Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:21][CH3:22])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:21][CH3:22])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: CCN(c1cc(Cl)cc(C(=O)OC)c1OC)C1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(c1cc(Cl)cc(C(=O)O)c1OC)C1CCOCC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 90.7 %

Procedure:
To a solution of methyl 5-chloro-3-[ethyl(oxan-4-yl)amino]-2-methoxybenzoate (127 mg, 0.39 mmol) in THF (4 ml) was added 4M NaOH (3.87 ml). The reaction mixture was stirred at 50° C. for 24 hours. The reaction mixture was acidified to pH 2-3 with 6M HCl and extracted with DCM (5×15 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give 111 mg (91%) of the title compound as a yellow oil. LC-MS 80%, 1.25 min (3 minute LC-MS method), m/z=314.4/315.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 10.02-9.55 (m, 1H), 8.01-7.47 (m, 1H), 7.36-6.96 (m, 1H), 4.15-3.86 (m, 5H), 3.76 (t, J=6.6 Hz, 2H), 3.55-3.12 (m, 3H), 1.95-1.59 (m, 4H), 1.15-0.88 (m, 3H).
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.Cl.[NH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:5]1[N:4]=[C:3]([NH:31][CH2:32][CH2:33][NH:34][C:35]2[N:36]=[CH:37][C:38]([C:39]#[N:40])=[CH:41][CH:42]=2)[N:8]2[N:9]=[C:10]([CH:12]3[CH2:13][CH2:14][N:15]([CH:18]([CH3:19])[CH3:20])[CH2:16][CH2:17]3)[N:11]=[C:7]2[CH:6]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Reactant: N#Cc1ccc(NCCN)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C#N)cn4)n3n2)CC1
Temperature: 130 °C

Procedure:
50 mg (0.12 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 40A), 28 mg (0.14 mmol) of 6-[(2-aminoethyl)-amino]pyridine-3-carbonitrile dihydrochloride (Example 2A) and 0.125 ml (3.5 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 48 mg (74% of theory) of the product as a solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:35]([Mg]Cl)([CH3:37])[CH3:36]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([OH:34])([CH:35]([CH3:37])[CH3:36])[CH3:33])=[CH:30][CH:31]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)[Mg]Cl
Reactant: CC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
To a solution of 1-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-ethanone (prepared as in Example 64, 450 mg, 0.95 mmol) in dry tetrahydrofuran (20 mL) at 0° C. was added isopropylmagnesium chloride solution in tetrahydrofuran (2 M, 1.05 mL, 2.1 mmol) dropwise. After stirring at 0° C. for 3 h, the reaction was quenched with a saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 2-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-3-methyl-butan-2-ol (90 mg, 20%) as a white solid: LC/MS m/e calcd for C31H34N2O3S [M+H]+ 515.69, observed 515.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.ClC1C=C(C=CC=1)C(OO)=[O:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:22])=[CH:4][C:3]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(Cc2cnccc2Cl)cc1
Product: COc1ccc(Cc2c[n+]([O-])ccc2Cl)cc1

Procedure:
The product of step A is oxidized to the title compound with m-chloroperoxybenzoic acid (1.1 molar equivalents).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14](Cl)=[O:15])=[C:12]([CH3:17])[O:11][N:10]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][C:36]([F:39])([F:38])[F:37])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH2:35][C:36]([F:38])([F:39])[F:37])[CH2:26][CH2:27]2)=[O:15])=[C:12]([CH3:17])[O:11][N:10]=1
Reactant: NCCCN1CCN(c2ccccc2OCC(F)(F)F)CC1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)NCCCN1CCN(c2ccccc2OCC(F)(F)F)CC1
Yield: 92 %

Procedure:
The title compound was synthesised according to the procedure described in Example 8 but using 3-(2-chloro-6-fluorophenyl)-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 (92%) as an oil.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:6])[CH2:4][Br:5].[CH3:7][O:8][CH2:9]OC>C(Cl)Cl>[Br:1][CH2:2][CH:3]([O:6][CH2:7][O:8][CH3:9])[CH2:4][Br:5]
Reactant: COCOC
Reactant: OC(CBr)CBr
Solvent: ClCCl
Product: COCOC(CBr)CBr

Procedure:
1,3-Dibromo-2-propanol, dimethoxymethane, and boron trifluoride diethyl ether complex were reacted in methylene chloride at room temperature to obtain 1,3-dibromo-2-(methoxymethoxy)propane.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:3]=1[C:20]#[N:21].[OH:22]O.[OH-].[Na+]>O1CCCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[NH2:1][C:2]1[N:6]([C:7]([CH3:9])([CH3:10])[CH3:8])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:3]=1[C:20]([NH2:21])=[O:22]
Reactant: CC(C)(C)n1nc(-c2ccc([N+](=O)[O-])cc2)c(C#N)c1N
Reactant: OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)n1nc(-c2ccc([N+](=O)[O-])cc2)c(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-amino-1-tert-butyl-3-(4-nitro-phenyl)-1H-pyrazole-4-carbonitrile (2.85 g, 10 mmol) in 40 mL of tetrahydrofuran were added a 30% aqueous solution of hydrogen peroxide (80 mL), a 1 M solution of sodium hydroxide (20 mL) and 3 g of tetrabutylammonium hydrogensulfate. The reaction mixture was stirred for 48 hours at room temperature and extracted with ethyl acetate (2×200 mL). The organic layers were combined, washed with brine, dried over solid MgSO4, filtered and evaporated. The yellow residue was purified by normal phase silica column chromatography (100% ethyl acetate) to give 750 mg of pure 5-amino-1-tert-butyl-3-(4-nitro-phenyl)-1H-pyrazole-4-carboxylic acid amide. 1H-NMR (DMSO-d6): ppm 1.54 (s, 9H), 6.11 (br s, 2H), 7.81 (d, 2H, J=7.6 Hz), 8.22 (d, 2H, J=7.6 Hz). LC MS (m/e)=304.2 (MH+).
Reaction SMILES: [C@H:1]1([O:12][C@H:13]2[C@H:18]([OH:19])[C@@H:17]([CH2:20][O:21][C@H:22]3[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@@H:23]3[OH:24])[O:16][C@H:15]([O:33][CH2:34][CH2:35][NH:36][C:37](=[O:66])[CH2:38][CH2:39][C@H:40]([NH:44][C:45](=[O:65])[CH2:46][CH2:47][CH2:48][C:49](=[O:64])[NH:50][CH2:51][CH2:52][O:53][C@@H:54]3[O:62][C@@H:61]([CH3:63])[C@@H:59]([OH:60])[C@@H:57]([OH:58])[C@@H:55]3[OH:56])[C:41]([OH:43])=[O:42])[C@H:14]2[OH:67])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[B-](F)(F)(F)F.CN(C(O[N:81]1[C:86](=[O:87])[CH2:85][CH2:84][C:82]1=[O:83])=[N+](C)C)C.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.C(C#N)(C)=O>CN(C=O)C>[C@H:1]1([O:12][C@H:13]2[C@H:18]([OH:19])[C@@H:17]([CH2:20][O:21][C@H:22]3[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@@H:23]3[OH:24])[O:16][C@H:15]([O:33][CH2:34][CH2:35][NH:36][C:37](=[O:66])[CH2:38][CH2:39][C@H:40]([NH:44][C:45](=[O:65])[CH2:46][CH2:47][CH2:48][C:49](=[O:64])[NH:50][CH2:51][CH2:52][O:53][C@@H:54]3[O:62][C@@H:61]([CH3:63])[C@@H:59]([OH:60])[C@@H:57]([OH:58])[C@@H:55]3[OH:56])[C:41]([O:43][N:81]3[C:86](=[O:87])[CH2:85][CH2:84][C:82]3=[O:83])=[O:42])[C@H:14]2[OH:67])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CCCC(=O)N[C@@H](CCC(=O)NCCO[C@H]2O[C@H](CO[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)[C@@H](O)[C@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)[C@@H]2O)C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Agent: CC(=O)C#N
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H]1O[C@@H](OCCNC(=O)CCCC(=O)N[C@@H](CCC(=O)NCCO[C@H]2O[C@H](CO[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)[C@@H](O)[C@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)[C@@H]2O)C(=O)ON2C(=O)CCC2=O)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-5-[(2-{[α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranosyl]oxy}ethyl)amino]-5-oxo-2-[5-oxo-5-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)pentanamido]pentanoic acid (366 mg, 0.373 mmol) in DMF (2 mL) at 0° C. was added TSTU (115 mg, 0.381 mmol) and DIPEA (0.1 mL, 0.573 mmol). After stirring at 0° C. for 1 hour, the reaction was quenched with TFA (60 μL, 0.784 mmol). The reaction mixture was transferred dropwise, via autopipette, to a tube containing AcCN (45 mL). The resulting white suspension was centrifuged (3000 rpm, 15 minutes, at 4° C.) to generate a clear supernatant and a white pellet. The supernatant was discarded and the white pellet was washed with AcCN (1 mL) and dried to yield title compound UPLC Method B: calculated for C42H68N4O28 1076.40, observed m/e: 1077.28 [M+1]; Rt=0.90 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=23)[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Product: COc1cccc(Nc2nc(-c3cccnc3)nc3c2cnn3C)c1

Procedure:
6-Chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6, from Example 4, was reacted with pyridine-3-boronic acid using General Procedure A. Purification on silica yielded 124. NMR: (CDCl3): 3.88 (s, 3H, CH3), 4.13 (s, 3H, CH3), 6.88-6.90 (m, H, ArH), 7.16 (m, H, ArH), 7.30 (s, H, ArH), 7.38-7.46 (m, 2H, 2×ArH), 7.50 (sbr, H, NH), 8.72 (m, H, ArH), 8.79-8.82 (m, H, ArH) 9.76 (m, H, ArH). MS: (ESI+) MH+=333.24
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[C:20]([CH:24]=2)[C:21](O)=[O:22])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.[NH2:34][C@@H:35]([CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[C:20]([CH:24]=2)[C:21]([NH:34][C@@H:35]([CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])[C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])=[O:22])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCS(C)(=O)=O
Reactant: O=C(O)c1cc(OC(Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CC(C)(C)OC(=O)[C@H](CCS(C)(=O)=O)NC(=O)c1cc(OC(Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
A mixture of 5-[(1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy)]-2-(4-fluorophenethyl)benzoic acid (800 mg, 1.79 mmol), tert-butyl (2S)-2-amino-4-(methylsulfonyl)butanoate (L-methionine sulphone tert-butyl ester) (630 mg, 2.68 mmol), and DMAP (870 mg, 7.1 mmol), was treated with EDC.HCl (510 mg, 2.7 mmol) was stirred at ambient temperature for 16 hours. The reaction mixture was washed with aqueous citirc acid (1M, 2×), brine, dried (MgSO4) and evaporated to dryness. The residue was purified by chromatography on silica (40 gm Dynamax column, gradient elution 2-10% methanol/dichloromethane) to give a gum which, when triturated with diethyl ether/iso-hexane, gave the title compound as a cream solid (889 mg, 74%).
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].[F:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]3[CH:16]=[N:17][C:18]([C:19]#[N:20])=[C:14]3[C@@H:13]3[CH2:21][CH2:22][N:12]3[C:11](=[O:23])[C:10]=2[CH:24]=1>CO>[F:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]3[CH:16]=[N:17][C:18]([C:19](=[N:3][OH:4])[NH2:20])=[C:14]3[C@@H:13]3[CH2:21][CH2:22][N:12]3[C:11](=[O:23])[C:10]=2[CH:24]=1
Reactant: NO
Reactant: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Agent: Cl
Agent: [Na]
Solvent: CO
Product: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Yield: 86.7 %

Procedure:
4.2 g (180 mmol) of sodium were dissolved in 225 ml of methanol. 13.55 g (195 mmol) of hydroxylamine hydrochloride and 40 g (149 mmol) of (S)-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile were added and the reaction mixture was stirred at boiling temperature overnight. The suspension was cooled to 5° and suction filtered. The crystals were rinsed with water and dried. There were obtained 38.9 g (87%) of (S)-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime, which was used in the next step without further purification.
Reaction SMILES: [Cl:1]Cl.[Cl:3][CH:4]([Cl:13])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].C([O-])(=O)C.[Na+]>>[Cl:3][C:4]([Cl:1])([Cl:13])[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: ClCl
Reactant: O=C(c1ccccc1)C(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=C(c1ccccc1)C(Cl)(Cl)Cl

Procedure:
The synthetic method described in U.S. Pat. No. 4,642,384 involves the preparation of 2,5-bis(2,2,2-trifluoroethoxy)-.,a-dichloroacetophenone as an intermediate by chlorinating the a-unsubstituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone with chlorine gas at a moderate temperature, such as 50-60° C. The α,α-dichloroacetophenone intermediate is further chlorinated in the presence of a buffering base, such as sodium acetate, at a slightly higher temperature, such as 80-100° C. to yield the α,α,α-trichloroacetophenone. The α,α,α-trichloroacetophenone is reacted with 2-aminomethylpyridine to yield a benzamide, and the pyridine ring is reduced to yield 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide.
Reaction SMILES: O[C:2]1([C:26]2[C:27]([OH:35])=[CH:28][C:29]3[O:33][CH2:32][CH2:31][C:30]=3[CH:34]=2)[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][CH2:13][O:14][C:7]3=[CH:6][C:5]=2[N:4]([CH2:15][C:16]2[O:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[C:3]1=[O:25].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[OH:35][C:27]1[C:26]([CH:2]2[C:10]3[CH:9]=[C:8]4[O:11][CH2:12][CH2:13][O:14][C:7]4=[CH:6][C:5]=3[N:4]([CH2:15][C:16]3[O:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[C:3]2=[O:25])=[CH:34][C:30]2[CH2:31][CH2:32][O:33][C:29]=2[CH:28]=1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cc3c(cc2C1(O)c1cc2c(cc1O)OCC2)OCCO3
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C(c2cc3c(cc2O)OCC3)c2cc3c(cc2N1Cc1ccc(C(F)(F)F)o1)OCCO3
Yield: 97.1 %

Procedure:
To a solution of 8-hydroxy-8-(6-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-((5-(trifluoromethyl)furan-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-one (1.81 g, 3.70 mmol) in dichloromethane (50 mL) were added triethylsilane (6.0 mL) and trifluoroacetic acid (10 mL) at 0° C. The resultant mixture was stirred at 0° C. for 2 h and concentrated in vacuo to dryness to afford 8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-6-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one (1.70 g, 97%): MS (ES+) m/z 473.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][NH:12][C@@:11]([C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH:30]3[CH3:35])=[O:28])(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:10]2)=[CH:5][CH:4]=1.Cl[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=1)=[O:40]>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=3)=[O:40])[C@H:11]([C:27]([N:29]3[CH2:34][CH2:33][N:32]([C:39]([O:41][CH2:42][C:43]4[CH:44]=[CH:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:47][CH:48]=4)=[O:40])[CH2:31][CH:30]3[CH3:35])=[O:28])[CH2:10]2)=[CH:36][CH:37]=1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@@H]2CN[C@](C(=O)OCc3ccc([N+](=O)[O-])cc3)(C(=O)N3CCNCC3C)C2)cc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3C)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 154.3 %

Procedure:
0.51 g of 4-dimethylaminopyridine was added dropwise at room temperature to a solution of 1.83 g of (2S,4S)-4-(4-methoxybenzylthio)-2-(2-methylpiperazin-1-ylcarbonyl)-2-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (ii) above] in 25 ml of dry acetonitrile, and then a solution of 0.90 g of 4-nitrobenzyl chloroformate in 15 ml of dry acetonitrile was added dropwise to the resulting mixture, whilst ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes, after which it was concentrated by evaporation under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with water and with an aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 7:3 by volume mixture of ethyl acetate and cyclohexane as the eluent, to give 2.28 g of the title compound, as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1[O:6][C:7]2[C:13]([CH2:14][CH:15]=[CH2:16])=[CH:12][C:11](Cl)=[CH:10][C:8]=2[N:9]=1.C(BCCC(C)C)CC(C)C.CC(=CC)C.[OH-:38].[Na+].OO>C1COCC1>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1[O:6][C:7]2[C:13]([CH2:14][CH2:15][CH2:16][OH:38])=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: C=CCc1cc(Cl)cc2nc(Cc3ccccc3Cl)oc12
Reactant: [OH-]
Agent: CC(C)CCBCCC(C)C
Agent: CC=C(C)C
Agent: OO
Solvent: C1CCOC1
Product: OCCCc1cccc2nc(Cc3ccccc3Cl)oc12
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of 2-(2-chlorobenzyl)-5-chloro-7-allylbenzoxazole (5.0 g, 0.018 mole) in THF was added to a solution of di-iso-amylborane prepared from borane-THF complex (1.60g, 0.018 mol) and 2-methyl-2-butene (2.80 g, 0.04 mol) in THF. The reaction mixture was stirred overnight and cooled to −20° C. then treated with 3 N sodium hydroxide (6.5 ml) and 30% hydrogen peroxide (6.5 ml). The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The product was isolated by partitioning between dichloromethane and water. Flash chromatography over flash chromatographic silica gel with dichloromethane afforded nearly pure title compound which was recrystallized from ether-hexane to give 290 mg of pure title compound, mp 66-68° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:13](=[O:18])[NH:14][NH:15][C:16]=2[CH3:17])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:25](OC(=O)C)(=[O:27])[CH3:26].C(O)(=O)C>CN(C)C=O.O>[C:25]([N:15]1[C:16]([CH3:17])=[C:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=2)[C:13](=[O:18])[NH:14]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1[nH][nH]c(=O)c1Cc1ccc(OC(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)n1[nH]c(=O)c(Cc2ccc(OC(C)C)cc2)c1C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
1,2-Dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one (1.00 g) was suspended in N,N-dimethyl-formamide (5 mL) at room temperature. In addition, potassium carbonate (0.319 g) was added to the suspension, and the mixture was stirred for 30 minutes. Acetic anhydride (0.412 g) was added to the mixture in a dropwise manner at room temperature. The mixture was stirred at room temperature overnight and at 50° C. for 2 hours. In addition, the mixed solution of glacial acetic acid (0.139 g) and water (5.0 g) was added to the reaction mixture under stirring at room temperature. After confirming the precipitation of the crystals, water (25 g) was added to the mixture. The obtained crystals were collected by filtration, washed with water and dried under reduced pressure to give a white solid of 1-acetyl-1,2-dihydro-4-[(4-isopropoxy-phenyl)methyl]-5-methyl-3H-pyrazol-3-one (0.90 g).
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C:16](=O)[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C/C(=[N:56]\[OH:57])/C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1>>[CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15](/[C:16](=[N:56]/[OH:57])/[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1
Reactant: C[C@]12CCCCC1CC(=O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCCCC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCCCC1C/C(=N\O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Yield: 95 %

Procedure:
17,17-Bis(ethylendioxy)-7(E)-hydroxyiminoandrostane was prepared in 95% yield from 3,3:17,17-bis(ethylendioxy)androstane-7-one by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-6(E)-hydroxyiminoandrostane (Prepn. 20). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography (SiO2, CH2Cl2/MeOH 9/1). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS: δ 10.17 (s, 1H), 3.88-3.70 (m, 8H), 2.89 (m, 1H), 2.23-0.71 (m, 19H), 0.90 (s, 3H), 0.77 (s, 3H).