Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH2:19])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[N:20]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH3:28])[C@H:21]([C:25](O)=[O:26])[CH:22]([CH3:24])[CH3:23].O>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:25](=[O:26])[CH:21]([N:20]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH3:28])[CH:22]([CH3:24])[CH3:23])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)c1cc(CC(N)c2nccs2)ccc1O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of 2-(3-tert-butyl-4-hydroxylphenyl)-1-(thiazol-2-yl)ethylamine (4.67 g, 16.64 mmol), Boc-N-Me-Val-OH (5.0 g, 21.63 mmol) and CMPI (5.53 g, 21.63 mmol) in THF (110 ml), TEA (5.33 ml, 38.27 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methanol:aqueous ammonia:methylene chloride=3:0.1:100), giving the titled compound (8.10 g, 100%).
Reaction SMILES: [NH2:1][C:2]([CH2:26][CH2:27][O:28][CH3:29])([CH2:22][CH2:23][O:24][CH3:25])[CH2:3][NH:4][C:5](=[O:21])[O:6][CH2:7][CH:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.[CH:30](=O)[CH2:31][CH2:32][C:33]#[CH:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[CH3:29][O:28][CH2:27][CH2:26][C:2]([CH2:22][CH2:23][O:24][CH3:25])([NH:1][CH2:34][CH2:33][CH2:32][C:31]#[CH:30])[CH2:3][NH:4][C:5](=[O:21])[O:6][CH2:7][CH:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: COCCC(N)(CCOC)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: C#CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C#CCCCNC(CCOC)(CCOC)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 3 h

Procedure:
To a solution of (9H-fluoren-9-yl)methyl (2-amino-4-methoxy-2-(2-methoxyethyl)butyl)carbamate (G23, 186 mg) and 4-pentynal (42 mg) in methylene chloride (5 mL), sodium triacetoxyborohydride (247 mg) and acetic acid (26 μL) were added at room temperature, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 60 to 0% hexane in ethyl acetate) to obtain (9H-fluoren-9-yl)methyl (4-methoxy-2-(2-methoxyethyl)-2-((4-pentyn-1-yl)amino)butyl)carbamate (G24, 102 mg).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:27])[C:10]([NH:12][C:13]1[C:14]([NH:23][CH:24]2[CH2:26][CH2:25]2)=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])=O)=O)(C)(C)C.Cl>CC(O)=O.O1CCOCC1>[NH2:8][C@H:9]([C:10]1[N:23]([CH:24]2[CH2:26][CH2:25]2)[C:14]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=[CH:22][C:13]=2[N:12]=1)[CH3:27]
Reactant: COC(=O)c1cccc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1NC1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)c1cccc2nc([C@H](C)N)n(C3CC3)c12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A stirred solution of (S)-methyl 3-(2-(tert-butoxycarbonylamino)propanamido)-2-(cyclopropylamino)benzoate (600 mg, 1.6 mmol) in HOAc (20 mL) was heated at 60° C. for 1.5 h, and cooled to rt. After concentration of the mixture in vacuo, the residue was subjected to 4M HCl in dioxane (10 mL), and stirred at rt for 40 min. The mixture was concentrated in vacuo, dissolved in water (5 mL) and basified with 1N NaOH to pH 9.5. The mixture was concentrated and MeOH-DCM (1:1) was added to the residue to get the desired product into solution. The solution was concentrated in vacuo and the residue was purified by column chromatography on a silica gel column using DCM-MeOH—NH4OH (9:1:0.05) as eluent to give (S)-methyl 2-(1-aminoethyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate: 1H NMR (400 MHz, CDCl3) δ 7.86 (1H, d, J=8.0 Hz), 7.63 (1H, d, J=8.0 Hz), 7.27 (1H, t, J=8.0 Hz), 4.62 (1H, q, J=8.0 Hz), 4.01 (3H, s), 3.58-3.50 (3H, m), 1.65 (3H, d, J=8.0 Hz), 1.22-1.06 (2H, m), 0.95-0.65 (2H, m); LC-MS (ESI) m/z 260.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.Cl.[NH2:10][C@@H:11]([CH3:20])[C:12]([NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[O:13].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(OC(=O)C)C>[Br:1][C:2]1[N:3]=[C:4]([NH:10][C@@H:11]([CH3:20])[C:12]([NH:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)C(=O)NCC(F)(F)F
Reactant: Fc1cccc(Br)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cccc(Br)n1)C(=O)NCC(F)(F)F
Temperature: 220 °C
Yield: 65.7 %

Procedure:
A solution of 2-bromo-6-fluoropyridine (1.23 g, 7 mmol) and (S)-2-amino-N-(2,2,2-trifluoroethyl)propanamide hydrochloride (FF) (1.44 g, 7 mmol) in NMP (10 mL) was treated with DIPEA (2.4 mL, 14 mmol) and heated at 220° C. for 40 min in the microwave. After complete reaction, the mixture was diluted with ethylacetate (100 mL) then washed with water (5×25 mL), brine (1×25 mL) then dried over Na2SO4. The solvent was removed and the residue purified with silica-gel chromatography using hexane:ethyl acetate (4:1) to afford 1.5 g (66% yield) of a white solid, GG. LC-MS: 2.8 min, 327.8 ES+; 1H NMR (500 MHz, dmso-d6) d 8.56 (m, 1H), 7.29 (t, 1H), 7.13 (d, 1H), 6.68 (d, 1H), 6.55 (d, 1H), 4.36 (m, 1H), 3.90 (m, 2H), 1.30 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20](O)=[O:21])[CH:16]=1)[CH3:13])(=[O:11])=[O:10].C1N=CN(C(N2C=NC=C2)=O)C=1.[N:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:37][CH:36]=1>ClCCCl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([N:12]([CH3:13])[CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20]([N:46]2[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][C:38]3[CH:37]=[CH:36][N:35]=[CH:40][CH:39]=3)[CH2:44][CH2:45]2)=[O:21])[CH:16]=1)(=[O:10])=[O:11]
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1c(Cl)cccc1Cl
Reactant: c1cc(CCN2CCNCC2)ccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: CN(Cc1cc(C(=O)N2CCN(CCc3ccncc3)CC2)co1)S(=O)(=O)c1c(Cl)cccc1Cl
Reaction time: 1 h

Procedure:
5-({[(2,6-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (465 mg, 1.3 mmol) was dissolved in DCE (40 mL) and CDI (422 mg, 2.6 mmol) was added. The reaction was stirred for 1 h. 4 mL of activated acid solution in DCE was added to a vial containing 1-[2-(pyridin-4-yl)ethyl]piperazine (50 mg, 0.261 mmol). The reaction was stirred at ambient temperature for 3 days, then washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and shaken with PL-MIA and Ambersep resins, then filtered. The solvent was removed in vacuo and a portion of the crude product purified using prep method B.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.[Cl:33][C:34]1[CH:44]=[CH:43][C:37]([O:38][CH2:39][C:40](Cl)=[O:41])=[CH:36][CH:35]=1>O1CCOCC1.ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([C:40](=[O:41])[CH2:39][O:38][C:37]3[CH:43]=[CH:44][C:34]([Cl:33])=[CH:35][CH:36]=3)[CH2:20][CH2:19]2)[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: Nc1nc(N2CCNCC2)c2c(-c3ccc(F)cc3)csc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2c(-c3ccc(F)cc3)csc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 1 (135 mg, 0.41 mmol) in 1,4-dioxane (15 mL) were added N,N-diisopropylethylamine (169 μL, 1.02 mmol) and 4-chlorophenoxyacetyl chloride (0.45 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and the organic layer was extracted several times with water. The combined organic layers were evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 0.5% to 1% methanol in dichloromethane), yielding the title compound as a white powder. MS (m/z) 498 [M+H]+.
Reaction SMILES: ClS([N:5]=C=O)(=O)=O.[C@@H:8]1([C:14]([O:16][CH3:17])=[O:15])[CH2:10][C@@H:9]1[C:11](O)=O.CN(C=O)C.O>C1C=CC=CC=1>[C:11]([C@H:9]1[CH2:10][C@H:8]1[C:14]([O:16][CH3:17])=[O:15])#[N:5]
Reactant: COC(=O)[C@@H]1C[C@@H]1C(=O)O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H]1C#N
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
In 25 ml of benzene was dissolved 13.77 g (97 mmol) of chlorosulfonyl isocyanate, and to the solution was added 12.7 g (88 mmol) of cis-methyl hydrogen cyclopropane-1,2-dicarboxylate which had been synthesized by the process of Journal of Organic Chemistry, Vol. 36, pp. 3356-3361 (1971). The mixture was stirred on an oil bath at 60° C. for 30 minutes. After cooling, 13.6 ml (176 mmol) of DMF was added thereto, followed by stirring for 30 minutes. Water was added thereto, and the reaction mixture was extracted with benzene. The organic layer was washed successively with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was distilled under reduced pressure to obtain 6.14 g (55.7%) of methyl cis-2-cyanocyclopropanecarboxylate.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][C:26]=1[Cl:33])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:8]([N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:27][C:26]=1[Cl:33])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: Clc1cc(CBr)ccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)c(Cl)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (20 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1-benzyloxy-4-bromomethyl-2-chloro-benzene (CAB02128, 1.56 g, 5.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (75 mL) was added. The mixture was transferred into a separation funnel and washed with water (two times 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was suspended in 2-propanol (20 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 1.38 g (66°/e). 1H-NMR (400 MHz, d6-DMSO) δ=4.99 (s, 2H), 5.17 (s, 2H), 6.76 (d, J=9.0 Hz, 2H), 7.16 (d, J=8.6 Hz, 1H), 7.20 (dd, J=8.6, 2.2 Hz, 1H), 7.32-7.47 (m, 6H), 7.76 (d, J=9.0 Hz, 2H), 8.81 (s, 2H). LRMS (FAB+): 416.1 (100, [M+H]+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][Si](C)(C)C)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([NH:8][C:9]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[CH:19])=[CH:16][CH:17]=2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1ccc(C2(NCc3ccccc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(NCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; benzyl-[1-(4-trimethylsilanylethynyl-phenyl)-cyclopropyl]-amine (Intermediate 126, 85.0 mg, 0.27 mmol) in methanol (5 mL) was treated with potassium carbonate (50.0 mg, 0.37 mmol) and stirred overnight at ambient temperature. The crude alkyne (65 mg, 100%) was used directly in the next reaction.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:15])[O:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[OH:8][CH:1]([CH:10]1[CH2:11][CH2:12][CH2:13][O:14][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCO1
Reactant: O=Cc1ccccc1
Product: O=C1OCCCC1C(O)c1ccccc1

Procedure:
Employing a procedure which is similar to that described in Example I, benzaldehyde is reacted with δ-valerolactone to produce 2-(1-hydroxy-1-phenylmethyl)-δ-valerolactone. ##STR8##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9](Br)[CH3:10])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[F:21][C:22]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:23]=1[NH2:24]>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:22]=2[F:21])[CH3:10])=[CH:4][N:3]=1
Reactant: CC(Br)c1cnc(Cl)nc1Cl
Reactant: COc1ccc(N)c(F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(C)c2cnc(Cl)nc2Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (±)-2,4-dichloro-5-(1-bromoethyl)-pyrimidine (0.20 g; 0.79 mmol) (from Example 1c supra), N,N-diisopropylethyl-amine (140 μL; 0.80 mmol) (Aldrich) and 2-fluoro-4-methoxyaniline (0.11 g; 0.78 mmol) (from Example 8a supra) were combined in acetonitrile (3 mL) and stirred at room temperature overnight. The reaction was found to be incomplete and was then heated in an oil bath at 40–50° C. overnight. Upon cooling, the reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage, 40S; 10:90 to 20:80 ethyl acetate-hexanes gradient) gave (±)-[1-(2,4-dichloro-pyrimidin-5-yl)-ethyl]-(2-fluoro-4-methoxy-phenyl)-amine. (Yield 0.12 g; 49.1%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[N:4][C:5](Cl)([O:8][CH3:9])[NH:6][CH:7]=1.C([CH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:19]#[N:20])#N.[H-].[Na+].CN(C)C=[O:30]>>[Br:1][C:2]1[C:7]([C:15]([C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:19]#[N:20])=[O:30])=[N:6][C:5]([O:8][CH3:9])=[N:4][C:3]=1[O:11][CH3:12]
Reactant: Cc1cc(C#N)cc(CC#N)c1
Reactant: COC1=NC(Cl)(OC)NC=C1Br
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC)c(Br)c(C(=O)c2cc(C)cc(C#N)c2)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
5-Bromo-2-chloro-2,4-dimethoxy-pyrimidine (980 mg, 3.87 mmol) and 3-cyanomethyl-5-methyl-benzonitrile (666.4 mg, 4.26 mmol) were dissolved in dimethyl formamide (10 mL) at room temperature. The solution was cooled to 0° C. Sodium hydride in mineral oil (60%, 170 mg, 4.26 mmol) was added, the reaction mixture was allowed to warm to room temperature and stirring was continued. After 18 hours, a second batch of sodium hydride suspension in mineral oil (60%, 170 mg, 4.26 mmol) was added and stirring was continued for 30 minutes. The reaction was placed under an atmosphere of oxygen and stirring at room temperature was continued. After 72 hours, the reaction was quenched with aqueous ammonium chloride solution and extracted with diethyl ether. The combined organic layers were dried over sodium sulfate. Filtration and evaporation of solvents yielded the crude material. The crude material was purified by flash chromatography on silica gel (eluent: ethyl acetate in hexanes) to yield the product (445 mg, 1.23 mmol). 1H (CDCl3): δ=7.93 (s, 1H), 7.87 (s, 1H), 7.70 (s, 1H), 4.13 (s, 3H), 3.98 (s, 3H), 2.46 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:32])[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@H:9]([O:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[Cl:33][C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:32])[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@H:9]([O:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[Cl:33])[CH:23]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: Nc1ccccc1Cl
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc(C=O)c2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc(CNc3ccccc3Cl)c2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.9 %

Procedure:
To a solution of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]3-formylbenzoate (332 mg, 0.697 mmol) and 2-chloroaniline (0.077 mL, 0.732 mmol) in anhydrous DCM (3.5 mL) was added acetic acid (0.042 mL, 0.732 mmol). The mixture was stirred at room temperature for 24 hours. NaBH(OAc)3 (369 mg, 1.74 mmol) was added, and the mixture was stirred at room temperature for 24 hours. After addition of water (2.5 mL), the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through a phase separator, and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography eluting with 1:1 DCM:EtOAc to afford the title compound as a white solid (274 mg, 67%).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH2:20][CH:21]2[NH2:24])=[CH:17][CH:16]=1.[CH3:25][S:26][CH2:27][CH2:28][NH2:29]>>[CH3:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH2:20][CH:21]2[NH:24][C:6]2[CH:5]=[CH:4][C:3]3[C:2]([NH:29][CH2:28][CH2:27][S:26][CH3:25])=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=2)=[CH:17][CH:16]=1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: CSCCN
Reactant: COc1ccc2c(c1)C(N)CC2
Product: COc1ccc2c(c1)C(Nc1ccc3c(NCCSC)cccc3n1)CC2

Procedure:
The title compound, MS: m/e=380.5 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline, 6-methoxyindan-1-ylamine (CAS 103028-81-5) and 2-(methylthio)ethylamine.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][C@@H:6]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[NH:7][C:8](=[O:10])[CH3:9])C.[Li+].[OH-]>C1COCC1.O>[C:8]([NH:7][C@H:6]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:5][C:4]([OH:17])=[O:3])(=[O:10])[CH3:9]
Reactant: CCOC(=O)C[C@H](NC(C)=O)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N[C@@H](CC(=O)O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-14 (0.049 g, 0.102 mmol) in THF (1 mL) and water (0.3 mL) at 0° C. was added 1M LiOH (0.112 ml, 0.112 mmol). After warming to ambient temperature and stirring for 2 h, the solvents were evaporated and the residue was chromatographed (silica gel, 25:10:1:1 ethyl acetate/EtOH/water/NH4OH to give 3-15 as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>C1C=CC=CC=1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[CH:20]([C:19]1[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1)[O:12][CH2:11][CH2:10]2
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CCO)cc1Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COc1cc2c(cc1Br)CCOC2c1ccc([N+](=O)[O-])cc1
Yield: 67 %

Procedure:
Hydrogen chloride gas that is dried for 5 hours is introduced into a suspension of 7.50 g (32.4 mmol) of 2-(3-bromo-4-methoxy-phenyl)-ethanol, 4.90 g (32.4 mmol) of 4-nitro-benzaldehyde and 4.39 g (32.4 mmol) of freshly melted zinc chloride in anhydrous benzene (96 ml). The reaction mixture is then diluted with ethyl acetate and washed neutral with water. After drying and concentration by evaporation, the solid residue is recrystallized from ethyl acetate (25 ml). 7.91 g (67%) of 6-bromo-7-methoxy-l-(4-nitrophenyl)-isochroman, melting point 144-147° C., is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8](=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:4]1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:34](O)=[O:35].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([N:5]2[CH2:6][CH2:7][CH:3]([CH2:2][NH:1][C:34](=[O:35])[C:33]3[CH:32]=[C:31]([O:30][CH3:29])[C:39]([O:40][CH3:41])=[C:38]([O:42][CH3:43])[CH:37]=3)[CH2:4]2)=[O:28])=[CH:15][CH:16]=1
Reactant: NCC1CCN(C(=O)CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)C1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cc(C(=O)NCC2CCN(C(=O)CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3-aminomethyl-pyrrolidin-1-yl)-6,6-bis-(4-fluoro-phenyl)-hexan-1-one (0.69 g, 1.78 mmol) in dry CH2Cl2 (40 ml) was added 3,4,5-trimethoxy benzoic acid (0.38 g, 1.78 mmol) under nitrogen. To the reaction was added EDC (0.68 g, 3.56 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give a desired product in good yield
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH3:12][Mg]Br.Cl>O1CCCC1.C(OCC)C>[F:1][C:2]1[C:3]([C:9]([OH:11])([CH3:12])[CH3:10])=[CH:4][CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CC(=O)c1cccc(O)c1F
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)c1cccc(O)c1F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of 1-(2-fluoro-3-hydroxy-phenyl)-ethanone (8.50 g, 55.0 mmol) in tetrahydrofuran (80 mL) was slowly added a methyl magnesium bromide solution in diethyl ether (3.0 M, 46.5 mL, 0.15 mol) at −78° C. The resulting mixture was stirred at −78° C. for 10 min and then allowed to come to room temperature and stirred for an additional 40 min. The reaction mixture was diluted with diethyl ether (100 mL) and cooled in an ice bath before an aqueous hydrochloric acid solution (1N, 200 mL) was added dropwise. The biphasic mixture was separated and the aqueous phase extracted with diethyl ether (2×60 mL). The combined organic phases were washed with water, brine and dried over sodium sulfate. The resulting mixture was filtered and evaporated and the resulting oil was dried under vacuum which afforded 2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenol (9.40 g, 100%) as an off-white solid.