Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][S:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36]>>[CH3:31][S:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH:36][CH2:22][C:21]1[CH:20]=[C:19]([C:18]2[C:17]3[C:12](=[C:13]([C:27]([F:30])([F:28])[F:29])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:26]=[CH:25][CH:24]=1
Reactant: CSc1ccccc1CN
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CSc1ccccc1CNCc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 2-methylthio benzylamine according to the procedure of Example 66. MS (ES) m/z 543.2.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[CH2:15]([Mg]Cl)[CH2:16][CH2:17][CH3:18].BrC1C=C2C(C(C(C)C)=CC(C)(C)O2)=CC=1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCCC[Mg]Cl
Reactant: CC1(C)CC(=O)c2ccc(Br)cc2O1
Agent: CC(C)C1=CC(C)(C)Oc2cc(Br)ccc21
Product: CCCCC1=CC(C)(C)Oc2cc(Br)ccc21

Procedure:
7-bromo-2,2-dimethyl-chroman-4-one (Compound 65, 1.58 g, 6.20 mmol) was treated by the procedure described above (using n-butyl magnesium chloride) for the preparation of Compound 66 to produce the title compound as a clear oil: (1.07 g, 59%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[C:7]2[C:8]([O:10][C:11](=[O:12])[C:6]=12)=O)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26].CC([O-])=O.[Na+]>C(O)(=O)C>[O:10]=[C:8]1[C:7]2[C:6](=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:15]=[CH:14][CH:13]=2)[C:11](=[O:12])[N:23]1[CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]
Reactant: CC(=O)Oc1cccc2c1C(=O)OC2=O
Reactant: NC1CCC(=O)NC1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC(=O)Oc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 57 %

Procedure:
1,3-Dioxo-2-(2,6-dioxopiperidin-3-yl)-4-acetoxyisoindoline was prepared and isolated as follows. A mixture of 3-acetoxyphthalic anhydride (40 mg), aminoglutarimide trifluoroacetate (47 mg), and NaOAc (32 mg) in acetic acid (2 mL) was refluxed for 5 h. The solvent was evaporated, water (10 mL) was added, and the resulting solution was stirred for several minutes. The solid was filtered out and recrystallized from ethyl acetate to give 1,3-dioxo-2-(2,6-dioxopiperidin -3-yl)-4-acetoxyisoindoline as pale yellow crystals (35 mg, 66%): 1H NMR (DMSO) δ 11.16 (s, 1H), 11.07 (s, 1H), 7.64 (t, J=7.2 Hz, 1H), 7.22-7.31 (m, 2H), 5.05 (dd, J=5.4 Hz, J=12.5 Hz, 1H), 2.87-2.92 (m, 2H), 2.48 (s, 3H), 2.08-2.00 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:8]=[C:7]([C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=1.[C:12]1([S:18]([N:21]2[C:29]3[CH:28]=[C:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]5[NH:36][CH:37]=[CH:38][C:31]=45)[CH:26]=[C:25]([NH2:39])[C:24]=3[CH:23]=[N:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.C(Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH:39][C:25]2[CH:26]=[C:27]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]4[NH:36][CH:37]=[CH:38][C:31]=34)[CH:28]=[C:29]3[C:24]=2[CH:23]=[N:22][N:21]3[S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cc(-c2ccnc3[nH]ccc23)cc2c1cnn2S(=O)(=O)c1ccccc1
Reactant: O=C(Cl)c1cccc(CCl)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cc(-c2ccnc3[nH]ccc23)cc2c1cnn2S(=O)(=O)c1ccccc1)c1cccc(CCl)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-(hydroxymethyl)-2-pyridinecarboxylic acid (500 mg, 3.27 mmol) in chloroform (10 ml) and N,N-dimethylformamide (DMF) (0.1 ml) was added thionyl chloride (1 ml, 13.70 mmol) and the mixture heated at 65° C. for 1 hr. Solvent was removed in vacuo and the residue was azeotroped with chloroform (5 ml) then dried on a high vacuum line for 30 mins to afford an orange oil (650 mg), presumed to be 6-(chloromethyl)-2-pyridinecarbonyl chloride. To solution of 1-(phenylsulfonyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-4-amine (1.63 g, 4.19 mmol) in chloroform (25 ml) at 0° C. was added DIPEA (1.462 ml, 8.37 mmol). 6-(chloromethyl)-2-pyridinecarbonyl chloride (1.193 g, 6.28 mmol) in Chloroform (20 ml) was then added dropwise and the mixture was stirred at 0° C. for 15 min. A further portion of 6-(chloromethyl)-2-pyridinecarbonyl chloride (1.193 g, 6.28 mmol) in chloroform (20 ml) was added and the mixture was stirred at 0° C. for 15 min then warmed to room temperature and stirred for 18 h. The reaction mixture was quenched with water (100 ml) and extracted with DCM (100 ml). The solvent was removed in vacuo to give an orange solid. Trituration with DCM afforded the title compound (370 mg). The filtrate from the trituration was concentrated in vacuo to ˜5 ml volume and then added to the top of 2×100 g silica SPE cartridges. The cartridges were eluted with a gradient of 0-100% EtOAc/DCM over 60 mins on the Flash Master II. The product-containing fractions were combined and the solvent removed in vacuo to give a further portion of the title compound as an off-white solid (530 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][N:15]=3)[CH:10]=[C:9]([C:17]([O:19]CC)=[O:18])[C:8]2=[O:22])[CH:3]=1.Cl>C(O)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][N:15]=3)[CH:10]=[C:9]([C:17]([OH:19])=[O:18])[C:8]2=[O:22])[CH:3]=1
Reactant: CCOC(=O)c1cc2cccnc2n(-c2cc(C)on2)c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(-n2c(=O)c(C(=O)O)cc3cccnc32)no1
Temperature: 60 °C
Reaction time: 5 h
Yield: 104.5 %

Procedure:
1.8 g (6.0 mmol) of ethyl 1-(5-methyl-3-isoxazolyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in acetic acid (50 mL), and 6 N hydrochloric acid (10 mL) was added to this solution at room temperature. The resulting mixture was stirred for 5 hours at 60° C. The solvent was distilled off from the reaction mixture, and the residue was dissolved in toluene. The solvent was distilled off under reduced pressure, and thus 1.7 g of the title compound was obtained as colorless crystals (yield: quantitative).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN(C)C(=O)C.Br[C:21]1[C:22](Cl)=[N:23][CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1>[Pd].C(O)(=O)C.O>[N+:27]([C:25]1[CH:26]=[C:21]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:13][C:22]2=[N:23][CH:24]=1)([O-:29])=[O:28]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1cnc2oc3ccccc3c2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
Potassium carbonate (87 mg) and phenol (47 mg) were added to an N,N-dimethylacetamide (1 ml) solution containing 3-bromo-2-chloro-5-nitropyridine (100 mg), followed by stirring at 70° C. for 3 hours. Acetic acid palladium (20 mg) was added in a nitrogen atmosphere, followed by stirring at 100° C. for 3.5 hours. Water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, hexane and ethyl acetate were added to the obtained residue, an insoluble precipitate was collected by filtration, and a light yellow solid of 3-nitrobenzofuro[2,3-b]pyridine (47.1 mg) was thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[N:23][NH:24][CH:25]=4)[CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[ClH:28].[Cl:29][CH2:30][CH2:31][NH:32][CH3:33].[Cl-].[NH4+]>C(#N)C.S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[ClH:29].[ClH:28].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:25]=[N:24][N:23]([CH2:30][CH2:31][NH:32][CH3:33])[CH:22]=4)[CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: CNCCCl
Reactant: Fc1ccc(-c2nccnc2N2CCN(Cc3cn[nH]c3)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CO
Solvent: CC#N
Product: CNCCn1cc(CN2CCN(c3nccnc3-c3ccc(F)cc3)CC2)cn1
Yield: 22.3 %

Procedure:
Dissolve 3′-(4-fluoro-phenyl)-4-(1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.450 g, 1.33 mmol) in acetonitrile (3 mL) and add solid sodium hydroxide (0.186 g, 4.65 mmol). After 30 min. add (2-chloro-ethyl)-methyl-amine hydrochloride (0.190 g, 1.46 mmol) and tetrabutylammonium bisulfate (18 mg, 0.0531 mmol) then reflux the mixture for 20 hr. Cool and filter the mixture then evaporate. Purify using silica gel chromatography, eluting with 6:94 2N ammonia in methanol:DCM to give a yellow oil. Dissolve the solid in methanol and add ammonium chloride then sonicate the mixture for 10 min. Evaporate the solution to give the title compound as a white solid (0.139 g, 23%). MS (ES): m/z=396 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9].[NH3:14]>C1(C)C=CC=CC=1>[NH2:14][C:12]([NH:11][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:10])=[O:9])=[O:13]
Reactant: N
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: NC(=O)NS(=O)(=O)c1ccccc1Cl
Temperature: 0 °C

Procedure:
A solution of 314 g of 2-chlorobenzenesulfonyl isocyanate in 2 L of toluene was cooled to 0° C. and treated with 27 g of anhydrous liquid ammonia, added dropwise at a rate that maintained the temperature around 0° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature. The solids were collected by filtration, and washed with hexane and acetonitrile. The yield of N-(aminocarbonyl)-2-chlorobenzenesulfonamide was 313 g as a white solid, m.p. 160°-163° C.; IR (nujol): 3400, 3300, 1700, 1650, 1550, 1250, 1150 cm-1.
Reaction SMILES: CN.C1COCC1.[CH2:8]([N:10](CC)CC)C.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21].O>ClCCl>[CH3:8][NH:10][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([C:16]([F:27])([F:26])[F:15])[CH:18]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCN(CC)CC
Agent: CN
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 2M methylamine-THF solution (20 ml) was added to a solution of triethylamine (7 ml) in dichloromethane (70 ml), a solution of 3-(trifluoromethyl)benzoyl chloride (5.0 g) in dichloromethane (30 ml) was added dropwise thereto under ice cooling, followed by stirring at room temperature for 72 hours. The reaction solution was poured into water, followed by extraction with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then saturated brine in this order and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was dissolved again in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and then saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting solid was washed with diisopropylether, to obtain, as a colorless solid, N-methyl-3-(trifluoromethyl)benzamide (1.34 g).
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)#[N:4].Br[C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][NH:21][C:22]2=[O:25])=[CH:17][CH:16]=1>O.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][NH:21][C:22]3=[O:25])=[CH:17][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)#[N:4]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=c1[nH]ccc2ccc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1cccc(-c2ccc3cc[nH]c(=O)c3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A solution of sodium hydroxide (214 g, 5.35 mol) in water (10 L) was added to a stirred suspension of 3-cyanophenylboronic acid (24% water content, 1.13 kg, 5.8 mol) and 7-bromoisoquinolinone (1.0 kg, 4.46 mol) in methanol (10 L) and the mixture stirred for 1 hour. Palladium acetate (10 g, 44.5 mmol) was added and the mixture was heated at reflux under N2 for 5 hours and then cooled to room temperature and stirred overnight. The light grey solid was collected by filtration. The damp solid was reslurried in water (10 L) and heated to 80° C. for 30 minutes. The mixture was then cooled to room temperature and the solid collected by filtration, washed with water (2 L) then methanol (2 L) and dried in vacuo at 50° C. to give 7-(3-cyanophenyl)isoquinolinone (1.09 kg, 4.43 mol, 99%) as a light grey solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][CH:15]2[O:22][CH2:23][CH:24]=[CH2:25])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O>O1CCCC1>[OH:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][CH:15]2[O:22][CH2:23][CH:24]=[CH2:25]
Reactant: C=CCOC1CCN(CC)c2c(CO[Si](C)(C)C(C)(C)C)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC1CCN(CC)c2c(CO)cccc21
Reaction time: 1 h
Yield: 105 %

Procedure:
8-t-Butyldimethylsilyloxymethyl-4-allyloxy-1-ethyl-1,2,3,4-tetrahydroquinoline (1.81 g) was dissolved in tetrahydrofuran (20 ml), and to this solution was added dropwise 1M tetrabutylammonium fluoride-tetrahydrofuran solution (6 ml) under ice-cooling. The mixture was stirred for 1 hour at the same temperature. Water was added to the reaction mixture and after distilling off tetrahydrofuran, the residue was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and distilled off then 8-hydroxymethyl-4-allyloxy-1-ethyl-1,2,3,4-tetrahydroquinoline (1.30 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[C:9]([N+:21]([O-])=O)[CH:8]=1.[Cl-].[NH4+]>O.C(O)C.[Fe]>[NH2:21][C:9]1[CH:8]=[C:7]([O:6][CH2:5][C:4]2[CH:24]=[CH:25][CH:26]=[C:2]([Br:1])[CH:3]=2)[CH:20]=[CH:19][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cc(OCc2cccc(Br)c2)ccc1Oc1ccc(O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(OCc2cccc(Br)c2)ccc1Oc1ccc(O)cc1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
A mixture of the product from Example 218A (384.6 mg, 0.924 mmol), iron powder (317.4 mg, 5.683 mmol), and ammonium chloride (323.7 mg, 6.052 mmol) in water (3 mL) and ethanol (6 mL) was heated at 70° under a nitrogen atmosphere for 1 hour. The reaction was cooled to room temperature and vacuum filtered, washing the residue with methanol. The filtrate was concentrated under vacuum and azeotroped with toluene (50 mL). The residue was purified by silica gel flash chromatography using a gradient of 7% to 10% ethyl acetate/methylene chloride as eluent to provide the title compound as a beige solid (272 mg, 0.704 mmol, 76%).
Reaction SMILES: [CH2:1]([C@@:8]12[CH2:21][C:20](=[O:22])[C@:19]([OH:29])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][C@H:17]1[CH2:16][CH2:15][C:14]1[CH:13]=[C:12]([C:30](O)=[O:31])[CH:11]=[CH:10][C:9]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[C:35]([CH3:40])=[N:36][CH:37]=[CH:38][CH:39]=1.CN1C=CN=C1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(#N)C.C(OCC)(=O)C>[CH2:1]([C@@:8]12[CH2:21][C:20](=[O:22])[C@:19]([OH:29])([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:18][C@H:17]1[CH2:16][CH2:15][C:14]1[CH:13]=[C:12]([C:30]([NH:33][C:34]3[C:35]([CH3:40])=[N:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH:11]=[CH:10][C:9]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2c(c1)CC[C@@H]1C[C@@](O)(c3ccccc3)C(=O)C[C@@]21Cc1ccccc1
Reactant: Cc1ncccc1N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cn1ccnc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ncccc1NC(=O)c1ccc2c(c1)CC[C@@H]1C[C@@](O)(c3ccccc3)C(=O)C[C@@]21Cc1ccccc1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
(4bR,7R,8aR)-4b-benzyl-7-hydroxy-6-oxo-7-phenyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxylic acid (21 g, 49.2 mmol), 3-amino-2-picoline (5.8 g, 52.2 mmol) and 1-methylimidazole (20 mL, 246.2 mmol) were dissolved in anhydrous acetonitrile (105 mL). 1-Propanephosphonic acid cyclic anhydride (50 wt % in ethyl acetate) (47 mL, 78.8 mmol) was slowly added to control the mild exotherm. The mixture was stirred at 25° C. until the reaction was completed (less than an hour). Ethyl acetate (86 mL) was added to the mixture. The mixture was washed with water (4×100 mL). The organic phase was dried with MgSO4 and concentrated to dryness. The title product (22.3 g, 89% yield) was obtained as a light-yellow foam. 1H NMR (DMSO): δ 1.95 (m, 2H), 2.10 (m, 3H), 2.35 (s, 3H), 2.75 (m, 3H), 3.0 (d, 1H), 3.05 (m, 2H), 5.70 (s, 1H), 6.15 (d, 1H), 6.60 (m, 2H), 7.10 (m, 3H), 7.25 (m, 2H), 7.30 (m, 5H), 7.65 (d,
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]2([CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:17][N:14]1[CH2:15][CH2:16][C:10]2([CH2:11][NH:8][CH2:9]2)[CH2:12][CH2:13]1
Reactant: CN1CCC2(CC1)CN(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC2(CC1)CNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester hydrochloride (100 mg, 0.381 mmol) in DCE (10 mL) was added an aqueous solution of formaldehyde (37% w/w, 40 μL, 0.537 mmol). The mixture was stirred at RT for 10 min, then sodium triacetoxyborohydride (121 mg, 0.571 mmol) was added and stirring was continued for 1 h. Water was added to the reaction mixture before being loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give 7-methyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester. To a solution of 7-methyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester in DCM (5 mL) was added TFA (1 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a colourless oil (45 mg, 84%).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:39]=[CH:38][CH:37]=[CH:36][C:8]=2[C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:19]([N+:33]([O-])=O)[CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]>C(O)C.C(O)(=O)C.[Fe]>[CH2:1]([C:5]1[O:6][C:7]2[CH:39]=[CH:38][CH:37]=[CH:36][C:8]=2[C:9]=1[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:19]([NH2:33])[CH:18]=2)=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1Cc1ccc(-c2ccc(OCCCc3ccccc3)c([N+](=O)[O-])c2)cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCc1oc2ccccc2c1Cc1ccc(-c2ccc(OCCCc3ccccc3)c(N)c2)cc1
Temperature: 120 °C
Yield: 28.2 %

Procedure:
A solution of 2-butyl-3-[3′-nitro-4′-(3-phenyl-propoxy)-biphenyl-4-ylmethyl]-benzofuran (53 mg, 0.105 mmol) in ethanol (1 mL) and acetic acid (1 mL) was treated with Fe (26.4 mg, 4.5 equiv., 0.472 mmol) and heated to 120° C. for 3 h. After cooling to room temperature, the solution was poured into a 20% aq NaOH/ice water solution (Ph>8) and extracted with ether (3×20 mL). The combined organic layers were washed with water, sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by prep thin layer chromatography (25% ethyl acetate in heptane) afforded 4′-(2-butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-ylamine (14.5 mg, 29%).
Reaction SMILES: C(OC(NCCN(C1C=C(C)C=CC=1C#N)CCNC(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:31].CCOCC.[C:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1)(=[O:39])C.[BH4-:46].[Na+:47]>CO>[N:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[CH:37]=[O:39].[BH4-:46].[Na+:47].[ClH:31]
Reactant: CC(=O)c1ccccn1
Agent: Cc1ccc(C#N)c(N(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [BH4-]
Solvent: CCOCC
Solvent: CO
Product: O=Cc1ccccn1

Procedure:
The resultant bis(2-tert-butoxycarbonylaminoethyl)amino-4-methylphenylcyanide was deprotected using HCl/ether, condensed with 2-acetyl pyridine (0.01 mol) in MeOH, and then reduced by NaBH4. After sequential treatments with pyridine-2-carboxaldehyde, NaBH4, and HCl, compound 110 was obtained in 75% overall yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([CH2:8][CH2:9][CH2:10]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:7]=1.[C-:23]#[N:24].[Na+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([CH2:8][CH2:9][CH2:10][C:23]#[N:24])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2cc(Br)ccc2F)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCCc1cc(Br)ccc1F
Temperature: 80 °C
Yield: 101.9 %

Procedure:
A solution of Toluene-4-sulfonic acid 3-(5-bromo-2-fluoro-phenyl)-propyl ester (0.59 g, 1.5 mmol) in anhydrous DMSO (3.0 mL) was added sodium cyanide (0.112 g, 2.3 mmol) and heated to 80° C. for 12 h. The mixture was cooled and partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layers were washed with brine (1×15 mL), dried (MgSO4), filtered and concentrated under reduced pressure. Silica gel chromatography (10-20% Ethyl acetate/petroleum ether) gave the title compound as a clear oil (0.37 g, 99%), and was used directly in the next step.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:5]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].O>CN(C=O)C>[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[N:8]([S:30]([C:24]3[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=3)(=[O:32])=[O:31])[C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1-c1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)n2c(=O)n(-c3ccccc3)c3cc(Cl)ccc32)cc1OC
Reaction time: 0.5 h

Procedure:
66 mg of sodium hydride as an 80% dispersion in oil were added in portions to a solution of 490 mg of 5-chloro-1,3-dihydro-3-phenyl-2H-benzimidazol-2-one in 5 ml of DMF and the reaction medium was stirred for 30 minutes. 520 mg of 3,4-dimethoxybenzenesulfonyl chloride were then introduced and the reaction medium was stirred overnight at room temperature. The solvent was then evaporated off under vacuum and the residue obtained was taken up with water. It was then extracted with DCM, washed with water and then dried over sodium sulfate and the solvent was evaporated off to dryness. The residue obtained was chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give the expected product in the form of a white solid, which crystallized from absolute EtOH. m=0.71 g. M.p.=154° C.