Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:12](=[O:13])[N:11]([C:14]2[N:19]=[CH:18][C:17]([S:20]([N:23]([CH2:29][CH2:30][CH2:31][O:32]CC3C=CC=CC=3)[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[NH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[CH2:1]([C:8]1[C:12](=[O:13])[N:11]([C:14]2[N:19]=[CH:18][C:17]([S:20]([N:23]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:29][CH2:30][CH2:31][OH:32])(=[O:21])=[O:22])=[CH:16][CH:15]=2)[NH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(Cc2ccccc2)c[nH]n1-c1ccc(S(=O)(=O)N(CCCOCc2ccccc2)C2CCCC2)cn1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=c1c(Cc2ccccc2)c[nH]n1-c1ccc(S(=O)(=O)N(CCCO)C2CCCC2)cn1
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 150 mg (0.27 mmol) of 6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-[3-(benzyloxy)propyl]-N-cyclopentylpyridine-3-sulfonamide in 2 mL of DCM is added dropwise, at −78° C. under argon, 0.82 mL (0.82 mmol) of boron tribromide (1M in DCM). Stirring is continued for 1 hour at −78° C., and 2 mL of MeOH are then added at 0° C. The medium is taken up in 40 mL of DCM, washed successively with saturated NaHCO3 solution (30 mL) and brine (30 mL), dried over Na2SO4 and then concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a 9/1 DCM/MeOH mixture. 106 mg of 6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-cyclopentyl-N-(3-hydroxypropyl)pyridine-3-sulfonamide are thus obtained in the form of a powder.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][C:12]([CH3:18])([CH2:15][NH:16][NH2:17])[C:13]#[N:14].C(N(CC)CC)C>O1CCOCC1>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:16]([CH2:15][C:12]([CH3:18])([CH3:11])[C:13]#[N:14])[NH2:17]
Reactant: CC(C)(C#N)CNN
Reactant: Clc1nc2ccccc2o1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C#N)CN(N)c1nc2ccccc2o1
Reaction time: 8 h

Procedure:
A solution of 2,2-dimethyl-2-cyanoacetaldehyde (9.4 g.) in ethanol (100 ml.) is added dropwise to a solution of hydrazine hydrate (40 g.) in ethanol (400 ml.), heated under reflux over a period of 3 hours. The solvent and excess of reagent are removed in vacuo to give 2,2-dimethyl-2-cyanoacetaldehyde hydrazone. This is dissolved in ethanol (100 ml.) and treated at room temperature with sodium borohydride (3.7 g.). The reaction mixture is stirred for two hours, acidified with acetic acid to pH 5, diluted with water and extracted with methylene chloride. The organic phase is dried and concentrated in vacuo to give 2,2-dimethyl-3-hydrazinopropanenitrile. A solution of 2-chlorobenzoxazole (15.3 g.) in dioxane (150 ml.) is added dropwise at 0° C. to a solution of 2,2-dimethyl-3-hydrazinopropanenitrile (11.3 g.) and triethylamine (10.1 g.) in dioxane (400 ml.). Stirring is continued overnight at room temperature. The precipitate is filtered and the filtrate concentrated in vacuo. The residue is washed with water and crystallized to give 3-[1-(2-benzoxazolyl) hydrazino)-2,2-dimethylpropanenitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]([N:19]3[CH2:23][CH2:22][CH2:21][C@@H:20]3[CH3:24])=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:25]([O:27]C)=[O:26])[CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]([N:19]3[CH2:23][CH2:22][CH2:21][C@@H:20]3[CH3:24])=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:25]([OH:27])=[O:26])[CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)c(F)c3)c(N3CCC[C@@H]3C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a solution of (S)-methyl 2-(3,4-difluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (80 mg, 0.23 mmol) in methanol (10 mL) was added sodium hydroxide (40 mg, 1 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted the pH to 6 with 3N HCl, and filtered to give (S)-2-(3,4-difluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a light yellow solid (44.5 mg, 58%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]2=[O:22])=[C:4]([CH3:23])[CH:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]([C:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]=2[O:22][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(C)c1C1C(=O)CC(CC2CCOCC2)C1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Br)cc(C)c1C1=C(OC(=O)C(C)(C)C)CC(CC2CCOCC2)C1=O

Procedure:
To a solution of rac-2-(4-bromo-2,6-dimethylphenyl)-4-(tetrahydropyran-4-ylmethyl)cyclopentane-1,3-dione (1.0 g, 2.6 mmol) in dichloromethane (20 ml) is added triethylamine (1.09 ml, 7.8 mmol) then pivaloyl chloride (1.10 ml, 7.8 mmol), and the resulting solution is stirred at room temperature for 4 hours. The reaction mixture is diluted with dichloromethane (100 ml), washed with distilled water (50 ml×3), and the organic fractions are combined, dried over sodium sulphate, filtered and the filtrate concentrated in vacuo to afford rac-2,2-dimethylpropionic acid 2-(4-bromo-2,6-dimethylphenyl)-3-oxo-4-(tetrahydropyran-4-ylmethyl)cyclopent-1-enyl ester. This material is used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2([CH2:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28].[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]2([CH2:21][NH:22][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][Cl:23])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Reactant: O=C(Cl)CCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CCCCl)NCC1(CCN2CCN(Cc3ccccc3)CC2)CCCC1

Procedure:
A solution of [1-[2-(4-benzyl-1-piperazinyl)ethyl]cyclopentyl]methylamine (675 mg, 2.32 mmol) and 4-chlorobutanoylchloride (491 mg, 3.48 mmol) in tetrahydrofuran (3.48 ml) and aqueous 2 N NaOH (1.74 ml) was stirred at ambient temperature for 15 hours. The organic layers were extracted with dichloromethane (10 ml), washed with brine (4 ml) and dried over magnesium sulfate filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel, 230-400 mesh/30 g/hexane:ethyl acetate=1:1) to give a yellow oil (684 mg/75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C1C(=O)N([Br:16])C(=O)C1>C(#N)C>[Br:16][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccccn1
Solvent: CC#N
Product: COc1ccc(Br)cn1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of 2-methoxy-pyridine (100 g, 0.92 mole), NBS (180 g, 1.0 mole) in acetonitrile (1.0 L) was stirred at reflux for 21 h. TLC showed reaction complete. The reaction mixture was cooled to room temperature and concentrated. ˜900 ml solvent was collected. The resulting suspension was filtered and washed with n-hexane (˜400 mL). The filtrate was concentrated again to afford crude product. The crude product was distilled at reduced pressure (30° C./˜0.3 mmHg) to afford the title compound as clear oil (146 g, 84%). LCMS (m/z): 190.0 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 3.90 (s, 3H), 6.65 (d, J=8.8 Hz, 1H), 7.62 (dd, J=8.8 Hz, 2.4 Hz, 1H), 8.19 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].C(O)C.Cl>O>[S:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:27]1[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:35])=[O:3])=[CH:14][CH:13]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccc(-c3cccs3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-thiophen-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4-thiophen-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) 8.74 (2H, m), 8.39 (2H, d), 8.26 (1H, m), 8.16 (2H, m), 7.64 (2H, d), 7.55 (2H, d), 4.18 (2H, t), 3.00 (2H, t) 2.39 (3H, s), 1.53 (6H, s)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:48])[C:5]([CH2:17][O:18][C:19](=[O:47])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[C:31]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:29])=[C:23]([OH:46])[CH:22]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(N(CC)CC)C.[C:56](Cl)(=[O:58])[CH3:57]>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:17][O:18][C:19](=[O:47])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[C:31]([C:36]3[CH:37]=[CH:38][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:40][CH:41]=3)=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:29])=[C:23]([O:46][C:56](=[O:58])[CH3:57])[CH:22]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:48])[CH3:10]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(COC(=O)Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(O)c1)(C(=O)OCC)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(COC(=O)Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(OC(C)=O)c1)(C(=O)OCC)c1ccccc1
Yield: 77.6 %

Procedure:
2-(2-{3-Hydroxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)amino]phenyl}acetoxymethyl)-2-phenylmalonic acid diethyl ester (0.200 g) obtained in Example 1-a) was dissolved in toluene (4 mL), and to this solution was added triethylamine (0.040 g). After dropwise addition of a solution of acetyl chloride (0.026 g) in toluene (1 mL), the resultant mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with toluene (5 mL) and washed with saturated aqueous sodium bicarbonate (5 mL), 1N hydrochloric acid (5 mL) and water (5 mL). The toluene layer was concentrated and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=2:3) to give the title compound (0.165 g) as a colorless crystal. The physicochemical properties of the product are shown in Table 3 below.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCOC(C)=O.[C:44]([NH:47][CH2:48][CH2:49]O)(=[O:46])[CH3:45]>C1COCC1>[C:44]([NH:47][CH2:48][CH2:49][O:12][C:11](=[O:13])[CH:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=1)[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:25])[F:1])[CH:4]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)NCCO
Reactant: O=C(O)C(Cc1cccc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NCCOC(=O)C(Cc1cccc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1
Temperature: 23.5 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
3-(3-Trifluoromethylphenyl)-2-(4-trifluoromethylphenyl)-propionic acid (105, 2.43 g, crude) was dissolved in anhydrous THF (6 mL) at ambient temperature. CDI (1.64 g, 10.1 mmol) was charged as a solid, followed by EtOAc (4 mL), to rinse the vial. The internal temperature remained between 20-21° C. during the addition. N-acetylethanolamine (3.6 mL, 39 mmol) was added, whereupon the temperature rose to 24.5° C. The mixture was stirred overnight (16 h) at 23-24° C. and then rotary evaporated to a gummy residue. This was chromatographed on silica gel using EtOAc: hexane (70:30 v/v) (Rf=0.35-0.40) to afford 2-acetamidoethyl-3-(3-trifluoromethylphenyl)-2-(4-trifluoromethylphenyl)propionate 105A (1.85 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:13]=[C:12]1[CH2:24][CH2:25][CH2:26][CH3:27])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:34].S(=O)(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:16]([O-:34])=[CH:15][C:14]=2[N:13]=[C:12]1[CH2:24][CH2:25][CH2:26][CH3:27])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 2 h

Procedure:
The product from step (iv) (0.9 g) was dissolved in DCM (25 mL) and cooled to 5° C. 3-Chloroperoxybenzoic acid (0.203 g) was added and the reaction was allowed to warm to rt. The reaction mixture was stirred for 2 h, more 3-chloroperoxybenzoic acid (0.30 g) was added and the reaction mixture stirred for a further 2 h. The reaction mixture was poured into saturated sodium bisulfate solution, extracted with DCM, dried, filtered and evaporated to give the subtitle (0.9 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][F:18]>CN(C)C=O>[F:18][CH2:17][CH2:16][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: Oc1ccccc1Br
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FCCOc1ccccc1Br
Yield: 77.1 %

Procedure:
In a manner similar to that disclosed in German Offenlegungschrift DE No. 3,402,483, the reaction of 5.0 grams (0.029 mole) of 2-bromophenol, 6.0 grams (0.043 mole) of potassium carbonate, and 5.5 grams (0.03 mole) of 1-bromo-2-fluoroethane in 50 ml of N,N-dimethylformamide yielded 4.9 grams of 2-bromophenyl 2-fluoroethyl ether as an oil.
Reaction SMILES: Br[C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[C:8]([S-:10])#[N:9].[K+]>CC(C)=O>[CH3:6][C:2]([S:10][C:8]#[N:9])([CH3:7])[C:3](=[O:5])[CH3:4]
Reactant: N#C[S-]
Reactant: CC(=O)C(C)(C)Br
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)C(C)(C)SC#N

Procedure:
16.5 g. (0.1 mol) of 3-bromo-3-methyl-2-butanone and 11.6 g. (0.12 mol) of potassium rhodanide were refluxed for 1-2 hours in 150 ml. of anhydrous acetone. After cooling, the separated potassium bromide was filtered under suction, back-washed with a small amount of acetone and evaporated to dryness in vacuo at 50° C. The residue was taken up in 200 ml. of ether and washed three times with 100 ml. of water. The ether phase was dried over sodium sulfate and evaporated to dryness in vacuo. The crude product was fractionated on a short Vigreux column to yield 3-methyl-3-thiocyanato-2-butanone, b.p. (0.04 mm), 52° C.
Reaction SMILES: Br[C:2]1[N:3]([CH3:28])[CH:4]=[C:5]([C:7]([N:9]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)=[O:8])[N:6]=1.[CH3:29][O-:30].[Na+]>O1CCCC1>[CH3:29][O:30][C:2]1[N:3]([CH3:28])[CH:4]=[C:5]([C:7]([N:9]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)=[O:8])[N:6]=1
Reactant: C[O-]
Reactant: Cn1cc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)C2CCOCC2)nc1Br
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)C2CCOCC2)cn1C
Temperature: 60 °C
Reaction time: 72 h
Yield: 6.7 %

Procedure:
A mixture of 2-bromo-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-N-[3-(trifluoromethoxy)benzyl]-1H-imidazole-4-carboxamide (100 mg), sodium methoxide (14 mg) and tetrahydrofuran (1 mL) was stirred at 60° C. for 3 days. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography (NH silica gel cartridge; hexane/ethyl acetate=3:1 to 1:1) and TLC (NH silica gel plate; hexane/ethyl acetate=1:1) to give the titled compound (6 mg).
Reaction SMILES: [O-]CC.[Na+].[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[O:15][CH2:16][CH:17]=[CH2:18])=[CH:9][CH:8]=1)=O.[CH2:20]([O:22][C:23](=[O:28])[CH2:24][N:25]=[N+:26]=[N-:27])[CH3:21].O1CCCC1>C(O)C>[CH2:16]([O:15][C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7](/[CH:5]=[C:24](/[N:25]=[N+:26]=[N-:27])\[C:23]([O:22][CH2:20][CH3:21])=[O:28])=[CH:8][CH:9]=1)=[O:19])[CH:17]=[CH2:18]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: C=CCOC(=O)Nc1ccc(C=O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CCOC(=O)Nc1ccc(/C=C(/N=[N+]=[N-])C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49.9 %

Procedure:
To a solution of 689 mg (10.13 mmol) sodium ethoxide in 5 mL absolute ethanol at 0° C. was added a solution of 500 mg (2.44 mmol) of allyl 4-formylphenylcarbamate and 1.25 g (9.75 mmol) ethylazidoacetate dissolved in 5 mL absolute ethanol and 1 mL tetrahydrofuran dropwise over 5 minutes. The mixture was stirred at 0° C. for 1.5 h, then partitioned between ethyl acetate and 1 N HCl until neutral. The organic phase was dried over magnesium sulfate, concentrated and purified by column chromatography, eluting with 25% ethyl acetate/hexane to provide 385 mg of ethyl (2E)-3-(4-{[(allyloxy)carbonyl]amino}phenyl)-2-azidoprop-2-enoate as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[C:5](=[O:15])[CH2:4][CH2:3]1>CCOC(C)=O>[CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[C:5](=[O:15])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: CCOC(C)=O
Product: CC1(C)CCC(=O)c2cc(N)ccc21

Procedure:
A solution of 230.0 mg (1.05 mmol) 3,4-dihydro-4,4-dimethyl-7-nitro-naphthalen-1(2H)-one (Compound D8) in 5.0 mL of EtOAc was stirred at room temperature with a catalytic amount of 10% Pd--C under 1 atm of H2 for 24 h. The catalyst was removed by filtration through a pad of Celite, and the filtrate concentrated under reduced pressure to give the title compound as a dark green oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:2]1=2.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:15]1([S:21]([N:1]2[CH2:6][CH2:5][O:4][C:3]3[N:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:2]2=3)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cnc2c(c1)NCCO2
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc2c(c1)N(S(=O)(=O)c1ccccc1)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.3 %

Procedure:
To a solution of methyl 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (278.9 mg, 1.436 mmol) in DCM (20 mL) was added benzenesulfonyl chloride (278 μL, 2.156 mmol), DIPEA (753 μL, 4.31 mmol) and DMAP (88 mg, 0.719 mmol). The reaction was stirred at room temperature for 16 hours. LCMS analysis indicated a predominance of product in the reaction mixture. The solvent was removed under reduced pressure and the resulting oil was purified by flash column chromatography using a gradient elution of hexanes with 25-70% EtOAc to provide methyl 1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (280 mg, 0.837 mmol, 58.3% yield) as a yellow glass. LCMS (+ESI) m/z=334.8 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]1[N:17]=[CH:18][S:19][CH:20]=1>CN(C)C=O>[O:4]1[CH2:5][CH2:6][N:1]([CH2:15][C:16]2[N:17]=[CH:18][S:19][CH:20]=2)[CH2:2][CH2:3]1
Reactant: BrCc1cscn1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1nc(CN2CCOCC2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Methylthiazole (1.98 g), N-bromosuccinimide (3.56 g) and α,α′-azobisisobutyronitrile (164 mg) were dissolved in carbon tetrachloride (200 ml), and the solution was heated under reflux for 2 hours. After completion of the reaction, insoluble matter was removed by filtration, N,N-dimethylformamide (20 ml) was added to the filtrate, and carbon tetrachloride was distilled off under reduced pressure to obtain an N,N-dimethylformamide solution (about 20 ml) of 4-(bromomethyl)thiazole. Morpholine (871 μl), triethylamine (2.79 ml) and N,N-dimethylformamide (10 ml) were successively added to this N,N-dimethyl-formamide solution (about 10 ml) of 4-(bromomethyl)-thiazole, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, dichloromethane and a saturated aqueous solution of sodium hydrogen carbonate were added to the residue and an organic layer was separated. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:19) to obtain the title compound (700 mg) as a yellow oil.
Reaction SMILES: CS(O[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([CH2:39][P:40]([O:45][CH2:46][CH3:47])([O:42][CH2:43][CH3:44])=[O:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:17]3[C:13]=2[CH2:14][N:15]([CH3:51])[C:16]3=[O:50])[CH2:8][CH2:7]1)(=O)=O.[CH3:52][N:53](C=O)C>>[C:52]([C@@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([CH2:39][P:40](=[O:41])([O:42][CH2:43][CH3:44])[O:45][CH2:46][CH3:47])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:17]3[C:13]=2[CH2:14][N:15]([CH3:51])[C:16]3=[O:50])[CH2:8][CH2:7]1)#[N:53]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](OS(C)(=O)=O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](C#N)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 100 °C

Procedure:
In 25 mL Schlenk tube, trans-4-(7-{[2-({4-[(diethoxyphosphoryl)methyl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexyl methanesulfonate (Compound 283A, 130.0 mg, 0.17 mmol) was dissolved in DMF (13.0 mL, 168 mmol) and was added degassed (3×) with argon. The reaction was heated at 100° C. under an atmosphere of argon for 7 hrs. The reaction was dissolved in EtOAc and washed with water (2×) and brine (1×) respectfully. The organic layer was collected and concentrated in vacuo to a solid and was purified by CombiFlash®Rf 4X Organic Purification System [dried loaded on 12 g silica load cartridge, 40 g RediSep® Normal-phase GOLD Silica Flash Column, elution gradient: 0>4% MeOH in DCM] to afford 37.4 mg (31.7%) of the desired product. 1H NMR (400 MHz, MeOD) δ 8.49 (br. s., 1H), 8.33 (s, 1H), 7.85 (d, J=7.58 Hz, 1H), 7.33 (d, J=8.59 Hz, 1H), 7.03-7.09 (m, 1H), 6.93 (td, J=2.27, 8.08 Hz, 1H), 4.51 (s, 2H), 4.08 (quin, J=7.26 Hz, 4H), 3.90 (s, 3H), 3.33 (s, 1H), 3.27 (s, 1H), 3.17 (s, 4H), 2.68 (d, J=5.56 Hz, 1H), 2.10 (d, J=10.36 Hz, 2H), 1.75-1.93 (m, 6H), 1.28 (t, J=7.07 Hz, 6H). MS (ES+): m/z 687.17/688.20 (100/70) [MH+]. HPLC: tR=1.54 min (Micromass TOF: polar—3 min).