Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][NH2:15])[CH3:11].Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][NH:15][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:9])[CH3:11]
Reactant: CCOC(CN)OCC
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(CNC(=O)c1ccc(Cl)s1)OCC
Temperature: 4 °C
Yield: 64.8 %

Procedure:
Add 5-chlorothiophene-2-carboxylic acid (100 g, 0.60 mol) and dichloromethane (1000 mL) to a 3 L three-necked round bottom flask equipped with an overhead stirrer, nitrogen inlet/outlet, addition funnel, and thermocouple. Stir the resulting solution under nitrogen while cooling to 4° C. Add via addition funnel 2,2-diethyoxyethylamine (88.5 ml, 0.60 mol) in dichloromethane (35 mL) over 12 min. Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (123 g, 0.64 mol) to the chilled mixture. Add additional dichloromethane (165 mL) and stir the reaction mixture for 22 h at RT. Quench the reaction with water (1000 mL) and separate the resulting layers. Back extract the aqueous layer with dichloromethane (500 mL) and combine the organic layers. Dry over sodium sulfate and purify through a silica gel bed eluting with dichloromethane followed by a mixture of 1% MeOH in dichloromethane and then a mixture of 10% MeOH in dichloromethane to afford 108 g (65%) of the title compound as a white solid. 1H NMR (500 MHz, CDCl3): δ 1.19 (t, J=7.5 Hz, 6H), 3.48-3.57 (m, 4H), 3.68-3.74 (m, 2H), 3.68-3.74 (m, 2H), 6.37 (bs, 1H), 6.85 (d, J=3.5 Hz, 1H), 7.26 (d, J=3.5 Hz, 1H).
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:7]=[CH:8][C:9]([F:12])=[N:10][CH:11]=1)[CH3:5])=[N+]=[N-]>C(O)C.O=[Pt]=O>[F:12][C:9]1[N:10]=[CH:11][C:6]([CH:4]([NH2:1])[CH3:5])=[CH:7][CH:8]=1
Reactant: CC(N=[N+]=[N-])c1ccc(F)nc1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(N)c1ccc(F)nc1
Yield: 91.4 %

Procedure:
Hydrogenate 5-(1-azido-ethyl)-2-fluoro-pyridine (4.09 g, 24.59 mmol) under a 60 psi pressure in ethanol (200 mL) in presence of PtO2 (6% w/w). Filter the mixture after 4 hours, remove the solvent on a rotovap, and dry the resulting oil under vacuum to obtain the product (3.149 g). GCMS (EI) m/z 140 M+.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:30]3[CH2:31][CH2:32][N:27]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:28][CH2:29]3)=[N:10][C:4]=2[CH:3]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)N=C(N1CCN(Cc3ccccc3)CC1)c1cccc3c1N2CC3
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 7.88 g (0.0250 mole) of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine-6-one and 1200 ml of toluene was heated under nitrogen until a solution resulted. Then there was added 44.1 g (0.250 mole) of N-benzylpiperazine, followed by 14.2 g (0.0750 mole) of titanium tetrachloride. The mixture was heated under reflux for 3 hours, cooled to room temperature and treated with 500 ml of 2N sodium hydroxide. After stirring vigorously for 15 minutes, the layers were separated. The aqueous phase was extracted further with 300 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was taken up in 50 ml of hot methanol, from which 7.00 g (59%) of product crystallized. Recrystallization from a solution of dichloromethane (10 ml) to which methanol (50 ml) was added afforded the analytical sample, mp 129°-131° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:15]([O:14][C:10](=[O:13])[CH:11]=[CH:12][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([F:1])[CH:7]=1)[CH3:16]
Reactant: Oc1ccc(Br)cc1F
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc(O)c(F)c1
Temperature: 25 °C

Procedure:
A solution of 2-fluoro-4-bromophenol 15-1 (50 g, 261.8 mmol), ethyl acrylate (34 mL), Pd(OAc)2 (2.5 g), tri-o-tolylphosphine (5 g) and triethylamine (83 mL) was heated to 100° C. in a sealed tube for 12 h. The reaction was cooled to room temperature and diluted with dichloromethane (100 mL). The organic solution was washed with 10% aq. citric acid (40 mL), satd aq NaHCO3, and brine (40 mL). The organic solution was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (50:50 hexanes/EtOAc to 100% EtOAc) to give acrylic acid 15-2 as a white solid.
Reaction SMILES: [I:1][C:2]1[C:3]([NH:11]C(=O)C)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[OH-].[Na+]>C(O)C.O>[I:1][C:2]1[C:3]([NH2:11])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CC(=O)Nc1cc2c(cc1I)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc2c(cc1I)OCO2
Reaction time: 4 h
Yield: 98.5 %

Procedure:
A solution of N-(6-iodobenzo[d][1,3]dioxol-5-yl)acetamide (200 mg, 0.656 mmol) and NaOH (1.31 g, 32.8 mmol) in ethanol (26 mL) and water (6 mL) was heated to reflux with stirring for 4 h. The mixture was cooled and the solvent was removed under vacuum. The residue was partitioned between methylene chloride (100 mL) and water (100 mL). The organic layer was washed with water (2×100 mL), dried (MgSO4) and evaporated under vacuum to give 6-iodobenzo[d][1,3]dioxol-5-amine (170 mg, 98%) as orange solid. LCMS: 264 [M+1]+; 1H NMR (DMSO-d6) δ 4.88 (s, 2H), 5.87 (s, 2H), 6.47 (s, 1H), 7.07 (s, 1H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)[CH:5]=[CH:4][N:3]=[CH:2]1>C(O)C.[C].[Pd]>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccccc1NCCCn1ccnc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.7 %

Procedure:
10% of palladium-carbon (0.804 g) was added to a solution containing N-[3-(1H-imidazol-1-yl)propyl]-2-nitroaniline (4.000 g) in ethanol (40 ml) and stirred for 4.5 hours under a hydrogen gas atmosphere at room temperature. After the catalyst was removed out by filtration, the filtrate was concentrated, thereby yielding the entitled compound (3.503 g) as black solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH3:14])[C:11](=[O:15])[N:10]([CH3:16])[CH2:9]2)=[CH:4][C:3]=1[C:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.[C:24]([C:26]1[CH:27]=[C:28]([C:31](O)=[O:32])[NH:29][CH:30]=1)#[N:25].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:17]1([C:3]2[CH:4]=[C:5]([CH:8]3[CH2:9][N:10]([CH3:16])[C:11](=[O:15])[N:12]([CH3:14])[CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:31]([C:28]2[NH:29][CH:30]=[C:26]([C:24]#[N:25])[CH:27]=2)=[O:32])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: N#Cc1c[nH]c(C(=O)O)c1
Reactant: CN1CC(c2ccc(N)c(C3=CCCCCC3)c2)CN(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CC(c2ccc(NC(=O)c3cc(C#N)c[nH]3)c(C3=CCCCCC3)c2)CN(C)C1=O
Yield: 14 %

Procedure:
A mixture of 5-(4-amino-3-cyclohept-1-enyl-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-one (as prepared in Example 9, step (a), 21 mg, 0.067 mmol), 4-cyanopyrrolecarboxylic acid (Canadian J. Chem. 59: 2673 (1981)). (24.6 mg, 0.180 mmol), EDCI (19.4 mg, 0.101 mmol), HOBt (9.2 mg, 0.068 mmol), DIEA (35 μL, 0.20 mmol) in DCM (0.5 mL) was stirred at RT overnight. The reaction mixture was concentrated in vacuo and the residue was purified RP-HPLC eluting with 20% to 100% CH3CN in 0.1% TFA/H2O over 20 min on a C18 column to obtain the title compound (4.2 mg, 14%): 1H-NMR (CD3OD; 400 MHz): δ 7.58 (d, 1H, J=1.5 Hz), 7.44 (d, 1H, J=8.2 Hz), 7.15-7.24 (m, 3H), 5.93 (t, 1H, J=6.5 Hz), 3.38-3.61 (m, 5H), 2.96 (m, 6H), 2.48 (m, 2H), 2.28 (m, 2H), 1.82 (m, 2H), 1.45-1.23 (m, 4H); Mass spectrum (ESI, m/z): Calcd. for C25H29N5O2, 432.2 (M+H). found 432.2.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([SH:26])[CH:23]=[CH:24][CH:25]=1>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[C:3](=[O:4])[CH2:2][S:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=2)=[CH:11][CH:12]=1
Reactant: COc1cccc(S)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CBr
Product: COc1cccc(SCC(=O)c2c(C)noc2-c2ccc(Br)cc2)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 2-bromo-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanone and 3-methoxy-benzenethiol.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[S:12])[N:8]([CH2:13][CH2:14][O:15][CH3:16])[C:7]2=[O:17].[C:18]([O-])([O-])=O.[K+].[K+].CI>C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH3:18])[N:8]([CH2:13][CH2:14][O:15][CH3:16])[C:7]2=[O:17]
Reactant: O=C([O-])[O-]
Reactant: COCCn1c(=S)[nH]c2c(I)cccc2c1=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COCCn1c(SC)nc2c(I)cccc2c1=O
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
A sealable flask was charged with 2-amino-3-iodobenzoic acid (5.02 g, 19.09 mmol) and 2-methoxyethyl isothiocyanate (3.35 g, 28.6 mmol) in tBuOH (30 mL) followed by TEA (3.98 mL, 28.6 mmol). The flask was sealed and heated in an oil bath at 100° C. for 4 h with a blast shield. The reaction mixture was cooled to RT and the off white solid was filtered, rinsed with 2×25 mL of ether and dried to give 8-iodo-3-(2-methoxyethyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (6.21 g, 17.15 mmol, 90% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (1H, s), 8.26 (1H, dd, J=7.6, 1.2 Hz), 8.00 (1H, dd, J=7.9, 1.3 Hz), 7.17 (1H, t, J=7.7 Hz), 4.60 (2H, t, J=6.5 Hz), 3.65 (2H, t, J=6.6 Hz), 3.31 (3H, s). m/z (ESI, +ve) 362.8 (M+H)+. To a 500-mL round-bottomed flask was added sequentially 8-iodo-3-(2-methoxyethyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (6.01 g, 16.59 mmol), THF (75 mL K2CO3 (5.73 g, 41.5 mmol), and MeI (2.06 mL, 33.2 mmol). The reaction mixture was heated in an oil bath at 65° C. for 6 h. The mixture was concentrated to half of its volume, poured into ice/water (100 mL) and stirred for 10 min. The suspension was filtered and the solid was washed with cold water (20 mL) and cold ether (20 mL). The off-white solid was dried to give 8-iodo-3-(2-methoxyethyl)-2-(methylthio)quinazolin-4(3H)-one (715a; 4.91 g). The filtrate was extracted with 50 mL of EtOAc. The EtOAc layer was concentrated and the brown solid was stirred in 5 mL of ether and 5 mL of hexanes. The solid was filtered and dried to give 8-iodo-3-(2-methoxyethyl)-2-(methylthio)quinazolin-4(3H)-one (715a; 1.1 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.34 (1H, dd, J=7.6, 1.4 Hz), 8.09 (1H, dd, J=7.9, 1.3 Hz), 7.22 (1H, t, J=7.7 Hz), 4.25 (2H, t, J=6.2 Hz), 3.65 (2H, t, J=6.2 Hz), 3.30 (3H, s), 2.75 (3H, s). m/z (ESI, +ve) 376.7 (M+H)+.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6]([C:9]1[CH:14]=[C:13]([SH:15])[CH:12]=[C:11]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=1[OH:20])([CH3:8])[CH3:7].Cl[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>C(O)C>[CH3:17][C:16]([C:11]1[CH:12]=[C:13]([S:15][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:14]=[C:9]([C:6]([CH3:5])([CH3:7])[CH3:8])[C:10]=1[OH:20])([CH3:19])[CH3:18]
Reactant: CCCCCCl
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of freshly prepared sodium ethoxide (ca. 17 mmole) in ethanol (12 ml) was added with stirring 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (4.0 g, 17 mmole). After one hour, 1-chloropentane (4 ml, ca. 34 mmole) was added and the reaction mixture was stirred at room temperature for 20 hours. Water was added, and the mixture was extracted with diethyl ether. The ether layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. Chromatography on silica gel and recrystallization from pentane gave the title compound, m.p. 54°-55°.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:9]=[C:8]([S:10][CH3:11])[NH:7][N:6]=1.[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17]>C(Cl)Cl>[CH3:11][S:10][C:8]1[N:9]=[C:5]2[CH2:4][C:3]3[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=3[NH:1][C:16](=[O:17])[N:6]2[N:7]=1
Reactant: CSc1nc(Cc2ccccc2N)n[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CSc1nc2n(n1)C(=O)Nc1ccccc1C2

Procedure:
A mixture of 7 g of 3-(o-aminobenzyl)-5-methylmercapto-1,2,4-triazole, 5.26 g of 1,1'-carbonyldiimidazole and 179 ml of methylene chloride is heated at reflux overnight. Most of the solvent is removed in vacuo, the solids are filtered and washed with small amount of methylene chloride to give 2-methylmercapto-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine-5(6H)-one, m.p. 250°-252° (intermediate 5/b).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)[CH3:2].CC([O-])(C)C.[K+].C[N:19](C=O)C>>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH2:19])[CH:4]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCc1c[nH]c2ncccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCc1cn(N)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Ethyl-1H-pyrrolo[2,3-b]pyridine (0.91 g, 6.2 mmol) and KOtBu (1.39 g, 12.4 mmol) are dissolved in DMF (28 mL) and stirred for 2 h at rt. While vigorously sparging with nitrogen, NH2Cl (92 ml 0.15 M in ether) is added in portions. The reaction mixture is stirred at rt for 2 h. The mixture is cooled 0° C. and then quenched with Na2S2O3 (2.7 g) in water (50 mL). After standing at rt for 18 h, the mixture is concentrated, triturated in DCM and filtered. The filtrate is concentrated and chromatographed through silica gel eluting with 10% MeOH in DCM to afford 3-ethyl-pyrrolo[2,3-b]pyridin-1-yl-amine (380 mg). MS: 162 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.32 (d, 1H), 7.90 (d, 1H), 7.04-7.13(m, 2H), 4.96 (broad s, 2H), 2.76 (q, 2H), 1.33 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.P(Cl)(Cl)Cl.C([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)(C)C>ClC1C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:31][C:30]1[CH:29]=[CH:28][C:27]([O:1][CH:2]([CH3:10])[CH3:3])=[CH:33][CH:32]=1)=[O:6]
Reactant: O=C(O)c1cc(S(=O)(=O)N2CCCCC2)ccc1O
Reactant: CC(C)c1ccc(N)cc1
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: CC(C)Oc1ccc(NC(=O)c2cc(S(=O)(=O)N3CCCCC3)ccc2O)cc1
Yield: 149.4 %

Procedure:
Chlorobenzene (2.0 mL) was added to 2-hydroxy-5-(piperidin-1-ylsulfonyl)benzoic acid (470 mg), and under stirring, phosphorus trichloride (0.072 mL) was added thereto and kept stirred at 130° C. for 1 hour. 4-Isopropylaniline (249 mg) was added to it, and stirred at 130° C. for 16 hours. The solvent was evaporated off under reduced pressure, then ethyl acetate was added thereto, washed with water and saturated brine in that order, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 50%, gradient) to give the intended product (515 mg, 75%) as a colorless solid.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:10])[CH2:6][CH:7]([CH3:9])[CH3:8].O.[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:8][CH:7]([CH3:9])[CH2:6][C:5]([C:16]1[CH:17]=[CH:18][C:13]([CH3:19])=[CH:14][CH:15]=1)=[O:10]
Reactant: CC(C)CC(=O)Cl
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(C(=O)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
Portionwise add aluminum trichloride (3.35 g, 25 mmol) to a solution of isovaleryl chloride (2 mL, 16.4 mmol) in anhydrous toluene (50 mL) at 0° C. Warm to room temperature and stir 12 h. Cool to 0° C. and slowly add cold water (500 mL). Extract with EtOAc, wash the organic phase with brine, dry over Na2SO4 and concentrate in vacuo to obtain the desired intermediate (2.8 g, 97%) as an orange oil suitable for use without additional purification. MS (APCI+) m/z: 176 (M+).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27](O)=[O:28])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH2:40])(=[O:39])=[O:38].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([NH:40][S:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[CH3:30])(=[O:38])=[O:39])=[O:28])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4C(=O)O)ccc3o2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 0 °C
Yield: 101.7 %

Procedure:
A solution of 4-tert-butyl-2-[5-(2-carboxyphenylmethoxy)benzofuran-2-yl]thiazole (0.2 g), 2-methylbenzenesulfonamide (0.11 g), 4-dimethylaminopyridine (0.12 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.19 g) in N,N-dimethylformamide (10 ml) was stirred at ambient temperature for 1 day. The resulting mixture was poured into ice-water. The resulting precipitates were collected by filtration and washed with water. The crude compound was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (40:1). The fractions containing object compound were combined and concentrated under reduced pressure to give an oil. The oil was crystallized with ethanol and filtered to give 4-tert-butyl-2-{5-[2-(2-methylbenzenesulfonamidocarbonyl)phenylmethoxy]benzofuran-2-yl}thiazole (0.28 g).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][CH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[N:10]=[C:11]([O:20][CH3:21])[C:12]([O:18][CH3:19])=[N:13]2.[N+:22]([O-])([O:24]C(C)C)=[O:23]>>[Br:6][CH2:7][C:8]1[CH:17]=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=[C:14]2[C:9]=1[N:10]=[C:11]([O:20][CH3:21])[C:12]([O:18][CH3:19])=[N:13]2
Reactant: CC(C)O[N+](=O)[O-]
Reactant: COc1nc2cccc(CBr)c2nc1OC
Agent: O=S(=O)(O)O
Product: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
25 ml of sulfuric acid are cooled to 0° C. and then 9.5 g (33.55 mmol) of 5-bromomethyl-2,3-dimethoxy-quinoxaline are added. After a further 10 minutes, 3.39 ml (1 equiv.) of isopropyl nitrate are added and the mixture is stirred at 0° C. for 1 hour. The mixture is poured onto ice, and the solid is filtered off and washed with water. The title compound is obtained in the form of a beige solid.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[F:19])[NH2:15]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:15][C:14]1[CH:16]=[CH:17][C:18]([F:19])=[C:12]([F:11])[CH:13]=1
Reactant: Nc1ccc(F)c(F)c1
Reactant: Clc1nc2ccccc2[nH]1
Product: Fc1ccc(Nc2nc3ccccc3[nH]2)cc1F

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3,4-difluoroaniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 283-284° C.). MS(ES+) m/z 246 ([M+1]+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6](F)[CH:7]=1.[CH3:13][NH2:14].C1COCC1>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[NH:14][CH3:13]
Reactant: CN
Reactant: Cc1cc(Br)cc(F)c1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CNc1cc(Br)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99 %

Procedure:
A MW vial was charged with 5-bromo-1-fluoro-3-methyl-2-nitrobenzene (500 mg, 2.137 mmol) and methylamine 2M in THF (5 mL, 10.0 mmol). The MW vial was sealed and the reaction mixture was submitted to MW irradiation for 30 min at 100° C. The reaction was cooled down to RT and concentrated under reduced pressure to afford the title product (520 mg, 2.122 mmol, 99% yield) as yellow solid. tR: 1.19 min (LC-MS 2); ESI-MS: no ionisation (LC-MS 2).
Reaction SMILES: C[O-].[Na+].[NH:4]([CH2:11][CH2:12][C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:15][NH:16][C:17]1[CH:18]=[C:19]([CH:27]=[C:28]([NH:30][CH3:31])[CH:29]=1)[CH:20](O)CS(C)(=O)=O.CS(C)=O>O>[NH:4]([CH:11]=[C:12]([CH2:20][C:19]1[CH:27]=[C:28]([NH:30][CH3:31])[CH:29]=[C:17]([NH:16][CH3:15])[CH:18]=1)[C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CCCNc1ccccc1
Reactant: CNc1cc(NC)cc(C(O)CS(C)(=O)=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc(CC(C#N)=CNc2ccccc2)cc(NC)c1

Procedure:
A mixture of 8.6 g. of sodium methylate, 12.4 g. of β-anilinopropionitrile and 20.4 g. of 3,5-bis(methylamino)-α-[(methylsulfonyl)methyl]benzyl alcohol in 100 ml. of absolute dimethylsulfoxide was stirred for 1 hour at 50° C. and then treated with 1 liter of water. The precipitated product was extracted with 3 liters of ethyl acetate. The ethyl acetate extract was washed with 1 liter of water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on 1 kg. of silica gel with methylene chloride/ethyl acetate (3:1), there being obtained α-(anilinomethylene)-3,5-bis(methylamino)hydrocinnamonitrile as a brownish-colored oil.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].I[CH:18]([CH3:20])[CH3:19]>CC(C)=O>[CH:18]([O:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[N:2]([CH3:10])[CH3:1])([CH3:20])[CH3:19]
Reactant: CC(C)I
Reactant: CN(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cccc(N(C)C)c1
Temperature: 25 °C

Procedure:
To a solution of 3-(dimethylamino)phenol (2.0 g, 14.60 mmol) in acetone (40.0 mL) were added K2CO3 (20.2 g, 146.0 mmol) and 2-iodopropane (2.20 mL, 21.90 mmol), and the reaction was refluxed for 18 h, then cooled to room temperature, and filtered through Celite. The solvent was removed under vacuum, and the residue was purified by silica gel chromatography using ethyl acetate (20%) and hexanes (80%) as eluent to produce Compound 135 as yellow oil.
Reaction SMILES: F[C:2]1[C:3]([C:16]#[N:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>>[CH:18]1([NH:21][C:2]2[C:3]([C:16]#[N:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[CH:7]=2)[CH2:20][CH2:19]1
Reactant: NC1CC1
Reactant: N#Cc1ncc(Cc2ccc(F)cc2)cc1F
Product: N#Cc1ncc(Cc2ccc(F)cc2)cc1NC1CC1
Temperature: 75 °C
Reaction time: 0.2 h
Yield: 66 %

Procedure:
3-Fluoro-5-[(4-fluorophenyl)methyl]-2-pyridinecarbonitrile (546 mg, 2.4 mmol) was taken up in cyclopropylamine (8 mL) and heated at 75° C. in a microwave for 10 minutes and then again for 12 minutes. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography to give 3-(cyclopropylamino)-5-[(4-fluorophenyl)methyl]-2-pyridinecarbonitrile (417 mg, 66%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J=1.9 Hz, 1 H), 7.19 (dd, J=8.2, 5.9 Hz, 2 H), 7.19 (d, J=2.4 Hz, 1 H), 7.06 (t, J=8.6 Hz, 2 H), 5.02 (s, 1 H), 4.00 (s, 2 H), 2.48 (m, 1 H), 0.86 (m, 2 H), 0.61 (m, 2 H).