Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:72][C:73]1[C:78]([NH2:79])=[CH:77][CH:76]=[CH:75][N:74]=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:72][C:73]1[C:78]([NH:79][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)(=[O:10])=[O:9])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=2)=[CH:77][CH:76]=[CH:75][N:74]=1
Reactant: O=S(=O)(NCC1CC1)c1ccc(Br)cc1C(F)(F)F
Reactant: Nc1cccnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=S(=O)(NCC1CC1)c1ccc(Nc2cccnc2Cl)cc1C(F)(F)F
Reaction time: 12 h

Procedure:
A mixture of 4-Bromo-N-cyclopropylmethyl-2-trifluoromethyl-benzenesulfonamide (150 mg), Pd(OAc)2 (9.5 mg), BINAP (26 mg), cesium carbonate (164 mg) and 2-Chloro-pyridin-3-ylamine (108 mg) in 15 ml toluene was relaxed for 12 hours. The reaction mixture was eluted through a silica bed with Toluene and then with PE:EtOAc (1:1). The toluene fraction was discarded and the solvent of the PE:EtOAc fraction was removed under reduced pressure. The crude product was purified by Combiflash (linear gradient PE-THF). Yield 25 mg, 15%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([OH:21])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].Cl>CN(C)C=O>[CH2:27]([O:21][C@@H:17]1[CH2:18][CH2:19][CH2:20][C@H:15]([O:14][CH2:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH3:22])[CH2:16]1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@@H]1CCC[C@H](OCc2nc(-c3ccc(F)cc3)oc2C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 g of cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol are dissolved in 15 ml of dimethylformamide, and 0.3 g of sodium hydride is added. After 30 minutes, 2.4 g of allyl bromide are added dropwise. The mixture is stirred at room temperature for 5 hours. 15 ml of 1N hydrochloric acid are then added to the reaction mixture, and the mixture is washed three times with 15 ml of ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 2.4 g of 4-(cis-3-allyloxycyclohexyloxymethyl)-2-(4-fluorophenyl)-5-methyloxazole as a yellowish oil. C20H24FNO3 (345.42), MS (ESI): 346 (M+H+)
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH2:25].[BH4-].[Na+]>CO>[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH:25][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: CC(C)(C)CCN
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC(C)(C)C)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 45.9 %

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.700 g, 2.56 mmol), 3,3-dimethylbutylamine (0.272 g, 2.69 mmol) and 3 Å molecular sieves in a vial. Add methanol (12.8 mL), cap and stir overnight. Add NaBH4 (0.0969 g, 2.56 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting t-rough a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes. Concentrate the fraction containing the product, then take it up in EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it over Na2SO4, filter and concentrate. Dissolve the product in ether:dichloromethane (5:1) (25 mL), add hexanes (20 mL), and then concentrate to about a quarter of the volume. Filter the precipitate to give the title compound (0.421 g, 45.9%): TOF MS ES+ 359.2 (M+H)+, HRMS calcd for C19H27N4O3 359.2083 (M+H)+, found 359.2093, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.0 min, 98.0% purity.
Reaction SMILES: OO.[C:3]([O-:11])(=[O:10])[CH:4]([CH2:6][C:7]([O-:9])=[O:8])[OH:5].[CH3:12][S:13][CH2:14][CH2:15][NH3+:16].[CH3:17][S:18][CH2:19][CH2:20][NH3+:21]>CO>[C:3]([O-:11])(=[O:10])[CH:4]([CH2:6][C:7]([O-:9])=[O:8])[OH:5].[CH3:12][S:13]([CH2:14][CH2:15][NH3+:16])=[O:5].[CH3:17][S:18]([CH2:19][CH2:20][NH3+:21])=[O:5]
Reactant: CSCC[NH3+]
Agent: O=C([O-])CC(O)C(=O)[O-]
Agent: OO
Solvent: CO
Product: CS(=O)CC[NH3+]
Reaction time: 4 h

Procedure:
5.5 ml of H2O2 (30%) are added to a suspension of 11.25 g of 2-methylthio ethylammonium malate in 50 ml of methanol. The temperature is reduced to 30° C during this addition. The solution obtained is agitated for 4 hours. The sulfoxide formed is precipitated by the addition of ethanol while cooling, yielding 11.2 g of a white product melting at 106° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]4[S:22][CH:21]=[C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:29][C:25]1[CH:24]=[C:23]([C:20]2[C:18]3[N:19]=[C:14]([NH:13][C:10]4[CH:11]=[N:12][C:7]([N:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)=[CH:8][CH:9]=4)[N:15]=[CH:16][C:17]=3[S:22][CH:21]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1cccc(-c2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cccc(-c2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
N-(6-Morpholinopyridin-3-yl)-7-(3-nitro phenyl)thieno[3,2-d]pyrimidin-2-amine (476 mg, 1.10 mmol) was dissolved in ethanol (3.5 mL) and tin(II) chloride dihydrate (1238 mg, 5.48 mmol) was added. The reaction mixture was stirred at 80° C. for 2 hours. After removing ethanol by distillation under reduced pressure, ammonia water was slowly added to make pH 5. Sodium carbonate was added to thus prepared yellow precipitate until the pH reached 7. The precipitate was filtered and washed several times with ethyl acetate. The filtrate was concentrated and the resultant target compound (338 mg, 76%) was used without purification.
Reaction SMILES: [CH2:1]([OH:6])[C:2]#[C:3][CH2:4][OH:5].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1>CCOCC>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:5][CH2:4][C:3]#[C:2][CH2:1][OH:6]
Reactant: OCC#CCO
Reactant: C1=COCCC1
Solvent: CCOCC
Product: OCC#CCOC1CCCCO1
Yield: 68.8 %

Procedure:
To a mixture of 5.0 g of 2-butyne-1,4-diol and 10 milligrams of p-toluenesulfonic add and 150 ml of dry ether there was added dropwise with stirring at room temperature 4.9 g of 3,4-dihydro-2H-pyran. After stirring overnight at ambient temperature the ether was evaporated and the residue was poured into 200 ml of water. The aqueous solution was extracted with hexane (2×100 ml) and then re-extracted with ether (3×100 ml). The combined ether extracts were washed with 100 ml of brine, dried over magnesium sulfate and evaporated to yield 6.8 g of 4-tetrahydropyranoxy-2-butyn-1-ol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH:19]1[CH:26]2[CH2:27][C:22]3([OH:29])[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:18][CH:19]1[CH:20]2[CH2:28][CH:24]3[CH2:23][C:22]([OH:29])([CH2:27][CH:26]1[CH2:25]3)[CH2:21]2)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(OCc2ccccc2)c1

Procedure:
Prepared from 3-(benzyloxy)benzoic acid and 4-amino-1-hydroxyadamantane to give the title compound as a mixture of two isomers. 1H NMR (300 MHz, CDCl3): δ 7.69-7.74 (m, 1H), 7.29-7.48 (m, 7H), 7.20-7.24 (m, 0.5H), 7.09-7.13 (m, 0.5; H), 6.27 (d, 1H), 5.12 (s, 2H), 4.18-4.23 (m, 1H), 2.16-2.27 (m, 3H), 1.91-1.98 (m, 2H), 1.71-1.84 (m, 6H), 1.54-1.61 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][C:3]=1[C:30](OCC)([O:34]CC)[O:31][CH2:32][CH3:33].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][C:3]=1[C:30]([O:31][CH2:32][CH3:33])=[O:34]
Reactant: CCOC(OCC)(OCC)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a solution of 4-[7-chloro-2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (375 mg, 0.677 mmol) in acetone (8 mL) and water (2 mL) was added p-toluenesulfonic acid monohydrate (321 mg, 1.69 mmol). The reaction mixture was stirred at room temperature for 2 hours, then quenched with ice water. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, then concentrated in vacuo to remove the majority of the acetone. The resultant mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (29:1 dichloromethane:methanol) provided ethyl 7-chloro-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylate (175 mg, 54%) as a brown solid. Rf 0.08 (29:1 dichloromethane:methanol); 1H NMR (400 MHz, CDCl3) δ 8.36 (d, 1H), 8.09 (d, 1H), 7.82 (d, 1H), 7.65 (m, 2H), 7.14 (t, 2H), 6.30 (d, 1H), 5.19 (d, 1H), 4.46 (q, 2H), 4.32 (m, 1H), 2.06 (m, 2H), 1.77–1.21 (m, 9H); MS m/z 480 (M+1).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([N+:10]([O-])=O)[CH:7]=[CH:8][CH:9]=1.O>[Zn].CCOCC>[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCOCC
Solvent: O
Product: Clc1cccc(NNc2cccc(Cl)c2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a stirred solution of 50% NaOH (3 mL) was added 3-chloronitrobenzene (10 g, 64 mM). The suspension was warmed to 60° C. and zinc (9 g, 138 mM) was added. During the addition, the temperature of the reaction mixture was kept between 60° and 80° C. After the addition was complete, a solution of 20% NaOH (18 mL, 90 mM) was added followed by water (30 mL). An additional portion of zinc (12 g, 189 mM) was then added and the resulting mixture was stirred between 75°-80° C. for 2 hours. After cooling to room temperature, the mixture was added to ether (200 mL), stirred, and the liquid was decanted. The solids were then resuspended in ether and the extraction was repeated 3 times. The ether extracts were combined, dried (Na2SO4), and concentrated to give a yellow solid. This was purified by flash column chromatography using CH2Cl2 as elutant which afforded the titled compound as a yellow solid (5.5 g, 68%). NMR (CDCl3): 7.12 (t, J=8 Hz, 2H), 6.80 (m, 4H), 6.67 (dd, J1 =1 Hz, J2 =8 Hz, 2H), 5.66 (br s, 2H).
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].C[Si](C)(C)N[Si](C)(C)C.C(O[CH2:25][O:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])(=O)C.O>CC(C)=O.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>[C:30]([O:29][CH2:28][CH2:27][O:26][CH2:25][N:6]1[CH:7]=[N:8][C:9]2[C:10](=[O:11])[NH:1][C:2]([NH2:3])=[N:4][C:5]1=2)(=[O:32])[CH3:31]
Reactant: CC(=O)OCCOCOC(C)=O
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)OCCOCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 130 °C
Yield: 57.3 %

Procedure:
A mixture of 10 gms (66 mmoles) of guanine, 50 ml of hexamethyldisilazane, and 0.4 gms (3 mmmol) of ammonium sulfate was heated to 115°-118° C. for 18 hours. The ammonia gas was removed as it was formed. After 18 hours of heating, a solution was formed indicating the completion of silylation. To this solution was added 15 gms (85 mmol) of 2-oxa-1,4-butanediol diacetate and 0.1 ml of trimethylsilyl triftriflate. The mixture was heated to 130° C. for a period of 4.5 hours. The solution was cooled to 50° C. and 10 ml of water dissolved in 100 ml of acetone was added. The mixture was heated to reflux and a precipitate was formed immediately. The mixture was cooled and the solid was collected by filtration to yield 10.1 g (58% yield) of 9-(2-acetoxyethoxy)methylguanine, with a 13:1 ratio of N-9 to N-7 isomer. Characteristic analytical data are as follows: 1H NMR (DMSO-d6) δ1.90 (3H, singlet, --OAc) , 3.58 (2H, multiplet, --OCH2 --) , 4.0 (2H, multiplet, --CH2OAc) , 5.25 (2H, singlet, --NCH2O--), 6.5 (2H, br singlet, --NH2), 7.75 (1H, singlet, --N=CH--N--).
Reaction SMILES: C(S([C:6]1[CH:38]=[CH:37][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][N:21]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)[C@@H:20]([CH:34]([CH3:36])[CH3:35])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)(=O)=O)C.C([C@H]1C2=NC=C(C(NCC3C=CC([C:59]([O:61][CH3:62])=[O:60])=CC=3)=O)C=C2CN1)(C)C>>[CH:34]([C@H:20]1[C:17]2=[N:18][CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:9]3[CH:8]=[CH:7][C:6]([C:59]([O:61][CH3:62])=[O:60])=[CH:38][CH:37]=3)=[O:13])[CH:15]=[C:16]2[CH2:22][N:21]1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=1)([CH3:36])[CH3:35]
Reactant: COC(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN[C@H]3C(C)C)cc1
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(Cc2ccc(C(F)(F)F)cc2)[C@H]3C(C)C)cc1
Product: COC(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(Cc2ccc(C(F)(F)F)cc2)[C@H]3C(C)C)cc1
Reaction time: 0.03 h

Procedure:
Procedure same as that for (S)-N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6-(4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide, using methyl(S)-4-((7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamido)methyl)benzoate as a starting material. LC-MS tR=1.34 min in 2 min chromatography, MS (ESI) m/z 512 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19])[NH2:14]>>[F:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([C:18]([F:19])([F:20])[F:21])=[C:11]([F:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[C:18]([F:19])([F:20])[F:21]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(C(F)(F)F)c(F)c1
Product: Fc1cc(Nc2ncc(F)c(Nc3ccc(C(F)(F)F)c(F)c3)n2)ccc1C(F)(F)F

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-fluoro-4-trifluoromethylaniline were reacted to yield N2,N4-bis(3-fluoro-4-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.01 (d, 1H, J=3 Hz), 7.77 (m, 3H), 7.61 (dt, 1H, J=4.2 and 3 Hz), 7.20 (t, 1H, 8.7 Hz), 7.12 (t, 1H, J=9.3 Hz), 6.95 (s, 1H), 6.82 (s, 1H); 19F NMR (CDCl3): δ −17505 (s, 3F), −17517 (s, 3F), −17525 (s, F), −17537 (s, F), −46835 (s, 1F); LCMS: ret. time: 32.39 min.; purity: 95%, MS (m/e): 453 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C@@H:7](N3CCNCC3)[C:6]=2[CH:23]=1.CS(O)(=O)=[O:26]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([OH:26])[C:6]=2[CH:23]=1
Reactant: Cc1ccc2c(c1)C[C@@H](N1CCNCC1)c1cc(F)ccc1S2
Reactant: CS(=O)(=O)O
Product: Cc1ccc2c(c1)CC(O)c1cc(F)ccc1S2

Procedure:
2.3 G. of enriched (R)-1-(8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-piperazine [αD = -25.0° (chloroform; c = 2.50%)] are heated to reflux with stirring for 24 hours in 0.57-M methanesulfonic acid and worked up in a manner analogous to that described in Example 13. For purification, the benzene extract is chromatographed on silica gel (0.2-0.5 mm) with chloroform. The eluted oily racemic 8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-ol melts at 90.5° C. after recrystallization from n-hexane.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5](=[O:13])[N:6]([CH2:9][C:10]([OH:12])=[O:11])[C:7]=1[CH3:8].[OH-].[K+]>O>[CH3:8][C:7]1[N:6]([CH2:9][C:10]([OH:12])=[O:11])[C:5](=[O:13])[C:4]([NH:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:3][CH:2]=1
Reactant: Cc1c(Cl)nc(NCCc2ccccc2)c(=O)n1CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cnc(NCCc2ccccc2)c(=O)n1CC(=O)O
Reaction time: 16 h

Procedure:
(5-Chloro-6-methyl-2-oxo-3-phenethylamino-2H-pyrazin-1-yl)acetic acid (13.4 g, 41.6 mmol) was added to a stirred solution of potassium hydroxide (7.28 g, 110 mmol, assuming 15% water in the pellets) in water (600 ml). After degassing the resulting solution with argon, 10% Pd/C (6.3 g) was added and the mixture then stirred under a balloon of hydrogen. After 16 h, HPLC analysis showed that 1% of the starting material remained. The mixture was filtered through Celite and the filtrate was adjusted to pH 2 with 3N KHSO4 solution. The resulting precipitate was collected by filtration and washed with water. Drying for 16 h at 0.5 mm Hg gave 1-5 as a crystalline solid: 1H NMR (DMSO-d6) δ2.11 (s, 3 H, Me), 2.87 (t, J=7.6 Hz, 2 H, PhCH2), 3.53 (br s, 2 H, CH2NH), 4.68 (s, 2 H, CH2CO2), 6.68 (s, 1 H, pyrazinone H-5), 7.20-7.31 (m, 5 H, Ph), 8.16 (br s, 1 H, NH).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=O.C(N=CC)(C)(C)C.ClP(=O)(OCC)[O:26][CH2:27][CH3:28].C(O)(=O)C(O)=O>CCCCCC.O1CCCC1>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[CH:28][CH:27]=[O:26]
Reactant: CCOP(=O)(Cl)OCC
Reactant: O=C(c1ccccc1F)c1ccccc1F
Agent: CC=NC(C)(C)C
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=CC=C(c1ccccc1F)c1ccccc1F
Temperature: 85 °C

Procedure:
The compound was prepared according to the procedure described in Example 84. The following reagents were used: 2,2'-difluorobenzophenone (6.0 g) diisopropylamine (28.8 mL) 1.6M n-butyl lithium in hexane (129 mL). acetaldehyde N-tert-butylimine (13.2 mL), diethyl chlorophosphonate (14.85 mL) and tetrahydrofurane (100 mL). The reaction was worked up in the usual manner, with the exception that the oxalic acid catalyzed hydrolysis was slow and it was necessary to heat the mixture to 85° C. for one hour to complete the conversion. The crude product (5.8 g), obtained as an orange oil, was crystallized from hexane to give 4.6 g of 3,3-bis(2-fluorophenyl)-2-propenal mp 75°-77° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH2:24])[CH:18]=1>C(O)C>[N:9]1([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:24][CH2:23][C:19]3[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=3)=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: NCc1cccnc1
Reactant: O=[N+]([O-])c1cc(Cn2ccnc2)ccc1F
Solvent: CCO
Product: O=[N+]([O-])c1cc(Cn2ccnc2)ccc1NCc1cccnc1
Reaction time: 4 h
Yield: 82 %

Procedure:
(a-3) A mixture of 4.4 parts of 1-[(4-fluoro-3-nitrophenyl)methyl]-1H-imidazole, 4.33 parts of 3-pyridinemethanamine and 80 parts of absolute ethanol was stirred for 4 hours at reflux temperature. The reaction mixture was evaporated. 50 Parts of water were added to the residue. The product was extracted twice with 130 parts of trichloromethane. The combined trichloromethane layers were dried, filtered and evaporated. The residue was crystallized from 48 parts of 2-propanol. The product was filtered off and dried, yielding 5.1 parts (82%) of N-[4-(1H-imidazol-1-ylmethyl)-2-nitrophenyl]-3-pyridinemethanamine; mp. 171.0° C. (int. 71).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[CH:9]=[N+:10]([O-:17])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15].[CH2:18]([NH:20]CC)[CH3:19].C(N)C>C1COCC1>[CH2:18]([NH:20][C:8]1[CH:9]=[N+:10]([O-:17])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH3:19]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Cl
Reactant: CCNCC
Agent: CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCNc1c[n+]([O-])ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous K2CO3 (19 g, 144.5 mmol) is suspended in a solution of 3-chloro-4-nitro-pyridine-1-oxide (10 g, 57.8 mmol) in anhydrous acetonitrle (100 mL). Excess diethyl amine (2.0 M) in THF is added to the above suspension with ice-bath cooling. After complete addition of ethylamine, the reaction mixture is allowed to warm to room temperature and stir overnight. The reaction mixture is filtered to remove K2CO3 and the filtrate is evaporated under reduced pressure to remove volatile solvents. The organic residue is subjected to chromatography eluting with 30% EtOAc-hexanes to afford 3-ethylamino-4-nitro-pyridine-1-oxide as an orange solid (8.2 g); 1H NMR (300 MHz, CDCl3): δ 8.0 1 (d, J=7.5 Hz, 1H), 7.91(s, 1H), 7.8 (brs, NH), 7.44 (d, J=7.2 Hz, 1H), 3.30 (t, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H), m/z 184 [M+1]
Reaction SMILES: C([O:3][C:4]([C:6]([C:13]1[C:14]([F:29])=[C:15]([C:25]([O:27]C)=[O:26])[C:16](=[C:21]([F:24])[C:22]=1[F:23])[C:17]([O:19]C)=[O:18])(C(OCC)=O)[CH3:7])=[O:5])C.Cl>C(O)(=O)C>[C:4]([CH:6]([C:13]1[C:14]([F:29])=[C:15]([C:25]([OH:27])=[O:26])[C:16](=[C:21]([F:24])[C:22]=1[F:23])[C:17]([OH:19])=[O:18])[CH3:7])([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1c(F)c(F)c(C(=O)OC)c(C(=O)OC)c1F
Agent: Cl
Solvent: CC(=O)O
Product: CC(C(=O)O)c1c(F)c(F)c(C(=O)O)c(C(=O)O)c1F
Yield: 100.3 %

Procedure:
A mixture of dimethyl 4-(1,1-bis-ethoxycarbonylethyl)-3,5,6-trifluorophthalate (12.9 g, 30.7 mmol), hydrochloric acid (120 ml), and acetic acid (120 ml, was refluxed for 24 h. The reaction mixture was concentrated to dryness to give 9.0 g of the title compound as colorless crystals.