Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][NH2:20])=[O:7].C(N(CC)CC)C.[CH2:29]([O:36][C:37](OC1CC(=O)NC1=O)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][NH:20][C:37](=[O:38])[O:36][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1sccc1-c1ccccc1CN
Reactant: O=C1CC(OC(=O)OCc2ccccc2)C(=O)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCNC(=O)c1sccc1-c1ccccc1CNC(=O)OCc1ccccc1

Procedure:
27 mg (0.09 mmol) of 3-(2-aminomethylphenyl)thiophene-2-carboxylic acid (3-methylbutyl)amide were dissolved in 3 ml of dry dichloromethane, and the solution was treated with 10 mg (0.1 mmol) of triethylamine and 24 mg (0.1 mmol) of benzyloxycarbonyloxysuccinimide. After a reaction time of 18 h, the mixture was diluted with 20 ml of dichloromethane, washed with saturated NaHCO3 solution and the organic phase was dried and concentrated. After purification by RP-HPLC, 27 mg (70%) of a colorless substance were obtained. MS (ES+): m/z=437 (M+1). 1H-NMR (CDCl3): δ=7.54-7.24 (10H, m), 6.90 (1H, d, J=4.8 Hz), 5.52 (1H, br s), 5.05 (3H, br s), 4.17 (2H, d, J=6.2 Hz), 3.16 (2H, m), 1.14 (1H, m), 1.07 (2H, q, J=7.0 Hz), 0.73 (6H, d, J=6.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:18][CH:17]([CH:19]([CH3:21])[CH3:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[C:26](C)[CH:25]=1.[C:34]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:34][C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH2:30])=[O:29])=[CH:31][CH:32]=2)[CH:12]2[CH2:18][CH:17]([CH:19]([CH3:20])[CH3:21])[CH2:16][CH2:15][NH:14][C:13]2=[O:22])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)C1CCNC(=O)C(NS(=O)(=O)c2ccc(Cl)cc2)C1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)ccc1C(N)=O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C1CCNC(=O)C(N(Cc2ccc(C(N)=O)cc2)S(=O)(=O)c2ccc(Cl)cc2)C1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
4-Chloro-N-(5-isopropyl-2-oxo-azepan-3-yl)-benzenesulfonamide (0.06 g, 0.17 mmol), 4-bromo-methyl-benzamide (0.06 g, 0.25 mmol), K2CO3 (0.24 g, 1.7 mmol), KI (0.01 g, 0.06 mmol) were added to dry DMF (5 ml) and the resultant reaction mixture was shaken overnight at 65° C. under an argon atmosphere. The solvent was removed under reduced pressure and the residue taken up in ethyl acetate and washed with 5% KHSO4/10% K2SO4 (2×), water, brine, dried (MgSO4), filtered, concentrated under reduced pressure and purified using preparative RP(C18) chromatography: lyophilisate 23 mg; MS: m/e=478.3 (MH+), 495.4 (MNH4+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[C:12]1([CH:22]=O)[C:21]2[C:15]([CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:14][CH:13]=1.N1CCCC1>C(O)C>[C:12]1(/[CH:22]=[C:7]2\[C:8](=[O:11])[NH:9][C:10]3[C:6]\2=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[C:21]2[C:15]([CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:14][CH:13]=1
Reactant: O=C1Cc2cccc(Cl)c2N1
Reactant: O=Cc1ccc2cccccc1-2
Solvent: C1CCNC1
Solvent: CCO
Product: O=C1Nc2c(Cl)cccc2/C1=C/c1ccc2cccccc1-2
Yield: 57.5 %

Procedure:
0.3519 g 7-chlorooxindole (0.0021 mole) and 0.323 g azulene aldehyde (0.0021 mole) were dissolved in 30 mL dried ethanol. 1.5 mL pyrrolidine (1M) was then added and uniformly stirred at reflux temperature for two hours. After removal of dried ethanol, the results were extracted by dichloromethane and citric acid aqueous solution. The organic layer was collected, dried with anhydrous magnesium sulfate, filtered, concentrated under vacuum, and separated by silica gel column chromatography to give Z-form Compound 042 (0.3693 g). The total weight of 7-chlorooxindole-azulene was 0.3693 g (57.56%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17]COC(=O)C(C)(C)C)=[O:16])=[C:13]([CH3:26])[N:12]([CH2:27][O:28][CH3:29])[C:11]([CH3:30])=[C:10]1[C:31]([O:33][CH2:34][O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:32]>C(OC(C)C)(C)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:31]([O:33][CH2:34][O:35][C:36](=[O:41])[C:37]([CH3:38])([CH3:39])[CH3:40])=[O:32])=[C:11]([CH3:30])[N:12]([CH2:27][O:28][CH3:29])[C:13]([CH3:26])=[C:14]1[C:15]([OH:17])=[O:16]
Reactant: COCN1C(C)=C(C(=O)OCOC(=O)C(C)(C)C)C(c2cccc(Cl)c2Cl)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Solvent: O
Solvent: CC(C)OC(C)C
Product: COCN1C(C)=C(C(=O)O)C(c2cccc(Cl)c2Cl)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
In 15 ml of isopropyl ether saturated with water was dissolved 614 mg of bis(pivaloyloxymethyl) 4-(2,3-dichloro-phenyl)-1,4-dihydro-2,6-dimethyl-l-methoxymethyl-3,5-pyridinedicarboxylate obtained in Example 6, and 100 mg of Lipase B was added thereto, followed by stirring at 25° C. for 4 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to obtain 405 mg (yield: 81%) of (+)-4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-1-methoxymethyl-5-pivaloyloxymethoxycarbonyl-3-pyridinecarboxylic acid as a colorless crystal.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]2[C@@H:11]3[C@@H:16]([CH2:17][CH2:18][O:19][C:7]=2[CH:6]=1)[NH:15][CH2:14][CH2:13][O:12]3)[CH3:3].C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C(Cl)Cl>[Cl:27][CH2:28][C:29]([N:15]1[CH2:14][CH2:13][O:12][C@@H:11]2[C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:2][CH3:3])=[CH:6][C:7]=3[O:19][CH2:18][CH2:17][C@@H:16]12)=[O:30]
Reactant: O=C(Cl)CCl
Reactant: CCOc1ccc2c(c1)OCC[C@H]1NCCO[C@H]21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc2c(c1)OCC[C@@H]1[C@@H]2OCCN1C(=O)CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.21 g of trans-3,4,4a,5,6,11b-hexahydro-9-ethoxy-2H-[1]benzoxepino[5,4-b]-1,4-oxazine hydrochloride, prepared via an analogous procedure to the preceding Example, and 1.65 ml of triethylamine in 25 ml of methylene chloride is treated dropwise with a solution of 0.70 ml of chloroacetyl chloride dissolved in 10 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature, washed with a dilute solution of hydrochloric acid, followed by a water wash, a wash of dilute sodium hydroxide solution and finally by a wash of a saturated solution of sodium chloride. The reaction mixture is dried over anhydrous magnesium sulfate and evaporated to dryness to obtain 1.44 g of trans-N-chloroacetyl-3,4,4a,5,6,11b-hexahydro-9-ethoxy-2H-[1]benzoxepino[5,4-b]-1,4-oxazine.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[Br-].[Mg+2].[Br-].O=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]1[C:30]([O:32]CC)=[O:31]>C1COCC1.CCOCC.CCOCC>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:16]2[C:30]([OH:32])=[O:31])=[CH:4][CH:5]=1
Reactant: COc1ccc(Br)cc1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1=O
Agent: [Br-]
Agent: [Mg+2]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2c3ccccc3C(c3ccccc3)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethyl (1RS)[1-Hydroxy-1-(4-methoxyphenyl)]-3-phenylindene-2-carboxylate. To dry magnesium turnings (0.88 g, 36 mmol) under an argon atmosphere was added, portionwise, a solution of p-bromoanisole (4.5 ml, 36 mmol) in 5% THF/Et2O (37 ml). The resulting p-methoxyphenyt magnesium bromide solution was added to a solution of ethyl 1-oxo-3-phenylindene-2-carboxylate (5.0 g, 18 mmol) in Et2O (300 ml) under an argon atmosphere at 0° C. The resulting mixture was allowed to warm to room temperature and was stirred for 10 min. The mixture was partitioned between 3M HCl (100 ml) and EtOAc (200 ml). The organic extract was washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (Na2SO4). The solvent was removed in vacuo to provide a yellow oil which was treated with Et2O/ hexanes. The solid which formed was collected by filtration (3.47 g). The filtrate was concentrated under reduced pressure and purified by flash chromatography. The material which was isolated was treated with Et2O/ hexanes, and the additional solid which formed (1.76 g, 75% total yield) was collected by filtration to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH:16]=O)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:18])[O:7]1)=[O:5])C.[CH3:19][O:20][C:21](=[O:31])[C@@H:22]([NH2:30])[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([CH2:14][C:15]=1[CH2:16][NH:30][C@H:22]([C:21]([O:20][CH3:19])=[O:31])[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[C:12]([Cl:18])[CH:11]=[CH:10][CH:9]=2)=[O:5]
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)C1Oc2cccc(Cl)c2C=C1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=C(CN[C@@H](CC2CCCCC2)C(=O)OC)Cc2c(Cl)cccc2O1
Temperature: 25 °C
Reaction time: 10 h
Yield: 47.5 %

Procedure:
To a solution of 5-chloro-3-formyl-2H-chromene-2-carboxylic acid ethyl ester (1.0 g, 3.74 mmol) in methanol (20 mL) containing molecular sieves (0.7 g) was added commercially available (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (0.83 g, 3.74 mmol) and N,N′-diisopropylethylamine (1.30 mL, 7.49 mmol). The mixture was stirred at 25° C. for 10 hours. At this time, sodium cyanoborohydride (0.47 g, 7.49 mmol) and acetic acid (0.47 mL, 7.49 mmol) were added simultaneously to the reaction mixture, and the reaction mixture was stirred for additional 16 hours at 25° C. The reaction mixture was then filtered through celite and washed with methanol. The filtrate was concentrated in vacuo. Flash column chromatography (eluant-ethyl acetate:petroleum ether 1:19, Rf=0.6) over neutral alumina afforded 5-chloro-3-[((S)-2-cyclohexyl-1-methoxycarbonyl-ethylamino)-methyl]-4H-chromene-2 carboxylic acid methyl ester (0.75 g, 46.6%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][C@@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: N[C@H]1CCc2ccccc21
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: CCO
Product: Cc1cc(N[C@H]2CCc3ccccc32)nc(Cl)n1
Yield: 4.8 %

Procedure:
2,4-Dichloro-6-methylpyrimidine (2.54 g, 0.156 mol) was dissolved in ethanol (100 mL) and N,N-Diisporopylethylamine (4.07 mL, 0.23 mol) was added followed by (S)-1-Aminoindan (2.00 mL, 0.156 mol). The solution was heated to reflux for 2 hours, TLC indicated complete conversion. The solvent was removed in vacuo and the residue was purified using chromatography on silica gel using gradient 0 to 50% ethyl acetate in hexane to afford the title compound (1.95 g, 46%). LC/MS: Rt=1.90 min, ES+ 260 (AA standard).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O-:10])=[O:9])[CH:4]=1.[CH3:11][C:12]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])[CH3:13].[CH3:19][CH2:20]N(CC)CC>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:9][C:8]([C:5]1[CH:4]=[C:3]([CH2:2][O:1][Si:15]([C:12]([CH3:14])([CH3:13])[CH3:11])([CH3:17])[CH3:16])[O:7][N:6]=1)=[O:10])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C([O-])c1cc(CO)on1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(CO[Si](C)(C)C(C)(C)C)on1
Reaction time: 0.5 h

Procedure:
To a solution of 5-(hydroxymethyl)isoxazole-3-carboxylate (4.0 g, 23 mmol) and TBSCL (3.7 g, 25 mmol) in DMF is added Et3N (3.4 mL, 24 mmol) dropwise over 20 minutes. The reaction is allowed to stir for 30 minutes after which it is diluted with EtOAc (300 mL), washed with 1 M HCl (3×100 mL), 5% CuSO4 (2×50 mL) and concentrated in vacuo to yield ethyl-5-({[tert-butyl(dimethylsilyl)]oxy}methyl)isoxazole-3-carboxylate as an oily material.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6](C(O)=O)=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([N:24]([CH2:27]C)CC)C.P(N=[N+]=[N-])(=O)(OC1C=CC=CC=1)[O:30]C1C=CC=CC=1>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:24][C:27](=[O:30])[N:15]([CH:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(O)c1cnc2ccc(Br)cc2c1NC1CCOCC1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1[nH]c2cnc3ccc(Br)cc3c2n1C1CCOCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
On a larger scale, 6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxylic acid (2011 g, (2005 g active), 5.71 mol) was added to the vessel with DMF (18.2 L). Triethylamine (4.7 L, 33.72 mol) was added with an endotherm observed from 21-18° C. Diphenyl phosphorazidate (1600 mL, 7.42 mol) was added over 10 minutes with an observed exotherm from 21° C. to 23° C. over the addition. The exotherm continued with the batch reaching 55° C. after 1 h (jacket held at 30° C.) with gas evolution. The reaction initially went into solution with a precipitate then forming after ˜30 minutes. Once the temperature had stabilised the batch was analysed by HPLC showing consumption of starting material and 99% product. The batch was heated to 60° C. for h with HPLC again indicating consumption of starting material and 98% product. The batch was concentrated in vacuo to a minimum volume (˜3 volumes) and the residue added to water (17 L) rinsing in with a further portion of water (10 L). The mixture was slurried for 1 h and filtered, washing with water (2×17 L). The solid was then returned to the vessel and slurried in sat. NaHCO3 solution (10 L) and MeOH (495 ml) for 1 h. The solid was collected by filtration, washing with water (2×3.5 L) and then oven dried in vacuo at 40° C. for 116 h to obtain 2023 g of desired material. Analytical data was consistent with that obtained from previous batches.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].N1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].[CH2:17]1[CH2:22]NC(=O)[CH2:18]1.[Br:23][Br-]Br.[O:26]1[CH2:30]CCC1>>[Br:23][CH:2]([CH3:3])[C:1]([C:5]1[CH:10]=[CH:9][C:8]([O:16][CH2:12][C:13]2[CH:18]=[CH:17][CH:22]=[CH:15][CH:14]=2)=[C:7]([CH2:30][OH:26])[CH:6]=1)=[O:4]
Reactant: O=C1CCCN1
Reactant: C1CCOC1
Reactant: CCC(=O)c1ccccc1
Product: CC(Br)C(=O)c1ccc(OCc2ccccc2)c(CO)c1

Procedure:
200 ml of tetrahydrofuran and 6 g of the previously prepared propiophenone are placed in a 500 ml conical flask. 2.07 g (1.84 ml) of pyrrolidinone and 12.05 g of pyrrolidinone hydrotribromide are added and the mixture is heated under reflux for one hour. A whitish precipitate forms and is filtered off, the filtrate is evaporated to dryness, the residual oil is taken up in chloroform and the organic phase thus obtained is washed, dried and evaporated and the residue crystallized from a mixture of toluene and pentane. 7 g of a product which melts at 80° C. are thus isolated.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([C:10]([OH:13])([CH3:11])[CH3:12])=[CH:9][C:2]=1[F:1]
Reactant: CC(C)(O)c1ccc(C#N)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(CN)c(F)c1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
To a stirred solution of 2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzonitrile (1.95 g, 11.0 mmol) in tetrahydrofuran (30 mL) at 0° C. was added drop-wise a 1.0 M solution of lithium aluminium hydride in tetrahydrofuran (34 mL, 34.0 mmol). The reaction mixture was warmed to ambient temperature then refluxed for 30 minutes. The reaction mixture was cooled to 0° C., then quenched with methanol (20 mL) added drop-wise. The reaction mixture was then diluted with chloroform (700 mL) and washed with water (100 mL). The resulting suspension was filtered through Celite, after which the organic extract contained in the filtrate was separated, dried over magnesium sulfate (MgSO4), and concentrated to give 1.6 g 2-(4-aminomethyl-3-fluoro-phenyl)-propan-2-ol as an amber gum.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C@H:6]([O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:7][CH:8]=[CH2:9])C=C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl>[CH3:16][O:15][CH2:14][CH2:13][O:12][CH2:11][O:10][C@@H:6]1[CH2:7][CH:8]=[CH:9][CH2:1][O:4][CH2:5]1
Reactant: C=CCOC[C@@H](CC=C)OCOCCOC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: COCCOCO[C@@H]1CC=CCOC1
Temperature: 45 °C
Yield: 95.4 %

Procedure:
A mixture of 11 (100 mg, 0.43 mmol) and 2nd generation Grubbs catalyst (18 mg, 0.02 mmol) in CH2Cl2 (10 mL) was heated to 45° C. for 1 h. After this time, the solvent was removed and the residue was purified by flash-chromatography (5:1 CHCl3/EtOAc) to afford 83 mg (94%) of 12 as a colourless oil: 1H NMR (CDCl3) δ 5.87-5.66 (m, 2H), 4.77-4.18 (m, 2H), 4.18-4.14 (m, 2H), 4.01-3.89 (m, 2H), 3.75-3.68 (m, 3H), 3.56-3.53 (m, 2H), 3.38 (s, 3H), 2.54-2.51 (m, 2H); 13C NMR (CDCl3) δ 130.6, 125.9, 94.3, 75.6, 75.1, 71.6, 70.3, 66.8, 58.9, 31.8.
Reaction SMILES: C(Cl)(=[O:3])C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=C(C#N)[CH:15]=[CH:14][C:13]=2[O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)=[CH:8][CH:7]=1.[CH2:25]([OH:27])[CH3:26]>>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:26]([C:25]([OH:3])=[O:27])[CH:15]=[CH:14][C:13]=2[O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)=[CH:8][CH:7]=1
Reactant: CC(=O)Cl
Reactant: CCO
Reactant: N#Cc1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Product: O=C(O)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 70.31 %

Procedure:
8.27 g acetylchloride was added dropwise to 120 mL ethanol at 0° C. After 5 minutes, 6 g 6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carbonitrile was added at 0° C. The reaction mixture was stirred at 90° C. over 20 h. The reaction mixture was partitioned between water and ethyl acetate; then extracted. The organic phase was washed with brine; then dried over MgSO4. The crude product was stirred at room temperature in tetrahydrofuran:water 45:20. 1.77 g lithium hydroxide was added. The reaction mixture was stirred at 80° C. over 7 hours. The reaction mixture was added over acetic acid and extracted with dichloromethane. The organic phase was washed with water; then dried over MgSO4 and purified by chromatography on silica gel with a gradient of heptane to heptane:ethyl acetate 2:1 to yield 4.50 g (70.31%) of the title compound as light yellow solid, MS 304.1 (M+H)+.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:30]=[CH:29][C:11]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:10][CH:9]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:40][O:41][CH2:42][C:43](Cl)=[O:44]>O1CCCC1>[ClH:28].[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:8]1[CH:30]=[CH:29][C:11]([C:12]([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:18][CH2:19]2)=[O:13])=[CH:10][CH:9]=1)[C:43](=[O:44])[CH2:42][O:41][CH3:40])([CH3:3])[CH3:2]
Reactant: CC(C)OCCNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reactant: COCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCC(=O)N(CCOC(C)C)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Product: Cl

Procedure:
5 g of 1-{4-[N-(2-isopropyloxyethyl)amino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine (Example 1) are dissolved in 50 ml of absolute tetrahydrofuran and cooled to 3° with stirring. There are added thereto 1.8 g of Hunig base and then, dropwise, within a period of 5 minutes, a solution of 1.38 g of methoxyacetyl chloride in 5 ml of absolute tetrahydrofuran. The mixture is stirred for 30 minutes at RT and concentrated by evaporation. The residue is taken up in water and ethyl acetate and the organic phase is washed until neutral with sodium hydrogen carbonate solution and water and concentrated by evaporation. The brown oil is chromatographed over silica gel. The mixture is treated with ethereal hydrochloric acid. Recrystallisation from acetone and ether yield 1-{4-[N-(2-isopropyloxyethyl)-N-methoxyacetylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]-piperazine hydrochloride having a melting point of 149°-151°.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[C:5]([CH3:15])[CH:6]=[C:7]([CH2:13]O)[CH:8]=2)[N:3]=1.S(Cl)([Cl:18])=O>C(Cl)Cl>[ClH:18].[Cl:18][CH2:13][C:7]1[CH:8]=[C:9]2[C:4](=[C:5]([CH3:15])[CH:6]=1)[N:3]=[C:2]([CH3:1])[C:11]([CH3:12])=[N:10]2
Reactant: Cc1nc2cc(CO)cc(C)c2nc1C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nc2cc(CCl)cc(C)c2nc1C
Product: Cl

Procedure:
Prepared by treating (2,3,8-trimethyl-quinoxalin-6-yl)-methanol with thionyl chloride in methylene chloride.
Reaction SMILES: [O:1]1[CH2:5][C@H:4]([OH:6])[C@H:3]2[O:7][CH2:8][C@H:9]([OH:10])[C@@H:2]12.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:6][C@@H:4]1[C@H:3]2[O:7][CH2:8][C@H:9]([OH:10])[C@H:2]2[O:1][CH2:5]1
Reactant: C1=COCCC1
Reactant: O[C@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Solvent: ClCCl
Product: O[C@H]1CO[C@H]2[C@@H]1OC[C@@H]2OC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3S,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diol (0.57 g, 3.90 mmol) and 3,4-dihydro-2H-pyran (0.41 g, 4.88 mmol) in DCM (15 ml), toluene-4-solfonic acid monohydrate (0.0074 g, 0.039 mmol) was added and the mixture was stirred at room temperature for 3 hrs. Then the reaction mixture was washed with a saturated solution of NaHCO3 and brine. The organic extract was dried over sodium sulfate and the solvent, was evaporated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 30 to 100%), affording the title product as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[S:19])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([N+:14]([O-])=O)[C:6]=1[CH2:17][CH3:18])[CH3:2]>O1CCCC1.[Ni].C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[S:19])[C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([NH2:14])[C:6]=1[CH2:17][CH3:18])[CH3:2]
Reactant: CCOC(=S)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1CC
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=S)c1cc(N)cc(N)c1CC

Procedure:
25.9 g (0.0862 mol) of 3,5-dinitro-2-ethylthiobenzoic acid ethyl ester are dissolved in 260 ml of tetrahydrofuran and hydrogenated at 30°-35° C. in the presence of 10 g of Raney nickel. The catalyst is then isolated by filtration, and the residue is taken up in ethyl acetate, dried over magnesium sulfate, filtered and concentrated.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](C#N)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N1C2C(=CC=CC=2)C=C1C#N>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: N#Cc1cc2ccccc2[nH]1
Product: c1ccc2[nH]ccc2c1

Procedure:
The A ring indole of compounds 31 and 32 was synthesized using the same approach as 8f described in Scheme 3 above from 1H-indole-5-carbonitrile or 1H-indole-2-carbonitrile as starting material. Crude product was purified by column chromatography.