Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])/[CH:6]=[CH:7]/[C:8]([OH:10])=O.[C:22]([O:25][CH2:26][CH3:27])(=[S:24])[CH3:23]>C(OCC)(=O)C>[CH2:26]([O:25][C:22](=[S:24])[CH2:23][C:8](=[O:10])/[CH:7]=[CH:6]/[C:5]1[CH:11]=[CH:12][C:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:27]
Reactant: COc1cc(/C=C/C(=O)O)ccc1O[Si](C)(C)C(C)(C)C
Reactant: CCOC(C)=S
Solvent: CCOC(C)=O
Product: CCOC(=S)CC(=O)/C=C/c1ccc(O[Si](C)(C)C(C)(C)C)c(OC)c1
Yield: 60 %

Procedure:
The title compound was prepared in the same manner as in Step 1 of Example C-1, except that an equimolar amount of each of trans-3-methoxy-4-tert-butyldimethylsilyloxy-cinnamic acid prepared in Step 1 of Example C-10 and ethyl thioacetate was used in place of trans-cinnamic acid and ethyl acetate.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[C@@H:10]([NH:20]C(=O)OC(C)(C)C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:28]>O1CCOCC1>[ClH:28].[NH2:20][C@@H:10]1[C:11](=[O:19])[NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(Cc2ccccc2)c2ccccc2NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CN(Cc2ccccc2)c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
357.5 mg of 15 (0.97 mmol) prepared according to the procedure described in step 1 are taken up in a 25 mL round-bottomed flask and 6.3 ml of dioxane and 7.5 mL of a solution of hydrochloric acid in dioxane (4M) are added. The medium is stirred overnight at RT under argon. A precipitate forms which is drained and washed with isopropyl ether (15 mL) and dried under vacuum. 280 mg of expected product 16 (white solid) are obtained in hydrochloride form.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].Br[C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[C:25]1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.BrCC1CCCCC1.BrCC1OC(C(F)(F)F)=CC=1>>[CH:24]1([CH2:25][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:23]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCC1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(CC2CCCCC2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and bromomethyl cyclohexane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (74%) as a white solid: mp 153-154° C.; 1H NMR (300 MHz, CDCl3) δ 7.30 (td, 1H), 7.16 (d, 1H), 7.04 (t, 1H), 6.90 (d, 1H), 6.51 (s, 1H), 6.14 (s, 1H), 5.90-5.84 (m, 2H), 4.91 (d, 1H), 4.65 (d, 1H), 3.72-3.44 (m, 2H), 1.94-1.60 (m, 6H), 1.32-0.99 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 177.8, 156.1, 148.9, 143.0, 142.4, 132.5, 128.9, 124.0, 123.2, 119.7, 109.0, 103.2, 101.6, 93.7, 80.8, 58.3, 46.8, 36.3, 31.1, 31.0, 26.4, 25.9, 25.8; MS (ES+) m/z 378 (M+1), 400 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)=[CH:4][C:3]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(Cl)c(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(Oc2cc(C=C3CCNCC3)ccc2Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.6 %

Procedure:
To a solution of tert-butyl 4-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (280 mg, 0.597 mmol) in CH2Cl2 (3 mL) cooled to 0° C. was added TFA (0.46 mL, 5.97 mmol). The resulting mixture was stirred for 2 h at RT. The reaction was concentrated and then partitioned between saturated NaHCO3 solution and CH2Cl2. The organic extract was dried over Na2SO4, and concentrated under reduced pressure to give the title compound (250 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([O:13][CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.C(OC(=O)[C@@H](OC)CC1C=CC(O[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=CC=1)C>>[CH3:1][O:2][C:3](=[O:15])[CH:4]([O:13][CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:7]=1
Reactant: COC(=O)C(Cc1cccc(O)c1)OC
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)OC(C)(C)C)cc1)OC
Product: COC(=O)C(Cc1cccc(OCC(=O)OC(C)(C)C)c1)OC

Procedure:
The title compound was prepared from 3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (example 9, step 4) via the same procedure used to prepare (2S)-3-(4-tert-butoxycarbonylmethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 1) to produce a yellow oil. MS (ES) for C17H24O6 [M+H]+: 325.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH2:12][NH2:13]>CCO>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:12][NH2:13])=[O:5]
Reactant: NN
Reactant: COC(=O)c1ccccc1Br
Solvent: CCO
Product: NNC(=O)c1ccccc1Br

Procedure:
A solution of methyl 2-bromobenzoate (1.0 g, 4.7 mmol) in EtOH (15 mL) was treated with hydrazine (0.18 mL, 5.6 mmol) and heated to reflux for 15 hours. The resulting solution was concentrated to a white powder (998 mg).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[CH:9]2[O:16][CH:10]2[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+:19]>C(O)C>[C:1]1([NH:7][C:8](=[O:17])[CH:9]2[O:16][CH:10]2[C:11]([O-:13])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[K+:19]
Reactant: CCOC(=O)C1OC1C(=O)Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])C1OC1C(=O)Nc1ccccc1
Yield: 74.6 %

Procedure:
Ethyl N-phenyl-2,3-epoxysuccinamate (Compound No. 1) (0.9 g) was dissolved in ethyl alcohol (30 ml) and an ethyl alcohol solution (5 ml) containing KOH (0.27 g) was added to the solution under ice-cooling, followed by stirring for an hour. The precipitate produced was collected on a filter and recrystallized from a mixture of ethyl alcohol-water to give 0.7 g of potassium N-phenyl-2,3-epoxysuccinamate (Compound No. 95) as colorless powder melting over 300° C. (decomposition).
Reaction SMILES: [C:1]([N:6]=[C:7]=[O:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:9]([OH:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCCl>[C:1]([NH:6][C:7](=[O:8])[O:18][CH2:9][CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: OCC=Cc1ccccc1
Reactant: C=C(C)C(=O)N=C=O
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)OCC=Cc1ccccc1
Reaction time: 0.17 h
Yield: 98 %

Procedure:
Into a three-necked flask purged with nitrogen gas, methacryloyl isocyanate (1.11 g; 10 mmol) was charged, and 1,2-dichloroethane (20 ml) was added thereto. A solution of cinnamyl alcohol (1.34 g) in 1,2-dichloroethane (20 ml) was dropwise added thereto under nitrogen stream in 10 minutes while stirring. 1,2-Dichloroethane was removed by evaporation under reduced pressure to give cinnamyl N-methacryloylcarbamate (2.4 g), which was washed with hexane and purified by silica gel column chromatography to give colorless needles. M.P., 66°-67° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[C:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31]Cl.[Cl-].[Na+]>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[O:11][CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)[CH:4]=[C:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cc2c(C)ccc(O)c2n1C
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)ccc(OCc3ccccn3)c2n1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
A mixture of 2.00 g (8.57 mmol) of ethyl 1,4-dimethyl-7-hydroxy-2-indolecarboxylate, 4.74 g (34.3 mmol) of potassium carbonate, 1.55 g (9.43 mmol) of 2-picolyl chloride hydrochloride and 40 ml of dimethylformamide was stirred at 50° C. for 2 hours. The reaction mixture was poured into 5% sodium chloride aqueous solution. The mixture was extracted with ethyl acetate. After washing with 5% sodium hydrogencarbonate aqueous solution, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 2.54 g of ethyl 1,4-dimethyl-7-[(pyridin-2-yl)methoxy]-2-indolecarboxylate.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[N:19]3[C:20]4[N:12]([C:13](=[O:22])[NH:14][C:15](=[O:21])[C:16]=4[N:17]=[CH:18]3)[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:27]I>CN(C)C=O>[CH3:27][N:14]1[C:15](=[O:21])[C:16]2[N:17]=[CH:18][N:19]3[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=4)=[CH:10][CH2:11][N:12]([C:20]=23)[C:13]1=[O:22]
Reactant: CI
Reactant: O=c1[nH]c(=O)n2c3c1ncn3C(c1cccc(C(F)(F)F)c1)=CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2ncn3c2n(c1=O)CC=C3c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of 2.0 g of 4-[3-(trifluoromethyl)phenyl]-6H,8H-pyrimido[1,2,3-cd]purine-8,10-(9H)-dione (Example 41) in 20 ml of dry N,N-dimethylformamide was added 310 mg of sodium hydride (60% dispersion in mineral oil). The mixture was stirred at room temperature for 3 hours. To this mixture was added 2.0 ml of methyl iodide with continued stirring for 20 hours. The mixture was concentrated and the residue was treated with water to give a precipitate. The precipitate was collected by filtration, washed with water and dried to give 1.5 g of the desired product which was recrystallized from isopropyl alcohol/acetonitrile, as a white solid, mp 287°-290° C.
Reaction SMILES: [NH2:1][C:2](=[N:13][NH:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=O)[CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5]>C(O)C>[C:7]1([S:4]([CH2:3][C:2]2[N:1]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:14][N:13]=2)(=[O:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(CS(=O)(=O)c1ccccc1)=NNC(=O)c1ccccn1
Solvent: CCO
Product: O=S(=O)(Cc1n[nH]c(-c2ccccn2)n1)c1ccccc1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
7.70 g (0.025 mol) Pyridine-2-carboxylic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide were heated at 200° C. for 20 minutes. The molten mass was then cooled, dissolved in 30 ml hot ethanol and stirred for two hous at room temperature. The precipitated crystals were filtered off and dried to yield 6.22 g (84%) 3-benzenesulfonylmethyl-5-pyridin-2-yl-1H-[1,2,4]triazole. MS m/e (%): 300 (M+, 100).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH2:8][CH2:9][N:10](C(OCC2C=CC=CC=2)=O)[CH2:11][CH:12]=1>[Pd]>[NH:10]1[CH2:9][CH2:8][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1
Reactant: O=C(OCc1ccccc1)N1CC=C(c2ccccn2)CC1
Agent: [Pd]
Product: c1ccc(C2CCNCC2)nc1
Yield: 88 %

Procedure:
The product from Example 36B was treated with 10% Pd/C (250 mg) at 60 psi and 50° C. for 40 hours to provide the title compound (150 mg, 88% yield). MS (DCI/NH3) m/e 163 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]3[C:15]([O:17]CC)=[O:16])[S:8][C:4]=2[CH:3]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]3[C:15]([OH:17])=[O:16])[S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)[C@@H]1CCCCN1c1nc2ccc(Cl)cc2s1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCCCN1c1nc2ccc(Cl)cc2s1

Procedure:
The title compound was prepared by a similar method to Preparation 3 from ethyl (2S)-1-(6-chloro-1,3-benzothiazol-2-yl)-2-piperidinecarboxylate [see Preparation 44] and 1N aqueous lithium hydroxide solution to afford (2S)-1-(6-chloro-1,3-benzothiazol-2-yl)-2-piperidinecarboxylic acid as a solid.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[C:11]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]([OH:28])=[O:27])=[CH:15][CH:14]=2)=O)(C)(C)C.[ClH:33]>O1CCCC1.C(OCC)(=O)C>[ClH:33].[ClH:33].[NH2:8][CH2:9][C:10]1[C:11]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]([OH:28])=[O:27])=[CH:15][CH:14]=2
Reactant: CC(C)Cc1nc2ccc(C(=O)O)cc2c(-c2ccccc2)c1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Cc1nc2ccc(C(=O)O)cc2c(-c2ccccc2)c1CN
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a solution of 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-phenylquinoline-6-carboxylic acid (0.10 g, 0.23 mmol) in tetrahydrofuran (4 ml) was added 4N solution of hydrogen chloride in ethyl acetate (4 ml), and the mixture was stirred at room temperature for 4 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether-ethyl acetate to give the title compound (0.078 g, yield 82%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:25]3[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]3)[S:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: OCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: OCCN1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
To a solution of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde (1.1 g, 3.9 mmol) in 1,2-dichloroethane (20 mL) was added 1-(2-hydroxyethyl)piperazine (0.7 mL, 5.4 mmol), and AcOH (3.9 mmol). After the reaction mixture stirred 10 min at room temperature, Na(OAc)3BH (4.6 mmol) was added then the mixture stirred 72 h at room temperature. The reaction was quenched by the addition of saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over Na2SO4 and concentrated in vacuo. 2-(4-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)ethanol was purified by silica gel chromatography (0-20% MeOH in CH2Cl2) to afford 2-(4-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)ethanol (0.8 g). MS (Q1) 398 (M)+
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[Li]CCCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:32])([F:31])[C:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])=[O:22])=[N:18][CH:19]=1>CCOCC>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:31])([F:32])[C:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])([C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)[OH:22])=[N:18][CH:19]=1
Reactant: Brc1cncnc1
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)c1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1cncnc1)(c1ccc(F)cc1F)C(F)(F)c1ccc(Br)cn1
Reaction time: 1 h
Yield: 13.2 %

Procedure:
To a stirred solution of 5-bromopyrimidine (0.45 g, 2.87 mmol) in Et2O (30 mL) was added n-BuLi (1.6 M in hexane; 1.8 mL, 2.87 mmol) at −78° C., and the mixture was stirred for 1 h under inert atmosphere. A solution of compound E (1.0 g, 2.87 mmol) in Et2O (10 mL) was added to the reaction mixture at −78° C., and stirring was continued for another 1 h. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with satd NH4Cl solution (20 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 40% EtOAc/hexanes) afforded 58 (0.16 g, 0.38 mmol, 13.3%) as a light yellow solid. 1H NMR (500 MHz, CDCl3): δ 9.10 (s, 1H), 8.80 (s, 2H), 8.55 (s, 1H), 8.06 (dd, J=8.5, 1.5 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.71-7.67 (m, 1H), 7.00 (br s, OH), 6.88-6.86 (m, 1H), 6.74-6.70 (m, 1H). MS (ESI): m/z 429 [M+H]+. HPLC: 98%.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:6][C@@H:5]2[C:7]([CH2:12][O:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][C@@H:9]([CH:10]=[CH2:11])[C@@H:4]2[O:3]1.CC(C)=[O:36]>CC1(C)OO1>[CH3:1][C:2]1([CH3:33])[O:6][C@@H:5]2[C:7]([CH2:12][O:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:8][C@@H:9]([C@H:10]3[CH2:11][O:36]3)[C@@H:4]2[O:3]1
Reactant: C=C[C@@H]1C=C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]2OC(C)(C)O[C@@H]12
Reactant: CC(C)=O
Agent: CC1(C)OO1
Product: CC1(C)O[C@H]2[C@H]([C@H]3CO3)C=C(COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2O1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
(3aS,4R,6aR)-2,2-dimethyl-6-(trityl oxymethyl)-4-vinyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole (1-3) (1.4 g, 3.19 mmol, 1.0 equiv) was dissolved in a freshly prepared solution of DMDO (dimethyl dioxirane) in acetone (37.7 mL, 0.076 M, 0.9 equiv). The resulting mixture was stirred at 0° C. for 4 hours, then concentrated and purified via flash chromatography on silica gel column (ethyl acetate/hexanes) to yield (3aS,4S,6aR)-2,2-dimethyl-4-((S)-oxiran-2-yl)-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole (1-5). 1H NMR (500 MHz, CDCl3) δ 7.21-7.47 (m, 15H), 5.83 (2 s, 1H), 4.99 (t, 1H, J=5 Hz), 4.63 (t, 1H, J=5 Hz), 3.86 (d, 1H, J=14 Hz), 3.67 (d, 1H, J=14 Hz), 2.85-2.97 (m, 2H), 2.77 (m, 1H), 2.60 (m, 1H), 1.35 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].CN(C=O)C>CC#N.O>[O:22]([CH2:21][CH2:20][O:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1O
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1cc([N+](=O)[O-])ccc1C=O
Temperature: 25 °C
Yield: 63.8 %

Procedure:
To a stirred suspension of 2-hydroxy-4-nitrobenzaldehyde (0.500 g, 2.992 mmol) and anhydrous potassium carbonate (0.621 g, 4.488 mmol) in dry MeCN (20 ml) at room temperature was added 2-bromo-1-tert-butyldimethylsiloxyethane (83%, 1.293 g, 4.488 mmol), and the reaction mixture was heated under reflux for 40 min which resulted in the appearance of a thick, dark red precipitate. The reaction mixture was left to cool to room temperature and dry DMF (10 ml) was added. The reaction mixture was heated at 100° C. for 4 h and on cooling was added to water (250 ml) and extracted with EtOAc (3×80 ml). The combined organic extracts were washed with water (3×100 ml), brine (100 ml) and dried (Na2SO4) and the solvent was removed under reduced pressure to give a light brown solid which was purified by flash chromatography (2:1 Hexane/Et2O). Recrystallisation from hexane gave the title compound (0.621 g, 64%) as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=3)([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[OH:20])[CH:8]=2)[N:3]=1.C1(C)C=CC=CC=1.[CH3:40][O-:41].[Na+]>CCOC(C)=O>[Cl:18][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=3)([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[OH:20])[CH:8]=2)[N:3]=[C:2]([O:41][CH3:40])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cn1cncc1C(O)(c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1)c1ncccn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1nc2ccc(C(O)(c3ncccn3)c3cncn3C)cc2c(Cl)c1-c1ccccc1

Procedure:
(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol (156 mg, 0.337 mmol, Example 55), toluene (2 mL), and sodium methoxide (365 mg, 6.75 mmol) were combined in a round bottom flask equipped with a stirbar and condenser under an N2 atmosphere. The contents were heated to reflux and refluxed overnight. The reaction was cooled and the contents were transferred to a separatory funnel with EtOAc dilution, and extracted with saturated, aqueous NH4Cl then saturated, aqueous NaHCO3 solutions. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with 0.05% trifluoroacetic acid in water as eluent. The fractions from the purification containing the desired product were transferred to a separatory funnel with EtOAc and extracted with a saturated, aqueous NaHCO3 solution. The aqueous layer was separated, extracted with EtOAc, then the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound. MS (ESI): mass calcd. for C25H20ClN5O2, 457.1; m/z found, 458.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 8.81 (d, J=4.9 Hz, 2H), 8.48 (d, J=1.8 Hz, 1H), 7.92-7.81 (m, 2H), 7.54-7.39 (m, 4H), 7.36-7.28 (m, 3H), 6.55 (s, 1H), 6.15 (s, 1H), 3.98 (s, 3H), 3.40 (s, 3H).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[O:5][CH2:6][CH3:7])\[CH3:4].C(N(CC)CC)C.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>CN(C=O)C>[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([O:1]/[N:2]=[C:3](/[O:5][CH2:6][CH3:7])\[CH3:4])(=[O:25])=[O:26]
Reactant: CCO/C(C)=N/O
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCO/C(C)=N/OS(=O)(=O)c1c(C)cc(C)cc1C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
To a solution of ethyl (1E)-N-hydroxyethanimidate (8.4 g, 81.5 mmol) in DMF (20 mL) is added triethylamine (12 mL, 86.24 mmol) and the mixture is stirred for 20 minutes. 2,4,6-Trimethylbenzene-1-sulfonyl chloride (20 g, 81.5 mmol) is added and the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts are dried over sodium sulphate, filtered, and evaporated to dryness to give the title compound as white solid (15 g, 64%). The crude material is used without further purification.