Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH:44]([C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=1)([CH2:46][CH3:47])[CH3:45]>C1COCC1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:52][C:51]1[CH:53]=[CH:54][C:48]([CH:44]([CH2:46][CH3:47])[CH3:45])=[CH:49][CH:50]=1)=[O:6]
Reactant: CCC(C)c1ccc(N)cc1
Reactant: CS(=O)(=O)c1ccc(N)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCC(C)c1ccc(NC(=O)c2cc(S(C)(=O)=O)ccc2N)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 2-amino-5-methanesulfonyl-benzoic acid (0.750 g, 3.48 mmol) in THF (50 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.730 g, 3.83 mmol), 1-hydroxybenzotriazole (0.510 g, 3.83 mmol), and 4-methylmorpholine (0.380 g, 3.83 mmol). The reaction mixture was stirred at room temperature for 5 minutes and then 4-sec-butyl-aniline (0.780 g, 5.22 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo, water was added, and the product was extracted with ethyl acetate. The solvent was evaporated in vacuo and the residue was washed with ether to obtain 2-amino-N-(4-sec-butyl-phenyl)-5-methanesulfonyl-benzamide as white solid. Yield: 0.75 g (62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:20][C:21]#[C:22][CH3:23])([CH2:16][C:17]#[C:18][CH3:19])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:25][OH:26]>>[OH:26][NH:25][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH2:20][C:21]#[C:22][CH3:23])[CH2:16][C:17]#[C:18][CH3:19]
Reactant: CC#CCC(CC#CC)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Product: CC#CCC(CC#CC)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 89 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid hydroxyamide was prepared according to the method as outlined in example 1. Starting from 2-(4-methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid (0.27 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.23 g of the product was isolated. Yield 89%; white solid; mp 135-137° C.; MS: 349.9 (M+H)+1; 1H NMR (300 MHz, DMSO-d6) δ 1.67 (s, 6H), 2.70-3.10 (m, 4H), 3.88 (s, 3H), 7.15 (d, J=10.0 Hz, 2H), 7.71 (d, J=10.0 Hz, 2H), 9.20 (brs, 1H), 10.90 (brs, 1H); IR (KBr, cm−1): 3301 s, 3161 m, 2922 m, 1640 m, 1595 s, 1500 m.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=O.C(=O)([O-])O.[Na+].O>C(O)CC>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:1]=[C:2]3[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]3[CH:10]=2)=[CH:14][CH:15]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: Nc1ccc(I)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Solvent: O
Product: Clc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 80 °C
Yield: 68.5 %

Procedure:
5.0 g of 2-amino-5-iodopyridine, 5.3 g of 2-bromo-1-(4-chlorophenyl)ethanone and 2.67 g of sodium hydrogen carbonate in 150 ml of n-propanol are placed in a round-bottomed flask. The mixture is heated at 80° C. for 40 h and left to cool, and 700 ml of water are added. The precipitate is recovered by filtration, washed with water and dried under reduced pressure. 5.51 g of compound are obtained.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8](Br)[CH:7]=1)=[O:5])C.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.Cl.C(=O)(O)[O-].[Na+]>CS(C)=O.O>[CH2:19]([NH:18][C:16]([NH:15][C:13]1[N:14]=[C:10]2[CH:9]=[C:8]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:7]=[C:6]([C:4]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:5])[N:11]2[N:12]=1)=[O:17])[CH3:20]
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)OCC)n2n1
Reactant: C1CCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(N3CCCC3)cc(C(=O)N3CCCC3)n2n1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 7-bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester prepared as in Example 16, Step 1 (0.080 g, 0.22 mmol) in dimethylsulfoxide (1 mL) was added pyrrolidine (0.2 mL). The reaction was stirred at 23° C. for 30 minutes, then 80° C. for 3 days. The reaction was then diluted with 2 volumes of water, acidified with 1N aqueous hydrogen chloride, then neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give a colorless oily solid that was purified by silica gel chromatography (gradient elution: 0-20% isopropanol/dichloromethane) to give 1-ethyl-3-[5-(pyrrolidine-1-carbonyl)-7-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-urea MS (APCI)=372.2 [M+H]
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21]([NH:23][C:24]3[N:28]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)[N:27]=[C:26]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:25]=3)=[O:22])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[CH3:40][O:41][CH2:42][C:43](Cl)=[O:44].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[C:36]([C:26]1[CH:25]=[C:24]([NH:23][C:21](=[O:22])[NH:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([O:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:43](=[O:44])[CH2:42][O:41][CH3:40])[N:7]=3)=[CH:11][CH:12]=2)[N:28]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[N:27]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: COCC(=O)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(N)n3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1nccc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
A suspension of 1-(4-((2-aminopyrimidin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate H) (52 mg, 0.100 mmol) in DCM (1.0 mL) and DMF (100 μl) was treated with methoxyacetyl chloride (27 μl, 0.299 mmol) followed by DIPEA (52. μl, 0.299 mmol). After stirring overnight at RT, the volatiles were evaporated and the residue suspended in a mixture of MeOH (2.0 mL) and AcOH (2.0 mL). The suspension was subjected to SCX capture and release. Very little material eluted off hence the SCX from the cartridge was removed and extracted with MeOH (50 mL). After evaporation, an off white solid was obtained and this was triturated from MeOH (1.0 mL) and diethyl ether (5.0 mL) to give N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyrimidin-2-yl)-2-methoxy acetamide (Example 23) as a white solid (12 mg, 19% yield): m/z 594 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.40 (3H, s), 3.34 (3H, s), 4.24 (2H, s), 5.34 (2H, s), 6.35 (1H, s), 7.02 (1H, d), 7.35 (2H, d), 7.44 (3H, m), 7.60 (3H, m), 7.95 (1H, m), 8.36 (1H, m), 8.59 (1H, br s), 8.68 (1H, d), 8.80 (1H, br s), 10.44 (1H, br s).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCCCC.C(O[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1)(C)C.C(O)(=O)C>O1CCCC1.O>[CH3:1][N:2]1[C:6]([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1cccn1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C

Procedure:
N-Methylpyrazole (6.0 kg, 1 mol eq, limiting reagent) was charged, followed by anhydrous tetrahydrofuran (84 L, 14 rel vol) and the reaction mixture was cooled to −10° C. n-Hexyllithium (2.3 M solution in hexanes, 23.6 kg, 1.05 mol eq) was charged keeping the temperature below −5° C., followed by a line rinse of iso-hexane (1.2 L, 0.2 rel vol). The reaction mixture was stirred at below −5° C. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (14.9 kg, 1.1 mol eq) was diluted with anhydrous tetrahydrofuran (6.0 L, 1 rel vol) and was charged to the reaction keeping the temperature below 0° C. A line rinse with anhydrous tetrahydrofuran (3.0 L, 0.5 rel vol) was charged and the reaction mixture was stirred for around 30 minutes. The reaction was warmed to 25° C. A solution of glacial acetic acid (6.6 kg, 1.5 mol eq) in water (36 L, 6 rel vol) was charged to the reaction over about 30 minutes. The reaction mixture was stirred for around 30 minutes. The phases were separated and the organic layer retained. Change of solvent to acetonitrile by distillation afforded the title compound as a solution in acetonitrile. The solution yield of the title compound was determined by GC assay; 1H NMR (d6-DMSO): δ 1.31 (s, 12H), 3.98 (s, 3H), 6.62 (d, 1H, J=1.9 Hz), 7.45 (d, 1H, J=2.1 Hz) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:15](O)[CH3:16]>Cl>[CH2:15]([O:13][C:12](=[O:14])[CH2:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([OH:1])[CH:3]=1)[CH3:16]
Reactant: CCO
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])c(O)c1
Agent: Cl
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])c(O)c1

Procedure:
A solution of (3-hydroxy-4-nitro-phenyl)-acetic acid (4.0 g, prepared according to the procedure described by Meyer et al, J. Med. Chem., 1997, 40, pages 1049–1062) in ethanol (approximately 100 mL) was treated with concentrated hydrochloric acid (5–8 drops) was heated at reflux temperature for 3 hours then evaporated. The residue was dissolved in tert-butyl methyl ether and the solution was washed with saturated aqueous sodium bicarbonate solution, then with water, then dried, and then evaporated to give the title compound (5.0 g) as a light yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[CH2:9][C@@H:8]([CH2:10][OH:11])[NH:7][C:6]1=[O:12].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14].C(N(CC)CC)C.S(C1C=CC([N+]([O-])=O)=CC=1)([O-])(=O)=O>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([S:22]([O:11][CH2:10][C@@H:8]2[CH2:9][C@@H:5]([CH2:4][CH2:3][CH2:2][Cl:1])[C:6](=[O:12])[NH:7]2)(=[O:24])=[O:23])=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1N[C@H](CO)C[C@H]1CCCCl
Agent: CN(C)c1ccncc1
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1N[C@H](COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C[C@H]1CCCCl
Temperature: 25 °C
Reaction time: 17 h
Yield: 85.7 %

Procedure:
The (3R,5S)-3-(3-chloropropyl)-5-(hydroxymethyl)pyrrolidin-2-one (8.31 g, 43.4 mmol, 1.0 equiv), p-nitrobenzenesulfonylchloride (10.57 g, 47.7 mmol, 1.1 equiv) and DMAP (0.53 g, 4.4 mmol, 0.1 equiv) were added to a 500 mL round-bottom flask and dissolved in THF (100 mL) under nitrogen. Triethylamine (8.77 g, 12.1 mL, 86.7 mmol, 2.0 equiv) was added via syringe and the resulting solution stirred for 17 h at ambient temperature. After this time complete formation of the desired nosylate was observed by LC/MS analysis. The mixture was diluted with 50 mL of EtOAc and the amines quenched by addition of 100 mL of 1.0 M HCl. The layers were separated and the organic layer washed with brine, dried over Na2SO4, filtered and evaporated. The pale yellow solid was washed with ether and residual solvent removed in vacuo. This afforded 14.02 g (86% yield) of ((2S,4R)-4-(3-chloropropyl)-5-oxopyrrolidin-2-yl)methyl 4-nitrobenzenesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]1SCCCS1.[CH:17]1([CH:23]=[CH:24][C:25](OCC)=[O:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>[Ni]>[CH:17]1([CH:23]2[CH2:11][C:4]3[C:5](=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=3[O:2][CH3:1])[C:25](=[O:26])[CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)C=CC1CCCCC1
Reactant: COc1cccc(C2SCCCS2)c1OC
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1OC)CC(C1CCCCC1)CC2=O

Procedure:
2-(2',3'-Dimethoxyphenyl)-1,3-dithiane, from Step 1 of Example 1, Method B, and ethyl 3-cyclohexylpropenoate, from Step 1 of this Example, were condensed as described in Step 2 of Example 1, Method B. The adduct was treated with Raney nickel and sodium hydroxide to give the corresponding acid. The acid was cyclized with polyphosphoric acid as described in Step 6 of Example 1, Method A, to give 3-cyclohexyl-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-one. This ketone was treated with trimethylsilylcyanide in the presence of aluminum chloride and reduced with lithium aluminum hydride as described in Step 1 of Example 2 to give 1-aminomethyl-5,6-dimethoxy-1-hydroxy-3-cyclohexyl-1,2,3,4-tetrahydronaphthalene. The hydroxy group was eliminated by treatment with anhydrous hydrogen chloride in isopropyl alcohol as described in Step 2 of Example 2 to give 1-aminomethyl-3-cyclohexyl-5,6-dimethoxy-3,4-dihydronaphthalene hydrochloride, m.p. 178°-179° C.; 1H NMR (d6 -DMSO) δ: 1.0-1.4 (m, 7H), 1.5-1.9 (m, 6H), 2.0-2.2 (m, 1H), 2.5 (dd, 1H), 2.7 (dd, 1H), 3.6 (s, 3H), 3.81 (s, 3H), 5.8 (d, 1H), 6.6 (m, 2H).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])[C:5]=2[S:4][CH2:3][CH2:2]1.C[Al](C)C.C[O:20][C:21](=O)[NH:22][C:23]1[N:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([CH3:31])[N:24]=1.O>C(Cl)Cl.Cl.C(O)(=O)C>[CH3:30][O:29][C:27]1[CH:26]=[C:25]([CH3:31])[N:24]=[C:23]([NH:22][C:21]([NH:14][S:11]([C:10]2[C:5]3[S:4][CH2:3][CH2:2][S:1][C:6]=3[CH:7]=[CH:8][CH:9]=2)(=[O:12])=[O:13])=[O:20])[N:28]=1
Reactant: COC(=O)Nc1nc(C)cc(OC)n1
Reactant: NS(=O)(=O)c1cccc2c1SCCS2
Agent: C[Al](C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2SCCS3)n1
Temperature: 25 °C

Procedure:
To a solution of 2.5 g 1,4-benzodithian-5-sulfonamide, prepared in Example 18, in 50 ml methylene chloride at ambient temperature under nitrogen is added 5.5 ml trimethylaluminum (2M in toluene). After stirring 15 minutes at ambient temperature 2.0 g of methyl[4-methoxy-6-methylpyrimidin-2-yl]carbamate, prepared according to the procedure of Example 3, is added and the reaction mixture is heated at reflux for 16 hours. The reaction mixture is cooled to ambient temperature and 75 ml water, 10 ml glacial acetic acid, and 10 drops hydrochloric acid are sequentially added. The organic phase is separated, dried, and the solvent removed under reduced pressure to give an oil. Crystallization of the oil from n-butyl chloride/ether gives a solid.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:27])[C:15]([C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH3:26])[CH:18]=1)=[O:16])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]#[N:37]>CN(C=O)C>[Br:1][C:2]1[C:11]([O:12][CH2:35][C:36]#[N:37])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:27])[C:15]([C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH3:26])[CH:18]=1)=[O:16])=[CH:7]2
Reactant: N#CCBr
Reactant: CN(Cc1ccc2c(Br)c(O)ccc2c1)C(=O)c1cn(C)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc2c(Br)c(OCC#N)ccc2c1)C(=O)c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A mixture of 1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (2.0 g, 4.72 mmol), prepared in the previous step, potassium carbonate (3.26 g, 23.6 mmol) and bromoacetonitrile (0.39 mL, 5.67 mmol) in 60 mL of DMF was stirred under nitrogen at room temperature for 24 h (overnight). The reaction was partitioned between ethyl acetate and water. The organic layer was separated, extracted five times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (2.06 g, 94.5%) as a tan solid, mp 148-150° C.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:51])([CH3:50])[CH2:38][CH2:39][O:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:45]3[CH:44]=[CH:43][CH:42]=[C:41]([O:40][CH2:39][CH2:38][C:37]([CH3:51])([CH3:50])[CH3:36])[CH:46]=3)=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:24][CH:25]=2)[CH:9]=1
Reactant: CC(C)(C)CCOc1cccc(B(O)O)c1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: CC(C)(C)CCOc1cccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)c1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 3-(3,3-dimethyl-butoxy)phenylboronic acid (45 mg, 0.2 mmol, prepared according to general procedure H) to give 5-(4-{4-(2,4-dichloro-phenyl)-2-[3′-(3,3-dimethyl-butoxy)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[NH:12][CH:13]=[O:14].[CH3:15][C:16]([CH3:18])=O>>[CH3:15][C:16]1([CH3:18])[NH:12][C:13](=[O:14])[N:6]2[C:2](=[N:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=32)[NH:1]1
Reactant: O=CNCl
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CC(C)=O
Product: CC1(C)NC(=O)n2c(nc3ccccc32)N1
Reaction time: 72 h

Procedure:
A mixture of 16 g (0.12 mole) of 2-aminobenzimidazole, 100 ml of acetone and 16 g of 3A molecular sieves was stirred and heated under reflux, adding 8 g of additional sieves after 24 hours. Refluxing was continued for a total period of 3 days, after which the mixture was allowed to cool and a solution of 4.77 g (0.06 mole) of N-chloroformamide(1) in ~25 ml. of acetone added dropwise with stirring. The mixture was warmed to the reflux point several times and the rate of N-chloroformamide addition adjusted to keep the temperature just below the reflux point. An additional 50 ml of acetone were added to facilitate stirring of the thickening reaction mixture. Upon completion of the feed, the reaction flask was fitted with a drying tube and the mixture stirred for 3 days at room temperature. The reaction mixture was then evaporated under reduced pressure to give 9.3 g of a tan solid. The latter was extracted with boiling acetone to separate an insoluble fraction and the acetone solution evaporated to give the crude solid product. The latter material was chromatographed on silica, eluting with CHCl3 /CH3OH (80:5). Fractions 3 through 8 were combined and evaporated to give 3.9 g of product, mp 178°-180° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[C:11]([S:12][CH3:13])=[C:10]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CO.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[C:11]([S:12][CH3:13])=[C:10]([C:14]([F:20])([F:19])[C:15]([F:16])([F:18])[F:17])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(F)(F)C(F)(F)F)c(SC)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1c(C(F)(F)C(F)(F)F)ccc(C(=O)O)c1C
Temperature: 25 °C

Procedure:
530 mg (1.69 mmol) of methyl 2-methyl-3-(methylthio)-4-(pentafluoroethyl)benzoate were introduced into 10 ml of methanol and admixed with 0.5 ml of 20% strength aqueous sodium hydroxide solution. The contents were stirred at RT until a check on the reaction by thin-layer chromatography indicated complete conversion. The mixture was freed from the solvent, and the residue was taken up in a little water. The mixture was acidified with 1M hydrochloric acid, then stirred for 5 minutes and finally filtered. The residue obtained was 470 mg of clean product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][C@@H:19]3[CH3:24])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:25]([O:27][CH3:28])=[O:26])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][CH2:36]I>CN(C)C=O.O>[CH2:35]([N:21]1[CH2:22][CH2:23][N:18]([C:17]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:25]([O:27][CH3:28])=[O:26])=[CH:12][CH:11]=3)[C@@H:19]([CH3:24])[CH2:20]1)[CH3:36]
Reactant: CCI
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCNC[C@@H]3C)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCN(c2nc3cc(C(=O)OC)ccc3nc2-c2ccc(F)cc2)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-methyl 2-(4-fluorophenyl)-3-(2-methylpiperazin-1-yl)quinoxaline-6-carboxylate (160 mg, 0.42 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (174 mg, 1.26 mmol) and CH3CH2I (68.8 mg, 0.44 mmol), and the reaction was stirred overnight at room temperature. The reaction solution was diluted with water (150 mL), extracted with dichloromethane (3×30 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (1% methanol in dichloromethane) to afford (S)-methyl 3-(4-ethyl-2-methylpiperazin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as light yellow oil (80 mg, crude).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]2([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[NH:12][C:11](=[O:21])[C:10]=1[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]2([CH2:14][CH2:15][N:16]([O:19][CH3:20])[CH2:17][CH2:18]2)[N:12]([CH3:31])[C:11](=[O:21])[C:10]=1[C:22]1[C:23]([CH3:30])=[CH:24][C:25]([CH3:29])=[CH:26][C:27]=1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON1CCC2(CC1)NC(=O)C(c1c(C)cc(C)cc1C)=C2OCc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CON1CCC2(CC1)C(OCc1ccccc1)=C(c1c(C)cc(C)cc1C)C(=O)N2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-benzyloxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (40.0 g, 98.4 mmol) in tetrahydrofuran (500 ml) at 0° C. was added a 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (108.3 ml, 108.3 mmol) dropwise over one hour. The mixture was stirred at 0° C. for 30 minutes and at room temperature for 30 minutes, then treated with methyl iodide (6.75 ml, 15.4 g, 108.2 mmol) dropwise at 0° C. over 10 minutes. Stirring was continued at room temperature overnight and the reaction mixture was quenched with cold saturated aqueous ammonium chloride. The layers were separated, the aqueous phase extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulfate and concentrated. The residue was suspended in diethyl ether, stirred for 30 minutes, filtered and dried. Yield: 28.6 g of 4-benzyloxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P3.5) as a solid, mp 139-141° C.
Reaction SMILES: [C:1]([O-:4])([O-:3])=O.[K+].[K+].[NH:7]1[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8]1>CC(C)=O>[C:9]([O:3][C:1]([N:7]1[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8]1)=[O:4])([CH3:11])([CH3:10])[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1CNC1
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Yield: 91 %

Procedure:
Using a procedure analogous to Example 1-C (K2CO3, acetone), azetidine-3-carboxylic acid gave the title compound as a solid (3.61 g, 91%).