Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:27])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([OH:26])[C:23]([OH:25])=[O:24].[CH3:28][C:29]1[CH:33]=[CH:32][S:31][C:30]=1[C:34](Cl)=[O:35].Cl.C(Cl)Cl>N1C=CC=CC=1>[O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:27])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:34]([C:30]1[S:31][CH:32]=[CH:33][C:29]=1[CH3:28])=[O:35])[C:23]([OH:25])=[O:24]
Reactant: C[C@@H]1CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@]2(C)[C@@]1(O)C(=O)O
Reactant: Cc1ccsc1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccsc1C(=O)O[C@]1(C(=O)O)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(6S,9S,10S,11S,13S,16R,17R)-9,11-Epoxy-6-fluoro-17-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid (20 g) is dissolved in pyridine (50 mL) and cooled to 0° C. 3-Methylthiophene-2-carbonyl chloride (9.39 g) is added and the reaction is stirred at room temperature. After 2 hours, the reaction mixture is added dropwise to a vigorously stirred solution of 6M HCl. DCM is added, the phases are separated and the organic phase is washed with water and brine. After drying over magnesium sulphate, evaporation is followed by flash column chromatography on silica gel eluting with DCM-methanol (25:1) to afford 3-methylthiophene-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-carboxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Selected 1H-NMR signals (CDCl3) δ 0.90 (3H, d), 0.95 (3H, s), 1.40 (3H, s), 2.40 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)#[N:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]([S:26]([C:23]2[CH:22]=[CH:21][C:20]([C:18]#[N:19])=[CH:25][CH:24]=2)(=[O:28])=[O:27])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCNCCc1ccc(OC)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
To a solution of methyl 3-[(4-methoxy-phenethyl)amino]-propionate (3.0 g, 12.6 mmol) in anhydrous methylene chloride (35 mL) was added 4-cyanobenzenesulfonyl chloride (2.6 g, 12.6 mmol), followed by triethylamine (2.6 g, 25.3 mmol). After stirring for 18 h at room temperature, the mixture was quenched with 1 N HCl solution (150 mL) and extracted with methylene chloride (2×100 mL). Combined organic layers was washed successively with 1 N HCl solution (100 mL) and brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel flash chromatography (2/1: hexanes/EtOAc) to provide methyl 3-[(4-methoxyphenethyl)-(4-cyanobenzenesulfonyl)-amino]-propionate (3.14 g, 7.8 mmol).
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][C:5]1([CH3:27])[O:10][CH:9]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]([CH:19]=CC2C=CC=CC=2)[O:6]1>C(Cl)Cl>[CH:19]([CH:7]1[O:6][C:5]([CH3:4])([CH3:27])[O:10][CH:9]([CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8]1)=[O:1]
Reactant: O=[O+][O-]
Reactant: CC(C)(C)OC(=O)CC1CC(C=Cc2ccccc2)OC(C)(C)O1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC1CC(C=O)OC(C)(C)O1
Reaction time: 18 h

Procedure:
Ozone was bubbled into a solution of 1,1-dimethylethyl 2,2-dimethyl-6-(2-phenylethenyl)-1,3-dioxane-4-acetate (3.0 g, 9 mmol) in 100 mL of methylene chloride at -78° C. until a blue color persisted. Nitrogen was then bubbled into the solution without cooling until the color disappeared. The temperature had risen to -20° C. Methyl sulfide (3 mL) was added and the solution stirred for 18 hours. The solvent was removed in vacuo and the residue purified by chromatography on silica eluting with 20% ethyl acetate in hexane to give 1.78 g of the title compound. Recrystallization from pentane gave the compound as a white solid; m.p.=71°-73° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: C1CCNC1
Reactant: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1
Product: Fc1ccc(-c2csc3cc(OCCCCN4CCCC4)ccc23)cc1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and pyrrolidine were converted to yield 1-{4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-pyrrolidine as white semisolid, MS: 370 (MH+).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)O)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Al+3].[Cl-].[Cl-].[Cl-].[Si]([C:31]#[N:32])(C)(C)C.C([O-])([O-])=O.[K+].[K+]>ClCCCl.CCOC(C)=O>[N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:31]#[N:32])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: C[Si](C)(C)C#N
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
To a suspension of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.3055 g, 1.04 mmol) in 1,2-dichloroethane (17 mL) was added AlCl3 (0.6675 g, 5.04 mmol). The reaction was allowed to stir for 10 min and then TMSCN (0.68 mL, 5.10 mmol) was added. The reaction was sealed and heated to 85° C. for overnight. The reaction mixture was poured into a separatory funnel containing K2CO3 (aq. sat.) (100 mL) and EtOAc (100 mL). The aqueous phase was separated and further extracted with EtOAc (3×100 mL) was performed. The combined organics were dried over MgSO4, filtered and concentrated under vacuum. The residue was dissolved in DMSO and purified by Gilson preparatory HPLC (w/0.1% TFA). The combined fractions were concentrated down under vacuum to remove CH3CN. The resulting water layer was basified to pH=12 with 6N NaOH, and then extracted with EtOAc. The combined organic fractions were dried over MgSO4, filtered, and concentrated under vacuum to give the title compound (0.185 g, 59.7%). EI-MS ml/z 303 (M+H+) Rt (1.76 min).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH:9]2[CH:12]3[CH2:17][CH2:16][CH:15]([CH:8]2[S:7]1(=[O:19])=[O:18])[CH:14]=[CH:13]3.C(N(CC)CC)C.Cl.[Cl:28][C:29]1[N:34]=[C:33]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:32]=[N:31][CH:30]=1>CN(C)C=O>[ClH:28].[Cl:28][C:29]1[N:34]=[C:33]([N:35]2[CH2:36][CH2:37][N:38]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[CH:9]4[CH:12]5[CH2:17][CH2:16][CH:15]([CH:8]4[S:7]3(=[O:19])=[O:18])[CH:14]=[CH:13]5)[CH2:39][CH2:40]2)[CH:32]=[N:31][CH:30]=1
Reactant: O=C1C2C3C=CC(CC3)C2S(=O)(=O)N1CCCCBr
Reactant: Clc1cncc(N2CCNCC2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1C2C3C=CC(CC3)C2S(=O)(=O)N1CCCCN1CCN(c2cncc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 1.0 g (2.9 mmol) of 3a,4,7,7a-tetrahydro-2-(4-bromobutyl)-4,7-ethano-1,2-benzisothiazol-3(2H)-one 1,1-dioxide in 25 ml of anhydrous dimethylformamide is treated with 1.6 g (16 mmol) of triethylamine and 866 mg (3.2 mmol) of 1-(6-chloro-2-pyrazinyl)piperazine, monohydrochloride salt. The mixture is maintained at room temperature with stirring for 15 hours and then is partitioned between water and methylene chloride. The methylene chloride extracts are combined, dried over MgSO4, filtered and rotoevaporated to give crude free base. Preparative HPLC (silica gel; ethyl acetate: methylene chloride (9:1)) followed by evaporation of the appropriate fractions, treatment with ethanolic hydrochloric acid and recrystallization from methanol gives the title compound: mp. 263°-267° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:20][C:21]([NH2:23])=[O:22].[C:24](OCC)(=[O:30])[C:25](OCC)=[O:26].CC(C)([O-])C.[K+].Cl>CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[C:20]1[C:21](=[O:22])[NH:23][C:25](=[O:26])[C:24]=1[OH:30]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC1(CC2CCCC2)Cc2cc(CC(N)=O)c(Cl)c(Cl)c2C1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(CC2CCCC2)Cc2cc(C3=C(O)C(=O)NC3=O)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
(6,7-Dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamide (5 g., 0.0141 mole) and diethyl oxalate (2.19 g., 0.015 mole) are dissolved in dry dimethylformamide (30 ml.) and stirred in an ice bath under nitrogen for 20 minutes. Potassium t-butoxide (3.53 g., 0.0315 mole) is then added in two portions 15 minutes apart. The mixture is stirred while cooling in the ice bath for another 45 minutes, then stirred at room temperature for 18 hours and poured into ice water (500 ml). The mixture is acidified with hydrochloric acid and extracted with ether (4×125 ml.). The combined organic extracts are washed with water and then repeatedly extracted with dilute sodium carbonate. The combined aqueous extracts are acidified with hydrochloric acid, extracted with methylene chloride and then with ether. The combined organic extracts are washed with water, dried over magnesium sulfate and concentrated under vacuum. The residue is chromatographed on silica (175 g.) with a mixture of toluene, dioxane and acetic acid (50:5:1). The appropriate product fractions are concentrated under vacuum and the residue is dissolved in ether and extracted with dilute sodium bicarbonate. The aqueous extracts are acidified with hydrochloric acid and extracted with methylene chloride and then with ether. The combined organic extracts are washed with water, dried over magnesium sulfate and concentrated under vacuum to obtain the 3-(6,7-Dichloro-2-cyclopentylmethyl-2,3-dihydro- 2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione as a foam which was then dried under high vacuum at 90° C. for 2 hours to give 3.6 g. (63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.[CH3:21][O:22][C:23]([C:25]1[O:26][C:27](Br)=[CH:28][CH:29]=1)=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:21][O:22][C:23]([C:25]1[O:26][C:27]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:3]=2[O:2][CH3:1])=[CH:28][CH:29]=1)=[O:24]
Reactant: COC(=O)c1ccc(Br)o1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
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: C1COCCO1
Product: COC(=O)c1ccc(-c2cccc([N+](=O)[O-])c2OC)o1
Yield: 18 %

Procedure:
2-(2-Methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 6a (3.6 g, 12 mmol), 5-bromofuran-2-carboxylic acid methyl ester (2.05 g, 10 mmol), tetrakis(triphenylphosphine)palladium (1.55 g, 0.5 mmol) and sodium carbonate (2.12 g, 20 mmol) were dissolved in 1,4-dioxane. The reaction mixture was heated to reflux for 3 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with 30 mL of water and 50 mL of ethyl acetate. The separated organic layer was concentrated under reduced pressure and recrystallized from a solvent mixture of ethyl acetate and n-hexane to obtain the title compound 5-(2-methoxy-3-nitro-phenyl)-furan-2-carboxylic acid methyl ester 54a (500 mg, yield 18%) as a yellow solid.
Reaction SMILES: [Na].N.[C:3]1([C:9]2[C:18]3[C:13](=[C:14](Cl)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20](#[N:22])[CH3:21]>[Fe](Cl)(Cl)Cl>[C:3]1([C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:21][C:20]#[N:22])[C:13]=3[CH:12]=[CH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC#N
Reactant: Clc1cccc2c(-c3ccccc3)nccc12
Agent: Cl[Fe](Cl)Cl
Agent: N
Agent: [Na]
Product: N#CCc1cccc2c(-c3ccccc3)nccc12
Reaction time: 5 h

Procedure:
Metallic sodium (1.15 g) was added to 100 ml of liquid ammonia, and 1.3 g of acetonitrile and 2.39 g of 1-phenyl-5-chloroisoquinoline were added to the solution. A small amount of iron trichloride was added, and the reaction was performed for 5 hours. After the reaction, ammonia was distilled off, and ice water was carefully added to the residue. The resulting oily product was extracted with ether, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was chromatographed to afford 1-phenylisoquinoline-5-acetonitrile as an oil.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:34][C:35]1[CH:42]=[C:41]([OH:43])[CH:40]=[CH:39][C:36]=1[C:37]#[N:38].O[CH2:45][C:46]1[CH:47]=[C:48]([CH2:52][CH2:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH:49]=[CH:50][CH:51]=1>O1CCCC1>[C:37]([C:36]1[CH:39]=[CH:40][C:41]([O:43][CH2:45][C:46]2[CH:47]=[C:48]([CH2:52][CH2:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH:49]=[CH:50][CH:51]=2)=[CH:42][C:35]=1[F:34])#[N:38]
Reactant: CC(C)(C)OC(=O)CCc1cccc(CO)c1
Reactant: N#Cc1ccc(O)cc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1cccc(COc2ccc(C#N)c(F)c2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 13.3 %

Procedure:
Diisopropyl azodicarboxylate (2.6 g) is added portionwise to a stirred solution of triphenylphosphine (3.4 g) in dry tetrahydrofuran (40 mL) at 0° C. under nitrogen. The reaction mixture is stirred at 0° C. for 15 minutes then treated with a solution of 2-fluoro-4-hydroxybenzonitrile (0.87 g) and t-butyl 3-(3-hydroxymethylphenyl)propionate (1.5 g) in dry tetrahydrofuran (10 mL) whilst maintaining the temperature at 0-5° C. Stirring is continued at this temperature for 1 hour when the reaction mixture is allowed to warm up to room temperature. The reaction mixture is evaporated to low bulk and partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase is washed with water (50 mL), dried over magnesium sulphate and evaporated. The residue is purified by flash chromatography on silica eluting with a mixture of cyclohexane and ethyl acetate (4:1 v/v). Fractions homogeneous in the required product are combined and evaporated to give tert-butyl 3-[3-(4-cyano-3-fluoro-phenoxymethyl)phenyl]propionate (0.3 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[O-:13][C:14]#[N:15].[K+]>Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]([NH2:15])=[O:13])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: N#C[O-]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Product: NC(=O)Nc1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2500 mg (13.957 mmol) of 4-fluoro-3-(trifluoromethyl)aniline were dissolved in 15 ml of 1 N hydrochloric acid, and 1132 mg (13.957 mmol) of potassium cyanate were added. The suspension was stirred at room temperature overnight and then diluted with ethyl acetate such that a clear two-phase solution was formed. The organic phase was separated off and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried and the solvent was removed on a rotary evaporator, and the crude product was then chromatographed on silica gel (mobile phase: dichloromethane/methanol 80:1, then 10:1). This gave 2180 mg (70% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21.C[Si](C)(C)[C:27]([F:30])([F:29])[F:28].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:24])[C:27]([F:30])([F:29])[F:28])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
To a stirred solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (500 mg, 1.31 mmol) and trimethyl(trifluoromethyl)silane (582 μL, 3.94 mmol) in tetrahydrofuran (6.5 mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 131 μL, 0.131 mmol) at 0° C. After 15 min, hydrochloric acid (1.0 M, 2.0 mL) was added. After 30 min, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a colorless solid (590 mg, 1.30 mmol, 99%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:18][CH2:17][C@:13]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[NH:14][O:15][CH2:16][C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@]1(C2C=CC(F)=CC=2F)[C@H](CO)CCOC1>>[NH2:14][C@@:13]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:17][O:18][C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][C@H:12]1[CH2:16][OH:15]
Reactant: Fc1ccccc1[C@]12CO[C@@H](COCc3ccccc3)C[C@H]1CON2
Agent: N[C@@]1(c2ccc(F)cc2F)COCC[C@H]1CO
Product: N[C@@]1(c2ccccc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO

Procedure:
Compound C14 was prepared from (3aR,5R,7aS)-5-[(benzyloxy)methyl]-7a-(2-fluorophenyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C13) according to the general procedure for the synthesis of [(3S,4R)-3-amino-3-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C11) in Example 1. The product was used directly in the following step. LCMS m/z 346.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.65 (ddd, J=14.0, 4.3, 2.5 Hz, 1H), 2.01-2.14 (m, 1H), 2.32-2.41 (m, 1H), 3.35 (dd, J=11.5, 2.9 Hz, 1H), 3.47-3.61 (m, 3H), 3.66 (dd, J=10.2, 6.6 Hz, 1H), 3.84-3.92 (m, 1H), 4.27 (dd, J=11.5, 2.0 Hz, 1H), 4.61 (AB quartet, JAB=12.1 Hz, ΔνAB=25.1 Hz, 2H), 7.06 (ddd, J=13.0, 8.1, 1.3 Hz, 1H), 7.20-7.26 (m, 1H), 7.28-7.41 (m, 6H), 7.64-7.72 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:13][OH:14])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:5][C:4]=2[N:3]=1.Cl.Cl.Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1.[H-].[Na+].CN(C)CCCON=C1CC(C2C=C(F)C=CC=2C2C=CC=CC=2)CC2N=C(N)N=C(C)C1=2>O>[CH3:39][N:36]1[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][CH2:30][O:14][N:13]=[C:8]2[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:5][C:4]3[N:3]=[C:2]([NH2:1])[N:11]=[C:10]([CH3:12])[C:9]2=3)[CH2:34][CH2:35]1
Reactant: CN1CCN(CCCCl)CC1
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Agent: Cc1nc(N)nc2c1C(=NOCCCN(C)C)CC(c1cc(F)ccc1-c1ccccc1)C2
Agent: Cl
Agent: [H-]
Solvent: O
Product: Cc1nc(N)nc2c1C(=NOCCCN1CCN(C)CC1)CC(c1ccccc1-c1ccccc1)C2

Procedure:
The title compound was prepared from 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime, compound 66, (100 mg, 0.290 mmol), 1-(3-chloro-propyl)-4-methyl-piperazine dihydrochloride (87 mg, 0.348 mmol) and sodium hydride (60% dispersion in oil) (52 mg, 1.31 mmol), following the same procedure used for 2-amino-7-(4-fluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-(3-dimethylamino-propyl)-oxime (compound 88), except after addition of water the solvent was removed under reduced pressure. The crude material was taken up in ethylacetate (20 ml) and the resulting solution was filtered. The solvent was removed under reduced pressure and the title compound was purified by column chromatography eluting with dichloromethane/methanol (90/10).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([C:14]2[CH:22]=[CH:21][C:17]3[NH:18][N:19]=[N:20][C:16]=3[CH:15]=2)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CN(C)C=O>[Cl:3][C:4]1[C:5]([C:14]2[CH:22]=[CH:21][C:17]3[N:18]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:19]=[N:20][C:16]=3[CH:15]=2)=[N:6][CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: FC(F)(F)c1cnc(-c2ccc3[nH]nnc3c2)c(Cl)c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nnc2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Reaction time: 0.25 h

Procedure:
0.5 g of sodium hydride (80% strength by weight suspension in mineral oil) in 25 ml of anhydrous dimethylformamide was treated dropwise with a solution of 4.4 g of 5-(3-chloro-5-trifluoromethylpyridin-2-yl)benzotriazole in 25 ml of dimethylformamide. After stirring for 15 min, 2.6 g of ethyl bromoacetate were added dropwise, after which the mixture was stirred at 23° C. for 20 hours. The batch was then poured into 200 ml of water. After extracting three times with 100 ml of tert-butyl methyl ether each time, the combined organic phases were washed with 100 ml of water, dried over sodium sulfate and concentrated. The oil residue was purified by means of chromatography on silica gel (eluent: cyclohexane/ethyl acetate=6:1). The following were eluted in succession (without taking into account mixed fractions): 1.0 g of 5-(3-chloro-5-trifluoromethylpyridin-2yl)-2-ethoxycarbonylmethylbenzotriazole; m.p.: 127-129° C.
Reaction SMILES: O.O.O.O.O.O.[Cl-].[Cr+3:8].[Cl-].[Cl-].[P:11]([O:23][CH2:24][C@H:25]1[O:29][C@@H:28]([N:30]2[C:39]3[N:38]=[CH:37][N:36]=[C:34]([NH2:35])[C:33]=3[N:32]=[CH:31]2)[C@H:27]([OH:40])[C@@H:26]1[OH:41])([O:14][P:15]([O:18][P:19]([OH:22])([OH:21])=[O:20])([OH:17])=[O:16])(=[O:13])[OH:12]>O>[Cr:8].[P:11]([O:23][CH2:24][C@H:25]1[O:29][C@@H:28]([N:30]2[C:39]3[N:38]=[CH:37][N:36]=[C:34]([NH2:35])[C:33]=3[N:32]=[CH:31]2)[C@H:27]([OH:40])[C@@H:26]1[OH:41])([O:14][P:15]([O:18][P:19]([OH:21])([OH:22])=[O:20])([OH:17])=[O:16])(=[O:12])[OH:13]
Reactant: [Cr+3]
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: [Cl-]
Solvent: O
Product: [Cr]
Reaction time: 1.5 h

Procedure:
Equimolar amounts of chromium chloride hexahydrate and ATP (10 mM each) were mixed in 50 ml of water at a pH of around 3. The mixture was then incubated at room temperature for 1-2 hours to form the chromium-ATP complex. This complex was purified by loading 50 ml of the 10 mM chromium-ATP mixture onto a SE53 ion-exchange column having a bed volume of approximately 30 ml. The loaded column was washed with 100 ml of water in order to wash off unbound materials. The bound chromium complex was then eluted with 0.25 M ammonium hydroxide. The eluted fractions (4 ml/fraction) were monitored with a UV spectrophotometer for absorption at wavelengths A260 and A280. The peak fraction (the one with the highest absorbance) was collected and lyophilized.