Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)Cl>[C:13]([O:12][C:11]([NH:10][CH2:9][CH2:8][C:4]1[CH:5]=[N+:6]([O-:26])[CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:17])([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCc1cncc(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1cc(Cl)c[n+]([O-])c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl (2-(5-chloropyridin-3-yl)ethyl)carbamate (93 mg, 0.36 mmol) in DCM (4 mL) was added 3-chloroperbenzoic acid (85%, 94.8 mg, 0.54 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction was quenched with aqueous solution of sodium thiosulfate and extracted with DCM. The combined organic layers were washed with aqueous solution of potassium carbonate and brine, dried over sodium sulfate and concentrate to give a crude product, which was used directly in the next step without further purification (90 mg, crude). MS (ESI) m/z 273.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].S(OC)(O[CH3:18])(=O)=O>>[CH3:18][O:10][C:4]1[CH:5]=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1c(O)cc(F)c(F)c1F
Reactant: COS(=O)(=O)OC
Product: COc1cc(F)c(F)c(F)c1[N+](=O)[O-]

Procedure:
Staring from 3,4,5-trifluoro-2-nitrophenol and dimethyl sulfate in place of allyl bromide and using a procedure analogous to that used to prepare Intermediate 6,3,4,5-trifluoro-2-nitro-phenyl methyl ether was prepared.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][OH:10].[F:11][CH2:12][CH2:13][N:14]1[C:19]2[CH:20]=[CH:21][C:22]([O:24][C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:23][C:18]=2[S:17](=[O:34])(=[O:33])[N:16]=[CH:15]1>CS(C)=O>[F:11][CH2:12][CH2:13][N:14]1[C:19]2[CH:20]=[CH:21][C:22]([O:24][C:25]3[CH:26]=[C:27]([C:28](=[N:9][OH:10])[NH2:29])[CH:30]=[CH:31][CH:32]=3)=[CH:23][C:18]=2[S:17](=[O:33])(=[O:34])[N:16]=[CH:15]1
Reactant: N#Cc1cccc(Oc2ccc3c(c2)S(=O)(=O)N=CN3CCF)c1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: NC(=NO)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=CN3CCF)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
770 μL (5.52 mmol) of triethylamine are added to a solution of hydroxylamine hydrochloride (384 mg, 5.52 mmol) in 1.8 ml of DMSO, and the suspension is stirred for 20 minutes at ambient temperature. The precipitate is filtered off and the filtrate is concentrated in vacuo. To the resulting filtrate there are added 225 mg (0.921 mmol) of the compound of Step A above and the solution is stirred at 75° C. for 4 hours. The reaction mixture is cooled to ambient temperature and the reaction mixture is precipitated from water. A white, non-filterable, gummy paste is obtained which is separated from the aqueous phase by simple decanting. The gum is triturated in ethanol until crystallisation occurs. The solid is filtered off to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Br:8].[CH2:13]([Zn]CC)C>CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][C@H:10]2[CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Br:8]
Reactant: CC[Zn]CC
Reactant: OCC=Cc1ccc(Br)c(Br)c1
Solvent: CCCCCC
Product: OC[C@@H]1C[C@H]1c1ccc(Br)c(Br)c1

Procedure:
The above alcohol (2 g) was treated with diethyl zinc (35 ml) and dioodomethyl 15.52 ml) in hexane in the usual manner to give (±)-[Trans-2-(3,4-dibromophenyl)cyclopropyl]methanol (1.3 g). NMR 1H: 7.40(1H,d), 7.30(1H,d), 6.76(1H,dd), 3.53(2H,d), 2.30(1H,s), 1.68(1H,m), 1.33(1H,m), 0.87(2H,m).
Reaction SMILES: [NH2:1][CH:2]([CH3:21])[CH2:3][N:4]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:20].[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(O)(=O)C>[C:22]([NH:1][CH:2]([CH3:21])[CH2:3][N:4]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:20])(=[O:24])[CH3:23]
Reactant: CC(N)Cn1cc(-c2ccccc2)c2ccccc2c1=O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NC(C)Cn1cc(-c2ccccc2)c2ccccc2c1=O
Temperature: 0 °C
Yield: 83 %

Procedure:
A mixture of 5 g of 2-(2-aminopropyl)-4-phenyl-1(2H)-isoquinolone, 10 ml of acetic anhydride and 10 ml of glacial acetic acid was warmed on a water bath for 3 hours and the resulting reaction mixture was poured into ice-water. The precipitated crystals were extracted with dichloromethane, and the extract was thoroughly washed successively with a 5% aqueous solution of sodium hydroxide and water, and then dried over anhydrous sodium sulfate. The crystals obtained by distilling off the solvent was recrystallized from ethanol to obtain 4.8 g (83% yield) of 2-(2-acetamidopropyl-4-phenyl-1(2H)-isoquinolone having a melting point of 177° C. as colorless needles.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12](OC)[CH2:13][Cl:14]>ClCCl>[CH3:10][O:11][CH:12]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][Cl:14]
Reactant: COC(CCl)OC
Reactant: NC(=O)c1ccccc1
Solvent: ClCCl
Product: COC(CCl)NC(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 41.3 %

Procedure:
9.6 g of benzamide and 49.8 g of chloroacetaldehyde dimethyl acetal, and an amount of strongly acidic ion exchanging resin having an exchange capacity corresponding to the benzamide were agitated for 3 hours at a temperature of 60° C. The reaction fluid was cooled to 40° C., and 30 ml of dichloromethane was added thereto. The ion exchanging resin was removed by filtration under reduced pressure, and the dichloromethane and excess chloroacetaldehyde dimethyl acetal were removed from the filtrate by vacuum distillation, 100 ml of hexane was added thereto and crystals were precipitated, and these were then filtered and desiccated to obtain 7.0 g of compound (1).
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][S:5][C@H:4]2[CH2:17][CH2:18][CH2:19][C@@H:20]([CH:21]=[CH2:22])[N:3]12.[H][H]>CO.[Pd]>[CH2:21]([C@H:20]1[N:3]2[C@@H:4]([S:5][CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]2=[O:1])[CH2:17][CH2:18][CH2:19]1)[CH3:22]
Reactant: [H][H]
Reactant: C=C[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)OC(C)(C)C)C(=O)N12
Agent: [Pd]
Solvent: CO
Product: CC[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)OC(C)(C)C)C(=O)N12
Yield: 80 %

Procedure:
A solution of tert-butyl (4S,7S,10aS)-5-oxo-7-vinyloctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (66 mg, 0.20 mmol) in MeOH (2 mL) was purged with argon for 2 min. Then, 10% Pd/C (80 mg, 0.75 mmol) was added. The reaction mixture was stirred for under a hydrogen balloon for 3 days. The reaction mixture was filtered. The filtrate was concentrated and dried under the high vacuum to give tert-butyl (4S,7R,10 aS)-7-ethyl-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (52 mg, 0.16 mmol, 78% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 6.02 (d, J=5.5 Hz, 1H), 5.39-5.15 (m, 1H), 4.92-4.66 (m, 1H), 4.53-4.30 (m, 1H), 3.38-3.14 (m, 1H), 2.97-2.66 (m, 1H), 2.46-2.20 (m, 1H), 2.15-1.62 (m, 8H), 1.62-1.35 (m, 10H), 0.93 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH:1]1([N:6]([CH3:33])[C:7]2[C:8]([CH3:32])=[C:9]([CH:23]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:25]=2)[C:10]([NH:12][CH2:13][C:14]2[C:15](=[O:22])[NH:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:36]([BH3-])#N.[Na+]>CO>[CH:1]1([N:6]([CH3:33])[C:7]2[C:8]([CH3:32])=[C:9]([CH:23]=[C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH3:36])[CH2:28][CH2:27]3)[CH:25]=2)[C:10]([NH:12][CH2:13][C:14]2[C:15](=[O:22])[NH:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: Cc1cc(C)c(CNC(=O)c2cc(N3CCNCC3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCN(C)CC3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
3-(Cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(piperazin-1-yl)benzamide (free base) (0.100 g, 0.223 mmol) was dissolved in methanol (5 mL) and cooled to 0° C. before formalin (0.033 g, 1.1 mL, 2.23 mmol) was added. The resulting reaction mixture was stirred at same temperature for 30 minutes. Sodium cyanoborohydride (0.013 g, 0.22 mmol) was added to above reaction mixture and stirred at room temperature for 4 h. After completion, solvent was removed under reduced pressure and water added to the residue, with extraction carried out using DCM. The combined organic layers were dried, concentrated and purified by column chromatography to provide desired 3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide (0.037 g, 36%).
Reaction SMILES: [F:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].Cl>C1COCC1.CCOC(C)=O>[Cl:10][C:9]1[C:2]([F:1])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH2:4][NH:5][C:11](=[O:14])[CH:12]=[CH2:13]
Reactant: NCc1cccc(Cl)c1F
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC(=O)NCc1cccc(Cl)c1F
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a solution of 2-fluoro-3-chlorobenzylamine (1 g, 6.27 mmol) and TEA (1.05 mL, 7.52 mmol) in THF (20.9 mL) was added acryloyl chloride (0.61 mL, 7.52 mmol) dropwise and the reaction mixture was stirred at 23° C. for 2 h. The reaction mixture was diluted in EtOAc, HCl 1N was added and the layers separated. The aqueous layer was extracted again with EtOAc and the combined organic layers were dried, filtered and concentrated to dryness. The crude residue was purified by flash column chromatography on silica gel (xyclohexane/EtOAc gradient 100:0 to 1:1) to give the desired material. TLC, Rf (c-hexane/EtOAc 5:5)=0.41; MS (LC/MS): 214.0 [M+H]+; tR (HPLC conditions b): 3.35 min.
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]3[NH:21][C:20]4[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](=[O:26])[NH:16][C:15]=4[N:14]=3)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=O.[BH4-].[Li+]>C1COCC1.CO>[OH:2][CH2:3][C:5]12[CH2:10][CH2:9][C:8]([C:13]3[NH:21][C:20]4[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](=[O:26])[NH:16][C:15]=4[N:14]=3)([CH2:11][CH2:12]1)[CH2:7][CH2:6]2
Reactant: CCCn1c(=O)[nH]c2nc(C34CCC(C(=O)OC)(CC3)CC4)[nH]c2c1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCn1c(=O)[nH]c2nc(C34CCC(CO)(CC3)CC4)[nH]c2c1=O

Procedure:
To a solution of 4-(2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (2.4 g, 0.006 moles) in THF (35 ml), methanol (0.4 ml) was added. To this mixture, lithium borohydride (1.45 g, 0.066 mole) was added slowly and refluxed overnight. Reaction mixture was concentrated under reduced pressure and quenched with 1N HCl. Water was added to the residue and extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:34]([CH3:35])=[CH:33][C:15]2[N:16]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][C:21]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)([CH3:25])[CH2:20]3)[S:18][C:14]=2[C:13]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:34]([CH3:35])=[CH:33][C:15]2[N:16]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][C:21]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)([CH3:25])[CH2:20]3)[S:18][C:14]=2[C:13]=1[C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCOC(C)(c4ccc(Cl)cc4)C3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(N3CCOC(C)(c4ccc(Cl)cc4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To a solution of (2S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(4-chlorophenyl)-2-methylmorpholino)-5-methylbenzo[d]thiazol-6-yl)acetate (63.7 mg, 0.101 mmol) in CH3OH/THF (1:1, 4 mL) was added NaOH (2N, 1 mL, 2 mmol), the resulting mixture was heated at 50° C. for 14 hr. The mixture was evaporated to a small volume, acidified to pH 3 and taken into partitioned between CH2Cl2 and brine. The organic layer was separated, dried (Na2SO4), filtered and evaporated to dryness. The residue was purified on CombiFlash (50% EtOAc/Hex) to give (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(4-chlorophenyl)-2-methylmorpholino)-5-methylbenzo[d]thiazol-6-yl)acetic acid. LCMS-ESI+: calc'd for C31H32Cl2N2O4S: 599.2, 601.2 (M+H+); found: 599.2, 601.2 (M+H+). 1H-NMR: 400 MHz, (CD3OD) δ: 7.62 (m, 1H), 7.44-7.53 (m, 5H), 7.32 (m, 3H), 5.13 (s, 1H), 4.31 (t, J=14.4 Hz, 1H), 3.81 (m, 1H), 3.62 (m, 1H), 3.44-3.53 (m, 3H), 2.50 (s, 3H), 1.46 (s, 3H), 0.95 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][C:15]#[N:16])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.FC(F)(F)C1C=CC(C2(CC(N)=[NH:33])CCCC2)=CC=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][C:15]([NH2:33])=[NH:16])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CCC1(c2ccc(Cl)c(Cl)c2)CCCC1
Reactant: N=C(N)CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Agent: Cl
Product: N=C(N)CC1(c2ccc(Cl)c(Cl)c2)CCCC1

Procedure:
2-(1-(3,4-Dichlorophenyl)-cyclopentyl)-acetamidine hydrochloride (486) was synthesized from 2-(1-(3,4-dichlorophenyl)cyclopentyl)acetonitrile (485) following the procedure described for the HCl-salt of 2-[1-(4-trifluoromethyl-phenyl)-cyclopentyl]-acetamidine hydrochloride (242).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:14]2[N:13]([CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[C:12](=[O:22])[N:11](C(OC(C)(C)C)=O)[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH:19]([O:18][C:16](=[O:17])[CH2:15][N:13]1[C:14]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[CH:9][C:10]=2[NH:11][C:12]1=[O:22])([CH3:20])[CH3:21]
Reactant: CCC(CC)c1cccc2c1n(CC(=O)OC(C)C)c(=O)n2C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCC(CC)c1cccc2[nH]c(=O)n(CC(=O)OC(C)C)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of tert-butyl 4-(1-ethylpropyl)-3-(2-isopropoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (8.95 g, 22.1 mmol) in ethyl acetate (10 ml) was added a 4N solution of hydrogen chloride in ethyl acetate (20 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (X2). The combined organic layer was washed with brine (X1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 5-20% ethyl acetate/hexane gradient mixture. The residual solid was washed with hexane to give 5.76 g (18.9 mmol, 85.6%) of the title compound as a colorless solid.
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[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[C:22]([CH3:24])[CH:21]=[N:20]1)=[O:11].Cl[C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[C:22]([CH3:24])[CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1
Reactant: Cc1ccc(-n2ncc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Product: Cc1ccc(-n2ncc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)nn2)c1

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)(5-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. ESI-MS (m/z): 474 [M+1]+.
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[C:9]([CH:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[OH:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]1([C:7]2[S:11][CH:10]=[C:9]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C(O)c2csc(-c3ccccc3)c2)cc(OC)c1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(C(=O)c2csc(-c3ccccc3)c2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To a solution of 40f (0.260 g, 0.73 mmoL) in 20 mL anhydrous CH2Cl2 was added Dess-Martin reagent (0.465 g, 1.36 mmol). The mixture was allowed to stir for 30 min and quenched with sat. Na2S2O3 solution, extracted with ethyl acetate and dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to give pure compound 1f as light yellow crystals (60.9%). NMR (CDCl3) δ 7.97 (d, 1H, J=1.5 Hz), 7.82 (d, 1H, J=1.5 Hz), 7.59-7.57 (m, 2H), 7.45-7.34 (m, 3H), 7.19 (s, 2H), 3.95 (s, 3H), 3.93 (s, 6H); MS (ESI) m/z 355.1 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:46]=[CH:45][N:14]3[C:15](=[O:44])[C:16]([C:30]4[N:34]([CH2:35][C:36]5[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=5)[N:33]=[N:32][N:31]=4)=[C:17](OS(C4C=CC(C)=CC=4)(=O)=O)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>O1CCCC1>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:46]=[CH:45][N:14]3[C:15](=[O:44])[C:16]([C:30]4[N:34]([CH2:35][C:36]5[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=5)[N:33]=[N:32][N:31]=4)=[C:17]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: COc1ccc(Cn2nnnc2-c2c(OS(=O)(=O)c3ccc(C)cc3)nc3cc(CCc4nc(C(C)C)cs4)ccn3c2=O)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnnc2-c2c(N3CCOCC3)nc3cc(CCc4nc(C(C)C)cs4)ccn3c2=O)cc1
Reaction time: 8 h
Yield: 59 %

Procedure:
The 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-tosyloxy-3-[(4-methoxybenzyl)-tetrazol-5-yl]-4H-pyrido[1,2-a]pyrimidin-4-one (61 mg) obtained in (B) was dissolved in tetrahydrofuran (1 ml), added with morpholine (40 ml) at room temperature, and stirred overnight at the same temperature. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (31 mg, 59%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:15]1(=O)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17](=[O:24])[O:16]1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:15](=[O:16])[C:19]2[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]1=[O:24])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CN(CCCCN)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CN(CCCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C

Procedure:
2 g (9.9 mmol) of tert-butyl(4-aminobutyl)methylcarbamate and 1.46 g (9.9 mmol; 1 equivalent) of 2-benzofuran-1,3-dione are solubilized in 50 ml of toluene and the reaction mixture is maintained under reflux for 24 hours in a Dean-Stark. The solvent is evaporated off under reduced pressure and the expected product is purified on a silica column (eluent: dichloromethane/methanol: 90/10).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:23]#[N:24].[O:25]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[N:17]1([CH2:16][CH2:15][N:14]2[C:8]3[C:9](=[CH:10][C:11]4[C:2]([NH:36][C:35]5[CH:34]=[CH:33][C:32]([O:25][C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[CH:38][CH:37]=5)=[C:3]([C:23]#[N:24])[CH:4]=[N:5][C:6]=4[CH:7]=3)[N:12]=[CH:13]2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: N#Cc1cnc2cc3c(cc2c1Cl)ncn3CCN1CCOCC1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: N#Cc1cnc2cc3c(cc2c1Nc1ccc(Oc2ccccc2)cc1)ncn3CCN1CCOCC1
Yield: 69 %

Procedure:
Following the procedure of Example 7, a mixture of 82.2 mg (0.24 mmol) of 8-chloro-3-[2-(4-morpholinyl)ethyl]-3H-imidazo[4,5-g]quinoline-7-carbonitrile, 53.3 mg (0.29 mmol) of 4-phenoxyaniline and 33.5 mg (0.29 mmol) of pyridine hydrochloride in 3.5 mL of 2-ethoxyethanol is heated at 130–135° C. for 1 hour to yield 81.2 mg (69%) of the product as a yellow solid, mp>260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[F:34][CH2:35][CH2:36][O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=O)=[CH:40][CH:39]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:42][C:41]1[CH:40]=[CH:39][C:38]([O:37][CH2:36][CH2:35][F:34])=[CH:46][CH:45]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: O=C(Cl)c1ccc(OCCF)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc(OCCF)cc3)c3c(Cl)cccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 1-(3) and 4-(2-fluoroethyloxy)benzoyl chloride were treated in a manner similar to Example 3 to give the titled compound as a colorless powder. APCI-Mass m/Z 466/468 (M+H). 1H-NMR (DMSO-d6) δ 3.24 (td, J=8.8, 5.7 Hz, 1H), 3.38-3.47 (m, 3H), 3.62-3.69 (m, 2H), 4.14-4.16 (m, 1H), 4.20 (s, 2H), 4.20-4.22 (m, 1H), 4.53 (t, J=5.5 Hz, 1H), 4.66-4.67 (m, 1H), 4.76-4.77 (m, 1H), 5.09 (d, J=5.31 Hz, 1H), 5.15 (d, J=5.0 Hz, 1H), 5.21 (d, J=5.8 Hz, 1H), 5.39 (d, J=9.0 Hz, 1H), 6.87 (d, J=8.7 Hz, 2H), 7.02 (d, J=7.5 Hz, 1H), 7.09 (t, J=7.9 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H), 7.22 (s, 1H), 7.53 (d, J=8.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH2:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[C:29](Cl)(=[O:31])[CH3:30]>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH:28][C:29](=[O:31])[CH3:30])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-ethanamine (90 mg, 0.23 mmol) was dissolved in THF (2.3 mL) before acetyl chloride (33 μl, 0.462 mmol) was added and stirred at ambient temperature for 2 h. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 75 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound after purification via preparatory LC. MS (ESI) m/z: Calculated: 431.1; Observed: 432.1 (M++H).