Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:8]([N:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[O:25][CH3:26])[CH3:11])=[O:9].CCN(C(C)C)C(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45].[NH4+].[Cl-]>C(Cl)Cl>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:10]([CH3:11])[C:8](=[O:9])[C:7]2[CH:27]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:29]=[C:5]([S:4][CH2:3][CH2:2][NH:1][S:44]([CH3:43])(=[O:46])=[O:45])[CH:6]=2)=[C:19]([O:25][CH3:26])[CH:20]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCN)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCNS(C)(=O)=O)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To an ice-cold solution of 3-(2-aminoethylthio)-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-5-(trifluoromethyl)benzamide (0.12 g, 250 μmol, example 237) and DIPEA (64.7 mg, 87.4 μL, 501 μmol) in CH2Cl2 (2 mL) was added methanesulfonyl chloride (35.8 mg, 24.4 μL, 313 μmol) and the clear colorless solution was stirred at 0° C. for 2.5 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted three times with CH2Cl2. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 5 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless foam (0.121 g; 86%). MS (ESI): m/z=558.11 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.Cl.CN.C[CH2:17][N:18](C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([NH:18][CH3:17])[N:3]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNc1cc(C(=O)OC)nc(Cl)n1
Reaction time: 1 h

Procedure:
To a mixture of methyl 2,6-dichloropyrimidine-4-carboxylate (2 g), methylamine hydrochloride (0.72 g) in CH2Cl2 (48 mL) at 0° C. was added Hunig's base (3.7 mL) dropwise, and the reaction mixture was stirred at ice bath for 1 h and then rt for 1 h. The solvent was removed in vacuo, and the white residue was purified directly by Biotage eluting with 40-600% EtOAc/Hexanes (1000 mL) followed by 90% CH2Cl2/10% MeOH (4 L) to give the title compound as a white solid (1.8 g). These fractions were combined and evaporated in vacuo. During the solvent removal, some white solid was formed. Several filtrations gave the title compound as a white solid (1.8 g, very white solid).). LC-MS (M+H)+=202.00
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[CH2:14]([S:18](Cl)(=[O:20])=[O:19])[CH2:15][CH2:16][CH3:17]>C1COCC1>[CH2:14]([S:18]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)(=[O:20])=[O:19])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCS(=O)(=O)Cl
Reactant: Nc1nccs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)Nc1nccs1
Reaction time: 20 h
Yield: 55.4 %

Procedure:
7.4 g of 2-aminothiazole (73.7 mmol) and 10.2 ml of triethylamine (7.4 g, 73.7 mmol) were dissolved at room temperature in 100 ml of THF. Again at room temperature 9.6 ml of n-butanesulfonyl chloride (11.5 g, 73.7 mmol) were added dropwise to this solution over the course of one hour. After 21 h of stirring at room temperature a further 4 ml of n-butanesulfonyl chloride (4.8 g, 30.8 mmol) were added and stirring was continued at room temperature for 20 h. The reaction mixture was washed twice with 100 ml of 1 N NaOH and then washed to neutrality (pH 6–7) with water. The organic phase was dried over magnesium sulphate and then freed from the solvent. The 9.0 g of crude product obtained were recrystallized from 80 ml of tert-butyl methyl ether. This gave 3.2 g of the target compound, whose constitution was verified by NMR spectroscopy.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([CH2:12][NH:13][C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1.[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[N:25]1.[OH-].[Li+]>ClCCl>[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([CH2:12][N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[S:29]([C:26]2[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=2)(=[O:31])=[O:30])=[CH:10][CH:9]=1
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Reactant: Oc1cccc(NCc2ccc(Cl)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2cccc(O)c2)n1
Temperature: 50 °C
Reaction time: 48 h
Yield: 77.6 %

Procedure:
Pyridine (520 μl, 6.4 mmol) was added to a stirred solution of 3-(4-chloro-benzylamino)-phenol (500 mg, 2.2 mmol) and 1-methylpyrazole-3-sulfonyl chloride (181 mg, 4.5 mmol) in anhydrous dichloromethane (22 ml). The reaction was stirred under nitrogen at 50° C. for 48 hours and then quenched with water (50 ml). The reaction was extracted with dichloromethane (3×25 ml), and the organics combined, washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulphate and then concentrated in vacuo. The crude product was dissolved in a solution of tetrahydrofuran/methanol/water (1:1:1) (25 ml), treated with lithium hydroxide (271 mg, 6.45 mmol) and the mixture was stirred at 85° C. for 2 hours. The reaction was cooled, quenched with 2M hydrochloric acid (aq) until slightly acidic and extracted with ethyl acetate (2×50 ml). The organic extracts were combined, washed with water (100 ml), dried over anhydrous sodium sulphate and concentrated in vacuo to obtain a white solid (645 mg, 27% yield). HPLC retention time 5.59 min Mass spectrum (ES+) m/z 378 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH:25]([CH3:27])[CH3:26])[C:3]1[C:4]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([CH3:24])=[CH:18]3)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]#[N:14])=[CH:8][CH:7]=2.[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O.O.[Zn+2].[Br-].[Br-]>[CH:25]([N:2]([CH3:1])[C:3]1[C:4]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([CH3:24])=[CH:18]3)=[N:5][C:6]2[C:11](=[CH:10][C:9]([C:13]3[NH:30][N:29]=[N:28][N:14]=3)=[CH:8][CH:7]=2)[N:12]=1)([CH3:27])[CH3:26]
Reactant: Cc1cc2cc(-c3nc4ccc(C#N)cc4nc3N(C)C(C)C)ccc2[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2cc(-c3nc4ccc(-c5nnn[nH]5)cc4nc3N(C)C(C)C)ccc2[nH]1
Temperature: 130 °C
Reaction time: 8 h
Yield: 21.2 %

Procedure:
To a solution of 3-[methyl(propan-2-yl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carbonitrile (200 mg, 0.56 mmol) in DMSO (20 ml) was added NaN3 (110 mg, 1.69 mmol) in water (2 ml), and ZnBr2 (64 mg, 0.28 mmol). The resulting solution was stirred overnight at 130° C. and then quenched with water (200 ml). The pH was adjusted to 3 with HCl (2N). Then the solution was extracted with ethyl acetate (4×50 ml) and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (10%-15% dichloromethane in methanol) to afford N-isopropyl-N-methyl-3-(2-methyl-1H-indol-5-yl)-7-(1H-tetrazol-5-yl)quinoxalin-2-amine as an orange solid (47.4 mg, 21%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[N:13]1([C:18]2[CH:19]=[C:20]([C@@H:24]([NH2:26])[CH3:25])[CH:21]=[CH:22][CH:23]=2)[CH:17]=[N:16][CH:15]=[N:14]1>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:26][C@H:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH:19]=1)[CH3:25])=[O:8]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: C[C@H](N)c1cccc(-n2cncn2)c1
Product: C[C@H](NC(=O)C=Cc1ccccc1F)c1cccc(-n2cncn2)c1

Procedure:
The title compound was prepared from 2-fluorocinnamic acid and (S)-1-(3-[1,2,4]triazol-1-yl-phenyl)-ethylamine following the general procedures as described for Example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O:14][CH:15]1[C:18]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:17](=O)[NH:16]1)(=O)C.C(OCC)(=O)C>[OH-].[Na+].CC(C)=O>[CH2:19]([C:18]1([CH2:21][CH3:22])[C:15](=[O:14])[NH:16][CH:17]1[O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:20]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCC1(CC)C(=O)NC1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCC1(CC)C(=O)NC1Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.7 %

Procedure:
A solution of 4-nitrophenol (2.37 gm, 17.0 mmol) in 2.5N sodium hydroxide (6.82 mL) was added to a solution of 2-acetoxy-3,3-diethyl-4-oxoazetidine (1.05 gm, 5.7 mmol) in acetone (5 mL). After stirring at room temperature for 2.5 hours, ethyl acetate (100 mL) was added and the solution successively washed with water (3×20 mL) and saturated salt solution (20 mL). The solution was dried over anhydrous sodium sulfate and the solvent removed by rotoevaporated. The product was purified by flash column chromatography on silica gel eluted with 25% ethyl acetate in hexanes and isolated as a beige solid (1.20 gm, 80% yield): 1H-NMR δ (CDCl3) 0.94 (6H, t, J=7 Hz), 1.62-1.92 (4H, m), 5.38 (1H, s), 6.90 (2H, d, J=9 Hz), 7.66 (1H, s), 8.10 (2H, d, J= 9 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1.[CH3:13][C:14](O)([CH3:16])[CH3:15].OS(O)(=O)=O>FC(F)(F)C(O)=O>[C:14]([N:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])=[N:12][N:11]=[N:10]1)([CH3:16])([CH3:15])[CH3:13]
Reactant: Brc1ccccc1-c1nnn[nH]1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1nnnc1-c1ccccc1Br
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a solution of 5-(2-bromophenyl)-1H-tetrazole (7.9 g, 0.035 mol) in trifluoroacetic acid (35 mL) was added tBuOH (5.2 g, 0.070 mol) and H2SO4 (1.0 mL, 0.0175 mol). After 18 h, the solution was concentrated and the residue was taken up in EtOAc. The mixture was washed with water, 2.5 N NaOH, water, dried (MgSO4), and concentrated. Purification by flash chromatography (20% EtOAc/hexane) gave 6.6 g (67%) of product as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([C:13]3[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=3)=[CH:11][CH:10]=[N:9][C:8]=12)[OH:3].C(O)(=O)C>[O-2].[O-2].[O-2].[Cr+6].O>[F:21][C:19]([F:20])([F:22])[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]2[N:7]3[N:6]=[CH:5][C:4]([C:2]([CH3:1])=[O:3])=[C:8]3[N:9]=[CH:10][CH:11]=2)[CH:14]=1
Reactant: CC(O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Reaction time: 1 h

Procedure:
A mixture of 3.0 g. of α-methyl-7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine-3-methanol and one gram of chromium trioxide in 75 ml. glacial acetic acid is allowed to remain at room temperature for 1 hour and then poured into water. The resultant solid is removed by filtration and then recrystallized from methylene chloride-n-hexane to yield the desired methyl ketone, m.p. 127°-130° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[CH:13]1[CH:14]=[CH:15][N:16]=[C:17]([NH:19][S:20]([C:23]2[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:18]=1>>[O:12]=[C:4]1[NH:5][C:6]2[C:11](/[C:3]/1=[CH:2]/[NH:29][C:26]1[CH:25]=[CH:24][C:23]([S:20]([NH:19][C:17]3[CH:18]=[CH:13][CH:14]=[CH:15][N:16]=3)(=[O:22])=[O:21])=[CH:28][CH:27]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C1Nc2ccccc2C1=CO
Reactant: Nc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Product: O=C1Nc2ccccc2/C1=C/Nc1ccc(S(=O)(=O)Nc2ccccn2)cc1

Procedure:
The title compound was prepared analogous to Example 5 from 3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one and sulfapyridine. Electrospray MS 393 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=3.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:18]3[CH2:19][O:20]3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=3
Reactant: ClCC1CO1
Reactant: Cc1ccc2[nH]c3ccc(C)cc3c2c1
Product: Cc1ccc2c(c1)c1cc(C)ccc1n2CC1CO1
Yield: 69 %

Procedure:
Following Representative Procedure 1, 3,6-dimethyl carbazole (Beyer et al., O. J. Org. Chem. 2003, 68, 2209-2215) was added to epichlorohydrin in 69% yield.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:5][CH:4]([N:6]2[C:10]3[N:11]=[C:12](S(C)=O)[N:13]=[C:14]([C:15]4[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=4)[C:9]=3[CH2:8][CH2:7]2)[CH2:3]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][C@H:27]1[CH2:32][OH:33].[F-].[Cs+]>C(#N)C>[NH2:21][C:18]1[N:17]=[CH:16][C:15]([C:14]2[C:9]3[CH2:8][CH2:7][N:6]([CH:4]4[CH2:5][C:2]([F:25])([F:1])[CH2:3]4)[C:10]=3[N:11]=[C:12]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C@H:27]3[CH2:32][OH:33])[N:13]=2)=[CH:20][N:19]=1
Reactant: CS(=O)c1nc(-c2cnc(N)nc2)c2c(n1)N(C1CC(F)(F)C1)CC2
Reactant: OC[C@@H]1COCCN1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: Nc1ncc(-c2nc(N3CCOC[C@H]3CO)nc3c2CCN3C2CC(F)(F)C2)cn1
Temperature: 120 °C

Procedure:
To a solution of 5-[7-(3,3-difluorocyclobutyl)-2-(methylsulfinyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amine (35 mg, 0.096 mmol) in acetonitrile (0.3 mL) was added (3R)-morpholin-3-ylmethanol (68 mg, 0.576 mmol) and CsF (56 mg, 0.288 mmol), and the reaction mixture was sealed and heated at 120° C. for 96 h.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:8]2[CH2:15][C:14](=[O:16])[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1.CN(C)CCN(C)C.Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:28]=1[CH2:36]Br>C1COCC1>[Cl:6][C:7]1[C:8]2[C:15]3([CH2:36][C:28]4[C:27](=[CH:32][CH:31]=[C:30]([N+:33]([O-:35])=[O:34])[CH:29]=4)[CH2:26]3)[C:14](=[O:16])[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2ncnc(Cl)c2C12Cc1ccc([N+](=O)[O-])cc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Butyllithium (0.29 ml, 0.74 mmol, 2.5 M) was added to a stirred solution of 4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one from Step B (50 mg, 0.295 mmol) at −78° C. in THF (30 mL). After complete addition of butyllithium, N,N,N′,N′-tetramethylethane-1,2-diamine (0.31 mL, 0.77 mmol) was added. After 1 h at −78° C., 1,2-bis(bromomethyl)-4-nitrobenzene (91 mg, 0.295 mmol, described in Intermediate 2) was added and the reaction warmed to ambient temperature. After 8 h, the reaction was quenched with H2O and the mixture was partitioned between EtOAc and H2O. The aqueous solution was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=317 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[N:9]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=3)[N:12]([CH3:23])[C:11](=[O:24])[C:10]=12)=[O:5])[CH3:2].C([O-])(=[O:28])C.[K+].O>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([OH:28])[N:9]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=3)[N:12]([CH3:23])[C:11](=[O:24])[C:10]=12)=[O:5])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1nc(Br)n2c1c(=O)n(C)c1cc(C(F)(F)F)ccc12
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1nc(O)n2c1c(=O)n(C)c1cc(C(F)(F)F)ccc12
Yield: 84.6 %

Procedure:
To a solution of 1-bromo-5-methyl-4-oxo-7-trifluoromethyl-4,5-dihydroimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (3.2 g) in dimethylsulfoxide (DMSO) (30 ml) was added potassium acetate (2.5 g) with stirring. The mixture was heated on a steam bath for one hour. Water was then added to cause the precipitation of crude product as a white solid (2.3 g, 85% yield). Recrystallized from a mixture of acetonitrile, chloroform and methanol, m.p. >300° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](Cl)=[O:31]>C1COCC1>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:30](=[O:31])[C:29]1[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=[C:27]([C:26]([F:25])([F:40])[F:41])[CH:28]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To a solution of methyl-(4-phenyl-pyridin-3-yl)-amine (160 mg, 0.87 mmol) in THF (4 mL) under nitrogen was added LiHMDS (1.3 mL, 1.3 mmol, 1M solution in THF) at −78° C. and the resulting reaction mixture was stirred for 30 min at −78° C. Then 3,5-bis(trifluoromethyl)-benzoyl chloride (480 mg, 1.74 mmol, CAS RN 1271-19-8) in THF (1 mL) was added to the reaction mixture at −78° C. and the reaction mixture was stirred for another 12 hours at 25° C. The reaction mixture was quenched with 10 mL saturated NH4Cl solution and extracted with EtOAc (2×20 mL). The combined organic layers were dried and evaporated. The crude product was purified by preparative HPLC (ammonium acetate/acetonitrile) to furnish the desired compound as off-white solid (125 mg, 34%). MS (ESI): m/z=425.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][CH:13]=1)#[CH:11].CCN(CC)CC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([C:10]#[C:11][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C#Cc1ccc(CCCCCC)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A mixture of 4-bromobenzaldehyde (5.00 g, 27.0 mmol), 1-ethynyl-4-hexylbenzene (6.29 g, 33.4 mmol), Et3N (4.70 mL, 33.4 mmol), bis(triphenylphosphine)palladium chloride (950 mg, 1.35 mmol) and triphenylphosphine (180 mg, 0.68 mmol) in anhydrous THF (100 mL) was stirred at rt for 30 min under inert atmosphere. Then copper(I) bromide (82 mg, 0.43 mmol) was added and the resulting mixture was stirred overnight at rt. The solvent was evaporated off. The residue was dissolved in Et2O (100 mL), washed with water (50 mL), dried over MgSO4 and the solvent was removed under reduced pressure. The resulting brown solid was triturated in hexane (25 mL), filtered off and washed with hexane to give the title compound as a beige solid (7.73 g, 91%). HPLC (Condition A), Rt: 5.88 min (HPLC purity: 91.9%).
Reaction SMILES: CO[C:3]1=[N:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9]1.[C:10]1([C:16]2[O:17][C:18](=[O:21])[CH2:19][N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.[OH-].[Li+].O>C1COCC1>[C:10]1([C:16]2[N:4]3[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:3]3=[C:19]([C:18]([OH:21])=[O:17])[N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC1=NCCOCC1
Reactant: O=C1CN=C(c2ccccc2)O1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(-c2ccccc2)n2c1CCOCC2
Temperature: 150 °C

Procedure:
(E)-5-methoxy-2,3,6,7-tetrahydro-1,4-oxazepine (50 mg, 0.387 mmol) was dissolved in THF (1 mL) in a screw-cap vial and 2-phenyloxazol-5(4H)-one (62.4 mg, 0.387 mmol) was added to give a orange solution. The reaction was heated to 150° C. for 5 minutes. LCMS shows two peaks of the corresponding product mass (tautomers of the condensation), Rt 0.73 and 0.78 minutes. The reaction was concentrated under reduced pressure and the residue was dissolved in 1 mL MeOH and treated with lithium hydroxide monohydrate (81 mg, 1.936 mmol) and water (200 μL). The reaction was heated at 120° C. for 5 minutes using microwave irradiation to provide a new desired product (same MW as intermediate) with Rt=0.50 minutes. The reaction was concentrated to remove MeOH and then diluted with water (1 mL). The solution was acidified to pH2 with 5N HCl. The solution was extracted with DCM (3×2 mL). The combined organic extracts were dried and evaporated to provide the title compound as a brown oil (23 mg). Additional material was recovered by concentrating the aqueous layer and repeated extraction with DCM. The combined material (45 mg, 45%) was used without further purification. LCMS (+ESI) m/z: 130.2 [M+H]+
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C(N(CC)CC)C.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>O1CCCC1>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4]2)=[O:25])=[CH:22][CH:21]=1
Reactant: NC1Cc2ccccc2C1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1Cc2ccccc2C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
43.70 g (258 mol) 2-aminoindane hydrochloride and 53.43 g (528 mmol) triethylamine were added to 250 ml of tetrahydrofuran, 42.89 g (270 mmol) 4-fluorobenzoylchloride were added, and the mixture was stirred for 2 h at RT.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:14]1[CH:24]=[CH:23][C:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=2[CH:15]=1)[C:9]([O:11]C)=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].O>C1COCC1>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:14]1[CH:24]=[CH:23][C:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=2[CH:15]=1)[C:9]([OH:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC(C)(C)O2)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H](Cc1ccc2c(c1)OC(C)(C)O2)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of (S)-methyl 2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propanoate (5000 mg, 14229 μmol) in 100 mL of THF at 0° C. was added lithium hydroxide (0.2 M, 28458 μl, 14229 μmol) over 10 minutes. After stirring at 0° C. for 1 hour the reaction was poured into a separatory funnel and 100 mL of water was added. The mixture was washed with 150 mL of ether, then acidified to pH 2-3- with 1 N HCl. Ethyl acetate was added, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organics were washed with water and then brine before being dried over sodium sulfate, filtered and concentrated to furnish (S)-2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propanoic acid (4005 mg, 83% yield) as a colorless viscous oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>C(O)(=O)C>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)[N:6]([CH2:16][CH:18]1[O:20][CH2:19]1)[CH2:16][CH:18]1[O:20][CH2:19]1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: ClCC1CO1
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(N(CC2CO2)CC2CO2)cc(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 57.2 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)aniline (22.9 g) and epichlorohydrin (37 g) in glacial acetic acid (10.6 g) were heated at about 100° C. for about 11 hours. Excess epichlorohydrin was distilled off under reduced pressure. Benzene (100 cm3), a solution of sodium hydroxide (8 g) in water (30 cm3) and benzyltriethylammonium chloride (0.3 g) was added to the residue and the mixture stirred at about room temperature for about 15 minutes, followed by 15 minutes at about 60° C. The aqueous layer was discarded. The dehydrochlorination procedure was repeated three times in order to effect complete conversion. The solvent was removed and the product was purified by preparative high performance liquid chromatography to give 19.5 g of 3,5-bis(trifluoromethyl)-N,N-bis(2,3-epoxypropyl)aniline.