Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>C(Cl)Cl.CN(C=O)C>[CH2:20]([N:22]([CH2:23][CH3:24])[C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[C:2]([F:1])([F:13])[F:12])[CH3:21]
Reactant: CCNCC
Reactant: O=C(O)c1ccccc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
To a solution of 2-trifluoromethylbenzoic acid (20.0 g, 105 mmol) in 500 mL of methylene chloride was added oxalyl chloride (18.4 mL, 210 mmol) followed by ˜8 drops of DMF. The reaction was allowed to stir at ambient temperature for 4 h and then was concentrated in vacuo to a solid. The solid was taken up in 500 mL of methylene chloride and then there was added diethylamine (24 mL, 231 mmol) dropwise as a solution in 50 mL of methylene chloride. The resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was concentrated in vacuo. The residue was diluted with EtOAc, washed sequentially with 1N HCl, sat'd. aq. NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated to afford 22 g (85%) of the title compound as an oil. 1H NMR (CDCl3): δ 7.68 (d, 1H, J=7.7 Hz), 7.57 (t, 1H, J=7.4 Hz), 7.49 (t, 1H, J=7.7 Hz), 7.32 (d, 1H, J=7.1 Hz), 3.90-3.82 (m, 2H), 3.29-3.22 (m, 2H), 1.23 (t, 3H, J=7.2 Hz), 1.03 (t, 3H, J=7.2 Hz). LRMS (ESI): 246.12 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([NH2:10])=O)[C:5]([CH3:11])=[N:4]1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8](=[S:21])[NH2:10])[C:5]([CH3:11])=[N:4]1)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCn1cc(C(N)=O)c(C)n1
Solvent: Cc1ccccc1
Product: CCn1cc(C(N)=S)c(C)n1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
To a suspension of 1-ethyl-3-methyl-1H-pyrazole-4-carboxamide (1.7 g, 11 mmol) produced in the above in toluene (80 mL) was added Lawesson's reagent (7.0 g, 17 mmol), and the mixture was heated under reflux for 1.5 hr. The reaction solution was cooled to room temperature and purified by basic silica gel column chromatography (ethyl acetate/hexane=0/100→20/80) to give the title compound (445 mg, 24%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:18])=[CH:16][S:17][C:11]3=[N:10][C:9]=2[C@@H:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20])[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.O.[OH-].[Na+]>Cl>[NH2:21][C@H:19]([C:9]1[N:10]=[C:11]2[S:17][CH:16]=[C:15]([CH3:18])[N:12]2[C:13](=[O:14])[C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:20]
Reactant: Cc1csc2nc([C@H](C)NC(=O)OC(C)(C)C)c(-c3cccc(F)c3)c(=O)n12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1csc2nc([C@H](C)N)c(-c3cccc(F)c3)c(=O)n12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 105.6 %

Procedure:
(S)-tert-Butyl 1-(6-(3-fluorophenyl)-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethylcarbamate (4.15 g, 10.3 mmol) was dissolved in a 4.0 M solution of hydrogen chloride in 1,4-dioxane (25.7 mL, 102.8 mmol) and the solution was stirred at room temperature for 45 min. HPLC indicated that the reaction was complete. To the solution was added water (10 mL) followed by 3 N aqueous sodium hydroxide solution at 0-5° C. to adjust the pH to 10. The aqueous mixture was extracted with ethyl acetate (2×30 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-7-(1-Aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (3.30 g, 10.88 mmol, 103% yield). LCMS calculated for C15H15FN3OS (M+H)+: m/z 304.08. Found 303.9. 1H NMR (400 MHz, DMSO-d6) δ 7.45 (ddd, J=8.1, 7.9, 5.9 Hz, 1H), 7.19 (m, 1H), 7.12 (m, 2H) 7.04 (q, J=1.1 Hz, 1H), 3.57 (q, J=6.6 Hz, 1H), 2.64 (d, J=1.3 Hz, 3H), 1.10 (d, J=6.7 Hz, 3H)
Reaction SMILES: [CH2:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13]([C:17](=[O:19])[CH3:18])=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:2][CH3:3].[C:20](OCC)(=[O:22])[CH3:21].CC(C)([O-])C.[K+].Cl>O>[CH2:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13]([C:17](=[O:19])[CH2:18][C:20](=[O:22])[CH3:21])=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:2][CH3:3]
Reactant: CCOC(C)=O
Reactant: CCCn1c2ccccc2c2cc(C(C)=O)ccc21
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCn1c2ccccc2c2cc(C(=O)CC(C)=O)ccc21
Temperature: 25 °C
Yield: 78.9 %

Procedure:
A 200 ml four-necked flask equipped with a stirrer, a nitrogen inlet tube, a reflex condenser, and a thermometer was charged with 25.13 g of 1-(9-propyl-9H-carbazol-3-yl)ethanone, 88.11 g of ethyl acetate, and 16.83 g of potassium t-butoxide, and the mixture was refluxed in a nitrogen atmosphere for 5 hours. After cooling to room temperature, 50 ml of ion exchanged water and 50 ml of 6N hydrochloric acid were successively added, followed by stirring. The organic phase was separated and mixed with 200 ml of ethyl acetate, and the mixture was washed with a sodium chloride aqueous solution until neutral. The upper layer was dried with magnesium sulfate, and the solvent was removed by evaporation. The solid thus precipitated was dissolved in 10 ml of ethyl acetate under reflux, and n-hexane was added thereto. The precipitate thus formed was collected by filtration and dried under reduced pressure to give 23.15 g (79%) of yellow crystals, which had a melting point of 97° C. and was identified by various analyses to be β-diketone compound No. 1 having a carbazolyl group.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH:11]3[CH2:14][O:13][CH2:12]3)[N:7]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=3)[C:6]=2[CH:22]=1>COCCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[N:7]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=3)[C:6]=2[CH:22]=1
Reactant: Nc1nccc(-n2c(OC3COC3)nc3ccc(Br)cc32)n1
Solvent: COCCO
Product: COCCOc1nc2ccc(Br)cc2n1-c1ccnc(N)n1

Procedure:
The title compound was prepared by the procedure described for the synthesis of 4-[6-bromo-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine, by replacing oxetan-3-ol with 2-methoxyethanol: 1H NMR (500 MHz, DMSO) delta 3.31 (3H, s), 3.83-3.72 (2 H, m), 4.77-4.61 (2H, m), 7.02 (1H, d, J=5.5 Hz), 7.12 (2H, s), 7.48-7.33 (2H, m), 8.38 (1H, d, J=5.5 Hz), 8.45 (1H, d, J=1.8 Hz); LC-MS: m/z=+364/366 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](C(OC)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: CC(C)OC(=O)Cl
Product: CC(C)OC(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 42 %

Procedure:
According to the procedure for compound 476 using isopropyl chloroformate (20 mg, 0.21 mmol) afforded 11.3 mg (42% yield) of 477, as a trifluoroacetic acid salt after preparatory HPLC purification.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18])([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
2-Nitroaniline (2.15 g (15.6 mmol)) was dissolved in 10.0 ml of pyridine. To this, p-toluenesulfonyl chloride (3.55 g (18.6 mmol)) was added with stirring at room temperature. After stirring for 15 hours at room temperature, water (100 ml) was added to the reaction mixture to bring about separation of crystals. The crystals were filtered, washed with water, dried and then subjected to silica gel column chromatography with ethyl acetate-hexane (2:3) as eluent to give 2.88 g (53%) of 2′-nitro-p-toluenesulfonanilide as yellow crystals, and 1.17 g (17%) of N,N-bis(p-toluenesulfonyl)-2′-nitroaniline (Compound No. 39) as pale yellow crystals. Physical Constants of 2′-nitro-p-toluenesulfonanilide
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[Cl:18])[C:5](OC)=[O:6].Cl.[CH:21]([NH2:23])=[NH:22]>>[Cl:18][C:11]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=1[O:9][C:4]1[C:5]([OH:6])=[N:22][CH:21]=[N:23][C:3]=1[OH:2]
Reactant: COC(=O)C(Oc1cc(OC)ccc1Cl)C(=O)OC
Reactant: N=CN
Agent: Cl
Product: COc1ccc(Cl)c(Oc2c(O)ncnc2O)c1

Procedure:
5-(2-Chloro-5-methoxy-phenoxy)-pyrimidine-4,6-diol was prepared from 2-(2-chloro-5-methoxy-phenoxy)-malonic acid dimethyl ester and formamidine hydrochloride according to the procedure described in Referential Example 1c.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:23]([NH:25][NH:26][CH2:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[O:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:37]1([CH2:42][C:43](O)=[O:44])[CH:41]=[CH:40][N:39]=[N:38]1>>[CH2:1]([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:23]([NH:25][N:26]([CH2:27][CH:28]([CH2:29][CH3:30])[CH2:31][CH3:32])[C:43](=[O:44])[CH2:42][N:37]1[CH:41]=[CH:40][N:39]=[N:38]1)=[O:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1
Reactant: O=C(O)Cn1ccnn1
Product: CCC(CC)CN(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1)C(=O)Cn1ccnn1

Procedure:
In a manner analogous to that described in Example 8 from (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-2′-(2-ethylbutyl)-4-methylvalerohydrazide and using 1,2,3-triazole-1-acetic acid in place of N-tert-butoxycarbonyl-β-alanine there was obtained (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-2′-(2-ethylbutyl)-4-methyl-2′-[2-(1H-1,2,3-triazol-1-yl)acetyl]valerohydrazide in the form of a gum.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=S)[CH:9]([NH:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][O:33][CH:34]([O:37][CH3:38])[CH2:35][NH2:36]>C1COCC1>[CH3:32][O:33][CH:34]([O:37][CH3:38])[CH2:35][N:36]=[C:10]1[CH:9]([NH:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11]1
Reactant: O=C(CCc1ccc(Cl)cc1Cl)NC1N=C(c2ccccc2)c2ccccc2NC1=S
Reactant: COC(CN)OC
Solvent: C1CCOC1
Product: COC(CN=C1Nc2ccccc2C(c2ccccc2)=NC1NC(=O)CCc1ccc(Cl)cc1Cl)OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of N-(2,3-dihydro-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl)-3-(2,4-dichlorophenyl)propanamide (234 mg, 0.5 mmol) and 2,2-dimethoxyethylamine (210 mg, 2 mmol) in THF (6 mL) was stirred at room temperature for 17 h. Mercuric chloride (0.20 g, 0.75 mmol) was added and the mixture was stirred at 55° C. for 3 h. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (20 mL). The mixture was washed with aqueous citric acid (10%, 5 mL), brine (5 mL), saturated aqueous sodium carbonate (5 mL) and brine (5 mL), dried (Na2 SO4) and the solvent was evaporated under reduced pressure to give N-[2,3-dihydro-2-(2,2-dimethoxyethylimino)-5-phenyl-1H-1,4-benzodiazepin-3-yl)-3-(2,4-dichlorophenyl)propanamide as a solid. The residue was dissolved in aqueous sulfuric acid (50%, 1 mL) and mercuric chloride (0.20 g, 0.75 mmol) was added. The mixture was stirred at room temperature for 18 h., cooled to 0° C. and the pH was adjusted to 7.0 with aqueous sodium hydroxide (10%). The mixture was extracted with ethyl acetate and the combined organic fractions were washed with water and brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH (99.5:0.5) to give 3-(2,4-dichlorophenyI)-N-{6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl}propanamide as a solid, m.p. 183°-184° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:40])[CH2:36][C:37](=O)[CH3:38])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:35](=[O:40])/[CH:36]=[C:37](\[NH:1][C@@H:2]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:9][CH:8]=2)[C:3]([OH:5])=[O:4])/[CH3:38])=[CH:33][CH:34]=1
Reactant: CC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: C/C(=C/C(=O)c1ccc(Cl)cc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 100 mg (0.27 mmol) of Intermediate 45 and 54 mg (0.27 mmol) of Intermediate 28 to yield 76 mg of Example 24: TLC (DCM/MeOH (4:1): Rf=0.52; 1H NMR (DMSO-d6, 300 MHz) δ11.52 (d, 1H, J=9.6), 7.97 (m, 2H), 7.87 (d, 2H, J=8.6), 7.55 (m, 5H), 7.18 (d, 2H, J=8.5), 6.86 (d, 2H, J=8.5), 5.59 (s, 1H), 4.21 (t, 2H, J=6.1), 4.09 (m, 1H), 3.22 (m, 1H), 2.96 (t, 2H, J=6.1), 2.78 (dd, 1H, J=13.9, 9.4), 2.39 (s, 3H), 1.73 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[N:10]1([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH2:11][CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(N2CCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCC2)cc1
Reaction time: 8 h
Yield: 100.3 %

Procedure:
10% Pd/C (70 mg) was added to a solution of 1-(4-nitrophenyl)azetidine (0.7 g, 3.9 mmol) in EtOH (15 mL) at r.t. under N2. After stirring under 50 psi H2 overnight, the reaction mixture was filtered through Celite and concentrated to give 580 mg (99%) of the title compound as a brown oil. [M+H] Calc'd for C9H12N2, 149. Found, 149.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH2:6][C:7]1[C:8]([CH3:24])=[N:9][N:10]([C:19]2[S:23][CH:22]=[N:21][CH:20]=2)[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1>CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[N:10]([C:19]3[S:23][CH:22]=[N:21][CH:20]=3)[N:9]=[C:8]([CH3:24])[C:7]=2[CH2:6][C:5]([OH:25])=[O:4])=[CH:13][CH:14]=1
Reactant: COC(=O)Cc1c(C)nn(-c2cncs2)c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nn(-c2cncs2)c(-c2ccc(Cl)cc2)c1CC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1 ml of 2 molar aqueous sodium hydroxide solution was added to 0.289 g (0.83 mmol) of methyl[5-(4-chlorophenyl)-3-methyl-1-(1,3-thiazol-5-yl)-1H-pyrazol-4-yl]acetat in 10 ml methanol, and the mixture was stirred at room temperature for four hours and allowed to stand overnight. The mixture was then concentrated, ice-water was added to the residue, and the mixture was adjusted to pH 3-4 by addition of 2 molar aqueous hydrochloric acid and extracted with dichloromethane. The combined organic phases were dried with magnesium sulfate, filtered and dried. The crude product was dried under high vacuum. This gave 0.187 g of product (60.7% of theory); NMR (CDCl3, 400 MHz): 2.33 (s, 3H); 3.39 (s, 2H); 7.24 (d, 2H); 7.31 (br s, 1H); 7.42 (d, 2H); 8.56 (br s, 1H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=[O:11])/[CH:8]=[CH:9]/[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:11])/[CH:8]=[CH:9]/[CH3:10]
Reactant: C/C=C/C(=O)Cl
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C/C=C/C(=O)c1ccccc1

Procedure:
Benzene (1 mL), crotonoyl chloride (236 mg), and aluminium chloride (280 mg) were reacted in dichloromethane (1.5 mL) at from −30° C. to room temperature for 16 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (66 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=O)=[N:9]2)=[N:6][CH:7]=1.[NH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23]>>[OH:23][CH2:22][C:21]([NH:20][C:17]([C:10]1[C:11]2[CH2:12][C@H:13]3[CH2:16][C@H:14]3[C:15]=2[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[N:9]=1)=[O:19])([CH3:25])[CH3:24]
Reactant: O=C(O)c1nn(-c2ccc(F)cn2)c2c1C[C@H]1C[C@@H]21
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)c1nn(-c2ccc(F)cn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G using (1aR,5aR)-2-(5-fluoropyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and 2-amino-2-methylpropan-1-ol. LCMS m/z=331.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.45 (td, J=4.7, 3.3 Hz, 1H), 1.24 (td, J=7.9, 4.8 Hz, 1H), 1.404 (s, 3H), 1.408 (s, 3H), 2.24-2.30 (m, 1H), 2.74-2.79 (m, 1H), 2.91 (d, J=16.7 Hz, 1H), 3.00 (dd, J=16.6, 6.2 Hz, 1H), 3.70 (d, J=6.2 Hz, 2H), 4.72 (t, J=6.3 Hz, 1H), 6.92 (s, 1H), 7.55 (ddd, J=9.1, 7.6, 3.0 Hz, 1H), 7.91 (dd, J=9.1, 3.9 Hz, 1H), 8.31 (d, J=2.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:16])([CH3:15])[C:10](OCC)=[O:11])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:16])([CH3:15])[CH2:10][OH:11])=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:3]=1
Reactant: CCOC(=O)C(C)(C)Cc1ccc(N)cc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)Cc1ccc(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 64.4 %

Procedure:
To a mixture of ethyl 3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (2 g, 6.91 mmol) in THF (200 mL) was added LAH (0.525 g, 13.83 mmol) in portions. The mixture was stirred at 25° C. for 10 h. The mixture was quenched with 15% aqueous NaOH solution (10 mL). The mixture was dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica column chromatography (PE/EA=8:1). All fractions found to contain product by TLC (PE/EA=2:1, Rf=0.35) were combined and concentrated to yield a light yellow oil of 3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol (1.1 g, 4.45 mmol, 64% yield): 1H NMR (400 MHz, CD3Cl) δ: 7.17 (d, J=8.4 Hz, 1H), 6.98 (d, J=2.4 Hz, 1H), 6.84 (dd, J=2.4, 8.0 Hz, 1H), 3.31 (s, 2H), 2.67 (d, J=1.2 Hz, 2H), 0.84 (s, 6H); ES-LCMS m/z 248 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[CH:10][C:9]2=[O:24])=[CH:4][C:3]=1[O:25][CH3:26].[F-].[Cs+].[N+](C1C=C(S(O[CH2:42][C@H:43]2[CH2:45][O:44]2)(=O)=O)C=CC=1)([O-])=O>CN(C=O)C.C(Cl)Cl>[CH3:26][O:25][C:3]1[CH:4]=[C:5]([N:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=3)=[CH:10][C:9]2=[O:24])[CH:6]=[CH:7][C:2]=1[O:1][CH2:42][C@H:43]1[CH2:45][O:44]1
Reactant: COc1cc(-n2ccc(-c3ccc(C(F)(F)F)cc3)cc2=O)ccc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(-n2ccc(-c3ccc(C(F)(F)F)cc3)cc2=O)ccc1OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
A mixture of 1-(4-hydroxy-3-methoxyphenyl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one Part B of Procedure 14 (38 mg, 0.105 mmol) and cesium fluoride (48 mg, 0.32 mmol) in DMF (1 mL) was stirred at RT for 30 min. Then, (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (35 mg, 0.13 mmol) was added and stirred overnight at RT. Diluted with DCM, washed with water, sat. NaHCO3, dried (Na2SO4), and concentrated. The crude was purified using ISCO flash chromatography (silica gel/hexanes/ethyl acetate 100:0 to 0:100 gradient) to afford the desired product (R)-1-(3-methoxy-4-(oxiran-2-ylmethoxy)phenyl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one 15A (32.1 mg, 0.08 mmol, 73.1% yield) as a light yellow solid. LC/MS 418 (M+H)+, tR 0.93 min (method 5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:24][CH2:25]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:9]([O:11][CH2:24][CH3:25])=[O:10])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of bis(4-chlorophenyl)acetic acid (5.00 g, 17.8 mmol) in EtOH (100 mL) in a 500 mL round bottom flask, was added H2SO4, 36N (0.0988 mL, 1.78 mmol). The mixture was stirred at 100° C. for 18 hours. The mixture was then concentrated in vacuo, diluted with EtOAc (200 mL), and washed with deionized water (3×100 mL) and then with brine (100 mL). The organic layer was dried over MgSO4, concentrated, and dried in vacuo to give the crude product ethyl 2,2-bis(4-chlorophenyl)acetate (5.473 g). MS m/e=309 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[C:12](\[CH2:18][P:19]([O:25]CC)([CH2:21][CH:22]([CH3:24])[CH3:23])=[O:20])/[C:13]([O:15]CC)=[O:14])[CH2:2][CH2:3][CH3:4].CO.O.[ClH:35]>>[ClH:35].[CH2:28]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[C:12](\[CH2:18][P:19]([OH:25])([CH2:21][CH:22]([CH3:24])[CH3:23])=[O:20])/[C:13]([OH:15])=[O:14])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCN(CCCC)CCCCC/C=C(\CP(=O)(CC(C)C)OCC)C(=O)OCC
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCCN(CCCC)CCCCC/C=C(\CP(=O)(O)CC(C)C)C(=O)O
Temperature: 90 °C
Reaction time: 5.5 h
Yield: 94 %

Procedure:
Ethyl (Z)-8-dibutylamino-2-(ethoxyisobutylphosphinoyl)methyl-2-octenoate (200 mg; 0.43 millimole) was dissolved in 5 ml of concentrated hydrochloric acid, and the solution was stirred at 90° C. for 5.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography [Lobar column (a product of E. Merck & Co.), size B, Lichroprep RP-18, methanol/water (7:3)] to give 178 mg (yield 94%) of the captioned compound as a pale yellow oil.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2>C(OCC)(=O)C>[Br:10][C:11]1[CH:19]=[CH:18][C:17]2[C:13](=[CH:14][N:15]([CH3:6])[N:16]=2)[CH:12]=1
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: Cn1cc2cc(Br)ccc2n1
Yield: 70 %

Procedure:
Add at room temperature under nitrogen, trimethyloxonium tetrafluoroborate (229.34; g, 1.52; mol) portion wise to a mixture of 5-bromo-1H-indazole (199.6; g, 1.01 mol) in ethyl acetate (3.04; L, 31.06; mol), stir 2.5; h and filter to give a white solid. Wash the recovered solid twice with ethyl acetate (500; mL) and then add it portion wise to a cooled aqueous solution of 2; M sodium hydroxide (3.80; L, 7.60; mol) in an ice bath. Stir the mixture for 1; h, sonicate for 15; min., filter and wash the recovered solid twice with water (200; mL). Dry the solid overnight under vacuum, slurry in dichloromethane (1; L) and filter. Concentrate the filtrate and purify by silica gel chromatography eluting with dichloromethane to give the title compound as a yellow solid (149.77; g, 70%). MS (m/z): 211, 213; (M+1).