Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:21]=[C:20]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])[CH:19]=[CH:18][C:7]=1[O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>>[C:22]([C:20]1[CH:21]=[C:6]([C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])[C:7]2[O:8][C:9]3[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:12])[C:18]=2[CH:19]=1)([CH2:25][CH3:26])([CH3:24])[CH3:23]
Reactant: CCC(C)(C)c1ccc(Oc2ccccc2C(=O)O)c(C(C)(C)CC)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CCC(C)(C)c1cc(C(C)(C)CC)c2oc3ccccc3c(=O)c2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Finally, 2,4-di-(tert-amyl)xanthen-9-one (S-13) was prepared. To a suspension of 2,4-di-(tert-amyl)phenoxybenzoic acid (4.8 g, 13.6 mmol) in acetic anhydride (27.7 g, 272 mmol) was added dropwise sulfuric acid (1.33 g, 13.6 mmol), and then the mixture was held at 80° C. for 3 h. The reaction mixture was cooled to ambient and poured into 100 mL of ice water. The aqueous phase was extracted twice with dichloromethane, and the combined organic extracts were washed with water and then with brine. The solution was dried (Na2SO4) and concentrated deposit a brown solid. The product was purified by column chromatography to provide 3.5 g (76% of theory) of a white solid. 1H NMR (CDCl3): δ 0.75 (t, 6H), 1.3 (s, 6H), 1.4 (s, 6H), 1.65 (q, 2H), 1.80 (q, 2H), 3.85 (s, 3H), 6.80 (d, 2H), 7.15 (m, 2H), 7.35 (br s, 1H), 7.45 (t, 1H), 8.2 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13]C2)[CH:3]=1.O1C2(CCC(C3C=C(N)N4N=CC=C4N=3)C2)OCC1.O1C2(CCC(C3C=C(N)N4N=CC=C4N=3)CC2)OCC1>>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13]2)[CH:3]=1
Reactant: Nc1cc(C2CCC(=O)CC2)nc2ccnn12
Agent: Nc1cc(C2CCC3(C2)OCCO3)nc2ccnn12
Agent: Nc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Product: Nc1cc(C2CCC(=O)C2)nc2ccnn12

Procedure:
3-(7-Aminopyrazolo[1,5-a]pyrimidin-5-yl)cyclopentanone was synthesized in a manner similar to the synthesis of 4-(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone, but 5-(1,4-dioxaspiro[4.4]nonan-7-yl)pyrazolo[1,5-a]pyrimidin-7-amine substituted for 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-amine.
Reaction SMILES: [Br:1][C:2]1[C:14]([F:15])=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:8][C:9]=1[NH:10]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][CH:5]=3)[NH:10][C:11]=2[C:12]([C:16]([OH:18])=[O:17])=[CH:13][C:14]=1[F:15]
Reactant: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)cc(F)c(Br)c23)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(=O)O)cc(F)c(Br)c12
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A solution of 5-bromo-2-(ethoxycarbonyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (2.87 g, 7.47 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (3.73 g, 16.4 mmol) in THF (45 mL) was heated at 60° C. for 90 min. The cooled mixture was diluted with EtOAc (about 50 mL) and stirred for 60 min. The resulting precipitate was collected by filtration, washed with EtOAc and dried. The filtrate was concentrated, and the residue was triturated with MeOH with sonication, filtered, and the precipitate was washed with MeOH and dried. The two precipitates were combined to give 4-bromo-7-ethoxycarbonyl-3-fluoro-9H-carbazole-1-carboxylic acid as a pale yellow solid (2.39 g, 84% yield). Mass spectrum m/z 380, 382 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:14]([N:16]2[C:24](=[O:25])[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([C:26]([O:28]C)=[O:27])[C:18]=3[CH2:17]2)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[OH-].[Na+].Cl>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:14]([N:16]2[C:24](=[O:25])[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([C:26]([OH:28])=[O:27])[C:18]=3[CH2:17]2)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:11])[F:13]
Reactant: COC(=O)c1nccc2c1CN(C(C)c1cnc(OCC(F)(F)F)c(C)c1)C2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)O)C2=O)cnc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.9 %

Procedure:
To a solution of methyl 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (300 mg, 0.73 mmol, Step-1, single enantiomer) in THF (8.0 mL) is added 2 M aqueous sodium hydroxide (1.1 mL, 2.2 mmol) at rt, and the reaction mixture is stirred overnight at rt. The reaction mixture is neutralized by the addition of 2 M aqueous hydrochloric acid (1.1 mL, 2.2 mmol). The mixture is extracted with DCM, and the organic layer is dried over sodium sulfate. After filtration, the filtrate, and volatiles are removed to give 297 mg (>99% yield) of the title compound as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[CH2:25][C@H:14]23)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)ccc1N
Yield: 59 %

Procedure:
The title compound is prepared from 4-amino-3-methoxy-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 59% of theory; LC (method 4): tR=1.80 min; Mass spectrum (ESI+): m/z=323 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:25]=[CH:24][C:12]([CH2:13][NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>O=[Pt]=O.C(O)C>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:25]=[CH:24][C:12]([CH2:13][NH:14][C:15]3[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1NCc1ccc(OCCN2CCCC2)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1ccccc1NCc1ccc(OCCN2CCCC2)cc1
Yield: 99.6 %

Procedure:
Adam's catalyst (50 mg, 20% wt.), was added to a degassed solution of N-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]-2-nitroaniline (240 mg, 0.703 mmol) in absolute ethanol (5 mL). The atmosphere was replaced with hydrogen then the reaction was stirred vigorously at ambient temperature until all of the nitro compound had been consumed as determined by tic (9:1 CHCl3:MeOH, 1% TEA). The reaction mixture was filtered through a bed of diatomaceous earth, then the solvent was removed under reduced pressure to give the desired product as a brown yellow oil (218 mg, 100%).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([O:15][C:16](=[O:40])[CH2:17][NH:18][C:19]1[C:23]([C:24](=[O:38])[NH:25][C:26](=O)[CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=2[F:36])=[CH:22][N:21]([CH3:39])[N:20]=1)[CH3:14].ClCCl>C1(C)C=CC=CC=1>[CH2:13]([O:15][C:16](=[O:40])[CH2:17][N:18]1[C:19]2=[N:20][N:21]([CH3:39])[CH:22]=[C:23]2[C:24](=[O:38])[N:25]=[C:26]1[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[F:36])[CH3:14]
Reactant: CCOC(=O)CNc1nn(C)cc1C(=O)NC(=O)CCc1cccc(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2cn(C)nc21
Yield: 56.8 %

Procedure:
A suspension of p-toluenesulfonic acid monohydrate (200 mg) and 2-(4-(3-(2,3-difluorophenyl)-propanoylcarbamoyl)-1-methyl-1H-pyrazol-3-ylamino)-acetic acid ethyl ester (Int B60) (1.2 g, 3.04 mmol) in toluene (100 ml) was refluxed for 3 h. The mixture was cooled and dichloromethane (200 ml) was added. The resulting solution was washed with aqueous sodium bicarbonate solution, brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography (silica, 5% methanol/dichloromethane) to give the title compound as a cream solid (650 mg, 57%). 1H-NMR (DMSO) δ 1.20 (3H, t), 2.94-3.09 (4H, m), 3.95 (3H, s), 4.18 (2H, q), 5.05 (2H, s), 7.11-7.29 (3H, m), 8.39 (1H, s); MS (APCI+) found (M+1)=377; C18H18F2N4O3 requires 376.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[CH:3]=1.[F:10][C:11]([F:18])([F:17])[CH2:12][CH2:13][C:14](O)=[O:15].C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:14](=[O:15])[CH2:13][CH2:12][C:11]([F:18])([F:17])[F:10]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: O=C(O)CCC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cc(O)c(C(=O)CCC(F)(F)F)c(=O)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.2 %

Procedure:
In 240 ml of toluene, 14.1 g of 4-hydroxy-6-methyl-2-pyrone was suspended, and 1.94 g of 4-dimethylaminopyridine, 16.6 g of 4, 4,4-trifluorobutyric acid and 21.9 g of dicyclohexylcarbodiimide were added thereto. The reaction mixture was stirred for 1 hour at room temperature and further stirred for 20 hours at 70° C. After cooling to room temperature, it was subjected to filtration. The filtrate was washed with 1% hydrochloric acid twice and saturated brine once in this order. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 5.38 g of 4-hydroxy-6-methyl-3-(4,4,4-trifluorobutyryl)-2-pyrone (hereinafter, referred to as the present compound (A)) mp 104° C.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][CH3:11].IC1C(OC)=CC=CC=1OC.COC1C=CC=C(OC)C=1.Br[C:34]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37].IC1C=CC([N+]([O-])=O)=CC=1C(OC)=O.[N+](C1C=CC(OS(C(F)(F)F)(=O)=O)=C(C=1)C(OC)=O)([O-])=O.C(OC(=O)C)(C)C>[Cl-].[Cl-].[Zn+2]>[CH3:11][O:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[C:34]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=1
Reactant: COc1cccc(OC)c1Br
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: COC(=O)c1cc([N+](=O)[O-])ccc1I
Agent: COC(=O)c1cc([N+](=O)[O-])ccc1OS(=O)(=O)C(F)(F)F
Agent: COc1cccc(OC)c1
Solvent: CC(=O)OC(C)C
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1c(OC)cccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The process comprising treating 2-bromo-1,3-dimethoxybenzene, 2-iodo-1,3-dimethoxybenzene or 1,3-dimethoxybenzene with an organolithium reagent in a first solvent at a temperature of about −5° C. to about 15° C., preferably about 0° C. to about 5° C., after complete addition of the organolithium reagent, the temperature is allowed to warm to ambient temperature and the reaction mixture is stirred for about 1 to 4 hours, preferably about 2 hours, recooling the reaction mixture to about 0° C. and then adding ZnCl2 while maintaining the temperature between −5° C. and 15° C., preferably about −5° C. to about 5° C., after complete addition of ZnCl2 allowing the temperature to warm to ambient temperature and allowing the reaction mixture to stir for about 1 to 4 hours, preferably about 2 hours, recooling the reaction mixture to about 0° C. and adding methyl 2-bromo-5-nitrobenzoate, methyl 2-iodo-5-nitrobenzoate or methyl 5-nitro-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate followed by addition of first transition metal catalyst and maintaining the reaction temperature between about 10° C. and about 55° C., preferably between about 20° C. and about 45° C., about 30 minutes after complete addition of first transition metal catalyst adding isopropylacetate and stirring for about 20 to about 90 minutes and then filtering to provide methyl 2′,6′-dimethoxy-4-nitro-1,1′-biphenyl-2-carboxylate;
Reaction SMILES: [N:1]1([C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:15])[CH3:14])[CH2:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([C:12]2[CH2:11][N:10]([C:13](=[O:15])[CH3:14])[CH2:9][CH2:8][C:7]=2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(=O)N1CC=C(N2CCCCC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(N2CCCCC2)=C(C(=O)c2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of crude 1-(3,4,5,6,3′,6′-hexahydro-2H,2′H-[1,4′]bipyridinyl-1′-yl)-ethanone in CH2Cl2 (1.5 L) was treated with Et3N (108 mL, 0.78 mol) and then cooled to 0° C. A solution of 4-fluorobenzoyl chloride (107 g, 0.68 mol) in CH2Cl2 (150 mL) was added over 1 h. The reaction mixture was stirred at rt for 2 h, then was concentrated to give a crude material which was directly used on next reaction. HPLC: RT=7.52 min. MS (ESI): exact mass calcd. for C19H23FN2O2, 330.17; m/z found, 331.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][C:7]=1[Br:8].[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[Br:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])[CH:5]=[CH:6][C:7]=1[Br:8]
Reactant: O=[N+]([O-])O
Reactant: O=C(Nc1ccc(Br)c(Br)c1)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=C(Nc1ccc(Br)c(Br)c1[N+](=O)[O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a solution of 12.95 g (37.3 mmol) of 3,4-dibromo-(trifluoroacetamido)benzene in 150 mL of conc. H2SO4 cooled at 8° C. was added 7.0 mL of 70% HNO3 (110 mmol) over 30 min. After the addition, the stirring was continued within 10°-12° C. for 1 h and then poured into ice-water (600 mL). The precipitate was collected by vacuum filtration, washed with H2O (6×50 mL), dried at 40° C. under 1 mmHg for 12 h, affording 13.90 g (95%) of the crude product. It was crystallized from hexanes (about 180 mL) to give 10.05 g (69%) of 3,4-dibromo-2-nitro-(trifluoroacetamido)benzene. mp. 107°-9° C. IR (KBr) 3331, 3256, 1745, 1551, 1203, 1141 cm-1. 1H NMR (DMSO-d6) 11.834 (s, 1H), 8.448 (s, 1H), 8.082 (s, 1H).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10](=[O:18])[CH:9]=1)[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:23]O>>[NH2:2][CH:3]([CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10](=[O:18])[CH:9]=1)[C:4]([O:6][CH3:23])=[O:5]
Reactant: CO
Reactant: NC(Cc1cc(=O)[nH]c2ccccc12)C(=O)O
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)Cc1cc(=O)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4 Grams of 2-amino-3-(2-quinolon-4-yl)propionic acid hydrochloride was suspended in 50 ml of methanol. Under an ice-cooled condition with strring, 5.3 g of thionyl chloride was added dropwise thereto, the reaction mixture was stirred at a room temperature overnight. Methanol and thionyl chloride were removed by distillation under a reduced pressure, then the residue obtained was recrystallized from methanolacetone to obtain 2.4 g of methyl 2-amino-3-(2-quinolon-4-yl)propionate in the form of white powdery product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[C:6]=2[CH:15]=1.C([Li])CCC.C1(P([N:35]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].[H-].[OH-].[Na+]>O1CCCC1.O>[NH2:35][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[C:6]=2[CH:15]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CN(C)CCc1csc2ccc(Br)cc12
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCc1csc2ccc(N)cc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 18 %

Procedure:
A solution of 0.193 gm (0.68 mMol) 5-bromo-3-(N',N'-dimethyl-2-aminoethyl)benzothiophene in 10 mL tetrahydrofuran was cooled to -78° C. and then to it were added 0.425 mL (0.68 mMol) n-butyllithium (1.6M in hexane). The reaction mixture was stirred at -78° C. for 10 minutes and then this solution was cannulated into a solution of 0.18 mL (0.83 mMol) diphenylphosphoryl azide in 10 mL tetrahydrofuran at -78° C. The reaction mixture was maintained at this temperature for 2 hours and then 1 mL (3.56 mmol) sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) was added and the reaction mixture warmed to 0° C. The reaction mixture was maintained at this temperature for 30 minutes and then at room temperature for 30 minutes. The reaction mixture was cooled again to 0° C. and water added to decompose excess hydride reagent. The pH of the solution was adjusted to about 12 by the addition of 2N sodium hydroxide and was then extracted first with ethyl acetate and then with dichloromethane. The combined organic extracts were dried over sodium sulfate and then concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing 6% methanol and 0.5% ammonium hydroxide. Fractions containing the desired product were combined and concentrated under reduced pressure to provide 0.027 gm (18%) of 5-amino-3-(N',N'-dimethyl-2-aminoethyl)benzothiophene. The oxalate salt was formed to provide the title compound.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]1([N:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]3[N:38]=[N:39][NH:40][CH:41]=3)=[C:31]([O:42][CH3:43])[C:30]2=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:23]1([N:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]3[N:38]=[N:39][NH:40][CH:41]=3)=[C:31]([O:42][CH3:43])[C:30]2=[S:10])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1c(CCc2c[nH]nn2)ccn(-c2ccccc2)c1=O
Solvent: Cc1ccccc1
Product: COc1c(CCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Yield: 121.1 %

Procedure:
To a stirring solution of Lawesson's reagent (0.075 g, 0.185 mmol) in toluene (10 mL), was added starting material 158a (0.10 g, 0.33 mmol). Reaction mixture was heated to reflux temperature. After overnight reaction, solvent was evaporated under reduced pressure. Crude product was dissolved in small amount of CH2Cl2 to load onto preparative-TLC and eluted with CHCl3:Acetone:EtOH (10:1:0.2) to give pure yellow solid 160 (0.07 g, 68%). 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=7.4 Hz, 2H), 7.56 (s, 1H), 7.35 (t, J=7.5 Hz, 2H), 7.28 (m, 1H), 6.97 (d, J=6.6 Hz, 1H), 6.62 (d, J=7.8 Hz, 1H), 6.37 (m, 1H), 5.13 (t, J=5.6 Hz, 2H), 5.03 (t, J=5.6 Hz, 2H), 3.86 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 171.92, 158.94, 147.52, 132.68, 129.92, 128.69, 128.14, 125.43, 120.96, 111.72, 110.22, 56.72, 56.63, 46.38. HRMS (EI) calcd for C16H16N4OS [M]+ 312.104. found 312.1039.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[OH:14][C:15]1[CH:20]=[C:19]([CH:21]([CH3:26])[CH2:22][CH2:23][CH:24]=O)[O:18][C:17](=[O:27])[C:16]=1[C:28](=[O:31])[CH2:29][CH3:30]>C1COCC1>[OH:14][C:15]1[CH:20]=[C:19]([CH:21]([CH3:26])[CH2:22][CH2:23]/[CH:24]=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])[O:18][C:17](=[O:27])[C:16]=1[C:28](=[O:31])[CH2:29][CH3:30]
Reactant: CCC(=O)c1c(O)cc(C(C)CCC=O)oc1=O
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)c1c(O)cc(C(C)CC/C=C/C(=O)OC)oc1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (0.06 g; 1.5 mmol; 60% dispersion in mineral oil; Aldrich) was added to trimethyl phosphonoacetate (0.190 g; 1.0 mmol; Aldrich) in 10 ml THF. The reaction mixture was stirred at 25° C. for 15 min, after which 4-(4-hydroxy-2-oxo-3-propionyl-2H-pyran-6-yl)pentanal (VI; 0.124 g; 0.5 mmol) in 10 ml THF was added. The reaction mixture was stirred at 25° C. for 4 h, quenched with saturated NH4Cl, extracted with 3×20 ml EtOAc, dried with anhydrous Na2SO4, and evaporated. The product was purified via silica flash chromatography (40% EtOAc in hexanes).
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([N:29]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]([CH2:38][C:39]#[CH:40])[C:30]2=[O:41])[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:40]#[C:39][CH2:38][N:31]3[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:30]3=[O:41])[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#CCn1c(=O)n(-c2ccccc2)c2ccccc21
Solvent: CCO
Solvent: ClCCl
Product: Cc1nnc2n1-c1sc(C#CCn3c(=O)n(-c4ccccc4)c4ccccc43)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was prepared 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 1,3-dihydro-1-phenyl 3-(2-propynyl)-2H-benzimidazol-2-one under the conditions used 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. The clean fractions were combined and evaporated and the residue was crystallized from methanol/ethyl acetate and recrystallized from methanol to yield off white crystals of 1-{3-[4-(2-chlorophenyl)-9-methyl-6H thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]-2-propynyl }-1,3-dihydro-3-phenyl-2H-benzimidazol-2-one with m.p.176°-179°. These crystals contained 0.66 mol of water according the analytical data.
Reaction SMILES: C[O:2][C:3](=[O:31])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:27](=[CH:28][CH:29]=1)[O:26][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:30].Cl>CC(O)=O>[C:20]1([CH2:19][CH2:18][N:14]2[CH2:15][CH2:16][CH2:17][C:11]3([CH2:10][C:9](=[O:30])[C:8]4[C:27](=[CH:28][CH:29]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:31])=[O:2])[CH:7]=4)[O:26]3)[CH2:12][CH2:13]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(CCc3ccccc3)CC1)O2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(CCc3ccccc3)CC1)O2
Yield: 101.2 %

Procedure:
(±)-(E)-3-[1′-(2-Phenyl-ethyl)-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester was obtained starting from the hydrochloride salt of (±)-(E)-3-[4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester (1 g, 2.85 mmol, Intermediate 3) and phenethyl bromide (0.846 ml, 6.27 mmol), according to the procedure described in Example 24, Step A. The reaction was carried out for 15 days at RT and the methyl ester was obtained as a yellow solid (203 mg, 17%). (±)-(E)-3-[1′-(2-Phenyl-ethyl)-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester (200 mg, 0.48 mmol) was hydrolyzed with HCl and AcOH following the procedure described in Example 22, Step A, giving (±)-(E)-3-[1′-(2-phenyl-ethyl)-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid as a white solid (197 mg, 93%). The acid was treated with NH2OTHP according to the procedure described in Example 22, Step C, giving (E)-3-[1′(2-phenyl-ethyl)-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (183 mg, 83%). Finally, removal of THP protecting group following the procedure described in Example 22, Step D and purification using preparative HPLC gave (±)-(E)-3-[1′-(2-phenyl-ethyl)-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]N-hydroxy-acrylamide (77.5 mg, 40%) as its trifluoroacetate salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].[Br:15][C:16]1[S:20][C:19]2=[N:21][C:22]([C:24](O)=[O:25])=[CH:23][N:18]2[CH:17]=1>>[Br:15][C:16]1[S:20][C:19]2=[N:21][C:22]([C:24]([NH:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:10][C:11]([F:13])([F:12])[F:14])[CH:4]=3)=[O:25])=[CH:23][N:18]2[CH:17]=1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: NCc1ccc(F)c(OC(F)(F)F)c1
Product: O=C(NCc1ccc(F)c(OC(F)(F)F)c1)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (4-fluoro-3-(trifluoromethoxy)phenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.