Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([Cl:15])[N:9]=1)[CH3:2].Cl[C:19](OCC)=[O:20].Cl>>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][N:7]1[C:8]2[N:9]=[C:10]([Cl:15])[CH:11]=[CH:12][C:13]=2[N:14]=[C:19]1[OH:20])[CH3:17]
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CCCNc1nc(Cl)ccc1N
Agent: Cl
Product: CCN(CC)CCCn1c(O)nc2ccc(Cl)nc21

Procedure:
The production was carried out in a manner analogous to Example 1 from 20 grams of 2-(3-diethylamino-propylamino)-3-amino-6-chloropyridine and 9 ml of ethyl chloroformate. M.P. of the hydrochloride of the title compound was 203°-205° C.; yield: 14 grams.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>CN1C(=O)CCC1>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
A solution of N-benzyl-5-bromo-2-nitrobenzenamine (100 mg, 0.32 mmol) and 1-methylpiperazine (65 mg, 0.65 mmol) in NMP (1 mL) was heated to 110° C. for 16 h. The solution was cooled to room temperature to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 2 mL of water, dried (high vacuum, 14 h) to furnish N-benzyl-5-(4-methylpiperazin-1-yl)-2-nitrobenzenamine (73 mg, 0.22 mmol), 69% yield. 1H NMR (500 MHz, DMSO-D6) d (ppm) 8.81 (m, 1H), 7.90 (d, J=9.5 Hz, 1H), 7.44-7.34 (m, 4H), 7.30-7.25 (m, 1H), 6.41 (dd, J=2.5 Hz, 10 Hz, 1H), 5.97 (d, J=2.5 Hz, 1H), 4.58 (d, J=6 Hz, 2H) 3.4-3.2 (m, 4H), 2.34 (m, 4H), 2.19 (s, 3H).+ESI HRMS (calcd for C18H23N4O2, M+1) 327.1821, found 327.1816
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[N:12]=2)[NH:7][CH:6]=1)#[CH:4].[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>CN(C=O)C>[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[CH:18][CH:19]=3)[N:12]=2)[N:7]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:6]=1)#[CH:4]
Reactant: C#Cc1c[nH]c2ncc(-c3ccc(S(=O)(=O)C(C)C)cc3)nc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#Cc1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(S(=O)(=O)C(C)C)cc3)nc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 60% dispersion of sodium hydride in mineral oil (19.79 mg, 0.5164 mmol) was added slowly to a stirred solution of 7-ethynyl-2-(4-isopropylsulfonylphenyl)-5H-pyrrolo[2,3-b]pyrazine (140 mg, 0.4303 mmol) in DMF (1.2 mL) at 0° C. The reaction mixture was stirred at this temperature for 20 minutes then tosyl chloride (82.04 mg, 0.4303 mmol) was added and reaction mixture allowed to warm to ambient temperature over 16 hours. The reaction mixture was quenched by the slow addition of water (30 mL) and the mixture stirred for 20 minutes. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated form DCM/diethyl ether and the resultant precipitate isolated by filtration to give the sub-tile compound as an off-white solid (112.6 mg, 59% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.19 (d, 6H), 2.37 (s, 3H), 3.45-3.50 (m, 1H), 4.55 (s, 1H), 7.49 (d, 2H), 8.01 (d, 2H), 8.08 (d, 2H), 8.41 (d, 2H), 8.75 (s, 1H) and 9.22 (s, 1H) ppm; MS (ES+) 480.0.
Reaction SMILES: [Na].[C:2]1([C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH3:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]1[CH2:19][CH:18]=[CH:17][CH:16]=1.O>CO>[CH3:12][C:11]1[CH:10]=[CH:9][C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:15]2[C:16]=1[CH:17]=[CH:18][CH2:19]2
Reactant: C1=CCC=C1
Reactant: CC(=O)CCC(=O)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2ccccc2)c2c1C=CC2
Temperature: 0 °C

Procedure:
5 g (0.21 mol}of sodium were dissolved in 100 ml of methanol in a Schlenk tube and the solution was cooled to 0° C. A mixture of 15.8 g (0.84 mol) of 1-phenyl-1,4-pentanedione and 7.3 ml (5.8 g, 0.08 mol) of cyclopentadiene was added dropwise in the course of 15 minutes. The red solution was stirred at room temperature overnight, hydrolyzed with 200 ml of water and extracted five times with 75 ml of petroleum ether each time. The combined organic extracts were filtered and concentrated to dryness and the residue was subjected to fractional distillation.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=O>O>[CH3:7][C:8](=[CH:9][CH2:10][CH2:1][C:2](=[CH:3][CH:4]=[O:5])[CH3:6])[CH3:12]
Reactant: CC(C)=CC=O
Reactant: CC(C)=CCO
Solvent: O
Product: CC(C)=CCCC(C)=CC=O
Temperature: 140 °C
Yield: 76 %

Procedure:
Air is blown for five minutes through a mixture of 100 parts of 3-methyl-2-buten-1-ol (prenol) and 100 parts of 3,3-dimethylacrolein. The reaction mixture containing peroxide is then heated for six hours at 140° C. The water formed in the reaction is removed continuously by injecting pentane into the reaction chamber. The reaction product is worked up by distillation. 59.2 parts of citral having a boiling point of 103° to 106° C. at 12 mm is obtained, equivalent to a yield of 76% of theory based on 3,3-dimethylacrolein at a conversion of 43%.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][O:8][CH3:9])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([CH3:24])[CH:16]=1.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:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[O:6][C:5]([CH2:7][O:8][CH3:9])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=2)=[C:17]([CH3:24])[CH:16]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: COCc1oc(Br)cc1C(=O)OC
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: COCCOC
Solvent: O
Product: COCc1oc(-c2ccc(F)cc2C)cc1C(=O)OC
Yield: 93.1 %

Procedure:
A mixture of methyl 5-bromo-2-(methoxymethyl)-3-furancarboxylate (2.5 g), 4-fluoro-2-methylphenylboronic acid (1.9 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight 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 20% ethyl acetate/hexane) to give the title compound (2.6 g, 92%) as an oil.
Reaction SMILES: [Mg].II.[CH:4]1(Br)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:11][N:12]1[CH2:35][CH2:34][C:15]2[N:16]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[O:26])[C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][C:22]=3[C:14]=2[CH2:13]1.C1([Mg]Br)CCCCC1>C1COCC1>[CH:4]1([C:25]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)([OH:26])[CH2:24][N:16]2[C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][C:22]=3[C:14]3[CH2:13][N:12]([CH3:11])[CH2:35][CH2:34][C:15]2=3)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: BrC1CCCCC1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)c2ccc(F)cc2)CCN(C)C1
Agent: Br[Mg]C1CCCCC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(O)(c2ccc(F)cc2)C2CCCCC2)CCN(C)C1
Reaction time: 0.25 h

Procedure:
Activated magnesium turnings (480 mg, 20 g/atom) and 2-3 crystals of iodine were stirred under anhydrous conditions. The excess of iodine was removed by heating with a heat gun. The magnesium turnings were now yellow in color. To this was added diethyl ether (15 mL) at 0° C. and stirred for 15 min (until the color of the magnesium becomes white). To this was added cyclohexyl bromide (2.5 mL, 20 mmol) dropwise with constant stirring. The reaction mixture was stirred until a dark grey-colored solution was obtained. Into a separate flask was placed 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethanone (168 mg, 5 mmol) in THF under anhydrous conditions. The solution of the prepared cyclohexylmagnesium bromide (5 mL) was added dropwise. After addition, the mixture was allowed to come to RT and stirred at RT for 2 h. The reaction was monitored by TLC and NMR. The reaction was quenched with ice water and the product extracted into EtOAc. The organic extracts were concentrated and the residue purified by silica gel column chromatography (#100-200 mesh) using 0-3% MeOH:DCM as eluent. The compound was further purified by HPLC. 1HNMR (CD3OD, TFA salt) d (ppm): 7.25 (m, 2H), 7.10 (d, 1H), 6.92 (m, 1H), 6.80 (m, 3H), 4.60 (m, 1H), 4.65 (m, 1H), 4.22 (m, 2H), 3.70 (m, 1H), 3.40 (m, 1H), 3.20 (m, 2H), 3.0 (s, 3H), 2.70 (m, 1H), 2.38 (s, 3H), 2.20 (m, 2H), 1.80 (m, 2H), 1.70 (m, 3H), 1.50-1.20 (m, 4H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:19]O>>[I:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: Cc1ccc(I)c(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc(C)ccc1I
Temperature: 16 °C
Yield: 98 %

Procedure:
A visually clean 100 L flask equipped with a mechanical stirrer thermocouple and water chilled condenser was charged with MeOH (50 L). 2-iodo-5-methylbenzoic acid (5.85 kg, 22.32 mol) was then added while stirring. Concentrated sulfuric acid (0.595 L, 11.16 mol) was then added portion-wise which caused an increase in temperature from 17° C. to 22° C. This mixture was gradually brought to an internal temperature of 64.6° C. and aged overnight (˜18 h). The next morning the reaction had reached >98% conversion by HPLC. The flask was cooled to 16° C. by placing in an ice bath and 850 mL of 10 N NaOH (0.98 equiv.) was added slowly (over 10 minutes) while monitoring the pH. After the addition the pH was 5-6 (caution: bringing pH over 9 can result in saponification during the work-up). The solution was then concentrated to about 16 L and this suspension was transferred to a 100 L extractor. The flask was rinsed with 8 L of IPAc and 4 L of water which were also transferred to the extractor. 32 L of IPAc were added along with 10 L of 5 w % NaHCO3 and 10 L of 15 w % Brine. The layers were cut and the aqueous layers were back-extracted with 20 L of IPAc. The organic layers were then combined and washed with 10 L of 15 w % Brine. The organic layers were collected to provide B-1 (6.055 kg, 2193 mol, 98% yield) in 98.3% purity. 1H NMR (500 MHz, CDCl3, 293K, TMS): 7.84 (1 H, d, =8.07 Hz), 7.62 (1 H, d, J=2.14 Hz), 6.97 (1 H, dd, J=8.08, 2.14 Hz), 3.97-3.86 (3 H, m), 2.33 (3 H, s).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][C:12]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1)=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.[Sn:29](Cl)([CH3:32])([CH3:31])[CH3:30]>C(OCC)C.C1COCC1>[CH3:23][C:18]1[CH:17]=[C:16]([C:12]2[CH:13]=[CH:14][C:15]3[C:10]([CH:11]=2)=[N:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:2]=3[Sn:29]([CH3:32])([CH3:31])[CH3:30])[CH:21]=[C:20]([CH3:22])[CH:19]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1cc(C)cc(-c2ccc3c(Br)c4ccccc4nc3c2)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2ccc3c([Sn](C)(C)C)c4ccccc4nc3c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
A solution of 9-bromo-3-(3,5-dimethylphenyl)acridine, 29, (0.6 g, 1.6 mmol) in 10 ml anhydrous diethyl ether:THF (1:1) was cooled to −78° C. To the solution was added 1.6 M n-BuLi in hexanes (2.4 mmol, 1.5 mL) dropwise over a period of 15 min and then a 1.0 M solution of Me3SnCl in hexanes (3 mL, 3 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 18 hours and concentrated in vacuo. Purification of the orange residue by flash chromatography (100:30:1 hexanes:ethyl acetate:triethylamine) afforded 30 (0.65 g, 91%) as a yellow solid. GC-MS revealed contamination of the product with 5-10% 3-(3,5-dimethylphenyl)acridine that could not be separated by chromatography. The stannane was therefore employed in the Stille cross-coupling with 1,8-dibromonaphthalene without filter purification. 1H-NMR δ=0.70 (s, 9H), 2.44 (s, 6H), 7.08-7.10 (m, 1H), 7.49-7.56 (m, 3H), 7.76 (ddd, J=1.4 Hz, 6.6 Hz, 8.8 Hz, 1H), 7.88 (dd, J=1.9 Hz, 9.1 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H), 8.22 (d, J=9.1 Hz, 1H), 8.27 (d, J=8.5 Hz, 1H), 8.49 (m, 1H). 13C-NMR δ=−4.2, 21.8, 125.3, 125.4, 125.5, 127.7, 129.6, 129.8, 130.1, 130.4, 130.8, 132.8, 133.5, 138.4, 139.8, 142.0, 148.2, 148.2, 156.4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])([O-:3])=[O:2].[C:17]1([N:27]=[C:28]=[S:29])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>ClCCl>[C:17]1([NH:27][C:28]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:6]2[CH:14]=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[S:29])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: S=C=Nc1cccc2ccccc12
Reactant: NCCCCCOc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(OCCCCCNC(=S)Nc2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of 5-(3-nitro-phenoxy)-pentylamine (867 mg, 3.87 mmol) in dichloromethane (5 mL) was added 1-naphthyl isothiocyanate (788 mg, 4.26 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. After removal of the solvent, the residue was purified by silica gel column chromatography to give 1-naphthalen-1-yl-3-[5-(3-nitro-phenoxy)-pentyl]-thiourea (1.3 g, 3.18 mmol, 82%) as a yellow gel.
Reaction SMILES: ClC(N(C)C)=C(C)C.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[C:17]1[S:18][CH:19]=[C:20]([C:22]([OH:24])=O)[N:21]=1.[NH2:25][C:26]1[C:27]([N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:36]2)=[C:28]2[S:34][CH:33]=[CH:32][C:29]2=[N:30][CH:31]=1.N1C=CC=CC=1>C(Cl)Cl>[F:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[C:11]=1[C:17]1[S:18][CH:19]=[C:20]([C:22]([NH:25][C:26]2[C:27]([N:35]3[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:36]3)=[C:28]3[S:34][CH:33]=[CH:32][C:29]3=[N:30][CH:31]=2)=[O:24])[N:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3ccsc23)C1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3ccsc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A solution of 1-chloro-N,N,2-trimethylpropenylamine (68.8 mg, 0.515 mmol) in DCM (1.0 mL) was added slowly to a suspension of 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 2, step 2, 45.4 mg, 0.188 mmol) in DCM (0.5 mL). The mixture was stirred at room temperature for 2 h. A solution of tert-butyl [(3S)-1-(6-aminothieno[3,2-b]pyridin-7-yl)piperidin-3-yl]carbamate (58.8 mg, 0.169 mmol) in DCM (2.0 mL) was then added, followed by pyridine (123.7 mg, 1.564 mmol) and the mixture was stirred at room temperature for a further 2 h. The mixture was concentrated under reduced pressure and the resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a pale yellow oil (92.2 mg, 96%). LCMS calc. for C27H28F2N5O3S2 (M+H)+: m/z=572.2. found 572.2.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.Cl[CH2:12]/[CH:13]=[CH:14]\[CH2:15]Cl>>[C:4]1([C@@H:7]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12]2)[CH2:8][OH:9])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: ClC/C=C\CCl
Product: OC[C@@H](c1ccccc1)N1CC=CC1
Yield: 58 %

Procedure:
This was prepared from R-(−)-2-phenylglycinol and cis-1,4-dichloro-2-butene in 58% yield according to the procedures similar to those described in Preparation 1,
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=[N:15][OH:16])=[N:5][O:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Cl.O>CN(C=O)C>[CH3:1][NH:2][C:3](=[O:17])[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=[N:15][O:16][CH2:28][C:27]1[CH:30]=[CH:31][CH:32]=[C:25]([Cl:24])[CH:26]=1)=[N:5][O:6][CH3:7]
Reactant: ClCc1cccc(Cl)c1
Reactant: CNC(=O)C(=NOC)c1ccccc1C=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1C=NOCc1cccc(Cl)c1
Temperature: 110 °C
Yield: 58.7 %

Procedure:
To a solution of 1 g (4.26 mmol) of N-methyl-2-{2-(hydroxyiminomethyl)phenyl}-2-methoxyiminoacetamide and 0.62 g (4.5 mmol) of potassium carbonate in 10 ml of DMF, was added 0.69 g (4.29 mmol) of 3-chlorobenzyl chloride and the mixture was stirred under heating at 110° C. for 3 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, successively washed with water and a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was chromatographed over SiO2 to give 0.9 g of the title compound (yield: 58.8%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:11]=1)([O-])=O>CC(O)=O.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1C1C=C(c2ccncc2[N+](=O)[O-])CCC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cnccc1C1CCCC(N2C(=O)c3ccccc3C2=O)C1

Procedure:
A solution of 2-[3-(3-nitropyridin-4-yl)cyclohex-2-en-1-yl]-1H-isoindole-1,3(2H)-dione (0.100 g, 0.286 mmol) in AcOH (3.0 mL) was mixed with 10% Pd on carbon (0.046 g, 0.043 mmol) and hydrogenated at 30 psi for 16 h. The reaction mixture was diluted in MeOH (50 mL), filtered and concentrated under vacuum. The residue was dissolved in EtOAc and washed with 1 M NaOH. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the sub-title compound. LCMS calc. for C19H20N3O2 (M+H)+: m/z=322.2. Found: 322.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:12]=[CH:13][C:14]2[O:18][CH:17]=[CH:16][C:15]=2[CH:19]=1.C(N(CC)CC)C>CCO>[O:18]1[C:14]2[CH:13]=[CH:12][C:11]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:19][C:15]=2[CH:16]=[CH:17]1
Reactant: OB(O)c1cccnc1
Reactant: Brc1ccc2occc2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1cncc(-c2ccc3occc3c2)c1
Yield: 63.7 %

Procedure:
A solution of 5 pyridin-3-ylboronic acid (390 mg, 3.18 mmol), 5-bromobenzofuran (500 mg, 2.54 mmol), palladiumdichlorobis(triphenylphosphine) (111 mg, 0.16 mmol) and triethylamine (8.8 mL, 63.5 mmol) in EtOH was irradiated in the microwave at 100° C. for 1200 s. Removal of the solvents followed by dissolving in CH2Cl2 and filtering gave the residue after concentration of the solvent under reduced pressure. The compound was purified on ISCO to afford 316 mg of the title compound as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.60 (d, 1H), 7.90 (d, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.55 (d, 1H), 7.50 (d, 1H) 7.38 (dd, 1H), 6.85 (dd, 1H). MS (ESI) m/z: Calculated: 195.07; Observed: 196.30 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#N)=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1.C([O-])(=[O:14])C.[Na+].CO>[Ni].O>[Cl:1][C:2]1[C:7]([CH:8]=[O:14])=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc(C#N)c(Cl)nc1C
Reactant: CC(=O)[O-]
Agent: [Ni]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(C=O)c(Cl)nc1C
Yield: 60.5 %

Procedure:
A mixture of 2-chloro-3-cyano-5,6-dimethylpyridine (21.5 g) semicarbazide hydrochloride (24.0 g), sodium acetate (42.3 g), water (225 ml) and methanol (475 ml) was hydrogenated at 344 kPa at 50° using Raney nickel catalyst (5 g). The mixture was added to water (750 ml) and filtered. The solid filtered off was suspended in water (130 ml) and concentrated hydrochloric acid (70 ml) was added and the mixture was heated at 100° for 1 hour, formalin (40% w/w, 120 ml) was added and the mixture was heated at 100° for a further 0.5 hour and allowed to cool. Sodium acetate (95 g) and water (250 ml) were added and the mixture was extracted with ether and the extracts were washed with 5% aqueous potassium carbonate and evaporated to give 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde (13.24 g, 60%) m.p. 69°-70°.
Reaction SMILES: [CH3:1][C@:2]1([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:9][CH2:8][CH2:7][C@:4]2([O:6][CH2:5]2)[CH2:3]1.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[CH:26][C:25]=1[NH2:32]>C(O)(C)C>[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[CH:26][C:25]=1[NH:32][CH2:5][C@:4]1([OH:6])[CH2:7][CH2:8][CH2:9][C@@:2]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)([CH3:1])[CH2:3]1
Reactant: COc1cc(OC)c(N)cn1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CO2)C1
Solvent: CC(C)O
Product: COc1cc(OC)c(NC[C@]2(O)CCC[C@](C)(Cn3cnc4ccc(C#N)cc43)C2)cn1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A mixture of 1-(((3S,5S)-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.355 mmol) and 4,6-bis(methyloxy)-3-pyridinamine (110 mg, 0.711 mmol) in isopropanol (10 mL) was heated to reflux overnight. The reaction mixture was cooled to RT, and solvent was removed. The residue was redissolved in DCM and hexane was added. The solvent was removed, and the residue was purified via silica gel chromatography (ISCO, 40 g Silica, 40 mL/min, 0%-10% MeOH/CH2Cl2). Fractions with product were collected and concentrated to afford 1-(((1S,3S)-3-(((4,6-dimethoxypyridin-3-yl)amino)methyl)-3-hydroxy-1-methylcyclohexaneyl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 64.6% yield). MS (m/z) 436 (M+H+).