Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[Cl:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[N:14]=C(S(C)(=O)=O)[N:12]=1.Cl>O1CCCC1.O>[NH:3]([C:1]1[N:12]=[C:11]([Cl:10])[CH:16]=[C:15]([O:17][CH3:18])[N:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc(Cl)nc(S(C)(=O)=O)n1
Reactant: O=CNc1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)nc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
1.8 g of formanilide was dissolved in 50 ml of tetrahydrofuran, and 0.4 g of sodium hydride from which the oily matter had been removed beforehand with n-hexane was slowly added to the resulting solution at 10° to 20° C. while cooling with ice water. To the suspension thus obtained was added 3 3 g of 4-chloro-2-methanesulfonyl-6-methoxypyrimidine, and the mixture was stirred for 1 hour at room temperature. Then, 15 ml of 4N hydrochloric acid was added, and reaction was effected for 1 hour under reflux. The reaction liquid was poured in water, extracted with ether, and the ether layer was washed with water, dried over magnesium sulfate, and then the ether was stripped by concentration The residual crystals were recrystallized from n-hexane, and 4.0 g of 2-anilino-4-chloro-6-methoxypyrimidine was obtained (yield 87%). Melting point: 101°-103° C.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.CN.C[CH2:18][N:19]=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:18][NH:19][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.7 %

Procedure:
BOC-β-alanine (0.50 g, 2.64 mmol) was dissolved in 4 mL DMF. Methylamine hydrochloride (198 mg, 2.93 mmol) and DMAP (427.2 mg, 3.50 mmol) were added, followed by EDCI (1.06 g, 5.53 mmol). After stirring at room temperature for 2 days the solvent was removed in a stream of nitrogen and the residue dried in vacuo. It was dissolved in 5 mL 1 M HCl, and the solution was extracted five times with ethyl acetate. The combined organic extracts were dried over MgSO4 and concentrated to yield 0.43 g (2.13 mmol, 81%) of BOC-β-alanine methylamide (14) as a white solid. mp. 117-118° C., 1H-NMR (300 MHz, CDCl3) δ 5.78 (b, NH), 5.15 (b, NH), 3.38 (q, J=6.1 Hz, 2 H), 2.78 (d, J=4.8 Hz, 3 H), 2.36 (t, J=6.1 Hz, 2 H), 1.40 (s, 9 H) 13C-NMR (75.5 MHz, CDCl3) δ 171.74 (C), 79.15 (C), 36.41 (CH2), 36.03 (CH2), 28.17 (3 CH3), 26.04 (CH3). ##STR27##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[C:17](=[O:18])[NH:16][C:15]4[CH:19]=[C:20]([CH2:23][CH2:24][O:25][C:26]5[CH:31]=[CH:30][C:29]([N:32]6[CH2:37][CH2:36][O:35][CH2:34][CH2:33]6)=[CH:28][CH:27]=5)[CH:21]=[CH:22][C:14]=4[NH:13][C:12]=3[CH:38]=2)=[CH:4][C:3]=1[O:39][CH3:40].Cl.Cl[CH2:43][C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:40][O:39][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[C:17](=[O:18])[NH:16][C:15]4[CH:19]=[C:20]([CH2:23][CH2:24][O:25][C:26]5[CH:31]=[CH:30][C:29]([N:32]6[CH2:33][CH2:34][O:35][CH2:36][CH2:37]6)=[CH:28][CH:27]=5)[CH:21]=[CH:22][C:14]=4[NH:13][C:12]=3[CH:38]=2)[CH:6]=[CH:7][C:2]=1[O:1][CH2:43][C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1
Reactant: COc1cc(-c2ccc3c(c2)Nc2ccc(CCOc4ccc(N5CCOCC5)cc4)cc2NC3=O)ccc1O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(CCOc4ccc(N5CCOCC5)cc4)cc2NC3=O)ccc1OCc1ccncc1
Temperature: 80 °C

Procedure:
A mixture of Example 474 (26.9 mg, 0.05 mmol) and 4-chloromethylpyridine hydrochloride (24.6 mg, 0.15 mmol) in DMF (1 mL) was treated with K2CO3 (34.6 mg, 0.25 mmol) and heated at 80° C. for 7 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to provide the title compound as the di-TFA salt. MS (ESI) m/e 629 (M+H)+; 1H NMR (300 MHz, DMSO-d6) 9.77 (s, 1H), 8.79 (br s, 2H), 7.85 (s, 1H), 7.8 (d, J=4.1 Hz, 2H), 7.73 (d, J=8.5 Hz, 1H), 7.26 (dd, J=3.6, 1.9 Hz, 2H), 7.08-7.20 (m, 3H), 6.82-6.95 (m, 7H), 5.38 (s, 2H), 4.04 (t, J=6.8 Hz, 2H), 3.91 (s, 3H), 3.71-3.74 (m, 4H), 2.99-3.02 (m, 4H), 2.86 (t, J=6.8 Hz, 2H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:20](C3CCCCO3)[N:19]=2)=O)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl>C1COCC1>[CH2:1]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([NH:15][CH2:16][C:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[NH:20][N:19]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc(NCc2ccccc2)n1)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Fc1ccc(-c2cc(CNc3cccc(NCc4ccccc4)n3)n[nH]2)cc1
Yield: 14.1 %

Procedure:
Boran dimethylsufide (50 μL) was added to a solution of N-(6-(benzylamino)pyridin-2-yl)-5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide 4 (180 mg, 0.38 mmol) in THF (10 ml). The reaction mixture was refluxed over night and cooled. MeOH was added, followed by conc. HCl and the reaction mixture was heated for 5 hrs. Then the reaction mixture was concentrated in vacuum, diluted with water (5 ml) and extracted with chloroform (50 ml×2). The combined organic layers were washed with water and brine, then dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified on silica gel (50% EtOAc: pet-ether) to give N2-benzyl-N6-((5-(4-fluorophenyl)-1H-pyrazol-3-yl)methyl)pyridine-2,6-diamine 5 (20 mg) as an oily material, which was treated with methanolic hydrochloric acid for 2 hrs. The solvent was evaporated under reduced pressure to give a gummy material (20 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1>>[N:13]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: c1cn[nH]c1
Reactant: Oc1cccc2ccc(Cl)nc12
Product: Oc1cccc2ccc(-n3cccn3)nc12

Procedure:
A mixture of 2-chloro-quinolin-8-ol 3 (80 mg, 0.447 mmol) and pyrazole (152 mg, 2.233 mmol) was heated at 175° C. in a steel autoclave for 48 h. The crude product was then purified by column chromatography on silica (ethyl acetate/hexane, 1:1) to give 2-pyrazol-1-yl-quinolin-8-ol (compound ID 964) I1 as a white solid (68 mg, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[C:22]([CH:25]=[C:26]=[O:27])(=[O:24])[CH3:23]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:26](=[O:27])[CH2:25][C:22](=[O:24])[CH3:23])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCN(CCCCCC)c1ccc(N)cc1Br
Reactant: CC(=O)C=C=O
Solvent: CCOC(C)=O
Product: CCCCCCN(CCCCCC)c1ccc(NC(=O)CC(C)=O)cc1Br
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of 2-bromo-N1,N1-dihexylbenzene-1,4-diamine (4.40 g, 12.4 mmol) in EtOAc (120 mL) was added acetyl ketene (1.57 g, 18.7 mmol), and the mixture was stirred at 80° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as colorless oil (5.10 g, 94%).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]=[C:10]=[O:11])=[C:4]([F:12])[CH:3]=1.[NH:13]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:14]1[C:15](O)=[O:16].[OH-].[Na+]>ClC1C=CC=CC=1.O>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:15](=[O:16])[CH:14]3[CH2:18][CH2:19][CH2:20][CH2:21][N:13]3[C:10]2=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: O=C=Nc1cc(O)c(Br)cc1F
Reactant: O=C(O)C1CCCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Clc1ccccc1
Product: O=C1C2CCCCN2C(=O)N1c1cc(O)c(Br)cc1F
Temperature: 20 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
4-Bromo-2-fluoro-5-hydroxyphenyl isocyanate (3 g) was dissolved in chlorobenzene (5 ml), and a solution of pipecolic acid (1.7 g) and sodium hydroxide (0.56 g) in water (5 ml) was added thereto, followed by stirring at room temperature (ca. 20° C.) overnight. The aqueous layer was washed with ether, made acidic with an aqueous hydrochloric acid solution and heated under reflux for 2 hours. After allowed to cool, the resulting mixture was extracted with methylene chloride (300 ml). The extract was washed with sodium bicarbonate solution, dried and concentrated. The residue was recrystallized from ether to give 1.75 g of 2-(4-bromo-2-fluoro-5-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1,3(2H,8aH)-dione. M.P., 196°-199° C.
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:36])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][S:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[O:24][CH2:23]2)[CH:17]([CH:37]([OH:39])[CH3:38])[C:16]3=[O:40])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:45].O>[Pd].O1CCOCC1>[Na+:45].[F:35][C:32]1[CH:33]=[CH:34][C:29]([S:28][CH2:27][CH:25]2[O:24][CH2:23][CH:22]([S:21][C:20]3[CH:19]([CH3:36])[CH:18]4[N:15]([C:16](=[O:40])[CH:17]4[CH:37]([OH:39])[CH3:38])[C:14]=3[C:12]([O-:13])=[O:11])[CH2:26]2)=[CH:30][CH:31]=1
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CSc4ccc(F)cc4)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(CSc4ccc(F)cc4)C3)C(C)C12
Yield: 33.4 %

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.230 g of product from Example 41, 0.118 g of 10% palladium/carbon, 0.038 g of sodium bicarbonate, 2.5 ml of water and 6.0 ml of dioxane to give 0.062 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[N:29][NH:30]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][C:24]2[CH:32]=[C:31]3[C:27]([CH:28]=[N:29][NH:30]3)=[CH:26][CH:25]=2)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Temperature: 45 °C
Yield: 60.9 %

Procedure:
To a mixture of 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.5 g, 3.2 mmol) in n-butyl alcohol (12 mL) was added 6-aminoindazole (0.47 g, 3.52 mol) and DIPEA (0.86 mL, 4.80 mmol). After heating at 45° C. for 15 h, the mixture was cooled to room temperature, and the resulting precipitates were collected by filtration to give 2-chloro-N-(1H-indazol-6-yl)-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.[Li]C(CC)C.C(Br)(Br)(Br)[Br:27]>C1COCC1>[Br:27][C:7]1[C:2]([Cl:1])=[C:3]2[CH:10]=[CH:9][N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[C:4]2=[N:5][CH:6]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(Br)cnc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
4-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyri dine (0.55 g, 1.78 mmol) was dissolved in THF (15 mL) and cooled to −78° C. s-BuLi (2.80 mL, 3.92 mmol) was then added dropwise. The solution was then stirred at −78° C. for 30 minutes. CBr4 (1.48 g, 4.45 mmol) was then added as a THF (2 mL) solution. The reaction was stirred for an additional 30 minutes as it was allowed to warm to 0° C. The reaction was then quenched with saturated NH4Cl and allowed to warm to room temperature. The reaction was then extracted with DCM (3×50 mL), dried, and filtered to give a crude residue. The crude residue was purified by chromatography with hexane to give 5-bromo-4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (0.502 g, 72.7% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[C:26]([OH:28])=[O:27])[C:19]([C:29]#[C:30][CH2:31][CH2:32][CH2:33][CH2:34]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:18][CH:17]=1)[OH:15])([CH3:3])[CH3:2].[N-:46]=[N+:47]=[N-:48].[Na+].[Cl-].[Na+]>C(O)(=O)C>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[N:13]=[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[C:26]([OH:28])=[O:27])[C:19]([C:29]#[C:30][CH2:31][CH2:32][CH2:33][CH2:34][N:46]=[N+:47]=[N-:48])=[CH:18][CH:17]=1)[OH:15])([CH3:11])[CH3:12]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCCCC#Cc2ccc(C(O)=Nc3c(C(C)C)cccc3C(C)C)c3c(C(=O)O)cccc23)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cccc(C(C)C)c1N=C(O)c1ccc(C#CCCCCN=[N+]=[N-])c2cccc(C(=O)O)c12

Procedure:
A solution of 0.50 g (0.82 mmol) N-(2,6-diisopropylphenyl)-4-(6-tosyloxy-1-hexinyl)-naphthaline-1,8-dicarboxylic acid imide and 0.36 g (5.5 mmol) sodium azide were stirred for 17 hours at room temperature under nitrogen atmosphere. 250 ml acetic acid and saturated sodium chloride solution were added to the reaction mixture. After mixing, the organic phase was removed and washed once with saturated sodium chloride solution and two times with water. The organic phase was dried with MgSO4 and the solvent was evaporated in a rotary evaporator at a temperature of the water-bath of 25° C. The obtained oil (0.40 g) was purified on silica gel ((60 Å, 60-200 μm) free flow agent: methylene chloride. 0.10 g (25% of the theoretical yield) of a orange-yellow solid material were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([I:11])[S:10][C:3]=12.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([F:22])[CH:16]=1)([O-:14])=[O:13].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[F:22][C:17]1[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=[CH:19][C:18]=1[O:21][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([I:11])[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ccnc2cc(I)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Temperature: 25 °C
Yield: 74 %

Procedure:
A mixture of the 7-chloro-2-iodothieno[3,2-b]pyridine (23) (Ragan J. A. et al, Organic Process Research and Development 2003, 7, 676-683) (7.0 g, 23.7 mmol), 2-fluoro-4-nitrophenol (3) (11.15 g, 71.1 mmol), K2CO3 (13.08 g, 94.8 mmol) in Ph2O (30 ml) was heated at 200° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with DCM and filtered; the filtrate was collected and then concentrated. The resultant solid was triturated with diethyl ether, to afford intermediate 24 (7.3 g, 74% yield), which was used directly in the next step with no additional purification. MS (m/z): 417.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([SH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].I[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(=O)CC>[C:12]([C:3]1[CH:4]=[CH:5][C:6]([S:11][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C@H:23]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])=[CH:21][CH:22]=2)=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:14])[CH3:13]
Reactant: CCCc1c(S)ccc(C(C)=O)c1O
Reactant: N#Cc1cccc([C@@H](OC2CCCCO2)c2ccc(CI)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCc1c(SCc2ccc([C@H](OC3CCCCO3)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Yield: 53.4 %

Procedure:
Stir a mixture of 1-(2-Hydroxy-4-mercapto-3-propyl-phenyl)-ethanone (250 mg, 1.18 mmol), (S)-3-[(4-Iodomethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (515 mg, 1.18 mmol) and cesium carbonate (769 mg, 2.36 mmol) in 2-butanone (10 ml) at room temperature under argon for 24 hours. Pour the mixture into water (85 ml) and extract with ethyl acetate (3×25 ml). Combine the organic extracts and wash with water, brine, then dry over sodium sulfate, filter and concentrate. Purify the crude product via silica chromatography eluting with 1:4 ethyl acetate:hexanes to give the title compound (325 mg, 53%). MS (m/z) 514 (M−H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([SH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[C:12]3[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.Cl[CH2:22][C:23]([O:25][CH:26]1[CH:30]([O:31][C:32](=[O:34])[CH3:33])[CH2:29][O:28][CH2:27]1)=[O:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[C:32]([O:31][CH:30]1[CH2:29][O:28][CH2:27][CH:26]1[O:25][C:23]([CH2:22][S:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:20])=[C:5]([N:9]2[C:10](=[O:19])[C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][C:12]=3[C:13]2=[O:14])[CH:6]=1)=[O:24])(=[O:34])[CH3:33]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(S)c(Cl)cc1F
Reactant: CC(=O)OC1COCC1OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)OC1COCC1OC(=O)CSc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Reaction time: 5 h
Yield: 64.8 %

Procedure:
A mixture of 14.0 g of N-(4-chloro-2-fluoro-5-mercaptophenyl)-3,4,5,6-tetrahydrophthalimide, 11.0 g of 4-acetoxytetrahydrofuran-3-yl chloroacetate, 7.46 g of potassium carbonate, 1.5 g of potassium iodide and 150 ml of acetone was refluxed under stirring for 5 hours. After cooling, the salt was filtered off, and the residue was purified by chromatography on a silica gel column (eluted with ethyl acetate/hexane=2/3), to obtain 14.5 g of a compound described in Table 1 (No. 6) (65 %).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.Cl>O.CN(C=O)C>[CH2:7]([S:14][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: SCc1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(SCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a stirred mixture of cesium carbonate (12.81 g, 39.33 mmol), benzyl mercaptan (4.7 mL, 39 mmol), and N,N,-dimethylformamide (80 mL) was added 4-fluorobenzaldehyde, slowly over several minutes. The reaction mixture was stirred at 40° C. overnight. The reaction mixture was cooled to room temperature, then diluted with water (500 mL). The resulting mixture was acidified to pH 4 using 1 N aqueous HCl, then extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated. A solution of the crude product and dichloromethane was concentrated over silica gel, and the resulting silica gel supported crude product was loaded onto an Analogix SuperFlash™ column. Flash chromatography (100% hexanes -15% ethyl acetate in hexanes) afforded 7.70 g (90%) of 4-(benzylsulfanyl)-benzaldehyde as a slightly pink solid.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[N:12][O:13][C:9]=2[C:8]=1[Cl:23])C.[OH-].[Na+].Cl>C(O)C.O>[Cl:23][C:8]1[C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[C:10]=2[CH:21]=[CH:22][C:7]=1[O:6][CH2:5][C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)COc1ccc2c(-c3ccc(C)cc3)noc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2noc3c(Cl)c(OCC(=O)O)ccc23)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 20 g of ethyl{[7-chloro-3-(4-tolyl)-1,2-benzisoxazol-6-yl]oxy}acetate, Example 12, and 15 ml of 50% sodium hydroxide in 600 ml of ethyl alcohol is refluxed for 1 hour. Thereafter, the hot mixture is diluted with 500 ml of water and acidified with concentrated hydrochloric acid. The acidified suspension is, successively, stirred for 30 minutes and filtered and the filter cake is recrystallized from dimethylformamide to yield the product {[7-chloro-3-(4-tolyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid having a melting point of 257° to 260° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH2:11])[N:6]=1.[C:12]([NH:14][C:15](=[N:18][CH3:19])SC)#[N:13]>>[NH2:1][C:2]1[NH:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:15]([NH:14][C:12]#[N:13])=[N:18][CH3:19])[N:6]=1
Reactant: NCCSCc1c[nH]c(N)n1
Reactant: CN=C(NC#N)SC
Product: CN=C(NC#N)NCCSCc1c[nH]c(N)n1

Procedure:
By the procedure of Example 75, 2-amino-4-[(2-aminoethyl)-thiomethyl]imidazole is reacted with N-cyano-N',S-dimethylisothiourea to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][CH2:9]O)[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]=1)[CH3:2].S(Cl)([Cl:17])=O>ClC(Cl)Cl>[Cl:17][CH2:9][CH2:8][N:7]1[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]=[C:3]1[CH2:1][CH3:2]
Reactant: CCc1nc2ccccc2n1CCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCc1nc2ccccc2n1CCCl
Reaction time: 2 h

Procedure:
To a stirred and refluxing mixture of 7 parts of 2-ethyl-1H-benzimidazole-1-ethanol and 150 parts of trichloromethane are added dropwise 16 parts of sulfinyl chloride. Upon completion, the whole is heated to reflux and stirring is continued for 2 hours at reflux temperature. The reaction mixture is cooled and evaporated. Water is added to the residue and the whole is stirred with activated charcoal. The latter is filtered off and the filtrate is alkalized. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 1-(2-chloroethyl)-2-ethyl-1H-benzimidazole.
Reaction SMILES: [NH2:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1.[C:13]([O:17][C:18]([NH:20][C:21]([CH3:27])([CH3:26])[CH2:22][C:23](O)=[O:24])=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([NH:20][C:21]([CH3:27])([CH3:26])[CH2:22][C:23]([NH:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1)=[O:24])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: NC1Sc2ccccc2NC1=O
Product: CC(C)(CC(=O)NC1Sc2ccccc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 2-amino-3,4-dihydro-3-oxo-2H-1,4-benzothiazine (Step A) and 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CD3OD): 1.26 (s,6H), 1.36 (s,9H), 2.47 (d,13 Hz,1H), 2.57 (d,13 Hz,1H), 5.52 (br s,1H), 6.31 (br s,1H), 7.00 (m,2H), 7.22 (m,2H). FAB-MS: calculated for C18H25N3O4S 379; found 380 (M+H,26%).
Reaction SMILES: Cl[C:2]1[N:3]([CH3:16])[C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2.C([O-])([O-])=O.[K+].[K+].[SH:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].O>CO>[CH3:16][N:3]1[C:4]2[C:9](=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2)[C:10]2[CH:11]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[S:23][C:2]1=2
Reactant: COC(=O)CS
Reactant: Cn1c(Cl)c(C=O)c2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc2c3cc([N+](=O)[O-])ccc3n(C)c2s1
Reaction time: 8 h

Procedure:
1.4 g of (66) was added to a slurry of excess K2CO3 in 100 ml of MeOH. 2 ml of methyl 2-mercaptoacetate was added and the mixture left with stirring overnight. Addition of water precipitated the product, which was washed with MeOH and water to give 640 mg of (67). M.p. 269°-71° C.