Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][N:5]=1.[OH:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1>>[OH:1][CH:2]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][N:5]=1)[CH2:3][N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([OH:15])[CH2:17]1
Reactant: OC1CCCNC1
Reactant: c1ccc(-c2cc(C3CO3)no2)cc1
Product: OC1CCCN(CC(O)c2cc(-c3ccccc3)on2)C1
Temperature: 70 °C
Yield: 77.3 %

Procedure:
A mixture of 3-(1,2-epoxyethyl)-5-phenylisoxazole (1.05 g) and 3-hydroxypiperidine (1.13 g) is heated at 70°C for 20 minutes and then chromatographed on silica gel to give 3-[1-hydroxy-2-(3-hydroxypiperidino)ethyl]-5-phenylisoxazole (1.25 g). To a suspension of the compound in water (6.5 ml) is added 60% perchloric acid (516 ml), the precipitate is collected by filtration, and recrystallized from a mixture of 99% ethanol (2 ml) and ethyl acetate (8 ml) to give the perchlorate which melts at 151°-153°C. The perchlorate is suspended in aqueous sodium hydroxide solution and extracted with methylene chloride. After being dried with sodium sulfate, the extract is evaporated to give 3-[1-hydroxy-2-(3-hydroxypiperidino) ethyl]-5-phenylisoxazole (544 mg). Recrystallization from a mixture of ethyl acetate and hexane gives colorless prisms (388 mg) melting at 94°-96°C.
Reaction SMILES: C(OP(CC1[N:11]=[CH:12][N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)(=O)OCC)C.[CH3:34][C:35]([O-])(C)C.[K+].[C:40]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=O)[CH2:41][CH3:42]>C1COCC1.C(OCC)(=O)C>[C:44]1([C:40]([CH2:34][CH3:35])=[CH:41][C:42]2[N:11]=[CH:12][N:13]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:14]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCC(=O)c1ccccc1
Reactant: CCOP(=O)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OCC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of (1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester (1.24 g; CAS 473659-21-1) at room temperature (r.t.) in THF (20 ml) under an argon atmosphere was added potassium tert-butylate (301 mg). After 15 minutes stirring at room temperature, propiophenone (0.3 ml) was added in one portion. The mixture was heated to 80° C. and stirring at that temperature was continued for 2 days. The compact suspension was cooled to r.t. and the solid was filtered off and washed with THF. The filtrate was concentrated to leave a dark violet viscous oil. This was taken up in ethyl acetate (EtOAc) and washed with brine. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient cyclohexane→cyclohexane/EtOAc 3:2) to give 4-(2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (269 mg; not completely pure) as an off-white solid. MS (ISP): 243.2 ([Trt]+)
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:13]([O:11][C:5]1[C:4]([CH3:12])=[CH:3][C:2]([F:1])=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(F)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
A mixture of 4-fluoro-2-methyl-5-nitrophenol (4.69 g, 27 mmol), benzyl bromide (3.59 ml, 30 mmol) and potassium carbonate (7.58 g, 55 mmol) in DMF (100 ml) was heated at 80° C. for 4 hours. The mixture was allowed to cool and diluted with water and stirred for 15 minutes. The precipitated product was collected by filtration, washed with water and dried to give 5-benzyloxy-2-fluoro-4-methyl-1-nitrobenzene (6.4 g, 89%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=1.[OH-:22].[Na+]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:5]([CH2:20][C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=2)=[O:22])[CH2:20][C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=2)=[O:21])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(F)cccc1C=O
Reactant: COc1cccc(C(C)=O)c1
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cccc(C(=O)CC(CC(=O)c2cccc(OC)c2)c2cccc(F)c2C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.4 %

Procedure:
To a stirred solution of 3-fluoro-2-methylbenzaldehyde (75.0 g, 543 mmol) and 3′-methoxyacetophenone (179 g, 1.32 mol) in dichloromethane (1.5 L) was added 10% aq NaOH (750 mL) and tetrabutylammonium bromide (30.8 g, 95.7 mmol) portion-wise using a water/ice bath to maintain room temperature. The resulting mixture was stirred vigorously at room temperature for 16 h during which time a precipitate formed. An additional portion of tetrabutylammonium bromide (10.0 g, 31.1 mmol) was added and the mixture stirred an additional 3 h. The layers were separated, the aqueous phase was extracted with dichloromethane (500 mL), and the combined organic phases were washed with water. The organic layer was then dried over MgSO4, filtered, and concentrated under vacuum to give 279.1 g of crude product as a viscous brown oil. Purification over silica gel using 25-50% EtOAc/hexanes followed by slurrying of the concentrated yellow oil with 50% ether/hexanes and 100% ether gave the desired product, 3-(3-fluoro-2-methylphenyl)-1,5-bis(3-methoxyphenyl)pentane-1,5-dione (71.6 g, 31.4% yield), (characterized by 1H NMR).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[H][H].S(O[CH:27]1[CH2:31][CH2:30][O:29][CH2:28]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:27]3[CH2:31][CH2:30][O:29][CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: [H][H]
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncnc2c1c(I)cn2C1CCOC1
Temperature: 0 °C

Procedure:
4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.0 g) was added to a mixture of sodium hydride (0.79 g of a 60% dispersion in mineral oil) in dimethylformamide (100 ml) with stirring under nitrogen at 0° C. The mixture was stirred until hydrogen evolution ceased. 3-Tosyloxytetrahydrofuran (4.65 g) was added at 0° C. and then the mixture was warmed to 90° C. The mixture was stirred at this temperature for 2 hours and then overnight at ambient temperature. Water (100 ml) was added cautiously and the mixture was extracted with ethyl acetate to give 4-chloro-5-iodo-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidine, m.p. 184-186° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([NH2:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[N:27]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=2)[N:26]=[CH:25][C:24]=1[C:38](Cl)=[O:39].C(N(CC)CC)C.O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]=[CH:16][C:17]([NH:21][C:38]([C:24]3[CH:25]=[N:26][N:27]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][N:29]=4)[C:23]=3[CH3:22])=[O:39])=[CH:18][C:19]=2[CH3:20])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N)cnc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cn1
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of 4-(5-amino-3-methylpyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (4.4 g) in pyridine (50 ml) was added 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid chloride (5.16 g) described in Reference Example 180 at 0° C., and stirred at room temperature for 1 hour. To the reaction solution was added triethylamine (6.33 ml), then water was added thereto, and the precipitated solid was washed with water and ethyl acetate to give N-[6-(1-tert-butyloxycarbonylpiperidin-4-yl)-5-methylpyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (7.0 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:27])[C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][S:22][CH2:21][C:20]4=[O:25])=[C:15]([CH3:26])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:27])[C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][S:22](=[O:38])[CH2:21][C:20]4=[O:25])=[C:15]([CH3:26])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCSCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCS(=O)CC1=O
Temperature: -12.5 °C
Reaction time: 1 h

Procedure:
204 mg (0.48 mmol) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(thiomorpholin-3-on-4-yl)-benzamide are dissolved in a mixture of 12 ml dichloromethane and 1.2 ml acetic acid at −15° C. and combined with 110 mg (0.48 mmol) 3-chloroperbenzoic acid. The mixture is then stirred for one hour at −15 to −10° C., heated to ambient temperature and stirred for a further 3 hours. Then the reaction mixture is combined with semi-concentrated sodium hydrogen carbonate solution and extracted with a solvent mixture dichloromethane/methanol 19:1. The combined organic phases are washed with water, dried over magnesium sulphate, evaporated down i. vac. and purified by chromatography on silica gel (eluting gradient: ethyl acetate/(ethanol/conc. ammonia solution 19:1)=1:0→4:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]O)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.S(Cl)([Cl:25])=O.C(N(CC)CC)C.[OH-].[Na+]>C(Cl)(Cl)Cl.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][Cl:25])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: O=S(Cl)Cl
Reactant: CCN1c2ncc(CO)cc2C(=O)N(C)c2ccc(Cl)nc21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
The 2-chloro-5,11-dihydro-11-ethyl-8-hydroxymethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.52 g, 1.6 mmol) was dissolved in chloroform (10 mL) and treated with thionyl chloride (0.12 mL, 1.6 mmol) followed by triethylamine (0.23 mL, 1.6 mmol). After 0.5 hours stirring the mixture was made alkaline with 15% aqueous sodium hydroxide, diluted with brine (10 mL) and the organic layer was separated. The aqueous layer was then extracted with dichloromethane (2×20 mL). The combined organics were dried over sodium sulfate, filtered, concentrated and the residue was purified by flash chromatography (gradient hexanes to 1:1 hexanes/ethyl acetate) to give the title compound (0.51 g, 93%), m.p. 133°-134° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:29])=[C:25]([CH2:27][OH:28])[CH:26]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:29][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)=[CH:26][C:25]=1[CH2:27][OH:28]
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Nc1ccc(F)c(CO)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)Nc2ccc(F)c(CO)c2)nc(N2CCOCC2)cc1=O
Yield: 45.9 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 184 mg of (5-amino-2-fluorophenyl)methanol, and 285 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 2 ml of N,N-dimethylformamide. 157 mg of N-[4-fluoro-3-(hydroxymethyl)phenyl]-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a grey solid, the characteristics of which are the following:
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[C:22]1(=O)[CH2:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH:22]1([N:8]2[CH2:9][CH2:10][C:4]3=[CH:3][N:2]([C:11]4[CH:12]=[CH:13][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:15][CH:16]=4)[N:1]=[C:5]3[CH2:6][CH2:7]2)[CH2:25][CH2:24][CH2:23]1
Reactant: CS(=O)(=O)Nc1ccc(-n2cc3c(n2)CCNCC3)cc1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc(-n2cc3c(n2)CCN(C2CCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]methanesulfonamide (may be prepared as described in Description 40) (12 mg, 0.04 mmol) in dichloromethane (2 ml) was added cyclobutanone (14 mg, 0.20 mmol) and acetic acid (1 drop). The resulting mixture was stirred at room temperature, under argon, for 30 minutes. Sodium triacetoxyborohydride (42 mg, 0.20 mmol) was added and stirring continued for 1 hour. The resulting reaction mixture was diluted with methanol and purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (E29). MS (ES+) m/e 361 [M+H]+.
Reaction SMILES: F[C:2]1(F)[O:6][C:5]2[CH:7]=CC=CC=2[O:3]1.C([Li])CCC.C[N:18]([CH2:20][CH2:21]N(C)C)C.[O:25]1[CH2:29]C[CH2:27][CH2:26]1>CCCCCC>[CH2:5]([O:6][C:2](=[O:3])[C:21](=[CH:29][O:25][CH2:26][CH3:27])[C:20]#[N:18])[CH3:7]
Reactant: C1CCOC1
Reactant: FC1(F)Oc2ccccc2O1
Reactant: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCOC=C(C#N)C(=O)OCC

Procedure:
7.9 g (50 mmol) of 2,2-difluoro-1,3-benzodioxole are metallated according to Example 2 at -15° C. with 35 ml (55 mmol) of n-butyllithium (1.60M in hexane) and 6.5 g (55 mmol) of TMEDA in 60 ml of hexane. To the 2,2-difluoro-1,3-benzodioxol-4-yllithium which precipitates there is added at -20° C., over a period of 30 minutes, a solution of 9.3 g (55 mmol) of ethoxymethylenecyanoacetic acid ethyl ester in 30 ml of tetrahydrofuran, an orange-red turbid solution being formed during the reaction, which is exothermic. After stirring for 20 minutes at -15° C., the solution is hydrolysed with 50 ml of 2N hydrochloric acid. The aqueous phase is extracted twice with 80 ml of diethyl ether each time. The organic solutions are washed twice with 50 ml of water each time, dried over MgSO4 and concentrated to dryness by evaporation in a vacuum rotary evaporator. The residue is crystallised from ethanol/water 4:1, affording 10.1 g (72%) of colourless platelets of m.p. 87°-88° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH3:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:5])[C:3]=1[C:15]([OH:17])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[C:50]([NH2:56])=[N:51][CH:52]=[C:53]([Br:55])[CH:54]=2)=[CH:45][CH:44]=1>C(Cl)Cl.CN(C=O)C.O>[NH2:56][C:50]1[C:49]([C:46]2[CH:45]=[CH:44][C:43]([NH:42][C:15]([C:3]3[C:4](=[O:5])[N:6]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:7]([CH3:8])[C:2]=3[CH3:1])=[O:17])=[CH:48][CH:47]=2)=[CH:54][C:53]([Br:55])=[CH:52][N:51]=1
Reactant: Nc1ccc(-c2cc(Br)cnc2N)cc1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(-c3cc(Br)cnc3N)cc2)c(=O)n(-c2ccccc2)n1C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To the antipyric acid (0.163 g) in 5 mL of DCM, 0.5 mL of DMF and TEA (1.4 mmol) was added the HATU (0.266 g) and stirred for 30 minutes. To the activated ester was added the compound prepared in Example 43 (0.185 g) and stirred for 1 hour. The reaction mixture was diluted with water, extracted with additional DCM, and the organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The DCM layer was filtered and concentrated, and the crude was chromatographed on silica gel using 10:1 DCM:MeOH to give the title compound (0.3 g) having the following physical data.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>C(O)C.O.[Pd]>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1cccc(NCCCn2ccnc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Nc1cccc(NCCCn2ccnc2)c1
Reaction time: 12 h
Yield: 74 %

Procedure:
28 g N-3-(imidazol-1-yl)propyl-3-nitroaniline was dissolved in 450 ml ethanol and 50 ml water, and 0.3 Pd/C (5%) was added. After purging with nitrogen, hydrogenation was performed for 12 h at 50° C. under 50 bar of hydrogen pressure. After cooling, nitrogen purging was repeated, the catalyst was filtered off, and the filtrate was reduced on a rotary evaporator. 18.2 g of black oil was obtained; this was distilled in a ball tube (265–387° C., 0.06–0.08 mbar). The product obtained was an amorphous orange solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:4].[OH-].[K+].O>CO>[C:3]([C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1C(=O)O
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A mixture of 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene (1.2 g), KOH (0.33 g) and water (5 mL) in MeOH (45 mL) was stirred at room temp. overnight and then heated at the reflux temp. for 4 h. The resulting mixture was cooled to room temp. and concentrated under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous mixture was made acidic with a 1N HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (1.04 g).
Reaction SMILES: [NH2:1][C:2](=[N:46][C:47]([O:49][CH2:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C:33]2[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]([O:41][CH2:42][CH2:43][OH:44])[C:34]=2[F:45])[C:11]2[N:12]=[C:13]([O:22][CH2:23][O:24][C:25]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[N:14]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:77](O)(=[O:79])[CH3:78]>CN(C1C=CN=CC=1)C.CN(C=O)C.ClCCl>[C:77]([O:44][CH2:43][CH2:42][O:41][C:35]1[C:34]([F:45])=[C:33]([C@@H:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([NH2:1])=[N:46][C:47]([O:49][CH2:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])=[CH:8][CH:7]=2)[C:11]2[N:12]=[C:13]([O:22][CH2:23][O:24][C:25]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:26])[N:14]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:15]=2)[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=1)(=[O:79])[CH3:78]
Reactant: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nc(OCOC(=O)C3CCCCC3)n(-c3ncccn3)n2)c1
Reactant: CC(=O)O
Agent: CN(C)C(F)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(OCCOC(C)=O)c(F)c([C@@H](Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nc(OCOC(=O)C3CCCCC3)n(-c3ncccn3)n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cyclohexanecarboxylic acid 5-{(R)-(4-{amino[2,2-dimethylpropoxycarbonylimino]methyl}phenylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}-2-pyrimidin-2-yl-2H-[1,2,4]-triazol-3-yloxymethyl ester (42 mg), DMAP (1 mg), and triethylamine (0.0648 mL) were dissolved in DMF (3 mL) and dichloromethane (3 mL). To the solution, a mixture of TFFH (30.7 mg), acetic acid (0.00665 mL), and dichloromethane (3 mL) was slowly added, and the resulting mixture was stirred at room temperature for 3 hours. After concentrating the reaction mixture under reduced pressure, ice, THF, saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous ammonium chloride solution were added to the residue obtained, and the resulting mixture was extracted with a mixture of THF and ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was crudely purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain a crudely purified product of the captioned compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1.[Cl:19][C:20]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:21]=1[C:22](Cl)=[O:23].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:19][C:20]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:21]=1[C:22]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][C:9]=2[F:11])[C:5]([C:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=2)=[CH:6]1)=[O:23]
Reactant: CN1CC=C(c2c[nH]c3c(F)cc(F)cc23)CC1
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(C(=O)c3cc(Cl)ccc3Cl)c3c(F)cc(F)cc23)CC1

Procedure:
(5.6 mg, 33%); from 5,7-difluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4g, 10 mg, 0.04 mmol) and 2,5-dichlorobenzoyl chloride (12.6 mg, 0.06 mmol) with 1M NaN(TMS)2 (60 μL, 0.06 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2=[CH:9][S:10][CH:11]=[C:6]2[O:5][CH2:4]1.[C:12]([O-:15])(=[O:14])[CH3:13].[K+]>CS(C)=O>[C:12]([O:15][CH2:2][CH:3]1[O:8][C:7]2=[CH:9][S:10][CH:11]=[C:6]2[O:5][CH2:4]1)(=[O:14])[CH3:13]
Reactant: CC(=O)[O-]
Reactant: BrCC1COc2cscc2O1
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)OCC1COc2cscc2O1
Reaction time: 1 h
Yield: 90 %

Procedure:
In a 50 mL Schlenk tube 1.00 g of to 2-(bromomethyl)-2,3-dihydrothieno[3,4-b][1,4]dioxine was combined with 0.5 g (0.0051 mol) potassium acetate and 25 mL DMSO. The tube was sealed and stirred for 1 h at 100 C. At this time TLC indicated complete consumption of starting material. The reaction was poured into water and extracted with ether. After removing the ether under reduced pressure column chromatography was performed using 90% methylene chloride in hexane to isolate a light yellow oil in 90% yield. The structure and purity were confirmed by 1H/13C NMR and GC-MS.