Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[O:25][CH3:26]>CS(C)=O.O>[Br:1][C:2]1[C:3](=[O:8])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=2[O:25][CH3:26])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]cccc1Br
Reactant: COc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
70 g (403 mmol) of 3-bromopyridin-2(1H)-one are dissolved in 1 l of anhydrous dimethyl sulphoxide, and 54 g (484 mmol) of potassium tert-butoxide are added at room temperature. The suspension is stirred at this temperature for 1 h. 69 g (403 mmol) of 1-fluoro-2-methoxy-4-nitrobenzene are added, and the reaction solution is heated at 80° C. for 20 h. Carefully, the mixture is diluted with 5 l of water. The precipitated solid is filtered off, washed with water and dried under reduced pressure. This gives 103 g (72% of theory) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:35][O:36][CH:37]([F:39])[F:38])[C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O-:32])=[O:31])=[C:15]([CH2:18][N+:19]4[N:20]([CH2:27][CH2:28][OH:29])[C:21]([NH:24]C=O)=[CH:22][CH:23]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.Cl.C(OCC)(=O)C>CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:35][O:36][CH:37]([F:38])[F:39])[C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O-:32])=[O:31])=[C:15]([CH2:18][N+:19]4[N:20]([CH2:27][CH2:28][OH:29])[C:21]([NH2:24])=[CH:22][CH:23]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(C(=NOC(F)F)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccc(NC=O)n4CCO)CS[C@H]23)cs1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1nc(C(=NOC(F)F)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccc(N)n4CCO)CS[C@H]23)cs1
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To a suspension of 7β-[2-(2-aminothiazol-4-yl)-2(difluoromethoxyimino)acetamido]-3-[3-formamido-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (syn isomer) (0.7 g) in methanol (3.5 ml) was added concentrated hydrochloric acid (0.42 ml) at ambient temperature. After being stirred at the same temperature for 2 hours, the mixture was poured into ethyl acetate. The resulting precipitate was collected by filtration. The precipitate was dissolved in water, and adjusted to pH 2 with 5% aqueous sodium bicarbonate solution. This solution was subjected to a column chromatography on macroporous non-ionic adsorption resin "Diaion HP20". The object compound was eluted with 10% diisopropyl alcohol, and lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-(difluoromethoxyimino)acetamido]-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (syn isomer) (0.41 g).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].Cl[C:19]1[C:24]([Cl:25])=[CH:23][C:22]([CH:26]=[CH2:27])=[CH:21][N:20]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:24]1[C:19]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=2)=[N:20][CH:21]=[C:22]([CH:26]=[CH2:27])[CH:23]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: C=Cc1cnc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=Cc1cnc(-c2ccc(C=O)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
4.1 g of Na2CO3 (39 mmol), 2.0 g of 4-formylphenylboronic acid (13 mmol), and 0.45 g of Pd(PPh3)4 were added to 2.5 g of compound (8) (14.9 mmol) prepared in Example 5 dissolved in 50 mL of 1,2-dimethoxyethane and 50 mL of distilled water, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, and concentrated about 50% under reduced pressure. The aqueous layer was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: ethyl acetate/hexane=1/4) to obtain 3.0 g 4-(3-chloro-5-vinylpyridin-2-yl)benzaldehyde (yield 82%).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Cl.[CH3:12]O>>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([SH:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1cccc(S)c1
Agent: Cl
Product: COC(=O)c1cccc(S)c1
Reaction time: 1 h

Procedure:
To a solution of 3-mercaptobenzoic acid (4.8 g, 31 mmol) in methanol (50 mL) at 0° C. was added a solution of hydrochloric acid in methanol (1M, 200 mL, 0.2 mol). The mixture was heated at reflux, stirred for 1 hour and concentrated under reduced pressure. The residue was taken up in ethyl acetate and the solution was washed consecutively with saturated aqueous sodium hydrogen carbonate (100 mL), distilled water (100 mL), and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give the title compound as a colourless oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][N:7]=1.Cl[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C>O1CCCC1>[CH3:21][O:20][C:18]([NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][N:7]=1)=[O:19]
Reactant: COC(=O)Cl
Reactant: NCCOc1cc(-c2ccccc2)on1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)NCCOc1cc(-c2ccccc2)on1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
3-(2-Aminoethoxy)-5-phenylisoxazole hydrochloride (240 mg) was suspended in anhydrous tetrahydrofuran (5 ml), and the suspension was cooled to 5° C. Then, methyl chloroformate (113 mg) and triethylamine (243 mg) were added thereto, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, the reaction mixture was added to ice-cold water (40 ml) and extracted with ethyl acetate (40 ml×2). Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The crystals thus obtained were recrystallized from a mixture of ethyl acetate and ether to obtain the title compound (233 mg, 89%) as colorless crystals.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][N:8]([C@H](C2C=CC=CC=2)C)[C@@H:7]1[C:19]([NH2:21])=[O:20])(=[O:3])[CH3:2]>[Pd].O>[C:1]([NH:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][NH:8][C@@H:7]1[C:19]([NH2:21])=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@@H]1CCN([C@@H](C)c2ccccc2)[C@@H]1C(N)=O
Agent: [Pd]
Solvent: O
Product: CC(=O)NC[C@@H]1CCN[C@@H]1C(N)=O

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.8 but (2S,3S)-3-(acetylamino-methyl)-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid amide (Step 5.2) was used instead of (2S,3R)-3-methyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid amide. Moreover, 10% Pd on charcoal, wet with 50% H2O (Aldrich 330108) was used instead of the dry catalyst.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C:8]2[O:9][C:10]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([CH:19]=O)[C:11]=3[CH:12]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.Cl.[CH3:22][NH2:23]>>[CH:1]1([NH:5][C:6]([C:8]2[O:9][C:10]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([CH2:19][NH:23][CH3:22])[C:11]=3[CH:12]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)c2cc(C(=O)NC3CCC3)oc12
Reactant: CN
Agent: Cl
Product: CNCc1ccc(OC)c2oc(C(=O)NC3CCC3)cc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and cyclobutylamine to give N-Cyclobutyl-7-methoxybenzofuran-2-carboxamide (Compound 289a). Successively, it was formylated to give N-cyclobutyl-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 289b), then compound 289b was reacted with methylamine hydrochloride to give Compound 289 as a white solid.
Reaction SMILES: [CH2:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([O:12][C@@H:13]2[CH2:17][CH2:16][NH:15][C:14]2=[O:18])=[CH:8][CH:7]=1.Br[C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][CH2:25][C:26]2=[O:29])=[C:22]([F:30])[CH:21]=1>O1CCOCC1>[CH:2]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([O:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:20]4[CH:28]=[C:27]5[C:23](=[C:22]([F:30])[CH:21]=4)[CH2:24][CH2:25][C:26]5=[O:29])[C:14]3=[O:18])=[CH:8][CH:7]=2)[CH2:3][CH2:1]1
Reactant: O=C1CCc2c(F)cc(Br)cc21
Reactant: O=C1NCC[C@H]1Oc1ccc(OCC2CC2)nc1
Solvent: C1COCCO1
Product: O=C1CCc2c(F)cc(N3CC[C@@H](Oc4ccc(OCC5CC5)nc4)C3=O)cc21
Temperature: 80 °C

Procedure:
A mixture of (R)-3-[6-(2-cyclopropyl-methoxy)-pyridin-3-yloxy]-pyrrolidin-2-one (100 mg), 6-bromo-4-fluoro-2,3-dihydro-1H-inden-1-one (92 mg) and 1,4-dioxane (2 mL) was purged with argon. N,N′-Dimethyl-ethylene-diamine (355 mg), cesium carbonate (263 mg) and copper(I) iodide (8 mg) were added. The mixture was heated to 80° C. for 4 hours. After cooling to r.t. the mixture was filtered and the filtrate purified by preparative HPLC to provide Example 1-11. 1H-NMR (400 MHz, DMSO) δ 7.99 (1H, dd, J=11.2, 1.8 Hz), 7.95 (1H, d, J=3.1 Hz), 7.77 (1H, d, J=1.8 Hz), 7.53 (1H, dd, J=9.0, 3.1 Hz), 6.79 (1H, d, J=9.0 Hz), 5.22 (1H, dd, J=8.3, 8.3 Hz), 4.03 (2H, d, J=7.1 Hz), 3.96 (1H, m), 3.86 (1H, m), 3.10 (2H, m), 2.72 (2H, m), 2.68 (1H, m), 2.13 (1H, m), 1.22 (1H, m), 0.54 (2H, m), 0.30 (2H, m).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:6]=2[CH:5]=[C:4]([F:19])[CH:3]=1.[C:20](Cl)(=[O:22])[CH3:21].ClCCl.[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[Br:1][C:2]1[C:10]2[O:9][C:8]([C:20](=[O:22])[CH3:21])=[C:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:6]=2[CH:5]=[C:4]([F:19])[CH:3]=1
Reactant: Fc1cccc(Cc2coc3c(Br)cc(F)cc23)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1oc2c(Br)cc(F)cc2c1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
7-Bromo-5-fluoro-3-(3-fluoro-benzyl)-benzofuran (1.29 gm, 4 mmol), acetyl chloride (0.57 ml, 8 mmol) and dichloromethane (16 ml) were added to an oven dried flask and chilled in ice bath. Aluminum chloride (1.067 gm, 8 mmol) was added and after 5 minutes the reddish brown mixture was allowed to warm to room temperature and stir overnight. The mixture was diluted with hydrochloric acid (0.1M) and extracted three times with dichloromethane. The extracts were dried over magnesium sulfate and purified by column chromatography (ethyl acetate/hexane gradient) to give 1-[7-Bromo-5-fluoro-3-(3-fluoro-benzyl)-benzofuran-2-yl]-ethanone (1.2 gm, 82% yield).
Reaction SMILES: O.O.[Sn](Cl)Cl.[NH2:6][C:7]1[C:8]([N+:21]([O-])=O)=[CH:9][C:10]([Cl:20])=[C:11]([N:13]2[CH2:17][CH2:16][CH:15]([C:18]#[N:19])[CH2:14]2)[CH:12]=1>CCOC(C)=O.O.N>[NH2:21][C:8]1[C:7]([NH2:6])=[CH:12][C:11]([N:13]2[CH2:17][CH2:16][CH:15]([C:18]#[N:19])[CH2:14]2)=[C:10]([Cl:20])[CH:9]=1
Reactant: N#CC1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)C1
Agent: Cl[Sn]Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC1CCN(c2cc(N)c(N)cc2Cl)C1

Procedure:
Tin dichloride dihydrate (410 mg, 1.8 mmol) was added to 1-(5-amino-2-chloro-4-nitro-phenyl)-pyrrolidine-3-carbonitrile (100 mg, 0.4 mmol) in EtOAc (5 mL). The reaction mixture was stirred at reflux for 1.5 h, cooled, diluted with EtOAc and water and basified with conc. ammonia. The mixture was filtered through a pad of celite. The organic layer was dried over Na2SO4 and concentrated to give the sub-title compound.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[Cl:21][C:22]1[C:27]([F:28])=[CH:26][N:25]=[C:24]([CH3:29])[CH:23]=1.C(I)C>C1COCC1>[Cl:21][C:22]1[C:27]([F:28])=[CH:26][N:25]=[C:24]([CH2:29][CH2:1][CH3:2])[CH:23]=1
Reactant: Cc1cc(Cl)c(F)cn1
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCCc1cc(Cl)c(F)cn1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
Diisopropylamine (924 μL, 6.59 mmol) was dissolved in 9 mL of dry THF and the resultant solution was cooled to 0° C. in an ice bath. n-Butyllithium (3.07 mL of a 2.05M solution in THF, 6.29 mmol) was added via syringe to the amine solution and the resultant solution was stirred for 30 minutes at 0° C. The lithium diisopropylamide (LDA) solution was then cooled to -50° C. in an isopropyl alcohol/dry ice bath. To the cold LDA solution was added, dropwise from an addition funnel, over a 15 min period, a solution of 4-chloro-5-fluoro-2-picoline (435 μL, 3.0 mmol), the product of Example 64, in 9 mL of THF. The reaction solution turned dark orange-brown in color. The reaction solution was stirred at a temperature in the range -50° C. to -45° C. for 5 hours and then was cooled over a 15 min period to -78° C. Ethyl iodide (792 μL, 9.9 mmol) was added in one portion and the reaction solution was stirred at -78° C. for 20 min. The reaction was then quenched by pouring the reaction solution into 60 mL of 10% aqueous ammonium chloride solution. The aqueous mixture was extracted with 2×50 mL of methylene chloride. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and the residue was distilled to afford the title compound, b.p. 80°-82° C. (12 mm Hg); MS DCI-NH3M/Z: 174 (M+H)+ 40%; 1H NMR (CDCl3) d 0.96 (t, 3H, J=7.5 Hz), 1.73 (spt, 2H, J=7.5 Hz), 2.73 (t, 2H, J=7.5 Hz), 7.21 (d, 1H, J=6.0 Hz), 8.38 (s, 1H).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[OH:9][CH2:10][CH2:11][N:12]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:14][OH:15]
Reactant: OCCNCCO
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCCN(CCO)Cc1ccccc1

Procedure:
The process according to claim 2 which comprises adding one molar equivalent of benzyl chloride to a warmed mixture containing one molar equivalent of N,N-bis(2-hydroxyethyl)amine and one molar equivalent of sodium carbonate, the addition rate of benzyl chloride being so as to maintain the exothermic reaction temperature at about 70° to 100° C.; maintaining the reaction temperature at about 70° to 100° C. for a short period; adding toluene to the reaction mixture; cooling the mixture to about 50° to 65° C.; filtering the mixture to remove inorganics; washing the filter-cake with toluene; drving the combined filtrate and washings by azeotropic distillation to produce a dry toluene solution containing a substantially quantitative yield of N,N-bis(2-hydroxyethyl)benzylamine.
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:15](=[O:19])[NH:14][C:13]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[N:12][C:11]1=2.N#N.C([C@@]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO[C:40]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C@@H](O)C1)(=O)C(C)C>>[CH3:56][O:55][C:52]1[CH:51]=[CH:50][C:49]([C:40]([O:9][CH2:8][C@H:5]2[O:4][C@@H:3]([N:10]3[CH:18]=[N:17][C:16]4[C:15](=[O:19])[NH:14][C:13]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])=[N:12][C:11]3=4)[C@@H:2]([F:1])[C@@H:6]2[OH:7])([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[CH:54][CH:53]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@](C(=O)C(C)C)(n3cnc4c(=O)[nH]c(N)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)[nH]1
Agent: N#N
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)C(C)C)nc43)[C@@H](F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
This compound is prepared from 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-N2 -isobutyrylguanine by the same procedure used for the preparation of N2 -isobutyryl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxyguanosine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:20][CH2:21][CH2:22][N:23]1[CH:28]=[C:27]([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24]1=[O:42])(=O)=O.O>CN(C=O)C>[C:30]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:27]2[CH:26]=[CH:25][C:24](=[O:42])[N:23]([CH2:22][CH2:21][CH2:20][S:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=3)[CH:28]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Oc1cccc(S)c1
Reactant: CS(=O)(=O)OCCCn1cc(C(c2ccccc2)c2ccccc2)ccc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1CCCSc1cccc(O)c1
Reaction time: 7 h
Yield: 81.1 %

Procedure:
To a solution of 3-hydroxythiophenol (222 mg) in DMF (15 mL) were added K2CO3 (243 mg) and 3-[5-(diphenylmethyl)-2-oxopyridin-1(2H)-yl]propyl methanesulfonate (700 mg) at ambient temperature and the mixture was stirred for 7 hours. Water was added to the mixture at ambient temperature and the resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=1:1) to afford 5-(diphenylmethyl)-1-{3-[(3-hydroxyphenyl)sulfanyl]propyl}pyridin-2(1H)-one (610 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:30]#[C:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#Cc1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: Cc1nnc2n1-c1sc(C#Cc3ccccc3)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was obtained by reacting 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with phenylacetylene under the conditions described in EXAMPLE 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride for elution. The combined clean fractions were evaporated and the residue was crystallized from ethyl acetate to give colorless crystals of 4-(2-chlorophenyl)-9-methyl-2-(phenylethynyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepine with m.p. 215°-217°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].I[CH3:15]>CN(C=O)C>[CH3:15][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(C#N)ccc21
Reaction time: 0.5 h
Yield: 122 %

Procedure:
To a solution of 1H-indole-5-carbonitrile (600 mg, 4.2 mmol) in DMF (5 mL) at 0° C. was added NaH (201 mg, 60% in oil, 8.4 mmol) with vigorous stirring. The solution was stirred 30 min, then iodomethane (1.8 g, 12.6 mmol) was added. The reaction mixture was stirred at RT for 4 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (3×100 mL). The organic layers were combined, dried (MgSO4), filtered, and concentrated under reduced pressure to afford 800 mg of 1-methyl-1H-indole-5-carbonitrile (294) as white solid: MS (ESI) m/z=157.3 [M+1]+.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl([O-])(=O)(=O)=O.[Li+]>>[F:19][C:20]1[CH:21]=[C:22]([NH:23][CH2:2][C:3]2([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CO2
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: O=C(OCc1ccccc1)N1CCC(O)(CNc2cccc(F)c2)CC1

Procedure:
The object product (2.53 g, 94%) was obtained in the same manner as in Example 24(1) and using benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (1.98 g), 3-fluoroaniline (889 mg) and lithium perchlorate (960 mg).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[S:14][CH:13]=1)C>C1COCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]2[S:14][CH:13]=[C:12]([CH2:11][CH2:10][OH:9])[C:16]=2[CH:17]=1
Reactant: CCOC(=O)Cc1csc2ccc(Cl)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1csc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of LiAlH4 (200 mg, excess) in THF at 0° C., ethyl(5-chloro-1-benzothiophene-3-yl)acetate (1.27 g, 5 mmol) in THF (20 mL) was added slowly. After the addition, the reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH4Cl solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO4; filtered and concentrated. The product, 2-(5-chloro-1-benzothiophene-3-yl)ethanol, was obtained as white oil, was pure enough and taken to the next step without purification. Yield: 920 mg (86%); 213 (M+H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[C:12]([C:18]([O:20][CH3:21])=[O:19])#[C:13][C:14]([O:16][CH3:17])=[O:15]>CO>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:6]/[C:13](=[CH:12]/[C:18]([O:20][CH3:21])=[O:19])/[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)/C=C(/Nc1cccc(C(F)(F)F)c1)C(=O)OC

Procedure:
3-(Trifluoromethyl)aniline (10.0 g, 62.0 mmol) and dimethyl acetylenedicarboxylate (8.4 mL, 68.4 mmol) were dissolved in methanol (100 mL) and the mixture was refluxed for 2 hours. After cooling, the mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel eluting with 0-30% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 3.71 (s, 3H), 3.73 (s, 3H), 5.49 (s, 1H), 7.16 (m, 2H), 7.36 (d, J=7.80 Hz, 1H), 7.48 (t, J=7.80 Hz, 1H). MS (ESI) m/z 303.97 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[C:33]([F:36])([F:35])[F:34])[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)=[S:3].[Cl:37][C:38]1[CH:47]=[CH:46][CH:45]=[CH:44][C:39]=1[C:40](=O)[CH2:41]Br>>[F:35][C:33]([F:34])([F:36])[C:24]1[CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=[CH:28][C:23]=1[CH2:22][N:4]([C:2]1[S:3][CH:41]=[C:40]([C:39]2[CH:44]=[CH:45][CH:46]=[CH:47][C:38]=2[Cl:37])[N:1]=1)[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([OH:15])=[O:14])=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(N)=S)cc1
Reactant: O=C(CBr)c1ccccc1Cl
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2nc(-c3ccccc3Cl)cs2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(aminocarbonothioyl)[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 2-chlorophenacyl bromide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1B(O)O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:16]3[CH:15]=[CH:14][C:13]([F:12])=[CH:18][C:17]=3[F:19])=[CH:9][N:10]=2)[CH:7]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Brc1ccc2ncc(I)n2c1
Product: Fc1ccc(-c2cnc3ccc(Br)cn23)c(F)c1

Procedure:
The title compound, off-white solid (0.33 g, 49%), MS (ISP) m/z=309.4 [(M+H)+], mp 137.5° C., was prepared in accordance with the general method of intermediate E from commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available 2,4-difluoro-phenylboronic acid (0.38 g, 2.38 mmol).