Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[C:4]([C:17]#[N:18])[CH:3]=1.N.[H][H]>CO.[Ni]>[NH2:18][CH2:17][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10]
Reactant: N#Cc1cc(Br)ccc1NC(=O)c1ccccn1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cc(Br)ccc1NC(=O)c1ccccn1
Yield: 95.7 %

Procedure:
2-2 (3 g, 0.0099 moles) was immediately taken up in a solution of 2.0M ammonia in methanol. To this solution was added catalytic Raney nickel. The reaction was stirred with a hydrogen balloon attached until complete by TLC. Upon completion, the reaction was filtered and the solvent was removed yielding 2.9 grams of 2-3. Analytical LCMS: (CH3CN/H2O/1% TFA, 4 min gradient), 95% pure, M+1 peak m/e 306.
Reaction SMILES: CO.[CH3:3][C:4]1[C@@H:9]2[CH2:10][C@H:11]([O:36][C:37](/[CH:39]=[CH:40]/[C:41]3[N:45]=[CH:44][N:43]([CH3:46])[CH:42]=3)=[O:38])[C@@:12]3([CH3:35])[O:16][C@@:15]([O:33]C)([C:17]([CH2:19][O:20][C@@H:21]4[O:26][CH2:25][C@@H:24]([OH:27])[C@@H:23]([OH:28])[C@@H:22]4[O:29][C:30]([CH3:32])=[O:31])=[CH:18][C@@H:8]2[C@@H:7]([CH:47]([CH3:49])[CH3:48])[CH2:6][CH:5]=1)[CH:14]=[CH:13]3>>[CH3:3][C:4]1[C@@H:9]2[CH2:10][C@H:11]([O:36][C:37](/[CH:39]=[CH:40]/[C:41]3[N:45]=[CH:44][N:43]([CH3:46])[CH:42]=3)=[O:38])[C@@:12]3([CH3:35])[O:16][C@@:15]([OH:33])([C:17]([CH2:19][O:20][C@@H:21]4[O:26][CH2:25][C@@H:24]([OH:27])[C@@H:23]([OH:28])[C@@H:22]4[O:29][C:30]([CH3:32])=[O:31])=[CH:18][C@@H:8]2[C@@H:7]([CH:47]([CH3:49])[CH3:48])[CH2:6][CH:5]=1)[CH:14]=[CH:13]3
Reactant: CO[C@]12C=C[C@](C)(O1)[C@@H](OC(=O)/C=C/c1cn(C)cn1)C[C@H]1C(C)=CC[C@H](C(C)C)[C@H]1C=C2CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O
Agent: CC(=O)O[C@@H]1[C@H](OC/C2=C/[C@@H]3[C@@H](C(C)C)CC=C(C)[C@@H]3C[C@H](OC(=O)/C=C/c3cn(C)cn3)[C@]3(C)C=C[C@@]2(O)O3)OC[C@@H](O)[C@H]1O
Agent: CO[C@]12C=C[C@](C)(O1)[C@@H](OC(=O)/C=C/c1cn(C)cn1)C[C@H]1C(C)=CC[C@H](C(C)C)[C@H]1/C=C\2CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O
Solvent: CO
Product: CC(=O)O[C@@H]1[C@H](OCC2=C[C@@H]3[C@@H](C(C)C)CC=C(C)[C@@H]3C[C@H](OC(=O)/C=C/c3cn(C)cn3)[C@]3(C)C=C[C@@]2(O)O3)OC[C@@H](O)[C@H]1O

Procedure:
Eleutherobin is an Artifact Derived From Desmethyleleutherobin. Erythropodium caribaeorum was exhaustively extracted with ethanol at room temperature and the ethanol extract was fractionated as described above (and in FIG. 3) for the methanol extract. This procedure yielded only desmethyleleutherobin and the ethylketal analog of eleutherobin which has a C-4 ethoxyl group. Eleutherobin was not detected. This demonstrates that the methyl ketal of C-4 in eleutherobin is an artifact formed by reaction of desmethyleleutherobin with a methanol extraction solvent in the first instance. We have found that desmethyleleutherobin can be converted quantitatively to eleutherobin by treatment with a catalytic amount of pyridinium p-toluenesulfonate in methanol at room temperature. Simply leaving desmethyleleutherobin sitting in methanol without pyridinium p-toluenesulfonate results in no detectable conversion to eleutherobin. However, the initial crude methanol extract of E. caribaeorum has a pH of approximately 4, which is acidic enough to catalyze the conversion of desmethyleleutherobin to eleutherobin during the extraction procedure with methanol or to the ethylketal analog during an extraction procedure with ethanol. Therefore, a preferred extraction procedure for obtaining exclusively desmethyleleutherobin involves freeze-drying freshly collected samples (to reduce water content) and then extracting pulverized dried material multiple times with ethyl acetate. Concentration of combined ethyl acetate extracts in vacuo provides a crude extract that could be purified as described above to give pure desmethyleleutherobin without the formation of eleutherobin.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=3[O:21][CH3:22])[C:6]=2[CH:23]=1.N1C(C)=CC=CC=1C.Cl[C:33]([O:35][CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:34]>ClCCl>[CH:36]1([O:35][C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[CH:8][N:7]([CH2:10][C:11]4[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=4[O:21][CH3:22])[C:6]=3[CH:23]=2)=[O:34])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: COC(=O)c1ccc(Cn2cnc3ccc(N)cc32)c(OC)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2cnc3ccc(NC(=O)OC4CCCC4)cc32)c(OC)c1
Reaction time: 24 h
Yield: 66.5 %

Procedure:
A solution of methyl 4-(6-aminobenzimidazol-1-ylmethyl)-3-methoxybenzoate (J) (0.63 g.) and 2,6-lutidine (0.36 ml.) in dichloromethane (10 ml.) was treated with cyclopentyl chloroformate (0.33 g.). After stirring for 24 hours the solution was diluted with dichloromethane. The mixture was washed successively with 20% w/v sodium hydroxide, water, and brine, then dried (MgSO4) and evaporated. The resultant residue was purified by flash chromatography on a 6×20 cm. silica gel column using 1:3 v/v hexane:ethyl acetate as the eluent to give the title compound (0.57 g., 93%); NMR: 1.7[m,8H, (CH2)4 ], 3.8(s,3H, OCH3), 3.9(s,3H, OCH3) 5.2(m, 1H, CHO), 6.17-7.0(br m,3H), 7.5-7.8(br m,4H).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.Cl.[NH2:63][C@@H:64]([CH2:78][C:79]1[CH:84]=[C:83]([F:85])[CH:82]=[C:81]([F:86])[CH:80]=1)[C@H:65]([OH:77])[CH2:66][NH:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][CH3:76])[CH:70]=1>C(Cl)Cl>[CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]([NH:63][C@@H:64]([CH2:78][C:79]3[CH:80]=[C:81]([F:86])[CH:82]=[C:83]([F:85])[CH:84]=3)[C@H:65]([OH:77])[CH2:66][NH:67][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][CH3:76])[CH:70]=3)=[O:17])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCOc2ccc(C(=O)O)cc21
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN1CCOc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Reaction time: 8 h
Yield: 17.9 %

Procedure:
A solution of 4-Butyl-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (43 mg), HATU (104 mg), HOBt (37 mg), and diisopropylethylamine (47 μL) was stirred in methylene chloride (1.0 mL) for 15 min. A solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride (62 mg) and diisopropylethylamine (47 μL) in methylene chloride (1.0 mL) was added and the reaction mixture was stirred overnight. The mixture was diluted with methylene chloride, washed with 1 N hydrochloric acid (15 mL), saturated sodium bicarbonate (15 mL), and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) provided 15 mg of the title compound: APCI MS m/z 552 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]([CH3:20])[CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH3:19])[CH:2]=[CH2:3].I[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>>[CH2:1]([N:4]([CH3:20])[CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)[CH:14]=[C:13]2[CH3:19])[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCC#Cc1ccc2[nH]cc(C)c2c1
Reactant: FC(F)(F)c1ccc(I)cc1
Product: C=CCN(C)CCCC#Cc1ccc2c(c1)c(C)cn2-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 17.1, Allyl-methyl-[5-(3-methyl-1H-indol-5-yl)-pent-4-ynyl]-amine and 1-Iodo-4-trifluoromethyl-benzene were converted to yield Allyl-methyl-{5-[3-methyl-1-(4-trifluoromethyl-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-amine as yellow oil, MS: 411 (MH+).
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:33])=[C:18]([C:24]([O:30][CH2:31][CH3:32])=[C:25]([CH:27](O)[CH3:28])[CH:26]=1)[C:19]([NH:21][CH2:22][CH3:23])=[O:20]>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH3:33])=[C:18]([C:24]([O:30][CH2:31][CH3:32])=[C:25]([CH:27]([Cl:3])[CH3:28])[CH:26]=1)[C:19]([NH:21][CH2:22][CH3:23])=[O:20]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCNC(=O)c1c(C)c(Cl)cc(C(C)O)c1OCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCNC(=O)c1c(C)c(Cl)cc(C(C)Cl)c1OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
A mixture of cyanuric chloride (0.15 g, 0.84 mmol) and N,N-dimethylformamide (0.065 mL, 0.84 mmol) was stirred at room temperature for 10 min and then a solution of 3-chloro-6-ethoxy-N-ethyl-5-(1-hydroxyethyl)-2-methylbenzamide (0.16 g, 0.56 mmol) in methylene chloride (3.1 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with water, concentrated and purified on silica gel (eluting with 0 to 40% EtOAc in hexanes) to give the desired product (0.13 g, 76%). LCMS calculated for C14H20Cl2NO2 (M+H)+: m/z=304.1; Found: 304.1.
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:24]3[C:23]([NH2:25])=[N:22][CH:21]=[N:20][C:19]=3[NH:18][CH:17]=2)=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(O[CH:31]1[CH2:37][CH:36]2[N:38]([CH3:39])[CH:33]([CH2:34][CH2:35]2)[CH2:32]1)(C)(=O)=O>CN(C)C=O>[NH2:25][C:23]1[C:24]2[C:16]([C:13]3[CH:12]=[CH:11][C:10]([O:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:15][CH:14]=3)=[CH:17][N:18]([CH:31]3[CH2:32][CH:33]4[N:38]([CH3:39])[CH:36]([CH2:35][CH2:34]4)[CH2:37]3)[C:19]=2[N:20]=[CH:21][N:22]=1
Reactant: CN1C2CCC1CC(OS(C)(=O)=O)C2
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C2CCC1CC(n1cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc31)C2
Temperature: 75 °C
Reaction time: 168 h

Procedure:
Sodium hydride (168 mg, of a 60% dispersion in mineral oil) was added to a mixture of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (770 mg, in dimethylformamide (30 ml). 3-Mesyloxy-8-methyl-8-azabicyclo[3.2.1 ]octane (900 mg, prepared as described in J.A.C.S. 1958, 80, 4679) in dimethylformamide (10 ml) was added under nitrogen with stirring. The mixture was warmed at 75° C. for 5 hours (and left standing at ambient temperature for 7 days). The solvent was removed under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate to give a residue which was purified by flash column chromatography on silica using ethyl acetate/methanol (50:50) as the mobile phase to remove starting material and then a mixture of ethyl acetate/methanol/triethylamine (5:5:1) as the mobile phase to elute the product. Appropriate fractions were combined and evaporated to give a solid which was triturated with ether and filtered to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-8-methyl-8-azabicyclo[3.2.1]octane, m.p. 238-250° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:12]=[O:13])[C:5]([CH:18]([CH3:20])[CH3:19])=[C:4]([Cl:21])[N:3]=1.[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CC(=O)OCC>[Cl:1][C:2]1[N:3]=[C:4]([Cl:21])[C:5]([CH:18]([CH3:19])[CH3:20])=[C:6]([O:8][C:9]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:11]([CH:12]3[O:24][CH2:23][CH2:22][O:13]3)[CH:10]=2)[N:7]=1
Reactant: OCCO
Reactant: Cc1cc(C=O)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(Oc2nc(Cl)nc(Cl)c2C(C)C)cc(C2OCCO2)c1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A mixture of (6) (1.71 g, 5.25 mmol), ethylene glycol (0.88 ml, 15.75 mmol), and p-toluenesulfonic acid (263 mg, 0.26 mmol) in toluene (20 ml) was refluxed for 3 hr., using a reflux condenser equipped with a Dean-Stark trap. After cooling to room temperature, the mixture was diluted with EA, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:15)) to afford 1.79 g (92%) of a colorless syrup; 1H NMR (200 MHz, CDCl3) δ 1.40 (6H, d, J=7.0 Hz), 2.40 (3H, s), 3.58 (1H, m), 3.99-4.16 (4H, m), 5.82 (1H, s), 6.92 (1H, s), 7.03 (1H, s), 7.21 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[C:12]3[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:27](I)([CH3:29])[CH3:28].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH:27]([CH3:29])[CH3:28])=[CH:6][C:5]([N:9]2[C:10](=[O:19])[C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][C:12]=3[C:13]2=[O:14])=[C:4]([F:20])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 35.6 %

Procedure:
To a solution of N-(4-chloro-2-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (2.95 g) in dimethylformamide (20 ml), there was added anhydrous potassium carbonate (0.8 g) while stirring at room temperature. After stirring for 10 minutes at about 40° C., isopropyl iodide (1.7 g) was added thereto, and the resultant mixture was stirred for 3 hours at 70°-80° C. After being allowed to cool to room temperature, the mixture was poured into water and extracted with toluene. The toluene layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography to obtain 1.2 g of N-(4-chloro-2-fluoro-5-isopropoxyphenyl)3,4,5,6-tetrahydrophthalimide (Compound No. 1). M.P., 81°-82° C.
Reaction SMILES: [CH:1]1([S:5](Cl)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[F:9][C:10]1[C:15]([F:16])=[C:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])[C:13]([NH2:26])=[C:12]([O:27][CH3:28])[CH:11]=1>>[F:16][C:15]1[C:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])=[C:13]([NH:26][S:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[C:12]([O:27][CH3:28])=[CH:11][C:10]=1[F:9]
Reactant: O=S(=O)(Cl)C1CCC1
Reactant: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Product: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1NS(=O)(=O)C1CCC1
Yield: 75 %

Procedure:
According to the general procedure B, the cyclobutylsulfonyl chloride prepared in the step above was reacted with 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxy-benzene-1,2-diamine to obtain the title product. Yield: 75%. 1H-NMR (300 MHz, CDCl3): δ=7.44 (s, 1H, br), 7.41-7.36 (dd, 1H), 7.24-7.23 (m, 1H), 6.54-6.38 (m, 2H), 5.90 (s, 1H, br), 3.85-3.75 (m, 5H), 2.60-2.40 (m, 2H), 2.25-2.15 (m, 1H), 2.15-1.95 (m, 2H); m/z=511 [M−1]−.
Reaction SMILES: IC.[CH2:3]([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH2:21][C:22]([C:24]3[C:25]([C:31]([O:33][CH3:34])=[O:32])=[C:26]([CH3:30])[NH:27][C:28]=3[CH3:29])=[O:23])[CH:17]=[CH:18][C:19]=2[F:20])=[O:13])[CH2:8][CH2:7]1)[CH3:4].[C:35](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:3]([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH2:21][C:22]([C:24]3[C:25]([C:31]([O:33][CH3:34])=[O:32])=[C:26]([CH3:30])[N:27]([CH3:35])[C:28]=3[CH3:29])=[O:23])[CH:17]=[CH:18][C:19]=2[F:20])=[O:13])[CH2:8][CH2:7]1)[CH3:4]
Reactant: CCOC1CCN(C(=O)c2cc(CC(=O)c3c(C)[nH]c(C)c3C(=O)OC)ccc2F)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCOC1CCN(C(=O)c2cc(CC(=O)c3c(C(=O)OC)c(C)n(C)c3C)ccc2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
Iodomethane (0.056 mL, 0.90 mmol) was added to methyl 4-(2-(3-(4-ethoxypiperidine-1-carbonyl)-4-fluorophenyl)acetyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (53) (0.200 g, 0.45 mmol) and potassium carbonate (0.249 g, 1.80 mmol) in DMF (10 mL). The resulting suspension was stirred at room temperature for 2 hours. The reaction mixture was poured into water (75 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (50 mL) and saturated brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a yellow gum (0.158 g, 77% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.14 (3H, t), 1.43-1.65 (2H, m), 1.72 (1H, m), 1.85 (1H, m), 2.05 (3H, s), 2.38 (3H, s), 3.06 (1H, m), 3.32 (3H, s), 3.45 (5H, m), 3.74 (3H, s), 3.91 (2H, s), 3.99 (1H, m), 6.93 (1H, t), 7.08 (1H, m), 7.17 (1H, m); m/z (LC-MS, ESI+), RT=2.15 min (M+H=459.36).
Reaction SMILES: C1(=O)[N:5]([CH:6]2[C:12](=[O:13])[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]([CH3:18])[CH2:7]2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[N:8]([CH3:18])[CH2:7]1
Reactant: CN1CC(N2C(=O)c3ccccc3C2=O)C(=O)Nc2ccccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: CN1CC(N)C(=O)Nc2ccccc21
Temperature: 25 °C

Procedure:
A suspension of 1.93 g of 3-phthalimido-5-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one in 60 ml of absolute ethanol is treated with 0.31 ml of hydrazine hydrate and the reaction mixture is heated to reflux for 1.5 hr. After cooling at room temperature, the solid is removed by filtration and the filtrate is concentrated in vacuo. The residue is dissolved in chloroform and filtered and concentrated again to afford 3-amino-5-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[C:42]1([S:52](Cl)(=[O:54])=[O:53])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1>C(#N)C>[C:42]1([S:52]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:54])=[O:53])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc4ccccc34)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 61.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0358 g, 0.0776 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0650 mL, 0.465 mmol) and 1-naphthalenesulfonyl chloride (0.0530 g, 0.233 mmol) to obtain 4-(1-naphthalenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0309 g, yield 61%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH3:13]>>[NH2:13][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: N
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: Nc1ncc(C(F)(F)F)cc1Cl
Reaction time: 5 h

Procedure:
6.5 g of 2,3-dichloro-5-trifluoromethylpyridine and 20 ml of 28% aqueous ammonia were placed in a 50 ml autoclave, and the mixture was reacted for 24 hours at 100° C., and further for 5 hours at 125° C. (inner pressure: about 2 atms.). After completion of the reaction, the reaction product was allowed to cool to obtain crystals. The thus obtained crystals were then washed with water and dried to obtain 1.5 g of 2-amino-3-chloro-5-trifluoromethylpyridine having a melting point of 90° to 92° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.CC(C)([O-])C.[Na+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.Cl[C:57]1[N:58]=[N:59][C:60]([C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=2)=[CH:61][C:62]=1[CH2:63][CH3:64]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:63]([C:62]1[CH:61]=[C:60]([C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=2)[N:59]=[N:58][C:57]=1[NH:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][N:5]=3)[N:10]=[CH:9][CH:8]=2)=[CH:15][CH:16]=1)[CH3:64]
Reactant: COc1cnc2c(Sc3ccc(N)cc3)ccnc2c1
Reactant: CCc1cc(-c2ccc(C)cc2)nnc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: CCc1cc(-c2ccc(C)cc2)nnc1Nc1ccc(Sc2ccnc3cc(OC)cnc23)cc1
Temperature: 100 °C

Procedure:
A pyrex reaction tube was charged with tris(dibenzylideneacetone)dipalladium (20 mg, 0.021 mmol), 4-(7-methoxy-1,5-naphthyridin-4-ylthio)benzenamine (122 mg, 0.430 mmol), sodium tert-butoxide (99 mg, 1.031 mmol), S-Phos (35 mg, 0.086 mmol), and 3-chloro-4-ethyl-6-p-tolylpyridazine (100 mg, 0.430 mmol). The reaction tube was purged with nitrogen. 1.3 mL of toluene was added, and the tube was sealed. The reaction mixture was heated at 100° C. for 3 h. Upon cooling, the mixture was diluted with 5% iPrOH/EtOAc and washed with water. The organic portion was dried with MgSO4, filtered and concentrated. The crude material was purified by silica gel chromatography (90/10/1 CH2Cl2/MeOH/NH4OH) and reverse phase chromatography (Gilson, 10-95% CH3CN over 15 min) to provide 4-ethyl-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-6-p-tolylpyridazin-3-amine as a light yellow solid. MS m/z=480 [M+H]+. Calc'd for C28H25N5OS: 479.60.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].Br[CH2:15][C:16]([CH3:25])=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>C(OCC)(=O)C.CCCCCC>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH:17]=[C:16]([CH3:25])[CH2:15][O:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[CH:19][CH:20]=1
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: CC(=Cc1ccc(F)cc1)CBr
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=Cc1ccc(F)cc1)COc1cc(C)c(NC=O)c(C)c1C
Yield: 52 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and 1-(3-bromo-2-methyl-1-propenyl)-4-fluorobenzene, the title compound was synthesized according to Reference Example 17a. Yield: 52%. Melting point: 164-165° C. (Ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[Cl:22])[NH2:18])([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[C:17]([NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:19]=[CH:20][C:21]=1[Cl:22])([O-:14])=[O:13]
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-nitro-4-chloroaniline to yield 2-[(3-nitro-4-chlorophenyl)amino]phenylacetic acid.
Reaction SMILES: [C:1]1([S:7]([CH:9](Br)[CH3:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[CH3:13][SH:14]>C(#N)C>[C:1]1([S:7]([CH:9]([S:14][CH3:13])[CH3:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(Br)S(=O)c1ccccc1
Reactant: CS
Agent: [Na]
Solvent: CC#N
Product: CSC(C)S(=O)c1ccccc1
Yield: 75.4 %

Procedure:
832 mg of (1-bromoethyl) phenyl sulfoxide was dissolved in 1 ml. of acetonitrile, and with addition of 3.3 ml. of a 20% aqueous solution of sodium salt of methyl mercaptan, the mixture was heated at 40° C. for 10 hours. The product was extracted with 50 ml. of chloroform, and dried with anhydrous sodium sulfate. The solvent was removed at reduced pressure, and the product was separated by column-chromatography (silica gel, chloroform). There was obtained 170 mg of 1-methylthioethyl phenyl sulfoxide in a yield of 75.4%.