Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:21][CH2:20][CH2:19][C:18](=O)[CH2:17]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:15])[CH:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C1CCCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C1CCOCC1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.4 %

Procedure:
A mixture of 4-methylaminopiperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.93 mmol), tetrahydropyran-3-one (187 mg, 1.87 mmol), 4 Å powdered molecular sieves (550 mg) and DIPEA (323 μl, 241 mg, 1.87 mmol) in DCM (10 mL) was stirred at room temperature for 30 min before the addition of sodium triacetoxyborohydride (396 mg, 1.87 mmol). The reaction mixture was stirred at room temperature for 16 h then diluted with DCM and washed with H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording 4-[Methyl(tetrahydropyran-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester as an oil (101 mg, 36%). 1H NMR (CDCl3, 300 MHz): δ 4.24-4.07 (m, 2H); 4.06-3.96 (m, 2H); 3.43-3.32 (m, 2H); 2.78-2.63 (m, 4H); 2.25 (s, 3H); 1.77-1.60 (m, 8H); 1.46 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:11]([CH3:13])[CH3:12])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[F:14][C:15]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:16]=1[C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)Cl>[CH:11]([C:4]1[S:3][C:2]([NH:1][C:17](=[O:18])[C:16]2[CH:20]=[C:21]([C:24]([F:25])([F:26])[F:27])[CH:22]=[CH:23][C:15]=2[F:14])=[N:6][C:5]=1[C:7]([O:9][CH3:10])=[O:8])([CH3:13])[CH3:12]
Reactant: COC(=O)c1nc(N)sc1C(C)C
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1nc(NC(=O)c2cc(C(F)(F)F)ccc2F)sc1C(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 92.4 %

Procedure:
A mixture of commercially available methyl 2-amino-5-isopropylthiazole-4-carboxylate (1 g, 4.99 mmol) and 2-fluoro-5-(trifluoromethyl)benzoyl chloride (1.31 g, 5 mmol) in anhydrous CH2Cl2 (25 mL) was treated dropwise at 0° C. with triethylamine (0.84 mL, 6 mmol). The mixture was allowed to warm to room temperature and stirred for 14 hours. The mixture was then washed with water, brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with hexanes-EtOAc (1:1) to afford 1.8 g of the title compound. MS (DCI/NH3) m/z 391 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:49]=[CH:48][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][C:9]([C:40](=[O:47])[NH:41][CH2:42][CH2:43][N:44](C)C)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.NCC(N)=[O:53]>>[C:43]([CH2:42][NH:41][C:40]([C:9]1[CH:10]=[C:11]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]4[N:26]([CH:27]5[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]5)[C:25]5[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=5[N:23]=4)[CH:18]=3)[N:13]=2)[C:6]([C:5]2[CH:48]=[CH:49][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:7][CH:8]=1)=[O:47])(=[O:53])[NH2:44]
Reactant: NCC(N)=O
Reactant: CN(C)CCNC(=O)c1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Product: NC(=O)CNC(=O)c1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1

Procedure:
The title compound was synthesized as described for Compound 491, except glycine-amide was used instead of N1,N1-dimethyl-ethane-1,2-diamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13](Cl)=[O:14])=[C:11]([CH3:16])[O:10][N:9]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH2:34][C:35]([F:37])([F:38])[F:36])[CH2:25][CH2:26]2)=[O:14])=[C:11]([CH3:16])[O:10][N:9]=1
Reactant: NCCCN1CCN(c2ccccc2OCC(F)(F)F)CC1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NCCCN1CCN(c2ccccc2OCC(F)(F)F)CC1
Yield: 67.2 %

Procedure:
The title compound was synthesised according to the procedure described in Example 8 but using 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl chloride instead of the crude 3-(4-fluorophenyl)isoxazole-4-carbonyl chloride and Compound 12B instead of Compound 8B. Washing the reaction mixture with 2 N sodium hydroxide, followed by the usual work-up and purification by flash chromatography (chloroform-2 N ammonia in methanol 100:3) afforded the title compound (67.2%) as an oil.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][O:8][C:9]([C:11]1[CH:15]=[C:14]([CH3:16])[S:13][C:12]=1[NH2:17])=[O:10].O>CN(C)P(N(C)C)(N(C)C)=O>[C:9]([C:11]1[CH:15]=[C:14]([CH3:16])[S:13][C:12]=1[NH:17][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])([O:8][CH3:7])=[O:10]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1cc(C)sc1N
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1cc(C)sc1NC(=O)C(C)C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
isoButyryl chloride (22.4 g) was added dropwise during 40 minutes to a stirred solution of methyl-2-amino-5-methyl-3-thiophenecarboxylate (34.2 g, 0.2 mol) in dry hexamethylphosphoramide (100 ml) kept at 5°-10° C. This temperature was maintained for a further 1 hour and then the reaction was kept at room temperature for 16 hours. The reaction mixture was poured into water (1600 ml) and the yellow precipitate was filtered off, washed with water and dried at 50° C. Recrystallization of the solid from petroleum ether (b.p. 60°-80° C. yielded cream crystals (39.6 g, 88%), m.p. 63°-65° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:32][C:33](O)=[O:34]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:33](=[O:34])[CH2:32][C@@H:27]5[CH2:28][CH2:29][CH2:30][CH2:31][O:26]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C[C@@H]1CCCCO1
Agent: Cl
Product: O=C(C[C@@H]1CCCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, off-white solid (21.5 mg, 67.3%), MS (ISP) m/z=457.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.070 mmol) and (S)-2-(tetrahydro-2H-pyran-2-yl)acetic acid
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[S:11][CH:10]=[N:9][CH:8]=1.F[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]>CCCCCCC.C1COCC1>[CH3:6][C:7]1[S:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[N+:23]([O-:25])=[O:24])=[N:9][CH:8]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: Cc1cncs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])s1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 28.7 %

Procedure:
A solution of n-BuLi (2.5 mmol) in heptane (c=2.5 M) under nitrogen atmosphere was cooled to −78° C. To the solution was added drop-wise 5-methyl-thiazole (750 mg, 7.5 mmol) dissolved in anhydrous THF (10 ml). The reaction was stirred for 20 min at −78° C. followed by the addition of 1-fluoro-2-nitro-4-trifluoromethyl-benzene (1.56 g, 7.5 mmol) dissolved in anhydrous THF (10 ml). The reaction was stirred for 10 min at −78° C. and then allowed to reach ambient temperature. The reaction was quenched with aqueous sodium bicarbonate and the phases separated. The ether phase was washed with brine, dried with MgSO4 and filtered. The solvent was removed in vacuo and the residue purified by flash chromatography (Silica, Hexane/ethyl acetate) to afford the title compound (620 mg, 29%). LC/MS (Method I): tR=1.44 min, >90%, m/z (ESI+)=289 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[NH:20][C:21]([C:23]1[S:24][C:25]3[CH2:26][NH:27][CH2:28][CH2:29][C:30]=3[N:31]=1)=[O:22])=[O:13])=[CH:6]2.[CH2:32](N(CC)CC)[CH3:33].C(I)C>CN(C)C=O.Cl>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[NH:20][C:21]([C:23]1[S:24][C:25]3[CH2:26][N:27]([CH2:32][CH3:33])[CH2:28][CH2:29][C:30]=3[N:31]=1)=[O:22])=[O:13])=[CH:6]2
Reactant: O=C(N[C@@H]1CCC[C@H]1NC(=O)c1nc2c(s1)CNCC2)c1cc2cc(Cl)ccc2[nH]1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCI
Solvent: CN(C)C=O
Product: CCN1CCc2nc(C(=O)N[C@@H]3CCC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-trans-N1-[(5-Chloroindol-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine hydrochloride (500 mg) was dissolved in N,N-dimethylformamide (10 ml), and triethylamine (576 μl) and ethyl iodide (329 μl) were added to stir the mixture overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and water was added to the residue to collect insoluble matter by filtration. This product was purified by column chromatography on silica gel (dichloromethane:methanol=100:3) to obtain a pale brown foamy substance. This substance was suspended in 1N hydrochloric acid (2 ml), and the suspension was concentrated under reduced pressure to obtain the title compound (180 mg) as a pale yellow foamy substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=1.C(N(C(C)C)CC)(C)C.[CH3:31][C:32]([CH3:38])([CH3:37])[CH2:33][C:34](Cl)=[O:35]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:31][C:32]([CH3:38])([CH3:37])[CH2:33][C:34]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=2)=[CH:15][C:16]=1[F:21])=[O:35]
Reactant: CCCn1nc(-c2ccc(O)c(F)c2)c2cccc(Cl)c21
Reactant: CC(C)(C)CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCn1nc(-c2ccc(OC(=O)CC(C)(C)C)c(F)c2)c2cccc(Cl)c21
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of 4-(7-chloro-1-propyl-1H-indazole-3-yl)-2-fluorophenol (0.10 g, 0.33 mmol) in dichloromethane (20 mL) at −78° C. was added diisopropylethylamine (0.70 mL, 0.41 mmol), 3,3-dimethylbutanoyl chloride (0.05 mL, 0.35 mmol) and catalytic amount of 4-(dimethylamino)pyridine. The reaction was stirred at this temperature for 30 minutes. The mixture was diluted with dichloromethane and the organic layer washed with 1n hydrochloric acid solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the organic phase was filtered and the filtrate evaporated in vacuo to yield crude title compound. The oil was purified by silica gel column chromatography eluting with hexane/ethyl acetate (5/1) to provide the title compound as a white solid (0.11 g, 0.27 mmol, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH3:20]O>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:12]2[CH:17]=[N:16][CH:15]=[N:14][CH:13]=2)[CH:10]=1)[C:5]([O:7][CH3:20])=[O:6]
Reactant: O=C(O)c1cc(Cl)cc(Oc2cncnc2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc(Cl)cc(Oc2cncnc2)c1
Temperature: 75 °C
Yield: 84 %

Procedure:
3-Chloro-5-(pyrimidin-5-yloxy)benzoic acid (464 mg, 1.85 mmol, 1 eq) was dissolved in methanol (9.3 mL) in a microwave vial and H2SO4 (0.93 mL) was added dropwise. The vial was capped and heated at 75° C. for 3 h. The reaction was cooled to rt and neutralized with 1N NaOH. The reaction was extracted with EtOAc (2×), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 414 mg (84%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.74 (s, 2H), 7.75 (t, J=1.7 Hz, 1H), 7.65 (t, J=2.2 Hz, 1H), 7.54 (dd, J=1.4, 1.0 Hz, 1H), 3.84 (s, 3H); [M+1]+: 265.1.
Reaction SMILES: Cl[C:2]1[N:37]=[CH:36][CH:35]=[CH:34][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[C:9]([O:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:8]=1)=[O:5].[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=1>CCOC(C)=O.O>[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH:44][C:2]2[N:37]=[CH:36][CH:35]=[CH:34][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[C:9]([O:20][CH2:21][CH:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:8]=2)=[O:5])=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1cc(NC(=O)c2cccnc2Cl)ccc1C(F)(F)C(F)(F)F
Reactant: NCc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1COc1cc(NC(=O)c2cccnc2NCc2ccc(F)cc2)ccc1C(F)(F)C(F)(F)F
Temperature: 130 °C

Procedure:
2-Chloro-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide (442.8 mg) DIEA (351 μL) and 4-fluorobenzylamine (322 μL) were combined in a sealed tube and heated to 130° C. for 3 h. The mixture was diluted with EtOAc and H2O, the layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified with silica gel chromatography (1% MeOH/CH2Cl2) to obtain an off-white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:44])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:43])[CH2:9][CH2:10][C@@:11]3([C:27]([N:29]4[CH2:34][CH2:33][C:32]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)([C:35]#[N:36])[CH2:31][CH2:30]4)=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:46])[CH3:45].N1C=CC=CC=1.[CH3:53][C:54]1([CH3:61])[CH2:58][C:57](=[O:59])[O:56][C:55]1=[O:60]>C(OCC)(=O)C>[C:35]([C:32]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33][CH2:34][N:29]([C:27]([C@:11]23[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]2[C@@H:13]2[C@@:8]([CH3:43])([CH2:9][CH2:10]3)[C@@:7]3([CH3:44])[C@@H:16]([C@:17]4([CH3:20])[C@@H:4]([CH2:5][CH2:6]3)[C:3]([CH3:46])([CH3:45])[C@@H:2]([O:1][C:57](=[O:59])[CH2:58][C:54]([CH3:61])([CH3:53])[C:55]([OH:60])=[O:56])[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)=[O:28])[CH2:30][CH2:31]1)#[N:36]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(C#N)(c4ccccc4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(C#N)(c4ccccc4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of ((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl)-4-phenylpiperidine-4-carbonitrile (Example 76, 0.5 g, 0.80 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.2 g, 1.6 mmol) was added then 3,3-dimethyldihydrofuran-2,5-dione (0.82 ml) was added and the contents were refluxed for about 16 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, washed with water followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 19H); 1.23-1.78 (m, 23H); 2.15-2.59 (m, 11H); 2.77-3.58 (m, 16H); 4.33-4.70 (m, 4H); 5.58-5.60 (s, 1H); 5.78-5.80 (s, 1H); 7.44-7.47 (s, 1H); ES Mass: 753 (100%), [M+1].
Reaction SMILES: [C:1]([NH2:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].CN(C)C=O>O>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]#[N:10])[CH3:23]
Reactant: NC(=O)c1ccccc1N
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccccc1C#N

Procedure:
A mixture of anthranilamide (11.8 g), potassium carbonate (20 g), ethyl bromoacetate (18 g) and dimethylformamide (50 mL) was heated at reflux for 40 min. The reaction mixture was diluted with water and the product was extracted with ether. The organic layer was washed with water and brine, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was recrystallized from ethanol to afford N-(2-Cyanophenyl)glycine ethyl ester as a colorless solid.
Reaction SMILES: C(C1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]([CH3:17])([CH3:16])[CH:4]=1)#N.[C:18]([OH:21])(=[O:20])[CH3:19].S(=O)(=O)(O)O>O>[CH3:16][C:5]1([CH3:17])[CH:4]=[C:19]([C:18]([OH:21])=[O:20])[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6]1
Reactant: CC(=O)O
Reactant: CC1(C)C=C(C#N)c2cc([N+](=O)[O-])ccc2O1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(C)C=C(C(=O)O)c2cc([N+](=O)[O-])ccc2O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
MS: 230 (M+) ##STR41## A mixture of 13.0 g of 4-cyano-2,2-dimethyl-6-nitro-2H-1-benzopyran, 400 ml of acetic acid, 200 ml of water, and 100 ml of concentrated sulfuric acid was heated at reflux for 1.5 hours. After adding 100 ml of concentrated sulfuric acid, the refluxing was further continued for an additional period of 1 hour. The reaction mixture was poured into ice-water. The thus precipitated crystal was washed with water, dried, and recrystallized from a mixed solvent of acetonitrile and water to obtain 11.9 g of 2,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxylic acid represented by formula shown below.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:16])(=O)[CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14]>>[C:5]([Cl:3])(=[O:16])[CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14]
Reactant: O=S(Cl)Cl
Reactant: COCCOCCOCC(=O)O
Product: COCCOCCOCC(=O)Cl
Reaction time: 0.75 h

Procedure:
Thionyl chloride, 8.0 grams (0.112 mole) was stirred, and 10.0 grams (0.056 mole) of 3,6,9-trioxadecanoic acid was added dropwise during a 45 minute period. Upon completion of addition, the reaction mixture was warmed to reflux where it stirred for 45 minutes. The reaction mixture was cooled, yielding 3,6,9-trioxadecanoyl chloride. An 80% yield of acid chloride was assumed.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[ClH:11].[F:12][C:13]1[CH:18]=CC(ON)=[CH:15][CH:14]=1>Cl>[ClH:11].[F:12][C:13]1[CH:18]=[CH:2][C:3]2[O:4][C:5]3[CH2:10][CH2:9][NH:8][CH2:7][C:6]=3[C:15]=2[CH:14]=1
Reactant: NOc1ccc(F)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: Cl
Product: Fc1ccc2oc3c(c2c1)CNCC3
Yield: 43.9 %

Procedure:
1,4-dioxa-8-azaspiro[4,5]decane (0.12 mol) was added dropwise to a mixture of O-(4-fluorophenyl)hydroxylamine hydrochloride (1: 1) (0.1 mol) in a mixture of HCl and 1,1-oxybisethane (150 ml). The reaction mixture was stirred and refluxed for 4 hours and then cooled. The precipitate was filtered off and dried, then recrystallized from water, yielding 10 g (43.9%) 1,2,3,4-tetrahydro-8-fluorobenzofuro[3,2-c]pyridine hydrochloride (interm. 2; mp. >300° C.).
Reaction SMILES: Cl[C@H:2]([CH2:18][CH3:19])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=2)[C:7]([CH3:17])([CH3:16])[CH2:6]1)=[O:4].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]1[CH3:33])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C@H:2]([C:3]([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=3)[C:7]([CH3:17])([CH3:16])[CH2:6]2)=[O:4])[CH2:18][CH3:19])[CH2:29][C@H:28]1[CH3:33])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CC[C@@H](Cl)C(=O)N1CC(C)(C)c2ccc(C#N)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC[C@@H](C(=O)N1CC(C)(C)c2ccc(C#N)cc21)N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Temperature: 50 °C
Reaction time: 36 h
Yield: 14.5 %

Procedure:
To a suspension of (R)-1-(2-chlorobutanoyl)-3,3-dimethylindoline-6-carbonitrile (0.1 g, 0.36 mmol), (R)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.072 g, 0.36 mmol) in acetonitrile (2.5 mL) was added potassium carbonate (0.049 g, 0.36 mmol) and the reaction heated to 50° C. for 48 h followed by 80° C. for 24 h and 60° C. for 36 h. The reaction mixture was then diluted with ethyl acetate and washed with water. The organics were separated, dried with sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel; eluting with 20-30% ethyl acetate in heptane to give (R)-4-[(S)-1-(6-cyano-3,3-dimethyl-2,3-dihydro-indole-1-carbonyl)-propyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.023 g). MS: [M+H]+=441.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[CH:15][N:16]([CH3:18])[CH3:17])[C:7](=[O:11])[C:6]=2[CH:12]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1CCOc2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(C)C=C1COc2ccc(Cl)cc2C1=O
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A solution of 6-chloro-3,4-dihydro-4-oxo-2H-1-benzopyran (3.285 g), N,N-dimethylformamide dimethyl acetal (8.568 g), and triethylamine (2.727 g) in benzene (36 ml) was refluxed with stirring for 1 hour and then about three-fourths of the solvent was distilled slowly at atmospheric pressure over a period of approximately 1 hour. To the residue was added benzene (36 ml) and the solvent was distilled again. The residue was dissolved in a mixture of chloroform and ethyl acetate, treated with activated charcoal, and evaporated in vacuo. The residual solid was washed with a mixture of diethyl ether and ethyl acetate to give 6-chloro-3,4-dihydro-3-dimethylaminomethylene-4-oxo-2H-1-benzopyran (2.73 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[Cl-].[NH4+]>[Fe].O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 80 °C
Yield: 88.8 %

Procedure:
4-(4-Nitro-benzenesulfonyl)-piperazine-1-carboxylic acid benzyl ester (1.82 g, 4.5 mmol) was suspended in a 5:1 mixture of ethanol and water (30 ml). To this solution was added iron powder (0.65 g, 11.7 mmol) followed by saturated ammonium chloride solution (1 ml) and the mixture was heated to 80° C. for three hours. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of celite, the celite was washed with ethanol (10 ml) and ethyl acetate (50 ml) and the solution was concentrated under vacuum. The resulting residue was partitioned between DCM (50 ml) and water (20 ml), the organic layer was separated, dried with MgSO4, filtered and concentrated to afford the title compound (1.5 g, 89% yield) as a white solid. Tr=1.29 min, m/z (ES+) (M+H)+ 376