Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:14]=1)=O.BrCC(C1C2OCCCC=2C=CC=1)=O.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>C(O)C>[O:13]1[C:8]2[CH:7]=[CH:6][C:5]([C:3]3[N:29]=[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]4[CH:2]=3)=[CH:14][C:9]=2[CH2:10][CH2:11][CH2:12]1
Reactant: O=C(CBr)c1ccc2c(c1)CCCO2
Reactant: Nc1ccccn1
Agent: O=C(CBr)c1cccc2c1OCCC2
Solvent: CCO
Product: c1ccn2cc(-c3ccc4c(c3)CCCO4)nc2c1
Temperature: 60 °C
Yield: 64 %

Procedure:
A solution of the 80/20 mixture of 2-bromo-1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethan-1-one (19a) and 2-bromo-1-(3,4-dihydro-2H-1-benzopyran-8-yl)ethan-1-one (450 mg, 1.76 mmol) and 2-aminopyridine (166 mg, 1.76 mmol) in ethanol (10 mL) was heated at 60° C. overnight. The mixture was concentrated in vacuo. A 1M solution of sodium hydroxide (10 mL) and ethyl acetate (10 mL) were added. The aqueous layer was extracted with ethyl acetate (10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 40/60) to provide the desired imidazo-pyridine (19b) (228 mg, 0.91 mmol, 64%) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][C:3]=1[NH2:4].I[C:19]1[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([C:19]2[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=2)[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: CC1(C)OB(c2ccc(N)c(Cl)c2)OC1(C)C
Reactant: Cn1ccc(I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1ccc(-c2ccc(N)c(Cl)c2)n1
Temperature: 135 °C
Yield: 73.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.046 g, 0.039 mmol) was added to a solution of 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.1 g, 0.394 mmol), 3-iodo-1-methyl-1H-pyrazole (0.123 g, 0.592 mmol) and sodium carbonate (0.125 g, 1.183 mmol) in DME/H2O 3/1 (2.00 mL). The reaction mixture was heated for 1 hour at 135° C. under microwave irradiation before being diluted with EtOAc and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude mixture was purified via Biotage silica gel column chromatography eluting with (Cyclohexane/EtOAc 80/20 to 60/40) to afford the title product as a yellow solid (60 mg, 73%). 1H NMR (500 MHz, CDCl3): δ 3.93 (s, 3H), 4.09 (br s, 2H), 6.42 (d, J=2.3 Hz, 1H), 6.79 (d, J=8.3 Hz, 1H), 7.34 (d, J=2.3 Hz, 1H), 7.50 (dd, J=8.3, 2.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H). LC (Method B)-MS (ESI, m/z) tR 2.35 min, 208 [(M+H+), 100%].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH:7]=[CH:6]2.C1C(=O)N([Br:21])C(=O)C1>C(#N)C>[Br:21][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9](=[O:13])[NH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(=O)[nH]ccc2c1
Solvent: CC#N
Product: COc1ccc2c(=O)[nH]cc(Br)c2c1
Reaction time: 2 h
Yield: 55.2 %

Procedure:
To a solution of 6-methoxyisoquinolin-1(2H)-one (2.5 g, 14.27 mmol) in acetonitrile (10 ml) was added NBS (2.54 g, 14.27 mmol) at room temperature under argon atmosphere. The reaction mass was stirred at the same temperature for 2 hr. The precipitated solid was filtered to get crude compound (2 g, 55.2%). The crude compound was taken to the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.41 (s, 1H), 8.17-8.15 (d, J=8 Hz, 1H), 7.53 (s, 1H), 7.19-7.11 (m, 2H), 3.93 (s, 3H); MS: MS m/z 256.06 (M++2).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11](F)[C:12]=3[C:14]([F:17])([F:16])[F:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[NH:24]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:25]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([N:24]4[CH2:28][CH2:27][CH:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[CH2:25]4)[C:12]=3[C:14]([F:15])([F:17])[F:16])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: c1ccc(C2CCNC2)nc1
Reactant: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(N3CCC(c4ccccn4)C3)c(F)cc2c1=O
Yield: 74 %

Procedure:
Starting from 1-cyclopropyl-6, 7-difluoro-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylic acid (1.33 g, 4.0 mmol) and 2-(3-pyrrolidinyl)-pyridine, a procedure analogous to that given in Example 1 provided the title compound (1.36 g, 74%) as a yellow solid, mp 210°-212° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:17]([Cl:23])=[N:18][C:19](Cl)=[CH:20][CH:21]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:16]1[C:17]([Cl:23])=[N:18][C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:21]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(Cl)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(-c2ccccc2)nc1Cl
Temperature: 85 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
2,6-dichloropyridin-3-amine (9.39 g, 57.6 mmol), di-tert-butyldicarbonate (503 g, 230 mmol), DMAP (0.704 g, 5.76 mmol) and triethylamine (16.06 mL, 115 mmol) were combined in DCM (230 mL) and stirred at RT overnight. The solvent was evaporated and the residue was triturated with acetonitrile and filtered to provide di-tert-butyl(2,6-dichloropyridin-3-yl)imidodicarbonate. Di-tert-butyl(2,6-dichloropyridin-3-yl)imidodicarbonate (27.7 g, 76 mmol), phenyl boronic acid (13.95, 114 mmol) and sodium carbonate (114 mL, 229 mmol, 2M) were combined with dioxane (692 ml) and DMF (46 ml). The solution was purged with N2 for 20 min. Tetrakis(triphenylphosphine)palladium(0) (4.41 g, 3.81 mmol) was added and reaction heated to 85° C. for 3 h, then cooled to RT and stirred overnight. Reaction was poured into H2O (100 ml) and extracted with EtOAc (2×100) ml. The combined organics were washed with brine and dried over Na2SO4. Crude product was purified by flash chromatography on ISCO 330 g column. (0-20% EtOAc/Heptane). Major spot (TLC 10:1 Heptane/EtOAc) isolated to give 12.06 g of di-tert-butyl(2-chloro-6-phenylpyridin-3-yl)imidodicarbonate as a white solid. 1H NMR (CDCl3) δ 8.01 (d, J=7.0 Hz, 2H), 7.69 (d, J=8.1 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.41-7.48 (m, 3H), 1.40 (s, 18H); MS: cal'd 405 (MH+), exp 405 (MH+).
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[N+:26]([O-:27])=[N:25][C:24]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[N:23][C:22]=2[CH:34]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C(Cl)(Cl)Cl.N>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[N+:26]([O-:27])=[N:25][C:24]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[N+:23]([O-:6])[C:22]=2[CH:34]=1
Reactant: COc1ccc2c(c1)nc(NCCN(C)C)n[n+]2[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)[n+]([O-])c(NCCN(C)C)n[n+]2[O-]
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 66 %

Procedure:
Hydrogen peroxide (70%; 1.1 mL, ca. 22.6 mmol) was added dropwise to a stirred solution of trifluoroacetic anhydride (3.2 mL, 22.6 mmol) in DCM (15 mL) at 5° C. The solution was stirred at 5° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 5° C. and added to a stirred solution of 1-oxide 8 (597 mg, 2.3 mmol) and trifluoroacetic acid (350 μL, 4.5 mmol) in CHCl3 (15 mL) at 5° C. The solution was stirred at 5° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 9 (424 mg, 67%) as a red solid which was dissolved in HCl saturated MeOH, the solvent evaporated and the residue crystallized to give the hydrochloride, mp (MeOH/EtOAc) 170-174° C.; 1H NMR [(CD3)2SO] δ 10.57 (brs, 1 H, NH+Cl−), 8.45 (brs, 1 H, NH), 8.17 (d, J=9.6 Hz, 1 H, H-8), 7.39 (d, J=2.6 Hz, 1 H, H-5), 7.22 (dd, J=9.6, 2.6 Hz, 1 H, H-7), 4.01 (s, 3 H, OCH3), 3.78-3.82 (m, 2 H, CH2N), 3.33-3.37 (m, 2 H, CH2N), 2.82 [d, J=4.5 Hz, 6 H, N(CH3)2]; 13C NMR [(CD3)2SO] δ 165.6, 150.1, 139.7, 125.7,123.4, 119.4, 92.5, 56.8, 54.9, 42.3 (2), 36.0. Anal. Calcd for C12H18ClN5O3.1½H2O: C, 42.1; H, 6.2; N, 20.4. Found: C, 42.0; H, 5.9; N, 20.0%.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13]NCC3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].BrCCC[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]\[C:39]([OH:41])=[O:40].[C:44](#[N:46])[CH3:45]>C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]\[C:39]([OH:41])=[O:40].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH2:9][CH2:14][CH2:13][CH:27]([N:46]3[CH2:38][CH2:37][CH2:36][CH2:45][CH2:44]3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC#N
Reactant: COc1ccccc1CCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccccc1C(CCCc1noc2cc(F)ccc12)N1CCCCC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.36 g, 10.7 mmole), K2CO3 (2 g, 14.5 mmol) and 2-(4-bromobutyl)anisole (2.4 g, 10 mmol) in acetonitrile (100 ml) was heated at reflux for 2.5 hours. At the end of reaction, the solvent was removed. The residue was extracted into dichloromethane (200 ml) and filtered. The dichloromethane solution was concentrated. The crude oil obtained was purified on a flash chromatography column. The material thus purified was a light yellow oil (2.73 g, 53%). This oil was dissolved in ethanol and treated with maleic acid (607 mg, 1.0 eq) in ethanol. The 4-(6-fluoro-1,2-benzisoxazol-3-yl)-l-(2'-methoxyphenyl) -butylpiperidine maleate crystals formed on concentration and subsequent cooling to 0° C. These were collected and dried to yield 2.05 g,
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](C=C[CH:30]=1)[CH:7]=[CH:8][C:9]([CH2:11][C:12]([O:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1)=[O:13])=O)([O-:3])=[O:2].[NH2:31]/[C:32](/[CH3:39])=[CH:33]\[C:34]([O:36][CH2:37][CH3:38])=[O:35].[CH2:40](O)[CH3:41]>>[CH3:40][C:41]1[NH:31][C:32]([CH3:39])=[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:9]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:30]=2)[C:11]=1[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=1)=[O:13]
Reactant: CCO
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CC(=O)Nc1ccc(OCCOC(=O)CC(=O)C=Cc2cccc([N+](=O)[O-])c2)cc1
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(NC(C)=O)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: -5 °C
Yield: 75 %

Procedure:
12.28 g (0.03 moles) of 2-(4-acetylaminophenoxy)ethyl 2-(3-nitrobenzylidene)acetylacetate and 3.85 (0.03 moles) of ethyl 3-aminocrotonate are heated under reflux in 30 ml of ethanol for 8 hours. The solution is then cooled to -5° C. to obtain 2-(4-acetylaminophenoxy)ethyl 2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate as yellow crystals melting--after recrystallisation in ethanol--at 198°-200° C. The yield is 75% of the theoretical yield.
Reaction SMILES: [Cl:1][CH2:2][C:3](O)=O.C(N(CC)CC)C.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1>C(#N)C>[Cl:1][C:2]1[N:13]=[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]2[CH:3]=1
Reactant: O=C(O)CCl
Reactant: Nc1ccc(Cl)cn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Clc1ccc2nc(Cl)cn2c1
Yield: 11.2 %

Procedure:
Chloroacetic acid (9.5 g) is dissolved in 70 ml of acetonitrile, to which 10.1 g of triethylamine is portionwise added and further 12.9 g of 2-amino-5-chloropyrdine is added. The mixture is refluxed for 3 hours. After cooling, the precipitated 2-imino-5-chloro-1,2-dihydropyridin-1-ylacetic acid as crystals is collected by filtration and dried. The crystals are added to 40 ml of phosphorus oxychoride and refluxed for 5 hours. After cooling, the reaction mixture is poured into ice water and neutralized with aqueous ammonia. The precipitate collected by filtration is purified by silica gel chromatography(eluent: ethyl acetate) to give 2.1 g of the title compound as crystals. mp. 155°-156° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[C:11]([CH2:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22](O)=[O:23])[CH:18]=[CH:19][CH:20]=1)([OH:13])=[O:12].ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.CN(C)CCCN=C=NCC>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:22]([CH2:21][C:17]1[CH:16]=[C:15]([CH2:14][C:11]([OH:13])=[O:12])[CH:20]=[CH:19][CH:18]=1)=[O:23]
Reactant: COc1ccccc1CN
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CNC(=O)Cc1cccc(CC(=O)O)c1
Yield: 31 %

Procedure:
Prepared from 2-methoxy-benzylamine (1.4 g), (3-carboxymethyl-phenyl)-acetic acid (2 g), 1-hydroxybenzotriazole (1.4 g), Hunigs base (1.8 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.0 g), using the method of Example 44 (step a), to give 990 mg of the sub-titled compound as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]([NH2:11])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[N:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH3:1][CH:2]([NH:11][C:25]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:26])[CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[OH:10]
Reactant: O=C(Cl)N1CCOCC1
Reactant: C[C@@H](N)[C@@H](O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)N1CCOCC1)C(O)c1ccccc1
Reaction time: 16 h

Procedure:
A solution of 15.2 grams of norephedrine in 200 ml. of CH2Cl2 was cooled to 0-5° C. To this 11.0 grams of triethylamine was added with stirring. To the stirred mixture a solution of 14.9 grams of morpholine carbonyl chloride in 10 ml. of CH2Cl2 was added dropwise. The mixture was then stirred for 2 hours and left to stand at room temperature for 16 hours. The mixture was washed with water and the organic layer was dried over anhydrous sodium sulfate. The organic layer was then filtered and evaporated to a small volume. The hydroxyethylurea, N-(1-methyl-2-phenyl-2-hydroxyethyl)-4-morpholinecarboxamide was filtered off as a white solid and recrystallized from CH2Cl2.
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:15][CH:16]=1)=O)(C)(C)C>O1CCOCC1.ClCCl>[NH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:23])[CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[N:15][CH:16]=1
Reactant: CC(C)(C)CC(=O)c1ccc(CNC(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)CC(=O)c1ccc(CN)cn1
Reaction time: 8 h
Yield: 88.7 %

Procedure:
Add 4N hydrogen chloride in dioxane (1 mL) to a solution of 5-tert-butoxycarbonylaminomethyl-2-(3,3-dimethyl-butyryl)-pyridine (104 mg, 0.339 mmol) in anhydrous dichloromethane (4 mL) and stir the solution overnight. Concentrate in vacuo and partition the residue between saturated aqueous NaHCO3 and dichloromethane. Extract the aqueous phase with dichloromethane (2×15 mL) and EtOAc (2×15 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the title compound as an oil (62 mg, 88%) that was used without any further purification. MS (ES+) m/z: 207 (M+H)+.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[Br:20]Br.N([O-])=O.[Na+]>Br>[Br:20][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: BrBr
Reactant: Nc1nc(-c2ccccc2)cc(-c2ccccc2)n1
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Product: Brc1nc(-c2ccccc2)cc(-c2ccccc2)n1
Temperature: -20 °C
Yield: 80.3 %

Procedure:
48% HBr 50 mL was added to 11 g (44 mmol) of 2-amino-4,6-diphenylpyrimidine and stirred. The solution was cooled down to −20° C., and 8.5 g (53 mmol) of bromine was dropwise added thereto. Further, 3.1 g (44 mmol) of sodium nitrite was dropwise added thereto. The solution was stirred for 3 hours while elevating the temperature up to room temperature. After finishing the reaction, the solution was extracted with ethyl acetate, and the aqueous layer was removed. The organic layer was dried on anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was refined by silica gel chromatography to obtain 11 g (yield: 82%) of 2-bromo-4,6-diphenylpyrimidine.
Reaction SMILES: BrBr.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:19])[CH2:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:6][CH:5]=1.[C:20]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CCN(C(C)C)C(C)C>C(OCC)C.O1CCOCC1>[N:27]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:34][CH2:33][CH2:32][CH:28]1[C:29]([O:31][CH:11]([CH2:12][CH:13]1[O:14][CH2:15][CH2:16][CH2:17][O:18]1)[C:10]([C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=1)=[O:19])=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(CCC1OCCCO1)c1ccc(Br)cc1
Agent: BrBr
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)OC(CC1OCCCO1)C(=O)c1ccc(Br)cc1
Temperature: 24 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
Bromine (1.3 mL, 25.2 mmol) was added to a solution of Example J2, 1-(4-bromophenyl)-3-(1,3-dioxan-2-yl)propan-1-one (7.7 g, 25.7 mmol) in diethyl ether (60 mL) and 1,4-dioxane (40 mL) and the solution stirred 30 min at 24° C. (Until TLC indicated reaction complete). The solvent was removed by rotory evaporation and the residue was taken up in acetonitrile (350 mL). (S)—N-Boc-Proline (5.54 g, 25.7 mmol) was added followed by dropwise addition of Hunig's base (8.5 mL, 51.5 mmol) and the reaction was stirred 6 hours before being concentrated. The crude product was taken up in CH2Cl2 and charged to a 40 (M) Biotage silica gel cartridge. Gradient elution 15-100% B over 1 L (A=hexanes; B=ethyl acetate) gave Example J3, 2-(1-(4-bromophenyl)-3-(1,3-dioxan-2-yl)-1-oxopropan-2-yl) 1-tert-butyl pyrrolidine-1,2-dicarboxylate 13 g (100%).). RT=2.2 minutes (condition 1); LCMS: Anal. C23H30BrNO7 Calcd. 534. found: 534 (M+Na)+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1.CN(C([O:33][N:34]1[N:42]=[N:41][C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[S:22]([C:18]1[CH:17]=[C:16]([NH:15][C:12]([C:11]2[C:2]([O:33][N:34]3[C:35]4=[N:40][CH:39]=[CH:38][CH:37]=[C:36]4[N:41]=[N:42]3)=[N:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:14])[CH:21]=[CH:20][CH:19]=1)(=[O:23])(=[O:24])[NH2:25]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cc2ccccc2nc1Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: NS(=O)(=O)c1cccc(NC(=O)c2cc3ccccc3nc2On2nnc3cccnc32)c1
Temperature: 60 °C

Procedure:
2-Chloroquinoline-3-carboxylic acid (250 mg, 1.20 mmol), 3-aminobenzenesulfonamide (207.3 mg, 1.20 mmol) and HATU (457.8 mg, 1.20 mmol) were combined in DMF (2.5 mL) and treated with 4-methylmorpholine (397.1 μL, 3.61 mmol). The reaction was heated at 60° C. for 12 hours. The reaction was cooled to 25° C. The precipitate was filtered to yield N-(3-sulfamoylphenyl)-2-(triazolo[4,5-b]pyridin-3-yloxy)quinoline-3-carboxamide as a solid. ESI-MS m/z calc. 461.09, found 461.3 (M+1)+; Retention time: 1.35 minutes (3 minutes run).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]1(=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19].Br[CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O>[C:27]1([CH2:26][O:25][C:23](=[O:24])[CH2:22][C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=2[OH:20])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C1CCCCC1=O
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=C(CC1=C(O)C(=O)CCC1)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A 1.6M solution of n-butyl lithium (81 mL, 130 mmol) was added to a stirred solution of diisopropylamine (18.26 mL) in methyl-THF (150 mL) at −10° C. The resulting solution was stirred at −10° C. for 15 mins. 1,2-cyclohexanedione (6.84 g) was added to the reaction mixture as a solution in methyl-THF (30 mL). During the addition the internal temperature of the reaction was maintained between −15° C. and −5° C. by modulation of delivery rate. The resulting dark orange/brown solution was stirred at −10 to −20° C. for a further 15 mins. The reaction mixture was then cooled to −50° C. and benzyl bromoacetate (12.62 mL, 79 mmol) was added dropwise via syringe. The mixture was stirred at this temperature for 10 minutes then aged at −78° C. for 1½ hours. The reaction mixture was quenched at −78° C. by dropwise addition of 1M HCl (300 ml). Ethyl acetate (200 mL) was added and the mixture allowed to warm to room temperature. The layers were separated and the organic phase washed with saturated brine (150 mL) and dried over sodium sulfate then reduced in vacuo. The resulting solid was purified by column chromatography, eluting with 0-25% ethyl acetate in cyclohexane. The appropriate fractions were reduced in vacuo to provide the product as a 1:1 mixture of thermodynamic enol:kinetic enol (registered as thermodynamic enol)