Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][CH:10]=[C:11]3[C:16]=2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]3[CH3:20])[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.FC(F)(F)S(O[CH2:51][CH:52]1[CH2:56][C:55](=[O:57])[O:54][CH2:53]1)(=O)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH2:51][CH:52]3[CH2:56][C:55](=[O:57])[O:54][CH2:53]3)[CH:10]=[C:11]3[C:16]=2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]3[CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(COS(=O)(=O)C(F)(F)F)CO1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]cc2n(C)c1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC3COC(=O)C3)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-(3-Fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (2.50 g, 9.2 mmol) was added portionwise to a mixture of potassium tert-butoxide (1.18 g, 10.5 mmol) and 18-crown-6 (242 mg, 0.92 mmol) in THF (15 mL), and stirred at room temperature for 15 minutes. A solution of (5-oxotetrahydrofuran-3-yl)methyl trifluoromethanesulfonate (2.61 g, 10.5 mmol) in THF (7.5 mL) was then added, maintaining the temperature at ˜20° C. using a water bath. The solution was stirred at room temperature for 1 hour. The reaction was quenched with saturated NH4Cl(aq) (10 mL), diluted with dichloromethane (100 mL) and washed with saturated NH4Cl(aq) (2×50 mL). The organic phase was dried over magnesium sulfate and the solvent evaporated under vacuum. Purification by chromatography on silica, eluting with 40-100% EtOAc/hexane, afforded the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(C(F)(F)F)cn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1cc(CCl)ccc1Oc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To the solution of 5-(hydroxymethyl)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile (269 mg, 0.999 mmol) in DCM (20 mL), was added thionyl chloride (0.7 mL, 9.59 mmol) dropwise. The mixture was stirred at room temperature for 2 h. After removing the solvent, the residue was dissolved in DCM, then washed with water twice, dried over Na2SO4, and concentrated in vacuo to afford the title compound (275 mg, 96% yield) as a light green solid. LCMS: rt=3.54 min, [M+H+]=313
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:26]([CH3:27])=[N:25][C:18]3[N:19]=[C:20](SC)[N:21]=[CH:22][C:17]=3[CH:16]=2)[C:12]([CH3:28])=[CH:11][C:10]=1[F:29])=[O:7].C1C=C(Cl)C=C(C(OO)=O)C=1.[NH3:43]>C(Cl)Cl>[NH2:43][C:20]1[N:21]=[CH:22][C:17]2[CH:16]=[C:15]([C:13]3[C:12]([CH3:28])=[CH:11][C:10]([F:29])=[C:9]([NH:8][C:6]([NH:5][CH2:4][CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])=[O:7])[CH:14]=3)[C:26]([CH3:27])=[N:25][C:18]=2[N:19]=1
Reactant: N
Reactant: CSc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3C)c(C)nc2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(F)c(NC(=O)NCCC(C)(C)C)cc1-c1cc2cnc(N)nc2nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
Treat a suspension of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.248 g, 0.562 mmol) in DCM (20 mL) with 70 wt % mCPBA (0.208 g, 0.842 mmol) and stir the mixture at RT for 2 h. Add ammonia (0.5N in dioxane, 8.99 mL, 4.49 mmol) and stir the mixture at RT overnight. Add additional ammonia (7N in MeOH, 5 mL, 35 mmol) and stir at RT overnight. Concentrate the mixture to dryness, treat with saturated. Na2CO3 and extract with DCM (4×). Dry the combined organics over MgSO4, concentrate to dryness and purify via silica gel chromatography (50-100% EtOAc/Hex, then 0-10% MeOH/EtOAc) to afford the title compound as an off-white solid (57 mg, 24%). MS (m/z): 411.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5]([OH:7])=O.[NH2:29][CH:30]([CH3:33])[CH2:31][OH:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[NH:29][CH:30]([CH3:33])[CH2:31][OH:32])[CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: CC(N)CO
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Product: CC(CO)NC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and 2-aminopropan-1-ol were reacted by a procedure similar to that to prepare 137 in Example 47 to give 228. MS: (ESI+) 471.0
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.C([Li])CCC.[CH:30](=[O:32])[CH3:31]>C1COCC1>[CH2:16]([CH:15]([NH:14][C:11]1[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([O:6][C:5]2[C:21]([CH3:23])=[CH:22][C:2]([CH:30]([OH:32])[CH3:31])=[CH:3][C:4]=2[CH3:24])[C:12]=1[CH3:13])[CH2:18][CH3:19])[CH3:17]
Reactant: CC=O
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C(C)O)cc2C)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butyllithium at −78° C. After stirring at −78° C. for 10 min, acetaldehyde was added and the resulting mixture was stirred at −78° C. for 30 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 7.06(s,2H), 4.84(m,1H), 6.08(s,1H), 3.73(d,1H), 3.35(m,1H), 2.14(s,3H), 2.12(s,3H), 2.11 (s,6H), 1.4-1.7(m,4H), 1.51 (d,3H), 0.96(t,6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(=O)(O)O.[NH:15]([C:17](=[NH:19])[NH2:18])[NH2:16].ClCCl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:16][NH:15][C:17](=[NH:18])[NH2:19])=[O:5]
Reactant: N=C(N)NN
Reactant: O=C(Cl)c1ccccc1Cl
Agent: O=C(O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: N=C(N)NNC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chlorobenzoyl chloride (10 g, 60 mmol, 1.00 equiv) and hydrazinecarboximidamide carbonic acid salt (11.6 g, 85 mmol, 1.49 equiv) in pyridine (10 mL) and dichloromethane (100 g, 1.18 mol, 41.21 equiv) was stirred for 3 h at 25° C. After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was purified via silica gel column (ethyl acetate/petroleum ether (10/1)) resulting in 3 g (22%) of 2-(2-chlorobenzoyl)hydrazinecarboximidamide as yellow oil.
Reaction SMILES: [Cl:1]/[C:2](/[C:12]([F:15])([F:14])[F:13])=[CH:3]\[C@@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].C(N(CC)CC)C.S(Cl)([Cl:25])=O.S(=O)=O.Cl>C1(C)C=CC=CC=1>[Cl:1]/[C:2](/[C:12]([F:15])([F:14])[F:13])=[CH:3]\[C@@H:4]1[C@H:6]([C:7]([Cl:25])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: O=S=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Temperature: 45 °C
Reaction time: 5 h

Procedure:
A 1 liter dry, clean jacketed split reaction vessel equipped with agitator, thermometer, condenser, nitrogen blanket and vent to a scrubber system was charged with toluene (450 ml) and agitated whilst cis-Z (+) 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl-cyclopropane carboxylic acid (89.4 gm=0.369 mol) was added followed by triethylamine (0.21 gm=2.1 mmol). The reaction mixture was then heated to 45° C., using oil circulation on the jacket, and thionyl chloride (62.0 gm=0.52 mol) was then charged over 105 minutes maintaining on temperature. The reaction mass was then agitated for 5 hours at 45° C. then tested by GLC for completion of reaction showing 2% residual acid. A further addition of thionyl chloride (4.4 gm=37 mmol) was then made and the reaction mass allowed to cool with stirring overnight. The following day, residual thionyl chloride, dissolved sulphur dioxide and hydrogen chloride gases were removed by distillation of about 320 ml toluene under vacuum. GC, GCMS and NMR analysis of the product were consistent with the structure of the acid chloride (IIIa). Yield, 175 gm of a 54% solution of the acid chloride in toluene, ˜97% theory. αD=+46°
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][C@H:7]([CH:9]([CH3:11])[CH3:10])[N:6]([C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[N:31]=[CH:30][N:29](COCC[Si](C)(C)C)[N:28]=5)=[CH:23][CH:22]=4)=[C:14]3[N:13]=2)[C:5]1=[O:40].FC(F)(F)C(O)=O.[OH-].[Na+].CO>>[NH:29]1[CH:30]=[N:31][C:27]([C:24]2[CH:23]=[CH:22][C:21]([C:20]3[CH:19]=[N:18][N:15]4[CH:16]=[CH:17][C:12]([N:6]5[C@@H:7]([CH:9]([CH3:11])[CH3:10])[CH2:8][N:4]([CH2:3][CH2:2][OH:1])[C:5]5=[O:40])=[N:13][C:14]=34)=[CH:26][CH:25]=2)=[N:28]1
Reactant: CC(C)[C@H]1CN(CCO)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)[C@H]1CN(CCO)C(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 4.4 %

Procedure:
To (S)-1-(2-hydroxyethyl)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (0.18 g, 0.32 mmol) was added trifluoroacetic acid (5 mL) and the reaction was stirred at ambient temperature for 3 hours. The reaction was concentrated in vacuo and the material purified by reverse preparative HPLC to yield the crude product and the corresponding trifluoroacetate ester. To this material was added 1N NaOH/MeOH and the mixture stirred at ambient temperature for 2 hours. The mixture was concentrated in vacuo. The combined crude product was purified by reverse preparative HPLC to give (S)-3-(3-(4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-hydroxyethyl)-4-isopropylimidazolidin-2-one (0.0061 g, 0.014 mmol, 4.4% yield) as the mono TFA salt. LCMS (APCI+) m/z 433 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][NH2:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2c(CN)c[nH]c2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCc1c[nH]c2cc(C)ccc12
Reaction time: 0.33 h

Procedure:
To a solution of C-(6-methyl-1H-indol-3-yl)-methylamine (0.24 g) in dichloromethane (4 ml) was added acetic anhydride (0.14 ml) and pyridine (0.13 ml) and stirring was continued at 22° C. for 20 min. The mixture was washed with aqueous HCl (1N), the organic layer was dried and evaporated. The residue was chromatographed on silica using dichloromethane/methanol (70:1) to give the title compound as a colorless foam (0.15 g). MS: 203.1 ([M+H]+).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)#[N:33].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:38]3[CH:39]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:32]#[N:33])[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)c1
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 3-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (49%).
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][CH2:31]Br)[CH:26]=[CH:27][C:28]=1[Cl:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][CH2:31][N:13]2[CH2:14][CH2:15][CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12]2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: Clc1ccc(CCBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NC1CCN(CCc2ccc(Cl)c(Cl)c2)CC1)c1ccccc1
Temperature: 100 °C
Yield: 94.2 %

Procedure:
4-Benzamidopiperidine (204 mg.) and anhydrous potassium carbonate (138 ml.) were intimately ground together and added to 2-(3,4-dichlorophenyl)ethyl bromide (254 mg.). The resulting paste was heated at 100° C. for 2 hours to give a hard solid. This was broken up, washed well with water and ether and dried to give the title compound (355 mg.). Recrystallisation from ethanolic hydrogen chloride and ether gave the hydrochloride (237 mg.), m.p. 286.0° C. (Found: C, 58.2; H, 5.8; N, 6.8. C20H22Cl2N2O.HCl requires C, 58.05; H, 5.6; N, 6.8%).
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[N:13][CH:14]=1)=[O:7])([O-])=O.CO>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)=[N:13][CH:14]=1)=[O:7]
Reactant: O=C(Nc1cnc(-c2cccc(C(F)(F)F)c2)nc1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2cccc(C(F)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
Into a 50-mL 3-necked round bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 2-nitro-5-(piperidin-1-yl)-N-(2-(3-(trifluoromethyl)phenyl)pyrimidin-5-yl)benzamide (250 mg, 0.53 mmol, 1.00 equiv), methanol (15 mL), and ethyl acetate (5 mL). The mixture was treated with Pd/C (0.1 g, 0.10 equiv) and stirred under an atmosphere of hydrogen for 2 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 0.23 g (98%) of product as a light yellow solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1.N>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:1][N:2]=[C:3]([C:5]3[CH:10]=[CH:9][N:8]=[N:7][CH:6]=3)[N:4]=2)=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC(=NO)c1ccnnc1
Agent: N
Product: Fc1ccc(-c2nc(-c3ccnnc3)no2)cc1

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 4-fluorobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.36-7.45 (m, 2H), 8.29-8.40 (m, 3H), 9.45 (dd, J=5.6, 1.2 Hz, 1H), 9.86 (dd, J=2.4, 1.2 Hz, 1H) ppm; MS (DCI/NH3) m/z=243 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A suspension of 4-fluoro-2-methoxy-1-nitrobenzene (15 g, 87 mmol), tert-butyl piperazine-1-carboxylate (19.59 g, 105.2 mmol) and potassium carbonate (24 g, 174 mmol) in N,N-dimethylformamide (150 mL) was heated at 80′C for 8 hours. After cooling to ambient temperature, the mixture was poured in water (500 mL). The precipitate was filtered and washed with ethanol to give the title compound. MS: 338 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][C:8]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:23]=[O:24]>O1CCCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH:23]=[O:24])=[CH:9][C:8]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ccc1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1C(=O)OC(C)(C)C
Temperature: -95 °C
Reaction time: 1.25 h

Procedure:
A solution of 4-bromo-2-methyl-benzoic acid tert-butyl ester (Example 4.1) (75 g) in dry tetrahydrofuran (750 ml) was cooled to −100° C. A solution of butyl lithium (1.6M in hexane) (163 ml) was added dropwise at −100° C. Dimethylformamide (“DMF”) (1.14 ml) was added at −100° C. The reaction mixture was stirred at −95° C. for 75 minutes. The reaction was quenched by addition of aqueous ammonium chloride (saturated) (8 ml) at −90° C. The mixture was stirred for 10 minutes at −90° C., warmed to 0° C. and poured onto a mixture of ice and water. The mixture was allowed to warm to ambient temperature and then extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate, and concentrated to give 4-formyl-2-methyl-benzoic acid tert-butyl ester (60.3 g) as yellow oil. 1H-NMR (CDCl3, 400 MHz): 10.03 (s, 1H), 7.93 (d, 1H), 7.75 (m, 2H), 2.65 (s, 3H), 1.65 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[O:18])[N:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:21][CH:20]=4)[C:15](=[S:31])[NH:14][C:13]=3[N:32]=2)=[CH:5][CH:4]=1.I[CH2:36][CH3:37].[OH-].[Na+].Cl>O.CN(C)C=O>[CH2:36]([S:31][C:15]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([F:29])([F:28])[F:30])=[CH:21][CH:20]=2)[C:17](=[O:18])[C:12]2[CH:11]=[CH:10][C:9]([NH:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:34][CH:33]=3)=[N:32][C:13]=2[N:14]=1)[CH3:37]
Reactant: COc1ccc(CNc2ccc3c(=O)n(-c4ccc(OCC(F)(F)F)cc4)c(=S)[nH]c3n2)cc1
Reactant: CCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1nc2nc(NCc3ccc(OC)cc3)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
7-[(4-Methoxybenzyl)amino]-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (108 mg), iodoethane (53 μl) and 1M aqueous sodium hydroxide solution (220 μl) were added to N,N-dimethylformamide (2 ml), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1M hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the white title compound (63 mg).
Reaction SMILES: [F:1][N+]1C(C(F)(F)F)=CC(C(F)(F)F)=CC=1S([O-])(=O)=O.[OH:20][C:21]1[C:31]2[CH2:30][CH2:29][N:28]([C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:27][CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1.C(O)(C(F)(F)F)C(F)(F)F>C(Cl)Cl>[F:1][C:22]1[CH:23]=[CH:24][C:25]2[CH2:26][CH2:27][N:28]([C:32](=[O:37])[C:33]([F:36])([F:34])[F:35])[CH2:29][CH2:30][C:31]=2[C:21]=1[OH:20]
Reactant: O=C(N1CCc2cccc(O)c2CC1)C(F)(F)F
Reactant: O=S(=O)([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)[n+]1F
Solvent: OC(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C(N1CCc2ccc(F)c(O)c2CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.6 %

Procedure:
Add N-fluoro-4,6-bis(trifluoromethyl)-pyridinium 2-sulfonate (3.02 g, 9.6 mmol) to a stirred mixture of 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.5 g, 9.6 mmol) and hexafluoro-2-propanol (10 mL) in DCM (150 mL). Stir at ambient temperature for 16 h. Concentrate the reaction mixture and partition the residue between EtOAc and 1N aqueous HCl. Wash the organic fraction with saturated aqueous NaHCO3, brine, dry over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc (20:1, 10:1, 6:1, 5:1 and 3:1) to give 7-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a white solid (1.8 g, 68%). Dissolve 7-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.5 g, 5.41 mmol) in a mixture of DCM (20 mL) and pyridine (2 mL) and cool in an ice bath. Add dropwise to the stirred solution a mixture of trifluoromethanesulfonic anhydride (1.64 mL, 9.74 mmol) in DCM and stir the reaction for 1.5 h at ambient temperature. Dilute the reaction with DCM (300 mL) and wash with 2.5N aqueous HCl. Dry the organic fraction over Na2SO4, filter and concentrate to give the title product as a white solid (2.2 g, 99%). MS (ES+) m/z: 410 (M+H)+.
Reaction SMILES: Cl[CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:16][C:17]([F:22])([F:21])[C:18]([NH2:20])=[S:19].C([O-])([O-])=O.[Na+].[Na+]>CC#N>[C:10]1([C:2]2[S:19][C:18]([C:17]([F:22])([F:21])[F:16])=[N:20][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(=O)C(Cl)c1ccccc1
Reactant: NC(=S)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1nc(C(F)(F)F)sc1-c1ccccc1

Procedure:
A solution of ethyl 3-chloro-2-oxo-3-phenylpropanoate and trifluorothioacetamide in MeCN was heated under reflux. To the reaction mixture was added an aqueous Na2CO3 solution, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane: EtOAc) to obtain ethyl 5-phenyl-2-(trifluoromethyl)-1,3-thiazole-4-carboxylate as a white solid.
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2].N1C=CC=CC=1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:24])[CH3:25])[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[N:6]1[C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1NC2C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)C1OC2C(C(=O)N2C(C(=O)OCc2ccccc2)=C(C)C)N1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 108.9 %

Procedure:
To a solution of 5 g of benzyl α-(3ξ-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 100 ml of tetrahydrofuran are dropwise added 1.82 ml of pyridine and a solution of 2.86 g of benzoyl chloride in 20 ml of tetrahydrofuran at 0° C. under nitrogen atmosphere. After 20 minutes, the reaction mixture is warmed up to room temperature. After additional 2 hours, the mixture is diluted with ice water and extracted with ethyl acetate. The extract is washed with an aqueous sodium sulfate and condensed under reduced pressure to yield 7.02 g of benzyl α-(3ξ-carbomethoxy-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as crude product.