Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])O.[Na+].COCCOC>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.O>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:32]2[C:27]([Cl:26])=[N:28][CH:29]=[CH:30][CH:31]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccnc1Cl
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN(Cc1cc(-c2cccnc2Cl)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 3 h
Yield: 60.4 %

Procedure:
tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-chloropyridin-3-yl)boronic acid (237 mg), sodium hydrogencarbonate (126 mg) and tetrakis(triphenylphosphine)palladium (87 mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 100° C. for 3 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1→1:4) to give the title compound as a colorless oil (yield 280 mg, 60%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1c2n(c3c(-c4cccc(Cl)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (70 mg, 83%), MS (ISP) m/z=336.5 [(M+H)+], mp 254° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=2[C:5]2[C:6](=[O:19])[NH:7][C:8]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:9][C:10]=2[CH:11]=1.[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[Br:24][CH2:1][C:2]1[C:3]2[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=2[C:5]2[C:6](=[O:19])[NH:7][C:8]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:15])[CH3:16])=[N:9][C:10]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2nc(NC(=O)C(C)(C)C)[nH]c(=O)c2c2ccccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Nc1nc2cc(CBr)c3ccccc3c2c(=O)[nH]1

Procedure:
To a solution of N-(6-methyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (1.76 g, 5.7 mmoles) in dry benzene (150 ml) was added N-bromosuccinimide (1.01 g, 5.7 mmoles) and dibenzoyl peroxide (15 mg). The mixture was heated to reflux under a nitrogen atmosphere for 2.5 hours. After cooling, benzene was removed under reduced pressure, and the residue was purified on a silica gel column eluting with chloroform to give N-(6-(bromomethyl)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide as an off-white solid. (1.4 g, 57%) 1H NMR (DMSO-d6, 200 MHz) δ: 1.27(s, 9H, t-butyl); 5.26(s, 2H, CH2Br); 7.63-7.81(m, 3H, Ar); 8.26(dd, J=7.6, 2.0 Hz, 1H, Ar); g.81(dd, J=7.8, 2.0 Hz, 1H, Ar); 11.27(s, 1H, NH); 12.33(s, 1H, NH). Anal. Calculated for C18H18BrN3O2 : C, 55.68; H, 4.67; N, 10.82. Found C, 55.48; H, 4.84; N, 10.57.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[C:5]([N+:19]([O-])=O)[CH:4]=1>C(O)C.O1CCCC1.[Ni]>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[O:7][CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:19][C:5]=2[CH:4]=1
Reactant: COc1ccc(OCC(=O)c2ccccc2)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(c1)NC(c1ccccc1)CO2
Reaction time: 48 h

Procedure:
The compound obtained in Step A (3 g; 10.44 mmol) is dissolved in a Parr reactor with an ethanol/tetrahydrofuran mixture (1/1). Raney nickel (30% by weight, 900 mg) is then added. The mixture is left for 48 hours at 50° C. under a hydrogen pressure of 50 psi. After returning to ambient temperature, the solution is filtered over Celite and the filtrate is evaporated. The crude reaction product is purified by flash chromatography on silica gel (eluant: PE/AcOEt (85/15)). The title product is obtained in the form of a yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>ClCCl>[Cl:1][CH2:2][CH2:3][N:4]([CH2:5][C:6]([F:9])([F:8])[F:7])[C:18](=[O:19])[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: FC(F)(F)CNCCCl
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)N(CCCl)CC(F)(F)F
Temperature: 0 °C

Procedure:
Into a 500-mL round-bottom flask, was placed (2-chloroethyl)(2,2,2-trifluoroethyl)amine (15 g, 92.85 mmol, 1.00 equiv), a solution of triethylamine (16.4 g, 162.07 mmol, 1.75 equiv) in dichloromethane (200 mL). This was followed by the addition of phenyl chloroformate (20.3 g, 129.66 mmol, 1.40 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 100 mL of 1M HCl. The resulting mixture was washed with 2×100 mL of sodium bicarbonate (sat.). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether. This resulted in 10 g (22%) of phenyl N-(2-chloroethyl)-N-(2,2,2-trifluoroethyl)carbamate as light yellow oil. (ES, m/z): 283 [M+H]+
Reaction SMILES: [Si]([O:8][C:9]1[CH:22]=[C:21]2[C:12]([C@@:13]3([CH2:31][CH3:32])[C@H:18]([CH2:19][CH2:20]2)[CH2:17][C@:16]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)([OH:23])[C@@H:15]([OH:30])[CH2:14]3)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:31]([C@:13]12[C:12]3[C:21](=[CH:22][C:9]([OH:8])=[CH:10][CH:11]=3)[CH2:20][CH2:19][C@@H:18]1[CH2:17][C@:16]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)([OH:23])[C@@H:15]([OH:30])[CH2:14]2)[CH3:32]
Reactant: CC[C@@]12C[C@H](O)[C@](O)(c3cccnc3)C[C@H]1CCc1cc(O[Si](C)(C)C(C)(C)C)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC[C@@]12C[C@H](O)[C@](O)(c3cccnc3)C[C@H]1CCc1cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2R,3S,4aR,10aR)-7-(tert-butyl-dimethylsilanyloxy)-4a-ethyl-2-(pyridin-3-yl)-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-2,3-diol (13 mg, 0.03 mmol) and acetic acid (0.05 mL, 0.87 mmol) in tetrahydrofuran (2 mL) was added a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.13 mL, 0.13 mmol). The mixture was stirred overnight at room temperature and the concentrated under vacuum. The residue was taken up in ethyl acetate and filtered through a plug of silica gel. The title compound, a solid (4.2 mg, 43%) was obtained by evaporation of the solvent. 1H NMR (CDCl3) selected signals: δ 9.00 (br s, 1 H), 8.50 (d, J=8.3 Hz, 1 H), 8.26 (d, J=5.7 Hz, 1 H), 7.32 (dd, J=5.7, 7.8 Hz, 1 H), 6.94 (d, J=8.3 Hz, 1 H), 6.65 (dd, J=2.6, 8.3 Hz, 1 H), 6.60 (d, J=2.6 Hz, 1 H), 4.23 (dd, J=4.7, 13.0 Hz, 1 H). MS: m/e 340 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]2[C:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[S:7][CH:8]=1.[N:24]([CH2:27][CH3:28])=[C:25]=[O:26]>CN(C=O)C>[CH2:17]([O:16][C:15]1[C:10]([NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:25]([NH:24][CH2:27][CH3:28])=[O:26])[N:5]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCN=C=O
Reactant: NCCc1csc(Nc2ncccc2OCc2ccccc2)n1
Solvent: CN(C)C=O
Product: CCNC(=O)NCCc1csc(Nc2ncccc2OCc2ccccc2)n1
Reaction time: 2 h
Yield: 30.2 %

Procedure:
Crude 4-(2-aminoethyl)-N-(3-(benzyloxy)pyridin-2-yl)thiazol-2-amine (Example 134, Step A; 0.25 g, 0.766 mmol) was dissolved in DMF (20 mL), and isocyanatoethane (0.109 g, 1.53 mmol) was added. The reaction mixture was stirred for 2 hours, then partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried, and concentrated. The residue was purified via MPLC (Biotage) eluting with ethyl acetate to afford the title compound (0.092 g, 30.2% yield) as a light yellow powder. 1H NMR (DMSO-d6) δ 0.97 (t, 3H), 2.67 (t, 2H), 2.98 (m, 2H), 3.29 (m, 2H), 5.26 (s, 2H), 5.82 (bt, 2H), 6.64 (s, 1H), 6.88 (m, 1H), 7.32-7.43 (m, 4H), 7.58 (d, 2H), 7.85 (d, 1H), 7.95 (s, 1H), 9.91 (s, 1H).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[CH:25]=[N:24][C:23]([NH2:31])=[CH:22]2.C(OCC)(=O)C>ClCCl.C(OCC)(=O)C.CCCCCC>[N:31]([C:23]1[N:24]=[CH:25][C:26]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:18][CH3:17])=[C:28]([O:29][CH3:30])[CH:27]=2)=[C:1]=[S:2]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1cc2cnc(N)cc2cc1OC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc2cnc(N=C=S)cc2cc1OC

Procedure:
To a stirring solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (124.6 mg, 0.536 mmol) in dichloromethane (3 mL) was added a suspension of 6,7-dimethoxyisoquinolin-3-amine (105 mg, 0.514 mmol) in dichloromethane (5 mL). The reaction mixture was applied directly to a Biotage column in 15-25% ethyl acetate/hexane followed by 100% ethyl acetate to give 3-isothiocyanato-6,7-dimethoxyisoquinoline as a white solid. Yield 69.4 mg (55%) NMR 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.81 (1H, s), 7.31 (1H, s), 7.16 (1H, s), 6.98 (1H, s), 3.99 (6H, s)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C(Cl)Cl>[Br:33][CH2:12][CH2:11][CH2:10][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=1[F:1]
Reactant: OCCCc1ccc(F)c(F)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(CCCBr)c(F)c1F
Reaction time: 1 h
Yield: 81.4 %

Procedure:
Compound 70-2 (2.90 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (4.40 g) and N-bromosuccinimide (2.99 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.14 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[N:20]=[C:19]([N:21]([CH3:26])[CH2:22][C:23](O)=[O:24])[C:18]([C:27]#[N:28])=[C:17]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][OH:38])=[CH:31][CH:30]=4)[C:16]=3[C:39]#[N:40])[N:12]=2)=[CH:4][CH:3]=1.[CH3:41][N:42](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[N:20]=[C:19]([N:21]([CH3:26])[CH2:22][C:23]([NH:42][CH3:41])=[O:24])[C:18]([C:27]#[N:28])=[C:17]([C:29]4[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][OH:38])=[CH:33][CH:34]=4)[C:16]=3[C:39]#[N:40])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CN(CC(=O)O)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)CN(C)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 51 %

Procedure:
100 mg (0.162 mmol) of the compound from Example 34A were initially charged in 2 ml of DMF, cooled to 0° C., and 123 mg (0.324 mmol) of HATU were added. After 20 min, 243 μl (0.486 mmol) of methylamine and 56 ml (0.324 mmol) of N,N-diisopropylethylamine were added, and the mixture was then stirred at RT overnight. Water was added, and the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC (Chromasil, water/acetonitrile+0.15% conc. hydrochloric acid). This gave 37 mg of the desired compound. In addition, more solid precipitated from the aqueous phase overnight; this was filtered off and washed with a little water. This gave another 50 mg of the desired compound.
Reaction SMILES: Cl.[N:2]1([C:8](=[O:21])[CH2:9][C:10]2[CH:15]=[CH:14][C:13](N3C=NN=N3)=[CH:12][CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.N1([C:28]([O:30][C:31](C)(C)C)=[O:29])CCNCC1.O=C1C2C=CC(CC(O)=O)=CC=2CO1>>[O:21]=[C:8]([N:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1)[CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[C:28](=[O:29])[O:30][CH2:31][C:14]=2[CH:15]=1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: O=C(O)Cc1ccc2c(c1)COC2=O
Product: O=C1OCc2cc(CC(=O)N3CCNCC3)ccc21

Procedure:
5-[2-Oxo-2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one was prepared in an analogous fashion as described above in the synthesis of 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride starting from tert-butyl piperazine-1-carboxylate and (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetic acid.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([C:17]2[C:25]3[CH:24]=[N:23][CH:22]=[N:21][C:20]=3[N:19]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=2)=[O:16])[CH:14]=1)C)(C)(C)C.Cl>O1CCOCC1>[C:26]([N:19]1[C:20]2[N:21]=[CH:22][N:23]=[CH:24][C:25]=2[C:17]([C:15]([C:13]2[CH:12]=[N:11][CH:10]=[C:9]([NH:7][CH3:6])[CH:14]=2)=[O:16])=[CH:18]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CN(C(=O)OC(C)(C)C)c1cncc(C(=O)c2cn(C(C)(C)C)c3ncncc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: CNc1cncc(C(=O)c2cn(C(C)(C)C)c3ncncc23)c1
Yield: 100 %

Procedure:
[5-(7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-methyl-carbamic acid tert-butyl ester (Example 542) was treated with 4N HCl in Dioxane at room temperature for 2 hours. The solvent was removed in vacuo and the solid obtained was triturated with diethyl ether to afford the title compound as white solid in 100% yield, 76 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]#[N:22])[C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[N+:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)([O-:25])=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:4]1[C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[C:2]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N+:23]([O-:25])=[O:24])[CH:3]=1)#[N:22]
Reactant: N#Cc1ccccc1-c1cc(Br)cn(-c2ccccc2)c1=O
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1-c1cc(-c2ccccc2[N+](=O)[O-])cn(-c2ccccc2)c1=O
Temperature: 120 °C
Reaction time: 4 h
Yield: 31.2 %

Procedure:
5-Bromo-3-(2-cyanophenyl)-1-phenyl-1,2-dihydropyridin-2-one (100 mg), 60 mg of 2-nitrophenylboronic acid and 130 mg of cesium carbonate were suspended in 10 ml of dimethylformamide, then 20 mg of tetrakistriphenylphosphine palladium were added and the mixture was stirred at 120° C. in a nitrogen atmosphere for 4 hours. After allowing to cool, the reaction solution was poured into water, the mixture was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo and the residue was purified by a silica gel column chromatography (hexane-ethyl acetate system) to give 35 mg of the title compound.
Reaction SMILES: C([O:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)(=O)C1C=CC=CC=1.C1COCC1.CO.O.[OH-].[Li+]>O.CCOC(C)=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:12]2[C:13]([CH3:16])=[N:14][O:15][C:11]=2[CH2:10][OH:9])=[O:31])=[CH:25][CH:26]=1
Reactant: Cc1noc(COC(=O)c2ccccc2)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1noc(CO)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a round bottomed flask was added (4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methyl benzoate (32.7 mg, 0.076 mmol), THF (3 mL), MeOH (3 mL), and water (1.5 mL). This solution was cooled to 0° C. before addition of Lithium Hydroxide Monohydrate (9.53 mg, 0.227 mmol) and the reaction stirred at 0° C. for 1 h before diluting with water and EtOAc. The layers were separated and the aqueous extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated to afford crude (4-chlorophenyl)(2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)phenyl)methanone.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH2:11])[CH3:8].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29]Cl>CS(C)=O.O>[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH:11][CH2:29][CH2:28][CH2:27][O:26][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)[CH3:8]
Reactant: ClCCCOc1ccc2ccccc2c1
Reactant: CCCCC(CC)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCC(CC)CNCCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 2-ethyl-n-hexylamine (0.35 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(2-ethyl-n-hexyl)-(3-(naphthalen-2-yloxy) propyl)amine solid, m.p. 97° C., (yield 0.6 gm, 84.8%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a solution of the above alcohol (3.40 g, 10.6 mmol) in CH2Cl2 (50 mL) at room temperature was added SiO2 (13.60 g) and PCC (6.84 g, 31.70 mmol). The resulting mixture was stirred under N2 for 2 hours to afford 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid (3.00 g, 88%) after purification.
Reaction SMILES: C[O:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[C:11]([CH3:21])=[CH:12][C:13]([CH3:20])=[C:14]([CH:19]=2)[C:15]([O:17]C)=[O:16])=[C:7]([CH3:9])[N:8]=1>Br>[OH:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[C:11]([CH3:21])=[CH:12][C:13]([CH3:20])=[C:14]([CH:19]=2)[C:15]([OH:17])=[O:16])=[C:7]([CH3:9])[N:8]=1
Reactant: COCc1nc(C)c(-c2cc(C(=O)OC)c(C)cc2C)[nH]1
Agent: Br
Product: Cc1cc(C)c(-c2[nH]c(CO)nc2C)cc1C(=O)O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 222.4, 220 mg, 0.76 mmol) and HBr (20 mL, 40% in HOAc). The reaction mixture was stirred overnight at 80° C. The resulting mixture was concentrated under reduced pressure. This resulted in 190 ma (crude) of the title compound as a brown solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([OH:35])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2OCC(C)(C)C[O:18]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.CCCCCC>CC(C)=O>[C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([OH:35])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]=[O:18])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.1 %

Procedure:
In 4 ml of acetone was dissolved 4.9 mg (0.01 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-hydroxypregn-5-en-3β-yl acetate, followed by addition of 1 ml of a 1 mmol/1 solution of p-toluenesulfonic acid in acetone (containing 0.001 mmole of p-toluenesulfonic acid). The mixture was stirred at room temperature for 12 hours. From the reaction mixture thus obtained, the solvent was distilled off under reduced pressure and the residue was diluted with methylene chloride. This methylene chloride solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane =1:5, v/v) to recover 2.7 mg of 3β-acetoxy-1α,2α-epoxy-7α-hydroxypregn-5-ene-20-carbaldehyde (yield: 67%).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][N:35]([CH:37]3[CH2:40][N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:38]3)[CH:36]=2)O1>>[C:44]([O:43][C:41]([N:39]1[CH2:40][CH:37]([N:35]2[CH:36]=[C:32]([C:2]3[CH:23]=[CH:22][C:5]4[C:6]5[N:7]=[C:8]([C:14]6[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=6)[S:9][C:10]=5[CH2:11][CH2:12][O:13][C:4]=4[CH:3]=3)[CH:33]=[N:34]2)[CH2:38]1)=[O:42])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)ccc1-2

Procedure:
Similarly to as described in General Procedure C, 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 27 was reacted with tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate to give 3-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidine-1-carboxylic acid tert-butyl ester which was used without purification.