Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([F:13])[C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]=2[CH:12]=1.[C-:14]#[N:15].[K+].C(OCC)(=O)C>CN(C=O)C>[F:13][C:5]1[C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]=2[CH:12]=[C:3]([CH2:2][C:14]#[N:15])[CH:4]=1
Reactant: Fc1cc(CCl)cc2c1OCCO2
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCc1cc(F)c2c(c1)OCCO2
Temperature: 60 °C
Reaction time: 18 h
Yield: 47.8 %

Procedure:
A mixture of 7-(chloromethyl)-5-fluoro-2,3-dihydro-1,4-benzodioxine (0.92 g, 4.55 mmol) and potassium cyanide (1.55 g, 23.8 mmol) in DMF (10 mL) was stirred at 60° C. for 18 h. After cooling to rt ethyl acetate (100 mL) was added and the mixture was washed with water (2×30 mL) then brine (30 mL) and dried over sodium sulfate. Filtration and concentration followed by column chromatography on silica (4:1 hexanes/ethyl acetate) afforded (8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)acetonitrile (0.42 g, 46% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.61 (m, 2H), 4.30 (s, 4H), 3.62 (s, 2H)
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[N:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>CN(C=O)C.CCN(CC)CC.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:29]#[C:28][C:26]([OH:30])([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][N:20]=1)[CH3:27])[N:5]=2
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Reactant: C#CC(C)(O)c1cnccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CC(C)(O)c3cnccn3)nc21

Procedure:
A suspension of 1 g (3.56 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide in 25 ml of a DMF/Et3N mixture (V/V; 2.5/1) is placed in a 10 ml microwave tube. This suspension is sparged with argon for 10 minutes and then 0.792 g of (±)-2-pyrazin-2-ylbut-3-yn-2-ol (5.34 mmol), 0.068 g of CuI (0.36 mmol) and 0.125 g of bis(triphenylphosphine) palladium(II)dichloride (0.18 mmol) are successively added.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[Al](C)C.C([O:15][C:16]([C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:21]=[C:20]([CH3:31])[N:19]=1)=O)C>O1CCOCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:16]([C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:21]=[C:20]([CH3:31])[N:19]=2)=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)cc(C)n1
Reactant: Nc1cccc(Cl)c1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: CCCCCC
Product: Cc1cc(-c2ccc(F)cc2)cc(C(=O)Nc2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.9 %

Procedure:
To a solution of 113 μl (138 mg, 1.08 mmol, 4.0 equiv.) of 3-Chloroaniline in 7 ml of dry dioxane were added 540 μl (1.08 mmol, 4.0 equiv.) of a 2M solution of trimethylaluminium in hexane. The solution was stirred for 45 min at room temperature. Then a solution of 70.0 mg (0.27 mmol) of 4-(4-Fluoro-phenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in 1 ml of dry dioxane was added and the reaction was heated to 100° C. for 1 h. The reaction was quenched by cautious addition of 0.7 ml of water. Then approximately 1 g of anhydrous sodium sulfate were added to bind the water and the mixture was stirred vigorously for 5 min. The mixture was diluted by addition of 10 ml of methylenene chloride and filtered over Speedex filter aid which was washed with methylene chloride. The filtrate was concentrated in vaccuo and the residue (248 mg orange solid) was purified by flash chromatography (heptane/ethyl acetate 4:1) to yield the title compound (68.0 mg, 74%) as a crystalline white solid, MS (ISP): m/e=341.0, 343.0 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].N(CCO)(CCO)CCO.[C:16]1(=[O:21])[O:20][CH2:19][CH2:18][CH2:17]1>>[OH:21][CH2:16][CH2:17][CH2:18][C:19]([NH:2][CH2:3][CH2:4][SH:5])=[O:20]
Reactant: O=C1CCCO1
Reactant: NCCS
Agent: Cl
Solvent: OCCN(CCO)CCO
Product: O=C(CCCO)NCCS
Reaction time: 3 h

Procedure:
In a reactor there are introduced, at ambient temperature and under an inert atmosphere, 11.4 g of cysteamine hydrochloride and then slowly, with stirring, 13.5 cm3 of triethanolamine. To the resulting mixture, brought to a temperature of about 60° C., 7.7 cm3 of γ-butyrolactone are slowly added. At the end of the introduction the whole is brought to a temperature of 90° C. for three hours, at the end of which time all the γ-butyrolactone is transformed (VPC verification). 32 g of 4-hydroxy N-(2-mercaptoethyl) butyramide are obtained containing one equivalent of triethanolamine hydrochloride in the form of a pasty white solid that is conditioned under an inert atmosphere.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.C(S)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[CH2:10]([S:8][C:7]1[C:2]([Cl:1])=[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[N:4]=[C:5]([NH2:11])[N:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Reactant: SCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(SCc2ccccc2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, benzyl mercaptan and DBU in dioxane. ES-MS m/e (%): 320 (M{37Cl}+H+, 45), 318 (M{35Cl}+H+, 100).
Reaction SMILES: [OH:1][C:2]1[N:6]([CH:7](O)[CH3:8])[N:5]=[C:4]([CH3:10])[CH:3]=1.[OH:11][CH2:12][CH2:13][N:14]([CH2:23][CH2:24][OH:25])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C([OH:28])C>>[OH:25][CH2:24][CH2:23][N:14]([CH2:13][CH2:12][OH:11])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:3]2[C:4]([CH3:10])=[N:5][N:6]([CH2:7][CH2:8][OH:28])[C:2]2=[O:1])=[CH:17][CH:16]=1
Reactant: CCO
Reactant: Cc1cc(O)n(C(C)O)n1
Reactant: O=Cc1ccc(N(CCO)CCO)cc1
Product: CC1=NN(CCO)C(=O)C1=Cc1ccc(N(CCO)CCO)cc1

Procedure:
2.85 g of 5-hydroxy-1-hydroxyethyl-3-methyl-1H-pyrazole and 4-(di-(2-hydroxyethyl)amino)-benzaldehyde in ethanol were allowed to reflux for 4 hours. The reaction mixture was then evaporated, and the residue was caused to crystallize by addition of a small amount of isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.O1CCOCC1.[BH4-].[Na+].Cl>O.CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: OCc1ccc(Cl)cc1F
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
First, 25 g of 4-chloro-2-fluorobenzaldehyde was dissolved in a mixed solvent consisting of 250 ml of 1,4-dioxane and 25 ml of methanol, to which 2.4 g of sodium borohydride was added under ice cooling, and the mixture was stirred for 30 minutes. After completion of the reaction, a small amount of diluted aqueous hydrochloric acid was added, and the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 25 g of 4-chloro-2-fluorobenzyl alcohol.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:11]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25]OCCC(C)C)=[CH:21][CH:20]=2)=[CH:12][C@@H:13]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14]2)=[N:7][C:8]=1[O:9]C.C(=O)(O)[O-].[Na+].O>C(#N)C>[Br:1][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:11]([C:6]2[NH:7][C:8](=[O:9])[C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:12][C@H:13]2[CH2:14][CH2:15][C:16](=[O:18])[NH:17]2)=[CH:20][CH:21]=1
Reactant: COc1nc(C(=C[C@H]2CCC(=O)N2)c2ccc(COCCC(C)C)cc2)ccc1Cl
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1CC[C@H](C=C(c2ccc(CBr)cc2)c2ccc(Cl)c(=O)[nH]2)N1
Temperature: 70 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
48% hydrobromic acid (4 mL) was added to a solution of (5R)-5-[2-(5-chloro-6-methoxypyridin-2-yl)-2-{4-[(3-methylbutoxy)methyl]phenyl}ethenyl]pyrrolidin-2-one (E:Z=1:2 mixture) (396 mg) in acetonitrile (4 mL) at room temperature, and the mixture was stirred at 70° C. for three hours. Saturated aqueous sodium bicarbonate and water were sequentially added to the reaction solution at room temperature, followed by extraction with chloroform. The organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=50:1→5:1) to give 6-{1-[4-(bromomethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-chloropyridin-2(1H)-one (E:Z=1:2 mixture) (321 mg, 85%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:12]([NH:14][C@@H:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]([OH:18])=[O:17])=[O:13])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].C(OC([N:38]1[CH2:43][CH2:42][CH:41]([CH2:44]CN)[CH2:40][CH2:39]1)=O)(C)(C)C.C[N:48](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C>CN(C)C=O>[C:16]([OH:18])(=[O:17])[CH3:15].[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[C:12]([NH:14][C@@H:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16](=[O:18])[NH:48][CH2:44][CH:41]2[CH2:40][CH2:39][NH:38][CH2:43][CH2:42]2)=[O:13])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: N=C(N)c1ccc(CC(C(=O)N[C@H](C(=O)O)C2CCCCC2)C2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(=O)O
Product: N=C(N)c1ccc(CC(C(=O)N[C@H](C(=O)NCC2CCNCC2)C2CCCCC2)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (S)-[3-(4-carbamimidoyl-phenyl)-2-cyclohexyl-propionylamino]-cyclohexyl-acetic acid (50 mg, 0.12 mmol, less polar diastereomer, example 1 h) and 4-aminoethyl-piperidine-1-carboxylic acid tert-butyl ester (26 mg, 0.12 mmol) in dimethylformamide (5 ml) were added HATU (50 mg, 0.13 mmol) and collidine (16 mg, 0.13 mmol) at 0° C. The mixture was stirred for 1 hour and then allowed to warm to room temperature. The mixture was evaporated and treated with 2 ml of trifluoroacetic acid (containing 10% water) for 2 hours. After evaporation, the residue was purified by chromatography on Sephadex LH20 employing n-butanol (17): glacial acetic acid (1): water (2) as eluent. Pure fractions were combined. The solvent was evaporated, the residue was taken up in water, and the aqueous solution was lyophilized. Yield: 45 mg (59%), MS m/z: 510.5 (M+H)+, 255.8 (M+2H)2+.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[CH3:9].C(=O)([O-])[O-].[Na+].[Na+].[I:16]I.S([O-])([O-])=O.[Na+].[Na+].S([O-])([O-])=O>C1COCC1.CO>[NH2:1][C:2]1[CH2:7][CH2:6][CH:5]([I:16])[C:4](=[O:8])[C:3]=1[CH3:9]
Reactant: CC1=C(N)CCCC1=O
Reactant: II
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1=C(N)CCC(I)C1=O
Temperature: 10 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
50 g (0.4 mol, 1 eq) of 3-amino-2-methyl-2-cyclohexen-1-one and 106 g (1 ml, 2.5 eq) of sodium carbonate are dispensed into the reactor. 480 mL of MeOH is added. The mixture is cooled in an ice bath to 10° C. A solution of iodine in THF, made by dissolving 253 g (1 mol, 2.5 eq) of iodine in 300 ml of THF, is added to above suspension slowly so that the temperature does not exceed 25° C. The resulting dark suspension is stirred for ˜1 h at room temperature and HPLC shows the ending point of reaction (product area percentage at 265 nm was larger than 70%). To the reaction mixture in the ice bath, is added an aqueous saturated solution of sodium sulfite slowly, until the peroxide level is below 3 ppm (by peroxide test strips), and at same time, the sulfite level is below 50 ppm (by sulfite test strips). Approximately 1.5 q of sodium sulfite is used. The suspension is filtered through a celite pad and the pad is washed with 150 mL×3 of THF (washings not optimized). The combined filtrate and washes are concentrated under vacuum until solid crashes out. 250 mL of MTBE is added and the two layer mixture is concentrated again under vacuum until all upper layer evaporates. 250 mL of MTBE and 100 mL of H2O are added and the mixture is stirred at room temperature for 30 minutes. A dark yellow solid crashes out upon stirring and is filtered and washed with water to give 3-amino-6-iodo-2-methyl-2-cyclohexen-1-one 65 g (65% yield).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[F:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1
Reactant: COc1cccc(B(O)O)c1F
Reactant: Cc1oc(Br)cc1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2cc(C=O)c(C)o2)c1F
Reaction time: 8 h
Yield: 93.1 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.3 g), 2-fluoro-3-methoxyphenylboronic acid (1.4 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (9 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 30% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.5 g, 93%) as a yellow crystal.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3]([C:12](Cl)=[O:13])=[CH:2]1.[NH2:15][C:16]([NH2:18])=[O:17]>C1C=CC=CC=1.S(=O)(=O)(O)O>[O:11]=[C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:1][CH:2]=[C:3]1[C:12]([NH:15][C:16]([NH2:18])=[O:17])=[O:13]
Reactant: O=C(Cl)c1coc2ccccc2c1=O
Reactant: NC(N)=O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: NC(=O)NC(=O)c1coc2ccccc2c1=O
Yield: 63 %

Procedure:
A hot solution of 10.4 g (0.05 mol) of chromone-3-carbonylchloride in 150 ml of benzene was added over two minutes to a stirred boiling mixture of 3.6 g (0.06 mol) of urea, 100 ml of benzene and two drops of conc. sulfuric acid. The mixture was stirred at reflux for 2 hrs., cooled and filtered; wt 12.3 g; mp 200°-217°. Recrystallization from dimethylformamide gave 63% yield of pure product, mp 247°-250°.
Reaction SMILES: [OH:1][C@@H:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][NH:8][C:7](=[O:11])[C:6]=1[C:12]1[NH:13][C:14]2[C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1.[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH2:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH:35][C:21]([C:20]1[C:14]2[NH:13][C:12]([C:6]3[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=3[NH:4][CH2:3][C@@H:2]([OH:1])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:16][C:15]=2[CH:17]=[CH:18][CH:19]=1)=[O:22]
Reactant: NCc1cccc(F)c1
Reactant: O=C(O)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccc(F)c1)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 100 mL round-bottomed flask, 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid (0.84 g, 2.15 mmol), 3-fluoro-benzylamine (296 mg, 270 μL, 2.37 mmol) and DIEA (612 mg, 827 μL, 4.73 mmol) were combined with DMF (10 mL) to give a black solution and to this was added HATU (982 mg, 2.58 mmol). The reaction was stirred at room temperature overnight. The next day, the reaction was dripped into water and the resulting precipitate was filtered and washed with water, ethyl ether, and hexanes. The purple solid was incompletely dissolved in minimal boiling ethanol and the resulting solid that formed upon cooling was filtered and washed with ethanol and hexanes yielding 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid 3-fluoro-benzylamide as a light purple solid. LC/MS calcd for C28H24FN5O3 (m/e) 497.0, obsd 497.9 (M+H); 1H NMR (DMSO-d6-TFA) δ: 11.25 (br. s., 1H), 10.77 (br. s., 1H), 9.32 (t, J=5.8 Hz, 1H), 7.71-7.97 (m, 2H), 7.14-7.63 (m, 10H), 7.03-7.13 (m, 1H), 6.21 (d, J=7.5 Hz, 1H), 4.84 (br. s., 1H), 4.68 (br. s., 2H), 3.65 (d, J=12.5 Hz, 1H), 3.46 (d, J=7.0 Hz, 1H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[CH:7]=O.[CH3:9][NH2:10].[H][H]>O1CCCC1>[O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[CH2:7][NH:10][CH3:9]
Reactant: O=CC1CCC=CO1
Reactant: [H][H]
Reactant: CN
Solvent: C1CCOC1
Product: CNCC1CCC=CO1
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
3,4-Dihydro-2H-pyran-2-carbaldehyde (300 g, 2.68 mol) was dissolved in tetrahydrofuran (710 mL). Raney-Co catalyst (30 g, tetrahydrofuran moist) was added. Gaseous methyl amine (415.4 g, 13.4 mol) was transferred into the solution within 50 minutes (45° C.). Hydrogen (49.2 L) was added and the pressure adjusted to 100 bar and the solution was stirred for about 2 h at 100° C. The reaction vessel was cooled to room temperature, the gas removed and the solution degassed. The solution was concentrated under reduced pressure. The crude product (344.5 g) was distilled at reduced pressure to receive (3,4-Dihydro-2H-pyran-2-ylmethyl)-methyl-amine (289.8 g, 2.28 mol, 85% yield). Analytical data amine (3,4-Dihydro-2H-pyran-2-ylmethyl)-methyl-amine: Bp. 55-57° C. at 16 mbar; HPLC-MS: (M+H)+=128 at rt=0.619 min. (TIC), rt=0.596 min. (UV), rt=0.631 min. (ELS), Chromolith SpeedROD RP-18e 50-4.6 mm, solvent A: water+0.1% TFA, solvent B: acetonitrile+0.1% TFA, gradient: 4% solvent B at 0.0 min., 100% solvent B at 2.6 min., flow: 2.4 mL/min., UV: 220 nm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[BrH:11].BrBr>>[BrH:11].[Br:11][CH2:9][C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:10]
Reactant: CC(=O)c1cnccc1C
Agent: Br
Agent: BrBr
Product: Cc1ccncc1C(=O)CBr
Yield: 85 %

Procedure:
The title compound was synthesised according to Example 4 1-(4-methyl-pyridin-3-yl)-ethanone and HBr/bromine in 85% yield as grey solid. MS (m/e): 214.0 (M+H, 100%).
Reaction SMILES: C(N1CCN([CH2:14][CH2:15][CH2:16][N:17]2[CH:21]([CH3:22])[CH2:20][CH2:19][C:18]2=[O:23])CC1)C1C=CC=CC=1.CC1NC(=O)CC1.[H-].[Na+].[Br:33]CCCBr>O1CCCC1.O>[Br:33][CH2:14][CH2:15][CH2:16][N:17]1[CH:21]([CH3:22])[CH2:20][CH2:19][C:18]1=[O:23].[CH2:16]([N:17]1[CH:21]([CH3:22])[CH2:20][CH2:19][C:18]1=[O:23])[CH:15]=[CH2:14]
Reactant: CC1CCC(=O)N1CCCN1CCN(Cc2ccccc2)CC1
Reactant: BrCCCBr
Agent: CC1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCN1C(=O)CCC1C
Product: CC1CCC(=O)N1CCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[3-(4-Benzyl-1-piperazinyl)propyl]-5-methyl-2-pyrrolidinone A solution of 5-methyl-2-pyrrolidinone (0.99 g/10.0 mmol) in tetrahydrofuran (10 ml) was added to a suspension of sodium hydride(60% in oil, 0.6 g/1 5.0 mmol) in tetrahydrofuran (50 ml) at 0° C. and the resulting mixture was stirred for 1 hour at ambient temperature. To the mixture was added a solution of 1,3-dibromopropane (5.1 ml/50.0 mmol) in tetrahydrofuran (10 ml) and the mixture was stirred for 1 day. The mixture was poured into water (50 ml) and extracted with ethyl acetate (50 ml×2). The combined extracts were washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (Si, 230-400 mesh/dichloromethane:methanol=30:1) to give as a mixture of 1-(3-bromoproyl)-5-methyl-2-pyrrolidinone and 1-allyl-5-methyl-2-pyrrolidinone (0.8 g). The mixture was dissolved with ethanol (5 ml). To the solution was added 1-benzylpiperazine (0.4 mV/2.19 mmol), and the mixture was stand for 7 days. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (20 ml) and 2N-NaOH (20 ml). The aqueous layer was extracted with dichloromethane (20 ml). The combined extracts were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (Si, 230-400 mesh/dichloromethane:methanol=30:1-15:1) to give as the titled compound (0.59 g/19%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][C:24]1([OH:34])[CH2:33][CH2:32][C:27]2([O:31][CH2:30][CH2:29][O:28]2)[CH2:26][CH2:25]1>ClCCl.O>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:23][C:24]1([OH:34])[CH2:33][CH2:32][C:27]3([O:31][CH2:30][CH2:29][O:28]3)[CH2:26][CH2:25]1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCC1(O)CCC2(CC1)OCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a 0° C. solution of 4-chloro-3-nitroquinoline (7.50 g, 36.0 mmol) and triethylamine (7.5 mL, 54 mmol) in dichloromethane (150 mL) was added 8-(aminomethyl)-1,4-dioxaspiro[4.5]decan-8-ol (8.10 g, 43.1 mmol). The reaction was allowed to warm to rt and stir overnight, then was concentrated under reduced pressure to yield a yellow solid. The solid was stirred in water (500 mL) and was isolated by filtration, dried under vacuum, and recrystallized from toluene (280 mL) to yield 8-{[(3-nitroquinolin-4-yl)amino]methyl}-1,4-dioxaspiro[4.5]decan-8-ol as bright yellow crystals (12.3 g, 72%).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]([C:28]1[N:32](COCC[Si](C)(C)C)[C:31]2[CH:41]=[CH:42][C:43]([C:45]#[N:46])=[CH:44][C:30]=2[N:29]=1)([O:26][CH3:27])[C:4]1[C:12]([S:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].FC(F)(F)C(C1N(COCC[Si](C)(C)C)C2C=C(C#N)C=CC=2N=1)(OC)C1C(SC)=CC(C)=C2C=1C=CN2S(C1C=CC(C)=CC=1)(=O)=O.Cl>>[F:48][C:2]([F:1])([F:47])[C:3]([C:28]1[NH:32][C:31]2[CH:41]=[CH:42][C:43]([C:45]#[N:46])=[CH:44][C:30]=2[N:29]=1)([O:26][CH3:27])[C:4]1[C:12]([S:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=1)(=[O:18])=[O:17]
Reactant: COC(c1c(SC)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: COC(c1c(SC)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: Cl
Product: COC(c1nc2cc(C#N)ccc2[nH]1)(c1c(SC)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Temperature: 60 °C

Procedure:
To a mixture of (±)-2-(2,2,2-trifluoro-1-methoxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(2,2,2-trifluoro-1-methoxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (265 mg, 0.371 mmol) was added HCl (1.25M in MeOH, 2.9 mL, 3.71 mmol) and the mixture was stirred at 60° C. After 20 minutes the reaction was cooled to room temperature, concentrated and basified with aq. NH4OH. The mixture was further diluted with MeOH. The resulting residue was purified directly by flash chromatography (0-80% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 585.1 (M+H).