Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH:12]([C:18](=O)[CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH3:19][C:18]1[N:10]=[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:9][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(=S)Nc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1sc(Nc2ccccc2)nc1C
Yield: 91.5 %

Procedure:
To 70 ml of ethanol, 10.7 g (70 mmol) of phenylthiourea and 11.6 g (70 mmol) of ethyl 2-chloro-3-oxobutanate were dissolved, followed by heating under refluxing for 8 hours. The reaction liquid was concentrated and dissolved in ethyl acetate and the organic layer was washed with an aqueous solution of sodium carbonate, water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure. Solid obtained was washed with diisopropyl ether to obtain 16.8 g (yield: 91%) of ethyl 4-methyl-2-(N-phenylamino)thiazole-5-carboxylate. (2) To 50 ml of ethanol, 12.8 g (49 mmol) of ethyl-4-methyl-2-(N-phenylamino)thiazole-5-carboxylate was dissolved, followed by adding 24 g (150 mmol) of 25% sodium hydroxide aqueous solution, and stirring at 80° C. for 15 hours. The reaction liquid was poured into ice water, and acetic acid was added to make acidic. Crystal precipitated was filtered, washed with water and a mixed solvent of hexane/ethyl acetate and dried to obtain 5.50 g (yield: 48%) of 4-methyl-2-(N-phenylamino)thiazole-5-carboxylic acid.
Reaction SMILES: [Cl-].[C:2]1([C:8]2[C:20]3[C:19]4[CH2:18][CH2:17][NH2+:16][CH2:15][C:14]=4[CH:13]=[N:12][C:11]=3[NH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:30][CH:31]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:32](Cl)=[O:33].CN(C)C=O>ClCCl.O>[Cl:30][CH:31]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:32]([N:16]1[CH2:15][C:14]2[CH:13]=[N:12][C:11]3[NH:10][N:9]=[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:20]=3[C:19]=2[CH2:18][CH2:17]1)=[O:33]
Reactant: c1ccc(-c2n[nH]c3ncc4c(c23)CC[NH2+]C4)cc1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=C(C(Cl)c1ccccc1)N1CCc2c(cnc3[nH]nc(-c4ccccc4)c23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
To a suspension of 1-phenyl-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7-ium chloride (0.184 g, 0.57 mmol) in dichloromethane (15 mL) was added Hunig's Base (0.45 mL, 2.56 mmol). The mixture was vortexed to ensure dissolution of the reagents followed by the addition of 2-chloro-2-phenylacetyl chloride (0.103 mL, 0.64 mmol). Dimethylformamide (6 mL) and 2-chloro-2-phenylacetyl chloride (15 μL, 0.093 mmol)) was then added and the reaction stirred for another 30 minute at room temperature. On completion of the reaction, water (30 mL) were added and the aqueous layer extracted with EtOAc (50 mL). The organic layer was separated, washed with brine (2×10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product. The crude product was purified using flash column chromatography (SiO2, gradient from 60% EtOAc in hexane to 66% EtOAc in hexane) to give the pure desired product, 2-chloro-2-phenyl-1-(1-phenyl-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)ethanone as an off-white solid (0.120 g, 52%). 1H NMR (400 MHz, DMSO-d6) δ 13.72 (s, 1H), 8.40/8.25 (s, 1H, rotamers), 7.47 (m, 10H), 6.48 (s, 1H), 4.88 (m, 2H), 3.66 (m, 2H), 2.68 and 2.34 (m, 2H, rotamers); LCMS [M+H]: 403.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[C@H:22]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:21][CH2:20]2.[Li+].[OH-].O.Cl>C1COCC1.CCO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[C@H:22]([CH2:26][C:27]([OH:29])=[O:28])[CH2:21][CH2:20]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(C)cc4)oc3C)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2nc(CCOc3ccc4c(c3)CC[C@H]4CC(=O)O)c(C)o2)cc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
Ethyl 2-((1S)-5-[2-{5-methyl-2-(4-methylphenyl)(1,3-oxazol-4-yl)]ethoxy}indanyl)acetate (Example 136, 776.3 mg, 1.85 mmol) in THF (4.0 ml) was added to a mixture of aqueous LiOH (2 M, 3.7 ml, 7.4 mmol), water (2.0 ml), and EtOH (4.0 ml) at rt. The resulting mixture turned cloudy. This mixture was heated at 40° C. (oil-bath temperature). The reaction was completed after 1.5 hours. After cooling to rt, 1 N HCl solution was slowly added to the mixture until pH 4.0. The compound was extracted with EtOAc (3×20 ml). The combined EtOAc layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue gave 2-((1S)-5-{2-[5-methyl-2-(4-methylphenyl)(1,3-oxazol-4-yl)]ethoxy}indanyl)acetic acid (616.8 mg, 1.57 mmol, 85%) as a white solid. 1H NMR (CDCl3) δ 7.83 (d, 2H), 7.21 (d, 2H), 7.03 (d, 1H), 6.74 (d, 1H), 6.69 (dd, 1H), 4.19 (t, 2H), 3.45 (q, 1H), 2.93 (t, 2H), 2.78 (m, 2H), 2.51 (m, 2H), 2.30 (s, 3H), 2.25 (s, 3H), 1.53 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH3:13])([O-:3])=[O:2].[CH2:14]=[O:15]>C(O)(C)(C)C.CS(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13][CH2:14][OH:15])([O-:3])=[O:2]
Reactant: C=O
Reactant: Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1CCO
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
A solution of potassium tertiary-butylate (1.8 g, 8 mmol) in tert.-butanol (20 ml, synthesis quality, 99%) was added to 2,6-dinitrotoluene (18.2 g, 0.1 mol, dried for 3 d in high vacuum over silica gel) and paraformaldehyde (3 g, 0.1 mol) in DMSO (50 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å). After the addition of the potassium tertiary-butylate solution, a color change from yellow to deep violet occurred. The solution was stirred for 5 min at room temperature and for 10 min at 70° C. (oil bath temperature). It was then left to cool to room temperature, and the mixture was neutralized with conc. HCl, and diluted with H2O (300 ml) before NaCl was added until the mixture was saturated. The aqueous phase was extracted with EtOAc (3×500 ml). The combined organic phases were washed with a saturated NaCl solution (300 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product (24.3 g) was dissolved in a little EtAOc at boiling temperature, mixed with petroleum ether (henceforth referred to as PE) (100 ml) and crystallized inside a freezer. The precipitate was filtered by suction and purified by column chromatography (20.7 g crude product, 300 g SiO2, 18×6.5 cm, solvent: toluene/EtOAc 5:1, 4:1, 3:1). Mixed fractions were concentrated under reduced pressure and purified by renewed column chromatography (200 g SiO2, 20×5.3 cm, solvent: toluene/EtOAc 7:1). After concentrating the pooled pure product fractions in a rotating evaporator under reduced pressure, 2-(2,6-dinitrophenyl)ethanol (13.6 g, 64%) was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([O-:19])=[O:18].[Na+].Br[CH2:22][C:23]([O:25]CC1C=CC=CC=1)=[O:24]>CN(C=O)C>[C:23]([O:25][O:18][C:17](=[O:19])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])(=[O:24])[CH3:22]
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: O=C(CBr)OCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OOC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 50 °C
Reaction time: 3 h

Procedure:
50 g (0.166 moles) of sodium 2-[(2,6-dichlorophenyl)amino]phenylacetate were dissolved in 200 ml of N,N'-dimethylformamide under heating to 50° C., and 41.620 g (0.181 moles) of benzyl bromoacetate were added thereto. Under these conditions stirring was continued for 3 hours. Upon completion of the reaction, the solvent was removed at reduced pressure and the sodium salts were precipitated with addition of 400 ml of ether. The solution was then filtered and the ether phase was washed three times with 100 ml of water and dried on sodium sulphate. The resulting product was concentrated until an oil was obtained, which oil was washed twice with 100 ml of hexane and then crystallized with methanol, thus obtaining 45.28 (61%) of 2-[(2,6-dichlorophenyl)amino]phenylacetoxy acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:33]=[CH:32][C:31]([C:34]([O:36]C)=[O:35])=[CH:30][C:14]=3[C:15]=2[NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH2:21][CH2:20]2)=[O:18])=[O:10])=[N:6][CH:7]=1.[OH-].[Na+]>O1CCCC1CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:33]=[CH:32][C:31]([C:34]([OH:36])=[O:35])=[CH:30][C:14]=3[C:15]=2[NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH2:21][CH2:20]2)=[O:18])=[O:10])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](C(=O)N(C)C)CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Solvent: O
Product: CN(C)C(=O)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(C(=O)O)cc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 2-{[(5-chloropyridin-2-yl)amino]carbonyl}-3-[({trans-4-[(dimethylamino)carbonyl]cyclohexyl}carbonyl)-amino]benzofuran-5-carboxylate (1.35 g) obtained in Example 1 is suspended in tetrahydrofuran-methanol (4:1) (20 ml). After adding a solution of sodium hydroxide (205 mg) in water (5 ml), the mixture is warmed to room temperature and stirred for 18 hours. The reaction solution is concentrated under reduced pressure, thereto poured ice-water, and the mixture is acidified by addition of 10% hydrochloric acid. The precipitates are collected by filtration, washed with water, and dried to give the title compound (1.23 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Cl:10])=[CH:5][CH:4]=1.[OH:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].C(N(CC)CC)C>C(#N)C>[Cl:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:11][N:12]2[C:13](=[O:22])[C:14]3=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]3[C:16]2=[O:17])=[CH:4][CH:5]=1
Reactant: ClCc1ccc(CCl)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1OCc1ccc(CCl)cc1
Temperature: 0 °C
Yield: 59.2 %

Procedure:
A mixture of 1,4-bis(chloromethyl)benzene (25 g.), N-hydroxyphthalimide (23.4 g.) and triethylamine (14.5 g.) in acetonitrile (200 ml.) was heated under reflux for 1.5 hours. The reaction mixture was poured into ice-water (1 l.) and the precipitates were collected by filtration. The precipitates were washed with ethanol and dried to give N-(4-chloromethylbenzyloxy)phthalimide (25.5 g.).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]#[C:10][C:11]1[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[N:14]=[C:13]([C:22]([O:24]CC)=[O:23])[CH:12]=1.[OH-].[K+].[CH2:29]([OH:31])C>>[CH3:29][O:31][C:7]1[CH:8]=[CH:3][C:4]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([C:22]([OH:24])=[O:23])[N:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=2)=[CH:5][CH:6]=1
Reactant: CCO
Reactant: CCOC(=O)c1cc(C#Cc2ccccc2OC)cc(C(=O)OCC)n1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(C#Cc2cc(C(=O)O)nc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Methoxyphenyltrimethylsilylacetylene (8.2 g, 39 mmol) was dissolved in 100 mL of methanol with K2CO3 powder (0.5 g, 3.6 mmol). The mixture was stirred at room temperature for 4 hr. After the solvent was removed, 50 mL of water was introduced and the mixture was neutralized with dilute hydrochloric acid. The crude product, 4-methoxyphenylacetylene, was extracted with chloroform (2×50 ml) and purified by column chromatography (silica gel) using 3% chloroform/hexane (96%). 1HNMR (CDCl3), d 7.39 (d, 2H), 6.81 (d, 2H), 3.77 (s, 3H), 2.96 (s, 1H). Diethyl 4-bromo-2,6-pyridinedicarboxylate (2.0 g, 10 mmol) was dissolved in 70 mL of dry THF and 50 ml of anhydrous triethylamine with PdCl2 (75 mg), PPh3 (200 mg) and CuI (120 mg). The mixture was deaerated with argon for 5 min and 2.0 g of methoxyphenylacetylene (15 mmol) was introduced. The mixture was stirred under an atmosphere of argon at 55° for 6 hr. The solvent was removed, and the residue was treated with water and extracted with chloroform (2×75 ml). The crude product from the dried organic extract was purified by column chromatography (silica gel—10% ethyl acetate/hexane). The purified product was recrystallized from 50% chloroform/hexane to yield 1.8 g of white crystals (77%). 1HNMR (acetone-d6): 8.23 (s, 2H), 7.61 (d, 2H), 7.01 (d, 2H), 4.41 (t, 4H), 3.85 (s, 3H), 1.38 (q, 6H). Diethyl 4-(methoxyphenylethynyl)-2,6-pyridinedicarboxylate (1.8 g, 5.5 mmol) was dissolved in 100 ml of ethanol with 2.0 g of KOH. The mixture was stirred at room temperature for 4 hr. After solvent was removed in vacuo, 80 ml of water was added to the residue, and the solution filtered. The filtrate was acidified with dilute hydrochloric acid. The precipitate that resulted was filtered and dried in air, yielding 1.3 g of a white solid, 4-(4-methoxyphenylethynyl)-2,6-pyridinedicarboxylic acid: mp>300° C. 1HNMR (D2ONaOD), δ 8.16 (s, 2H), 7.58 (d, 2H), 7.00 (d, 2H), 3.77 (s, 3H).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH:8][C:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])C.C(O)(=O)C.Cl>C(O)C>[O:3]=[CH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10]
Reactant: CCOC(CCCNC(=O)C1CCCCC1)OCC
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: O=CCCCNC(=O)C1CCCCC1
Reaction time: 16 h

Procedure:
1.09 g (4 mmol) 20A, 5 mL acetic acid, 2.5 mL 1N aqueous hydrochloric acid and 20 mL ethanol are put together and stirred for 16 hours under argon atmosphere. Ethanol is evaporated. Then the resulting residue is dispersed in dichloromethane and extracted with saturated sodium bicarbonate solution. The organic phase is dried with sodium sulfate and the solvent evaporated in vacuum. The crude product is obtained in almost quantitative yield.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[C:17]([C:19]4[C:20]5[CH:27]=[CH:26][N:25](COCC[Si](C)(C)C)[C:21]=5[N:22]=[CH:23][N:24]=4)[CH:16]=[N:15]3)[CH2:11]2)[CH2:6][CH2:5]1.[F:39][C:40]1[C:45]([C:46](O)=[O:47])=[CH:44][C:43]([C:49]([F:52])([F:51])[F:50])=[N:42][CH:41]=1>>[F:39][C:40]1[C:45]([C:46]([N:4]2[CH2:9][CH2:8][CH:7]([N:10]3[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]4[CH:18]=[C:17]([C:19]5[C:20]6[CH:27]=[CH:26][NH:25][C:21]=6[N:22]=[CH:23][N:24]=5)[CH:16]=[N:15]4)[CH2:11]3)[CH2:6][CH2:5]2)=[O:47])=[CH:44][C:43]([C:49]([F:51])([F:50])[F:52])=[N:42][CH:41]=1
Reactant: O=C(O)c1cc(C(F)(F)F)ncc1F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Agent: Cl
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3cc(C(F)(F)F)ncc3F)CC2)C1

Procedure:
Reaction of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride with 5-fluoro-2-trifluoromethylisonicotinoic acid following the procedure described for Example 1, followed by HPLC purification (method B) provided the title compound. LC-MS: 554.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.08 (brs, 1H), 8.84 (s, 1H), 8.76 (s, 1H), 8.63 (s, 1H), 8.36 (s, 1H), 8.09 (d, J=4.80 Hz, 1H), 7.55 (d, J=3.60 Hz, 1H), 7.00 (d, J=3.60 Hz, 1H), 4.02 (m, 1H), 3.69 (m, 2H), 3.52 (m, 2H), 3.49 (s, 2H), 3.34 (m, 1H), 3.20 (m, 1H), 3.00 (m, 1H), 2.49 (m, 1H), 1.70 (m, 1H), 1.57 (m, 1H), 1.22 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:10])=[CH:5][C:6]=1[C:7](O)=[O:8].CN1CCOCC1.ClC(OCC(C)C)=O.C(N(CC)CC)C.[C:33]([O:37][C:38](=[O:50])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][C:42]=1[CH2:48][NH2:49])([CH3:36])([CH3:35])[CH3:34]>C1COCC1.CN(C=O)C>[C:33]([O:37][C:38](=[O:50])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][C:42]=1[CH2:48][NH:49][C:7]([C:6]1[CH:5]=[C:4]([Cl:10])[S:3][C:2]=1[Cl:1])=[O:8])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN
Reactant: O=C(O)c1cc(Cl)sc1Cl
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1CNC(=O)c1cc(Cl)sc1Cl
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 79.4 %

Procedure:
A solution of the 2,5-dichloro-thiophene-3-carboxylic acid (12.9 g, 65.5 mmol) and 4-methylmorpholine (7.17 mL, 65.2 mmol) in dry THF (400 mL) was cooled to −15° C. Isobutyl chloroformate (8.46 mL, 65.2 mmol) was added. The mixture was stirred 3 min and triethylamine (9.1 mL, 65 mmol) was added. A solution of 3-(2-aminomethyl-4-hydroxy-phenyl)-propionic acid tert-butyl ester (16.4 g, 65.3 mmol) in DMF (130 mL) pre-cooled to −15° C. was added via cannula over 15 min. After stirring 1 h, TLC indicated complete reaction. The reaction mixture was allowed to warm to ambient temperature. Solids were removed by filtration and washed with THF (100 mL). The filtrate was diluted with Et2O (500 mL) and washed with water (250 mL) then brine (150 mL). The organic layer was dried (Na2SO4) and concentrated. The crude brown oil was purified by silica gel chromatography (hexanes/EtOAc 2/1) and recrystallization (toluene) to afford the title compound as a white crystalline solid (22.3 g, 79.6%). MS (ES+) m/z 430.1 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH2:16][C:17]1[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=1>>[CH2:26]([O:25][C:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:13][CH:12]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C(C)c1ccc(O)cc1
Reactant: CCOC(=O)c1ccccc1CBr
Product: CCOC(=O)c1ccccc1COc1ccc(C(C)C(=O)OCC)cc1

Procedure:
Reaction of ethyl α-methyl-p-hydroxyphenylacetate with ethyl α-bromo-o-toluate by the method described in Example 1b provides ethyl 4-(2-ethoxycarbonylbenzyloxy)-α-methylphenylacetate as a clear oil.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:29][O:30][CH2:31][CH2:32]Br>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:32][CH2:31][O:30][CH3:29])=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCn1c(-c2ccc(O)cc2)c(C#N)c2ccc(OC)cc21
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2ccc(OCCOC)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
1-Ethyl-2-(4-hydroxy-phenyl)-6-methoxy-1H-indole-3-carbonitrile (40 mg, 0.14 mmol), prepared as in example 1Ga step B, is combined with K2CO3 (77 mg, 0.56 mmol), bromoethyl methyl ether (26 μL, 0.28 mmol), and DMF (450 μL). This is stirred at room temperature for 1 hour, and then at 75° C. for 3 hours. The reaction mixture is then partitioned between H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2, 0-5% EtOAc) yields 1-ethyl-6-methoxy-2-[4-(2-methoxyethoxy)-phenyl]-1H-indole-3-carbonitrile (44 mg, 90%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C>[N:19]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1-c1ccc(CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4'-bromomethylbiphenyl-2-carboxylate (5.0 g, 16.4 mmol) in DMF (40 ml) was added sodium azide (2.7 g, 41 mmol). The mixture was stirred overnight at room temperature, filtered, and the filtrate was partitioned between water and ethyl acetate (100 ml). The aqueous phase was extracted once more with ethyl acetate (100 ml) and the combined organic phase was washed with water (3×100 ml) and saturated aqueous sodium chloride (100 ml) before being dried (MgSO4), filtered and concentrated to an oily residue (3.9 g) which was used in the subsequent reaction without further purification: NMR (200 MHz; CDCl3,TMS)δ: 7.9-7.2 (m,8H), 4.37 (s,2H), and 3.60 (s,3H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][CH2:8][C:9](=[O:11])[N:10]=1.[N:16]1[C:25]2[C:20](=[N:21][C:22]([CH:26]=O)=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1.CN(C=O)C.O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:26][C:22]2[CH:23]=[CH:24][C:25]3[C:20](=[CH:19][CH:18]=[CH:17][N:16]=3)[N:21]=2)[C:9](=[O:11])[N:10]=1
Reactant: O=C1CSC(NCc2ccccc2Cl)=N1
Reactant: O=Cc1ccc2ncccc2n1
Agent: O=C(O)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C1N=C(NCc2ccccc2Cl)SC1=Cc1ccc2ncccc2n1
Temperature: 150 °C
Yield: 37.4 %

Procedure:
To a suspension of 2-(2-chloro-benzylamino)-thiazol-4-one (77.0 mg, 0.32 mmol), and 1,5-naphthyridine-6-carboxaldehyde (63.2 mg, 0.40 mmol) in toluene (1 mL) in a microwave tube were added benzoic acid (2.0 mg, 0.02 mmol) and piperidine (1.7 uM, 0.02 mmol). The reaction mixture was heated to 150° C. with microwave for 10 min. and then cooled to r.t. The solid was filtered off, washed with toluene to give a brown solid, which was dissolved in 1 mL hot DMF and diluted with water. The precipitates were collected and washed with water, acetone and ether, dried to give 2-(2-chloro-benzylamino)-5-[1,5] naphthyridin-2-ylmethylene-thiazol-4-one as a light brown solid (45.6 mg, 37.4%). HR-ES (+) m/e calcd. for C19H13ClN4OS: (M+H)+ 381.0572. Found: 381.0572.
Reaction SMILES: [C:1](Cl)(=O)C.[N+:5]([C:8]1[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([OH:13])=[O:12])[C:9]=1[C:17]([OH:19])=[O:18])([O-:7])=[O:6]>CO>[CH3:1][O:12][C:11](=[O:13])[C:10]1[C:9](=[C:8]([N+:5]([O-:7])=[O:6])[CH:16]=[CH:15][CH:14]=1)[C:17]([OH:19])=[O:18]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To MeOH (100 ml) at 0° C. was added acetyl chloride (14.5 mL, 203.4 mmol) and the solution stirred at rt for 1 h. 3-Nitrophthalic acid (25.7 g, 121.7 mmol) was added and the mixture heated at reflux for 22 h. The reaction was cooled to rt and partitioned between water (80 mL) and EtOAc (3×80 mL). The combined organic phase was dried (MgSO4) and solvent removed in vacuo to give the title compound: Data in agreement with previous reports (Roger, M. E.; Averill, B. A. J. Org. Chem. 1986, 51, 3308-3314).