Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([OH:28])=[C:20]([NH:23][C:24]([O:26]C)=O)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:29]1[CH2:34][CH:33]=[C:32]([C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:37][CH:36]=2)[CH2:31][CH2:30]1>CS(C)=O>[NH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:35]([C:32]2[CH2:33][CH2:34][N:29]([CH2:12][CH:13]3[O:18][C:17]4[C:16](=[CH:22][CH:21]=[C:20]5[NH:23][C:24](=[O:26])[O:28][C:19]5=4)[O:15][CH2:14]3)[CH2:30][CH:31]=2)=[CH:36]1
Reactant: COC(=O)Nc1ccc2c(c1O)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CS(C)=O
Product: O=c1[nH]c2ccc3c(c2o1)OC(CN1CC=C(c2c[nH]c4ccccc24)CC1)CO3
Temperature: 60 °C

Procedure:
0.85 g (2.08 mmole) of {(2R)-8-hydroxy-7-[(methoxycarbonyl)amino]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate and 1.13 g (5.70 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole were combined in DMSO (40 mL) and heated at 60° C. under nitrogen for 6 hours. After completion, the reaction was cooled to room temperature and partitioned between 300 mL each of ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuum to a viscous oil. The crude oil was dissolved in methylene chloride and was heated at reflux in the presence of carbonyl diimidazole (1.02 g) for 4 hours. The reaction was allowed to cool to room temperature and the solvent was removed in vacuum. The residue was column chromatographed on silica gel using first 20% hexane/methylene chloride, then methylene chloride and finally 2% methanol/methylene chloride as eluant. The product fractions were combined and concentrated in vacuum to give 0.080 g of the (S)-enantiomer of the title compound as a light yellow solid, m.p. 202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](Cl)=[O:6].C(N(CC)C(C)C)(C)C.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:6]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: CN1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
3-chloro-4-nitro-benzoyl chloride (Intermediate 54; 2.2 g, 10.00 mmol) was dissolved in DCM (20 mL) and N,N-diisopropylethylamine (2.095 mL, 12.00 mmol) added. The mixture was cooled in an ice/water bath and 4-amino-1-methylpiperidine (Fluorochem; 1.14 g, 10.00 mmol) in DCM (10 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred for 0.5 hr. A white precipitate resulted. The reaction mixture was washed with 2N NaOH, filtered and the filter cake washed with water and dried on a sinter over the weekend to give the title compound as a white solid (1.80 g, 60%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.[N:21]([C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=1)=[C:22]=[O:23].Cl>C(#N)C>[CH3:31][C:26]1[CH:25]=[C:24]([NH:21][C:22]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[N:7]([CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]2=[O:20])[CH2:6]3)=[O:23])[CH:29]=[C:28]([CH3:30])[CH:27]=1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1cc(C)cc(N=C=O)c1
Agent: Cl
Solvent: CC#N
Product: Cc1cc(C)cc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 1-isocyanato-3,5-dimethyl-benzene (0.17 mg, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture was stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding 1-(3,5-dimethyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (280 mg, 67%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4 in H2O: tR=3.4 min (96%); mp. 289-291° C. 1H NMR (DMSO-d6) δ 1.92-2.06 (m, 1H, CHH), 2.19 (s, 6H, CH3+CH3), 2.38 (qd, J=4.4, 13.1 Hz, 1H, CHH), 2.54-2.66 (m, 1H, CHH), 2.80-3.02 (m, 1H, CH—H), 4.17-4.58 (m, 4H, CH2+CHH), 5.11 (dd, J=5.2, 13.3 Hz, 1H, CHN), 6.54 (s, 1H, Ar), 6.69 (t, J=5.9 Hz, 1H, Ar), 7.03 (s, 2H, Ar), 7.44 (d, J=7.9 Hz, 1H, Ar), 7.51 (s, 1H, NH), 7.69 (d, J=7.7 Hz, 1H, Ar), 8.45 (s, 1H, NH), 10.98 (s, 1H, NH). 13C NMR (DMSO-d6) δ 21.12, 22.49, 31.20, 42.76, 47.10, 51.56, 115.54, 121.88, 122.78, 122.93, 126.91, 130.27, 137.49, 140.19, 142.38, 144.93, 155.21, 167.95, 170.99, 172.85; LCMS MH=421. Anal Calcd for: C23H24N4O4+0.1H2O: C, 65.42, H, 5.78; N, 13.27. found: C, 65.15; H, 5.58; N, 13.18.
Reaction SMILES: [N:1]([C:4]1([CH3:25])[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH2:15][CH2:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1)=C=O.[OH-].[Na+].Cl>C1COCC1.O>[NH2:1][C:4]1([CH3:25])[CH2:5][CH2:6][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH2:15][CH2:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:8][CH2:9]1
Reactant: CC1(N=C=O)CCN(C[C@@H]2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(N)CCN(C[C@@H]2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 132.6 %

Procedure:
A solution of (1R)-1-[(4-isocyanato-4-methyl-1-piperidinyl)methyl]-1,2,5,6-tetrahydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (561 mg, 1.638 mmol) in THF (10 ml) and water (10.00 ml) at rt was treated with sodium hydroxide (5 ml, 10.00 mmol), and stirred at rt for 1 h. Reaction was then treated with concentrated HCl (5 ml, 12M) and stirred at rt for 18 h, then evaporated. The resultant solid was treated with methanol (20 ml) and then the solvent was decanted from the solid and evaporated to give the product as an impure green solid (687 mg, 108%).
Reaction SMILES: C(OC(=O)C[C@@H](C([N:16]1[C@@H:20]([CH:21]([CH3:23])[CH3:22])[CH2:19][O:18][C:17]1=[O:24])=O)CCCCC)(C)(C)C.OO.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[CH:21]([C@H:20]1[CH2:19][O:18][C:17](=[O:24])[NH:16]1)([CH3:23])[CH3:22]
Reactant: CCCCC[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@@H]1C(C)C
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H]1COC(=O)N1
Reaction time: 3 h

Procedure:
A solution of 5 (25.5 g, 71.73 mmol) in THF (300 mL) and water (75 mL) under Ar is cooled to 0° C. To this is added via syringe H2O2 (30% in water, 30.6 mL, 0.300 mol) gradually over a period of 15 minutes. LiOHH2O (4.92 g, 0.12 mol) in water (150 mL) is added via syringe. The mixture is stirred for 3 h after which the septum is removed and Na2SO3 (37.8 g, 0.300 mol) in water (225 mL) is added slowly. The bulk of the THF is removed by rotavap at a bath temperature between 25-30° C. The residue is extracted with CH2Cl2 (100 ml×3). The combined organic layer is washed consecutively with 0.5 N HCl (100 mL), sat. NaHCO3 (100 mL), water (100 mL) and brine ( 100 mL). The solution is then dried over Na2SO4 and concentrated in vacuo. The residue is recrystallized in hexane/ethyl acetate to afford the Evan's chiral auxiliary 2 as white needles. The aqueous layer from the first extraction was acidified to pH 1 and extracted with ethyl acetate (100 mL×3). The combined organic layer is washed with 0.5 N HCl (100 mL) and then brine (100 mL). It is then dried over Na2SO4 and concentrated to yield 6 as a colorless oil (17.198 g, 70.39 mmol, 98%). 1H NMR (400 MHz, CDCl3) δ0.88 (t, J=6.8 Hz, 3 H), 1.21-1.37 (m, 6 H), 1.43 (s, 9 H), 1.40-1.70 (m, 2 H), 2.61 (dd, J=9.3 Hz, 1 H), 2.38 (dd, J=16.4, 5.1, 1 H), 2.61 (dd, J=16.4, 9.3, 1 H), 2.78 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ13.9, 17.5, 17.9, 22.3, 26.5, 27.9, 31.5, 37.0, 41.3, 94.9, 80.0, 171.1, 181.1. HRMS calcd for C13H25O4 (MH+): 245.1752. Found (DCI): 245.1766 (Δ=5.2 ppm).
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:22])[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CCOC(C)=O>[Cl:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:11])[NH:12][C:13](=[O:22])[C:14]([CH3:15])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:3]2=[O:23]
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1NC(=O)C(C)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CC1(c2ccccc2)C(=O)Nc2cc(Cl)c(Cl)cc2C1=O

Procedure:
The objective compound was prepared by the same procedure for the example 1, using a 4,5-dichloro-2-(2-phenyl-propionyl amino)-benzoic acid methyl ester (1.00 g, 2.84 mmol) and LiHMDS (8.52 mmol, 1M solution in THF). After normal workup, the pure objective compound (0.36 g, 40%; yellow solid) was obtained by a flash column chromatography (Hex:EtOAc=4:1): 1H NMR (200 MHz, CDCl3) δ 1.83 (s, 3H, CH3), 7.02 (s, 1H, ArH), 7.23-7.33 (m, 5H, ArH), 7.97 (s, 1H, ArH), 8.41 (br s, 1H, NH); m.p. 213-214° C.; MS(EI) m/e 319 [M+], 285, 132, 104 ; HRMS m/e cacld. for C16H11NO2Cl 319.0167, found 319.0168.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH:9]2C(=O)O[C:12](C)([CH3:16])[O:11][C:10]2=[O:18])=[C:4]([F:31])[CH:3]=1>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:9][C:10]([O:11][CH2:12][CH3:16])=[O:18])=[C:4]([F:31])[CH:3]=1
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3F)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(Cl)cc1F)c1c[nH]c2c(CSC)cccc12

Procedure:
5.0 mg (0.08 mmol) of copper powder were added to 3.60 g (7.79 mmol) of the compound from Example 15A in 56 ml of pyridine and 14 ml of ethanol. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered through silica gel and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 2.23 g (70% of theory) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:3]1=[O:30].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>O1CCCC1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[C:3]2=[O:30])=[O:40])=[CH:34][CH:33]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)NCc2ccccc2)C1=O
Solvent: C1CCOC1
Product: O=C(CN1C(=O)C(NC(=O)Nc2ccc(Cl)cc2)N=C(c2ccccc2)c2ccccc21)NCc1ccccc1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-phenylmethylaminocarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 260°-262° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)cc1

Procedure:
To 4-Hydroxy benzaldehyde (10 g) in acetone (200 ml), potassium carbonate (16.96 g) was added and stirred. To this, benzyl bromide (12.67 ml) was added and the reaction mixture was refluxed for 3 hours and then cooled. The reaction mixture was filtered and the filtrate was concentrated to obtain pale brown colored oil which got solidified at room temperature. Solid was crystallized from DCM-Petroleum ether to obtain the title compound as pale yellow solid. Yield: 13 g (74%); 1HNMR (CDCl3; 300 MHz): δ 9.91 (s, 1H), 7.87 (d, 2H), 7.33-7.43 (m, 5H), 7.12 (d, 21-1) 5.17 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].B(O)(O)[C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[CH:11]([C:9]1[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=[C:2]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:10]=1)=[O:12]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=Cc1cc(Br)cc(C(=O)O)c1
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2cc(C=O)cc(C(=O)O)c2)cc1
Yield: 57.2 %

Procedure:
To a mixture of 3-bromo-5-formylbenzoic acid (8.0 g, 34.9 mmol), p-tolylboronic acid (9.5 g, 70 mmol), toluene (300 mL), cesium carbonate (28 g, 87 mmol), and water (25 mL) under nitrogen was added tetrakis(triphenylphosphine)palladium(0) (2.0 g, 1.7 mmol). The mixture was heated under reflux for 5 h. After cooling, the mixture was filtered through Celite and the filter cake was washed with EtOAc. The filtrate was washed with brine, dried, and concentrated. The residue was purified by column chromatography using methylene chloride:methanol gradient (0-5%) to afford the title compound (4.8 g, 51%). LC-MS: 239.0 [M−1]−.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]([N:5]=[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][NH:7]1)=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:13][C:14]1[N:15]=[CH:16][C:17]([CH2:20][N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:3](=[O:4])[CH:2]([F:1])[F:12])=[CH:18][CH:19]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C(N=c1cccc[nH]1)C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(N=c1ccccn1Cc1ccc(Cl)nc1)C(F)F

Procedure:
100 mg (0.58 mmol) of the 2,2-difluoro-N-(pyridin-2(1H)-ylidene)acetamide obtained by the aforementioned method was dissolved in 10 ml of anhydrous acetonitrile, 94 mg (0.58 mmol) of 2-chloro-5-chloromethyl pyridine was dissolved in 5 ml of anhydrous acetonitrile and added thereto, and subsequently, 84 mg (0.63 mmol) of potassium carbonate was added thereto and the resulting mixture was heated and refluxed for 140 minutes. After the reaction was completed, the reaction solution was returned to room temperature to filter off insoluble materials, and the filtrate was concentrated under reduced pressure. Ether was added thereto to precipitate a solid, and thus the solid was collected and dried well to obtain the subject material. Amount obtained 63 mg (yield 37%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14](B(O)O)=[CH:13][C:12]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].Cl[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([CH3:34])[N:27]=1>CCO>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:26]3[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([CH3:34])[N:27]=3)=[CH:13][C:12]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cc2cc(Cc3ccccc3)ccc2o1
Reactant: Cc1nc(Cl)ccc1C=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1nc(-c2cc3cc(Cc4ccccc4)ccc3o2)ccc1C=O
Temperature: 80 °C

Procedure:
In a sealed flask, a mixture of 5-benzylbenzofuran-2-ylboronic acid (525 mg, 2.1 mmol) and potassium acetate (0.41 g, 4.2 mmol) was set under argon, treated with bis{di(tbutyl)phenyl}palladium(II) dichloride (0.078 g, 0.12 mmol), followed by a solution of 6-chloro-2-methylnicotinaldehyde (0.29 g, 1.9 mmol) in EtOH (10 mL). The resulting suspension was degassed again and heated to 80° C. for 2 h. The mixture was cooled to 24° C., treated with EtOAc and washed with saturated aqueous NaHCO3 and brine (each 1×). The combined organic layers were dried over MgSO4 and evaporated. Purification by flash chromatography (hexanes to hexanes/EtOAc=9:1) gave 6-(5-Benzylbenzofuran-2-yl)-2-methylnicotinaldehyde as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.33 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.97-7.95 (m, 2H), 7.51-7.49 (m, 2H), 7.31-7.29 (m, 2H), 7.24-7.21 (m, 3H), 4.10 (s, 2H), 3.07 (s, 3H). MS (ESI) m/z: Calculated: 327.4; Observed: 328.1 (M++1).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5](O)[CH2:4][C:3]1([CH3:12])[CH3:11].N(OC(C)(C)C)=O.[CH2:20]([O:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1N)[CH:21]=[CH2:22]>ClC1C=CC=CC=1>[O:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[CH:21]([CH2:22][O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:20]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: C=CCOc1ccccc1N
Agent: CC(C)(C)ON=O
Solvent: Clc1ccccc1
Product: CC1(C)CCCC(C)(C)N1OCC1COc2ccccc21
Yield: 61.4 %

Procedure:
The procedure of Example 1 is repeated using 1.95 g (12.5 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine, 3.10 g (30 mmol) of tert-butyl nitrite, 7.5 mg (0.012 mmol) of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) mmol) in 100 mL of chlorobenzene and 5.60 g (25 mmol) of 2-allyloxyaniline in 20 mL of chlorobenzene. The crude product obtained is purified by vacuum flash chromatography (25% ethyl acetate/heptane) to give 2.22 g of a viscous liquid in 61.5% yield.
Reaction SMILES: [CH3:1][S:2]([CH:5]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)(=[O:4])=O.Cl[C:21]1[CH:26]=CC=C(C(OO)=O)[CH:22]=1>>[CH2:1]([S:2]([CH:5]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:4])[CH2:22][CH2:21][CH3:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CCCCS(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
The procedure for making bis(p-chlorophenyl)methyl methyl sulfone was followed, using a slight excess of m-chloroperbenzoic acid (0.027 mole acid to 0.025 mole of bis(p-chlorophenyl)methyl n-butyl sulfoxide). A light amber liquid was formed and this gave crystals which were recrystallized from methanol as a white solid of bis(p-chlorophenyl) methyl n-butyl sulfoxide, melting point 116°-188° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=CC(S(O)(=O)=O)=CC=1.[Cl:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16]>CC(C)=O>[Cl:12][CH2:13][CH:14]1[CH2:15][O:16][C:1]([CH3:6])([CH3:11])[O:17]1
Reactant: OCC(O)CCl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(C)OCC(CCl)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 8177 %

Procedure:
p-Toluenesulfonic acid (1.79 g) was added to a mixture of 3-chloro-1,2-propanediol (104.49 g, 0.945 mol) and acetone (1500 ml) and the resulting mixture was stirred for 12 hours at 25° C. After completion of the reaction, acetone was removed in vacuo and the crude product was distilled to give 128.01 g of 4-chloromethyl-2,2-dimethyl-1,3-dioxolane (yield 89%, b.p. 45° C. at 5 mmHg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].C([Li])(CC)C.[C:15](=[O:17])=[O:16]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]([OH:17])=[O:16])=[C:3]([CH3:9])[CH:4]=1
Reactant: O=C=O
Reactant: Cc1cc(Cl)ccc1Br
Agent: [Li]C(C)CC
Product: Cc1cc(Cl)ccc1C(=O)O

Procedure:
Accordingly, the invention also provides a process for the preparation of N-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamine, characterized in that in the first stage a) according to the invention 2-bromo-5-chlorotoluene is reacted with a secondary or tertiary organolithium compound, particularly preferably sec-butyllithium, and CO2 to give the first intermediate 4-chloro-2-methylbenzoic acid, in stage b) a methylsulfonyl group is introduced by reacting 4-chloro-2-methylbenzoic acid with chlorosulfonic acid, sodium sulfite and methyl iodide to give the corresponding intermediate 2-methyl-4-chloro-5-methylsulfonylbenzoic acid,
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]2[CH:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=3[N+:17]([O-])=O)[CH2:7][CH2:8][C:2]=12.CCO>C1COCC1.[Pd]>[NH2:17][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=1[CH:6]1[N:3]2[CH:4]=[N:5][CH:1]=[C:2]2[CH2:8][CH2:7]1)[C:13]#[N:14]
Reactant: N#Cc1ccc(C2CCc3cncn32)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1ccc(C2CCc3cncn32)c(N)c1
Reaction time: 8 h

Procedure:
4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-nitrobenzonitrile (0.054 g, 0.212 mmol) is dissolved in THF (2 mL) and EtOH (2 mL) and 5% palladium on carbon (wet) (15 mg) is then added. The mixture is placed under an atmosphere of hydrogen overnight. The mixture is then filtered and concentrated. The residue is purified via HPLC (reversed phase, CH3CN/H2O) to give 3-amino-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile as a solid. MS (ESI) m/z 225.0 (M+H); 1H NMR (400 MHz, CH3CN) (TFA salt) δ ppm 2.45-2.57 (m, 1H), 2.99-3.16 (m, 3H), 4.47 (br s, 2H), 5.68-5.75 (m, 1H), 6.69 (d, J=7.8 Hz, 1H), 6.98 (d, J=1.5 Hz, 1H), 7.09 (d, J=1.8 Hz, 1H), 7.21 (s, 1H), 8.32 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=O.[NH2:9][C:10]1[CH:11]=[C:12]([CH:16]([OH:20])[CH2:17][C:18]#[N:19])[CH:13]=[CH:14][CH:15]=1.[BH4-].[Na+]>CO>[OH:20][CH:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:11]=1)[CH2:17][C:18]#[N:19]
Reactant: N#CCC(O)c1cccc(N)c1
Reactant: COCCCCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCCCCNc1cccc(C(O)CC#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-methoxypentanal (0.644 g, 5.54 mmol), 3-(3-aminophenyl)-3-hydroxypropanenitrile (12) (1.0 g, 6.16 mmol) and activated molecular sieves in methanol was stirred at RT for 8 hrs. NaBH4 (0.937 g, 24.6 mmol) was added portion wise to the reaction mixture at 0° C. The reaction mixture was stirred at RT overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. Purification by column chromatography (100-200 silica, 0% to 70% EtOAc—hexanes gradient) gave 3-hydroxy-3-(3-(5-methoxypentylamino)phenyl)propanenitrile as a yellow oil. Yield (0.34 g, 21%); 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J=8.0 Hz, 1H), 6.66 (d, J=7.6 Hz, 1H), 6.62 (s, 1H), 6.56 (d, J=8.0 Hz, 1H), 4.95 (t, J=6.4 Hz, 1H), 3.39 (t, J=6.4 Hz, 2H), 3.33 (s, 3H), 3.12 (t, J=7.2 Hz, 2H), 2.75 (d, J=6.4 Hz, 2H), 1.68-1.59 (m, 4H), 1.51-1.43 (m, 2H).