Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][C:4]=1[CH3:13].[Br:14]Br>C(O)(=O)C.[Cl-].[Na+].O>[Br:14][C:8]1[CH:7]=[C:6]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:4]([CH3:13])[C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc(CC(=O)O)cc1C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(C)cc(CC(=O)O)cc1Br

Procedure:
To a solution of 4-methoxy-3-methylphenylacetic acid (0.43 g) in glacial acetic acid (7 mL) was added 0.2 mL of neat bromine carefully while stirring. The mixture was stirred in dark at ambient temperature for 27 h. The resulting mixture was diluted with brine, extracted with ethyl acetate, dried and concentrated in vacuo to afford 3-bromo-5-methyl-4-methoxyphenylacetic acid. This crude product was dissolved in methanol (30 mL), treated with concentrated sulfuric acid (1 mL) carefully, stirred at reflux for 16 h. Cooled reaction mixture was concentrated under reduced pressure, diluted with brine, extracted with ethyl acetate. The combined organic layers were dried and concentrated in vacuo. The residue was dissolved in dichloromethane (10 mL), treated-with boron tribromide (1 M, 2 mL) under nitrogen and stirred at ambient temperature for 1 h. The reaction mixture was poured to stirring water and extracted with ethyl acetate from 1 N HCl. The combined organic layers were dried and concentrated. Flash column chromatography on silica gel with ethyl acetate/hexane (0-50% gradient elution) afforded 3-bromo-5-methyl-4-hydroxyphenylacetic acid methyl ester (0.21 g, 34%).
Reaction SMILES: [Br-].C(OC([NH:9][C:10]([C:13]1[N:14]=[N:15][N:16]([CH2:18][CH2:19][N+:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=1)([CH3:12])[CH3:11])=O)(C)(C)C.[ClH:24]>CO.O1CCOCC1>[ClH:24].[NH2:9][C:10]([C:13]1[N:14]=[N:15][N:16]([CH2:18][CH2:19][N+:20]([CH3:22])([CH3:21])[CH3:23])[CH:17]=1)([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cn(CC[N+](C)(C)C)nn1
Agent: Cl
Agent: [Br-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(N)c1cn(CC[N+](C)(C)C)nn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
2-(4-(2-(tert-Butoxycarbonylamino)propan-2-yl)-1H-1,2,3-triazol-1-yl)-N,N,N-trimethylethanaminium bromide (6.20 g, 15.8 mmol) was dissolved in methanol (15 ml). To the solution was added 4M hydrogen chloride in dioxane (150 ml), and the combined reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was concentrated and dissolved in water. Silver oxide (6.0 g) was added to the aqueous solution and the mixture was stirred at room temperature for 30 minutes. The solution was filtered through Celite®, and concentrated hydrochloric acid (2 ml) was added to the solution. The solution was filtered through Celite® a second time, and the aqueous solution was concentrated in vacuo. The crude material was purified by prep-HPLC (5-95% gradient of water/methanol with 0.05% acetic acid) to give 3.29 g (84%) 2-(4-(2-aminopropan-2-yl)-1H-1,2,3-triazol-1-yl)-N,N,N-trimethylethanaminium hydrochloride. 1H NMR (D2O) δ 8.27 (s, 1H), 5.07 (t, J=5.0 Hz, 2 H), 4.03 (t, J=5.1 Hz, 2 H), 3.21 (s, 9 H), 1.78 (s, 6 H); MS (ESI+) calculated for C10H22N5+: 212.19. Found: 212.2 (M+).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[OH:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH2:20][CH2:19][OH:18])[CH:23]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cccc(OCCO)c1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1cccc(OCCO)c1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and 3-(2-hydroxyethoxy)-benzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:37])[C@H:24]([CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:37])=[O:22])[CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc2ccccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccc3ccccc3c2)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to β-(2-naphthyl)-L-alanine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: C(S[C:5]1[C:10]([F:11])=[CH:9][N:8]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[C:7](=[O:17])[N:6]=1)C=C.[NH3:18]>CO>[NH2:18][C:5]1[C:10]([F:11])=[CH:9][N:8]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[C:7](=[O:17])[N:6]=1
Reactant: C=CCSc1nc(=O)n(-c2ccsc2)cc1F
Reactant: N
Solvent: CO
Product: Nc1nc(=O)n(-c2ccsc2)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
This material was prepared by the procedure described in J. Org. Chem. 2006, 71, 9183-9190. 4-(Allylthio)-5-fluoro-1-(thiophen-3-yl)pyrimidin-2(1H)-one (330 mg, 1.23 mmol) was dissolved in a methanol solution of ammonia (7 N, 5 mL). The reaction mixture was stirred overnight at 100° C. in a pressure vessel. After removal of solvent, the residue was purified by preparative thin layer chromatography to give 4-amino-5-fluoro-1-(thiophen-3-yl)pyrimidin-2(1H)-one (177 mg, 68%) as a yellow solid: mp 228-229° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=6.9 Hz, 1H), 7.89 (s, 1H), 7.65 (d, J=1.9 Hz, 2H), 7.56 (dd, J=5.1, 3.3 Hz, 1H), 7.29 (dd, J=5.1, 1.0 Hz, 1H); ESIMS m/z 212 ([M+H]+).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][C:11]#[CH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].O=O>CN(C)C=O.Cl[Cu]>[CH2:1]([N:3]([CH2:10][C:11]#[C:12][C:12]#[C:11][CH2:10][N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: C#CCN(CC)c1ccccc1
Agent: Cl[Cu]
Agent: O=O
Solvent: CN(C)C=O
Product: CCN(CC#CC#CCN(CC)c1ccccc1)c1ccccc1
Yield: 62 %

Procedure:
The procedure follows that of Schlier (Ph.D. Thesis, Universitat Freiburg (1980)). To a stirred mixture of CuCl (4.90 g, 0.0495 Moles) in 300 mL Dimethylformamide (DMF) at room temperature in a bubbler was added N,N,N,N-Tetramethylenediamine (5.54 g, 0.0478 Moles). To this mixture was added via dropping funnel over 45 minutes N-ethyl-N-propargylaniline (9.24 g, 0.0581 Moles) in 150 mL DMF. Oxygen was then allowed to bubble through the mixture while stirring. After 21 hours 100 mL of water to which 5 mL of concentrated Hydrochloric acid had been added was added to the reaction mixture dropwise. Then 500 mL of water was added in the same way. This mixture was filtered by suction and washed with a little Hydrochloric acid of the same dilution as previously and dried in a vacuum dissector to yield 5.67 g of light plates (62% yield). Separation on a silica column eluted with a 4:1 Hexane/Ethyl acetate mixture and evaporating to a small volume yielded a product of higher purity, M.P. 109.3-111.4; IR (KBR) 3064, 3029, 2975, 2878, 1599, 1505, 1427, 1385, 1327, 1248, 1185, 749, 693 cm-1 ; 1H NMR (CDCl3) δ1.25 (t, J=7.6), 3.46 (q, J=7.4), 4.11(s, 4), 7.05 (m, 4), 7.31 (d, 4); 13C NMR (CDCl3) δ13.0 (--CH3), 40.1 (N--CH2 --), 46.0 (N--CH2 --), 68.5 (yneC-), 75.4 (yneC--Cyne), 114.3 (arom), 118.3 (arom), 129.7 (arom), 148.2 (arom).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.O[C:30]1[C:38]2[N:37]=N[NH:35][C:34]=2[CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[NH2:35][C:34]1[CH:33]=[CH:32][CH:31]=[CH:30][C:38]=1[NH:37][C:26]([C:22]1[C:23]2[C:24](=[CH:25][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: Oc1cccc2[nH]nnc12
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Agent: Nc1ccccc1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)Nc5ccccc5N)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.8 %

Procedure:
6-(6,7-Dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (38.4 mg, 0.2 mmol), hydroxybenzotriazole (16.2 mg, 0.12 mmol), triethylamine (40.4 mg, 0.4 mmol) and o-phenylenediamine (43.2 mg, 0.4 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 200 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (39.1 mg, 84%) as a brown solid. 1H NMR (DMSO-d6) δ 4.01 (s, 6H, 2×OCH3), 4.97 (s, 2H, benzene-NH2), 6.65 (t, J=7.2 Hz, 1H, Ar—H), 6.82 (d, J=7.0 Hz, 1H, Ar—H), 7.00 (t, J=7.1 Hz, 1H, Ar—H), 7.38 (d, J=7.1 Hz, 1H, Ar—H), 7.42 (s, 1H, Ar—H), 7.60 (dd, J=2.4 and 9.2 Hz, 1H, Ar—H), 7.64-7.68 (m, 2H, Ar—H), 7.87 (d, J=6.7 Hz, 1H, Ar—H), 7.97 (d, J=2.3 Hz, 1H, Ar—H), 8.09 (d, J=8.2 Hz, 1H, Ar—H), 8.38 (d, J=9.2 Hz, 1H, Ar—H), 8.54 (s, 1H, Ar—H), 9.85 (s, 1H, benzene-NH). LC-MS (m/z) 467 (M+1).
Reaction SMILES: [H-].[Na+].[CH:3](=[N:10][OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:12][C:13]1[C:14]([N:23]=[CH:24][N:25]([CH3:27])[CH3:26])=[N:15][C:16](S(C)(=O)=O)=[N:17][CH:18]=1>CN(C=O)C.O>[F:12][C:13]1[C:14]([N:23]=[CH:24][N:25]([CH3:27])[CH3:26])=[N:15][C:16]([O:11][N:10]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:17][CH:18]=1
Reactant: CN(C)C=Nc1nc(S(C)(=O)=O)ncc1F
Reactant: ON=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C=Nc1nc(ON=Cc2ccccc2)ncc1F
Reaction time: 1 h
Yield: 30.8 %

Procedure:
To a suspension of sodium hydride (NaH, 60% dispersion in mineral oil; 0.037 g, 0.91 mmol) in DMF (2 mL) was added a solution of benzaldehyde oxime (0.125 g, 1.04 mmol) in DMF (1 mL), and the resulting frothy mixture was stirred for 1 h. To the resulting pale yellow mixture was added a solution of N′-(5-fluoro-2-methanesulfonylpyrimidin-4-yl)-N,N-dimethylformamidine (0.15 g, 0.61 mmol) in DMF (1 mL), and the homogeneous, pale-yellow solution was stirred at 25° C. for 16 h. The reaction mixture was diluted with H2O (50 mL) and was extracted with CH2Cl2 (2×100 mL). The organic extracts were combined, washed with H2O (5×50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to a colorless oil. Trituration with Et2O afforded N′-{5-fluoro-2-[1-phenylmethylideneaminooxy]pyrimidin-4-yl}-N,N-dimethylformamidine (0.054 g, 31%) as a white solid: mp 240-244° C. dec; 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.53 (s, 1H), 8.19 (d, J=2.4 Hz, 1H), 7.81-7.69 (m, 2H), 7.49-7.30 (m, 3H), 3.21 (s, 3H), 3.21 (s, 3H); ESIMS m/z 288 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:4])([CH3:3])[CH3:2].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[C:11]([CH2:13][Br:23])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(CC(=O)OC(C)(C)C)c(C(=O)OC(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)Cc1ccc(CBr)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 38.3 %

Procedure:
2- Tert-butoxycarbonylmethyl-5-methyl benzoic acid tert-butyl ester (4.751, 15.5 mmol) was dissolved in 75 ml of CCl4. To the solution was added N-bromosuccinimide (2.90 g, 16.3 mmol, 1.05 equivalents) and benzoyl peroxide (180 mg). The reaction mixture was refluxed under an argon atmosphere overnight; the reaction mixture was then cooled to room temperature, and the solid precipitate was filtered off, and washed with hexanes, the combined organic was taken to dryness and the residue was purified by chromatography to obtain 2-tert-butoxycarbonylmethyl-5-bromomethyl benzoic acid tert-butyl ester 2.286 g (38.3% yield) as an oil. 1H NMR (CDCl3): 7.920 (1H, d, J=2.2 Hz), 74.60 (1H, dd, J=1.95, 7.81 Hz), 7.193 (1H, d, J=7.81 Hz), 4.500 (2H, s), 3.953 (2H, s), 1.590 (9H, s), 1.444 (9H, s) FABMS (+Ve), m/z 387 [MH+, 81Br], 385 [MH+, 79Br], 331 [MH+—C4H8, 81Br], 329 [MH+—C4H8, 79Br], 275 [MH+—2C4H8, 81Br], 273 [NH+—2C4H8, 79Br]. Anal. calcd. for C18H25BrO4: C, 56.1; H, 6.5; Br, 20.7. Found: C, 56.27; H, 6.60; Br, 20.75.
Reaction SMILES: COC[O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[N:13][C:8]=2[S:7][C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20]([Li])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1.CCCCCC>[CH3:21][C:20]([C:12]1[CH:11]=[CH:10][C:9]2[C:5]([OH:4])=[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:7][C:8]=2[N:13]=1)([CH3:23])[CH3:22]
Reactant: COCOc1c(-c2ccccc2)sc2ncccc12
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc2c(O)c(-c3ccccc3)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 2.72 g (10.0 mmol) of 3-methoxymethoxy-2-phenyl-7-azabenzothiophene in 20 mL of dry tetrahydrofuran was cooled to -78° C. To this was added 11 mL of a 1.0M solution of t-butyllithium in hexane and the solution was allowed to warm to room temperature. The solution was quenched with methanol and stirred in air for 60 minutes, then partitioned between ether and water. The aqueous layer was washed with two portions of ether and the combined extracts were washed with brine, dried, and concentrated to an oil. The oil was dissolved in 10 mL methanol and 10 mL of 2M HCl and stirred at room temperature for 24 hours. The solution was partitioned between ether and water and the ether layer dried and concentrated. Recrystallization from ether-hexane afforded 2.43 g (84%) of pale yellow needles, m.p. 181°-183° C.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>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.CN(C=O)C.CCN(CC)CC>[NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[C:4][C:9]1[C:8]([F:7])=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:18]/[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24])/[C:12](=[O:17])[NH:13]2
Reactant: C#CC(C)(C)N
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC(C)(C)N)c21

Procedure:
Using Method C above, 3-amino-3-methyl-1-butyne (42.2 mg, 0.51 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (75 mg, 0.203 mmol) using (Ph3P)4Pd (23.5 mg) and Cul (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-4-[3-amino-3-methyl-1-butynyl]-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 44 mg, 67%).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[C:15]1([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[C:23]2[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=2)[NH:17][C:16]1=[O:25].ClC1C=C2C(C(NC3C=C(C=CC=3)C(O)=O)(CC3C=CC=C(Cl)C=3)C(=O)N2)=CC=1>>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:15]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)([O:1][C:2]3[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])[C:16](=[O:25])[NH:17]2)=[CH:22][CH:21]=1
Reactant: CC(C)c1cccc(C(=O)O)c1O
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Agent: O=C(O)c1cccc(NC2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)c1
Product: CC(C)c1cccc(C(=O)O)c1OC1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21

Procedure:
From 2-hydroxyl-3-isopropyl benzoic acid and rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one, the title compound was prepared following the similar procedure as rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoic acid. MS: [M−H]−=468
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH3:13])[CH:4]=1.[CH2:14]([OH:16])[CH3:15]>>[ClH:2].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([C:7](=[NH:8])[O:16][CH2:14][CH3:15])=[C:5]([O:11][CH2:12][CH3:13])[CH:4]=1
Reactant: CCO
Reactant: CCOc1cc(Cl)ccc1C#N
Agent: Cl
Product: CCOC(=N)c1ccc(Cl)cc1OCC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
Hydrogen chloride gas was passed through a solution of 4-chloro-2-ethoxy-benzonitrile (670 mg, 3.689 mmol) in anhydrous ethanol (25 mL) cooled to 0° C. After 45 min, the hydrogen chloride gas was stopped and the reaction vessel was sealed with a Teflon stopper. It was stirred at room temperature for 5 d. The reaction vessel was cooled to 0° C. and the stopper was removed. The solvent was removed and the residue was triturated in diethyl ether to afford ethyl 4-chloro-2-ethoxy-benzimidate hydrochloride (913 mg, 94%). It was used without further purification.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH2:32])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>C(O)(=O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][N:32]2[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[CH2:6][N:5]2[C:4](=[O:14])[C:3]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]3[C:1]2=[O:19])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(CCN)cc1OC
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Solvent: CC(=O)O
Product: COc1ccc(CCn2c(C)ccc2CN2C(=O)c3ccccc3C2=O)cc1OC

Procedure:
13.0 g (0.05 mol) of 6-phthalimido-2,5-hexanedione and 9.1 g (0.05 mol) of 2-(3,4-dimethoxyphenyl)-ethylamine are stirred in 250 ml of acetic acid at 80° C. for 7 hours. After working up as in Example 1, 7.3 g of product are obtained.
Reaction SMILES: [Li]I.O.[CH:4]([C:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)(C)[C:7](OC)=O)=[O:5]>CN(P(N(C)C)(N(C)C)=O)C>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:6]([CH3:7])[CH:4]=[O:5])=[CH:18][CH:17]=1)([CH3:21])([CH3:20])[CH3:22]
Reactant: COC(=O)C(C)(C=O)Cc1ccc(C(C)(C)C)cc1
Agent: [Li]I
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Reaction time: 0.02 h
Yield: 105.1 %

Procedure:
5 ml of hexamethylphosphortriamide (HMPT) and 1 g of LiI.H2O are heated to 240° C. under a nitrogen atmosphere. 1.1 g of crude methyl 2-formyl-2-p-tert.butyl-benzyl-propionate (82%) in 1 ml of HMPT are added thereto, the mixture is stirred for 1 minute, poured on to ice and extracted with hexane. After washing with 2N HCl, with sodium bicarbonate solution and water the organic phase is dried over magnesium sulphate and the solvent is evaporated. 0.9 g of crude p-tert.butyl-α-methyl-hydrocinnamaldehyde is obtained. After bulb-tube distillation 500 mg of this aldehyde give 300 mg of pure material. The yield therefore amounts to 78.8%.
Reaction SMILES: [C-:1]#[N:2].C([Al+]CC)C.[CH3:8][O:9][C:10]1[CH:28]=[CH:27][C:13]2[O:14][CH2:15][C@@H:16]3[C:18]([C:23]([O:25][CH3:26])=[O:24])([C:19]([O:21][CH3:22])=[O:20])[C@@H:17]3[C:12]=2[CH:11]=1.Cl>C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:28]=[CH:27][C:13]2[O:14][CH2:15][C@@H:16]([CH:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])[C@H:17]([C:1]#[N:2])[C:12]=2[CH:11]=1
Reactant: COC(=O)C1(C(=O)OC)[C@@H]2c3cc(OC)ccc3OC[C@@H]21
Reactant: [C-]#N
Agent: CC[Al+]CC
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)[C@@H]1COc2ccc(OC)cc2[C@H]1C#N
Reaction time: 2 h

Procedure:
Under nitrogen 425 ml of diethylaluminum cyanide (1.5M in toluene) is added to 93 g cis-dimethyl 1,1a,2,7b-tetrahydro-6-methoxybenzo[b]cyclopropa[d]pyran-1,1-dicarboxylate in 1250 ml toluene. After stirring 2 h at 25°, the reaction mixture is poured into 1250 ml 17.4% HCl. The aqueous phase is separated and extracted with three 100 ml portions of ethyl acetate and three 200 ml portions of CH2Cl2. The combined organic phases are washed with 500 ml 2N HCl, 500 ml brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give trans(±)-dimethyl 2-(3,4-dihydro-6-methoxy-4-cyano-2H-[1]benzopyran-3-yl)-propanedioate.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:11][CH3:12])[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.[C:13]([S:16][CH2:17][CH:18]([S:22][CH3:23])[C:19](Cl)=[O:20])(=[O:15])[CH3:14].SCC(SC)C(N1[C@H](C(O)=O)CC2(C(=O)CCC2=O)C1)=O>>[C:13]([S:16][CH2:17][CH:18]([S:22][CH3:23])[C:19]([N:6]1[CH2:7][C:3]([O:11][CH3:12])([O:2][CH3:1])[CH2:4][C@H:5]1[C:8]([OH:10])=[O:9])=[O:20])(=[O:15])[CH3:14]
Reactant: COC1(OC)CN[C@H](C(=O)O)C1
Reactant: CSC(CSC(C)=O)C(=O)Cl
Agent: CSC(CS)C(=O)N1CC2(C[C@H]1C(=O)O)C(=O)CCC2=O
Product: COC1(OC)C[C@@H](C(=O)O)N(C(=O)C(CSC(C)=O)SC)C1

Procedure:
4,4-Dimethoxy-L-proline is reacted with 3-(acetylthio)-2-(methylthio)propionic acid chloride according to the procedure of Example 3 (d) to yield 1-[3-(acetylthio)-2-methylthio-1-oxopropyl]-4,4-dimethoxy-L-proline.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:26]([O:29][CH2:30][CH2:31]Cl)[CH2:27]Cl>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:31][CH2:30][O:29][CH2:26][CH2:27]3)=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(Oc2ccc(N3CCOCC3)cc2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1-Acetyl-4-(4-aminophenyloxy)piperidine (1.77 g) obtained in Example 1 was dissolved in dimethylformamide (10 ml) and to the mixture were added potassium carbonate (2.1 g), potassium iodide (0.2 g) and 2,2'-dichloroethyl ether (0.9 ml), followed by heating with stirring at 100° C. overnight. The mixture was worked up according to the same manner as that described in Example 1 to obtain a colorless oily compound (1.4 g).
Reaction SMILES: [F:1][C:2]1([F:16])[O:7][C:6]([F:9])([F:8])[C:5]2[CH:10]=[C:11]([CH2:14]O)[CH:12]=[CH:13][C:4]=2[O:3]1.S(Cl)([Cl:19])=O>>[Cl:19][CH2:14][C:11]1[CH:12]=[CH:13][C:4]2[O:3][C:2]([F:16])([F:1])[O:7][C:6]([F:9])([F:8])[C:5]=2[CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Product: FC1(F)Oc2ccc(CCl)cc2C(F)(F)O1

Procedure:
A mixture of (2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxin-6-yl)-methanol (6.5 g) in thionyl chloride (75 mL) was heated at reflux overnight. The resulting mixture was concentrated under vacuum. The residue was basified with aqueous saturated NaHCO3. The aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic layers were dried over Na2SO4, filtrated, and concentrated under reduced pressure to give 6-chloromethyl-2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxine (6.2 g), which was used directly in the next step. 1H NMR (CDCl3, 300 MHz) δ 7.65 (s, 1H), 7.61 (dd, J=2.1, 8.7 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 4.60 (s, 2H).