H), 8.79 (brs, 1H), 8.08 (s, 1H), 7.61 (d, 1H), 7.50-7.59 (m, 3H), 7.20 (t, 1H), 7.02 (d, 1H), 6.81 (t, 1H), 4.45 (d, 2H), 2.70 (ddd, 2H), 1.45 (ddd, 2H), 0.97 (s, 9H).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[C:9](Cl)=[N:10][C:11]([S:15][CH3:16])=[N:12][C:13]=2[Cl:14])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[NH2:27][NH2:28]>C1COCC1>[Cl:14][C:13]1[N:12]=[C:11]([S:15][CH3:16])[N:10]=[C:9]2[NH:27][N:28]=[C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]=12
Reactant: CSc1nc(Cl)c(C(=O)C2CCCC2)c(Cl)n1
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CSc1nc(Cl)c2c(C3CCCC3)n[nH]c2n1
Temperature: 0 °C
Yield: 119.2 %

Procedure:
Cyclopentyl-(4,6-dichloro-2-methylsulfanyl-pyrimidin-5-yl)-methanone (2.0 g, 6.868 mmol) was dissolved in 25 mL dry THF and stirred at 0° C. under nitrogen. N,N-diisopropylethylamine (2.392 mL, 13.763 mmol) was added dropwise, and the reaction mixture was stirred for five minutes. Hydrazine (0.205 mL, 6.525 mmol) was added dropwise, and the reaction was stirred for 16 hours, during which time the reaction mixture was allowed to warm to room temperature. The reaction mixture was partitioned between water and ethyl acetate, and the organic phase was separated, washed with water, washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to give 2.09 g of 4-Chloro-3-cyclopentyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine. Mass Spec. M+H=270.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[CH:16]=[N:15][C:14]([C:18]([O:20]CC)=[O:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].O.[OH-].[Na+].O(C1C=C2C(C3C=CN=C(C)C=3N2CC)=CC=1)C>C(O)C>[CH2:1]([N:5]1[C:17]2[CH:16]=[N:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c2ccccc2c2cc(C(=O)OCC)ncc21
Agent: CCn1c2cc(OC)ccc2c2ccnc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCn1c2ccccc2c2cc(C(=O)O)ncc21
Yield: 100.6 %

Procedure:
Compound 32 (3.0 g, 10 mmol), 100 ml of water, 50 ml of ethanol, and NaOH (2.0 g, 50 mmol) were added into a 100 ml round-bottom flask. The mixture was refluxed for 2 h. The subsequent operational steps were conducted according to those for synthesizing compound 3 to obtain light yellow solids (2.7 g, 99%), and mp 182-184° C.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>C(OC(C)(C)C)(=O)C.O>[CH3:3][C:4]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1])([CH3:9])[CH3:5]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)(C)C
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Yield: 64 %

Procedure:
A solution of L-phenylalanine (62.6 g; 379 mol) in tert-butyl acetate (320 mL) cooled on an ice bath and stirred vigorously is slowly added with 70% aqueous HClO4 (35 mL, 407 mol). After stirring for 11 days at room temperature, the mixture is diluted with 100 mL of water and cooled on an ice bath. The mixture is basified with 5 N NaOH to precipitate a white solid (unreacted phenylalanine) which is filtered off. The mixture is then extracted with EtOAc (4×200 mL), the organic phases are combined and washed with water (2×200 mL) and 5% Na2CO3 (300 mL). After drying over Na2SO4 and carefully removing the solvent under vacuum, the desired compound is obtained as a colourless oil (53.53 g; 242 mol), which needs no further purifications and is stored at −18° C.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:13]([NH:15][C@@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[H][H].[C:39](O)(=O)C>[Pd]>[NH2:1][C@@H:2]([C:13]([NH:15][C@@H:16]([C:24]([O:26][CH3:39])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(=O)O
Reactant: O=C(N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12

Procedure:
A mixture of Z-D-Trp-D-Phe-Ome (2.00 g, 4.0 mmoles, described in Example 6) and 5% Pd/C (0.25 g) in acetic acid is stirred rapidly under an atmosphere of hydrogen. After completion of hydrogen uptake a stream of nitrogen is passed through the mixture for 15 min, the catalyst is removed by filtration, and the acetic acid is removed under reduced pressure. The residue is taken into benzene, evaporated under reduced pressure (twice), and dried under reduced pressure over KOH pellets to give H-D-Trp-D-Phe-OMe.CH3CO2H. The above product is dissolved in dry DMF (20 ml) and cooled to 0° C. N-ethylmorpholine (0.512 ml, 4 mmoles) is added, followed by ##STR97## (2.00 g, 4 mmoles). The solution is stirred at 0° C for 30 min and for 3 days at room temperature. The solvent is evaporated under reduced pressure, the residue is taken into EtOAc and washed with cold saturated NaHCO3 solution, water, cold citric acid (2N), water, saturated NaHCO3 solution and saturated NaCl solution. The EtOAc solution is dried with MgSO4 and evaporated under reduced pressure to afford the crude title product. After chromatography on a column of silica gel (300 g) with CHCl3 containing MeOH (5%) and pyridine (0.1%) as eluent, the chromatographically pure product is triturated with ether, filtered, dried under reduced pressure, and crystallized from MeOH-CH2Cl2 -isopropyl ether to give the title compound; mp 172° - 174° C, [α]D25 = +18.9° (c = 1, DMF).
Reaction SMILES: Cl[C:2]1[C:3](=[O:12])[N:4]([CH2:9][O:10][CH3:11])[N:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][O-:14].[Na+]>O1CCOCC1>[Cl:8][C:7]1[CH:6]=[N:5][N:4]([CH2:9][O:10][CH3:11])[C:3](=[O:12])[C:2]=1[O:14][CH3:13]
Reactant: COCn1ncc(Cl)c(Cl)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COCn1ncc(Cl)c(OC)c1=O
Reaction time: 19 h
Yield: 93.6 %

Procedure:
To a stirred solution of 4,5-dichloro-2-methoxymethyl-2H-pyridazin-3one (1.00 g, 4.78 mmol) in 1,4-dioxane (25 mL) at room temperature was added sodium methoxide (271 mg, 5.02 mmol). After 19 h, the reaction was added additional 271 mg of sodium methoxide and was continued to stir for 6 h. The reaction was filtered and the filtrate was concentrated to give 915 mg (93% crude) 5-chloro-4-methoxy-2-methoxymethyl-2H-pyridazin-3-one.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]2[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[C:17]([OH:18])[C:10]=2[S:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([N:8]1[C:12](=[O:13])[C:11]2[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[C:17]([O:18][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH3:22])[C:10]=2[S:9]1=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(O)c2c1C(=O)N(Cc1ccccc1)S2=O
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COCCOCCOc1ccc(OC)c2c1S(=O)N(Cc1ccccc1)C2=O
Yield: 63.6 %

Procedure:
Reaction of 3.03 g (0.01 mol) of 2-benzyl-7-hydroxy-4-methoxybenzisothiazol-3-one-1-oxide (Example 26A) with 2.01 g (0.011 mol) of 2-(2-methoxyethoxy) ethyl bromide in methyl ethyl ketone in the presence of 2 g (0.015 mol) of potassium carbonate afforded 2.58 g (64%) of 2-benzyl-4-methoxy-7-[2-(2-methoxyethoxy) ethoxy]benzisothiazol-3-one-1-oxide, which, on oxidation with 1.1 g (0.0063 mol) of 3-chloroperbenzoic acid in MDC, gave 2-benzyl-4-methoxy-7-[2-(2-methoxyethoxy)-ethoxy]saccharin. Debenzylation of 0.25 g (0.0006 mol) of the product with 0.13 g (0.0021 mol) of ammonium formate in methanol in the presence of 0.25 g of 10% palladium-on-charcoal gave 0.21 g (100%) of the ammonium salt of 4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin. Reaction of 1.4 g (0.004 mol) of the ammonium salt with 0.63 g (0.004 mol) of chloromethyl phenyl sulfide in DMF afforded 2-phenylthio-methyl-4 -methoxy-7-[2-(2-methoxyethoxy) ethoxy]saccharin, which, on reaction with sulfuryl chloride in MDC, afforded 0.53 g (35%) of 2-chloromethyl-4-methoxy-7-[2-(2-methoxyethoxy) ethoxy]saccharin.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[C:11]([C:15]1[C:16](=[O:26])[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][C:19](=O)[CH:20]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:22]([C:17]1[C:16](=[O:26])[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:20][C:19](=[N:1][C:2]2[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=2)[CH:18]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: N#CCc1ccc(N)cc1
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Product: CC(C)(C)C1=CC(=Nc2ccc(CC#N)cc2)C=C(C(C)(C)C)C1=O

Procedure:
Using the method of Example 1, 4-aminobenzylcyanide was reacted with 2,6-di-tertiary-butyl-p-benzoquinone to give 2,6-di-tertiary-butyl-4-(4'-cyanomethylphenylimino)-2,5-cyclohexadiene-1-one, m.p. 126.5°-127.5° C. Following the reduction method of Example 1, Step B, the corresponding anilino phenylacetonitrile, m.p. 146°-147° C., was obtained. This was converted to 5-[4-(3,5-di-t-butyl-4-hydroxyanilino)benzyl]tetrazole, m.p. 212°-214° C. (dec), following the method of Example 30, but carried out at 110° C. for 48 hours.