Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:19]1([CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[C:19]1([CH:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:26][N:13]2[CH2:14][CH2:15][CH2:16][N:10]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:18][CH:17]=3)[CH2:11][CH2:12]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(CN2CCCNCC2)cc1
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(CN2CCCN(CC(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The resulting 1-[4-(methylsulfonyl)benzyl]homopiperazine was dissolved in 5 mL of dichloromethane, followed by adding 223 mg of diphenylacetaldehyde and 217 mg of sodium triacetoxyborohydride. After the mixture was stirred at room temperature for 16 hours, it was mixed with 30 mL of aqueous saturated sodium hydrogencarbonate, and extracted with 30 mL×2 of ethyl acetate. The organic layers were combined, washed with 30 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate) to obtain 173 mg of the titled compound. This was treated with a hydrogen chloride solution in ether and the solvent was removed under reduced pressure, the residue was dried to give the hydrochloride salt of the titled compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([O:14]C)=[CH:13][C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].Cl>ClCCl>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=3[N:7]=[N:6]2)[CH2:2][CH2:3]1
Reactant: COc1ccc2c(c1)nnn2CC1CC1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: Oc1ccc2c(c1)nnn2CC1CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-(Cyclopropylmethyl)-5-methoxy-1H-benzotriazole (11.0 g, 54.1 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0° C. The mixture was treated with boron tribromide (108 mL, 1 M dichloromethane solution, 108 mmol, 2 equiv) and warmed to ambient temperature. After stirring for 3 hours, the mixture was carefully treated with sodium bicarbonate over 1 hour (˜100 mL, aqueous saturated) and the mixture was stirred for an additional 14 hours. The mixture was neutralized to pH <5 with 12 N aqueous hydrochloric acid dropwise and the mixture was extracted with dichloromethane containing 10% methanol (4×750 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH2:10][CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:27])CC>C(Cl)Cl>[CH2:1]([O:8][CH:9]([CH2:10][CH2:11][F:27])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CC(CCO)OCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1CC(CCF)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(benzyloxy)-4-o-tolylbutan-1-ol (3.0 g, 11.11 mmol) in DCM (50 ml) was added DAST (2.9 ml, 22.22 mmol) at 0° C. and stirred at room temperature for 5 h. Then cooled to 0° C. and quenched with NH4Cl (10 ml). The title compound was purified by separation methods A and E. (Yield 1.5 g).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40](O)=[O:41].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:21][CH2:22][N:23]([C:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=3)=[O:41])[CH2:24][CH2:25]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccn1
Reactant: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(c1ccccn1)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.2 %

Procedure:
To the solution of the compound obtained in Example 66 (391 mg, 0.80 mmol), picolinic acid (108 mg, 0.88 mmol) and 1-hydroxbenzotriazole (119 mg, 0.88 mmol) in DMF (8 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (307 mg, 1.60 mmol), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and to the concentrate were added a saturated aqueous solution of sodium hydrogen carbonate (15 mL) and water (5 mL). The mixture was extracted with ethyl acetate (15 mL×5). The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (5 mL×3), saturated sodium chloride solution (5 mL), successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (433 mg, 0.73 mmol, Yield 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][N:17]3[CH:21]=[N:20][C:19]([C:22]([O:24]C)=O)=[N:18]3)[CH:11]=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.[NH3:26]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:16][N:17]3[CH:21]=[N:20][C:19]([C:22]([NH2:26])=[O:24])=[N:18]3)[CH:11]=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: COC(=O)c1ncn(Cc2cnc(OC)c(-c3cccc(Cl)c3)c2)n1
Solvent: CO
Product: COc1ncc(Cn2cnc(C(N)=O)n2)cc1-c1cccc(Cl)c1
Yield: 77 %

Procedure:
To a solution of methyl 1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate (Example 141, 103 mg, 0.28 mmol) in methanol (2 mL) was added ammonia in methanol (2 mL of 7N solution, 14 mmol). The mixture was heated using microwave irradiation at 130° C. for 20 min. The LC/MS showed incomplete conversion. To the reaction mixture was added more ammonia in methanol (2 mL, 14 mmol) and irradiated in a microwave at 120° C. for an additional 20 min. The solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-5% MeOH/DCM) afforded the title compound (77 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.25 (d, J=2.3 Hz, 1H), 7.85 (d, J=2.3 Hz, 1H), 7.78-7.70 (m, 1H), 7.62-7.40 (m, 5H), 5.45 (s, 2H), 3.87 (s, 3H). [M+H]=354.18.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][OH:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN(CCO)c1ccccn1
Product: CN(CCOc1ccc(C=O)cc1)c1ccccn1

Procedure:
The title compound was prepared from 2-(N-methyl-N-(2-pyridyl)amino)ethanol (8.9 g) and 4-fluorobenzaldehyde by a similar procedure to that described in preparation 22.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:19][C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:21])([F:22])[F:10])=[CH:17][CH:16]=2)=[O:20])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Product: O=C(C=Cc1ccc(Cl)cc1)c1ccc(C(F)(F)F)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and p-(trifluoromethyl)acetophenone, 3-(4-chlorophenyl)-1-(4-(trifluoromethyl)-phenyl)prop-2-en-1-one was obtained as beige coloured solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][Li])[CH3:3].[O:8]1[CH:18]2[CH:9]1[CH2:10][C:11]1[C:16]([CH2:17]2)=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CCOCC>[CH3:1][N:2]([CH3:3])[CH2:4][CH2:5][CH2:6][C@@H:18]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[OH:8]
Reactant: [Li]CCCN(C)C
Reactant: c1ccc2c(c1)CC1OC1C2
Solvent: O
Solvent: CCOCC
Product: CN(C)CCC[C@@H]1Cc2ccccc2C[C@H]1O

Procedure:
to a solution of 0.1 mol of dimethylamino propyllithium in 500 ml of ether cooled to 0°-5° C. is added dropwise a solution of 7.3 g (0.05 mol) of 2,3-epoxy-1,2,3,4-tetrahydronaphthalene in 100 ml of ether. The reaction mixture is then heated under reflux for 2 hours and decomposed with water. The organic layer is separated and dried and the desired 1,2,3,4-tetrahydro-3-(3-dimethylaminopropyl)-2-naphthalenol separated from byproducts by column chromatography on neutral alumina.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[C:7](=[O:21])[CH:8]=[C:9]([C:16]([O:18]CC)=[O:17])[NH:10][C:11]=2[C:12]([F:15])=[CH:13][CH:14]=1)=[O:4]>Cl>[F:15][C:12]1[C:11]2[NH:10][C:9]([C:16]([OH:18])=[O:17])=[CH:8][C:7](=[O:21])[C:6]=2[C:5]([C:3]([OH:4])=[O:2])=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cc(=O)c2c(C(=O)OC)ccc(F)c2[nH]1
Agent: Cl
Product: O=C(O)c1cc(=O)c2c(C(=O)O)ccc(F)c2[nH]1
Temperature: 100 °C

Procedure:
To a 2 N aqueous HCl (200 mL) solution was added 34 (10.0 g, 34.1 mmol). The reaction mixture was heated at 100° C. for 18 h and then cooled to room temperature. The resulting precipitate was filtered and dried under vacuum at 60° C. for 18 h to afford an off-white solid (35, 8.11 g, 94.7%). 1H NMR (DMSO-d6, 300 MHz) δ ?7.65 (t, J=8.2, 1H), 7.39-7.43 (m, 1H), 6.93 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:19]1[CH:23]=[N:22][C:21]([NH2:24])=[N:20]1>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:19]1[CH:23]=[N:22][C:21]([NH:24][CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[S:4][N:3]=[C:2]([CH3:1])[N:6]=3)[CH2:8][CH2:9]2)=[N:20]1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1ncn(Cc2cccc(Cl)c2)n1
Product: Cc1nsc(N2CCC(Nc3ncn(Cc4cccc(Cl)c4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(3-chloro-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a colorless oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:25][O:26][CH:27]([CH3:30])[CH2:28][OH:29]>>[OH:29][CH2:28][CH:27]([O:26]/[N:25]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22])[CH3:30]
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: CC(CO)ON
Agent: Cl
Product: C/C(=N\OC(C)CO)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 90 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and 2-(aminooxy)propan-1-ol hydrochloride (intermediate Q) in 90% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.41 (s, 1H), 8.93 (m, 1H), 8.15 (m, 2H), 7.92 (s, 1H), 7.84 (dd, 1H), 7.43 (dd, 1H), 6.12 (s, 2H), 4.61 (m, 1H), 3.85 (m, 2H), 2.41 (s, 3H), 2.00 (s, 1H), 1.38 (d, 3H). LCMS (method B): [MH]+=378, tR=1.96 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][C@@H:30]([CH2:33][OH:34])[O:29][CH2:28]4)=[O:25])[N:13]([C@H](C4C=CC=CC=4)[C@@H](O)C4C=CC=CC=4)[C:12]43[CH2:52][C:51]([CH2:55][F:56])([CH2:53][F:54])[CH2:50]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[NH4+].[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][C@@H:30]([CH2:33][OH:34])[O:29][CH2:28]4)=[O:25])[NH:13][C:12]43[CH2:50][C:51]([CH2:55][F:56])([CH2:53][F:54])[CH2:52]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CC[C@@H](CO)OC1)[C@H]1[C@H](c2ccnc(Cl)c2F)C2(C(=O)Nc3cc(Cl)ccc32)C2(CC(CF)(CF)C2)N1[C@H](c1ccccc1)[C@@H](O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: CC#N
Solvent: O
Product: O=C(N[C@@H]1CC[C@@H](CO)OC1)[C@@H]1NC2(CC(CF)(CF)C2)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1ccnc(Cl)c1F
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
The compound (153 mg, 0.19 mmol) obtained in Step 2 above was dissolved in acetonitrile (10 ml) and water (3 ml), cerium (IV) diammonium nitrate (207 mg, 0.38 mmol) was added under ice cooling and the resulting mixture was stirred for 10 minutes. Potassium carbonate (104 mg, 0.76 mmol) was added to the reaction mixture and the precipitated insoluble matter was removed by filtration through celite. The filtrate was diluted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by NH-silica gel column chromatography (chloroform:methanol=100:0→40:1) and then the residue was dissolved in 2-propanol (10 ml) and stirred at 50° C. for 2 days. The solvent was evaporated under reduced pressure and then the residue was purified by chiral column liquid chromatography [fractionation conditions: CHIRALPAK IC, n-hexane:ethanol=2:3 (v/v)] to give 67 mg (57%) of the title compound as a colorless solid.
Reaction SMILES: BrC1C=[CH:6][C:5]([O:8]C(C)C)=[C:4](C(C2C=CC(C)=CC=2)=C)C=1.BrC1C=CC(CC(=O)C)=C(C(C2C=CC(C)=CC=2)=C)C=1.[Br:41][C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[C:44]([C:49]([C:51]2[CH:52]=[C:53]([CH3:57])[CH:54]=[CH:55][CH:56]=2)=[CH2:50])[CH:43]=1>>[Br:41][C:42]1[CH:47]=[CH:46][C:45]([O:8][CH:5]([CH3:6])[CH3:4])([OH:48])[CH:44]([C:49]([C:51]2[CH:52]=[C:53]([CH3:57])[CH:54]=[CH:55][CH:56]=2)=[CH2:50])[CH:43]=1
Reactant: C=C(c1cccc(C)c1)c1cc(Br)ccc1O
Reactant: C=C(c1ccc(C)cc1)c1cc(Br)ccc1OC(C)C
Agent: C=C(c1ccc(C)cc1)c1cc(Br)ccc1CC(C)=O
Product: C=C(c1cccc(C)c1)C1C=C(Br)C=CC1(O)OC(C)C

Procedure:
Employing the same general procedure as for the preparation of 4-bromo-1-isopropoxy-2-[(1-p-tolyl)vinyl]benzene (Compound S), 81.5 mg (0.3 mmol) of 4-bromo-2-[(1-m-tolyl)vinyl]phenol (Compound N) was converted into the title compound using 164 mg (0.6 mmol) of triphenylphosphine, 0.10 mL (108 mg, 0.6 mmol) of diethylazodicarboxylate, 0.05 mL (39 mg, 0.6 mmol) of isopropanol and 3 mL of tetrahydrofuran. The reaction was sluggish necessitating addition (after 23 hours of stirring at ambient temperature) of another equivalent of reagents (initially only 1/2 of the above amounts were added) and stirring for 4 additional days. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a pink oil.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C(NC1CCCCC1)(C)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][CH:19]=1.C(Br)C=C>O1CCCC1.C(OCC)C>[CH2:3]([CH:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)[C:25]#[N:26])[CH:2]=[CH2:1]
Reactant: COc1ccc(CC#N)cc1
Reactant: [Li]CCCC
Agent: CC(C)NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: C=CCBr
Product: C=CCC(C#N)c1ccc(OC)cc1
Reaction time: 1.5 h
Yield: 89 %

Procedure:
n-Butyl lithium (0.16 mole of 1.6 M in hexane) was added under a nitrogen atmosphere to dry tetrahydrofuran (100 ml.) which was cooled in a CO2 -acetone bath. This was followed by the successive dropwise additions during 10 minutes of solutions in tetrahydrofuran (10 ml. each) of N-isopropylcyclohexylamine (22.6 g., 0.160 mole) and p-methoxyphenylacetonitrile (21.2 g., 0.144 mole). The mixture was stirred in the cold for 10 minutes when allyl bromide (24.2 g., 0.20 mole) was added dropwise during 10 minutes. Stirring was continued in the cold for 15 minutes and then at ambient temperature for 1.5 hours. The solution was diluted with diethyl ether and washed successively with 4% hydrochloric acid (2 × 100 ml.) H2O and brine. The ethereal solution was dried (Na2SO4), concentrated, and the residue distilled to give 24.2 g. (89% yield) of the nitrile, b.p. 99°-114° (0.1 mm.).
Reaction SMILES: [NH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:8])=[CH:5][N:4]=1)[NH2:2].Cl.CN(C)[CH:22]=[C:23]([N:29]1[CH:34]=[CH:33][C:32](=[O:35])[CH:31]=[CH:30]1)[C:24](OCC)=[O:25].C(O)(=O)C>CC(O)C.CS(C)=O>[OH:25][C:24]1[N:1]([C:3]2[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:8])=[CH:5][N:4]=2)[N:2]=[CH:22][C:23]=1[N:29]1[CH:30]=[CH:31][C:32](=[O:35])[CH:33]=[CH:34]1
Reactant: CCOC(=O)C(=CN(C)C)n1ccc(=O)cc1
Reactant: NNc1ccc(C(=O)NCC2CCOCC2)cn1
Agent: Cl
Solvent: CS(C)=O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: O=C(NCC1CCOCC1)c1ccc(-n2ncc(-n3ccc(=O)cc3)c2O)nc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
Combined 6-hydrazinyl-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide, 1.0 HCl (30 mg, 0.105 mmol), ethyl 3-(dimethylamino)-2-(4-oxopyridin-1(4H)-yl)acrylate (37.1 mg, 0.157 mmol) and acetic acid (0.018 mL, 0.314 mmol) in 2-propanol (0.8 mL) and stirred at 20° C. for 1 hour and then at 50° C. for 16 hours and then 80° C. for 24 h. The reaction mixture was then diluted with 200 uL DMSO and purified by prep HPLC (ACN/water with formic acid) to give the title compound (11 mg, 26.6% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.32 (m, 2 H) 1.62 (d, J=13.4 Hz, 2 H) 1.73-1.90 (m, 1 H) 3.20 (t, J=6.2 Hz, 2 H) 3.25 (s, 2 H) 3.86 (dd, J=11.4, 2.8 Hz, 2 H) 6.56 (br. s., 2 H) 8.19 (br. s., 2 H) 8.40 (t, J=7.7 Hz, 3 H) 8.71 (t, J=5.3 Hz, 1 H) 8.91 (s, 1 H). MS m/z 396 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](=NO)[CH:11]=[CH:10][C:9]2=[O:16])([O-:3])=[O:2].Cl.[OH2:18]>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:18])[CH:11]=[CH:10][C:9]2=[O:16])([O-:3])=[O:2]
Reactant: O
Reactant: O=C1C=CC(=NO)c2c1cccc2[N+](=O)[O-]
Agent: [Fe+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Product: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 33 °C
Reaction time: 1.5 h

Procedure:
5.5 g of 8-nitro-1,4-naphthoquinone-1-oxime are suspended in 450 ml of 38 percent by weight aqueous hydrochloric acid, followed by heating to 33°C. 61 g (0.22 mol) of iron (II) sulphate heptahydrate are then introduced in portions with stirring. After 1.5 hours, the reaction mixture is poured into 1000 ml of water heated to approximately 50°C, followed by stirring for 1 hour at that temperature. The reaction product precipitated is filtered off under suction, washed with water until neutral and dried at approximately 50°C. The yield amounts to 4 g (78 percent of the theoretical yield) of 5-nitro-1,4-naphthoquinone melting at 160°C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([C:10](=O)[CH2:11][CH3:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[NH3:16].[BH4-].[Na+]>C(O)C.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([CH:10]([NH2:16])[CH2:11][CH3:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: CCC(=O)c1cc(Cl)c(C)c(Br)c1OC
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: CCC(N)c1cc(Cl)c(C)c(Br)c1OC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Titanium tetraisopropoxide (3.0 mL, 10 mmol) was added to a mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propan-1-one (2.5 g, 8.6 mmol) and 2.0 M ammonia in ethanol (21.4 mL) at 0° C. The reaction was heated and stirred at 60° C. under nitrogen for 3 hours. The reaction was allowed to cool to room temperature, cooled in an ice bath and the sodium tetrahydroborate (0.486 g, 12.9 mmol) was added, the solution was stirred at room temperature for another 2 hours. The reaction mixture was quenched with 2 M ammonia in water, and was stirred to form the precipitate. The slurry was filtered, the solids were washed with EtOAc and the organic layer was concentrated in vacuo. The residue was diluted with methylene chloride, washed with sat'd NaHCO3, water, brine, dried over MgSO4, filtered and concentrated to give 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propan-1-amine as an oil. This was diluted with 1,4-dioxane (48 mL) and DIPEA (5.0 mL) and the di-tert-butyldicarbonate (2.81 g, 12.9 mmol) was added. The reaction was allowed to stir at room temperature overnight. The reaction was complete by LC/MS, and the reaction mixture was diluted with EtOAc and washed with 1 N HCl, brine, dried over magnesium sulfate and concentrated to give the crude product as an oil. The product was purified by chromatography on silica gel eluting with a hexane: EtOAc gradient to give tert-butyl [1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propyl]carbamate as a semisolid (2.0 g, 80%). LCMS calculated for C11H13BrClO (M+H)+: m/z=274.9, 276.9. found: 274.9, 276.8. This racemic material was separated by chiral column HPLC: ChiralPak AD-H 20×250 mm, 3% ethanol:hexane, 18 mL/min, loading 10 mg/mL, to give the separated enantiomers. Peak 2 tert-butyl [1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propyl]carbamate was used further in synthesis.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:15]2[C@@H:6]([CH2:7][CH2:8][C:9]3[C@:14]2([CH3:16])[CH2:13][CH:12]([CH:17]=O)[C:11](=O)[CH:10]=3)[C@@H:5]2[CH2:20][CH2:21][C@:22]3([C:26]4([CH2:30][O:29][CH2:28][O:27]4)[O:25][CH2:24][O:23]3)[C@@:4]2([CH3:31])[CH2:3]1.[F:32][C:33]1[CH:34]=[C:35]([NH:40][NH2:41])[CH:36]=[C:37]([F:39])[CH:38]=1>>[F:32][C:33]1[CH:34]=[C:35]([N:40]2[C:11]3[CH:10]=[C:9]4[CH2:8][CH2:7][C@@H:6]5[C@@H:15]([C@@:14]4([CH3:16])[CH2:13][C:12]=3[CH:17]=[N:41]2)[C@@H:2]([OH:1])[CH2:3][C@:4]2([CH3:31])[C@:22]3([CH2:21][CH2:20][C@@H:5]52)[C:26]2([CH2:30][O:29][CH2:28][O:27]2)[O:25][CH2:24][O:23]3)[CH:36]=[C:37]([F:39])[CH:38]=1
Reactant: C[C@]12CC(C=O)C(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@@]21OCOC12COCO2
Reactant: NNc1cc(F)cc(F)c1
Product: C[C@]12Cc3cnn(-c4cc(F)cc(F)c4)c3C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@@]21OCOC12COCO2

Procedure:
The compound was prepared from (8S,9S,10R,11S,13S,14S,17R)-11-hydroxy-10,13-dimethyl-3-oxo-1,2,3,6,7,8,9,10,11,12,13,14,15,16-tetradecahydrodispiro[cyclopenta[a]phenanthrene-17,4′-[1,3]dioxolane-5′,4″[1,3]dioxolane]-2-carbaldehyde and (3,5-difluorophenyl)hydrazine according to the procedure for Intermediate 50. APCI-MS m/z: 541 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][CH2:30][O:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:29][CH2:30][O:31][CH3:32])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)(c2ccc(Br)cc2)CC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(C2(c3ccc(Br)cc3)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 0.08 h

Procedure:
A solution of 4-(4-Bromo-phenyl)-4-(4-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.23 mmol), 2-bromoethyl methylether (200 ul) and potassium carbonate (64 mg, 0.46 mmol) in dimethylformamide (2 ml) was heated in a CEM Explorer™ microwave to 50° C. for 30 minutes using 50 watts power. The reaction was poured into sodium hydroxide (2N, 4 ml), stirred for 5 minutes then extracted into ethyl acetate (2×30 ml). The combined organic liquors were dried (MgSO4), concentrated and the residue was purified by column chromatography (SiO2), eluting with ethyl acetate/petrol (25:75) gradient to (50:50) to afford the title compound (82 mg). LCMS: (PS-A2) Rt 4.00 [M+H]+490.