Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[N:8]=[C:9]([C:11]#[N:12])[NH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[Cl-].[OH:16][NH3+:17].C([O-])(=O)C.[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[N:8]=[C:9]([C:11](=[N:17][OH:16])[NH2:12])[NH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1nc2ccc([N+](=O)[O-])cc2[nH]1
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1nc2ccc([N+](=O)[O-])cc2[nH]1
Temperature: 0 °C
Yield: 68.1 %

Procedure:
2 g of 5-nitrobenzimidazole-2-carbonitrile (Lopyrev, V. A.; Larina, L. I.; Baumane, L. Kh.; Shibanova, E. F.; Gavar, R. A.; et al., Chem. Heterocycl. Compd. (Engl. Transl.), EN, 20, 9, 1984, 1021-1026, KGSSAQ, RU, 20, 9, 1984, 1246-1251) are dissolved in 60 ml of ethanol/water (5/1) and treated with 0.74 g of hydroxylammonium chloride and also 1.05 g of sodium acetate and refluxed for 2 h. The mixture is poured into ice water, and the brown precipitate is filtered off with suction and washed with water. 1.6 g of the title compound are obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][CH2:10][C:11]([NH2:14])([CH3:13])[CH3:12]>CCOCC>[NH2:14][C:11]([CH3:13])([CH3:12])[CH2:10][NH:9][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:7]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(C)(N)CN
Solvent: CCOCC
Product: CC(C)(N)CNC(=O)c1ccco1
Reaction time: 0.5 h

Procedure:
A solution of 2-furoyl chloride (12.0 g.) in dry ether (1.50 ml.) was stirred during the dropwise addition over 30 minutes of a solution of 1,2-diamino-2-methylpropane (9.63 ml.) in dry ether (58 ml.). The reaction mixture was stirred for a further 30 minutes. The solid precipitate was collected by filtration and washed with ether. The residual solid was suspended in hot water (250 ml.) and basified to pH 10 with powdered sodium carbonate. The cooled mixture was extracted with chloroform (3×100 ml.). The combined extracts were dried (MgSO4) and evaporated to give N-(2-amino-2-methylpropyl)furan-2-carboxamide (10.68 g.) as an oil, which was used without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[N:18][S:19]([CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:21])=[O:20])=[C:9]1[CH3:30])([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.[CH:36]([Mg]Br)=[CH2:37]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]([NH:18][S:19]([CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:21])=[O:20])[CH:36]=[CH2:37])=[C:9]1[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C=NS(=O)(=O)C=Cc2ccccc2)c2ccccc2n1CC(=O)OC(C)(C)C
Reactant: C=C[Mg]Br
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: C=CC(NS(=O)(=O)C=Cc1ccccc1)c1c(C)n(CC(=O)OC(C)(C)C)c2ccccc12
Temperature: 0 °C

Procedure:
The product of step b) (2.2 g, 5 mmol) was treated with 100 mL toluene. The slurry was stirred at 0° C. and treated with Me3Al (3.8 mL of 2 M in toluene) followed by vinyl magnesium bromide (10 mL of 1 M). The reaction was warmed to rt and stirred for 10 minutes. The reaction was cooled to 0° C., quenched with aqueous acetic acid, and partitioned between water and EtOAc (200 mL each). The organic layer was washed with 1 M NaOH, dried over MgSO4 and purified over silica gel (30% EtOAc/Hex) to give 1.25 g of the sub-title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:12])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH3:26][CH:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28].Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:29]([CH:27]([CH3:28])[CH3:26])(=[O:31])=[O:30])=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCC[C@@H]1Oc1ccc(Br)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1Oc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a slurry of cis-2-(4-bromophenoxy)cyclopentanamine (1.43 g, 5.58 mmol) in methylene chloride (38.5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.40 mL, 9.36 mmol), then 4-(dimethylamino)pyridine (915 mg, 7.49 mmol). The reaction mixture was cooled to 0° C. and propane-2-sulfonyl chloride (0.937 mL, 8.38 mmol) was added drop-wise. The mixture was then allowed to warm to room temperature and stir for 18 hours. The reaction was treated with 1N aqueous hydrochloric acid, and the organic layer was washed with saturated aqueous sodium chloride solution, dried over calcium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (Gradient: 0% to 15% ethyl acetate in heptane) to provide product as a colorless gum. Yield: 1.586 g, 4.38 mmol, 78%.
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:29]4[C:20](=[CH:21][C:22]5[O:27][CH2:26][CH2:25][O:24][C:23]=5[CH:28]=4)[O:19][CH2:18]3)[C:10]2=[O:30])=[N:4][CH:5]=[CH:6][CH:7]=1.[C-:31]#[N:32].[Na+].O>CN1CCCC1=O.O.O.O.O.O.O.[Ni](Cl)Cl>[O:30]=[C:10]1[CH:9]([CH2:8][C:3]2[C:2]([C:31]#[N:32])=[CH:7][CH:6]=[CH:5][N:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]21[C:29]1[C:20](=[CH:21][C:22]3[O:27][CH2:26][CH2:25][O:24][C:23]=3[CH:28]=1)[O:19][CH2:18]2
Reactant: [C-]#N
Reactant: O=C1C(Cc2ncccc2Br)c2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cl[Ni]Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cccnc1CC1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 200 °C
Yield: 289 %

Procedure:
3′-[(3-Bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one (0.233 g, 0.500 mmol), nickel (II) chloride hexahydrate (0.113 g, 0.500 mmol), and sodium cyanide (0.050 g, 1.0 mmol) were combined in 1-methyl-2-pyrrolidone (1 mL) and heated at 200° C. for 30 min under microwave irradiation. The reaction mixture was allowed to cool to ambient temperature, poured into water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (3×20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was subjected to column chromatography, and eluted with a 50% to 75% gradient of ethyl acetate in hexanes, to afford 2-[(2′-oxo-2,2′,3,3′-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-3′-yl)methyl]pyridine-3-carbonitrile (0.593 g, 29%) as a colorless solid: mp 230-233° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.71 (dd, J=4.8, 1.4 Hz, 1H), 8.38 (dd, J=7.9, 1.5 Hz, 1H), 7.56 (dd, J=7.8, 4.9 Hz, 1H), 7.27-7.15 (m, 2H), 7.04 (d, J=7.5 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 6.50 (s, 1H), 6.38 (s, 1H), 5.30 (s, 2H), 4.74 (ABq, 2H), 4.19-4.11 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.3, 158.2, 155.0, 153.1, 144.6, 143.1, 142.1, 138.2, 132.4, 129.1, 124.0, 123.4, 121.9, 116.5, 112.2, 109.8, 108.0, 99.1, 79.8, 64.7, 64.1, 57.7, 44.1; MS (ES+) m/z 412.0 (M+1).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.C(N(CC)CC)C.[C:19]1([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH2:31][NH:30][CH2:29][CH2:28]3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH3:10][C:7]1[N:6]=[C:5]([NH2:11])[C:4]([CH2:3][N:30]2[CH2:29][CH2:28][C:27]3[C:32](=[CH:33][CH:34]=[C:25]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:26]=3)[CH2:31]2)=[CH:9][N:8]=1
Reactant: c1ccc(-c2ccc3c(c2)CCNC3)cc1
Reactant: Cc1ncc(CCl)c(N)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(CN2CCc3cc(-c4ccccc4)ccc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 60.5 %

Procedure:
A suspension of 0.20 g (0.00080 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 10 ml of dimethylformamide was treated with 0.34 ml (0.0024 mol) of triethylamine and 0.19 g (0.00097 mol) of 6-phenyl-1,2,3,4-tetrahydro-isoquinoline and the mixture was stirred at room temperature under argon for 60 hours The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water, extracted, chromatographed over silica gel with acetonitrile/methanol 5:1 as the eluent and digested in diethyl ether. 0.16 g (61%) of 2-methyl-5-(6-phenyl-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-pyrimidin-4-ylamine was obtained as white crystals; m.p. 186°-188°. A further 0.03 g of pale yellow crystals was recovered from the mother liquor.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:27]=[CH:26][C:22]2[N:23]=[CH:24][NH:25][C:21]=2[CH:20]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[NH:23]1[C:22]2[CH:26]=[CH:27][C:19]([NH:18][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:16]#[N:17])=[CH:20][C:21]=2[N:25]=[CH:24]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc4[nH]cnc4c3)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 159.8 mg (1.2 mmol) of 5-aminobenzimdazole and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed for 1 hr. The work up gave 233.6 mg (67.7%) of the product as a brown solid, m.p. 230°0 C. (dce.), mass (electrospray, m/e): M+H 345.9. HRCIMS: calcd 346.1304 for C19H15N5O2 (M+), obsd 346.1325.
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]([CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[S:19][CH2:20][CH2:21][CH2:22][NH2+:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].CCN(CC)CC.[C:39](Cl)(=[O:44])[CH2:40][CH2:41][CH2:42][CH3:43]>ClCCCl>[C:2]([O:6][C:7](=[O:8])[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[S:19][CH2:20][CH2:21][CH2:22][N:23]([C:39](=[O:44])[CH2:40][CH2:41][CH2:42][CH3:43])[CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CCCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)Cn1c(SCCC[NH2+]CCc2ccccc2)nc2ccccc21
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCCC(=O)N(CCCSc1nc2ccccc2n1CC(=O)OC(C)(C)C)CCc1ccccc1
Reaction time: 2 h

Procedure:
[3-(1-tert-Butoxycarbonylmethyl-1H-benzoimidazol-2-ylsulfanyl)-propyl]-phenethyl-ammonium chloride (Precursor U-01b, 11.6 mg, 0.025 mmol) and Et3N (12.2 mg, 17.2 μl, 0.1 mmol) are dissolved in 1,2-dichloroethane (0.2 ml). To this solution is added valerylchloride (9 mg, 8.95 μl, 0.075 mmol) and the stirring is continued for 2 h. Then 1,2-dichloroethane (0.4 ml) and tris-(2-aminoethyl)amine polystyrene (3.4 mmol/g, 22 mg, 0.075 mmol) are added. After 30 min of shaking the resin is filtered off. Then methylisocyanate polystyrene (2.5 mmol/g, 30 mg, 0.075 mmol) is added as well as 1,2-dichloroethane (0.5 ml) and the resulting suspension is stirred for 2 h. It is filtered and the organic filtrate is washed with an aqueous KH2PO4 solution (pH=4) and water. Finally the organic phase is dried over Na2SO4 and evaporated to dryness yielding the title compound: tR=2.62 min (LC-2), ESI-MS (pos.): m/z 510.49 [M+H]+; 1H-NMR (DMSO-d6 at 100° C.): δ (ppm) 0.80 (t, 3H, CH2CH3), 1.19 (m, 2H, CH2CH3), 1.37 (m, 2H, CH2CH2CH3), 1.40 (s, 9H, tBu), 1.91 (m, 2H, CH2CH2N), 2.08 (m, 1H, COCHa), 2.24 (m, 1H, COCHb), 2.71-2.83 (m, 2H, CH2Ph), 3.30 (m, 2H), 3.32-3.43 (m, 4H), 4.98 (m, 2H, CH2CO2), 7.12-7.26 (m, 7 Harm), 7.50 (m, 2Harom).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:42][C:43](=[O:46])[CH2:44][CH3:45].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:42][C:43](=[O:46])[CH2:44][CH3:45])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:17]1=[O:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CCC(=O)CBr
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(=O)CN([C@H]1CCN([C@@H](C)C(=O)OC(C)(C)C)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reaction time: 72 h

Procedure:
A solution of tert-butyl (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.07 g) in THF (2 ml) was cooled to −78° C. under nitrogen, and treated with lithium bis(trimethylsilyl)amide (1.0M solution in THF; 0.186 ml), followed by 1-bromo-2-butanone (0.08 ml). The resultant solution was allowed to reach room temperature and stirred for a further 72 h. Methanol (1 ml) was added and the resultant solution concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with cyclohexane:ethyl acetate 10:1, 5:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:5, ethyl acetate and methanol:ethyl acetate 1:9) to give the title compound (0.07 g) as a gum.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[S:7][CH:8]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:10]=1[O:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:5])[CH3:4]>ClC(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[S:7][CH:8]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:10]=1[O:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: BrBr
Reactant: COC(=O)c1csc(C(C)=O)c1OC(=O)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1csc(C(=O)CBr)c1OC(=O)c1ccccc1
Temperature: 22.5 °C
Yield: 77 %

Procedure:
A solution of 1.28 mL of bromine in 24 mL of tetrachloromethane was added dropwise to a solution of 7.23 g of Compound 1C in 72 mL of tetrachloromethane over a period of 10 minutes and stirred at reflux. After a further 5 minutes at reflux, the mixture was cooled to 20-25° C. The precipitated solid was collected by filtration and washed with cold tetrachloromethane to yield 7 g (77%) of Compound 1D, melting at 115-118° C. The compound was contaminated with impurities 1B and methyl 2-(2,2-dibromoacetyl)-3-benzoyloxythiophene-4-carboxylate (2% and 6% mol. respectively, determined by 1H-NMR spectroscopy), but could be used without further purification in the next reaction step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[O:18][C:17](=[O:19])[NH:16][N:15]=2)=[CH:4][CH:3]=1.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)Cl>C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[O:18][C:17](=[O:19])[N:16]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:15]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2-c2n[nH]c(=O)o2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(=O)o2)cc1

Procedure:
2.03 g of the compound prepared in step B, 2.5 g of trityl chloride, 50 ml of DCM and 1.6 ml of triethylamine are placed in a round-bottomed flask and the mixture is refluxed for 1 and a half hours. It is evaporated, the residue is taken up with an ethyl ether/water mixture and the organic phase is washed with a 3% solution of potassium hydrogensulfate, dried over sodium sulfate, filtered and evaporated. The product is used in the crude form for the next step.
Reaction SMILES: [I-].I[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.BrC1C=CC=CC=1.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18]>ClC1C=CC=CC=1>[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH:18][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Ic1ccccc1
Reactant: C=CC(=O)OCC
Agent: [I-]
Solvent: Clc1ccccc1
Solvent: Brc1ccccc1
Product: CCOC(=O)C=Cc1ccccc1

Procedure:
More specifically, we have found that chlorobenzene reacts with ethyl acrylate to form ethyl cinnamate in relatively high yield by reacting the chlorobenzene with iodide and/or bromide ion to form a mixture of chlorobenzene, iodobenzene and/or bromobenzene, then reacting the mixture with ethyl acrylate in the presence of a catalyst to form ethyl cinnamate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:32]([NH:33][C:34](=[O:36])[CH3:35])=[C:13]3[C:14](=[O:31])[N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]3=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>O1CCCC1>[CH3:44][S:45]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:32]([NH:33][C:34](=[O:36])[CH3:35])=[C:13]3[C:14](=[O:31])[N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]3=[N:11]2)=[CH:8][CH:9]=1)(=[O:47])=[O:46]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Cn2c(=O)c3c(NC(C)=O)n(-c4ccc(CCO)cc4)nc3c3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c3c(NC(C)=O)n(-c4ccc(CCOS(C)(=O)=O)cc4)nc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of N-{2-[4-(2-hydroxyethyl)phenyl]-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-3-yl}acetamide (3.2 g) and triethylamine (1.85 ml) in tetrahydrofuran (400 ml) was added dropwise methanesulfonyl chloride (0.77 ml) at 0° C. The mixture was stirred at room temperature for 5 hours, triethylamine (0.46 ml) and methanesulfonyl chloride (0.19 ml) were added thereto, and stirred again for 3 hours. The mixture was concentrated under reduced pressure, and to the residue was added ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, water, saturated brine, dried and concentrated under reduced pressure to obtain the target compound (3.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH2:19])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:15]=[C:14]([NH2:19])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N)n2)cc1
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)Nc2cc(NCc3ccccc3)nc(N)n2)cc1
Temperature: 130 °C
Yield: 40.5 %

Procedure:
0.30 g (0.001 mol) of 4-amino-N-(2-amino-6-chloro-pyrimidin-4-yl)-benzenesulfonamide and 11 ml (0.1 mol) of benzylamine were dissolved in 15 ml of ethanol and stirred in an autoclave at 130° C. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 minutes. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.15 g (41%) of 4-amino-N-(2-amino-6-benzylamino-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p.;221° C. (dec.).
Reaction SMILES: [CH3:1][NH2:2].C(O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]=O)[CH:12]=[CH:11]2.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]=[N:2][CH3:1])[CH:12]=[CH:11]2
Reactant: CN
Reactant: COc1ccc2cc(C=O)ccc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: ClCCl
Product: CN=Cc1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 96 %

Procedure:
A mixture of an 8.03M solution of methylamine in ethanol (67 mL, 537 mmol) and 50 mL of methylene chloride was added dropwise under nitrogen to a mixture of 6-methoxy-naphthalene-2-carbaldehyde (20 g, 107.4 mmol), magnesium sulfate (20 g) and 200 mL of methylene chloride. The mixture stirred at room temperature under nitrogen for 17 h. The MgSO4 was removed by filtration and the solvent was removed under reduced pressure to give (6-methoxy-naphthalen-2-ylmethylene)-methyl-amine (20.59 g, 96%) as a yellow solid, mp 109-110° C.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4].[NH2:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[O:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:3]([C:5]2[S:9][C:8]([CH2:10][CH2:11][C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])=[N:7][CH:6]=2)=[O:4])[CH2:24][CH2:25]1
Reactant: CCCCc1noc(C)c1CCc1ncc(C(=O)OC)s1
Reactant: NC1CCOCC1
Product: CCCCc1noc(C)c1CCc1ncc(C(=O)NC2CCOCC2)s1
Yield: 76 %

Procedure:
As described for example 57b, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (90 mg, 0.29 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (50 mg, 76%) which was obtained as a light yellow solid. MS: m/e=378.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)=[O:32].C(=O)([O-])O.[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[C:37]1[CH:38]=[C:33]([CH:34]=[CH:35][CH:36]=1)[CH:31]=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1I
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1cccc(C=O)c1

Procedure:
5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-iodo-3-methyl-isoxazole (200 mg, 0.38 mmol), and 3-formylbenzene boronic acid (85 mg, 1.5 equiv.) were dissolved in DMF (12 ml) before 1M Sodium hydrogen carbonate solution (1.1 ml, 3.0 equiv) and Pd(Ph3P)2Cl2 (21 mg, 0.08 equiv.) were added with stirring. The reaction mixture was transferred to three microwave tubes which were sealed and the mixtures within degassed before being irradiated by an initial power of 200 W to a temperature of 150° C. for 15 minutes in a CEM microwave apparatus. Upon cooling the reaction mixtures were combined and partitioned between ethyl acetate (10 ml) and water (10 ml). The aqueous layer was separated and extracted again with ethyl acetate (10 ml). The organics were then combined washed with water (2×20 ml), brine (20 ml), dried over Na2SO4 before being condensed in vaccuo and purified by flash chromatography on silica gel, eluting with 25% ethyl acetate in hexane.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][C:7]=1[CH2:8][OH:9])[CH3:2].[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][C:26]=1[CH3:32].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:9][CH2:8][C:7]2[O:6][C:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:4][C:3]=2[CH2:1][CH3:2])=[CH:27][C:26]=1[CH3:32]
Reactant: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1CO
Reactant: COC(=O)CCc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1COc1ccc(CCC(=O)OC)c(C)c1
Reaction time: 8 h

Procedure:
To a solution of [4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol (0.108 g, 0.400 mmole) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.078 g, 0.400 mmole) in toluene (2 mL) at room temperature, is added tributylphosphine followed by a solution of 1,1′-(azodicarbonyl)-dipiperidine (0.201 g, 0.8 mmole) in toluene (2 mL). The reaction is stirred overnight, then diluted with hexane (10 mL). The precipitate is removed through filtration and the filtrate is concentrated, loaded to a silica gel column, eluted with ethyl acetate in hexane (0-15%) and concentrated to provide the titled compound as a white solid. Mass [EI+] 448 (M++H).