Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([C@@H:19]([NH:21][C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][N:25]=[C:24](Cl)[N:23]=1)[CH3:20])=[CH:7]2.[OH-].[NH4+:33]>C1COCC1>[NH2:33][C:24]1[N:23]=[C:22]([NH:21][C@H:19]([C:8]2[N:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:10](=[O:12])[C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[CH3:20])[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][N:25]=1
Reactant: [NH4+]
Reactant: C[C@H](Nc1nc(Cl)ncc1[N+](=O)[O-])c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(N)ncc1[N+](=O)[O-])c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Compound 75 (450 mg, 0.99 mmol) was dissolved in THF (45 mL), treated with concentrated ammonium hydroxide solution (9 mL), and stirred at ambient temperature for 16 h. The solvent was evaporated in vacuo and the residue suspended in water (50 mL) and brine (20 mL), and extracted with DCM (3×35 mL). The combined organic layers were washed with brine (15 mL each), dried over Na2SO4, and concentrated to afford (S)-3-(1-(2-amino-5-nitropyrimidin-4-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one 76, 430 mg (0.99 mmol, quant.). ESI-MS m/z: 437.16 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]2.S(O)(O)(=O)=O.[CH2:20]([N:22]([CH2:30][CH3:31])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[CH3:21].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:30]([N:22]([CH2:20][CH3:21])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:12]([CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=3)[CH2:10]2)=[O:14])=[CH:25][CH:24]=1)[CH3:31]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: O=C(O)C1CCc2cccc(O)c2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(NC(=O)C2CCc3cccc(O)c3C2)cc1
Reaction time: 8 h
Yield: 62 %

Procedure:
This phenol from Example 6A was dissolved in DMF (4.0 mL) and N,N-Diethyl-benzene-1,4-diamine sulfate (602 mg, 2.3 mmol), Et3N (707 mg, 7.0 mmol), and TBTU (738 mg, 2.3 mmol) were added at ambient temperature. The mixture was stirred overnight and purified by silica gel column chromatography to provide 8-hydroxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (4-diethylamino-phenyl)-amide (480 mg, 62%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[C:21]1([C:27]2[CH:36]=[CH:35][C:30]([O:31][CH2:32][CH2:33]O)=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:33][CH2:32][O:31][C:30]2[CH:35]=[CH:36][C:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:28][CH:29]=2)=[CH:7][CH:6]=1
Reactant: OCCOc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc(-c3ccccc3)cc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 29.7 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(4-phenylphenoxy)ethanol (1.4 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The crude dichloromethane extract was purified by HPLC (dichloromethane-hexane; 4:1) and the resulting solids were crystallized from dichloromethane-diethyl ether to provide 0.45 g of 4-[[2-[4-(1,1'-biphenyl)oxy]ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester as an 0.25 molar hydrate, mp 143°-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[CH:5][C:4]=1[OH:16].C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]>CC(C)=O>[CH3:15][C:13]1[N:14]=[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:16][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH:5]=2)[S:11][CH:12]=1
Reactant: CC(C)=CCBr
Reactant: COc1ccc(Nc2nc(C)cs2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Nc2nc(C)cs2)cc1OCC=C(C)C
Yield: 54 %

Procedure:
Following the general procedure for O-alkylation, Method A, a mixture of 2-methoxy-5-(4-methylthiazol-2-ylamino)phenol (30 mg, 0.10 mmol) and K2CO3 (15 mg, 0.11 mmol) in acetone (1.0 mL) was treated with 4-bromo-2-methyl-2-butene (0.014 mL, 0.12 mmol). The reaction mixture was heated at reflux for 4 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 54% yield (16 mg).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8](OCC)=[O:9])=[C:5]([CH3:7])[N:6]=1.[BH4-].[Na+]>CCO.O>[Br:1][C:2]1[S:3][C:4]([CH2:8][OH:9])=[C:5]([CH3:7])[N:6]=1
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1nc(Br)sc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a solution of ethyl 2-bromo-4-methylthiazole-5-carboxylate (7 g, 28 mmol) in EtOH (120 mL) and H2O (20 mL) was added portion-wise NaBH4 (3.2 g, 84 mmol). After the addition, the mixture was stirred at room temperature overnight. TLC (petroleum ether/EtOAc=5:1) showed the reaction was complete. The reaction mixture was carefully concentrated in vacuum. The residue was separated between EtOAc (50 mL) and H2O (50 mL). The inorganic layer was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuum to give the title compound as a colorless oil (3.8 g, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:17][C:16]=1[NH2:26])([O-:14])=[O:13].C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:26][C:16]2[CH:17]=[C:18]([C:21]3[NH:22][CH:23]=[CH:24][CH:25]=3)[CH:19]=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1cc(-c2ccc[nH]2)ccc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(-c3ccc[nH]3)ccc2[N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 101.1 %

Procedure:
A solution of 4-methoxybenzoyl chloride (145, 0.175 g, 1.0 mmol), aniline 144 (79.2 mg, 0.39 mmol) and 4-(dimethylamino)pyridine (catalytic amount) was stirred at room temperature for 24 h. The reaction mixture was diluted with DCM, treated with saturated NaHCO3, stirred for 3 h and diluted with AcOEt. Organic phase was collected, washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated to provide compound 146 (0.133 g, 100% yield).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]CC=C)=[CH:7][CH:6]=1.Cl[C:18]1[CH:23]=CC(Cl)=C[C:19]=1Cl>>[CH2:23]([C:7]1[CH:6]=[C:5]([O:4][CH2:3][C:2]([F:1])([F:15])[F:16])[CH:10]=[CH:9][C:8]=1[OH:11])[CH:18]=[CH2:19]
Reactant: C=CCOc1ccc(OCC(F)(F)F)cc1
Reactant: Clc1ccc(Cl)c(Cl)c1
Product: C=CCc1cc(OCC(F)(F)F)ccc1O

Procedure:
A solution of allyl 4-(2,2,2-trifluoroethoxy)phenyl ether (1.9 g, 8.2 mmol) in 1,2,4-trichlorobenzene 30 ml was heated to 180° C. for 24 hr. The solvent was removed under reduced pressure, and the crude product was chromatographed on silica gel eluting with 20% AcOEt/hexanes to give 0.9 g of 2-allyl-4-(2,2,2-trifluoroethoxy)phenol. This material was dissolved in 30 ml ethanol and was hydrogenated with 15 mg of 10% Pd/C in a Parr shaker under hydrogen atmosphere (50 psi) overnight. The catalyst was removed by suction-filtration through a pad of celite. The filtrate was concentrated to give the title compound 0.73 g as a clear oil.
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[CH3:18])[C@H:5]([OH:19])[C@@H:4]1[OH:20].[CH3:21][NH2:22].C(O)C>>[CH3:21][NH:22][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[CH3:18])[C@H:5]([OH:19])[C@@H:4]1[OH:20]
Reactant: CN
Reactant: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Solvent: CCO
Product: CNC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 90 °C

Procedure:
A mixture of 3a (660 mg, 2.20 mmol) in 33% methylamine/ethanol solution (30 mL) in a steel bomb was heated for 2 days at 90° C. The reaction mixture was concentrated to dryness and purified by column chromatography (elution with 4:1:0.3 chloroform:methanol:NH4OH). The desired fractions were combined, concentrated and dried in vacuo: yield 294 mg (45%); MS m/z 295 (M+H)+; 1HNMR (DMSO-d6) δ 8.08 (bs, 1H, H-2), 7.14 (bs, 2H, 6-NH2), 5.72 (d, 1H, H-1′, J1′,2′=6.5 Hz), 5.30 (d, 1H, 2′-OH, J2′-2′OH=6.3 Hz), 5.17 (bd, 1H, 3′-OH, J3′-3′OH=3.5 Hz), 5.01 (ddd, 1H, H-2′, J1′,2′=6.5 Hz, J2′,3′=5.5 Hz, J2′-2′OH=6.3 Hz), 4.16 (bs, 1H, H-3′), 3.96-4.0 (m, 1H, H-4′), 2.64-2.77 (bm, 2H, 5′-CH2), 2.53 (s, 3H, 8-CH3), 2.29 (s, 3H, 5′NH—CH3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[CH:15]1[C:27]2[CH:26]([CH2:28][O:29][C:30](ON3C(=O)CCC3=O)=[O:31])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.Cl>O.O1CCCC1>[CH:15]1[C:27]2[CH:26]([CH2:28][O:29][C:30]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]3)=[O:31])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: O=C(O)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
Piperidine-4-carboxylic acid (15.00 g, 116 mmol) was added to a solution of sodium hydrogen carbonate (12.7 g, 151 mmol) in water (200 mL) and the mixture was stirred for 10 min. A solution of 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy-2,5-pyrrolidinedione (Fmoc-OSu; 46.9 g, 139 mmol) in tetrahydrofuran (400 mL) was added. The solution was stirred at room temperature for 20 h and then acidified to pH 1 with 3 M HCl (500 mL). The mixture was extracted with ethyl acetate (200 mL then 100 mL) and the combined organic layers were washed with saturated brine (3×100 mL), dried (Na2SO4), filtered and concentrated to approximately 100 mL. Crystallization occurred on concentration. The mixture was allowed to stand for 2 h, then the solid was filtered off, washed with ethyl acetate and dried in a vacuum oven at 60° C. to give N-[(9H-fluoren-9-ylmethoxy)carbonyl]piperidine-4-carboxylic acid (34.51 g, 85%) as a white solid, mp 187-189° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:18])[CH:10]=[CH:11]C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][C:9](=[O:18])[CH:10]=[CH:11]2
Reactant: O=C(C=Cc1ccccc1)Nc1ccccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: O=c1ccc2cccc(Br)c2[nH]1
Temperature: 100 °C
Reaction time: 7 h
Yield: 65 %

Procedure:
A mixture of N-(2-bromophenyl)cinnamamide (172.3 g, 570.3 mmol), aluminum chloride (456 g, 342 mmol) and chlorobenzene (1000 ml) were allowed to stir at 100° C. for 7 hours followed by cooling to ambient temperature overnight. The resulting mixture was poured onto 2 kg of ice and was allowed to warm to ambient temperature over 1 hour. The resulting mixture was extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting solids were triturated with 1000 ml hexanes. The solids were vacuum dried to yield title compound. (83 g, 65% yield) MS ESI (+) m/z 224 and 226 (M+1 of each isotope) detected.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29](C)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[N:33]1(S(N2CCNCC2)(=O)=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Reactant: O=S(=O)(N1CCCCC1)N1CCNCC1
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)cc3c2)CC1
Yield: 87 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate b), and 1-(piperidin-1-yl-sulfonyl)-piperazine to afford the desired product as a light-brown solid (87%). MS (ISP): 531.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.Cl[CH2:21][C:22]1[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[O:25][CH:26]=1>>[CH3:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1/[CH:28]=[CH:27]/[C:24]1[O:25][CH:26]=[C:22]([CH2:21][O:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]3[CH:6]=[CH:7][N:8]=[C:4]3[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=2)[N:23]=1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Reactant: Cc1ccccc1/C=C/c1nc(CCl)co1
Product: Cc1ccccc1/C=C/c1nc(COc2ccc(CCCCn3ccnc3CCO)cc2)co1
Yield: 62.1 %

Procedure:
Using 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (153 mg) and (E)-4-chloromethyl-2-[2-(2-methylphenyl)ethenyl]oxazole (151 mg), the same reaction as Example 1 was carried out to yield the titled compound (167 mg) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.I.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](SC)=[NH:24].N>CCO.CO>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:23]([C:19]3[S:18][CH:22]=[CH:21][CH:20]=3)=[NH:24])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: CN(C)CCN1CCCc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: N
Solvent: CCO
Solvent: CO
Product: CN(C)CCN1CCCc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(2-(dimethylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine (900 mg, 4.10 mmol) in 25 mL EtOH was treated with methyl thiophene-2-carbimidothioate hydroiodide (2.34 g, 1.43 mmol) and stirred overnight at room temperature. Argon was bubbled through the mixture for 20 minutes then it was partitioned between CH2Cl2 (100 mL) and saturated sodium bicarbonate (20 mL). The organic layer was separated and the aqueous layer was extracted with an additional 50 mL CH2Cl2. The combined organic layers were rinsed with water, dried over sodium sulfate, filtered and concentrated to give a dark oil which was subjected to flash chromatography on silica gel using 5% MeOH/CH2CH2then 5% 2M NH3 in MeOH/CH2C12 to give an orange solid. 1H-NMR (DMSO-d6) δ: 7.66 (d, J=3.6 Hz, 1H), 7.55 (d, J=4.8 Hz, 1H), 7.08-7.05 (m, 1H), 6.57-6.48 (m, 3H), 6.25 (brs, 2H), 3.29-3.21 (m, 4H), 2.65 (t, J=6.3 Hz, 2H), 2.39 (t, J=6.3 Hz, 2H), 2.19 (s, 6H), 1.85-1.82 (m, 2H).
Reaction SMILES: CI.[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12](=[O:18])[NH:13][C:14](=[S:17])[NH:15][CH:16]=2)=[CH:6][CH:5]=1.[OH-].[Na+].[C:21](O)(=O)C>O>[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12](=[O:18])[NH:13][C:14]([S:17][CH3:21])=[N:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CSc1ncc(Cc2ccc(C)nc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (13.79 g) was added to a stirred solution of 5-(6-methyl-3-pyridylmethyl)-2-thiouracil (22.66 g) and sodium hydroxide (8.0 g) in water (250 ml), and the mixture was heated at 70° for 1 hour and stirred at room temperature overnight. Acetic acid was added until pH 5 and the volume of the mixture was evaporated to a volume of 50 ml. The solid was filtered off and was recrystallised from ethanol-acetic acid to give 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone (10.16 g) m.p. 197°-197.5°.
Reaction SMILES: [Cl:1]Cl.[CH3:3][O:4][CH2:5][C:6]([N:8]([CH:17]1[CH2:21][CH2:20][O:19][C:18]1=[O:22])[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])=[O:7]>C(O)=O.[Fe](Cl)(Cl)Cl>[CH3:3][O:4][CH2:5][C:6]([N:8]([CH:17]1[CH2:21][CH2:20][O:19][C:18]1=[O:22])[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([Cl:1])[C:10]=1[CH3:16])=[O:7]
Reactant: COCC(=O)N(c1c(C)cccc1C)C1CCOC1=O
Reactant: ClCl
Agent: Cl[Fe](Cl)Cl
Solvent: O=CO
Product: COCC(=O)N(c1c(C)ccc(Cl)c1C)C1CCOC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
Over 2 hours, 74.6 g (1.05 moles) of chlorine are introduced at 25°-30° C. into a solution of 277 g (1.0 mole) of N-methoxyacetyl-N-(2-oxotetrahydro-3-furyl)-2,6-dimethylaniline and 5 g of iron(III) chloride in 300 ml of 85% formic acid. The reaction is exothermic and virtually no gas evolves. When the addition of chlorine is complete, the reaction mixture is stirred for 30 minutes at 25° C., the formic acid is then distilled off in vacuo, the residue is taken up in 500 ml of toluene and the toluenic solution is washed with 100 ml of water. The oily residue obtained after the toluene has been distilled off is crystallised from a mixture of isopropanol and hexane, affording 287 g (92% of theory) of N-methoxyacetyl-N-(2-oxotetrahydro-3-furyl)-3-chloro-2,6-dimethylaniline with a melting point of 80°-82° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ncccc1C(=O)c1cc(Cl)ccc1N
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ncccc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone (243 mg, 1.0 mmol) and 4-tert-Butyl-benzenesulfonyl chloride (232 mg, 1.0 mmol) and purified by HPLC. 1H NMR (CDCl3) δ 10.71 (br s, 1H, NH), 8.63 (dd, 1H, J=5.1 Hz, J=1.6 Hz), 7.83 (d, 1H, J=8.8 Hz), 7.73 (dm, 2H, J=8.4 Hz), 7.49 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.43 (dm, 2H, J=8.5 Hz), 7.27 (dd, 1H, J=9.5 Hz, J=1.8 Hz), 7.18 (dd, 1H, J=7.7 Hz, J=4.8 Hz), 7.13 (d, 1H, J=2.6 Hz), 2.29 (s, 3H), 1.29 (s, 9H). MS: m/z 443 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([F:25])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]3[N:15]([CH3:16])[C:14]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:13]=4[N:12]=3)=[N:7][C:6]=2[CH:24]=1.CN.[CH3:28][N:29](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:28][NH:29][C:21]([C:19]1[CH:18]=[CH:17][C:14]2[N:15]([CH3:16])[C:11]([NH:10][C:8]3[S:9][C:5]4[CH:4]=[C:3]([F:25])[C:2]([F:1])=[CH:24][C:6]=4[N:7]=3)=[N:12][C:13]=2[CH:20]=1)=[O:23]
Reactant: Cn1c(Nc2nc3cc(F)c(F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3cc(F)c(F)cc3s1)n2C
Yield: 69.7 %

Procedure:
2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid methylamide (26 mg) was prepared by following General Procedure F using 2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (36 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg), and DIEA (0.2 ml). LCMS: m/z 375; and 1H NMR (DMSO-d6, 400 MHz): δ 8.30 (d, 1H), 8.04 (s, 1H), 7.93 (d, 1H), 7.60 (d, 1H), 7.49 (m, 2H), 7.29 (d, 1H), 3.62 (s, 3H), and 2.80 (d, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:5]=[CH:6][CH:7]=1.C(OC([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([Cl:33])[CH:31]=2)/[C:26](=[CH:34]/[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)/[C:25]1=[O:42])=O)(C)(C)C>C1(C)C=CC=CC=1>[Cl:33][C:30]1[CH:31]=[C:32]2[NH:24][C:25](=[O:42])[C:26]3([CH:34]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=4)[CH2:12][C:10](=[O:11])[NH:9][CH:8]3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=3)[C:27]2=[CH:28][CH:29]=1
Reactant: C=C(N=Cc1cccc(I)c1)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(I)c2)N1
Temperature: 140 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To a solution of 1-(3-iodophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 192a (1.2 g, 3.5 mmol) in toluene (40 mL) was added E/Z-6-chloro-3-(3-chlorobenzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 24a (0.5 g, 1.28 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 140° C. for 1 h. After the solution was cooled to room temperature and concentrated. The residue was dissolved in dichloromethane (20 mL) and trifluoroactic acid (10 mL) was added. After the reaction mixture was stirred at room temperature for 0.5 h, the mixture was concentrated. The residue was partitioned between saturated NaHCO3 solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:3 then 1:2) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-iodophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.56 g, 77%).
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[NH2:13][C:14]1[NH:18][C:17]([CH2:19][C:20]2[O:24][C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:21]=2)=[N:16][C:15]=1[C:30](=[O:32])[NH2:31].C(=O)([O-])O.[Na+].O>C1COCC1>[C:30]([C:15]1[N:16]=[C:17]([CH2:19][C:20]2[O:24][C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:21]=2)[NH:18][C:14]=1[NH:13][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1)(=[O:32])[NH2:31]
Reactant: CCOC(=O)c1ccc(Cc2nc(C(N)=O)c(N)[nH]2)o1
Reactant: CCCc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1ccc(C(=O)Nc2[nH]c(Cc3ccc(C(=O)OCC)o3)nc2C(N)=O)cc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 57 %

Procedure:
4-Propylbenzoyl chloride (2 ml; 11.9 mM) are added dropwise to 3 g (10.8 mM) of ethyl 5-(5-amino-4-carbamoyl-1H-imidazol-2-ylmethyl)furan-2-carboxylate and 1.8 g of sodium hydrogen carbonate (21.6 mM) in 15 ml of THF. The reaction medium is then stirred at 20° C. for 20 hours. After addition of water, a solid precipitate is formed, which is isolated and purified by chromatography on silica, first using a dichloromethane/acetone mixture (90/10) as eluent, and then a dichloromethane/methanol mixture (90/10) to give 2.9 g of ethyl 5-[4-carbamoyl-5-(4-propylbenzoylamino)-1H-imidazol-2-ylmethyl]furan-2-carboxylate in the form of a white solid.