Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)(=[O:4])[CH3:3].Cl[C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([CH:20]=1)[NH2:19]>C(O)C>[NH2:19][C:18]1[CH:20]=[C:14]([S:12][C:9]2[CH:10]=[CH:11][C:6]([NH:5][C:2](=[O:4])[CH3:3])=[CH:7][CH:8]=2)[CH:15]=[CH:16][C:17]=1[N+:21]([O-:23])=[O:22]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na]
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc([N+](=O)[O-])c(N)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
Sodium (0.269 g) was added to ethanol (20 ml) and the resultant solution was allowed to cool to ambient temperature and 4-acetamidothiophenol (1.94 g) was added. The mixture was stirred for 5 minutes and 5-chloro-2-nitroaniline (2 g) was added. The mixture was then heated under reflux under argon for 3 hours and allowed to cool. The resultant solid was collected by filtration, washed with ethanol then dried to give the title compound (2.46 g) as a solid. NMR: 2.05 (s, 3H), 6.3 (dd, 1H), 6.6 (s, 1H), 7.4 (brs, 2H), 7.5 (d, 2H), 7.7 (d, 2H), 7.9 (d, 1H); MS (ESP+): 304 (M+H)+.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=1.C1(B(O)O)C=CC=CC=1.C(=O)([O-])O.[Na+]>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.C(O)C>[N+:22]([C:11]1[CH:10]=[C:9]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:21]=[CH:20][C:12]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([O-:24])=[O:23]
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
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: OB(O)c1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To toluene 70 mL solution of tert-butyl 4-bromo-2-nitrobenzoate 8.8 g were added phenylboronic acid 4.3 g, sodium hydrogen carbonate 6.1 g, ethanol 26 mL, water 13 mL and tetrakis(triphenylphosphine)palladium (0) 1.7 g at room temperature sequentially, and it was heated and refluxed for 3 hours. After the reaction mixture was cooled to room temperature, water was added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Hexane was added to the obtained residue, solid matter was filtrated to give tert-butyl 2-nitro-4-phenylbenzoate 7.8 g of white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[CH2:10][CH2:9]2)[C:3]=1[CH2:16]O.P(Br)(Br)[Br:19]>ClCCl>[Br:19][CH2:16][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[CH2:10][CH2:9]1
Reactant: CCN1CCN(c2cccc(Cl)c2CO)CC1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CCN1CCN(c2cccc(Cl)c2CBr)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [2-chloro-6-(4-ethylpiperazin-1-yl)phenyl]methanol (6.31 g, 24.8 mmol) in anhydrous dichloromethane (200 mL) was added dropwise phosphorus tribromide (5 mL, 52.7 mmol). The mixture was stirred at room temperature for 3 hours. Dichloromethane was evaporated. The residue was dried in vacuo, affording 1-[2-(bromomethyl)-3-chlorophenyl]-4-ethylpiperazine. The product was used without further purification.
Reaction SMILES: [CH:1]([P:4]([CH:6]([CH3:8])[CH3:7])Cl)([CH3:3])[CH3:2].[C:9]1([CH3:17])[CH:14]=[CH:13][C:12]([Mg]Br)=[CH:11][CH:10]=1>C1COCC1>[CH:1]([P:4]([CH:6]([CH3:8])[CH3:7])[C:12]1[CH:13]=[CH:14][C:9]([CH3:17])=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: CC(C)P(Cl)C(C)C
Reactant: Cc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: Cc1ccc(P(C(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diisopropylchlorophosphine (2 mL, 12.57 mmol) in THF (25 mL) at −78° C. was added 4-tolylmagnesium bromide (12.57 mL, 12.57 mmol) dropwise. After 1 h at −78° C., the reaction mixture was let warm to RT. The solvent was removed and material was used without further purification. MS: cal'd 209 (MH+), exp 209 (MH+).
Reaction SMILES: F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[ClH:25].[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][C:28]=1[O:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([NH:43][C:44]2[S:45][CH:46]=[C:47]([CH3:49])[N:48]=2)[CH:38]=1.[NH2:50][CH2:51][CH2:52][N:53]1[CH2:57][CH2:56][CH2:55][CH2:54]1.CN(C=O)C>O>[ClH:25].[ClH:25].[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:50][CH2:51][CH2:52][N:53]2[CH2:57][CH2:56][CH2:55][CH2:54]2)=[O:33])=[CH:29][C:28]=1[O:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([NH:43][C:44]2[S:45][CH:46]=[C:47]([CH3:49])[N:48]=2)[CH:38]=1
Reactant: NCCN1CCCC1
Reactant: Cc1csc(Nc2cc(Oc3cc(C(=O)O)ccc3F)ccn2)n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc(Nc2cc(Oc3cc(C(=O)NCCN4CCCC4)ccc3F)ccn2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
A 3 dram vial was charged with bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (0.488 g, 1.05 mmol), 4-fluoro-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid hydrochloride (Example 107; 0.200 g, 0.524 mmol), N-(2-aminoethyl)pyrrolidine (0.179 g, 1.57 mmol) and DMF (3 mL). The reaction was stirred for 1 hour at ambient temperature. Water was added and the reaction was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography. 2M HCl in ether was added to the isolated material and the collected solids were dried over high vacuum to give the title compound (0.078 g, 28.9% yield) as a white solid. 1H NMR (d6-DMSO) δ 11.21 (bs, 1H), 9.75 (bs, 1H), 8.86 (t, 1H), 8.23 (m, 1H), 7.92 (m, 2H), 7.64 (dd, 1H), 6.62 (m, 2H), 6.58 (d, 1H), 3.60 (m, 4H), 3.32 (quart, 2H), 3.03 (m, 2H), 2.21 (d, 3H), 2.00 (d, 2H), 1.85 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH2:7][CH2:8][CH2:9][S:10]([CH2:13][CH2:14]Cl)(=[O:12])=[O:11])(=[O:6])=[O:5].C1(C=CC(O)=CC=1)O.C(N(CC)CC)C>C(OCC)(=O)C>[CH:13]([S:10]([CH2:9][CH2:8][CH2:7][S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])(=[O:12])=[O:11])=[CH2:14]
Reactant: O=S(=O)(CCCl)CCCS(=O)(=O)CCCl
Agent: Oc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CS(=O)(=O)CCCS(=O)(=O)C=C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1,3-Bis(2-chloroethylsulfonyl)propane (74.5 g., 0.249 mole) was suspended in 2,300 ml. of ethyl acetate containing 0.12 g. hydroquinone. Triethylamine (50.7 g., 0.50 mole) was dropped in with stirring, within 10 minutes at 25° C. The resulting mixture was stirred at 25° C. for 20 hours. The amine salt was filtered off and the ethyl acetate solution evaporated at 30° C. The tan-colored solid was washed with water, then recrystallized from ethanol; yield 32.8 g. (59 percent); m.p. 60°-63° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[OH:41][CH:42]([C@@H:53]1[CH2:57][C@H:56]([SH:58])[CH2:55][N:54]1[C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([N+:69]([O-:71])=[O:70])=[CH:65][CH:64]=1)=[O:60])[CH2:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]1)=[O:45]>>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:58][C@@H:56]3[CH2:55][N:54]([C:59]([O:61][CH2:62][C:63]4[CH:64]=[CH:65][C:66]([N+:69]([O-:71])=[O:70])=[CH:67][CH:68]=4)=[O:60])[C@H:53]([CH:42]([OH:41])[CH2:43][C:44]([N:46]4[CH2:47][CH2:48][N:49]([CH3:52])[CH2:50][CH2:51]4)=[O:45])[CH2:57]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: CN1CCN(C(=O)CC(O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(O)CC(=O)N4CCN(C)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 76.5 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (3.078 g) and (2S,4S)-2-[1-hydroxy-2-[4-methylpiperazin-1-ylcarbonyl]ethyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.232 g), reaction and purification were carried out in a similar manner to that described Example 40-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[1-hydroxy-2-[4-methylpiperazin-1-ylcarbonyl]ethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (3.007 g) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][C:9]2[C:13]3[C:14](=[O:28])[N:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]4[N:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]=3[NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-])=O>CN(C=O)C.CO.[C].[Pd]>[NH2:1][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][C:9]2[C:13]3[C:14](=[O:28])[N:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]4[N:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]=3[NH:11][N:10]=2)=[CH:6][CH:5]=1
Reactant: O=c1c2c(Cc3ccc([N+](=O)[O-])cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Reaction time: 72 h
Yield: 65.3 %

Procedure:
To a solution of 3-(4-nitrobenzyl)-5-phenyl-1H-pyrazolo [4,3-c][1,8]naphthyridin-4 (5H)-one (200 mg, 0.50 mmol, prepared in Example 24) in DMF (10 ml) and methanol (10 ml) was added activated carbon-palladium (20 mg), the mixture was stirred under hydrogen atmosphere for 3 days, and filtered. After methanol was distilled off, the resultant solution was admixed with water, and filtered to give precipitates which were dried to afford 3-(4-aminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (120 mg, 65%).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1>>[Cl:10][C:4]1[CH:3]=[C:2]([C:14]2[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=[C:12]([F:11])[CH:13]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: COc1cc(F)cc(B(O)O)c1
Reactant: Nc1c(F)cc(Br)cc1Cl
Product: COc1cc(F)cc(-c2cc(F)c(N)c(Cl)c2)c1
Yield: 59.8 %

Procedure:
The title compound (71 mg) was prepared from 4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.44 mmol) and 3-fluoro-5-methoxyphenylboronic acid (97 mg, 0.57 mmol) as a pale-yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.51-7.45 (m, 2H), 7.05 (d, J 10.3, 1H), 7.00 (s, 1H), 6.73 (dd, J 2.1, 4.2, 1H), 5.60 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][C:9]2[C:10](=[O:21])[C:11]3[C:16]([C:17](=[O:20])[C:18]=2Cl)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:4][CH:5]=[CH:6][CH:7]=1>OCC(CO)O>[Cl:1][C:2]1[C:3]2[N:4]([C:18]3[C:17](=[O:20])[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:10](=[O:21])[C:9]=3[N:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(Cl)=C(Nc2ncccc2Cl)C(=O)c2ccccc21
Solvent: OCC(O)CO
Product: O=C1c2ccccc2C(=O)c2c1nc1c(Cl)cccn21
Yield: 39.9 %

Procedure:
850 mg (2.66 mmol) of 2-(3-chloro-2-pyridylamino)-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in solution in 80 mL of glycerol is brought to 190° C. for 20 min. After complete cooling, the yellow precipitate obtained is filtered on fritted glass, washed w-th distilled water, and recrystallized in methanol after decoloration with animal black to produce 300 mg of 4-chloro-6,11-dihydro-6,11-dioxo-naptho[2',3':4,5]imidazo[1,2-a]pyridine in the form of yellow crystals.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:5]2=[N:4][C:3]=1[CH:13]([CH3:15])[CH3:14].[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]=[O:36])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]>>[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]([OH:36])[C:2]3[N:6]4[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:5]4=[N:4][C:3]=3[CH:13]([CH3:15])[CH3:14])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: COc1ccn2c(I)c(C(C)C)nc2n1
Product: COc1ccn2c(C(O)c3ccc4c(c3)COc3cc(F)ccc3/C4=C(\C)C#N)c(C(C)C)nc2n1
Yield: 62.7 %

Procedure:
[step 4] Using 3-iodo-2-isopropyl-7-methoxyimidazo[1,2-a]pyrimidine (649 mg, 2.05 mmol) obtained in step 3 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (300 mg, 1.02 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8A, step 3, (E)-2-{3-fluoro-8-[(hydroxy) (2-isopropyl-7-methoxyimidazo[1,2-a]pyrimidin-3-yl)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (310 mg, 63%) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14]C2C=CC=CC=2Br)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[ClH:22].[NH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2Br)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCNCC1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 0.0025 mole) in dry 1,2-dichloroethane (5 mL) under an atmosphere of nitrogen was added 2-bromoaniline (0.474 g, 0.00276 mole), acetic acid (0.18 g, 0.00301 mole) and sodium triacetoxyborohydride (0.638 g, 0.00301 mole). Stirring was continued at ambient temperature for 14 hours. The reaction mixture was quenched in cold aqueous 1N NaOH solution and the product extracted with ether. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford the crude product as transparent viscous liquid. Purification by column chromatography using silica gel 60-120 mesh (2% ethyl acetate in hexane) afforded 0.320 g (35%) of desired 4-(2-bromo-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (DMSO-d6): δ 7.44-7.38 (m, 1H), 7.2-7.12 (m, 1H), 6.84-6.78 (m, 1H), 6.58-6.48 (m, 1H), 4.65 (d, 1H), 3.9 (m, 2H), 3.5 (m, 1H), 3.0-2.8 (m, 2H), 2.0-1.8 (m, 2H), 1.4 (s, 9H). To a cooled solution (0° C.) of 4-(2-bromo-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.31 g, 0.00087 mole) in dioxane (0.5 mL) was added dioxane.HCl (2.5 mL). The mixture was stirred at the same temperature for 10 minutes, then gradually brought to ambient temperature with continued stirring for a further 15 minutes. The reaction mixture was evaporated under reduced pressure to afford a residue which was washed with dry ether to afford 0.106 g (42%) of 2-bromo-phenyl)-piperidin-4-yl-amine dihydrochloride.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:8]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[C:24]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:25]=1[C:26]([OH:28])=[O:27].C(=O)=O>CN(C)C=O>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:20][C:24]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:25]=2[C:26]([OH:28])=[O:27])=[CH:21][CH:22]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
To a 5 L 3-neck flask was added 284 g (2.06 moles) milled potassium carbonate and 1.0 L dimethylformamide. While stirring the resulting mixture at room temperature, 250 g (1.06 moles) 4-benzyloxyaniline hydrochloride was added portionwise over 15 minutes. After this was completed, 231 g (1.0 mole) 2-bromo-5-methoxybenzoic acid was added over 15 minutes and the mixture was stirred for another 15 minutes. The suspension was cooled to 10°-15° C. and 13.8 g cupric acetate monohydrate (0.06 moles) was added portionwise over 20 minutes. Gas evolved slowly and after stirring 15 minutes at room temperature the reaction was warmed on a steam bath over 40 minutes to 70° C. whereupon a vigorous evolution of carbon dioxide was observed. Stirring and heating was continued for 90 minutes at 80°-85°C., heat was removed and the mixture was allowed to cool to room temperature. The brownish red suspension was transferred to a 12 L flask containing 1 L ice-cold water. Acetic acid (650 ml) was added dropwise and the dark green precipitate was stirred vigorously until homogeneous. After filtering and washing well with water, the crude product was dried overnight at 55°-60° C. in a vacuum oven. The crude product (approximately 350 g) was diluted with 5.8 L toluene, heated to reflux temperature and filtered. The dark green filtrate was allowed to cool to room temperature for 2-3 hours, and the solid product was collected by filtration and rinsed with cold (5°-10° C.) toluene. The bright yellow crystalline product was obtained in 80% yield. A sample of the compound had the m.p. 167°-168° C. when recrystallized from a benzene-cyclohexane mixture.
Reaction SMILES: [C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([OH:24])=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O>CN(C)C=O.C(Cl)CCl>[C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([O:24][C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:1](=[O:8])[CH3:2])=[CH:11][CH:12]=3)=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(OC(=O)C2CCc3c(c4ccccc4n3C(=O)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 9.6 g. of 9-benzoyl-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 15 ml. of thionyl chloride and two drops of dry dimethylformamide in 100 ml. of ethylene dichloride was stirred at room temperature for 7 hours. The mixture was evaporated to dryness under reduced pressure, at room temperature, and to the resulting residue was added a solution of 6 g. of 4-acetamidophenol in 50 ml. of dry pyridine. The solution was stirred at room temperature for 30 minutes and diluted with water. The resulting solid was collected by filtration to give 6.74 g. of the title compound; m.p. 166°-168°C. (ethyl alcohol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([CH2:23]Br)[CH:22]=2)[O:19][C:18]([CH3:26])([CH3:25])[CH2:17][C:16]3([CH3:28])[CH3:27])=[CH:7][CH:6]=1.[CH3:30][Si:31]([C:34]#[CH:35])([CH3:33])[CH3:32].C(OCC)(=O)C>C(N(CC)CC)C.CN(C)C=O.CCCCCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([CH2:23][C:35]#[C:34][Si:31]([CH3:33])([CH3:32])[CH3:30])[CH:22]=2)[O:19][C:18]([CH3:26])([CH3:25])[CH2:17][C:16]3([CH3:28])[CH3:27])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(CBr)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)Cc1ccc(C#Cc2cc(CC#C[Si](C)(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Temperature: 95 °C
Yield: 63 %

Procedure:
A solution of {4-[8-bromomethyl-2,2,4,4-tetramethyl-chroman-6-ylethynyl]-phenyl}-acetic acid methyl ester (Compound 47, 1.1 g, 2.4 mmol) in triethyl amine (2 mL) and N,N-dimethylformamide (10 mL) was sparged with argon and treated with trimethylsilylacetylene (2 mL, 14.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.135 g, 0.192 mmol). The resulting reaction mixture was heated at 95° C. for 20 h at the end of which it was cooled to ambient temperature and subjected to flash column chromatography over silica gel (230-400 mesh) using 1-7% ethyl acetate in hexane as the eluent to afford the title compound as an oil (0.715 g, 63%). 1H NMR (300 MHz, CDCl3): δ7.49 (d, 1H, J=2.1 Hz), 7.47 (d, 2H, J=8.2 Hz), 7.37 (d, 1H, J=2.1 Hz), 7.25 (d, 2H, J=8.2 Hz), 3.70 (s, 3H), 3.63 (s, 2H) 3.55 (s, 2H), 1.83 (s, 2H), 1.35 (s, 6H), 1.34 (s, 6H), 0.20 (s, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH:10]=1.Cl.[CH3:26][O:27][C:28](=[O:35])[C@H:29]([CH2:31][CH2:32][S:33][CH3:34])[NH2:30]>>[CH3:26][O:27][C:28](=[O:35])[C@H:29]([CH2:31][CH2:32][S:33][CH3:34])[NH:30][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][C:9]([CH2:8][O:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:10][C:11]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: Cc1ccccc1-c1cc(COCc2cccs2)ccc1C(=O)O
Agent: Cl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(COCc2cccs2)cc1-c1ccccc1C

Procedure:
The desired compound was prepared by coupling 4-(2-thienylmethoxymethyl)-2-(2-methylphenyl)benzoic acid, prepared as in Example 272C, with methionine methyl ester hydrochloride using the procedure of Example 184A.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[S:9](N)(N)(=[O:11])=[O:10]>COCCOCCOC>[NH:7]1[S:9](=[O:11])(=[O:10])[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=2
Reactant: NS(N)(=O)=O
Reactant: Nc1ccccc1N
Solvent: COCCOCCOC
Product: O=S1(=O)Nc2ccccc2N1
Temperature: 25 °C

Procedure:
A solution of 1,2-phenylenediamine (91 mg, 0.84 mmol) and sulfamide (81 mg, 0.84 mmol) in diglyme (2.5 ml) is stirred at 155° C. for 1.5 h. After cooling to RT, the reaction solution is poured into ice-water (15 ml) and the product is extracted with ethyl acetate. The solvent is distilled off under reduced pressure and the red residue is purified by flash chromatography (1:1 ethyl acetate/toluene).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].[CH2:23]([O:25][C:26](=[O:29])[CH2:27]Br)[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:23]([O:25][C:26](=[O:29])[CH2:27][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:10]([C:9](=[O:20])[NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:22][CH:21]=2)[O:11][CH3:12])=[CH:14][CH:15]=1)[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)cc1

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-benzyl)-2-(4-hydroxy-phenyl)-2-methoxy-acetamide (example 21.2) was alkylated with ethylbromoacetate/cesium carbonate in DMF to give (RS)-{4-[(4-cyano-benzylcarbamoyl)-methoxy-methyl]-phenoxy}-acetic acid ethyl ester as a colorless solid. MS 383.3 ([M+H]+)
Reaction SMILES: C[O:2][C:3]1[C:4]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.B(Br)(Br)Br>ClCCl>[CH3:18][N:16]1[CH:17]=[C:13]([C:4]2[C:3]([OH:2])=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)[CH:14]=[N:15]1
Reactant: COc1ccc2ncccc2c1-c1cnn(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1cc(-c2c(O)ccc3ncccc23)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
A flask was charged with compound 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-quinoline (5.5 g, 0.023 mol) and dichloromethane (50 mL). A solution of boron tribromide (27.6 mL, 1M solution in dichloromethane, 27.6 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes, then the cooling bath was removed and the reaction was stirred for 1.5 hours at room temperature. The reaction was quenched by slowly adding excess 10% aqueous hydrochloric acid, then the solution was basified to pH=6 with 20% aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate and the organic phase was washed with brine, dried over Na2SO4, and filtered. Removal of the solvent gave 4 g of 5-(1-methyl-1H-pyrazol-4-yl)-quinolin-6-ol as a yellow solid.