Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:17])[CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][CH2:8][S:9][CH3:10].[N:18]12[CH2:25]C[CH:21]([CH2:22][CH2:23]1)[C@@H:20](O)[CH2:19]2>C1(C)C=CC=CC=1>[CH3:10][S:9][CH2:8][CH2:7][CH:6]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]([O:4][C@@H:3]1[CH:21]2[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]2)[CH2:25]1)=[O:17]
Reactant: COC(=O)C(CCSC)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CSCCC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Yield: 82.3 %

Procedure:
Sodium hydride (0.64 g, as an 80% dispersion in oil) was added to a mixture of methyl-(RS)-4-(methylthio)-2-phenylbutanoate (see Preparation 11) (19.1 g) and (R)-3-quinuclidinol (prepared as described in Acta. Pharm. Suec., 281, 16, 1979) (12.7 g) in toluene (440 ml). The mixture was refluxed with continuous removal of distillate and when necessary replacement with fresh toluene for 1.5 hours. The cooled mixture was extracted with 2M hydrochloric acid, the aqueous layer washed with ethylacetate, basified with potassium carbonate and extracted with chloroform. The organic layer was dried over sodium sulphate, evaporated and the residue partitioned between ethylacetate and aqueous 10% potassium carbonate. The organic layer was dried over sodium sulphate and evaporated to leave the title compound (22.4 g, 82%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([N:14]=[C:15]=[S:16])[N:8]=[C:7]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[C:6]=2[CH:22]=1.[N:23]1([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([NH2:39])=[CH:31][CH:30]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:39][C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:30][CH:31]=3)=[S:16])[N:8]=[C:7]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[C:6]=2[CH:22]=1
Reactant: CN1C(=O)C(N=C=S)N=C(c2ccsc2)c2cc(Cl)ccc21
Reactant: Nc1ccc(N2CCOCC2)c2ccccc12
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(NC(=S)Nc2ccc(N3CCOCC3)c3ccccc23)N=C(c2ccsc2)c2cc(Cl)ccc21
Temperature: 70 °C

Procedure:
This reaction was carried out in a multiwell plate. As illustrated in the scheme above, aA mixture of 7-chloro-1,3-dihydro-3-isothiocyanato-1-methyl-5-(3-thienyl)-2H-1,4-benzodiazepin-2-one (156 μL of a 0.128 M solution in (CH2Cl)2, 0.020 mmol), 4-(4-morpholinyl)-1-naphthalenamine (44 μL of a 0.5 M solution in DMA, 0.022 mmol), and (CH2Cl)2 (300 μL) was agitated and heated at 70° C. for 22 h. The reaction was cooled and concentrated in vacuo, and the residue was redissolved in DMA (25 μL) and (CH2Cl)2 (275 μL). Polyamine resin HL (NovaBiochem) was added (20 mg of 4.53 mmol/g, 0.091 mmol), and the mixture was agitated at room temperature overnight. The resin was removed by filtration and washed with additional (CH2Cl)2 and MeOH. The filtrate was concentrated in vacuo to provide the title compound. MS (ESI) (M+H)+=576.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:14]([CH:16]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17]O)[CH3:15].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.CN(C)C=O>[C:1]([O:9][CH2:17][CH:16]([CH2:14][CH3:15])[CH2:19][CH2:20][CH2:21][CH3:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: CCCCC(CC)CO
Reactant: O=C(O)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCCC(CC)COC(=O)c1cccnc1
Yield: 48.3 %

Procedure:
A mixture of 10 g of nicotinic acid (0.08 mol), 25 g of thionyl chloride (0.21 mol), 1.5 ml of dimethylformamide and 200 ml of benzene was refluxed in an eggplant type flask for 3 hours. The solvent was removed by distillation. To the residue were added 20.8 g (0.16 mol) of 2-ethylhexyl alcohol and benzene, and the mixture was refluxed for 4 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate. The benzene layer was separated, washed successively with a saturated sodium bicarbonate aqueous solution, water and a saturated sodium chloride aqueous solution, dried over sodium sulfate and distilled to remove the solvent. The residue was purified by distillation under reduced pressure and column chromatography to obtain 9.1 g (70%) of 2-ethylhexyl nicotinate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)([O-])=O.[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[CH:33][C:28]=2[CH2:27][CH2:26]1>>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([C:34]3[NH:22][C:21]4[CH:20]=[CH:19][C:6]([NH:7][C:8](=[O:18])[C:9]5[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:33][C:28]=2[CH2:27][CH2:26]1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: CN(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc5c(c4)CCO5)nc3c2)cc1

Procedure:
Compound 183 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-dimethylaminobenzoyl)aniline and 2,3-dihydrobenzofuran-5-carboxaldehyde. [M+H]+ calcd for C24H24N4O2: 399.18; found: 399.47.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:17][CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)[CH2:10]2)[C:5]([Cl:25])=[CH:4][N:3]=1.Cl.[CH3:27][N:28]1[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29]1.C(N(C(C)C)C(C)C)C>CCCCO>[Cl:25][C:5]1[C:6]([NH:8][CH:9]2[CH2:17][CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)[CH2:10]2)=[N:7][C:2]([NH:33][C:31]2[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(Nc3nc(Cl)ncc3Cl)CC2C1
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cn1cc(Nc2ncc(Cl)c(NC3CCC4CN(C(=O)OC(C)(C)C)CC4C3)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a suspension of tert-butyl 5-((2,5-dichloropyrimidin-4-yl)amino)hexahydro-1H-isoindole-2(3H)-carboxylate (767.3 mg, 1.98 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (411.5 mg, 3.08 mmol) in n-BuOH (5 mL) was added N-ethyldiisopropylamine (792.9 g, 6.14 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography ((EtOAc/PE (v/v)=1/1) to give the title compound as a pale yellow solid (493 mg, 55.6%).
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH:16]([NH2:19])([CH3:18])[CH3:17]>CO>[OH:1][CH:2]([CH2:15][NH:19][CH:16]([CH3:18])[CH3:17])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC(C)N
Reactant: COC(=O)c1ccccc1OCC1CO1
Solvent: CO
Product: COC(=O)c1ccccc1OCC(O)CNC(C)C
Yield: 63 %

Procedure:
A mixture of 2.1 g (0.01 mole) of methyl 2-(2,3-epoxypropoxy)benzoate, 10 mL of isopropylamine and 10 mL of methanol was heated to reflux for three hours. The reaction medium was then evaporated under reduced pressure to provide the amine as an oil. The oil was treated with hexane:ethyl acetate (9:1) to generate the free amine as a crystalline product in 63% yield: m.p. 78°-79° C. The NMR spectrum and elemental analysis were consistent with the assigned structure.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11]/[N:12]=[CH:13]/[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:15]=2)=[CH:6][C:5]=1[Br:30].[OH-].[Na+]>>[CH2:23]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](/[CH:13]=[N:12]/[O:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[C:5]([Br:30])[CH:6]=2)=[CH:15]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(CO/N=C/c2cn(Cc3ccccc3)c3ccccc23)cc1Br
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(CO/N=C/c2cn(Cc3ccccc3)c3ccccc23)cc1Br
Temperature: 25 °C
Yield: 77.1 %

Procedure:
To a solution of 4-[({[(1E)-(1-benzyl-1H-indol-3-yl)methylidene]amino}oxy)methyl]-2-bromobenzoic acid methyl ester (0.20 g, 0.42 mmol) in 10/5/3 tetrahydrofuran/ethanol/water (12 mL) was added 2.5 M sodium hydroxide solution (2 mL). This mixture was heated to reflux for 3 hours and then allowed to cool back to room temperature. The mixture was concentrated to approximately ¼ volume and partitioned between ethyl acetate and water. The aqueous layer was acidified to approximately pH 1 using 1 N hydrochloric acid. The layers were then separated. The aqueous layer was extracted with one additional portion of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was recrystallized one time from ethyl acetate/hexanes (1/10) to give the title compound (0.15 g, 75%) as a white powder. mp=107-109° C. 1H NMR (400 MHz, DMSO-d6); δ 13.33 (bs, 1H), 8.42 (s, 1H), 7.92 (s, 1H), 7.90 (d, 1H), 7.73 (d, 1H), 7.71 (s, 1H), 7.52 (d, 1H), 7.44 (d, 1H), 7.23 (m, 7H), 5.52 (s, 2H), 5.28 (s, 2H). Mass spec; (ES+) m/z 462.9, (ES−) m/z 463.2. Elemental analysis; Calculated for C24H19BrN2O3: C, 62.22; H, 4.13; N, 6.05. Found: C, 61.61; H, 4.03; N, 5.82.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][OH:12])=[CH:8][C:6]=2[N:7]=1.[H-].[Na+].[CH3:21]I>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[S:10][C:9]([CH2:11][O:12][CH3:21])=[CH:8][C:6]=2[N:7]=1
Reactant: CI
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol (300 mg) in DMF (10 mL) at 0° C. was added sodium hydride (46 mg). The mixture was stirred for 1 h at 0° C. and then methyliodide (0.07 mL) was added. The reaction mixture was stirred at room temperature for 16 h and then quenched with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4) and concentrated to give 2-chloro-6-methoxymethyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a yellow solid (92 mg).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1>C(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:1][CH:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: OC1CCCc2sccc21
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: c1cc2c(s1)CCCC2OC1CCCCO1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 19.0 g (0.123 mol) of product from Step A, 15.53 g (0.185 mol) of dihydropyran, 2.56 g (0.010 mol) of pyridinium-4-toluenesulfonate, and 700 ml CH2Cl2 was stirred at ambient temperature for 5 hours. The reaction mixture was washed twice with half saturated NaCl solution, dried (Na2SO4), filtered, and evaporated. The residual colorless oil was distilled (112° C., 0.05 mm Hg) yielding a quantitative amount of product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[N:9]=[C:10]([NH:13][C:14]2[CH:19]=[C:18]([S:20][C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[CH:17]=[CH:16][N:15]=2)[S:11][CH:12]=1.Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>CN(C=O)C.O>[CH3:7][C:8]1[N:9]=[C:10]([NH:13][C:14]2[CH:19]=[C:18]([S:20][C:21]3[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=3)[O:27][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:17]=[CH:16][N:15]=2)[S:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1csc(Nc2cc(Sc3cccc(O)c3)ccn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(Nc2cc(Sc3cccc(OCC(=O)OC(C)(C)C)c3)ccn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A mixture of potassium carbonate (1.08 g, 7.82 mmol), 3-(2-(4-methylthiazol-2-ylamino)pyridin-4-ylthio)phenol (0.274 g, 0.869 mmol), and tert-butyl 2-bromoacetate (0.169 g, 0.869 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature overnight, then diluted with water and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified using prepacked silica gel column chromatography with 15-20% ethyl acetate to afford the desired product (0.224 g, 58.8% yield) as light yellow solid. 1H NMR (CDCl3) δ 8.08 (d, 1H), 7.33 (t, 1H), 7.15 (m, 1H), 7.04 (t, 1H), 6.98 (m, 1H), 6.57 (dd, 1H), 6.49 (dd, 1H), 6.33 (d, 1H), 4.50 (s, 2H, 2.22 (d, 3H), 1.46 (s, 9H); Mass spectrum (esi) m/z=430 (100)(M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].Cl[CH2:14][C:15]1[CH:19]=[CH:18][S:17][CH:16]=1>CN(C)C=O>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:14][C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(O)cc1O
Reactant: ClCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccsc2)cc1O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
A stirred solution of 2,4-dihydroxybenzaldehyde (31.8 g) in dry dimethylformamide (150 mL) at ambient temperature is treated with sodium hydride (11.96 g; 60% w/v dispersion in mineral oil; 300 mmol), portionwise, during 30 minutes. After a further period of 15 minutes, the mixture is treated, dropwise, with a solution of 3-chloromethylthiophene (35 g) in dimethylformamide (50 mL). The mixture is stirred at 70° C. for 2 hours, then it is cooled and the solvent is evaporated. The residue is partitioned between ethyl acetate (200 mL) and hydrochloric acid (200 mL; 0.5 M), and the aqueous layer is extracted further with ethyl acetate (2×100 mL). The combined organic extracts are washed with brine (100 mL), dried over magnesium sulphate, and concentrated in vacuo. The residue is subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (1:4 v/v), to give a colourless oil, which crystallises on standing. This solid is recrystallised from diisopropyl ether, to give 2-hydroxy-4-(3-thienylmethoxy)benzaldehyde (8 g), in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Cl.Cl[C:13]([NH2:15])=[NH:14].CS(C)(=O)=O.[OH-].[Na+]>O>[NH2:15][C:13]1[N:14]=[C:9]([NH2:10])[C:3]2[N:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: N=C(N)Cl
Reactant: N#Cc1nc(Cl)ccc1N
Agent: CS(C)(=O)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1nc(N)c2nc(Cl)ccc2n1
Temperature: 165 °C
Yield: 68.2 %

Procedure:
A mixture consisting of 3-amino-6-chloro-pyridine-2-carbonitrile (4.6 g, 30 mmol), chloroformamidine hydrochloride (6.9 g, 60 mmol) and dimethylsulfon (12 g) was heated at 165° C. for 30 minutes. After cooling to room temperature, water (500 ml) was added. The solution was neutralized with a 30% NaOH solution to pH 9-10. The precipitate was filtered off, washed with water, dried over P2O5, resulting in the pure title compound as a yellow solid (4.0 g, yield: 68%) which was characterised as follows:
Reaction SMILES: [Na].C(O[C:5](=[O:23])[CH2:6][C@H:7]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[Br:22])[NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12])C.C[O-].[Na+]>CO>[Br:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C@@H:7]1[NH:8][C:9](=[O:14])/[C:10](=[C:11](/[OH:13])\[CH3:12])/[C:5](=[O:23])[CH2:6]1
Reactant: CCOC(=O)C[C@@H](NC(=O)CC(C)=O)c1ccc(F)cc1Br
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: C/C(O)=C1/C(=O)C[C@H](c2ccc(F)cc2Br)NC1=O
Temperature: 100 °C

Procedure:
To a flask containing 30 mL dry MeOH was added sodium metal (1.00 g, 43.5 mmol, 3.4 eq.). The mixture was stirred vigorously until sodium is dissolved. To a pressure vessel containing 31F (4.81 g, 12.9 mmol, 1.0 eq.) in MeOH (50 mL) was added the freshly prepared NaOMe solution. The pressure vessel was sealed and heated at 100° C. overnight. LC/MS analysis showed the product as the major signal. The reaction mixture was concentrated and then diluted with methylene chloride (500 mL) and aqueous 1 N NH4Cl (100 mL). The organic phase was further washed with aqueous 1 N NH4Cl (100 mL) and saturated aqueous NaCl (100 mL). The combined aqueous phases were extracted with methylene chloride (2×75 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give a dark yellow solid 31G which was deemed pure enough to take on to the next reaction without further purification (2.05 g, 49%). ESI-MS: m/z 328.2 (M+H)+
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([Br:40])=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[Br:40][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:2]2[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:26][CH:27]=3)[N:3]=2)=[C:37]2[C:33]=1[CH2:34][N:35]([CH3:39])[C:36]2=[O:38]
Reactant: CN1Cc2c(Br)ccc(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Yield: 37.9 %

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (50.0 mg, 0.118 mmol) and 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (34.14 mg, 0.1416 mmol). The reaction mixture was concentrated under reduced pressure to yield a yellow oil which was purified on an ISCO Combiflash system using (DCM/MeOH 100:0→95:5) as eluent to isolate 28.1 mg of the title compound (38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (t, J=7.07 Hz, 6 H), 3.09 (s, 3 H), 3.18-3.27 (m, 2 H), 3.92-4.03 (m, 4 H), 4.43 (s, 2 H), 7.23-7.33 (m, 8 H), 7.55 (br. s., 5 H), 7.63 (d, J=8.84 Hz, 4 H), 8.50 (s, 4 H), 9.95 (s, 4 H), 10.54 (br. s., 3 H). MS (ES+): m/z 627.95/629.93 (91/100) [MH+]. HPLC: tR=3.72 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23](I)=[CH:22][C:21]=3[O:27][CH2:28][CH3:29])=[N:9]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]([O:37][CH2:38][CH3:39])=[CH2:36])CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:35]([O:37][CH2:38][CH3:39])=[CH2:36])=[CH:22][C:21]=3[O:27][CH2:28][CH3:29])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCOc1cc(I)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2)c(OCC)c1
Temperature: 120 °C

Procedure:
4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-iodophenyl)-4,5-dihydro-1H-imidazole (0.900 g, 1.68 mmol), tributyl-(1-ethoxyvinyl)tin (0.679 mL, 2.01 mmol) and tetrakis(triphenyl-phosphine)-palladium(0) (0.194 g, 0.168 mmol) were combined in toluene (10 mL) in a flame-dried Schlenk tube then heat at 120° C. for 20 h. After evaporation of volatiles, the residue was purified by flash column chromatography (silica gel, eluting with a gradient of 2-5% methanol in chloroform) to give 4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-(1-ethoxyvinyl)phenyl]-4,5-dihydro-1H-imidazole as a faintly green foam (0.639 g, 79%). LC-MS: 481.4 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH:23]=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:30][CH2:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl([O-])=[O:35].[Na+].P([O-])(O)(O)=O.[Na+].CC(=CC)C>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([C:23]([OH:35])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:30][CH2:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCO[C@@H]1CN(c2nc(C=O)c(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Product: CCCO[C@@H]1CN(c2nc(C(=O)O)c(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 97.4 %

Procedure:
The same operation as in Example (33c) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl)-4-formyl-1,3-thiazole-5-carboxylate obtained in Example (74b) (445 mg, 0.89 mmol), sodium chlorite (180 mg, 1.99 mmol), sodium dihydrogenphosphate (557.6 mg, 3.57 mmol) and 2-methyl-2-butene (0.57 mL, 5.36 mmol), to obtain 445.4 mg of the title compound as a white solid (97%).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([C:16]([NH:18][C:19]1[CH:31]=[CH:30][C:22]2[S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:21]=2[CH:20]=1)=[O:17])([CH3:15])([CH3:14])[CH3:13].C(Cl)Cl>ClCCCl>[O:6]=[S:23]1[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:21]2[CH:20]=[C:19]([NH:18][C:16]([C:12]([CH3:15])([CH3:13])[CH3:14])=[O:17])[CH:31]=[CH:30][C:22]1=2
Reactant: CC(C)(C)C(=O)Nc1ccc2sc3ccccc3c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc2c(c1)-c1ccccc1S2=O
Yield: 8.9 %

Procedure:
m-Chloroperoxybenzoic acid (50% wt/wt, 770 mg, 2.0 mmol) was added to a solution of 2-(t-butylcarbonylamino)dibenzothiophene (Example 2; 566 mg, 2.0 mmol) in 1,2-dichloroethane and the resultant mixture warmed at 80% for 16 hours then cooled and DCM was added (50 ml). The mixture was washed with 2 M sodium hydroxide, water and brine, dried and evaporated in vacuo to a brown gum. This was purified by chromatography eluting with 0-2% methanol in DCM. The impure product thus obtained was purified by preparative HPLC (Dynamax C-18 60A column eluted with 40-95% acetonitrile in water plus 0.1% trifluoroacetic acid) to obtain the product (53.5 mg) NMR: 9.59 (s, 1H), 8.35 (d, 1H), 8.03 (d, 1H), 7.97 (d, 1H), 7.93 (d, 1H), 7.80 (dd, 1H), 7.70 (t, 1H), 7.56 (t, 1H), 1.16 (s, 9H); m/z 300.
Reaction SMILES: [ClH:1].C([O:6][C:7](=[O:31])[C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[S:13]([C:16]1[CH:25]=[C:24]2[C:19]([C:20]([Br:30])=[CH:21][N:22]=[C:23]2[NH:26][C:27]([NH2:29])=[NH:28])=[CH:18][CH:17]=1)(=[O:15])=[O:14])(C)(C)C.Cl>CCOC(C)=O>[ClH:1].[Br:30][C:20]1[C:19]2[C:24](=[CH:25][C:16]([S:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[C:7]([OH:31])=[O:6])(=[O:15])=[O:14])=[CH:17][CH:18]=2)[C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[N:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1S(=O)(=O)c1ccc2c(Br)cnc(NC(=N)N)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: N=C(N)Nc1ncc(Br)c2ccc(S(=O)(=O)N3CCC[C@@H]3C(=O)O)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.7 %

Procedure:
Anal. Found: C, 41.96: H, 4.65; N, 12.65. Calc. for C19H24BrN5O4S.HCl.90.5H2O: C, 41.96:, 4.82; N, 12.88%. N-[(4-Bromo-1-guanidino-7-isoquinolinyl)sulphonyl]-D-proline tert-butyl ester hydrochloride (150 mg, 0.28 mmol) was treated with an ice-cold solution of HCl in EtOAc (20 ml), and the reaction allowed to warm to room temperature, and stirred for 4 h. The solution was concentrated in vacuo and the crude product purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880 NH3 (90:10:1) as eluant. The product was treated with ethereal HCl, the resulting precipitate filtered, washed with Et2O and dried to afford N-[(4-bromo-1-guanidino-7-isoquinolinyl)sulphonyl]-D-proline hydrochloride (75 mg, 0.156 mmol) as a white powder.