Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH2:28])=[N:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[Cl:27])[CH2:16][CH2:15]2)=[CH:7][CH:8]=1.Cl[C:30](OC1C=CC([N+]([O-])=O)=CC=1)=[O:31].[Li+].CC([N-]C(C)C)C>C1COCC1>[Cl:27][C:21]1[C:22]([Cl:26])=[CH:23][CH:24]=[CH:25][C:20]=1[N:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][O:9][C:6]2[CH:7]=[CH:8][C:3]3[CH2:2][NH:1][C:30](=[O:31])[NH:28][C:4]=3[N:5]=2)[CH2:19][CH2:18]1
Reactant: NCc1ccc(OCCCCN2CCN(c3cccc(Cl)c3Cl)CC2)nc1N
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1NCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
A mixture of 3-aminomethyl-6-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-pyridin-2-ylamine (0.260 g, 0.61 mmol) in THF (10 mL) was treated with 4-nitrophenyl chloroformate (0.160 g, 0.79 mmol). The mixture was stirred at room temperature for 30 minutes, then cooled to 0° C. and treated with LDA (0.9 mL, 3.8 mmol, 2.0 M in heptane/THF/ethylbenzene). The brown mixture was stirred at room temperature for 1 hour, then quenched with water and extracted with EtOAc. The organic extracts were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (10% MeOH/EtOAc) to afford the title compound as a light yellow solid (0.071 g, 25%). mp 166–167° C.; 1 H NMR (400 MHz, CDCl3): δ 7.25 (s, 1H), 7.19–7.14 (m, 2H), 7.14–7.09 (br s, 1H), 6.99–6.94 (m, 1H), 6.32 (d, 1H), 5.57–5.51 (br s, 1H), 4.45 (s, 2H), 4.24 (t, 2H), 3.16–3.02 (m, 4H), 2.75–2.58 (m, 4H), 2.49 (t, 2H), 1.84–1.64 (m, 4H). MS ES: m/z=450.03, 452.02.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.CCN(C(C)C)C(C)C.[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:37])[F:38])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[CH2:7]1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CCN1
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl(2S)-2-methyl-1-piperazinecarboxylate (2.50 g, 12.5 mmol), DIPEA (4.58 ml, 26.2 mmol) and 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (3.25 g, 12.5 mmol) in DCM (200 ml) was stirred at room temperature overnight. The mixture was washed with saturated aqueous NaHCO3, then brine and concentrated under vacuum. The residue was redissolved in 1,4-dioxane (200 ml), then 4M HCl in dioxane (20 ml) and water (0.5 ml) were added and the mixture stirred overnight. The mixture was concentrated under vacuum and applied to an SCX-2 cartridge (20 g) washing with MeOH. The product was eluted with 0.5M NH3 in MeOH; concentration left the title compound as a white solid (2.56 g).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])=[O:5].[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.Cl>>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:27]1[CH2:26][CH2:25][N:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:30])([F:31])[F:16])[CH:19]=2)[CH2:29][CH2:28]1)([O-:15])=[O:14]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=C(CCBr)Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Product: O=C(CCN1CCN(c2cccc(C(F)(F)F)c2)CC1)Nc1ccccc1[N+](=O)[O-]

Procedure:
The compound was prepared from 3-bromo-N-(2-nitrophenyl)propionamide and 1-(3-trifluoromethylphenyl)piperazine according to the method described in J. Med. Chem. 33, 2970 (1990). Monohydrochloride salt. M.p. 185°-188° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:17][S:18][CH2:19][C:20](O)=[O:21])[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[CH:5][CH:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:38]1([C@H:44]2[CH2:48][O:47][C:46](=[O:49])[NH:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:17][S:18][CH2:19][C:20]([N:45]3[C@@H:44]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:48][O:47][C:46]3=[O:49])=[O:21])[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[CH:7][CH:8]=1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: COc1ccc(C2(CSCC(=O)O)OCC(C)(C)CO2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C2(CSCC(=O)N3C(=O)OC[C@@H]3c3ccccc3)OCC(C)(C)CO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
({[2-(4-Methoxyphenyl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)acetic acid (5.4 g, 16.5 mmol) was dissolved in dry CH2Cl2 (80 ml) and cooled to 0° C. N,N′-dicyclohexylcarbodiimide (DCC, 3.76 g; 18.2 mmol) in 20 ml of CH2Cl2 and 4-(dimethylamino)pyridine (DMAP, 4.04 g, 33.1 mmol) were added and the mixture was stirred at 0° C. for 30 minutes. (S)-(+)-4-Phenyl-2-oxazolidinone (2.69 g, 16.5 mmol) was added and the mixture was stirred at room temperature for 17 h. The mixture was filtered, concentrated under reduced pressure and purified by flash-chromatography (hexane:EtOAc 4:1 then 2:1). This afforded 5.69 g (73%) of the title compound as a white solid. 1H-NMR (CDCl3, 200 MHz): δ 0.6 (s, 3H), 1.3 (s, 3H), 2.8 (s, 2H), 3.4 (s, 4H), 3.8 (s, 2H), 3.8 (s, 3H), 4.3 (dd, 1H), 4.7 (t, 1H), 5.4 (dd, 1H), 6.9 (d, 2H), 7.3 (m, 7H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:14])[N:8]2[CH2:11][CH2:12][OH:13])=[C:4]([Cl:15])[N:3]=1.[C:16]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:16])[C:7](=[O:14])[N:8]2[CH2:11][CH2:12][OH:13])=[C:4]([Cl:15])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(Cl)c2[nH]c(=O)n(CCO)c2n1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCO)c2nc(N)nc(Cl)c21
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
A mixture of 2-amino-6-chloro-9-(2-hydroxyethyl)-7H-purin-8-one obtained in step 2 (13 g, 56.7 mmol), K2CO3 (11.5 g, 84 mmol), methyl iodide (12 g, 85.15 mmol) and DMF (130 ml) were stirred at 25-30° C. for 16 hours. The reaction mixture was concentrated and purified by column chromatography using 60-120 silica gel and 4% methanol in DCM as an eluent to obtain 2-amino-6-chloro-9-(2-hydroxyethyl)-7-methyl-purin-8-one (8 g, 58%) as an off white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[CH:8][C:7]=1[OH:14].[CH3:16][O:17][CH2:18][CH2:19]Br.O>CN(C)C=O>[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[CH:8][C:7]=1[O:14][CH2:19][CH2:18][O:17][CH3:16]
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc(N)c(Cl)cc1C(=O)OC
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
A suspension of 60% sodium hydride/oil dispersion (1.00 g, 25 mmol) in anhydrous dimethylformamide (40 ml) under nitrogen was treated with 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester (4.03 g, 20 mmol), stirred for 30 minutes, then treated with 2-bromoethyl methyl ether (3.48 g, 25 mmol). The mixture was heated to 95±5° C. for 1.5 hours, then cooled and added to water (250 mL). The aqueous suspension was filtered, and the solid was washed with water, air dried, collected, and recrystallized from ether/hexane to afford 2.75 g (53%) of the tile compound; mp 121.0°-122.5° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][N:6]2[C:7](=[O:9])[CH:8]=1.[C:17]([O-:20])(=[O:19])[CH3:18].[K+]>CN(C)C=O>[C:17]([O:20][CH2:2][C:3]1[N:4]=[C:5]2[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][N:6]2[C:7](=[O:9])[CH:8]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1cn2c(=O)cc(CCl)nc2s1
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn2c(=O)cc(COC(C)=O)nc2s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.9 %

Procedure:
7-chloromethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester (12.8 g), prepared according to Example 7, was dissolved in dimethylformamide and reacted with anhydrous potassium acetate (10 g) under stirring at room temperature for 20 hours. After dilution with ice water the precipitate was filtered and washed with water to give 7-acetoxymethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester (12.7 g) which was hydrolysed by treatment with 37% HCl (20 ml) in dioxane (100 ml) under stirring at room temperature for 2 hours. The reaction mixture was diluted with acetone and the precipitate was filtered and then treated with aqueous Na2HPO4 : filtration and washings with water until neutral gave 7-hydroxymethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester (7.1 g) which was reacted with dicyclohexylcarbodiimide (14.01 g) in benzene (90 ml) and dimethylsulphoxide (40 ml) in the presence of trifluoroacetic acid (1 ml) and pyridine (1.71 ml) under stirring at room temperature for 20 hours. After treatment with oxalic acid bihydrate (3.1 g) at room temperature, the precipitate of dicyclohexylurea was filtered off and the organic solution was concentrated in vacuo to dryness: the residue was purified over a SiO2 column using chloroform; methanol=95:5 as eluent. The 7-formyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester so obtained (2.7 g) was reacted with triphenylphosphoniumbenzyl chloride (2.94 g) under treatment with 50% NaH (0.43 g) in dimethylsulfoxide (10 ml) and dichloroethane (6 ml) at room temperature for 18 hours. After evaporation of the solvent in vacuo, the residue was diluted with ice water and the precipitate was filtered and washed with water: crystallization from isopropyl alcohol gave 1.9 g of 7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester, m.p. 183°-185° C., which was hydrolyzed by treatment with 0.5% KOH solution in 95% ethanol (80 ml) at reflux temperature for 1 hour. The precipitate was filtered and dissolved in dimethylformamide-formic acid: the solution was then diluted with ice water. The precipitate was filtered and washed with water until neutral: crystallization from CHCl3 -isopropyl alcohol gave 1.3 g of 7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, m.p. 246°-248° C., N.M.R. (CF3COOD-CDCl3) δ p.p.m.: 6.84 (s) (1H, C-6 proton), 7.12 (d) (1H, β-ethenyl proton), 7.45-7.74 (m) (5H, phenyl protons), 7.85 (d) (1H, α-ethenyl proton), 8.97 (s) (1H, C-3 proton), JHαHβ =16 Hz.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[O:8])[N:4]=[CH:3]1.[Br:9]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>C(=O)([O-])[O-].[Na+].[Na+]>[Br:9][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][C:5]=1[CH:7]=[O:8]
Reactant: Cn1cnc(C=O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1cnc(C=O)c1Br
Temperature: 0 °C
Yield: 43.1 %

Procedure:
A mixture of 1-methyl-1H-imidazole-4-carbaldehyde (0.50 g), N-bromosuccinimide (0.89 g) and chloroform (7.0 mL) was heated at reflux for 2 hours. The mixture was cooled to 0° C., diluted with saturated aqueous sodium carbonate solution (10 mL) and extracted with dichloromethane. The combined organic extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (0:1 to 7:10 by volume) to afford the title compound as a white solid (0.37 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:11]=[C:12]4[C:25]5([CH2:29][O:28][C:27]([NH2:30])=[N:26]5)[C:21]5([CH2:24][O:23][CH2:22]5)[C:17]5([CH2:20][CH2:19][CH2:18]5)[O:16][C:13]4=[CH:14][CH:15]=3)=[CH:6][N:5]2[CH:31]=1.C(O)(=O)C.[H][H]>CCO.O=[Pt]=O>[CH3:1][C:2]1[N:3]=[C:4]2[CH2:9][CH2:8][CH:7]([C:10]3[CH:11]=[C:12]4[C:25]5([CH2:29][O:28][C:27]([NH2:30])=[N:26]5)[C:21]5([CH2:24][O:23][CH2:22]5)[C:17]5([CH2:18][CH2:19][CH2:20]5)[O:16][C:13]4=[CH:14][CH:15]=3)[CH2:6][N:5]2[CH:31]=1
Reactant: Cc1cn2cc(-c3ccc4c(c3)C3(COC(N)=N3)C3(COC3)C3(CCC3)O4)ccc2n1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cn2c(n1)CCC(c1ccc3c(c1)C1(COC(N)=N1)C1(COC1)C1(CCC1)O3)C2
Temperature: 25 °C
Reaction time: 38 h
Yield: 83.2 %

Procedure:
A suspension of 6′-(2-methylimidazo[1,2-a]pyridin-6-yl)trispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-amine (66 mg, 0.16 mmol), acetic acid (27 μl, 0.06 mmol) and PtO2 (13 mg) in EtOH (3.3 ml) was stirred at room temperature under the hydrogen atmosphere at 3 atm for 8 hours. To the mixture was added acetic acid (63 μl), and the mixture was stirred at room temperature under hydrogen atmosphere at 3 atm for 38 hours. The mixture was filtrated through celite pad. And then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silicagel column chromatography (28% NH4OH/EtOH/CHCl3=2:20:80) followed by trituration in iPr2O and filtration to give 6′-(2-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)trispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-amine (56 mg).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([CH2:16][C:17]2[C:18]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:7]1[CH3:32])C.[OH-].[K+]>C1COCC1.O>[C:26]1([S:23]([C:18]2[C:17]([CH2:16][C:8]3[C:9]4[C:14](=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=4)[N:6]([CH2:5][C:4]([OH:33])=[O:3])[C:7]=3[CH3:32])=[CH:22][CH:21]=[CH:20][N:19]=2)(=[O:25])=[O:24])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cc2cccnc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.8 %

Procedure:
To a stirred solution of [3-(2-benzenesulfonyl-pyridin-3-ylmethyl)-5-fluoro-2-methyl-indol-1-yl]-acetic acid ethyl ester (1.20 g, 2.56 mmol) in THF (26 ml) was added a solution of potassium hydroxide (0.43 g, 7.68 mmol) in water (9 ml). The resulting solution was stirred at room temperature for 3.5 h. THF was removed in vacuo and the remaining aqueous layer was acidified with aqueous HCl (0.1 M, 25 ml). The product was collected by filtration, washed with water and dried in vacuo to afford 1.12 g (100%) of the title compound (LCMS RT=4.58 min, M+-H 437.2).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[N:13]([O-])=O.[Na+].[ClH:17]>O>[ClH:17].[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][NH2:13])=[CH:6][CH:5]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(OC(F)(F)F)cc1
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
A suspension of p-trifluoromethoxyaniline (5.0 g, 28 mmol) in 33 mL of concentrated HCl was diazotized at 0°-10° C. with a solution of sodium nitrite (2.0 g, 29 mmol) in H2O (17 mL). After stirring for 15 minutes at -5° C., the turbid solution was made clear by the addition of a few drops of water. A solution of stannous chloride (12.6 g, 56 mmol) in concentrated HCl (11 mL) was added in one portion. The mixture was stirred for 3 hours (with the ice bath removed after 1 hour), basified with 50% NaOH and extracted with EtOAc (2×). The organic phase was washed with 1N NaOH and brine, dried (KOH pellets) and acidified with anhydrous HCl. The precipitate was filtered and dried to give the title product as the white solid hydrochloride salt [4.83 g, mp 231° C. (dec.)]. A second crop was obtained by concentration of the mother liquors (0.62 g). Combined yield 5.45 g (85%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5](F)[C:6]([CH3:12])=[N:7]2.Cl.[CH3:15][C:16]1([NH2:19])[CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH:19][C:16]1([CH3:15])[CH2:18][CH2:17]1)[C:6]([CH3:12])=[N:7]2
Reactant: CC1(N)CC1
Reactant: Cc1nc2cccc(Br)c2nc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(Br)c2nc1NC1(C)CC1
Yield: 46 %

Procedure:
This compound (0.50 g, 45% yield) as a light yellow crystalline solid was prepared according to Example 174, using 5-bromo-3-fluoro-2-methylquinoxaline (126f; 0.96 g, 3.72 mmol), 1-methylcyclopropanamine hydrochloride (ChemBridge, San Diego, Calif.; 0.6 g, 5.58 mmol), and DIPEA (2.59 mL, 14.87 mmol) as starting materials: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.83 (dd, J=7.6, 1.2 Hz, 1H), 7.71 (dd, J=8.2, 1.2 Hz, 1H), 7.45-7.51 (m, 1H), 7.22 (t, J=7.8 Hz, 1H), 2.47 (s, 3H), 1.54 (s, 3H), 0.78-0.84 (m, 2H), 0.68-0.75 (m, 2H). m/z (ESI, +ve) 292/294 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([O:7][C:8]1[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].O.[NH2:21][NH2:22]>CCO>[F:1][C:2]([F:19])([O:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([NH:21][NH2:22])=[O:13])=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: NN
Reactant: CCOC(=O)c1ccc(OC(F)(F)C(F)(F)F)cc1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(OC(F)(F)C(F)(F)F)cc1
Temperature: 85 °C
Yield: 73 %

Procedure:
To a solution of ethyl 4-(perfluoroethoxy)benzoate (4.58 g, 16.1 mmol) in EtOH (16 mL) was added hydrazine monohydrate (1.96 mL, 40.3 mmol) and the reaction was heated at 85° C. for 36 hours. The reaction was cooled and poured into ice water (100 mL). A white gel-solid formed and was filtered through a Büchner funnel under vacuum. The solid was dried in a vacuum oven at 45° C. overnight to provide 4-(perfluoroethoxy)benzohydrazide as an off-white solid (3.177 g, 73%): mp 117-119.5° C.; 1H NMR (400 MHz, CDCl3) δ 7.83-7.76 (m, 2H), 7.36 (s, 1H), 7.31 (d, J=8.8 Hz, 2H), 4.13 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −86.01, −87.83; ESIMS m/z 269 [(M−H]−).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:29]=[CH:28][C:11]([CH2:12][NH:13][C:14]([C:16]3[CH:21]=[C:20]([NH2:22])[C:19]([C:23]#[N:24])=[C:18]([O:25][CH2:26][CH3:27])[N:17]=3)=[O:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=[O:32])C.OO.O>CN(C)C=O>[C:1]1([S:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:14]([C:16]3[CH:21]=[C:20]([NH2:22])[C:19]([C:23]#[N:24])=[C:18]([O:25][CH2:26][CH3:27])[N:17]=3)=[O:15])=[CH:28][CH:29]=2)=[O:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: CCOc1nc(C(=O)NCc2ccc(Sc3ccccc3)cc2)cc(N)c1C#N
Agent: OO
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nc(C(=O)NCc2ccc(S(=O)c3ccccc3)cc2)cc(N)c1C#N
Yield: 70 %

Procedure:
A mixture of Example 161B (61 mg, 0.15 mmol), 2 mL of acetic acid, 0.15 mL of hydrogen peroxide (30% solution in water) in 0.5 mL of N,N-dimethylformamide was stirred at room temperature for 2 h. Water was added, the resulting precipitate was then filtered. The solid was triturated with methanol to provide the titled compound as a beige solid (44 mg, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (t, J=7.1 Hz, 3H), 4.43-4.53 (m, 4H), 7.05 (s, 1H), 7.29 (bs, 2H), 7.43 (d, J=8.6 Hz, 2H), 7.46-7.55 (m, 3H), 7.63-7.72 (m, 4H), 9.08 (t, J=6.4 Hz, 1H). MS (ESI+) m/e=421 (M+H)+.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Br:9][C:10]1[N:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>CO>[Br:9][C:10]1[N:15]=[C:14]([I:1])[C:13]([OH:16])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(Br)nc1
Solvent: CO
Product: Oc1ccc(Br)nc1I
Reaction time: 3 h
Yield: 36.6 %

Procedure:
N-iodosuccinimide (6.47 g, 28.7 mmol) was added to a stirring solution of 6-bromopyridin-3-ol (5 g, 28.7 mmol) in MeOH (144 mL) at 45° C. It was allowed to stir for 3 hours. The mixture was concentrated and triturated with Et2O. The precipitate was discarded and the filtrate was concentrated and triturated with dichloromethane to give the expected product, 1 6-bromo-2-iodopyridin-3-ol (3150 mg, 10.50 mmol, 37% yield) by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.12 (1H, s), 7.42 (1H, d, J=8.28 Hz), 7.10 (1H, d, J=8.28 Hz). LC-MS retention time: 1.27 min; m/z (MH+): 300, 302. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:23])[N:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[CH:6](C(OCC)=O)[C:5]12[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Cl-].[Li+].O>CS(C)=O>[Br:1][C:2]1[C:3](=[O:23])[N:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[CH2:6][C:5]12[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)C1C(=O)c2c(C)cc(Br)c(=O)n2C12CCCCC2
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Br)c(=O)n2c1C(=O)CC21CCCCC1

Procedure:
To a solution of ethyl 6′-bromo-8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-indolizine]-2′-carboxylate (6, 1.0 mmol, 1.0 eq) in dimethylsulfoxide (15 mL) add lithium chloride (5.0 mmol, 5 eq) and heat the reaction at 140° C. for 16 h. After completion cool the reaction, add water and extract with dichloromethane. Remove the solvent under reduced pressure and purify the crude by silica gel column chromatography to get 6′-bromo-8′-methyl-2′H-spiro[cyclohexane-1,3′-indolizine]-1′,5′-dione (7).
Reaction SMILES: N#N.[CH3:3][N:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([Cl:16])[C:10]([C:17]([F:20])([F:19])[F:18])=[CH:9][C:8]=1[NH2:21])[CH3:5].[N+]([C:25]1C=C(C(F)(F)F)C=C([N+]([O-])=O)[C:30]=1NN)([O-])=O>[Pd].C(O)C>[N+:13]([C:12]1[C:7]2[N:6]([N:4]([CH3:3])[CH3:5])[C:25]([CH3:30])=[N:21][C:8]=2[CH:9]=[C:10]([C:17]([F:18])([F:20])[F:19])[C:11]=1[Cl:16])([O-:15])=[O:14]
Reactant: CN(C)Nc1c(N)cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Reactant: NNc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: Cc1nc2cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c2n1N(C)C

Procedure:
A solution of 5.2 g. of N2 -(dimethylamino)-4-chloro-3-nitro-5-trifluoromethyl-1,2-phenylenediamine (prepared by hydrogenation of the corresponding 3,5-dinitro-4-hydrazinobenzotrifluoride in the presence of palladium catalyst) and 7.5 g. of ethyl methylcarboximidate hydrochloride in 60 ml. of ethanol was refluxed for 26 hours. The resultant 7-nitrobenzimidazole was separated by fractionation on a silica gel column, m.p. 160° - 162°C.
Reaction SMILES: [F:1][C:2]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:3]=1[NH2:4].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[F:1][C:2]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:3]=1[NH:4][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)c(F)c1OC
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(OC)c(OC)c1F)C(=O)OCC
Temperature: 80 °C
Yield: 92.5 %

Procedure:
To a solution of 2-fluoro-3,4-dimethoxyaniline (39 g, 228 mmol) in Ethanol (200 mL) was added diethyl 2-(ethoxymethylene)malonate (45.7 mL, 228 mmol), and the resulting mixture was heated at 80° C. for 1 h. LCMS indicated completion of the reaction. The mixture was concentrated in vacuo to remove ethanol and then washed with hexane to afford diethyl 2-(((2-fluoro-3,4-dimethoxyphenyl)amino)methylene)malonate (72 g, 211 mmol, 93% yield) as a brown solid. LCMS (M+H)+: 342.1.