Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].S(Cl)([Cl:17])(=O)=O>>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:5]=1[C:6]([Cl:17])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=S(=O)(Cl)Cl
Product: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
A solution of 2-nitro-5-chlorobenzoic acid (200 mg) in sulfonylchloride (20 ml) was stirred for 4 hours at 99° C. in a stream of argon. After leaving to cool, the solution was concentrated under the reduced pressure to give the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:36])[NH:7][C:6]2[CH:8]=[C:9]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:11][C:5]=2[O:4][CH2:3]1.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39](B(O)O)[CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:25]([O:24][C:23](=[O:29])[NH:22][C:18]1([C:15]2[CH:16]=[CH:17][C:12]([C:10]3[C:9]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:8][C:6]4[N:7]([C:39]5[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=5)[S:2](=[O:1])(=[O:36])[CH2:3][O:4][C:5]=4[N:11]=3)=[CH:13][CH:14]=2)[CH2:21][CH2:20][CH2:19]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NS(=O)(=O)CO4)cc2)CCC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(c3cccnc3)S(=O)(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.1 %

Procedure:
In a 15 mL reaction tube was added tert-butyl (1-(4-(2,2-dioxido-7-phenyl-1H-pyrido[3,2-e][1,3,4]oxathiazin-6-yl)phenyl)cyclobutyl)carbamate (50 mg, 0.099 mmol), pyridin-3-ylboronic acid (24 mg, 0.197 mmol), copper(II)acetate (27 mg, 0.148 mmol) and 5 Å molecular sieves (30 mg) in anhydrous dichloromethane (1 ml). To this was added anhydrous pyridine (16 μl, 0.197 mmol) and the resulting black suspension stirred at room temperature under air for 24 hours. Further pyridine (1 mL) was added and the resulting black solution stirred at room temperature for 24 hours. Further pyridin-3-ylboronic acid (24 mg, 0.197 mmol) and copper (II)acetate (27 mg, 0.148 mmol) were added and the mixture stirred at room temperature for 72 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 88:12 to 0:100) to give the desired product as an off-white solid (40 mg 70% yield). 1H-NMR (500 MHz, CDCl3) δ 8.67-8.76 (2H, m), 7.89 (1H, d), 7.54 (1H, dd), 7.20-7.35 (7H, m), 7.06 (2H, d), 7.03 (1H, s), 5.38 (2H, s), 5.07 (1H, br s), 2.20-2.60 (4H, m), 2.00-2.15 (1H, m), 1.78-1.90 (1H, m), 1.10-1.50 (9H, br s). LCMS (Method A) RT=6.98 min, M+H+=584.99.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl[C:29]1[N:34]=[CH:33][C:32](/[CH:35]=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C>[C:1]12([C:11]3[CH:12]=[C:13]([C:29]4[N:30]=[CH:31][C:32](/[CH:35]=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:33][N:34]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OB(O)c1ccc(OCc2ccccc2)c(C23CC4CC(CC(C4)C2)C3)c1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cnc(-c2ccc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)c2)nc1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
To a solution of 3-(1-adamantyl)-4-benzyloxyphenylboronic acid (Zhang Y. et al., Blood, 2002; 100:2917-2925, Dawson M. I. et al., J. Med. Chem., 2004; 47:3518-3536) (3.62 g, 10.0 mmol) and ethyl (2E)-3-(2-chloro-5-pyrimidinyl)-2-propenoate (1.76 g, 8.30 mmol) in dimethoxyethane (50 mL) was added under argon tetrakis(triphenylphosphine)-palladium (1.15 g, 1.00 mmol) and 2 M aqueous Na2CO3 (10 mL). The reaction mixture was heated at reflux for 18 h, cooled to room temperature, diluted with ethyl acetate, washed (water and brine) and dried. After solvent removal at reduced pressure, the residue was chromatographed (9% to 14% ethyl acetate/hexane) to give 3.98 g (96%) of ethyl(E)-3-[2-(3-(1-adamantyl)-4-benzyloxyphenyl)-5-pyrimidinyl]-2-propenoate as a yellow solid, mp 164-167° C. IR 2903, 1710, 1432, 1225 cm−1; 1H NMR δ (CDCl3) 1.40 (t, J=7.2 Hz, 3H, OCH2CH3), 1.77 (bs, 6H, AdCH2), 2.11 (bs, 3H, AdCH), 2.26 (bs, 6H, AdCH2), 4.33 (q, J=7.2 Hz, 2H, OCH2CH3), 5.24 (s, 2H, CH2), 6.59 (d, J=16.2 Hz, 1H, CH═CHCO), 7.08 (d, J=8.7 Hz, 1H, 5-ArH), 7.35-7.58 (m, 5H, C6H5), 7.65 (d, J=16.2 Hz, 1H, CH═CHCO), 8.33 (dd, J=8.7 Hz, 2.1 Hz, 1H, 6-ArH), 8.47 (d, J=2.1 Hz, 1H, 2-ArH), 8.91 ppm (s, 2H, 4-PyrH, 6-PyrH). HRMS calcd C32H34N2O3 [M+H]+ 495.2642. found 495.2636.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Li])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CCCCCC.BrC1C=CC=C(Br)C=1.Cl[Si:29](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[CH:43]1[C:51]2[C:50]3[CH:52]=[CH:53][CH:54]=[CH:55][C:49]=3[S:48][C:47]=2[C:46]([Li])=[CH:45][CH:44]=1>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([Si:29]([C:55]2[C:49]3[S:48][C:47]4[CH:46]=[CH:45][CH:44]=[CH:43][C:51]=4[C:50]=3[CH:52]=[CH:53][CH:54]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [Li]c1cccc2c1sc1ccccc12
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: [Li]c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: Brc1cccc(Br)c1
Solvent: CCOCC
Solvent: CCCCCC
Product: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc3c2sc2ccccc23)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 31 %

Procedure:
In another flask was prepared a solution of m-bromophenyl lithium by addition of n-butyllithium solution in hexane (2.5 M, 9.48 mL, 23.70 mmol) into a solution of 1,3-dibromobenzene (2.56 mL, 21.20 mmol) in ether (70 mL) at −78° C. followed by stirring at this temperature for 3.5 h. This m-bromophenyl lithium solution was added dropwise into a solution of dichlorodiphenylsilane (4.88 mL, 23.70 mmol) in ether (70 mL) at −78° C. The resultant reaction solution was stirred at this temperature for 2 h before the dibenzo[b,d]thiophen-4-yl lithium solution prepared above was introduced dropwise. The resultant solution was allowed to slowly warm to room temperature overnight. It was quenched with water, extracted with ether and dried over Na2SO4. Upon evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane/DCM (9/1, v/v) as eluent to yield (3-bromophenyl)(dibenzo[b,d]thiophen-4-yl)diphenylsilane as a white powder (3.84 g, 31%).
Reaction SMILES: [CH3:1][C:2]([CH3:38])([O:4][C:5]([N:7]([CH2:32][C:33]1S[CH:35]=[CH:36][CH:37]=1)[CH2:8][CH2:9][C:10]([NH:12][NH:13][C:14]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][C:18]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:17]1=2)=[O:15])=[O:11])=[O:6])[CH3:3].CC(C)([O:42]C(N(CC1OC=CC=1)CCC(O)=O)=O)C.ClC1C=CC2OC3C=CC=CC=3CN(C(NN)=O)C=2C=1>>[CH3:1][C:2]([CH3:38])([O:4][C:5]([N:7]([CH2:32][C:33]1[O:42][CH:35]=[CH:36][CH:37]=1)[CH2:8][CH2:9][C:10]([NH:12][NH:13][C:14]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][C:18]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:17]1=2)=[O:15])=[O:11])=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)O)Cc1ccco1
Reactant: CC(C)(C)OC(=O)N(CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)Cc1cccs1
Agent: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: CC(C)(C)OC(=O)N(CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)Cc1ccco1

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[[(1,1-dimethylethoxy)carbonyl](2-furanylmethyl)amino]-1-oxopropyl]hydrazide (24) was prepared in the same manner as 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[[(1,1-dimethylethoxy)carbonyl](2-thienylmethyl)amino]-1-oxopropyl]hydrazide (17), as described above in Example 17, on a 0.63 mmol scale from 3-[[(1,1-dimethylethoxy)carbonyl](2-furanylmethyl)-amino]propanoic acid (23), prepared as described above in Example 23, and 8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, to yield 0.24 g (71%) of product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]O)=[C:6]([F:14])[C:5]=1[F:15])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][Br:36])=[C:6]([F:14])[C:5]=1[F:15])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCOc1ccc(CCCO)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOc1ccc(CCCBr)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
3-(4-Ethoxy-2,3-difluorophenyl)propanol (s21) (9.4 g) and triphenylphosphine (17.1 g) were dissolved in methylene chloride (100 ml). Carbon tetrabromide (17.3 g) in methylene chloride (100 ml) solution was slowly added dropwise to the solution at room temperature, and the mixture was stirred at room temperature for another 3 hours. The reaction mixture was treated with a saturated aqueous solution of sodium hydrogencarbonate, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to leave a residue, pale yellow solids. The residue was purified by column chromatography with heptane as an eluent and silica gel as a stationary phase powder to give 3-(4-ethoxy-2,3-difluorophenyl) bromopropane (s22) (11.5 g). The yield based on the compound (s21) was 94.8%.
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)(=O)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:29][CH:30]=[C:31]([CH2:33][CH2:34]O)[CH:32]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CS(C)=O.C(C(C)=O)C>[CH2:33]([C:31]1[CH:32]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[C:28]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:29][C:30]=1[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)[CH3:34]
Reactant: OCCc1ccc(OCc2ccccc2)c(-c2ccc(F)cc2)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCC(C)=O
Product: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCC1CCCN(C(=O)OC(C)(C)C)C1

Procedure:
3-(Methanesulfonyloxymethyl)-N-(tertbutoxycarbonyl)-piperidine (143 mg, 0.49 mmol) and 5-(4-fluorophenyl)-4-benzyloxy-2-hydroxyethylbenzene (150 mg, 0.47 mmol) were added to methyl ethyl ketone (7 mL) followed by potassium carbonate (113 mg, 0.82 mmol), potassium iodide (15.5 mg, 93 μmol), and dimethylsulfoxide (4 mL). The slurry was heated at reflux for 40 hours, when it was cooled, diluted with water (50 mL) and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to a clear oil which was not purified but used as is in the following step. Mass Spec (EI): 537.4 (M+NH4)
Reaction SMILES: F[C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].O>CS(C)=O>[C:6]([C:5]1[CH:8]=[C:9]([CH3:10])[C:2]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:3][CH:4]=1)#[N:7]
Reactant: Cc1cc(C#N)cnc1F
Reactant: CC(C)(C)OC(=O)CCCN
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C#N)cnc1NCCCC(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of 6-fluoro-5-methylnicotinonitrile (10.0 g, 73.4 mmol), tert-butyl 4-aminobutanoate (Bachem F-3755, 17.4 g, 88.1 mmol) and TEA (25.6 mL, 183.6 mmol) was prepared in DMSO (100 mL) under nitrogen, and the heated at 150° C. for 4 hours. The reaction mixture was cooled to 100° C., and then water was added (100 mL) drop wise. The resulting mixture was stirred at RT for 2 hours, and then the precipitate was filtered off, washed with water and dried under reduced pressure to afford the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.27 (1H, s), 7.53 (1H, s), 6.95 (1H, m), 3.40 (2H, t), 2.23 (2H, t), 2.03 (3H, s), 1.75 (2H, m), 1.37 (9H, s).
Reaction SMILES: COP([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(OC)=O.[H-].[Na+].[F:17][C:18]([F:24])([F:23])[CH:19]([CH3:22])[CH:20]=O>C1COCC1>[F:17][C:18]([F:24])([F:23])[CH:19]([CH3:22])/[CH:20]=[CH:7]/[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: CC(C=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(/C=C/C(=O)OC(C)(C)C)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
A solution of tert-butyl 2-(dimethoxyphosphoryl)acetate (9.78 g, 43.6 mmol) in THF (10 mL) was slowly transferred to a suspension of NaH (60% dispersion in mineral oil) (1.903 g, 47.6 mmol) in THF (30 mL) at 0° C. under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at 0° C. for 10 min, and then warmed to room temperature. After being stirred for 30 min, the reaction mixture was cooled to 0° C. again, and a solution of 3,3,3-trifluoro-2-methylpropanal (5 g, 39.7 mmol) in THF (10 mL) was added, and the ice bath was removed. After 12 h at 25° C., the mixture was partitioned between water (60 mL) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (60 mL), and the combined organic layers were successively washed with water (60 mL) and brine. The resulting solution was dried over MgSO4, concentration under reduced pressure, and purified by silica gel flash chromatography (330 g column, 0% to 15% EtOAc in hexane over 20 min) to obtain Intermediate S-5A (3.61 g, 16.10 mmol, 40.6% yield). 1H NMR (400 MHz, chloroform-d) δ 6.77 (dd, J=15.8, 7.7 Hz, 1H), 5.95 (dd, J=15.7, 0.6 Hz, 1H), 3.12-2.93 (m, 1H), 1.56-1.47 (m, 9H), 1.37-1.27 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O>>[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1
Reactant: O=Cc1cnc2ccc(Br)cn12
Reactant: OB(O)c1ccc[nH]1
Product: O=Cc1cnc2ccc(-c3ccc[nH]3)cn12
Yield: 21 %

Procedure:
The title compound was prepared by following the procedure as described for Intermediate 1 using 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and 1H-pyrrol-2-ylboronic acid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[CH3:22][N:23]([CH3:30])[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CCOC(C)=O.O>C(Cl)Cl>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[O:13][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][C:7]=1[S:9]([N:27]1[CH2:28][CH2:29][CH:24]([N:23]([CH3:30])[CH3:22])[CH2:25][CH2:26]1)(=[O:11])=[O:10]
Reactant: N#Cc1ccc(Oc2cc(F)ccc2F)c(S(=O)(=O)Cl)c1
Reactant: CN(C)C1CCNCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CN(C)C1CCN(S(=O)(=O)c2cc(C#N)ccc2Oc2cc(F)ccc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 840.3 %

Procedure:
To a solution of compound 23 (0.080 g, 0.24 mmol) in DCM (10.00 mL) was added 4-dimethylaminopiperidine (0.040 g, 0.31 mmol) and TEA (0.043 g, 0.31 mmol). The reaction was monitored with TLC (25% EtOAc in hexanes, Rf=0.0). The reaction was complete after stirring at room temperature for 30 min, as indicated by the absence of the starting material (TLC). Water was then added and extracted twice with DCM. Combined organic extracts were washed sequentially with water and brine, dried over MgSO4, filtered, and evaporated in vacuo to form a yellow oil. The oil was triturated with DCM and hexanes, and filtered to yield compound 59 as a white powder (0.85 g, 97.4% HPLC purity, 84% yield). 1H NMR (500 MHz, DMSO-d6): δ 8.27 (d, J=2 Hz, 1H), 8.08 (dd, J1=2 Hz, J2=8 Hz, 1H), 7.56 (m, 1H), 7.40 (m, 1H), 7.26 (m, 1H), 7.19 (d, J=9 Hz, 1H), 3.71 (d, J=13 Hz, 2H), 2.77 (t, J=13 Hz, 2H), 2.18 (m, 1H), 2.12 (s, 3H), 1.76 (d, J=11 Hz, 2H), 1.35 (m, 2H); MS (ESI, EI+): m/z=422 (MH+); melting point: 154-157° C.
Reaction SMILES: C([Si](CC1C=CC=CC=1)(CC1C=CC=CC=1)[O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@:12]3([O:32][C@@H:13]3[C@@H:14]([Cl:31])[C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[C@@H:17]3[CH2:30][C@@H:18]3[C:19]2=[O:29])[CH2:11]1)C1C=CC=CC=1.[CH3:47]O.S(=O)(=O)(O)O>O1CCCC1.CCOCC>[CH:13]([O:32][CH:12]([CH3:11])[CH3:25])([CH3:14])[CH3:47].[Cl:31][C@@H:14]1[C@H:13]2[O:32][C@:12]32[C@:25]([CH3:28])([CH2:26][CH2:27][C@H:10]([OH:9])[CH2:11]3)[C@@H:24]2[C@@H:15]1[C@H:16]1[C@@:20]([CH2:22][CH2:23]2)([CH3:21])[C:19](=[O:29])[C@H:18]2[CH2:30][C@@H:17]12
Reactant: CO
Reactant: C[C@]12CC[C@H]3[C@@H]([C@H](Cl)[C@H]4O[C@]45C[C@@H](O[Si](Cc4ccccc4)(Cc4ccccc4)Cc4ccccc4)CC[C@]35C)[C@@H]1[C@@H]1C[C@@H]1C2=O
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)OC(C)C
Product: C[C@]12CC[C@H]3[C@@H]([C@H](Cl)[C@H]4O[C@]45C[C@@H](O)CC[C@]35C)[C@@H]1[C@@H]1C[C@@H]1C2=O

Procedure:
19 g of 3β-tribenzylsilyloxy-7α-chloro-5,6β-epoxy-15β,16β-methylene-5β-androstan-17-one is dissolved in 50 ml of tetrahydrofuran and 50 ml of methanol and agitated with 15 ml of 8% sulfuric acid for 2 hours at room temperature. The mixture is thereafter diluted with ether, washed with saturated sodium bicarbonate solution and water, dried over sodium sulfate, and concentrated under vacuum. By trituration of the thus-obtained solid with diisopropyl ether, 8.7 g of 7α-chloro-5,6β-epoxy-3β-hydroxy-15β,16β-methylene-5β-androstan-17-one is obtained, mp 172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3Cl)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:27].[K+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3[OH:27])=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: O=C1C(Cl)=C(C2CCC(c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1C(O)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21

Procedure:
The product of stage (b) was suspended in 10 ml of boiling methanol and 0.55 g of potassium hydroxide in 5.5 ml of water was added dropwise over 15 mins. The mixture was refluxed until a dark red solution formed. (after ca. 6 hrs) when 2 ml of concentrated hydrochloric acid was cautiously added dropwise. The mixture was cooled and filtered, and the solid residue washed thoroughly with water. The water washings were re-acidified and filtered. The combined solid residues (500 mg) mp 200-200°, were recrystallised form acetonitrile to give the title product as the trans-isomer (300 mg) m.p. 216-219° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[C:8]([NH:10][C:11]([NH2:13])=[O:12])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.C([CH:30]([C:34](Cl)=[O:35])[C:31](Cl)=[O:32])C.[C:37](OCC)(=[O:39])[CH3:38]>C1(C)C=CC=CC=1>[CH2:37]([O:39][C:34](=[O:35])[CH2:30][C:31]([NH:13][C:11]([NH:10][C:8](=[O:9])[CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:12])=[O:32])[CH3:38]
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: NC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)NC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 32 %

Procedure:
A solution of [3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-urea (prepared in Example 1B-d, 402 mg, 1.22 mmol) and pyridine (0.15 mL, 1.83 mmol), in toluene (15 mL) was treated with ethyl malonyl chloride (0.19 mL, 1.5 mmol). The resulting reaction mixture was heated at reflux for 2 h. At this time, additional pyridine (0.15 mL, 1.83 mmol) and ethyl malonyl chloride (0.19 mL, 1.5 mmol) were added. The reaction was then heated at reflux for 90 min. The reaction was then cooled to 25° C., diluted with ethyl acetate (50 mL), washed with water (2×25 mL), and dried over magnesium sulfate. The solution was concentrated in vacuo. Flash column chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 hexane/ethyl acetate) afforded 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-3-oxo-propionic acid ethyl ester (172 mg, 32%) as a colorless gum: EI-HRMS m/e calcd for C20H24Cl2N2O5 (M+) 443.1140, found 443.1128.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2.CN(C)CCC=C1C2C=CC=CC=2C=CC2C=CC=CC1=2>>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2
Reactant: CN(C)CCC=C1c2ccccc2C=Cc2ccc(S(C)(=O)=O)cc21
Agent: CN(C)CCC=C1c2ccccc2C=Cc2ccccc21
Product: CNCCC=C1c2ccccc2C=Cc2ccc(S(C)(=O)=O)cc21

Procedure:
By substituting 5-(3-dimethylaminopropylidene)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (β-isomer), (Product of Example 23, Step G), for the 5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene of Example 6, and following substantially the procedure of Example 6, Steps A and B, 5-(3-methylaminopropylidene)-3-methylsulfonyl- 5H-dibenzo[a,d]cycloheptene (β-isomer) is obtained in the form of a yellow oil. The product is converted to the hydrogen maleate that melts at 175°-176°C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1>ClCCl>[Cl:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])[C:11]([O:12][CH3:13])=[N:10]2
Reactant: COc1nc2cc(Cl)ccc2nc1N
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 96 %

Procedure:
2-Amino-6-chloro-3-methoxyquinoxaline (629 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The resulting mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 811 mg of the titled compound (yield, 96%).