Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@H]1CN(C2N=CC=CN=2)C[C@H]1NC1C(CC)=NC(C2C(C)=NC(OC)=CC=2)=C(CC)N=1)C.Br[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.[Cl:42][C:43]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:44]=1[C:51]1[N:52]=[C:53]([CH2:68][CH3:69])[C:54]([NH:59][C@H:60]2[C@@H:64]([O:65][CH2:66][CH3:67])[CH2:63][NH:62][CH2:61]2)=[N:55][C:56]=1[CH2:57][CH3:58]>>[Cl:42][C:43]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:44]=1[C:51]1[N:52]=[C:53]([CH2:68][CH3:69])[C:54]([NH:59][C@H:60]2[C@@H:64]([O:65][CH2:66][CH3:67])[CH2:63][N:62]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH2:61]2)=[N:55][C:56]=1[CH2:57][CH3:58]
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC
Reactant: Brc1ccccn1
Agent: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Product: CCO[C@H]1CN(c2ccccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(3R,4S)-4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine but substituting 2-bromopyridine and 1,3-Bis(2,6-di-l-propylphenyl)-4,5-dihydro-imidzaolium tetrafluoroborate, and starting with 5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.17, 1.24–1.34, 2.51, 2.76, 3.56, 3.76, 3.86, 3.99, 4.25, 4.91, 5.25, 6.61, 6.90, 7.02, 7.25, 8.41; IR (diffuse reflectance) 2352 (w), 2340 (w), 2062 (w), 1940 (w), 1906 (w), 1600 (s), 1567, 1559, 1555, 1482 (s), 1474 (s), 1441 (s), 1392, 1287, 1229 cm−1 HRMS (ESI) calcd for C26H32N5O2Cl+H1 482.2322. found 482.2332.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[C:5]2[CH:17]=[C:18]([C:21](=[O:30])[NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:19]=[CH:20][C:4]=2[N:3]=1.[CH3:31][C:32]1[N:36]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-])=O)=[CH:40][CH:39]=2)[C:35]2[CH:47]=[CH:48][C:49]([C:51](=[O:60])[NH:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)=[CH:50][C:34]=2[N:33]=1.[H][H]>[Pd].CO>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:6]2[C:5]3[CH:17]=[C:18]([C:21](=[O:30])[NH:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH:19]=[CH:20][C:4]=3[N:3]=[C:2]2[CH3:1])=[CH:13][CH:12]=1.[NH2:44][C:41]1[CH:40]=[CH:39][C:38]([CH2:37][N:36]2[C:35]3[CH:47]=[CH:48][C:49]([C:51](=[O:60])[NH:52][CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=4)=[CH:50][C:34]=3[N:33]=[C:32]2[CH3:31])=[CH:43][CH:42]=1
Reactant: [H][H]
Reactant: Cc1nc2cc(C(=O)NCc3ccccn3)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: Cc1nc2cc(C(=O)NCc3ccccn3)ccc2n1Cc1ccc(N)cc1
Product: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2n1Cc1ccc(N)cc1

Procedure:
Thirty milliliters of methanol and 0.20 g of 5% palladium on carbon were added to 2.32 g of a mixture of 2-methyl-1-(4-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole and 2-methyl-1-(4-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]-benzimidazole, and the mixture was stirred in a hydrogen atmosphere at room temperature until the starting material disappeared. The solid material was separated through filtration, and the filtrate was concentrated. The resulting residue was purified through medium-pressure silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 85:15) to separate 1-(4-aminobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole and 1-(4-aminobenzyl)-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole. Each of these compounds was crystallized from a mixed solvent of chloroform and diethyl ether. The crystals were separated through filtration, and were dried to give 0.354 g of 1-(4-aminobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-benzimidazole (261) and 0.330 g of 1-(4-aminobenzyl)-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole (262).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[NH2:15][C:16]1[C:17]([C:24]([NH:26][CH2:27][C@@H:28]([N+:32]([CH2:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)([CH3:34])[CH3:33])[CH2:29][CH2:30][CH3:31])=[O:25])=[N:18][C:19]([Cl:23])=[C:20]([NH2:22])[N:21]=1.[CH2:45]1[O:47][C@H:46]1[CH2:48][OH:49]>CCO>[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[NH2:15][C:16]1[C:17]([C:24]([NH:26][CH2:27][C@@H:28]([N+:32]([CH2:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH2:45][C@@H:46]([OH:47])[CH2:48][OH:49])=[CH:40][CH:39]=2)([CH3:34])[CH3:33])[CH2:29][CH2:30][CH3:31])=[O:25])=[N:18][C:19]([Cl:23])=[C:20]([NH2:22])[N:21]=1
Reactant: OC[C@H]1CO1
Reactant: CCC[C@@H](CNC(=O)c1nc(Cl)c(N)nc1N)[N+](C)(C)CCCc1ccc(O)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCC[C@@H](CNC(=O)c1nc(Cl)c(N)nc1N)[N+](C)(C)CCCc1ccc(OC[C@@H](O)CO)cc1

Procedure:
Triethylamine (63.5 μL, 0.46 μmol) is added to a solution of ((S)-1-{[(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-butyl)-[3-(4-hydroxy-phenyl)-propyl]-dimethyl-ammonium trifluoroacetate (Example 121)(50 mg, 0.091 mmol) in EtOH (5 mL) and the solution is heated to reflux. Once at reflux (S)-glycidol (6.04 μL, 0.091 mmol) is added and the reaction is heated at reflux overnight. Two further portions of (S)-glycidol (2×6.04 μl, 2×0.091 mmol) are added and the reaction is heated at reflux for 24 h. The reaction mixture is concentrated in vacuo and purification by reverse phase chromatography (Isolute™ C18, 0-30% acetonitrile in water with 0.1% TFA) affords the title compound. M+ 509. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (1H, t), 8.20-7.18 (2H, br), 7.24-6.98 (2H, br), 6.99 (2H, d), 6.79 (2H, d), 5.70-3.98 (2H, br), 3.93-3.89 (1H, m), 3.85-3.67 (3H, m), 3.60-3.43 (3H, m), 3.42 (2H, d), 3.39-3.28 (1H, m), 3.04 (3H, s), 3.01 (3H, s), 2.48-2.32 (2H, m), 2.00-1.71 (3H, m), 1.61-1.37 (3H, m), 0.91 (3H, t).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH:23]([CH3:26])[CH2:24][OH:25])[C:18]1[CH:17]=[C:16]([C:27]#[N:28])[CH:15]=[CH:14][C:13]=1[S:12]2.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>C(Cl)Cl>[CH3:29][S:30]([O:25][CH2:24][CH:23]([N:19]1[C:18]2[CH:17]=[C:16]([C:27]#[N:28])[CH:15]=[CH:14][C:13]=2[S:12][C:11]2[C:20]1=[CH:21][CH:22]=[C:9]([Cl:8])[CH:10]=2)[CH3:26])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(COS(C)(=O)=O)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (30 cc) is added to a solution of 7-chloro-10-[(2RS)-1-hydroxy-2-propyl]-2-phenothiazinecarbonitrile (40 g) in methylene chloride (400 cc). The mixture is cooled to 0° C. and then treated dropwise in the course of 1 hour with methanesulphonyl chloride (16.6 cc). Distilled water (1 liter) is then added, after which the constituents of the mixture are allowed to settle and the organic phase is separated and washed with distilled water (500 cc). The organic phase is then dried over magnesium sulphate, filtered and concentrated under reduced pressure (30 mm Hg; 4 kPa) to a residual volume of 100 cc. Isopropyl ether (150 cc) is then introduced slowly and the mixture is left stirred for 30 minutes. Isopropyl ether (300 cc) is then added slowly and the suspension is stirred for 48 hours. The precipitate is filtered off, washed with isopropyl ether (2×50 cc) and dried at 40° C. under reduced pressure (5 mm Hg; 0.67 kPa) to give (2RS)-2-(7-chloro-2-cyano-10-phenothiazinyl)propyl methanesulphonate (34.53 g), m.p. 132° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]1.CN1CC[O:12][CH2:11]C1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.Cl.Cl.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:7][N:4]1[CH2:5][CH2:6][C@H:2]([O:1][C:11]([N:40]2[CH2:41][CH2:42][N:37]([C:34]3[CH:33]=[CH:32][C:31]([CH3:30])=[CH:36][CH:35]=3)[CH2:38][CH2:39]2)=[O:12])[CH2:3]1
Reactant: CN1CCOCC1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: CN1CC[C@H](O)C1
Agent: Cl
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(C(=O)O[C@H]3CCN(C)C3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.4 %

Procedure:
(S)-(+)-3-Hydroxy-N-methylpyrrolidine (1.51 g, 14.9 mmol) was dissolved in DCM (20 mL) and cooled to 0° C. NMM (1.70 mL, 15.5 mmol) and 4-nitrophenyl chloroformate (3.16 g, 15.7 mmol) were added. The reaction mixture was stirred at 0° C. for 30 minutes and then a solution of 4-(4-methylphenyl)piperazine dihydrochloride (3.71 g, 14.9 mmol) and DIPEA (7.40 mL, 44.7 mmol) in DMF (20 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and then washed with 1 M aq Na2CO3 solution (5×200 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (100 mL) and methyl isocyanate resin (2.0 g) was added, the reaction mixture was shaken for 14 h, filtered and then concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo. The resulting residue was purified by normal phase column chromatography (eluting with DCM, followed by a 90:10 mixture of DCM:MeOH) to give [(3S)-1-methylpyrrolidin-3-yl]-4-(4-methylphenyl)-piperazine-1-carboxylate (606 mg, 13.0%) as a yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:22]([O:24]CC)=[O:23])[CH:14]=[C:15]([CH:21]=3)[C:16]([O:18]CC)=[O:17])[CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:27]1[CH:28]=[C:29]([C:38]([O:40]CC)=[O:39])[CH:30]=[C:31]([CH:37]=1)[C:32]([O:34]CC)=[O:33]>C1COCC1.CO.[OH-].[Na+]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:22]([OH:24])=[O:23])[CH:14]=[C:15]([CH:21]=3)[C:16]([OH:18])=[O:17])[CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:27]1[CH:37]=[C:31]([C:32]([OH:34])=[O:33])[CH:30]=[C:29]([CH:28]=1)[C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)c1cc(C(=O)OCC)cc(-c2ccc3ccc(-c4cc(C(=O)OCC)cc(C(=O)OCC)c4)cc3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(C(=O)O)cc(-c2ccc3ccc(-c4cc(C(=O)O)cc(C(=O)O)c4)cc3c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g of tetraethyl 5,5′-(naphthalene-2,7-diyl)diisophthalate was dissolved in 60 mL of mixed solvent of THF and MeOH (v/v=1:1), 20 mL of 2N NaOH aqueous solution was added. The mixture was stirred at room temperature overnight. After the organic phase was removed, the aqueous phase was acidified with dilute hydrochloric acid to a white precipitate, which was filtered and washed with water several times. Yield: 1.46 g, 91%. 1H NMR (300 MHz, DMSO-d6): δ 7.95 (d, 2H), 8.11 (d, 2H), 8.53 (m, 8H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].F[C:11]1[CH:12]=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([CH3:17])[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[CH:12]=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([CH3:17])[CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(C)c2)CC1

Procedure:
1-Acetylpiperazine (6.23 g), 5-fluoro-2-nitrotoluene (7.51 g) and sodium carbonate (5.12 g) in dimethylformamide (40 ml) were stirred at 100° overnight, evaporated, and the residue partitioned between ethyl acetate and water. The organic layer was dried (sodium sulphate), evaporated, and the residue chromatographed over Merck (Trade Mark) t.l.c. grade silica, developing and eluting with 5% methanol in dichloromethane, yield 10.92 g of the title compound. A small portion was recrystallized from methanol/ethyl acetate, m.p. 133°-7°.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2C=CC(N3CCN(C)CC3)=C[N:11]=2)=[CH:5][C:4]([C:23]2[CH:33]=[CH:32][CH:31]=[C:30]([N:34]3[CH2:46][CH2:45][N:37]4[C:38]5[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=5[CH:44]=[C:36]4[C:35]3=[O:47])[C:24]=2[CH2:25][O:26][C:27](=[O:29])[CH3:28])=[CH:3]1.Br[C:49]1C=C[CH:57]=[C:56]([N:60]2[CH2:72]CN3C4CCCCC=4C=C3C2=O)[C:50]=1[CH2:51]OC(=O)C.C([O-])([O-])=[O:75].[Na+].[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>[C:27]([O:26][CH2:25][C:24]1[C:30]([N:34]2[CH2:46][CH2:45][N:37]3[C:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=4[CH:44]=[C:36]3[C:35]2=[O:47])=[CH:31][CH:32]=[CH:33][C:23]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:57]=[C:56]([C:50]([OH:75])([CH3:51])[CH3:49])[N:60]([CH3:72])[N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)(=[O:29])[CH3:28]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)OCc1c(Br)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)CC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C(C)(C)O)n(C)n3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 40 %

Procedure:
Following Example 119, 113b (120 mg, 0.35 mmol), 113a (180 mg, 0.39 mmol), 1N Na2CO3 (0.8 mL) and Palladium tetrakis (20 mg, 5 mol %) were reacted to give 134c (85 mg, 40% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[NH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=O)=[CH:12][CH:11]=1>C(=O)(O)[O-].[Na+]>[NH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]2[O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccccc1O
Reactant: Nc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 190 °C
Yield: 61.6 %

Procedure:
This provides an example of a benzoxazole instead of a benzothiazole. In accordance with synthetic Route A, a mixture of 2-aminophenol (1.5 g, 0.0136 mol) and 4-aminobenzoic acid (1.885 g, 0.0136 mol) in polyphosphoric acid (20 g) was heated at about 190° C. for 4 hours, then cooled and poured into 10% aqueous sodium bicarbonate (400 ml). The product was collected by filtration, washed with water and recrystallised from methanol-H2O (10:1) to give small pale yellow crystals (1.76 g, 62%), m.p. 176°-178° C. (lit 185° C.); vmax /cm-1 3472, 3322, 3186, 1614, 1500, 1454, 1312, 1242, 1170, 1066, 830, 742; δH (DMSO-d6) 7.87(2H, d, J8.6, 2',6'-H), 7.69-7.64(2H, m, 5, 6-H), 7.36-7.28(2H, m, 4, 7-H), 6.70(2H, d, J8.6, 3', 5'-H), 6.02 (2H, s, NH2).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:7]=[CH:6][C:5]=1[N+:19]([O-:21])=[O:20].[OH-].[Na+].Cl>O.CO>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[O:10][C:8]1[CH:7]=[CH:6][C:5]([N+:19]([O-:21])=[O:20])=[C:4]([CH:9]=1)[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1cc(Oc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Oc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To a solution of compound (1A) (66 g, 0.21 mol) in water/MeOH (180/180 mL) was added NaOH (27 g, 0.68 mol), and the mixture was heated to reflux for 2 h. After cooling to room temperature, the reaction was acidified with 10% HCl and extracted into EtOAc. The organic layer was washed with brine, dried over sodium sulfate, concentrated in vacuo, and crystallized from ether/hexane to afford 53 g of 5-(2,4-difluoro-phenoxy)-2-nitro-benzoic acid (1B).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)(=[O:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[CH3:7][C:5]1[O:6][C:2]([C:17]2[CH:18]=[CH:19][C:14]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:15][CH:16]=2)=[CH:3][C:4]=1[CH:8]=[O:9]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1oc(Br)cc1C=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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1oc(-c2ccc(S(C)(=O)=O)cc2)cc1C=O
Reaction time: 8 h
Yield: 62 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.5 g), 4-(methanesulfonyl)phenylboronic acid (2.0 g), tetrakis(triphenylphosphine)palladium(0) (0.5 g), 2N aqueous sodium carbonate solution (10 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 100% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.3 g, 64%) as a yellow crystal.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CN(C)C=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:42][C:43]1([CH3:60])[C:47]2[C:48]([O:52][C:53]3[N:58]=[CH:57][C:56]([NH2:59])=[CH:55][N:54]=3)=[CH:49][CH:50]=[CH:51][C:46]=2[O:45][CH2:44]1>C(OCC)(=O)C>[CH3:42][C:43]1([CH3:60])[C:47]2[C:48]([O:52][C:53]3[N:54]=[CH:55][C:56]([NH:59][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12])=[CH:57][N:58]=3)=[CH:49][CH:50]=[CH:51][C:46]=2[O:45][CH2:44]1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1(C)COc2cccc(Oc3ncc(N)cn3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2cccc3c2C(C)(C)CO3)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15 %

Procedure:
To a solution of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (20.14 mg, 0.099 mmol) in N,N-dimethylformamide (1.5 mL) DIPEA (0.029 mL, 0.165 mmol) and TBTU (33.9 mg, 0.106 mmol) were added. The mixture reaction was stirred during 15 minutes at room temperature, then 2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinamine (Intermediate 65, 17 mg) was added. The reaction mixture was stirred during 48 hours at room temperature. The mixture was diluted with ethyl acetate (5 ml) and washed with brine (3×5 ml). The organic layer was separated, dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel flash chromatography using a 10 g-SNAP column and cyclohexane/ethyl acetate from 100/0 to 40/60 as eluent to afford the title compound as a white solid (4.4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:32][CH:31]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23]C2CCCCO2)=[CH:19][CH:18]=1)(=[O:14])=[O:13].Cl>C(O)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1)[C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:34][CH:35]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1Cl)N(Cc1ccc(OC2CCCCO2)cc1)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1Cl)N(Cc1ccc(O)cc1)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.8 %

Procedure:
To a solution of crude 2-chloro-N-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-N-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-4-trifluoromethyl-benzenesulfonamide (0.096 g, 0.15 mmol) in 4 mL ethanol was added 1 mL of 1.2N HCl. The reaction mixture was stirred at room temperature for 24 hr. and was diluted with 10 mL saturated aqueous sodium bicarbonate. The aqueous solution was washed with methylene chloride (2×10 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by preparative TLC (1.0 mm silica gel layer, elution with 10% methanol/methylene chloride) to afford 0.039 g (84%) of the title compound. MS 555.3 (M+1)+
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9](=[O:14])[O:10][CH2:11]2)=[CH:7][C:6]=1[O:15][C:16](=[O:18])[CH3:17])(=O)C.N1CCOCC1>CN(C)C=O>[OH:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9](=[O:14])[O:10][CH2:11]2)=[CH:7][C:6]=1[O:15][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)Oc1cc2c(cc1OC(C)=O)C(=O)OC2
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CC(=O)Oc1cc2c(cc1O)COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic acid 6-acetoxy-3-oxo-1,3-dihydro-isobenzofuran-5-yl ester (5.0 g) was dissolved in N,N-dimethylformamide (100 ml) followed by addition of morpholine (1.78 ml). The solution was stirred at room temperature overnight followed by concentration in reduced pressure. Ethyl acetate (200 ml) was added to the remainder. The organic phase was washed two times with a mixture of aqueous HCl (50 ml, 2M) and brine (50 ml). The organic solvent was dried over anhydrous Na2SO4, filtered and evaporated to dryness.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:27])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:35][C:34]([C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=2)[C:39]#[N:40])=[CH:33][C:32](=O)[O:31]1>>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:27][C:32](=[O:31])[CH2:33][C:34]([C:36]1[CH:43]=[CH:42][CH:41]=[C:38]([C:39]#[N:40])[CH:37]=1)=[O:35])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(OC(F)(F)F)cc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(OC(F)(F)F)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 62.1 %

Procedure:
Prepared from [2-amino-4-(4-trifluoromethoxy-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G36) (196 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (126 mg, 0.55 mmol) according to the general procedure K. Obtained as an off-white solid (175 mg).
Reaction SMILES: [C:1]([CH:4]([NH:13][CH:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].C(=O)(O)[O-].[Na+].[CH2:31](I)[CH3:32]>CC(N(C)C)=O>[CH2:31]([O:2][C:1]([CH:4]([NH:13][CH:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:3])[CH3:32]
Reactant: O=C(O)C(CCc1ccccc1)NC1CCc2ccccc2NC1=O
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(CCc1ccccc1)NC1CCc2ccccc2NC1=O

Procedure:
A solution of 3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (6.0 g), sodium bicarbonate (4.0 g), and ethyl iodide (11.6 g) in dimethylacetamide (200 ml) was stirred at room temperature under nitrogen for 72 hours. The reaction mixture was filtered and evaporated under high vacuum. Water (250 ml) was added, and the resulting solution extracted with dichloromethane (2×400 ml). The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure to give 3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one as a mixture of isomers. NMR(CDCl3)δ 9.22(s, 1H), 4.10(2 superimposed quartets, 2H), 1.13(2 superimposed triplets, 3H).