Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[O:16][CH:15]([CH3:18])[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26](OCC)(=[O:28])C.Cl>>[CH3:26][O:28][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[O:16][CH:15]([CH3:18])[CH2:14][NH:13][CH2:12][C:11]=3[S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(-c3cccc(F)c3)c2O1
Reactant: CCOC(C)=O
Agent: Cl
Product: COc1cccc(-c2csc3c2OC(C)CNC3)c1
Yield: 92 %

Procedure:
tert-Butyl 8-(3-fluorophenyl)-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (274 mg) was stirred in 4N hydrogen chloride-ethyl acetate solution (5 mL) for 30 min. The precipitated crystals were washed with ethyl acetate to give 8-(3-fluorophenyl)-2-methyl-2,3,4,5-tetrahydrothieno[2,3-f][1,4]oxazepine 1 hydrochloride (207 mg, 92%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13](=[O:22])[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13](=[O:22])[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][CH2:10][O:11][S:31]([CH3:30])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC(CCO)c1ccccc1Br)c1c(F)cccc1F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC(NC(=O)c1c(F)cccc1F)c1ccccc1Br
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of 15.0 g of N-[1-(2-bromophenyl)-3-hydroxypropyl]-2,6-difluorobenzamide, 4.5 g of triethylamine in 150 ml of dichloromethane at room temperature, was added dropwise 5.1 g of methylsulfonyl chloride and stirring continued for an additional 30 minutes. The reaction mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to afford 18.0 g of N-[1-(2-bromophenyl)-3-(methylsulfonyloxy)propyl]-2, 6-difluorobenzamide.
Reaction SMILES: C([Li])CCC.[CH:6]1([O:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCCCCC.O1CCCC1>[C:18]([N:16]1[CH:12]([O:11][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:13][CH2:14][C:15]1=[O:17])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CCC(OC2CCCC2)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CCC(OC2CCCC2)N1C(=O)c1ccccc1
Yield: 70.2 %

Procedure:
11.8 cm3 of a 1.5M solution of butyllithium in hexane is added at -70° C. to a solution of 3 g of 5-cyclopentyloxy pyrrolidin-2-one in 140 cm3 of tetrahydrofuran. The mixture is maintained at this temperature for 20 minutes, then a solution of 2.49 g of benzoyl chloride in 20 cm3 of tetrahydrofuran is added. The whole is heated gently, then brought to dryness under reduced pressure. After chromatography on silica (eluent: hexane-ethyl acetate 7-3), 3.4 g of expected product is obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([OH:12])=[CH:4][CH:3]=1.[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[CH2:19]([O:12][C:5]1[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1nc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
A mixture of methyl 6-bromo-3-hydroxypicolinate (500 mg, 2.15 mmol), BnBr (443 mg, 3.25 mmol) and K2CO3 (595 mg, 4.31 mmol) in THF (5 mL) was stirred at RT for 3 h. Then water was added and the mixture was extracted with EtOAc (20 mL*3). The organic layer was dried over Na2SO4 and concentrated to give crude methyl 3-(benzyloxy)-6-bromopicolinate (500 mg, yield 72%), which was used for the next step without further purification. MS (M+H)+: 322/324.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21]>O1CCCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:20]([NH:19][CH2:18][CH2:17][Cl:16])=[O:21])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(NC(=O)NCCCl)c1
Yield: 132.8 %

Procedure:
A solution of (3-Amino-phenyl)-carbamic acid tert-butyl ester (0.5 g, 2.4 mmol) and 1-Chloro-2-isocyanato-ethane (0.25 ml, 2.9 mmol) in dry tetrahydrofuran (20 ml) were stirred at room temperature overnight. Reaction was quenched with water (50 ml) then extracted with dichloromethane (3×50 ml). Combined organics dried (magnesium sulphate) and concentrated in vacuo. The crude residue was purified by column chromatography (eluent 10% ethylacetate in dichloromethane) to afford the title compound (1 g). HPLC retention time 7.45 min. Mass spectrum (ES+) m/z 314 (M+H)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][NH2:13].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:11][C:4]1[N:3]=[C:2]([NH:13][CH3:12])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1nc(Cl)ccc1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
To a stirred solution of 10 g (52 mmol) of 2,6-dichloro-3-nitropyridine in 300 mL of N,N-dimethylformamide was added 26 mL (52 mmol) of methylamine (2M in tetrahydrofuran) and 9.3 g (88 mmol) of sodium carbonate and the resulting mixture was stirred for 24 h. The solution was diluted with 500 mL water and extracted with three 700 mL portions of ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and evaporated in vacuo to yield a viscous oil. The crude material was purified by flash chromatography on a Biotage Horizon® system (silica gel, 0 to 10% ethyl acetate/hexanes gradient) to give 6-chloro-N-methyl-3-nitropyridin-2-amine as a yellow solid. LC/MS 188.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[CH:14][C:13]=1[F:23])=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:27]=[N:26][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([N:18]3[N:19]=[CH:20][CH:21]=[N:22]3)=[CH:16][CH:15]=[CH:14][C:13]=2[F:23])=[O:11])=[N:30][CH:29]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-n2nccn2)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 430 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][N:11]([CH3:24])[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:20]([C:19]3[CH:22]=[CH:23][C:16]([O:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:24])[CH3:10])=[CH:17][CH:18]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: CN(C)CCCOc1ccc(C=O)cc1
Product: CN(C)CCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine (376 mg, 2 mmol) and 4-[3-(dimethylamino)-propoxy]benzaldehyde (420 mg, 2 mmol).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]2[C:13]3[CH:12]=[CH:11][C:10]([OH:14])=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:39]1[CH:43]=[CH:42][C:41]([CH2:44]O)=[CH:40]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:39]1[CH:43]=[CH:42][C:41]([CH2:44][O:14][C:10]2[CH:11]=[CH:12][C:13]3[C:4]4[N:3]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:2]([CH3:1])=[N:15][C:5]=4[CH:6]=[N:7][C:8]=3[CH:9]=2)=[CH:40]1
Reactant: OCc1ccoc1
Reactant: Cc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc2cnc3cc(OCc4ccoc4)ccc3c2n1CC(C)C
Reaction time: 144 h
Yield: 127.4 %

Procedure:
2-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (300 mg, 1.17 mmol), triphenylphosphine (921 mg, 3.51 mmol), and 3-furanmethanol (173 mg, 1.76 mmol) were slurried in 20 mL of anhydrous THF. After 5 minutes diisopropyl azodicarboxylate (710 mg, 3.51 mmol) was added dropwise to the mixture. The resulting homogeneous solution was stirred six days. Analysis of the reaction by HPLC indicated that mostly starting material was present. Additional portions of triphenylphosphine (150 mg), 3-furanmethanol (0.5 mL) were added followed by diisopropyl azodicarboxylate (1 mL). Analysis of the reaction after 1 hour indicated that all of the 2-methyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinolin-7-ol was consumed. The reaction was filtered through an acidic ion-exchange resin with methanol followed by 1M ammonia in methanol. The filtrate was concentrated to give 500 mg of 7-(furan-3-ylmethoxy)-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as a dark orange oil.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:22]3[S:23][CH2:24][CH2:25][N:26]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[CH2:20][S:21][C:22]1[S:23][CH2:24][CH2:25][N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSC3=NCCS3)c2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2c(c1CSC1=NCCS1)CCNCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-(4,5-dihydro-thiazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.77 g, 1.9 mmol) in anhydrous DCM (41 mL) at room temperature add trifluoroacetic acid (37.7 mL) and stir the solution at room temperature overnight. Concentrate in vacuo and elute the residue through a SCX column (10 g). Dissolve the residue in DCM, load the solution on to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (linear gradient: 100:0 to 90:10 DCM/2M ammonia in methanol over 30 min; 35 mL/min) to afford 7-chloro-6-(4,5-dihydro-thiazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.58 g, 100%). MS (ES+) m/z: 313.1 (M+H)+.
Reaction SMILES: [OH-].[Na+].[C-]#[N:4].[Na+].O.[OH:7][C:8]1[CH:18]=[CH:17][C:11]([CH:12](O)[C:13]([O-])=O)=[CH:10][CH:9]=1.[Na+].[Cl-].[Na+]>CN(C)C=O.O.C(O)=O>[OH:7][C:8]1[CH:18]=[CH:17][C:11]([CH2:12][C:13]#[N:4])=[CH:10][CH:9]=1
Reactant: [C-]#N
Reactant: O=C([O-])C(O)c1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(O)cc1
Temperature: 135 °C

Procedure:
Sodium hydroxide (4.0 g.) and sodium cyanide (5.0 g.) are added to a stirred suspension of sodium p-hydroxymandelate monohydrate (19 g. of 89% w/w material, the impurity being sodium chloride) in N,N-dimethylformamide (100 ml.) and the mixture is stirred and heated at 135° C. for 4 hours and then cooled. Formic acid (7.7 ml.) and water (200 ml.) are added and the mixture is extracted twice with methyl isobutyl ketone (100 ml. and 75 ml.). The combined extracts are washed twice with water (40 ml. each time) and are then concentrated by evaporation. There is thus obtained a solution of p-hydroxybenzyl cyanide in methyl isobutyl ketone which is suitable for conversion to p-hydroxyphenylacetamide without further purification.
Reaction SMILES: NCC(C1NC2C(C=1)=CC=CN=2)OC1CCCCO1.[Cl:20][C:21]1[CH:29]=[CH:28][N:27]=[C:26]2[C:22]=1[CH:23]=[C:24]([CH:30]([O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][O:45]1)[CH2:31][N:32]1C(=O)C3=CC=CC=C3C1=O)[NH:25]2.NN.O>CCO>[NH2:32][CH2:31][CH:30]([C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[C:21]([Cl:20])[CH:29]=[CH:28][N:27]=2)[O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][O:45]1
Reactant: O=C1c2ccccc2C(=O)N1CC(OC1CCCCO1)c1cc2c(Cl)ccnc2[nH]1
Agent: NCC(OC1CCCCO1)c1cc2cccnc2[nH]1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC(OC1CCCCO1)c1cc2c(Cl)ccnc2[nH]1
Yield: 98.4 %

Procedure:
Following the same procedure as for 9a, from 4-Chloro-2-[2-phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-7-azaindole (950 mg, 2.2 mmol) in EtOH (50 ml) and NH2NH2.H2O (250 μl, 4.4 mmol). After a reaction time of 3 h. a diastereomeric mixture (1:1) of 9c (640 mg, 97%/o) was obtained.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:13][C:14]([O:17][C:18]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:19])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>CS(C)=O>[C:14]([O:17][C:18](=[O:19])[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:23][CH2:22]1)([CH3:16])([CH3:13])[CH3:15]
Reactant: Cc1cc(F)cc(N)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc(N)c1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 3 h

Procedure:
5-Fluoro-3-methyl-2-nitro-phenylamine (0.97 g, 5.7 mmol), 4-N-BOC-aminopiperidine (1.60 g, 8.0 mmol), diisopropylethylamine (2.5 ml, 14 mmol) and DMSO (10 ml) are combined and stirred at 85° C. for 3 hours. The reaction mixture was poured on saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layers were washed with water (3×) and brine, dried over Na2SO4 and concentrated. Flash column chromatography on silica (eluent hexanes-ethyl acetate-triethylamine 50-50-1, then 33-66-1) gave the title compound as a yellow solid. (1.57 g, 79%). LCMS (M+H)+ m/z 351 (t=1.55 min.). 1H NMR (500 MHz, CD3OD) δ 6.70 (1H, broad s), 6.22 (1H, d, J=2.5 Hz)), 6.13 (1H, d, J=2.5 Hz), 3.88 (2H, d, J=13.3 Hz), 3.58 (1H, broad s), 2.98 (2H, t, J=11.8 Hz), 2.48 (3H, s), 1.92 (2H, J=11.3 Hz), 1.48 (2H, m), 1.45 (9H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]([Br:7])=[C:5]([N+:8]([O-:10])=[O:9])[N:4]=[C:3]1COC(=O)C.[BrH:16].[C:17](O)(=O)[CH3:18]>>[CH3:1][N:2]1[C:6]([Br:7])=[C:5]([N+:8]([O-:10])=[O:9])[N:4]=[C:3]1[CH2:17][CH2:18][Br:16]
Reactant: CC(=O)OCc1nc([N+](=O)[O-])c(Br)n1C
Reactant: CC(=O)O
Reactant: Br
Product: Cn1c(CCBr)nc([N+](=O)[O-])c1Br

Procedure:
0.596 G. (0.00214 moles) of 1-methyl-2-acetoxymethyl-4-nitro-5-bromoimidazole is dissolved in 20 ml. of acetic acid and treated with gaseous HBr for 5 minutes at room temperature. The reaction mixture is refluxed on a steam bath for 1 hour, cooled and evaporated to dryness. The residue is dissolved in chloroform, treated with 10% potassium bicarbonate solution. The chloroform layer is separated, dried and evaporated to dryness, affording 0.568 g. of 1-methyl-2-bromomethyl-4-nitro-5-bromoimidazole, recovered as an oil.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].[CH3:12][C:13]1[CH:17]=[CH:16][O:15][C:14]=1[C:18]([NH:20][C:21]1[CH:36]=[CH:35][C:24]([C:25](ON2C(=O)CCC2=O)=[O:26])=[CH:23][CH:22]=1)=[O:19].CN(C=O)C.C(N(CC)CC)C>C(OCC)C>[CH3:12][C:13]1[CH:17]=[CH:16][O:15][C:14]=1[C:18]([NH:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9])=[O:26])=[CH:23][CH:22]=1)=[O:19]
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Reactant: Cc1ccoc1C(=O)Nc1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccoc1C(=O)Nc1ccc(C(=O)N[C@H](CC(=O)[O-])C[N+](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43 %

Procedure:
(R)-aminocarnitine (20 mg, 0.12 mmol) and 2,5-dioxopyrrolidin-1-yl 4-(3-methylfuran-2-carboxamido)benzoate (82 mg, 0.24 mmol) were dissolved into DMF (1 mL). Triethylamine (50 μL, 0.36 mmol) was added and the solution was stirred at room temperature for 48 h. Diethyl ether (20 mL) was added and a white precipitate was collected. The powder was purified by silica gel chromatography (elution 10% MeOH/CH2Cl2 to 80% MeOH/CH2Cl2) to give the title compound as a white solid (20 mg, 43%). 1H NMR (400 MHz, D2O) δ 7.62 (d, 1H, J=1.4 Hz), 7.32-7.30 (m, 1H), 7.27-7.16 (m, 3H), 6.55 (d, 1H, J=1.8 Hz), 4.90-4.80 (m, 1H), 3.63-3.42 (m, 2H), 3.13 (s, 9H), 2.48-2.45 (m, 2H), 2.10 (s, 3H); MS ESI 388.2 [M+H]+, calcd for [C20H25N3O5+H]+ 388.18.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:18]2[N:26]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=2)=[CH:6]1.[I-:37].[Na+]>C(C(C)=O)C>[I:37][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:18]2[N:26]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=2)=[CH:6]1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCCl)c2cc1OC
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCI)c2cc1OC
Reaction time: 16 h

Procedure:
2-[1-(3-Chloropropyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)—1H-pyrrolo[2,3-b]pyridine (0.395 g; 753.8 μmol) and sodium iodide (0.169 g; 1.13 mmol) in methyl ethyl ketone (10 ml) are placed in a 50 ml single-necked flask, at reflux. After 16 hours, sodium iodide (0.169 g; 1.13 mmol) is added and reflux is maintained for a further 5 hours. The reaction mixture is evaporated under reduced pressure and the residue is then dissolved in 50 ml of ethyl acetate, transferred into a separating funnel and washed with 2 times 30 ml of distilled water. The organic extract is dried over magnesium sulfate, filtered and evaporated under reduced pressure, to give the crude compound, which is purified by chromatography on silica gel (10 μg, silica 20-40 μm), elution being carried out at 10 ml/min with a mixture of cyclohexane and ethyl acetate (70/30; v/v). The fractions containing the expected compound are combined and evaporated to give 2-[1-(3-iodopropyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in the form of an amorphous solid (0.287 g, 62%), the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([C:7]1[CH2:11][CH2:10][O:9][CH:8]=1)=[O:6])[CH3:2].[Br:13]N1C(=O)CCC1=O.[O:21]1[CH2:25]CCC1>CO>[CH2:1]([O:3][C:4](=[O:12])[C:5]([C:7]1([Br:13])[CH2:11][CH2:10][O:9][CH:8]1[O:21][CH3:25])=[O:6])[CH3:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(=O)C1=COCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: CCOC(=O)C(=O)C1(Br)CCOC1OC
Temperature: -2.5 °C
Reaction time: 12 h

Procedure:
Ethyl-2-(4,5-dihydrofuran-3-yl)-2-oxoacetate (45 g) was dissolved in tetrahydrofuran (225 ml) and Methanol (45 ml). The reaction mass was cooled to −5 to 0° C. N-bromosuccinimide (47 g) was added lot wise by maintaining temp below 0° C. Reaction mass was then stirred at 20-25° C. for 12 hrs. Reaction mass was concentrated to residue under vacuum at 40° C. Residue was dissolved in Ethyl acetate (450 ml) and washed with sodium sulphite solution (10%, 2×135 ml). Reaction mass was then concentrated to residue to get ethyl-2-(3-bromo-2-methoxytetrahydrofuran-3-yl)-2-oxoacetate (Yield 63 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([F:59])[C:52]=3[F:60])[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH2:61][OH:62])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([F:59])[C:52]=3[F:60])[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH:61]=[O:62])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 99.4 %

Procedure:
Oxalyl chloride was dissolved in 5 mL methylene chloride and cooled to −78° C., followed by dropwise addition of 3 ml solution of dimethyl sulfoxide ((0.26 mL, 3.59 mmol) in methylene chloride. The reaction mixture was stirred for 15 minutes, before 5 mL solution of [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 2j (1.25 g, 1.71 mmol) in methylene chloride was dropwise added. The mixture was stirred for 40 minutes. The triethylamine (1.19 mL, 8.55 mmol) was dropwise added, before the reaction mixture was warmed to room temperature and stirred for 1.5 hours. Thereafter, the reaction mixture was washed with 5 mL 1 M hydrochloric acid and the organic extract was collected, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 2k (1.24 g, yellow solid), which was used in the next step without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[CH:5]([CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](=O)[CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]2)[CH2:10][CH2:9]1)([CH3:7])[CH3:6].[C:29](#[N:32])[CH:30]=[CH2:31]>>[CH:5]([CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]([NH:1][CH2:2][CH2:3][NH:4][CH2:31][CH2:30][CH2:29][NH2:32])[CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]2)[CH2:10][CH2:9]1)([CH3:7])[CH3:6]
Reactant: NCCN
Reactant: CC(C)C1CCC(CCC(=O)CCC2CCC(C(C)C)CC2)CC1
Reactant: C=CC#N
Product: CC(C)C1CCC(CCC(CCC2CCC(C(C)C)CC2)NCCNCCCN)CC1

Procedure:
As an alternative to obtaining a mixture of Schiff bases VI and VI(a) or VI(b), the reaction can be conducted stepwise. For example, 1,2-diaminoethane may be converted to a Schiff base with 1,5-di-(4-isopropylcyclohexyl)-3-pentanone, catalytically reduced, then the ring nitrogen selectively cyanoethylated with acrylonitrile, followed by catalytic hydrogenation to furnish [1,5-di-(4-isopropylcyclohexyl)-3-pentyl]-1,4,8-triazaoctane.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:19](O)=[O:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[C:16]([F:15])[CH:17]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cccc(F)c2)c(F)c1
Yield: 65.1 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-fluoro-4-(3-fluorobenzyl)benzamide was prepared according to Method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.075 g; 0.318 mmol), 3-fluoro-4-(3-fluorobenzyl)benzoic acid (0.087 g; 349 mmol), HATU (0.121 g: 0.318 mmol) and N,N-diisopropylethylamine (0.139 mL; 0.795 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent: 0 to 10% of ethyl acetate in dichloromethane) followed by recrystallization from a mixture of dichloromethane/heptane, furnished 0.088 g (65%) of the title compound as a white solid.