Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3](=[CH:13]OCC)[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])#[N:2].Cl.[NH:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)[NH2:19].CCN(C(C)C)C(C)C>C(O)C>[NH2:2][C:1]1[N:18]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=2)[N:19]=[CH:13][C:3]=1[C:4](=[O:5])[NH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC=C(C#N)C(=O)NC1CCCCC1
Reactant: COC(=O)c1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2N)cc1
Temperature: 70 °C

Procedure:
2-cyano-N-cyclohexyl-3-ethoxy-prop-2-enamide (Intermediate #17) (605 mg, 2.73 mmol) and methyl 4-hydrazinylbenzoate hydrochloride (Intermediate#123) (552 mg, 2.73 mmol) were suspended in ethanol (20 mL). DIPEA (351 mg, 2.73 mmol) was added and the mixture heated to 70° C. for 1 h. The reaction mixture was cooled to ambient and the resulting precipitate recovered by filtration, washed with ether and dried in vacuo to give the title compound as a white solid. (618 mg 66%)
Reaction SMILES: C(O)C.Cl.[NH2:5][OH:6].[C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1)#[N:8].C[O-].[Na+]>O>[NH2:8][C:7](=[N:5][OH:6])[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: CCOC(=O)N1CCC(C#N)CC1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)N1CCC(C(N)=NO)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Ethanol (150 ml) was added to a solution of hydroxylamine hydrochloride (17.25 g) in water (48 ml). Ethyl 4-cyano-1-piperidinecarboxylate (45 g) was added and the mixture was cooled. Sodium methoxide (44.4 g) was added dropwise at RT and the reaction mixture was stirred for 30 minutes at 60° C. The reaction mixture was cooled, filtered and the filtrate evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent evaporated, yielding 25 g (40%) of ethyl 4-[amino(hydroxyimino)methyl]-1-piperidinecarboxylate. This fraction was redissolved in 2-propanone and converted into the hydrochloric acid salt (1:1) with HCl/2-propanol. The precipitate was filtered off and dried, yielding 22 g (35%) of ethyl 4-[amino(hydroxyimino)methyl]-1-piperidine-carboxylate hydrochloride (intermediate 2).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.[N:34]1([CH2:39][CH2:40]Cl)[CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:40][CH2:39][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC
Reactant: ClCCN1CCCC1
Product: COc1cc(-c2nc3ccc(OCCN4CCCC4)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 104 with 2-(pyrrolidin-1-yl)ethyl chloride essentially as previously described. mp 143° C., NMR, IR, MS 555.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]=[CH:12][CH2:13][OH:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(=[O:37])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[C:15]([O:14][CH2:13][CH:12]=[CH:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:37])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: O=C(OCC=CCO)c1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)Cl
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)OCC=CCOC(=O)c1ccccc1

Procedure:
4-Benzoyloxy-2-butenyl erucate was prepared by the procedure of Example 1 from 19 gms (0.1 mole) of 4-hydroxy-2-butenyl benzoate and 35.5 gms (0.1 mole) of erucoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][CH2:13][CH2:14][CH2:15][SH:16].[OH-].[K+]>C1COCC1>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[S:16][CH2:15][CH2:14][CH2:13][Cl:12]
Reactant: SCCCCl
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(Cl)c1SCCCCl
Temperature: 23 °C
Reaction time: 3.5 h
Yield: 99.1 %

Procedure:
To a dry THF (Aldrich anhydrous grade, 70 mL) solution of 2,3-dichloronitrobenzene (9.61 g, 50.1 mmol) and 3-chloropropanethiol (5.0 g, 45.5 mmol) was added in one portion at 23° C. KOH pellets. The resulting mixture was vigorously stirred at 23° C. for 3.5 h. The reaction mixture was filtered through a Celite plug to remove remaining KOH. The plug was washed with THF (2×50 mL). The filtrate was concentrated in vacuo to give crude 1-chloro-2-[(3-chloropropyl)sulfanyl]-3-nitrobenzene (12 g, ˜100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[C:10]([C:18]([NH:20][CH3:21])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.S1C=CN=C1C(O)(C#C)C.[CH3:32][C:33]1[O:37][N:36]=[C:35]([C@:38]([OH:42])([C:40]#[CH:41])[CH3:39])[CH:34]=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:41]#[C:40][C@@:38]([OH:42])([C:35]4[CH:34]=[C:33]([CH3:32])[O:37][N:36]=4)[CH3:39])[CH:15]=3)[C:10]([C:18]([NH:20][CH3:21])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CNC(=O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Agent: C#CC(C)(O)c1nccs1
Product: CNC(=O)c1nn(-c2ccnc(N)n2)c2cc(C#C[C@@](C)(O)c3cc(C)on3)ccc12

Procedure:
The title compound was prepared by procedure described in Example 62-c, by substituting 1-(2-aminopyrimidin-4-yl)-6-bromo-N,N-dimethylindazole-3-carboxamide with 1-(2-aminopyrimidin-4-yl)-6-bromo-N-methylindazole-3-carboxamide and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol with (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol in Step 3: 1H NMR (500 MHz, DMSO) delta 1.87 (3H, s), 2.42 (3H, s), 2.87 (3H, d, J=4.73 Hz), 6.42 (1H, s), 6.60 (1H, s), 7.17 (2H, br. s.), 7.32 (1H, d, J=5.36 Hz), 7.46 (1H, dd, J=8.35, 1.10 Hz), 8.27 (1H, d, J=8.20 Hz), 8.40 (1H, d, J=5.36 Hz), 8.78 (1H, d, J=4.73 Hz), 8.94 (1H, s); LC-MS: m/z=+418.05 (M+H)+.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[C:12]([O:16][C:17]([N:19]1[CH2:23][CH:22]=[C:21]([CH2:24]OC(=O)C)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C1COCC1.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:6][O:5][C:3](=[O:4])[CH:2]([CH2:24][C:21]1[CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:23][CH:22]=1)[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(=O)OCC1=CCN(C(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C(CC1=CCN(C(=O)OC(C)(C)C)C1)C(=O)OC
Temperature: 25 °C
Yield: 77.6 %

Procedure:
5.28 g (40 mmol) dimethyl malonate were cautiously added to an ice-cooled suspension of 864 mg (36 mmol) sodium hydride in 80 ml THF. The resulting clear solution was added to a solution of 4.82 g (20 mmol) 3-acetoxymethyl-2,5-dihydro-pyrrole-1-carboxylic acid tert.-butylester and 462 mg (0.4 mmol) Pd(PPh3)4 in 40 ml THF and the mixture was heated to reflux for 20 h. The reaction mixture was cooled to room temperature, diluted with ether and quenched with sat. NH4Cl. The organic layer was washed with sat. NH4Cl and brine, dried over MgSO4 and evaporated. The residue was purified by flash chromatography (ethyl acetate/petrol ether 4:1 to 2:1) and bulb-to-bulb distilled to yield 4.86 g (77%) of 2(1-tert.-butoxycarbonyl-2,5-dihydro-1H-pyrrol-3 -yl-methyl)-malonic acid dimetylester as a colorless oil, b.p. 130° C./0.2 mbar.
Reaction SMILES: O=C(OC1C=C([NH2:31])C=CC=1OC(=O)CCCCCCCCC)CCCCCCCCC.Br[CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.[I-].[Na+]>C(#N)C.CN(C=O)C>[C:38]1([CH2:37][O:36][C:34](=[O:35])[CH2:33][NH2:31])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCCCCCCCCC(=O)Oc1ccc(N)cc1OC(=O)CCCCCCCCC
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: NCC(=O)OCc1ccccc1

Procedure:
A mixture of 2.5 g (5.77 mmol) of 3,4-bis[(1-oxodecyl)oxy]benzenamine, 9.1 ml (57.7 mmol) of benzyl bromoacetate, 3.1 g (14.4 mmol) of 1,8-bis(dimethylamino)naphthalene and 0.34 g (2.3 mmol) of sodium iodide in 50 ml of acetonitrile and 10 ml of DMF was stirred at reflux for 48 hours. The solvents were removed at reduced pressure and the residue was treated with methylene chloride and water. The organic phase was separated, dried and concentrated to an oil which was purified by HPLC using 20% ethyl acetate-hexane to give 2.2 g (52% yield) of N-[3,4-bis[(1-oxodecyl)oxy]phenyl]-N-[2-oxo-2-phenylmethoxy)ethyl]glycine phenylmethyl ester as an oil. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:14]([CH3:29])=[C:15]([NH:21][C@H:22]([C@H:26]([OH:28])[CH3:27])[C:23](O)=[O:24])[CH:16]=[CH:17][C:18]=1[C:19]#[N:20]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:23](=[O:24])[C@H:22]([NH:21][C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[C:13]([Cl:12])[C:14]=2[CH3:29])[C@H:26]([OH:28])[CH3:27])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1ccc(Cl)cc1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Cl)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Yield: 92.7 %

Procedure:
4-Chloro-N′-((2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)benzohydrazide was prepared using 4-chlorobenzoic hydrazide (4.42 mmol, 1.1 equiv.) and (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (4.02 mmol, 1.0 equiv.) according to the procedure as described for intermediate 5a. The crude off-white solid was recrystallized using hot methylene chloride to provide the desired product as a white solid (1.57 g, 93% yield). Other data: 1H NMR (400 MHz, acetone-d6, δ in ppm) 9.94 (br. s, 1H), 9.48 (br. s, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.55 (m, 3H), 6.73 (d, J=8.5 Hz, 1H), 5.59 (br. d., J=7.1 Hz, 1H), 4.25 (m, 1H), 4.13 (m, 1H), 2.35 (s, 3H), 1.37 (d, J=6.4 Hz, 3H); LRMS (ESI+) exact mass calcd for C19H18Cl2N4O3 [M]+421.28, found 421.3; TLC Rf=0.32, 100% EtOAc, vanillin stain.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1.F[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[C:23]([F:26])([F:25])[F:24].Cl>CN(C=O)C>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([O:7][C:8]2[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=2)=[C:16]([C:23]([F:24])([F:25])[F:26])[CH:17]=1)#[N:20]
Reactant: Cc1cc(O)n[nH]1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(C#N)cc2C(F)(F)F)n[nH]1
Temperature: 80 °C
Yield: 42.4 %

Procedure:
Potassium carbonate (2.8 g, 20.0 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (1.47 g, 15.0 mmol) and 4-fluoro-3-trifluoromethylbenzonitrile (2.8 g, 15.0 mmol) in DMF (30 ml), and the mixture was stirred under heating at 80° C. for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (70 ml) and extracted with ethyl acetate (30 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a yellowish solid of 3-(4-cyano-2-trifluoromethylphenyloxy)-5-methylpyrazole (1.7 g, yield: 42.4%). mp: 123-125° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.28 (d, J=0.5 Hz, 3H), 5.75 (d, J=0.5 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.75 (dd, J=2.0 and 8.8 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 9.60-11.60 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:6]=2[N:20]=1.I[CH3:22].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:22])[C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:6]=2[N:20]=1
Reactant: CC1CN(C2CCOCC2)c2nc(Cl)ncc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(C2CCOCC2)c2nc(Cl)ncc2N(C)C1=O
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a cooled mixture of 1.57 g (0.00529 mole) of (rac)-2-chloro-7-methyl-9-(tetrahydro-pyran-4-yl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-45), 0.49 mL (0.00794 mole) of iodomethane and 15 mL of N,N-dimethyl-formamide at 0 degrees was added 0.32 g (0.00794 mole) of 60% oil dispersion of sodium hydride. The mixture was stirred at 0 degrees for 2 hours and then partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed successively with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-60:40) to give 1.64 g of (rac)-2-chloro-5,7-dimethyl-9-(tetrahydro-pyran-4-yl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-45) as white powder. HRMS (ES+) m/z Calcd for C14H19CIN4O2+H [(M+H)+]: 311.1270. Found: 311.1269.
Reaction SMILES: [CH2:1]([C:3]1([C:41]([OH:43])=[O:42])[CH2:8][CH2:7][N:6]([C:9]([C@:11]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:34])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([OH:33])[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)=[O:10])[CH2:5][CH2:4]1)[CH3:2].N1C=CC=CC=1.[CH3:50][C:51]1([CH3:58])[CH2:55][C:54](=[O:56])[O:53][C:52]1=[O:57]>C(OCC)(=O)C>[C:52]([C:51]([CH3:58])([CH3:50])[CH2:55][C:54]([O:33][C@H:20]1[CH2:19][CH2:18][C@@:17]2([CH3:34])[C@@H:22]([CH2:23][CH2:24][C@:25]3([CH3:30])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:26]3([CH3:29])[CH2:27][CH2:28][C@@:11]3([C:9]([N:6]4[CH2:5][CH2:4][C:3]([CH2:1][CH3:2])([C:41]([OH:43])=[O:42])[CH2:8][CH2:7]4)=[O:10])[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:12]32)[C:21]1([CH3:32])[CH3:31])=[O:56])([OH:57])=[O:53]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(CC)(C(=O)O)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: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(CC)(C(=O)O)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 4-ethyl-1-((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)piperidine-4-carboxylic acid (Example 84, 0.5 g, 0.80 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.2 g, 1.6 mmol) and 3,3-dimethyldihydrofuran-2,5-dione (0.82 ml) were added. The contents were refluxed for about 16 hours. After 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, water followed by brine then 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: 725 (100%), [M+1].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8][N:7]=1.[O:19]1[CH2:24][O:23][CH2:22][O:21][CH2:20]1.FC(F)(F)C(O)=O.C(OO)(C)(C)C>C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:20]2[O:21][CH2:22][O:23][CH2:24][O:19]2)=[N:8][N:7]=1
Reactant: Cc1cccc(Nc2nncc3ccccc23)c1
Reactant: C1OCOCO1
Agent: CC(C)(C)OO
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Nc2nnc(C3OCOCO3)c3ccccc23)c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
To a suspension of 9.6 g (40.8 mmol) 1-(3-methylanilino)phthalazine and 173 g 1,3,5-trioxane in 570 ml acetonitrile, 3.12 ml (40.8 mmol) trifluoroacetic acid, 11.0 ml (80% in tBuOOtBu; 87.4 mmol) tBuOOH and 190 mg (0.68 mmol) FeSO4·7 H2O are added, and the mixture stirred for 17 h at 80° C. The cooled reaction mixture is partly evaporated in the RE, diluted with EtOAc and water and adjusted to an alkaline pH with 1 N NaOH. The aqueous phase is separated off and twice extracted with EtOAc. The organic phases are washed twice with water and brine, dried (Na2SO4) and evaporated. Column chromatography (SiO2; EtOAc/toluene 1:3; applied as solution in dichloromethane/acetone 9:1) yields the title compound after crystallization with the addition of DIPE; m.p. 161° C.; DC (EtOAc/toluene 1:3) Rf=0.27; 1H-NMR (DMSO-d6) 9.27 (s, HN), 8.74 (m, 1H), 8.61 (m, 1H), 8.00 (m, 2H), 7.72 (s, 1H), 7.68 (d, 1H), 7.25 (t, 1H), 6.89 (d, 1H), 6.39 (s, 1H), 5.47 (d, 2H), 5.41 (d, 2H), 2.33 (s, 3H); FAB-MS (M+H)+=324; anal. calc.(C18H17N3O3) C, 66.86%; H, 5.30%; N, 13.00%; meas. C, 66.83%; H, 5.36%; N, 12.81%.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH2:14][NH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[I-:22].[Na+].[OH-].[Na+].Cl[O-].[Na+]>CO>[I:22][C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])=[CH:14][N:13]=2)[CH:20]=[CH:19][C:18]=1[OH:21]
Reactant: [I-]
Reactant: O=C(C1=CC=C(c2ccc(O)cc2)NC1)N1CCOCC1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CO
Product: O=C(c1ccc(-c2ccc(O)c(I)c2)nc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 12 h
Yield: 61.4 %

Procedure:
A mixture of Example 44B (4.25 g, 15.0 mmol) sodium iodide (2.36 g, 15.7 mmol) and sodium hydroxide (0.63 g, 15.7 mmol) was stirred in methanol (90 mL) with heating until a clear solution was obtained. The solution was then cooled to 0° C. and to this was slowly added sodium hypochlorite (22 mL of 5.25%, 1.15 g, 15.5 mmol) (Clorox™) over 45 minutes. While maintaining 0° C., two sequential additions of NaI (0.3 g, 1.5 mmol) and Clorox (2.2 mL, 0.12 g, 1.5 mmol) were made both 2 hours and 4 hours later. The mixture was stirred for 12 hours at ambient temperature, quenched by the sequential addition of aqueous sodium thiosulfate (10 mL), water (800 mL) and sufficient aqueous sodium dihydrogen phosphate (NaH2PO4) to adjust the pH to 7. The mixture was extracted with dichloromethane, and the combined extracts dried (Na2SO4), filtered and concentrated under reduced pressure to give a tan foam. The product was crystallized from ethanol to give the titled compounds as a tan solid (3.78 g, 61%). MS (DCI) m/z 411 (M+H)+;
Reaction SMILES: CI.[C:3](=[O:6])([O-])[O-].[K+].[K+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1O>O1CCCC1>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:6][CH3:3]
Reactant: Oc1c(F)cccc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Methyl iodide (850 μl, 13.646 mmol) and potassium carbonate (943 mg, 6.824 mmol) were added to 2-chloro-6-fluorophenol (1.0 g, 6.824 mmol) in tetrahydrofuran (10 ml) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between diethyl ether (50 ml) and water (50 ml). The organic phase was extracted and further washed with water (2×20 ml) then dried over sodium sulphate and concentrated in vacuo to afford the title compound as a colourless liquid in 94% yield, 1.03 g.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[BrH:12].N([O-])=O.[Na+].C(OCC)(=O)C>O>[Br:12][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: Br
Reactant: Nc1ccc(C(=O)O)c(O)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(Br)cc1O
Reaction time: 0.5 h
Yield: 73 %

Procedure:
4-Aminosalicylic acid (15.0 g, 98 mmol) and hydrobromic acid (47%, 100 ml) were mixed with water (100 ml). A solution of sodium nitrite (6.8 g, 98 mmol) in water (50 ml) was added dropwise to the mixture at 0° C., and the mixture was stirred at the same temperature for 30 minutes. A mixture of cuprous bromide (16.9 g, 117 mmol) and hydrobromic acid (47%, 45 ml) was added dropwise to the mixture at 0° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was combined with ethyl acetate and extracted. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (15.5 g, 73%) as a gray solid.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([S:15]([NH:18][C@H:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.COC(=O)[C@@H](C(C)C)N>O1CCOCC1.C(Cl)Cl>[N:12]1([S:15]([NH:18][C@H:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]1
Reactant: COC(=O)[C@@H](C)NS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: COC(=O)[C@H](N)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)NS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
Hydrogen chloride gas was bubbled through a solution of methyl 2-(R)-[(4-tert-butoxycarbonylpiperazine-1-sulfonyl)amino]propionate (3.6 g, 10.7 mmol) [prepared by proceeding as described in Example 2, but substituting 4-(5-chloropyridin-2-yloxy)piperidine and D-valine methyl ester with 1-tert-butoxycarbonyl-1,4-piperazine and D-alamine methyl ester, respectively] in 10% dioxane/methylene chloride (100 ml) for 10 min. The reaction was stirred at RT for 4 h and concentrated in vacuo to give methyl 2-(R)-[(piperazine-1-sulfonyl) amino]propionate (91%) as a white solid that was used without further purification.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][CH2:7]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Br:23]Br>C(Cl)Cl.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:23][C:13]1[CH:14]=[C:9]2[CH2:8][CH2:7][N:6]([Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:16])[CH3:15])[C:10]2=[N:11][CH:12]=1
Reactant: BrBr
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cccnc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)N1CCc2cc(Br)cnc21
Yield: 76.7 %

Procedure:
To a stirred and cooled (0° C.) solution of the azaindoline 3 (1.1 g, 4.7 mmol) in CH2Cl2 (25 mL) and pyridine (0.46 mL, 5.6 mmol) was added dropwise a solution of bromine (0.24 mL, 4.7 mmol) in CH2Cl2 (15 mL) over a period of 13 min. After a further 20 min stirring the mixture was diluted with a NaHCO3—Na2S2O3 (1:1 v/v) solution and stirred vigorously for 50 min. The resulting mixture was partitioned and the aqueous layer extracted with CH2Cl2 (3×). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by SGC with hexane:AcOEt as eluent (in gradient up to 1.3% AcOEt) to afford the bromo derivative 4 (1.13 g, 77%) as a pale yellow oil. 1H NMR (400 MHz; CDCl3) δ 0.31 (s, 6H), 0.95 (s, 9H), 2.99 (t, J=9.1 Hz, 2H), 3.67 (t, J=9.1 Hz, 2H), 7.20 (m, 1H), 7.79 (m, 1H).