Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)[CH2:11][CH2:10]1)=[O:5].[C:37](OC(=O)C)(=[O:39])[CH3:38].[OH-].[NH4+]>O>[C:37]([NH:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)[CH2:11][CH2:10]1)=[O:5])(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1C(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccccc1C(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 7.7 parts of 2-amino-N-[2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]benzamide, 20 parts of acetic acid anhydride and 80 parts of water was stirred for 4 hours at 100° C. Water was added and the whole was alkalized with ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and recrystallized from acetonitrile, yielding 7.7 parts of 2-(acetylamino)-N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]benzamide; mp. 170.9° C. (compound 51).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[C:7]([O:11][O:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH:15]([CH3:17])[OH:16])([CH3:10])([CH3:9])[CH3:8].[Cl-]>C(OC)(C)(C)C>[C:2]([Cl:4])(=[O:3])[C:1]([O:16][CH:15]([CH3:17])[CH2:14][C:13]([O:12][O:11][C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:18])[CH3:19])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(O)CC(C)(C)OOC(C)(C)C
Agent: [Cl-]
Solvent: COC(C)(C)C
Product: CC(CC(C)(C)OOC(C)(C)C)OC(=O)C(=O)Cl

Procedure:
A 250 mL three-neck flask equipped with a magnetic stirrer, a thermometer and an addition funnel was charged with 25.4 g (200 mmoles) of oxalyl chloride and 75 mL of methyl t-butyl ether (MTBE). Then to the resulting solution was added 20.6 g (100 mmoles) of 93% 3-t-butylperoxy-1,3-dimethylbutanol over a period of 30 minutes at 22°-28° C. The addition funnel was then replaced with a nitrogen gas tube and dry nitrogen gas was slowly bubbled through the reaction mass in order to remove HCl over a period of 4 hours at 25°-30° C. The MTBE, excess oxalyl chloride, and any remaining gas were removed in vacuo using a water aspirator. Obtained was 28.3 g (101% of theory, uncorrected) of a yellow liquid. An IR spectrum ofthe product showed no OH bands and showed carbonyl bands at 1800 cm-1 and 1760 cm-1. The assay of I-2, based upon hydrolyzable chloride content (theory, 12.63%; found, 12.37%), was 97.9% and the corrected yieldwas 98.6%.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH:6]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:5])[O:3]1
Reactant: O=Cc1ccccc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)C(Cc2ccccc2)C(=O)O1

Procedure:
Meldrum's acid (73) is treated with benzaldehyde in the presence of borane-triethylamine complex in toluene. The product is isolated by flash chromatography over silica gel to give (74).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[S:10][C:9]([N:11]3[CH2:15][CH2:14][O:13][C:12]3=[O:16])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][NH:35]3)O1>>[NH:35]1[C:36]2[C:32](=[C:31]([C:2]3[N:3]=[C:4]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:5]4[S:10][C:9]([N:11]5[CH2:15][CH2:14][O:13][C:12]5=[O:16])=[CH:8][C:6]=4[N:7]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: O=C1OCCN1c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: O=C1OCCN1c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)oxazolidin-2-one (46 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole via Procedure A. The product was purified by reverse phase HPLC to yield 8.6 mg of 439. MS (Q1) 423 (M)+
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([Cl:33])[C:17]=1[NH:18][C:19]1[C:28]2[C:23](=[C:24]([OH:31])[C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[O:22][C:21](=[O:32])[CH:20]=1>>[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([Cl:33])[C:17]=1[NH:18][C:19]1[C:28]2[C:23](=[C:24]([O:31][CH2:2][CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[O:22][C:21](=[O:32])[CH:20]=1
Reactant: BrCCCc1ccccc1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCc1ccccc1

Procedure:
The title compound was prepared from (3-bromopropyl)benzene and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, CDCl3): δ 8.61 (s, 2H), 7.39 (d, 1H), 7.35-7.15 (m, 5H), 6.97 (d, 1H), 6.54 (s, 1H), 5.14 (s, 1H), 4.19 (t, 2H), 3.98 (s, 3H), 2.91 (t, 2H), 2.15 (m, 2H); MS (ESI): 470.9.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[N:3]=1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>CC(N(C)C)=O.ClCCl>[CH:21]1([NH:24][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[N:3]=2)[CH2:23][CH2:22]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cc(F)c(N2CCN(C)CC2)nc1Cl
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(F)c(N2CCN(C)CC2)nc1NC1CC1
Temperature: 90 °C

Procedure:
A solution of ethyl 2-chloro-5-fluoro-6-(4-methylpiperazinyl)-3-pyridine-carboxylate (Example D-2, 1.00 g, 3.314 mmol) and cyclopropylamine (2 mL) in DMA (1 mL) was sealed in a pressure bottle and heated at 90° C. for 60 hours. The reaction mixture was diluted with dichloromethane (30 mL), washed with water, and dried on sodium sulfate. Flash chromatography on silica gel column using dichloromethane as eluent provided compound 0.85 g of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10][CH:9]1[C:17]([O-:19])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH2:24].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH:24][C:17]([CH:9]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1)=[O:19]
Reactant: Nc1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1c2ncccc2CC1C(=O)[O-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1c2ncccc2CC1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a suspension of lithium 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (589 mg, 2.18 mmol, Eq: 1.00) and 2,6-difluoroaniline (480 mg, 0.4 mL, 3.72 mmol, Eq: 1.71) in pyridine (7 mL) (ice-bath) was added dropwise phosphoryl trichloride (660 mg, 0.4 mL, 4.3 mmol, Eq: 1.97). The cooling bath was removed and the resulting yellow/orange suspension was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue was treated with water (20 mL). The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic layers were washed with brine (1×5 mL). The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 100% EtOAc in DCM/hexanes (1:1)). After the combined fractions were concentrated, the off-white solid was treated with 5% MeOH/ether (˜10 mL) to give tert-butyl 2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate as a white solid (532 mg).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1>>[N+:1]([C:12]1[CH:11]=[C:10]([S:13]([Cl:16])(=[O:14])=[O:15])[CH:9]=[CH:8][C:7]=1[O:6][CH3:5])([O-:4])=[O:2]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])O
Product: COc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
350 ml of fuming nitric acid (8.3 mol) was added very carefully in 25 ml aliquots to the crude product of Example 1 in a one-liter flask. To maintain control over the very vigorous reaction which immediately commenced, each portion of the nitric acid was allowed to react completely (i.e., until no fumes were evolved) before the next portion was added. When addition was complete, the solution was allowed to stand at room temperature for 30 minutes and then carefully poured over ice (1000 g). The resulting slurry was extracted with CH2Cl (3×250 ml) and the organic extracts were combined, dried over MgSO4 and filtered. The solvent was removed in a rotary evaporator and the yellow crystals thus obtained were recrystallized from 50% Et2O/hexane to yield pure 3-nitro-4-methoxy-benzenesulfonyl-chloride (161.3 g, 89% yield) as faintly yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][OH:23])[CH2:18][CH2:17]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:23][CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([NH:15][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[N:3]=3)[N:8]=[CH:7][C:6]=2[C:12](=[O:14])[CH3:13])[CH2:17][CH2:18]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-{6-chloro-4-[trans-4-(hydroxymethyl)cyclohexylamino]-1,5-naphthyridin-3-yl}ethanone (140 mg, 0.42 mmol) in methylene chloride (10 mL) was added triethylamine (0.12 mL, 0.84 mmol) and methanesulfonyl chloride (65 μL, 0.84 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with satd. aq. sodium bicarbonate, the layers were separated and the organic layer was concentrated to afford the crude product (180 mg) as a yellow solid which was used without further purification: 1H NMR (500 MHz, CDCl3) δ 10.90 (br s, 1H), 8.95 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 5.10-4.95 (m, 1H), 4.11 (d, J=6.5 Hz, 2H), 3.03 (s, 3H), 2.68 (s, 3H), 2.39-2.26 (m, 2H), 2.01-1.92 (m, 2H), 1.90-1.78 (m, 1H), 1.47-1.24 (m, 4H); ESI MS m/z 412 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH:16]2[OH:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29].O1CCOCC1>C(OCC)C>[ClH:29].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][NH:18][CH2:17][C@H:16]2[OH:28])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(O)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O[C@@H]1CNCC[C@@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (100 mg, 0.26 mmol) in 10 mL diethyl ether was added 4 M HCl in dioxane (1.3 mL, 5.2 mmol) and the resulting mixture was stirred at rt overnight. The solvent was evaporated off and the residue triturated with ether. Yield 80 mg (88%), LCMS (Method J) RT 0.73 min (92% AP), m/z 284.2 (MH+), 1H NMR (300 MHz, DMSO-d6) δ ppm 7.30-7.45 (m, 5H), 7.27 (d, J=8.4, 2H), 6.97 (d, J=8.7, 2H), 5.09 (s, 2H), 4.09 (s, 1H), 3.44 (d, J=12.6, 2H), 3.32-3.29 (m, 1H), 3.08-3.20 (m, 1H), 2.95 (d, J=12.6, 1H), 2.48-2.58 (m, 1H), 1.82 (d, J=13.2, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]=[C:15]1[O:19][C:17](=[O:18])[CH2:16]1>CN(C=O)C>[C:17]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)(=[O:18])[CH2:16][C:15]([CH3:14])=[O:19]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
1-tert-Butoxycarbonylpiperazine (103 g) was dissolved in DMF (600 mL) and diketene (56 mL) was added over 20 min at room temperature. The mixture was stirred for 2 hr. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate. The mixture washed with water and saturated brine and dried. The solvent was evaporated under reduced pressure to give 1-acetoacetyl-4-tert-butoxycarbonyl piperazine (129 g) as a pale-brown powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10]Cl)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4].[I-:28].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10][I:28])[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1nc(CI)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1

Procedure:
A solution of 106.2 g (0.250 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester and 56.2 g (0.375 mole) of sodium iodide in 2200 ml of acetone is refluxed for 40 minutes. The reaction mixture is thereupon concentrated in vacuo. Water is added to the residue, and extraction is performed twice with methylene chloride. The organic phase is washed twice with diluted aqueous sodium bisulphite solution and twice with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. The residue is dissolved in the minimum amount of methylene chloride, and 400 ml of ether is slowly added with stirring, whereupon the reaction product crystallises out. After filtration with suction and drying in vacuum, there is obtained 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(iodomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 125°-128°.
Reaction SMILES: [OH:1][CH:2]1[CH2:15][CH:14]([OH:16])[C@H:13]([S:17][CH2:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C@H:3]1[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH3:26][Mg]I.[Mg].CI>C(OCC)C>[OH:1][CH:2]1[CH2:15][CH:14]([OH:16])[C@H:13]([S:17][CH2:18][C:19]([OH:25])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C@H:3]1[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: C[Mg]I
Reactant: CCCCCC(=O)CS[C@H]1C(O)CC(O)[C@@H]1CC=CCCCC(=O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: CI
Product: CCCCCC(C)(O)CS[C@H]1C(O)CC(O)[C@@H]1CC=CCCCC(=O)O

Procedure:
Add dropwise 0.37 g. 9,11-dihydroxy-15-oxo-13-thia-5-prostenoic acid, dissolved in 10 ml. dry diethyl ether, to a methyl magnesium iodide solution, prepared from 0.024 g. magnesium shavings and 0.14 g. methyl iodide in 15 ml. dry diethyl ether, stir the reaction for one hour, pour into 50 ml. saturated aqueous NH4Cl solution, extract with diethyl ether, dry the organic phase over Na2SO4 and distill off the solvent to obtain, as the residue, 9,11,15-trihydroxy-15-methyl-13-thia-5-prostenoic acid.
Reaction SMILES: P(=O)(O)(O)O.Cl[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:16]([O-:18])=[O:17])[NH:9][CH:8]=1.[OH2:19]>COCCO>[N+:16]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:7][C:8](=[O:19])[NH:9]2)([O-:18])=[O:17]
Reactant: O
Reactant: O=[N+]([O-])c1cccc2[nH]cc(Cl)c12
Agent: O=P(O)(O)O
Solvent: COCCO
Product: O=C1Cc2c(cccc2[N+](=O)[O-])N1
Temperature: 95 °C
Reaction time: 3.5 h

Procedure:
Phosphoric acid (35 mL of 86%) is added to a solution of 3-chloro-4-nitroindole (1.27 g, 6.46 mmol) in 2-methoxyethanol (50 mL) at 100° C. The resulting brown colored solution is stirred at 95° C. for 3.5 hours. The reaction is cooled to room temperature and then poured into 500 mL of water. The aqueous layer is extracted three times with ethyl acetate. The ethyl acetate layer is dried over magnesium sulfate, filtered and the solvents removed by rotary evaporation. The crude material is purified via silica gel column chromatography using 2% methanol/methylene chloride as the eluent. The product containing fractions are combined and the solvents removed by rotary evaporation to yield 0.90 g of slightly impure 4-nitrooxindole as an orange solid.
Reaction SMILES: [Cu][C:2]#[N:3].Cl[C:5]1[CH:6]=[C:7]2[C:23]([CH3:24])=[C:22]([CH3:25])[NH:21][C:8]2=[C:9]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)[N:10]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[C:9]1[N:10]=[C:5]([C:2]#[N:3])[CH:6]=[C:7]2[C:23]([CH3:24])=[C:22]([CH3:25])[NH:21][C:8]=12
Reactant: N#C[Cu]
Reactant: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(Cl)cc2c1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(C#N)cc2c1C
Temperature: 25 °C
Yield: 24.1 %

Procedure:
Copper(I) cyanide (9.3 g, 102.6 mmol) was added to a solution of 2-(5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline (3.2 g, 10.3 mmol) prepared in Example 656 in anhydrous N,N-dimethylformamide (100 ml). The reaction mixture was refluxed for 24 hours and then cooled to room temperature. Ethyl acetate was added to the reaction mixture, which was then filtered to discard insoluble matertals. The reaction mixture washed with water. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 750 mg of the titled compound as a white solid. (Yield: 26%)
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.CCN(C(C)C)C(C)C.[CH:58]1([S:61](Cl)(=[O:63])=[O:62])[CH2:60][CH2:59]1>ClCCl>[CH:58]1([S:61]([N:46]2[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][NH:40][C@:5]34[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]3[C@@H:7]3[C@@:2]([CH3:1])([CH2:3][CH2:4]4)[C@@:19]4([CH3:20])[C@@H:10]([C@:11]5([CH3:33])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]4[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=4)=[CH:13][CH2:12]5)[CH2:9][CH2:8]3)[CH2:48][CH2:47]2)(=[O:63])=[O:62])[CH2:60][CH2:59]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(=O)(=O)C4CC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 20 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (26 mg, 0.040 mmol) and Hunig's Base (0.035 mL, 0.198 mmol) in dichloromethane (1 mL) was added a solution of cyclopropanesulfonyl chloride (11.14 mg, 0.079 mmol) in dichloromethane (1 mL) at room temperature. The reaction mixture was stirred for 2 hours at 20° C. or LCMS indicated the formation of desired product and consumption of starting material. The reaction mixture was diluted with distilled water (4 mL), extracted with dichloromethane (3×4 mL), the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the desired product as a yellow solid (30 mg, 100%). LCMS: m/e 760.61 (M+H)+, 2.40 min (method 11).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[CH2:17]O)[C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[CH2:17][Br:20])[C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1ccc(CO)c(OCc2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CBr)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4.3 g (18 mmol) of the alcohol (a) underwent substitution in 40 ml of THF with 7.9 g (24 mmol) of CBr4 and 6.3 g (24 mmol) of PPh3, which was added in portions over the course of 30 min. The reaction mixture was stirred at RT for 20 h. The product was purified by column chromatography (mobile phase: t-butyl methyl ether/petroleum ether 2:1). 4.6 g were obtained.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=2OC)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])ccc1OC1CCN(C(C)C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1CCC(Oc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
1-isopropyl-4-(2-methoxy-4-nitrophenoxy)piperidine (167 mg, 0.57 mmol) was dissolved in methanol (20 mL) and placed under a nitrogen atmosphere. A catalytic amount of 20% palladium hydroxide on carbon was added and a hydrogen balloon was connected to the reaction flask. The flask was flushed five times with hydrogen and stirred at room temperature under hydrogen atmosphere for 16 hours. The reaction mixture was filtered and washed with methanol. The filtrate was evaporated under reduced pressure. Acetonitrile (10 mL) was added to the residue, swirled for 10 min, and decanted away from white film. The acetonitrile layer was evaporated under reduced pressure yielding 4-(1-isopropylpiperidin-4-yloxy)aniline as a brown oil (131 mg, 87%). LC/MS (m/z): 265.2 (MH+), Rt 0.33 minutes.
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4]([C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:5][CH2:6][CH3:7]>>[CH3:3][C:4]([C:8]([CH3:1])([OH:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:5][CH2:6][CH3:7]
Reactant: [Li]C
Reactant: CCC=C(C)C(=O)CCCCC
Product: CCC=C(C)C(C)(O)CCCCC
Reaction time: 2.5 h

Procedure:
To a dry 5 liter multi-neck round bottom flask fitted with an air stirrer, nitrogen inlet condenser and an addition funnel 1.617 g of CH3Li was added and stirred. 336 g of 4-methyl-3-decene-5-one (see example A for preparation of 3-decene-4-methyl-5-one) was added dropwise over 105 minutes. The temperature of the reaction rose to 63° C. The reaction mixture was aged for 150 minutes and a first sample was taken at 37° C. 30 minutes later, a second sample was taken at 30° C. The mixture was quenched with acetic acid, allowed to settle and layers separated. The aqueous layer was washed twice with 100 ml of toluene. The toluene extracts were added to the organic layer and washed with Na2CO3. The NMR spectrum of the 4.5-Dimethyl-3-decene-5-ol is as follows: 0.88 ppm (t, 3H); 0.94 ppm (t, 3H); 1.28 ppm (s, 3H); 1.15-1.35 ppm (m, 6H); 1.50 ppm (s, 1H); 1.55 ppm (s,1H), 2.05 ppm (m, 2H); ; 5.45 ppm (m, 1 H) The IR spectrum of the 4.5-Dimethyl-3-decene-5-ol is as follows: OH-stretch broad at 3416 cm−1, CH-stretch saturated at 2960, 2933, 2872 cm−1, double bond stretch at 1680 cm−1, 1462 and 1372 due to CH stretch.