Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](#[N:18])[CH:16]=[CH2:17].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO.O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:17][CH2:16][C:15]#[N:18])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#CCCOc1ccc(Oc2ccccc2)cc1
Yield: 34.6 %

Procedure:
3-(p-Phenoxyphenoxy)propionitrile was prepared by heating under reflux for 18 hours a mixture of 25 g of p-phenoxyphenol, 28.4 g of acrylonitrile and 5 ml of a 40% solution of benzyltrimethylammonium hydroxide in methanol. It was worked up by cooling, diluting with 400 ml water, extracting using ethyl acetate; washing the organic layer with 5% aqueous sodium hydroxide, drying, evaporating the solvent, and recrystallizing from hexane to yield 11.1 g of 3-(p-phenoxyphenoxy)propionitrile m.p. 81-3° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:20][C:21]4[NH:22][S:23](=[O:29])(=[O:28])[CH2:24][O:25][C:26]=4[N:27]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:37](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(=O)(O)[O-].[Na+]>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:20][C:21]4[N:22]([CH3:37])[S:23](=[O:28])(=[O:29])[CH2:24][O:25][C:26]=4[N:27]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NS(=O)(=O)CO4)cc2)CCC1
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1c2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2OCS1(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
In a 15 mL reaction tube was added tert-butyl(1-(4-(2,2-dioxido-7-phenyl-1H-pyrido[3,2-e][1,3,4]oxathiazin-6-yl)phenyl)cyclobutyl)carbamate (50 mg, 0.099 mmol), potassium carbonate (41 mg, 0.296 mmol) and iodomethane (7.5 μL, 0.118 mmol) in anhydrous N,N-dimethylformamide (1 mL) to give an orange suspension. The reaction mixture was stirred at room temperature for 2 hours, then diluted with saturated sodium bicarbonate solution (5 mL) and extracted into dichloromethane (3×3 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a yellow oil. This was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the desired product as a colourless oil (50 mg, 97% yield). 1H-NMR (500 MHz, CDCl3) δ 7.24-7.47 (8H, m), 7.16-7.23 (2H, m), 5.23 (2H, s), 5.05 (1H, br s), 3.36 (3H, s), 2.20-2.65 (4H, m), 2.01-2.15 (1H, m), 1.77-1.90 (1H, m), 1.10-1.50 (9H, br m). LCMS (Method A) RT=7.16 min, M+H+=522.01.
Reaction SMILES: [OH-].[Na+].[C:3]([O:18]CC)(=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][O:14][CH2:15][CH3:16].Cl>CO>[C:3]([OH:18])(=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][O:14][CH2:15][CH3:16]
Reactant: CCOCCSCCCCCCCC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOCCSCCCCCCCC(=O)O
Reaction time: 7 h
Yield: 92 %

Procedure:
NaOH (lM, 24 mL, 24 mmol) was added to a solution of the above ethyl 9-thia-12-oxatetradecanoate. (6.8 mmol) in MeOH (20 mL). After stirring for 7 h, the reaction mixture was acidified with 10% HCl (pH 1) and extracted with ethyl acetate (2×100 mL). The organic phase was washed with water (50 mL), brine (50 mL), and dried (Na2SO4). The crude product was recrystallized from hexane to afford the title compound, 9-thia-12-oxatetradecanoic acid; yield 92%; bp 134° C.-136° C./0.005 torr; IR (neat): 3000 (broad) and 1735 cm-1NMR: 1.23 (3H, t, J=7.2 Hz), 1.28-1.46 (6H, m), 1.53-1.68 (4H, m), 2.35 (2H, t, J=7.3 Hz), 2.54 (2H, t, J=7.1 Hz), 2.70 (2H, t, J= 7.1 Hz), 3.52 (2H, q, J=7.2 Hz), 3.60 (2H, t, J=6.9 Hz), and 8.85 ppm (lH, br s); Found: C, 57.96, H, 9.77%. Calcd for C12H24SO3 : C, 58.03, H, 9.74%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=O)=[O:4].Cl.[CH2:15]([NH2:17])[CH3:16].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:15]([NH:17][C:8]([C:7]1[CH:11]=[CH:12][N:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=1)=[O:10])[CH3:16]
Reactant: CCN
Reactant: COC(=O)c1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccnc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a mixture of 2-(methoxycarbonyl)isonicotinic acid (150 mg, 0.83 mmol), ethylamine hydrochloride salt (203 mg, 2.48 mmol), and diisopropylethylamine (0.72 mL, 4.14 mmol) in DMF is added HBTU (377 mg, 0.99 mmol) at 0° C. After stirring at room temperature for 1 hour, the mixture is poured onto water (30 mL). The aqueous phase is extracted with dichloromethane (30 mL×2). The combined organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (2:1˜1:1) to give 83 mg (48% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=C(N)[O:9][C:5]=2[CH:4]=1.COC1C=CC([N+]([O-])=O)=C(O)C=1.CC(O)=O>CO.[Pd]>[NH2:7][C:6]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[OH:9]
Reactant: COc1ccc2nc(N)oc2c1
Agent: [Pd]
Agent: COc1ccc([N+](=O)[O-])c(O)c1
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(N)c(O)c1
Reaction time: 2 h
Yield: 100 %

Procedure:
General experimental procedure for the preparation of 6-methoxybenzo[d]oxazol-2-amine: A mixture of 5-methoxy-2-nitrophenol (0.51 g, 3.02 mmol), Pd/C (10% by weight, 70 mg), and HOAc (cat. amount) in MeOH (30 mL) was hydrogenated under H2 at room temperature for 2 hrs, and then was filtered through a short Celite pad. The filtrate was concentrated in vacuo to provide 2-amino-5-methoxyphenol as a brown solid (0.42 g, 100%). 1H NMR (CDCl3, 400 MHz) δ 6.79 (d, J=8.4 Hz, 1H), 6.44 (d, J=2.8 Hz, 1H), 6.35 (dd, J=8.4, 2.8 Hz, 1H), 3.74 (s, 3H). This product was used directly in the next step without any further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15]OS(C)(=O)=O)(=O)=O.C(#[N:23])C.[OH-].[NH4+].Cl>O>[CH2:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][NH:23][CH2:6]1
Reactant: CS(=O)(=O)OCCc1ccccc1CCOS(C)(=O)=O
Reactant: CC#N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: c1ccc2c(c1)CCNCC2
Temperature: 100 °C

Procedure:
A 350 mL pressure vessel was charged with the methanesulfonic acid 2-[2-(2-methanesulfonyloxy-ethyl)-phenyl]-ethyl ester (3.2 g/10 mmol) in a 1:1 mixture of acetonitrile and ammonium hydroxide (100 mL total volume). The vessel was sealed and heated to 100° C. for one hour (pressure rises to ca. 40 psi) and then gradually allowed to cool. The reaction contents were poured into water and acidified to ca. pH 4 with concentrated hydrochloric acid. The aqueous solution was extracted with diethyl ether (100 mL), basified to pH 14 with 30% aqueous sodium hydroxide and finally extracted repeatedly with 10% methanol/methylene chloride (4×50 mL). The combined organic extracts are dried over magnesium sulfate, filtered and concentrated to afford 2,3,4,5-tetrahydro-1H-benzo[d]azepine as a pale yellow oil (1.2 g/81%) that solidifies on standing. 1H NMR (400 MHz, CDCl3) δ 7.1 (m, 4H), 2.91 (m, 8H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([OH:25])[C:22](O)=[O:23])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:40]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:41](=[O:48])[C@@H:42]1[CH2:46][C@H:45]([F:47])[CH2:44][NH:43]1)=O)(C)(C)C>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@H:21]([OH:25])[C:22]([N:43]1[CH2:44][C@@H:45]([F:47])[CH2:46][C@H:42]1[C:41]([NH:40][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:48])=[O:23])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Reactant: CC(C)(C)OC(=O)N(C(=O)[C@@H]1C[C@H](F)CN1)C(C)(C)C
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](F)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Yield: 39.1 %

Procedure:
Following a procedure similar to that described in Example 1, but using 222 mg (0,5 mmol) of (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid and 144 mg (0.5 mmol) of (4S)-N-t-butoxycarbonyl-4-fluoro-N-t-butyl-L-prolinamide, 120 mg of the title compound were obtained as a colorless powder, melting at 95°-100° C.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[C:3](/[C:7]#[N:8])\[C:4](=[S:6])[NH2:5].OO>C(O)C>[NH2:5][C:4]1[S:6][N:1]=[C:2]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[C:3]=1[C:7]#[N:8]
Reactant: N#C/C(C(N)=S)=C(/N)c1ccc([N+](=O)[O-])cc1
Agent: OO
Solvent: CCO
Product: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A suspension of Example 96D (23 g, 9.26 mmol) in ethanol (100 mL) was treated with 31% H2O2 (2 mL, 1.85 mmol), stirred at room temperature overnight, poured into ice water, and filtered. The filter cake was washed with water and dried to provide 2.2 g (96% yield) of the desired product. MS(ESI(−)) m/e 245 (M−H)−.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[N:30]=[CH:29][C:28]3[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=3)[C:22]2=[O:36])=[N:8][CH:9]=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:51]=[C:50]([CH3:52])[O:49][N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[N:30]=[CH:29][C:28]3[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=3)[C:22]2=[O:36])=[N:8][CH:9]=[CH:10][C:11]=1[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:51]=[C:50]([CH3:52])[O:49][N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)no1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)on3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C
Yield: 87.3 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (438 mg, 1.06 mmol), 129a (150 mg, 0.60 mmol), Pd(dppf)Cl2 (19 mg, 0.026 mmol), K3PO4 (224 mg, 1.06 mmol), sodium acetate (87 mg, 1.06 mmol), water (5 drops), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the reaction mixture was heated at 100° C. for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The mixture was cooled down to room temperature and filtered. The filtrate was concentrated under reduced pressure to afford 129b (300 mg, 87%) as a dark oil, which was used in next step without further purification. MS-ESI: [M+H]+ 573.3
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:19][O:20][C:21]([CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1)=[O:22]>>[CH3:19][O:20][C:21]([CH:23]1[CH2:28][N:27]([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:26][CH2:25][NH:24]1)=[O:22]
Reactant: COC(=O)C1CNCCN1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Product: COC(=O)C1CN(c2c(C=O)c3ccccc3n2-c2ccccc2)CCN1
Yield: 9 %

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with piperazine-2-carboxylic acid methyl ester as described in Example 1 to afford 4-(3-formyl-1-phenyl-1H-indole-2-yl)-piperazine-2-carboxylic acid methyl ester (9% yield) as a yellow solid. LC/MS: MS 364 (M+H); RT 2.54 min; NMR (CDCl3): 10.29 (1H, s), 8.26 (1H, d), 7.07-7.65 (m, buried), 6.98 (1H, d), 3.60-4.10 (4H, m), 2.60-3.55 (6H, m).
Reaction SMILES: [CH3:1][CH:2]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:31])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:30])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[C:3](=[O:10])[CH2:4]C(OCC)=O.Br[CH2:33][C:34]([CH3:61])=[CH:35][CH2:36][CH2:37][C:38]([CH3:60])=[CH:39][CH2:40][CH2:41][C:42]([CH3:59])=[CH:43][CH2:44][CH2:45][C:46]([CH3:58])=[CH:47][CH2:48][CH2:49][C:50]([CH3:57])=[CH:51][CH2:52][O:53]C(=O)C.[H-].[Na+].[OH-].[K+]>CCOCC.C(O)C>[CH3:57][C:50]([CH2:49][CH2:48][CH:47]=[C:46]([CH3:58])[CH2:45][CH2:44][CH:43]=[C:42]([CH3:59])[CH2:41][CH2:40][CH:39]=[C:38]([CH3:60])[CH2:37][CH2:36][CH:35]=[C:34]([CH3:61])[CH2:33][CH2:4][C:3](=[O:10])[CH:2]([CH3:1])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:31])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:30])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])=[CH:51][CH2:52][OH:53]
Reactant: CC(=O)OCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CBr
Reactant: CCOC(=O)CC(=O)C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)C(=O)CCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCO
Yield: 95.2 %

Procedure:
As in Example 7 (4), ethyl 3,7,11,15,19-pentamethyl-6,10,14,18-eicosatetraen-2-one-1-carboxylate (4.3 g) and 1-bromo-2,6,10,14,18-pentamethyl-20-acetoxy-2,6,10,14,18-eicosapentaene (4.8 g) are reacted in ether (59 ml) in the presence of sodium hydride (0.26 g). The product is added to a solution of potassium hydroxide (1.68 g) in ethanol (32 ml), and the resultant mixture is treated as in Example 1 (4) to give 3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,26,30,34,38-tetracontanonaen-22-on-1-ol (6.8 g). IR: 3400, 1000 cm-1 (OH); 1705 cm-1 (C=O); 1668 cm-1 (C=C). NMR (carbon tetrachloride): δ 1.59 (s), 1.66 (s), 2.01 (m), 2.7 (m), 4.1 (m), 5.05 (m).
Reaction SMILES: C(OC1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18](O)=CC=2)C(=O)C=1)C1C=CC=CC=1.[CH3:23][C:24]([O:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]2[CH:41]=[CH:40][N:39]([C:42]3[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=3)[C:38](=[O:49])[CH:37]=2)=[CH:30][CH:29]=1)([CH3:26])[CH3:25]>>[CH3:26][C:24]([O:27][C:28]1[CH:29]=[CH:30][C:31](/[CH:34]=[CH:35]/[C:36]2[CH:41]=[CH:40][N:39]([C:42]3[CH:43]=[CH:44][C:45]([O:48][CH2:14][CH2:13][N:12]4[CH2:15][CH2:20][CH2:19][CH2:18]4)=[CH:46][CH:47]=3)[C:38](=[O:49])[CH:37]=2)=[CH:32][CH:33]=1)([CH3:23])[CH3:25]
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(O)cc1
Reactant: CC(C)(C)Oc1ccc(/C=C/c2ccn(-c3ccc(O)cc3)c(=O)c2)cc1
Product: CC(C)(C)Oc1ccc(/C=C/c2ccn(-c3ccc(OCCN4CCCC4)cc3)c(=O)c2)cc1

Procedure:
Step (3) of Example 12 was repeated except that 4-benzyloxy-1-(4-hydroxyphenyl)-1H-pyridin-2-one was replaced with 4-((E)-2-{4-[(2-methyl-2-propyl)oxy]phenyl}vinyl)-1-(4-hydroxyphenyl)-1H-pyridin-2-one, to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]([CH3:24])=[C:22]([C:25]([OH:27])=[O:26])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:28])[CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1.[OH-].[Na+:30]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]([CH3:24])=[C:22]([C:25]([O-:27])=[O:26])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:28])[CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1.[Na+:30]
Reactant: Cc1c(-c2ccc(-c3ccccc3F)cc2)nc2ccc(F)cc2c1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(-c2ccc(-c3ccccc3F)cc2)nc2ccc(F)cc2c1C(=O)[O-]
Yield: 99.7 %

Procedure:
The compound of Example 28 (37.5 g, 0.10 mole) was suspended in 1,000 ml of ethanol and treated with 1N NaOH (100 ml, 0.10 mole). The mixture was warmed and stirred until clear; the ethanol and water were evaporated at reduced pressure to give 39.6 g of the white solid sodium 2-(2'-fluoro-1,1'-biphenyl-4-yl)-6-fluoro-3-methylquinoline-4-carboxylate, m.p. >360°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:6][C:7]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:8]=1[O:9][CH2:10][C@@H:11]1[O:16][C@@H:15]([O:17][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[CH2:19]Br)[CH2:14][CH2:13][CH2:12]1.[I-].[Na+]>CN(C)C=O>[Cl:6][C:7]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:8]=1[O:9][CH2:10][C@@H:11]1[O:16][C@@H:15]([O:17][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[CH2:19][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:14][CH2:13][CH2:12]1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc(OC[C@H]2CCC[C@H](OC(CBr)c3ccc(Cl)cc3Cl)O2)c(Cl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(OC[C@H]2CCC[C@H](OC(Cn3ccnc3)c3ccc(Cl)cc3Cl)O2)c(Cl)c1
Temperature: 130 °C

Procedure:
A mixture of 163 mg of imidazole, 317 mg of the isomer of lesser polarity of trans-6-(2,4-dichlorophenoxymethyl)-2-[2-bromo-1-(2,4-dichlorophenyl)ethoxy]tetrahydropyran and 180 mg of sodium iodide in 5 ml of dimethylformamide was stirred whilst heating at 130° C. for 10 hours, and then treated and purified as in Example 34(b)(i), to give 136 mg of the isomer of lesser polarity of the title compound, as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([B:12]2[O:16][C:15](C)(C)C(C)(C)[O:13]2)=[C:8](CO)[CH:9]=1)([O-:3])=[O:2]>Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[B:12]([OH:13])[O:16][CH2:15][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2CO)OC1(C)C
Agent: Cl
Product: O=[N+]([O-])c1ccc2c(c1)COB2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
(5-Nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (CI) (1.25 g, 4.48 mmol) was dissolved in 6 M HCl (100 mL) at 60° C. and stirred overnight. The mixture was then cooled to the room temperature and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine and dried over anhydrous MgSO4 to give 5-nitrobenzo[c][1,2]oxaborol-1(3H)-ol (CII) as a brown solid (800 mg, 4.47 mmol, 99% yield). The crude product was used without further purification for step 4. ESIMS found for C7H6BNO4 m/z 180.1 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:7]=[C:6]2[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:22][CH:21]=1.[CH3:34][S:35]([Cl:38])(=[O:37])=[O:36].C(N(CC)CC)C>C1COCC1>[ClH:38].[CH:28]1([CH2:27][O:26][C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([NH:2][S:35]([CH3:34])(=[O:37])=[O:36])[CH:4]=4)[N:9]=[C:8]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:7]=3)=[CH:25][CH:24]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2nc(-c3ccccc3)cc(Nc3ccc(OCC4CCCCC4)cc3)c2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc2nc(-c3ccccc3)cc(Nc3ccc(OCC4CCCCC4)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a suspension of 6-amino-4-(p-cyclohexylmethoxyanilino) -2-phenylquinoline hydrochloride (0.21 g, 0.5 mmol) in anhydrous THF (10 ml) at 0° C. was added methanesulfonyl chloride (69 mg, 0.6 mmol) followed by addition of triethylamine (61 mg, 0.6 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The solvent was removed by rotary evaporation and the residue partitioned between ethyl acetate (EtOAc) and 1M hydrochloric acid. The layers were separated, the organic layer was washed with saturated sodium bicarbonate and dried (Na2SO4) and the solvent was removed by rotary evaporation. The crude material was dissolved in warm methanol and treated with 1M HCl in ether. After 2 hours at room temperature, the solvent was removed by rotary evaporation and the residue recrystallized from methanol/ether to give 4-(p-cyclohexylmethoxyanilino)-6-methylsulfonamido-2-phenylquinoline hydrochloride (38%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl.Cl[CH2:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=1)[O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.O>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=1)[O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: COCCO
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 70 °C

Procedure:
1.1 g (0.015 mol) of 2-methoxyethanol was dissolved in 50 ml THF. To this solution 1.5 g (0.03 mol, 50% oil dispersion) NaH, (0.015 mol) 2-(3-chloromethylphenoxymethyl)quinoline hydrochloride, was added slowly. After the addition was completed, the mixture was heated at 70° C. bath temperature for overnight. The reaction mixture was poured into water and extracted with ether. The ether extract was washed with water, dried and concentrated to dryness under reduced pressure. The residue was passed through a silica gel column using hexane/ethylacetate (3:1) as eluent. Evaporation of eluent gave light yellow oil (1.1 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])=[C:4]([C:9]2[C:10]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[C:11]=3[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].C(O)(=O)C.[N:43]([O-])=O.[Na+]>C(OCC)(=O)C.O>[F:38][C:32]1[CH:33]=[C:34]([F:37])[CH:35]=[CH:36][C:31]=1[O:30][C:3]1[C:2]2[N:1]=[N:43][NH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[CH:19]=[CH:18][N:17]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:21])=[O:22])[C:11]=2[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=1
Reactant: O=N[O-]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(N)c(N)c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5[nH]nnc5c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
A solution of 4-[3,4-diamino-2-(2,4-difluorophenoxyl)phenyl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.040 g, 0.074 mmol) in acetic acid (0.1 mL, 3 mmol) was treated with water (0.37 mL, 21 mmol) followed by sodium nitrite (0.026 g, 0.37 mmol) and stirred at 20° C. for 30 min. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate (2×) and brine, dried with magnesium sulfate, filtered, and concentrated to give the desired product (32 mg, 78%) as a crude brown residue that was used immediately without further purification. LCMS calculated for C27H20F2N5O4S (M+H)+: m/z=548.1. found: 548.1.