Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:50]=[CH:49][C:8]2[N:9]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C@@H:18]3[C@H:22]4[O:23][C:24]([CH3:27])([CH3:26])[O:25][C@H:21]4[C@H:20]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH:37][CH:38]6[CH2:40][CH2:39]6)[C:31]=5[CH:30]=[CH:29]4)[CH2:19]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>C(Cl)Cl>[CH:38]1([NH:37][C:36]2[C:31]3[CH:30]=[CH:29][N:28]([C@H:20]4[C@@H:21]5[O:25][C:24]([CH3:27])([CH3:26])[O:23][C@@H:22]5[C@@H:18]([CH2:17][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][C:10]5[N:9]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:8]6[CH:49]=[CH:50][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][C:7]=6[N:11]=5)[S:59]([CH3:58])(=[O:61])=[O:60])[CH2:19]4)[C:32]=3[N:33]=[CH:34][N:35]=2)[CH2:40][CH2:39]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)O[C@@H]2[C@@H](CNCCCCc3nc4cc(C(C)(C)C)ccc4n3COCC[Si](C)(C)C)C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)O[C@@H]2[C@@H](CN(CCCCc3nc4cc(C(C)(C)C)ccc4n3COCC[Si](C)(C)C)S(C)(=O)=O)C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Reaction time: 3 h
Yield: 48.5 %

Procedure:
7-[(3aS,4R,6R,6aR)-6-({[4-(5-tert-Butyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)butyl]amino}methyl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.052 g, 0.074 mmol) was dissolved in dry DCM (1 ml) and dry Et3N (0.02 ml, 0.148 mmol) and methanesulfonyl chloride (0.01 ml, 0.089 mmol) was added dropwise at r.t. under N2. The reaction was left for 3 hrs after which time LCMS analysis showed the reaction had gone to −80% completion. The reaction was concentrated in vacuo and purified by UV directed prep HPLC to give the product as a white solid (0.028 g, 48%): MS (ESI+) for C40H61N7O5SSi m/z 391.3 [M+2H]2+, 780.1 [M+H]+; LC purity 83% (UV), 100% ELS (ret. time, 1.80 min); 1H NMR (500 MHz, CDCl3) δ 8.29 (s, 1H), 7.59-7.79 (m, 1H), 7.29-7.45 (m, 2H), 6.97 (d, J=3.63 Hz, 1H), 6.64 (br. s., 1H), 5.50 (s, 2H), 4.88-5.06 (m, 2H), 4.58 (br. s., 1H), 3.51-3.60 (m, 2H), 3.39-3.51 (m, 1H), 3.32 (br. s., 3H), 2.98 (br. s., 3H), 2.84-2.92 (m, 3H), 2.46 (br. s., 2H), 2.16 (d, J=11.66 Hz, 1H), 1.90-2.02 (m, 2H), 1.77-1.89 (m, 2H), 1.48-1.58 (m, 3H), 1.33-1.44 (m, 9H), 1.20-1.32 (m, 4H), 0.83-0.99 (m, 4H), 0.61-0.78 (m, 2H), −0.12-0.03 (m, 9H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:17]1([C:23]2[N:24]=[C:25]([C:34]3[CH:35]([CH2:40][C:41]4[CH:42]=[C:43]([S:47](Cl)(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=4)[CH2:36][CH2:37][CH2:38][CH:39]=3)[O:26][C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.CCOC(C)=O>[C:17]1([C:23]2[N:24]=[C:25]([C:34]3[CH:35]([CH2:40][C:41]4[CH:42]=[C:43]([S:47]([NH:9][CH2:8][CH2:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=4)[CH2:36][CH2:37][CH2:38][CH:39]=3)[O:26][C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCc1ccccc1)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.5 %

Procedure:
To a solution of 2-phenylethylamine (0.082 ml, 0.65 mmol) and triethylamine (0.097 ml, 0.70 mmol) in methylene chloride (3 ml) was added a solution of crude 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzenesulfonyl chloride (213 mg, 0.44 mmol) in methylene chloride (3 ml) at 5° C. After stirring at room temperature for 1 hour, the reaction mixture was diluted with EtOAc, washed with 1N hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 5:1-3:1 elution) to give 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}-N-(phenethyl)benzenesulfonamide (54.3 mg, 22%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]([C:14](=[O:16])[CH3:15])[NH2:13].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]([C:14](=[O:16])[CH3:15])[NH2:13])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)N(N)c1ccc(C(F)(F)F)cc1N
Solvent: c1ccncc1
Product: CC(=O)N(N)c1ccc(C(F)(F)F)cc1NC(=O)c1ccccc1
Yield: 93.6 %

Procedure:
The process of Example 14 was followed by using 66.5 g of 2-amino-4-trifluoromethyl-N-acetylphenylhydrazine, 70 ml of pyridine and 32.9 ml of benzoyl chloride as starting materials to yield 90 g (93.6%) of 2-benzoylamino-4-trifluoromethyl-N-acetylphenylhydrazine, m.p.: 212°-214° C. after recrystallization from 96% ethanol.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([C:43]([OH:45])=O)[CH:33]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)[CH:35]=1)=[O:5])C.[CH3:46][NH:47][CH3:48]>>[C:4]([CH2:6][CH2:7][C:8]1[C:9]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)[CH:33]=[C:32]([C:43](=[O:45])[N:47]([CH3:48])[CH3:46])[CH:31]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([OH:3])=[O:5]
Reactant: CNC
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2cccc(F)c2)c1

Procedure:
The title compound was prepared according to the general procedure described in Steps 7 and 8 of Method C starting from 5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-3′-fluoro-biphenyl-3-carboxylic acid and dimethylamine (6% yield after two steps).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[N:3]=[CH:4][CH2:5][CH2:6][C:7]1[C:12](Cl)=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[CH2:6][CH:5]=[CH:4][N:3]2[N:2]([CH3:15])[CH3:1]
Reactant: CN(C)N=CCCc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CN(C)N1C=CCc2c(Cl)cccc21
Reaction time: 8 h
Yield: 35 %

Procedure:
5-Chloro-1-(dimethylamino)-4H-quinoline was prepared in the same manner as in Example 1 except that 3-(2,6-dichlorophenyl)propionaldehyde N,N-dimethylhydrazone was used in place of 2-chlorophenylacetaldehyde N,N-dimethylhydrazone, cesium carbonate was used in place of t-butoxysodium, and the reaction was conducted at 120° C. for 8 hours. (Yield: 35%).
Reaction SMILES: FC1C(F)=C(OCCCCCCCC)C=CC=1[B:18]([OH:20])[OH:19].Br[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:30]([F:43])[CH:29]=2)=[CH:24][CH:23]=1.C([Li])CCC.C(OB(OC(C)C)OC(C)C)(C)C>>[F:43][C:30]1[CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][C:22]([B:18]([OH:20])[OH:19])=[CH:23][CH:24]=2)[CH:33]=[CH:32][C:31]=1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1F
Reactant: CCCCCCCCOc1ccc(B(O)O)c(F)c1F
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: CCCCCCCCOc1ccc(-c2ccc(B(O)O)cc2)cc1F

Procedure:
This was prepared using a similar method to that described for compound 5. Quantities: 4'bromo-3-fluoro-4-octoxybiphenyl (4.95 g, 0.013 mol), n-butyllithium (5 ml, 2.5M/hexane, 0.013 mol), tri-isopropylborate (4.7 g, 0.026 mol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][O:19][C:20]2[C:30]([Br:31])=[CH:29][C:28]([O:32][S:33]([CH3:36])(=[O:35])=[O:34])=[C:27]([CH3:37])[C:21]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:13]([CH3:45])[CH:12]=[C:11]([CH3:46])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)O>ClCCl>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][NH:16][CH2:17][CH2:18][O:19][C:20]2[C:30]([Br:31])=[CH:29][C:28]([O:32][S:33]([CH3:36])(=[O:34])=[O:35])=[C:27]([CH3:37])[C:21]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:13]([CH3:45])[CH:12]=[C:11]([CH3:46])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)c(OS(C)(=O)=O)cc(Br)c1OCCN(Cc1c(C)cc(C)nc1OCc1ccccc1)C(=O)OC(C)(C)C
Agent: O=P(O)(O)O
Solvent: ClCCl
Product: CCOC(=O)c1c(C)c(OS(C)(=O)=O)cc(Br)c1OCCNCc1c(C)cc(C)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
To a solution of ethyl 2-(2-(((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)(tert-butoxycarbonyl)amino)ethoxy)-3-bromo-6-methyl-5-((methylsulfonyl)oxy)benzoate (116e, 0.58 g, 0.80 mmol) in dichloromethane (8 mL) was added 85% phosphoric acid (0.20 mL, 2.8 mmol). The mixture was stirred at room temperature for 2 hours then additional 85% phosphoric acid (0.20 mL, 2.8 mmol) was added and stirring was continued for 2 hours. The reaction was carefully quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (2×15 mL). The combined organic layers were washed with brine (15 mL), dried over magnesium sulfate, concentrated under vacuum, and purified by column chromatography (20% EtOAc/Heptane) to give ethyl 2-(2-(((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)amino)ethoxy)-3-bromo-6-methyl-5-((methylsulfonyl)oxy)benzoate (116f, 0.25 g, 50% yield) as a clear sticky solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.[C:29]([C:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[NH:35][N:34]=1)([CH3:32])([CH3:31])[CH3:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C1COCC1.C(Cl)Cl>[C:29]([C:33]1[CH:37]=[C:36]([C:38]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][CH:19]=4)[N:9]=3)[CH2:3]2)=[O:39])[NH:35][N:34]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1cc(C(=O)O)[nH]n1
Reactant: CCN(CC)c1ccc(Nc2nc(N3CCC[C@@H](N)C3)ccc2C(N)=O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(Nc2nc(N3CCC[C@@H](NC(=O)c4cc(C(C)(C)C)n[nH]4)C3)ccc2C(N)=O)cc1
Yield: 59 %

Procedure:
A solution of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(diethylamino)phenylamino)nicotinamide (40 mg, 0.105 mmol), 3-tert-butyl-1H-pyrazole-5-carboxylic acid (21.11 mg, 0.125 mmol), EDC (30.1 mg, 0.157 mmol), HOBT (24.02 mg, 0.157 mmol), and Et3N (0.022 mL, 0.157 mmol) in THF (1 mL) was stirred at rt for 4 h. The reaction mixture was diluted with CH2Cl2, washed with satd. NaHCO3, and concentrated. The residue was purified by prep-HPLC. The product containing fractions were collected, basified with satd. Na2CO3, separated, and concentrated to give 33 mg of (R)-6-(3-(3-tert-butyl-1H-pyrazole-5-carboxamido) piperidin-1-yl)-2-(4-(diethylamino)phenylamino) nicotinamide as a yellow solid. LCMS: (M+H)+=533.30. 1H NMR (400 MHz, CDCl3) δ ppm 10.96 (1H, br. s.), 10.52 (1H, s), 7.44 (1H, d, J=8.79 Hz), 7.36 (2H, d, J=8.79 Hz), 7.06 (1 H, br. s.), 6.59 (2H, d, J=9.23 Hz), 6.00 (1H, d, J=8.79 Hz), 5.75 (1H, br. s.), 4.16-4.27 (1H, m), 3.82 (1H, br. s.), 3.58-3.72 (3H, m), 3.27 (4H, q, J=7.18 Hz), 1.86-1.96 (2H, m), 1.78 (1H, d, J=5.71 Hz), 1.62-1.70 (1H, m), 1.60 (2H, s), 1.33 (9H, s), 1.10 (6H, t, J=7.03 Hz).
Reaction SMILES: [CH3:1][CH:2]1[CH2:15][CH:14]2[C:9]([NH:16]C(=O)OC)([CH2:10][CH:11]=[CH:12][CH2:13]2)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C[Si](C)(C)[O-].[K+].[ClH:27]>C1COCC1>[ClH:27].[CH3:1][CH:2]1[CH2:15][CH:14]2[C:9]([NH2:16])([CH2:10][CH:11]=[CH:12][CH2:13]2)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: COC(=O)NC12CC=CCC1CC(C)c1ccccc12
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC1CC2CC=CCC2(N)c2ccccc21
Yield: 54 %

Procedure:
A solution of the compound of Example 35 (0.5 g, 1.85 mmol) and potassium trimethylsilanolate (0.47 g, 3.69 mmol) in 20 ml THF was refluxed overnight. The reaction was worked up as previously described, and the ethereal solution of the free amine was treated with isopropanolic HCl to give the title compound (0.25 g, 54%), mp 234°-236° C.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.CS([Cl:21])(=O)=O>C1C=CC=CC=1>[Cl:21][CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ncccc1CO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ncccc1CCl
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxymethy-2-methylpyridine (0.65 g, 5.3 mmol) in dry benzene (5 ml) was added triethylamine (1.0 ml, 7.4 mmol) followed by methanesulfonyl chloride (0.78 ml, 10.1 mmol) dropwise over 5 min. The heterogeneous dark gummy mixture was stirred at room temp. overnight. The reaction was filtered through Celite and washed with benzene (2×). The combined filtrates were washed with brine, dried (Na2SO4), and concentrated in vacuo to the crude product as a yellow oil which was used as is.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:33])[C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[C:19]=4[CH3:34])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl.C1COCC1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([NH:24][C:20]2[C:19]([CH3:34])=[C:18]([C:7]3[C:6]4[C:5]5[C:13](=[CH:14][C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:3][CH:4]=5)[NH:12][C:11]=4[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=3)[CH:23]=[CH:22][CH:21]=2)=[O:33])=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(N)ccc3c12
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(NS(C)(=O)=O)ccc3c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 7-amino-4-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-1-carboxamide (Example 54-5, 30 mg, 0.066 mmol) and TEA (0.018 mL, 0.133 mmol) in DCM-THF (2:1, 3 mL) was treated with methanesulfonyl chloride (10 μL, 0.133 mmol). The mixture was stirred at rt for 1.5 h, and was concentrated and purified by preparative HPLC to provide 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-(methylsulfonamido)-9H-carbazole-1-carboxamide as a white solid (Example 59-1, 3.5 mg, 9%). 1H NMR (500 MHz, methanol-d4) δ 7.91-8.01 (2H, m), 7.83 (1H, d, J=7.8 Hz), 7.45 (1H, d, J=1.7 Hz), 7.42 (1H, d, J=7.8 Hz), 7.34 (1H, t, J=7.8 Hz), 7.12-7.20 (3H, m), 6.95 (1H, d, J=7.8 Hz), 6.88 (1H, d, J=8.6 Hz), 6.73 (1H, dd, J=8.5, 2.1 Hz), 2.85 (3H, s), 1.90 (3H, s). Mass spectrum m/z 531.0 (M+H)+. Also obtained was 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-(N-(methylsulfonyl)methylsulfonamido)-9H-carbazole-1-carboxamide as a white solid (Example 59-2, 14 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ 11.67 (1H, s), 10.08 (1H, s), 8.21 (1H, br. s.), 7.97-8.08 (3H, m), 7.79 (1H, d, J=1.8 Hz), 7.53 (1H, br. s.), 7.48 (1H, d, J=7.3 Hz), 7.26-7.39 (3H, m), 7.15 (1H, d, J=6.5 Hz), 6.93-7.03 (2H, m), 6.86 (1H, d, J=8.3 Hz), 3.46 (6H, d, J=9.0 Hz), 1.86 (3H, s). Mass spectrum m/z 607.2 (M−H)−.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][OH:9].[CH3:10][O:11][C:12](=[O:15])[CH2:13]Br>C1COCC1>[CH3:10][O:11][C:12](=[O:15])[CH2:13][O:9][CH2:8][C:4]1[S:3][CH:7]=[CH:6][N:5]=1
Reactant: COC(=O)CBr
Reactant: OCc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCc1nccs1
Temperature: 45 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
NaH (55% dispersion in oil, 1.4 g) was added to a stirred sol. of thiazol-2-ylmethanol (3.55 g, 30.8 mmol) in THF (155 mL). The suspension was then heated to 45° C. for 1 h, and methylbromoacetate (3.40 mL, 37.0 mmol) was added. Stirring was continued at 45° C. for 4 h. The reaction mixture was partitioned between EtOAc and H2O, the phases separated, and the aq. layer extracted with EtOAc (2×). The combined org. layers were dried over MgSO4, filtered, and the solvents were removed in vacuo. Purification of the crude by FC (MeOH/CH2Cl2 1:9) yielded the title compound (5.50 g, 95%) as an orange oil. LC-MS: tR=0.62 min, ES+: 188.14.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:16]1([CH:23]=[CH:22][C:20]([OH:21])=[CH:19][CH:18]=1)[OH:17].[OH-].[Na+]>CS(C)=O>[Cl:8][C:7]1[C:2]([O:17][C:16]2[CH:23]=[CH:22][C:20]([OH:21])=[CH:19][CH:18]=2)=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1

Procedure:
In procedures similar to those in Example 1 above, except that a 2,3,5-trichloropyridine was used in place of the bis reactant, it was found that reaction of equimolar amounts of the pyridine reactant, hydroquinone and 50% NaOH in dimethylsulfoxide (DMSO) at 100°-116° C. for about 11/2 hours gave product yields of 33% 1,4-((bis(3,5-dichloro-2-pyridinyl)oxy))benzene and about 49% of the desired mono compound, i.e., 4-(3,5-dichloro-2-pyridinyloxy)phenol. Reaction of 0.1 mole of the pyridine reactant with 0.2 mole of the hydroquinone and 0.15 mole of the 50% NaOH (added portionwise to the reaction mixture over a period of about 20 minutes) in 80 ml of DMSO at 90°-100° C. for about 5.5 hours resulted in a product yield of about 16.6% of the bis compound named above and about 75.9% of the desired mono compound. Further operations using equimolar amounts of pyridine reactant to hydroquinone reactant (0.4 mole each) and a mole ratio of base to hydroquinone of 2:1 (0.8 mole 50% caustic, 0.4 mole hydroquinone) in 250 ml of DMSO at temperatures of 100°-113° C. for about 2.5 hours resulted in a product yield of only 4% of the bis compound and 84.4% of the desired mono compound.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24](=[CH:25][C:14]=1[CH2:13]3)[CH:23]=[C:22](N)[CH:21]=[CH:20]2)=[O:11].N([O-])=[O:29].[Na+]>S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24]([CH:23]=[C:22]([OH:29])[CH:21]=[CH:20]2)=[CH:25][C:14]=1[CH2:13]3)=[O:11]
Reactant: O=N[O-]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(N)ccc3nc2-1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(O)ccc3nc2-1
Temperature: 0 °C
Yield: 55.8 %

Procedure:
10-Aminocamptothecin (50 mg, 0.138 m-mol) is dissolved in a 10% aqueous solution of sulfuric acid (5 ml). To this solution in a salted ice bath is added dropwise slowly an aqueous solution of sodium nitrite (9.5 mg, 0.138 m-mol) with stirring. After the addition of sodium nitrite, the mixture is further stirred for 10 minutes in a salted ice bath. To the reaction mixture is added conc. sulfuric acid (1 ml), and the whole is boiled under reflux for 2 hours. The reaction mixture is diluted with ice water (200 ml) and chloroform (200 ml) is added. The mixture is shaken in a separating funnel and the resultant emulsion is filtered through celite. The chloroform phase containing camptothecin formed as by-product by side reactions is dried over magnesium sulfate, filtered and evaporated until dryness under reduced pressure whereby camptothecin (8 mg) is recovered. On the other hand, a solid on the celite, which is insoluble in chloroform-water, is taken up in 20% MeOH-CHCl3 (200 ml) and the solution is evaporated until dryness under reduced pressure whereby 28 mg (yield: 66.5% ) of the title compound is obtained as light yellow crystals. M.P. (with decomp.) 270°-272° C. (from pyridine-methanol)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:34][C:33]1[CH:35]=[CH:36][C:30]([S:27]([O:14][CH2:13][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:29])=[O:28])=[CH:31][CH:32]=1
Reactant: O=C(N[C@@H](CO)c1ccccc1)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](NC(=O)OCc2ccccc2)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
53.9 g of (R)-2-benzyloxycarbonylamino-2-phenylethanol (198.7 mmol) were dissolved in a mixture of 500 ml of methylene chloride and 80.3 ml (993.5 mmol) of pyridine. 45.5 g (238.4 mmol) of tosyl chloride in 240 ml of methylene chloride were added at 0° C. with stirring and the mixture was stirred at room temperature for 7 hours. A further 11.36 g of tosyl chloride (59.61 mmol) were added. The mixture was stirred at 0° C. for 5 hours. The batch was then allowed to stand overnight at room temperature and concentrated in vacuo. The residue was taken up in ethyl acetate. The organic phase was washed three times with 10% strength aqueous citric acid solution and twice with water, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether, filtered off with suction, washed with diethyl ether and dried over phosphorus pentoxide. Yield: 60.9 g (72%). The mother liquor was concentrated, taken up in n-heptane/ethyl acetate (6/4) and chromatographed on silica gel to give an additional yield of 3.5 g (4.2%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[S:39]1[CH:43]=[C:42]([CH2:44][CH2:45][NH2:46])[N:41]=[CH:40]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:46][CH2:45][CH2:44][C:42]1[N:41]=[CH:40][S:39][CH:43]=1)=[O:5]
Reactant: NCCc1cscn1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCCc1cscn1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 47.8 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), 2-(thiazole-4-yl)ethylamine (11.89 mg, 0.093 mmol), and BOP (41.0 mg, 0.093 mmol). The reaction mixture was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(2-(thiazol-4-yl)ethyl)acetamide (11.8 mg, 0.022 mmol, 47.0% yield): LCMS=542.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.82 (1 H, d, J=2.01 Hz), 8.13 (2 H, d, J=8.28 Hz), 7.46-7.69 (7 H, m), 7.08 (1 H, d, J=2.01 Hz), 5.08 (1 H, s), 3.50-3.69 (2 H, m), 3.03 (2 H, t, J=6.90 Hz); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 90:10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.6 min.