Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(OCC)=O.CCN(CC)CC.[CH2:14]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]2[CH2:26][C@H:25]2[C:27]([OH:29])=O)=[CH:20][CH:19]=1)[CH:15]=[CH2:16].[N-:30]=[N+:31]=[N-:32].[Na+]>CC(C)=O.O>[CH2:14]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]2[CH2:26][C@H:25]2[C:27]([N:30]=[N+:31]=[N-:32])=[O:29])=[CH:20][CH:19]=1)[CH:15]=[CH2:16]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CCOc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc([C@@H]2C[C@H]2C(=O)N=[N+]=[N-])cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
Ethyl chloroformate (2.72 mL, 28.52 mmol) was added to a solution of Et3N (4.24 mL, 30.42 mmol) and (trans)-2-[4-(allyloxy)phenyl]cyclopropanecarboxylic acid (Intermediate G, 4.15 g, 19.01 mmol) in dry acetone (50 mL) cooled at −10° C., forming a white solid. After 1 h, a solution of NaN3 (2.23 g, 34.23 mmol) in water (10 mL) was added to the reaction and stirred for additional 30 min. The solvent was removed by rotatory evaporation and the residue was dissolved in CH2Cl2 (20 mL); the organic layer was consecutively washed with a mixture of water (200 mL) and HCl (10% aqueous solution, 10 mL) and a mixture of water (200 mL) and NaOH (10% aqueous solution, 10 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (10% EtOAc/Hexanes), affording 4.10 g of (trans)-2-[4-(allyloxy)phenyl]cyclopropanecarbonyl azide [Rf=0.75 (20% EtOAc/Hexanes), white solid, 89% yield].
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH2:11])([CH3:3])[CH3:2].[Br:12]Br>C(O)(=O)C>[Br:12][C:8]1[CH:7]=[C:6]([CH3:10])[C:5]([NH2:11])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1
Reactant: Cc1cccc(C(C)C)c1N
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc(Br)cc(C(C)C)c1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-isopropyl-6-methyl-phenylamine (1 ml, 6.4 mmol) in 6.5 mL acetic acid, was added bromine (0.33 ml, 6.4 mmol) dropwise over 10 minutes at room temperature. The mixture was stirred at room temperature under argon for 20 minutes. A precipitate was formed and collected by filtration and washed with ether to give pure 4-bromo-2-isopropyl-6-methyl-phenyl amine.
Reaction SMILES: O1CCCC1.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)[CH:11]=[CH:12][CH:13]=1.[H-].[Na+].[CH3:23][Si:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][O:27][CH2:28]Cl>O>[F:20][C:7]([F:6])([F:19])[C:8]1[CH:9]=[C:10]([C:14]2[N:15]=[CH:16][N:17]([CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:31])([CH3:30])[CH3:23])[CH:18]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1cccc(-c2c[nH]cn2)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(-c2cccc(C(F)(F)F)c2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69.8 %

Procedure:
To a 250 mL round bottom flask (fitted with rubber septum and nitrogen blanket and stir bar) add Tetrahydrofuran (30 mL; 368.66 mmoles; 30.00 mL; 26.58 g), 4-(3-Trifluoromethyl-phenyl)-1H-imidazole (1.047 g; 1.00 equiv; 4.93 mmoles; 1.05 g) and cool the mixture to 0° C. with stirring on and hold for 5 min. Add sodium hydride (0.138 g; 1.11 equiv; 5.46 mmoles; 138.00 mg) to the flask and stir the reaction for 20 min. Add 2-(trimethylsilyl)ethoxymethyl chloride (1.15 mL; 1.31 equiv; 6.49 mmoles; 1.15 mL; 1.08 g) and allow the reaction to warm to room temperature. Dilute the reaction with water and extract the mixture two times with ethyl acetate and discard the aqueous phase. Dry the material over Na2SO4, filter, and concentrate to dryness. Purify the crude mixture by flash chromatography on silica gel eluting with ethyl acetate/hexane from 10-60% EtOAc. Combine the appropriate fractions and concentrated to give 4-(3-Trifluoromethyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (1.178 g; 0.70 equiv; 3.44 mmoles; 1.18 g; 69.71% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.C(OC([NH:25][C@@H:26]([CH3:30])[C:27](O)=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.CN(C)CCCN=C=NCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:27]([C@@H:26]([NH2:25])[CH3:30])[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)[C:4]=2[CH:3]=1
Reactant: COc1cccc(Nc2cc(F)ccc2N)c1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: COc1cccc(-n2c([C@H](C)N)nc3ccc(F)cc32)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Fluoro-N2-(3-methoxyphenyl)benzene-1,2-diamine (0.7 g, 2.99 mmol) was dissolved in DCM (10 mL), under an atmosphere of nitrogen and (S)-2-tert-butoxycarbonylaminopropionic acid (0.63 g, 3.29 mmol) and HOAt (0.45 g, 3.29 mmol) added. The mixture was cooled to 0° C. before N-(3-dimethylaminopropyl)-N′ ethylcarbodiimide (0.63 g, 3.29 mmol) was added portion wise. The reaction mixture was stirred at 0° C. for 1 h, before being allowed to reach RT. It was then diluted with DCM (40 mL) and washed with 10% citric acid and brine (20 mL). The organic fraction was dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in acetic acid (10 mL) and heated at 70° C. overnight. The resultant mixture was allowed to cool to RT and concentrated in vacuo to afford a dark brown gum. This was purified by column chromatography (SiO2, gradient 0-5% MeOH in DCM) to afford boc protected title compound as a red gum, which solidified on standing (0.78 g, 68%). This was dissolved in DCM (10 mL) and TFA (3 mL) added. The reaction mixture was stirred at RT for 1 h. The resultant mixture was concentrated in vacuo and the residue dissolved in DCM (40 mL) and stirred vigorously with saturated aqueous NaHCO3 for 10 minutes. The layers were separated and the organic fraction washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a red gum (0.4 g, 70%). LCMS (Method B): RT 1.90 min [M+H]+ 286.0
Reaction SMILES: [C:1]([NH:5][CH:6]([OH:11])[C:7]([O:9][CH3:10])=[O:8])(=[O:4])[CH:2]=[CH2:3].CO.[CH3:14]OC.C1(C=CC(O)=CC=1)O.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>>[CH3:14][O:11][CH:6]([NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=CC(=O)NC(O)C(=O)OC
Reactant: COC
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: Oc1ccc(O)cc1
Solvent: CO
Product: C=CC(=O)NC(OC)C(=O)OC
Yield: 85 %

Procedure:
Methyl acrylamidoglycolate, as prepared in Example I, in the amount of 100 parts (0.63 mole) is combined with 200 parts of methanol (6.3 moles), 0.10 parts of the methyl ether of hydroquinone and 0.005 part of ethylene-diamine tetraacetic acid and 5.0 parts of a 40% aqueous solution of paratoluenesulfonic acid is added as catalyst. The reaction mixture is heated for 4 hours at reflux temperature and then cooled and filtered. Vacuum stripping of the methanol results in crystallization of the product. An 85% yield of methyl acrylamidoglycolate methyl ether is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:8]=[N:7][C:6]([C:9]([O-:11])=[O:10])=[N:5]1.[CH3:12][Si:13]([CH2:16][CH2:17][O:18]CCl)([CH3:15])[CH3:14].[CH3:21]N(C=O)C>>[CH3:21][O:10][C:9]([C:6]1[N:7]=[CH:8][N:4]([CH2:3][O:18][CH2:17][CH2:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[N:5]=1)=[O:11]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cn1cnc(C(=O)[O-])n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ncn(COCC[Si](C)(C)C)n1
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a suspension of NaH (60% dispersion) (200 mg, 5.00 mmol) in DMF (5 mL) at 0° C., a solution of methyl-1H-1,2,4-triazolecarboxylate (635 mg, 5.00 mmol) in DMF (5 mL) was added dropwise. The resulting suspension was stirred at the same temperature for 30 min and treated with SEMCl (0.90 mL, 5.0 mmol). The resulting solution was stirred at RT for 30 min and poured onto ice. The product was extracted with ether (3×20 mL). The ether layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue obtained was chromatographed on silica (10% EtOAc/hexane) to obtain the title compound (530 mg, 41%). Mass spectrum (ESI, m/z): Calcd. for C10H19N3O3Si, 258.1 (M+H), found 258.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][Cl:11])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:18]([NH2:20])=[S:19]>C(O)C>[ClH:11].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:18]2[S:19][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=3)[N:20]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Reactant: COc1ccc(C(N)=S)cc1OC
Solvent: CCO
Product: COc1ccc(-c2nc(-c3ccc(O)c(O)c3)cs2)cc1OC
Product: Cl
Yield: 22.2 %

Procedure:
In 20 ml of ethanol were suspended 367 mg of 3',4'-dihydroxy-2-chloroacetophenone and 430 mg of 3,4-dimethoxythiobenzamide. The suspension was refluxed for 3 hours with heating. After cooling, the resulting crystals were collected by filtration, ethanol-washed and dried. The dried material was recrystallized from ethanol to obtain 160 mg of 2-(3,4-dimethoxyphenyl)-4-(3,4-dihydroxyphenyl)thiazole hydrochloride as yellow acicular crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[N:10]2[C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([C:37]2[CH:38]=[C:39]([NH:43][C:44](=[O:48])[CH:45]([CH3:47])[CH3:46])[CH:40]=[CH:41][CH:42]=2)[CH2:33][CH2:32]1>>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[N:10]2[C:15]([NH:27][CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:44](=[O:48])[CH:45]([CH3:46])[CH3:47])[CH:38]=3)[CH2:33][CH2:32]2)=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1OC[C@H](c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)N3C(=O)OC[C@@H]3c3ccc(F)c(F)c3)CC2)c1

Procedure:
Prepared by Procedure AF and Scheme H using 4-nitrophenyl(4S)-4-(3,4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-carboxylate and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 529.1 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[N:5]1.Br[C:19]1[CH:20]=[C:21]([CH:30]=[CH:31][CH:32]=1)[CH2:22][CH2:23][O:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28]>O.CC1CCCO1>[CH3:3][N:4]1[CH:8]=[C:7]([C:19]2[CH:20]=[C:21]([CH:30]=[CH:31][CH:32]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:6]=[N:5]1
Reactant: O=C(O)CCOCCc1cccc(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: O
Product: Cn1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Temperature: 20 °C
Yield: 5.9 %

Procedure:
2-Methyltetrahydrofuran (142.1 mL) was added to Pd-118 (4.52 g) to give a red solution. To this solution was added a solution of sodium hydroxide (41.6 g) in water (473.5 mL), followed by a solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (81.81 g) in 2-methyltetrahydrofuran (142.1 mL), followed by the solution of 3-(3-bromophenethoxy)propanoic acid (94.7 g, prepared as in Preparation 3, Step (ii)) in 2-methyltetrahydrofuran (585 mL solution volume). The mixture was then heated to reflux and at reflux for 30 min then allowed to cool to 20° C. The mixture was filtered through GF/F filter paper then the layers separated. 20% w/w Citric acid (568.2 mL) was added to the separated aqueous layer, followed by 2-methyltetrahydrofuran (568.2 mL). After mixing, the layers were separated, the organic layer diluted with 2-methyltetrahydrofuran (to make the solution up to 950 mL) and filtered to give a small sample of the subtitled compound as an off-white solid (5.63 g). 800 mL of the filtrate (total volume 930 mL) was passed through a cartridge filter containing charcoal. The solution was partially evaporated under vacuum to give a solution measuring 490 mL and split into 2 portions. Firstly half of the solution was cooled to 20° C. and added to dibutyl ether (400 mL) at 20° C. to give a precipitate which was stirred at 20° C. for 2 h. The suspension was filtered, washed with dibutyl ether (100 mL) and dried at 50° C. under vacuum to afford the sub-titled compound (34.1 g). The second half of the solution was added to dibutyl ether (400 mL) at 65° C. to give a precipitate which was maintained at 65° C. for 10 min then cooled to 15° C. and stirred for 1 h. The suspension was filtered, washed with dibutyl ether (100 mL) and dried at 50° C. under vacuum to afford the subtitled compound as a white solid (30.5 g). MS [M+H]+=275.2 (MultiMode+) 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.09 (s, 1H), 7.83 (s, 1H), 7.43 (s 1H), 7.37 (d, 1H), 7.24 (t, 1H), 7.05 (d, 1H), 3.86 (s, 3H), 3.62 (t, 2H), 3.61 (t, 2H), 2.80 (t, 2H), 2.45 (t, 2H).
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:16]([O:20][C:21]([NH:23][C@:24]([C:33]1[O:37][C:36]([C:38]2[CH:39]=[C:40]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])[CH:41]=[C:42]([CH2:44]Br)[CH:43]=2)=[N:35][N:34]=1)([CH3:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.O>[C:16]([O:20][C:21]([NH:23][C@:24]([C:33]1[O:37][C:36]([C:38]2[CH:39]=[C:40]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])[CH:41]=[C:42]([CH2:44][O:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH:43]=2)=[N:35][N:34]=1)([CH3:32])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: OC1CCC1
Reactant: CN(c1cc(CBr)cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cc(COC2CCC2)cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O
Reaction time: 0.08 h

Procedure:
To a solution of cyclobutanol (0.009 mL, 0.115 mmol) in 0.26 mL DMF, cooled to 0° C., was added sodium bis(trimethylsilyl)amide dropwise. After stirring for 5 min, a solution of 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(bromomethyl)-N-methyl-N-(methylsulfonyl)benzenamine (13.5 mg, 0.023 mmol) in 0.25 mL DMF was added and the reaction was stirred at 0° C. for 1 h. The reaction mixture was diluted with water, extracted with EtOAc and washed with brine. Drying, solvent evaporation and flash chromatography (15-55% EtOAc/hexanes) gave 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(cyclobutoxymethyl)-N-methyl-N-(methylsulfonyl)benzenamine. 1H NMR (CDCl3) δ 7.90 (d, J=9.0 Hz, 2H), 7.58 (s, 1H), 7.27 (m, 3H), 7.06 (m, 2H), 5.09 (bs, 1H), 4.47 (s, 2H), 4.05 (m, 1H), 3.57 (d, J=13.6 Hz, 1H), 3.43 (m, 1H), 3.38 (s, 3H), 2.90 (s, 3H), 2.24 (m, 2H), 2.02 (m, 2H), 1.73 (s, 3H), 1.56 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([OH:20])=[O:19])[C:8]2=[O:25].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C.[N-]=C=O>CC(N(C)C)=O.C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[N:9]1[C:8](=[O:25])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:3][CH2:2][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:6]=2)[N:11]=[CH:10]1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCCl)cc2c1=O
Reactant: C1CCNC1
Agent: [N-]=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCN3CCCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-[6-(2-chloroethoxy)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (0.50 g), pyrrolidine (0.46 ml), N,N-diisopropylethylamine (0.98 ml) and KI (0.47 g) in DMA (2 ml) was heated to 120° C. for 30 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The reaction mixture was diluted with methylene chloride (20 ml), CombiZorb isocyanate resin (loading 1.03 mmol/g from Agilent) (6 g) added and stirred at room temperature for 16 hours. The resin was removed by filtration and the filtrate washed with water (50 ml). The aqueous phase was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 4-methyl-3-[4-oxo-6-(2-pyrrolidin-1-ylethoxy)quinazolin-3(4H)-yl]benzoic acid (0.195 g); NMR Spectrum: (DMSOd6) 1.70 (m, 4H), 2.13 (s, 3H), 2.64 (m, 4H), 2.92 (m, 2H), 4.24 (m, 2H), 7.53 (m, 3H), 7.69 (d, 1H), 7.89 (s, 1H), 7.96 (d, 1H), 8.15 (s, 1H); Mass Spectrum: M+H+ 394.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:16]=1.[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:6]=2[CH:16]=1
Reactant: Clc1ccc2oc(-c3ccccc3)cc2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)c2c(-c3ccccc3)oc3ccc(Cl)cc23)cc1

Procedure:
5-Chloro-2-phenylbenzofuran is acylated with p-anisoyl chloride according to the procedure described in Example 5 to give 5-chloro-3-(4-methoxybenzoyl)-2-phenylbenzofuran.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17](COCC[Si](C)(C)C)[C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1)[CH3:2].C1(OC)C=CC=CC=1.O1CCOCC1>Cl>[CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][NH:17][C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cncc(-c2cc3c(cn2)cnn3COCC[Si](C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: COc1ccccc1
Product: CCc1cncc(-c2cc3[nH]ncc3cn2)c1
Yield: 174.1 %

Procedure:
A solution of 2-[[6-(5-ethyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (0.2456 mmol; 106.8 mg) and anisole (1.228 mmol; 133 mg; 0.134 ml) in hydrogen chloride, 4.0 M in 1,4-dioxane (20 mmol; 5 ml) was stirred at room temperature overnight. The mixture was concentrated to afford 6-(5-ethyl-3-pyridyl)-1H-pyrazolo[4,3-c]pyridine (˜95.9 mg), which was used without purification.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:14][C:9]1[CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH2:6])=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cc(Br)cc(C(C)C)c1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
A three neck round bottom flask was charged with 2,6-diisopropylaniline (22.96 g, 130 mmol) and DMF (Volume: 250 ml). A solution of 1-bromopyrrolidine-2,5-dione (23.05 g, 130 mmol) in 100 ml DMF was added into reaction mixture drop wise at 0° C. After addition was over; reaction mixture was stirred for 2 days at room temperature. The reaction mixture was poured into 500 ml deionized water and extracted with 3×150 ml ether. The combined extracts were washed with 150 ml deionized water, 150 ml 10% lithium chloride, dried over MgSO4 and evaporated to dryness. The residue was purified by vacuum distillation to yield 4-bromo-2,6-diisopropylaniline (32.3 g; 97%).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:14]2[NH:13][C:12](=[O:15])[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C)C=O.O>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][N:13]1[C:14]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[CH:9][C:10]=2[N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:12]1=[O:15])[CH3:35]
Reactant: CCOC(=O)CBr
Reactant: CCC(CC)c1cccc2c1[nH]c(=O)n2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(C(=O)OC(C)(C)C)c2cccc(C(CC)CC)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
To a solution of tert-butyl 4-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (Reference Example 7; 4.94 g, 16.2 mmol) in N,N-dimethylformamide (40 mL) were added potassium carbonate (2.47 g, 17.9 mmol) and ethyl bromoacetate (1.98 mL, 17.9 mmol), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 5-20% ethyl acetate/n-hexane gradient mixture to give the title compound (6.17 g, 15.8 mmol, 98%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([C@@H:22]([CH3:32])[CH2:23][NH:24]C(=O)OC(C)(C)C)=[CH:18][CH:17]=2)=[C:4]([O:33][CH3:34])[CH:3]=1.C(O)(C(F)(F)F)=O>>[ClH:1].[NH2:24][CH2:23][C@@H:22]([C:19]1[CH:18]=[CH:17][C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([Cl:1])=[CH:3][C:4]=2[O:33][CH3:34])=[CH:21][CH:20]=1)[CH3:32]
Reactant: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CN)cc1
Product: Cl
Yield: 107.2 %

Procedure:
Following General Procedure C, (R)-tert-butyl 2-(4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (60 mg, 0.12 mmol) was reacted with TFA (4 mL) to afford the desired product (28 mg, 52%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 7.61 (d, J=5.4 Hz, 1H), 7.54-7.50 (m, 2H), 7.48 (dd, J=7.8, 1.7 Hz, 1H), 7.32-7.25 (m, 2H), 5.97 (d, J=5.4 Hz, 1H), 3.76 (s, 1H), 3.29-3.17 (m, 3H), 1.48 (d, J=6.5 Hz, 2H); ESI MS m/z 399 [C21H19ClN2O2S+H]+; HPLC >99% (AUC), tR=9.65 min.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[AlH4-].[Li+]>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Cl
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccnc1Cl
Temperature: 25 °C

Procedure:
To a stirred solution of 2-chloronicotinic acid (8.00 g, 51.0 mmol) in THF (120 mL) at 0° C. under nitrogen was slowly added lithium tetrahydroaluminate (51 mL, 51 mmol) over five minutes. The reaction was allowed to warm to RT over 2 h and was monitored by TLC. The reaction was quenched by addition of small amounts of ice followed by water. Extracted product into EtOAc, washed 2×H2O, 1×NaCl, dried with Mg2SO4, filtered through fritted funnel, and concentrated the solution to yield (2-chloropyridin-3-yl)methanol as an orange oil. Used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>ClCCl.C1CCN2C(=NCCC2)CC1>[OH:13][N:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=Nc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(c1ccc([N+](=O)[O-])cc1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 96.8 %

Procedure:
Scale up: DBU (3.8 mg, 0.025 mmol) was added under argon to a solution of 4-nitrobenzaldehyde (3 g, 20 mmol), nitrosobenzene (2.14 g, 20 mmol) and catalyst (9 mg, 0.025 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at room temperature for 2 min. The product precipitated as a yellow solid. The solvent was removed under vacuum, and the solid was washed with hexane and ether to yield a pure product (5 g).