Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:12][CH:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])=[CH:9][C:10]#[N:11].[CH:18]1([CH2:21][C:22](Cl)=[O:23])C[CH2:19]1.N1C=CC=CC=1>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:12][CH:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])=[C:9]([C:22](=[O:23])[CH2:21][CH2:18][CH3:19])[C:10]#[N:11]
Reactant: CC(C)C(C)NC(=CC#N)c1ccccc1Cl
Reactant: O=C(Cl)CC1CC1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CCCC(=O)C(C#N)=C(NC(C)C(C)C)c1ccccc1Cl
Temperature: 80 °C
Yield: 79 %

Procedure:
To a solution of 3-(2-chlorophenyl)-3-[(3-methylbutan-2-yl)amino]acrylonitrile (1 g, 4.02 mmol, 1 eq.) in 1,2-dichloroethane (2 ml) were added cyclopropylacetyl chloride (1.71 g, 16.08 mmol, 4 eq.) and pyridine (1.58 g, 20.1 mmol, Seq.) and the solution was heated to 80° C. for 8 h. The reaction was quenched with 1N aq. HCl (20 ml) and extracted with ethylacetate. The organic layers were combined and washed with 1N aq. NaOH (20 ml), dired over MgSO4 and concentration under vacuum. The residual oil was subjected to column chromatography to give 2-{(2-chlorophenyl)[(3-methylbutan-2-yl)amino]methylene}-3-oxohexanenitrile (1.012 g, 75% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[N-:13]=[N+:14]=[N-:15].[Na+]>CCO.O>[N:13]([CH2:2][CH2:3][CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])=[N+:14]=[N-:15]
Reactant: CCOP(=O)(CCCBr)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOP(=O)(CCCN=[N+]=[N-])OCC

Procedure:
To a solution of diethyl 3-bromopropylphosphonate (1 eq) in EtOH (2 M) was added sodium azide (5 eq) in water (4 M). The reaction mixture was heated at reflux overnight. The mixture was then diluted with water, extracted with DCM three times. The combined organic layers are washed with brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 80-100% EtOAc/Hex to give the product as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.O.[CH:11](=[O:14])[CH2:12][CH3:13]>CO>[OH:14][CH:11]([C:7]1[O:8][C:2]([CH3:1])=[CH:3][C:4](=[O:5])[C:6]=1[OH:9])[CH2:12][CH3:13]
Reactant: Cc1cc(=O)c(O)co1
Reactant: CCC=O
Solvent: CO
Solvent: O
Product: CCC(O)c1oc(C)cc(=O)c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.7 %

Procedure:
Allomaltol (12.6 g, 100 mmol, 1 eq.) was added to 100 ml water and the pH of the solution was adjusted to 10.5 using 50% aqueous sodium hydroxides. Propionaldehyde (8.7 g, 150 mmol, 1.5 eq.) dissolved in 50 ml methanol was slowly added dropwise over 1 hour and the solution allowed to stir at room temperature for 48 hours. After adjustment to pH 1 with 37% hydrochloric acid, the reaction mixture was evaporated to dryness and the residue taken up into 300 ml of dichloromethane. The organic layer was washed with water (150 ml), dried over anhydrous sodium sulphate, filtered and concentrated to yield the crude product. Recrystallisation from toluene afforded the pure product (14.5 g, 78.9%) as a white crystalline solid. m.p. 134-136° C. [lit. 132-135° C. Ellis (1993)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.Cl.[Cl:11][CH2:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.[OH-].[Na+]>C(#N)C>[Cl:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:8][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: NCCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: ClCCCNCc1ccc(Cl)nc1
Yield: 86.9 %

Procedure:
16.20 g (100 mmol) of 2-chloro-5-(chloromethyl)pyridine, 16.90 g (130 mmol) of 3-chloropropan-1-amine hydrochloride and 36.24 ml (260 mmol) of triethylamine in 200 ml acetonitrile stirred at 60° C. for 20 hours. After addition of 30.67 g (230 mmol) of 30 percent strength aqueous sodium hydroxide solution, the reaction mixture is concentrated under reduced pressure and the residue is extracted with chloroform. Concentration of the extract under reduced pressure gives 19.03 g (87% of theory) of 3-chloro-N-[(6-chloropyridin-3-yl)methyl]propan-1-amine which can be used without further purification for the next reaction (cf. Ex. II-2).
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[CH:15]=[C:14]2[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33].CN1CCOCC1.Cl>ClCCl>[CH:5]1([O:4][C:2]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[CH:15]=[C:14]3[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(N)cc23)c(OC)c1
Reactant: O=C(Cl)OC1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Reaction time: 2 h
Yield: 77.4 %

Procedure:
Cyclopentyl chloroformate (0.11 g.) was added to a stirred solution of methyl 4-(5-amino-1-methylindol-3-ylmethyl)-3-methoxybenzoate (D) (0.25 g.) and N-methylmorpholine (0.23 g.) in dichloromethane (3 ml.), under an atmosphere of nitrogen. The mixture was stirred for 2 hours and then poured into 1M hydrochloric acid (20 ml.). This acid mixture was extracted with ethyl acetate (2×30 ml.). The combined extracts were washed with saturated brine (20 ml.), dried (MgSO4), and evaporated to give a viscous oil. This was purified by flash chromatography on silica gel (50 ml.), eluting with 3:7 v/v ethyl acetate:hexane, to give the title compound as a foam (0.25 g., 74%): NMR: 1.62 [m,8 H, (CH2)4 ], 3.68 (s,3 H, NCH3), 3.83 (s,3 H, CO.OCH3), 3.91 (s,3 H, OCH3), 3.95 (s, 2 H, CH2.Ar), 5.05 (m,1 H, --CHO--), 7.11 (m,2 H), 7.26 (d, 1 H), 7.43 (m,2 H), 7.59 (br,1 H), 9.18 (br,1 H, NH).
Reaction SMILES: [Cl-].[F:2][C:3]([Zn+])([F:5])[F:4].Br[C:8]1[CH:12]=[C:11]([CH:13]([O:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[NH:10][C:9]=1[CH:29]([O:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:30]([F:39])([F:38])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33]>>[F:39][C:30]([F:38])([C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35])[CH:29]([C:9]1[NH:10][C:11]([CH:13]([O:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:17])([F:18])[F:19])=[CH:12][C:8]=1[C:3]([F:5])([F:4])[F:2])[O:40][Si:41]([CH3:42])([CH3:43])[CH3:44]
Reactant: C[Si](C)(C)OC(c1cc(Br)c(C(O[Si](C)(C)C)C(F)(F)C(F)(F)C(F)(F)F)[nH]1)C(F)(F)C(F)(F)C(F)(F)F
Reactant: FC(F)(F)[Zn+]
Agent: [Cl-]
Product: C[Si](C)(C)OC(c1cc(C(F)(F)F)c(C(O[Si](C)(C)C)C(F)(F)C(F)(F)C(F)(F)F)[nH]1)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Trifluoromethylzinc chloride is reacted with 3-bromo-2,5-bis(2,2,3,3,4,4,4-heptafluoro-1-trimethylsilyloxybutyl)pyrrole utilizing reaction and purification conditions described in Example 22.
Reaction SMILES: [OH-].[Na+].O.[CH:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11]1>CCCCCC>[OH:9][CH:4]([CH:11]1[CH2:12][CH2:13][CH2:14][C:10]1=[O:15])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC=O
Reactant: O=C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Product: CCCCC(O)C1CCCC1=O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
Into a 2-litter four-neck flask fitted with a thermometer, a reflux condenser and a stirrer were added sodium hydroxide (3.2 g) and water (300 ml). Then, a mixture of pentanal (86 g) and cyclopentanone (152 g) was added dropwise with stirring at 0-5° C. over a period of 2 hours. After the addition, the reaction mixture was stirred at room temperature for 1 hour to complete the reaction. Hexane (150 ml) was added to the reaction mixture and the layers were separated from each other. The resulting organic layer was washed with an aqueous solution (200 ml) of acetic acid (1 g) and then separated. The resulting organic layer was washed with saturated brine and separated. The organic layer was evaporated on a rotary evaporator under reduced pressure to recover hexane and unreacted cyclopentanone, whereby a crude product (173 g) was obtained. The product was distilled using a Claisen distillation apparatus to obtain 127 g of 2-(1-hydroxypentyl)cyclopentanone (boiling point: 115° C./933 Pa; GC purity: 95%). The remaining 5% was 2-pentylidenecyclopentanone which is a dehydration product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][NH:27][CH3:28])=[CH:24][CH:23]=1.O>CS(C)=O>[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][N:27]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=2)[CH3:28])=[CH:24][CH:23]=1
Reactant: CNCc1ccc(F)cc1
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1cc(N(C)Cc2ccc(F)cc2)ccc1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
4-Fluoro-2-isopropoxy-1-nitrobenzene (1.0 g) was dissolved in dry dimethylsulfoxide (25 mL). Potassium carbonate (1.4 g) and (4-fluorobenzyl)-(methyl)-amine (0.84 g) were added. The resulting mixture was heated to 90° C. over night. After cooling to room temperature, water (75 mL) was added, and the resulting mixture was extracted with ethyl acetate (3×75 mL). The organic phase was dried over sodium sulfate, filtered, and evaporated in vacuo to yield the title compound as slightly yellow solid (1.6 g, 100%).
Reaction SMILES: [NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:2]([C:6]([NH:8][C@H:9]([C:18](O)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].C1C=CC2N(O)N=NC=2C=1.[NH2:41][C@H:42]([C:55]([O:57][CH3:58])=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.O>[NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:2]([C:6]([NH:8][C@H:9]([C:18]([NH:41][C@H:42]([C:55]([O:57][CH3:58])=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[O:49])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
13.8 g of Z-Val-Tyr-OH [R. Schwyzer et al., Helv. Chim. acta. 41, 1273 (1958)] and 5.1 g of HOBt×H2O are dissolved in 100 ml of DMF and there is added thereto the above solution of H-Lys(Boc)-OMe in a small amount of DMF. The whole is cooled to 0°, 7.6 g of DCCI are added and the whole is stirred for 6 hours at 0° and for 10 hours at room temperature. The DCH which has separated out is filtered off and the filtrate is concentrated to dryness. Purification is carried out by triturating with diisopropyl ether and by dissolving and reprecipitating from trifluoroethanol/ethyl acetate/petroleum ether, yielding Z-Val-Tyr-Lys(Boc)-OMe; Rf (F)=0.39.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:21][C:22]([CH3:24])=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[C:14]([CH:9]1[CH2:10][NH:11][CH2:12][CH2:13][N:8]1[C:3]1[C:2]([NH:1][CH:22]([CH3:24])[CH3:21])=[CH:7][CH:6]=[CH:5][N:4]=1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)C1CNCCN1c1ncccc1N
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)Nc1cccnc1N1CCNCC1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-amino-2-(Boc-piperazine)pyridine 7 (3.813 g, about 11.16 mmol, crude) was dissolved in dichloroethane (75 mL). Acetone (1.7 mL, 23.12 mmol) was added, followed by an addition of HOAc (1.0 mL, 17.45 mmol) at room temperature. After about 10 min, NaBH(OAc)3 (7.46 g, 33.44 mmol) was added. An additional amount of dichloroethane (25 mL) was added. The resulting mixture was stirred at room temperature for 64 h. 5% aqueous NaHCO3 was added to quench the reaction. The organic phase was separated and the aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic solution was washed with brine, dried over anhydrous Na2SO4, concentrated. The residue was purified via flash column chromatography over silica gel with 5-35% ethyl acetate in hexane to afford the product as solid in quantitative yield. 1H-NMR (CDCl3): 7.673 (dd, J=5.0 Hz and 1.5 Hz, 1H, Ar—H), 6.904 (dd, J=8.0 Hz and 5.0 Hz, 1H, Ar—H), 6.812 (dd, J=8.0 Hz and 1.5 Hz, 1H, Ar—H), 4.150 (d, J=7.5 Hz, 1H, NH), 3.569-3.517 (m, 5H, 2CH2 and CH), 2.997 (t, J=5.0 Hz, 4H, 2 CH2), 1.477 (s, 9H, 3 CH3), 1.23 (d, J=6.0 Hz, 6H, 2 CH3). (ref. Romero D. L. et al. J. Med. Chem. 37, 999-1014, 1994.)
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:8]=2)[NH:3]1.[NH:15]1[C:19]2[CH:20]=[C:21]([CH:24]=O)[CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1>>[NH:17]1[C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[C:10]3/[C:2](=[O:1])[NH:3][C:4]4[C:9]/3=[CH:8][CH:7]=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=4)=[CH:20][C:19]=2[N:15]=[N:16]1
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Reactant: O=Cc1ccc2nn[nH]c2c1
Product: CC(=O)Nc1ccc2c(c1)NC(=O)/C2=C/c1ccc2[nH]nnc2c1

Procedure:
The title compound was synthesized according to the method described for Example A11B except substituting N-(2-oxoindolin-6-yl)acetamide (30 mg, 0.158 mmol) and 1H-benzo[d][1,2,3]triazole-6-carbaldehyde (26 mg, 0.174 mmol) to obtain 22 mg, 44%. 1H NMR (400 MHz, d6-DMSO) δ ˜16 (s, 1H), 10.60 (s, 1H), 10.10 (s, 1H), 8.23 (s, 1H), 8.01 (s, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.64 (s, 1H), 7.51 (s, 1H), 7.47 (d, J=8.0 Hz, 1H), 6.86 (d, J=7.4 Hz, 1H), 2.02 (s, 3H); MS ESI 320.1 [M+H]+, calcd for [C17H13N5O2+H]+ 320.11.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][NH:13]2)=[CH:9][CH:8]=1)[C:3]([OH:5])=O.[NH2:29][C:30]1[S:31][CH:32]=[CH:33][N:34]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][C:2]([CH3:28])([CH:6]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][NH:13]2)=[CH:9][CH:8]=1)[C:3]([NH:29][C:30]1[S:31][CH:32]=[CH:33][N:34]=1)=[O:5]
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2c(-c3ccccc3)n[nH]c2c1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C(=O)Nc1nccs1)C(c1ccccc1)c1ccc2c(-c3ccccc3)n[nH]c2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
To a stirred solution of 2,2-dimethyl-3-phenyl-3-(3-phenyl-1H-indazol-6-yl)propanoic acid (26 mg, 0.07 mmol), 2-aminothiazole (28 mg, 0.28 mmol), and diisopropylethylamine (0.05 mL) in anhydrous DMF (0.2 mL) was added HATU (106 mg, 0.28 mmol) under argon. After stirring at rt for 2.5 hr and 80° C. for 1 hr, the mixture was concentrated. Purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave 2,2-dimethyl-3-phenyl-3-(3-phenyl-1H-indazol-6-yl)-N-(thiazol-2-yl)propanamide (Example 112, 9 mg, 0.02 mmol, 28% yield) as a solid. MS found: (M+H)+=453. 1H-NMR (500 MHz, CDCl3) δ ppm 7.96 (1H, d, J=8.25 Hz) 7.86 (2H, d, J=8.25 Hz) 7.50 (1H, d, J=8.25 Hz) 7.46 (2H, d, J=8.25 Hz) 7.39-7.43 (2H, m) 7.35 (2H, d, J=7.70 Hz) 7.17-7.26 (4 H, m), 6.96 (1H, d, J=3.30 Hz) 4.62 (1H, s) 1.45 (6H, d, J=3.85 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18](=[O:27])[C@@H:19]([NH:23][C:24]([NH2:26])=[S:25])[CH:20]([CH3:22])[CH3:21])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:29][CH:30]=O>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18](=[O:27])[C@@H:19]([NH:23][C:24]3[S:25][CH:29]=[CH:30][N:26]=3)[CH:20]([CH3:21])[CH3:22])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(N)=S)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: O=CCCl
Solvent: CCO
Product: CC(C)[C@H](Nc1nccs1)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A solution of 1-((S)-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)thiourea (1.29 g, 2.86 mmol) was dissolved in EtOH (50 mL) and 2-chloroacetaldehyde (0.4 mL, 3.15 mmol) was added. The mixture was heated at 70° C. overnight. A further portion of 2-chloroacetaldehyde (0.4 mL, 3.15 mmol) was added and heating continued for a further 12 h. The solution was concentrated in vacuo and the residue was purified by column chromatography (biotage), eluting with 50% EtOAc in hexanes and then 10% MeOH in EtOAc. The desired product was isolated as a orange-brown foam (557.2 mg). LCMS (NH4OAc) shows this to be of sufficient purity. Eluting further with 100% MeOH gave a second fraction (980.8 mg) which was shown to contain the product by TLC (5:4.5:0.5 hex:EtOAc:MeOH). This second fraction from the column was re-purified to give a light orange-brown foam (426.6 mg). The two fractions were combined to afford the title compound as a orange brown foam (983.8 mg, 72%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([CH3:26])([CH3:25])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH3:24])=[CH:11][CH:10]=1)=O)C.O.[NH2:29][NH2:30]>C(#N)C>[CH3:25][C:6]1([CH3:26])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH3:24])=[CH:11][CH:10]=2)=[N:30][NH:29][C:4](=[O:3])[CH2:5]1
Reactant: CCOC(=O)CC(C)(C)C(=O)c1ccc(OCCCN2CCC[C@H]2C)cc1
Reactant: NN
Solvent: O
Solvent: CC#N
Product: C[C@@H]1CCCN1CCCOc1ccc(C2=NNC(=O)CC2(C)C)cc1

Procedure:
The product from step 4 (0.75 g, 2.1 mmol) and hydrazine hydrate (2.0 mL) in acetonitrile (25 mL) were heated to reflux for 24 h. The reaction was cooled, concentrated and the product recrystallized using Et2O-hexanes to give 600 mg (71%); Mp 118-121; MS m/z 344 (M+H).
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7](S(=O)(=O)NC)[CH:6]=1)=[O:4].[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][NH2:27]>C(O)(=O)C.O>[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][NH:27][C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)OC)c1)OCCO2
Reactant: CN1CCCC1CN
Solvent: CC(=O)O
Solvent: O
Product: CN1CCCC1CNC(=O)c1cccc2c1OCCO2
Yield: 112 %

Procedure:
169 g of methyl-7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate, 53 ml of water and 81 g of 1-methyl-2-aminomethylpyrrolidine were introduced into a balloon flask provided with a reflux condenser. The mixture was heated on a water bath until a test sample was totally soluble in dilute acids. The resulting crystals were dissolved in a solution of 50 ml of acetic acid in 1,250 ml of water and then the solution was filtered over carbon black and the base was reprecipitated by the addition of 100 ml of 20% ml of 20% ammonia. The crystals were dried off, washed with water and dried. 182 g of N-(1-methyl-2-pyrrolidylmethyl)-1,4-benzodioxane-5-carboxamide was produced (M.P.: 189°-190° C.; yield 83.6%).
Reaction SMILES: C([NH:8][C@H:9]([CH:14]=O)[CH2:10][CH:11]([CH3:13])[CH3:12])(OC(C)(C)C)=O.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]([CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])[CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[NH2:8][C@@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:14][N:34]1[CH2:33][CH2:32][CH:31]([N:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:29][CH:28]=2)[CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])[CH2:36][CH2:35]1
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCNCC1
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C[C@@H](N)CC(C)C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.3 %

Procedure:
Boc-L-leucinal (0.78 g. 3.64 mmol) was treated with a solution of (4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-piperidin-4-yl-amine (1.28 g, 3.64 mmol) in CH2Cl2 (36 mL), stirred 15 minutes, cooled to 0° C., and treated with NaBH(OAc)3 (1.16 g, 5.46 mmol). The reaction was allowed to warm to RT as ice melted and stir 4 hours. The reaction was diluted with EtOAc (200 mL), washed with saturated bicarbonate solution, and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 8% MeOH/CH2Cl2 to give 1.15 g (57%) of the desired product (Id).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].C(Cl)(Cl)Cl>CN(C=O)C>[Cl:12][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([Cl:11])[CH:8]=1)[O:4][CH2:3][CH2:2][N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18]
Reactant: Clc1cc(Cl)cc(OCCBr)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CCOc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A solution of 1-(2-bromo-ethoxy)-3,5-dichloro-benzene (2.41 g, 8.93 mmol) and potassium phthalimide (2.00 g, 10.64 mmol) in DMF (7.6 mL) was heated at 85° C. for 1 h. The reaction was cooled to room temperature and chloroform was added. The organic solution was washed with 0.2 N aqueous NaOH followed by water. The organic solution was dried (Na2SO4), filtered, and concentrated. The residue was suspended in Et2O and the solid was collected by filtration to provide the title compound (2.21 g). 1HNMR (400 MHz, CDCl3) δ 7.82 (m, 2H), 7.77 (m, 2H), 6.89 (m, 1H), 6.88 (m, 2H), 4.16 (t, 2H), 4.05 (t, 2H); MS 336 (M+).
Reaction SMILES: [H][H].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]1[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[N:26]O)[C:17]=2[CH:16]=[CH:15][CH:14]=1>C(O)C.O1CCCC1.[Ni]>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]1[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]([NH2:26])[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1ccc2ccccc2n1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: NC1c2ccccc2-c2c(-c3ccc4ccccc4n3)cccc21
Temperature: 60 °C

Procedure:
In a 100 mL autoclave, dissolve 0.9 g of equimolecular mixture of the Z and E isomers of 4-(quinolin-2-yl)-fluoren-9-one oxime, obtained in Stage 3, in a mixture of 40 mL of ethanol and 40 mL of tetrahydrofuran, add a spatula tip of Raney nickel, then submit to an initial hydrogen pressure of 1 bar and heat the autoclave at 60° C. for 2 hours. After cooling, filter the catalyst on Celite and concentrate the filtrate at reduced pressure. After purification by flash chromatography on silica gel (20-40 μm), eluting with a mixture of dichloromethane and methanol (95-05 by volume), we obtain 0.72 g of 4-(quinolin-2-yl)-9H-fluoren-9-(R,S)-yl-amine in the form of a white meringue with the following characteristics: