Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35](=[O:56])[NH:36][C@H:37]([C:45]1[O:46][C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[N:48][N:49]=1)[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].Cl.[O:68]=[C:69]1[CH:73]=[CH:72][C:71](=[O:74])[N:70]1[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80]([NH:82][NH2:83])=[O:81]>>[O:74]=[C:71]1[CH:72]=[CH:73][C:69](=[O:68])[N:70]1[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80]([NH:82][NH:83][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35](=[O:56])[NH:36][C@H:37]([C:45]1[O:46][C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[N:48][N:49]=1)[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:81]
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Agent: Cl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
7.4 mg (8.1 mmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and 6.3 mg (24.2 mmol) of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide hydrochloride were coupled and worked up in analogy to Intermediate 157. 1.6 mg (13% of theory) of the title compound were obtained as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C@@H:12]([NH2:14])[CH3:13])[CH:6]=1.C(N(CC)CC)C.CN1CCCC1=O.C(N[CH2:38][C@@H:39]([C:48]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[C:54]2[C:49]=1[CH:50]=[CH:51][C:52](=[O:66])[NH:53]2)[O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])C1C=CC=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C@@H:12]([NH:14][CH2:38][C@@H:39]([C:48]2[CH:57]=[CH:56][C:55]([O:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[C:54]3[C:49]=2[CH:50]=[CH:51][C:52](=[O:66])[NH:53]3)[O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH3:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(C[C@H](C)N)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cccc(C[C@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1
Yield: 21.7 %

Procedure:
A solution of [3-((S)-2-aminopropyl)phenyl]acetic acid methyl ester (632 mg, 3.05 mmol) and triethylamine (1.27 mL, 9.15 mmol) in N-methylpyrrolidinone (3.4 mL, 35 mmol) was added to 8-benzyloxy-5-[(R)-2-bromo-1-(tert-butyldimethylsilanyloxy)-ethyl]-1H-quinolin-2-one (1.5 g, 3.0 mmol) (see, e.g., U.S. Patent Publication No. 2006/0035931 A1, published Feb. 16, 2006). The resulting mixture was microwaved (300 watts) at 100° C. for 1.5 h. The mixture was then diluted with EtOAc (20 mL) and this solution was washed repeatedly with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-10% MeOH in DCM) to give the title compound (400 mg, 20% yield) as a yellow oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37](O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([O:19][C:18]2[C:13]3[C:12]4[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]=4[N:10]([S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:8])=[O:9])[C:14]=3[CH:15]=[N:16][C:17]=2[C:20]#[N:21])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1ncc2c(c1O)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(C#N)ncc3c2c2cc(Br)cnc2n3S(=O)(=O)c2ccccc2)CC1
Temperature: 50 °C
Yield: 78.1 %

Procedure:
A solution of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (15.8 g, 36.8 mmol), 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (18.5 g, 92.0 mmol) and triphenylphosphine (24.1 g, 92.0 mmol) in anhydrous THF (100 mL) was treated dropwise with diethyl azodicarboxylate (18.1 mL, 92.0 mmol) and the mixture heated to 50° C. for 40 minutes. After this time, the reaction mixture was concentrated in-vacuo and the resultant residue purified by flash chromatography (silica, 2×330 g column, ISCO, 0-10% ethyl acetate in dichloromethane). The resultant product was further purified by trituration with diethyl ether to afford the title compound as an off-white solid (17.6 g, 78%). 1H NMR (300 MHz, CDCl3): 9.57 (s, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.57 (d, J=2.3 Hz, 1H), 8.23-8.22 (m, 2H), 7.64-7.63 (m, 1H), 7.53-7.51 (m, 2H), 5.20-5.20 (m, 1H), 4.07 (d, J=13.6 Hz, 2H), 3.06 (t, J=12.1 Hz, 2H), 2.20-2.19 (m, 2H), 1.85-1.85 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:35][C:36]([F:51])([F:50])[C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1>>[CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:31])[F:32])[CH:24]=2)[CH:12]=[C:13]([C:39]2[CH:38]=[C:37]([C:36]([F:51])([F:50])[F:35])[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 50 %

Procedure:
The title compound was prepared in 50% yield from 2-(4′-chloro-5-trifluoromethanesulfonyloxy-3′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Intermediate C) and 3,5-bis-trifluoromethylphenylboronic acid under the conditions described in Example 26, step (d).
Reaction SMILES: Cl.[Si]([O:9][CH2:10][C@@H:11]([N:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C@H:33]3[CH2:38][CH2:37][O:36][CH2:35][C@H:34]3[F:39])[N:27]=2)=[CH:22][C:21]1=[O:40])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C>O1CCOCC1.CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:11]([N:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C@H:33]4[CH2:38][CH2:37][O:36][CH2:35][C@H:34]4[F:39])[N:27]=3)=[CH:22][C:21]2=[O:40])[CH2:10][OH:9])=[CH:13][C:14]=1[F:19]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(N[C@H]3CCOC[C@H]3F)n2)cc1=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=c1cc(-c2ccnc(N[C@H]3CCOC[C@H]3F)n2)ccn1[C@H](CO)c1ccc(Cl)c(F)c1
Reaction time: 1 h

Procedure:
A 4.0M solution of hydrogen chloride (18.6 mL, 74.5 mmol) in dioxane was slowly added to a cold (0° C.) solution of 1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one (8.6 g, 14.9 mmol) in MeOH (40 mL), and the mixture was stirred for 1 hour. The reaction mixture was concentrated, and the residue was taken up in saturated NaHCO3 and extracted with ethyl acetate (2×). The organic layer was dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (1:4) to give 1-((S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one as a solid (4.58 g, 66%; 97% e.e. by chiral HPLC (Chiral Tech, column OD-H, 4.6 mm×250 mm, 5u, 30% ethanol/70% hexanes, 1 mL/minute)). 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J=5.0 Hz, 1H), 7.41 (m, 2H), 7.21-7.09 (m, 3H), 6.89 (d, J=5.0 Hz, 1H), 6.76 (d, J=7.0 Hz, 1H), 6.20 (m, 1H), 5.55 (d, J=8.2 Hz, 1H), 4.75 (d, J=50 Hz, 1H), 4.38-4.18 (m, 4H), 4.05 (m, 1H), 3.69-3.53 (m, 2H), 3.12 (br, s, 1H), 2.08-1.84 (m, 2H); m/z (APCI-pos) M+1=463.1, 465.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([Cl:9])=[C:6](Br)[CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH:32]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)=[CH2:33].C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[Cl:9][C:5]1[N:4]=[CH:3][C:2]([NH2:1])=[CH:7][C:6]=1/[CH:33]=[CH:32]/[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1
Reactant: C=Cc1ccncc1
Reactant: Nc1cnc(Cl)c(Br)c1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1cnc(Cl)c(/C=C/c2ccncc2)c1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A solution of 3-amino-5-bromo-6-chloropyridine (2.0 g, 9.64 mmol), Pd2(dba)3 (440 mg, 0.48 mmol), tri-o-tolylphosphine (438 mg, 1.44 mmol), 4-vinylpyridine (2.08 mL, 19.28 mmol), and triethylamine (4.03 mL, 29 mmol) in DMF (30 mL) was stirred at 100° C. for 15 hours, cooled to room temperature, treated with ethyl acetate (200 mL), washed twice with brine, dried (MgSO4), filtered and concentrated. The residual solid recrystallized from hexanes/dichloromethane to provide desired product (1.86 g, 84%). MS (APCI) m/e 232 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)COc1ccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1ccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Yield: 59.6 %

Procedure:
A mixture of methyl 2-[4-[2-(4,5-diphenyl-2oxazolyl]ethyl]phenoxy]acetate (5 g, 12 mmold), 5N sodium hydroxide solution (7.26 mL) and methanol (100 mL) was heated on a steam bath for 45 minutes. The solution was concentrated in vacuo diluted with water and 2N HCl solution an a white solid filtered off. Recrystallization from methanol gave 2-[4-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid (2.88 g, 59%), m.p. 147°-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:18]4[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[CH3:25][C@H:26]1[O:31][C@H:30]([CH3:32])[CH2:29][NH:28][CH2:27]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:18]4[CH2:23][CH2:22][CH:21]([N:28]5[CH2:27][C@@H:26]([CH3:25])[O:31][C@H:30]([CH3:32])[CH2:29]5)[CH2:20][CH2:19]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: C[C@@H]1CNC[C@@H](C)O1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C2CCN(CC34CC(c5ccccc53)c3ccc(Cl)cc34)CC2)C[C@@H](C)O1

Procedure:
To a solution of 1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (380 mg, 1.12 mmol) in toluene (10 mL) under nitrogen was added trans 2,6-dimethylmorpholine (155 mg, 1.34 mmol, 1.23 eq). The trans 2,6-dimethylmorpholine isomer was obtained by spinning band distillation of the commercially available mixture of 2,6-dimethylmorpholines. The solution was heated to reflux passing the solvent through 3 A molecular sieves in a modified Dean Stark arrangement. After 2 h, the solvent was removed, replaced with tetrahydrofuran (1.0 mL), and cooled to 0° C. Excess hydrogen chloride gas was bubbled into the solution and then purged with nitrogen. The reaction was warmed to room temperature and a solution of sodium cyanoborohydride (210 mg, 3.35 mmol, 9 eq) in methanol (0.50 mL) was added. A significant amount of gas was evolved. The reaction was stirred for 18 h and quenched with 2.5N NaOH (10 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The reaction product was purified by flash chromatography over silica gel (40 mL, eluent: 30% ethyl acetate in hexane) to yield the title compound as a white solid (371 mg, 76%), mp 237° C. (dec); NMR (CDCl3, 300 MHz) 7.23 (dd, J=5.9, 1.6 Hz, 1H), 7.12 (m, 4H), 6.92 (m, 3H), 4.22 (s, 1H), 3.97 (m, 2H), 3.67 (t, J=6.3 Hz, 1H), 3.58 (t, J=6.2 Hz, 1H), 3.32 (s, 2H), 2.52 (dd, J=11.0, 3.1 Hz, 2H), 2.19 (m, 4H), 1.71 (m, 3H), 1.20 (d, J=6.4 Hz, 6H) MS (CI, CH4) m/z 437 (M+1,100), 439 (34), 465 (M+29,15) The free base was dissolved in diethyl ether and acidified with ethereal HCl. The hydrochloride salt was filtered, rinsed with fresh ether and dried in vacuo (50° C., 13 pascal, 18 h) to yield a white solid, mp 237°-240° C. (dec).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1>>[Cl:14][C:15]1[CH:20]=[C:19]([O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Oc1cccc2ccccc12
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Oc2cccc3ccccc23)ccn1
Yield: 94.8 %

Procedure:
Using the method of Example 3, Step A, naphthalen-1-ol (909 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) afforded 2-chloro-4-(naphthalen-1-yloxy)pyridine (1.53 g, 95% yield) as an oil. 1H NMR (CDCl3) δ 8.22 (d, 1H), 7.93 (d, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.48-7.56 (m, 3H), 7.21 (d, 1H), 6.79-6.83 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29](O)=[O:30])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)[N:4]=1.[CH:42]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH2:44][CH2:43]1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([NH:48][S:45]([CH:42]5[CH2:44][CH2:43]5)(=[O:47])=[O:46])=[O:30])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)[N:4]=1
Reactant: COc1cccc(-c2cc(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(OC)n2)c1
Reactant: NS(=O)(=O)C1CC1
Product: COc1cccc(-c2cc(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)nc(OC)n2)c1
Yield: 63.4 %

Procedure:
The acid 25 (150 mg, 0.26 mmol) was reacted with cyclopropane sulphonamide (64 mg, 0.53 mmol) according to the procedure described in Example 16 step g, which gave the title compound (110 mg, 62%), MS [M+1] 668.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][NH2:34].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:34][O:33][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32][O:27]4)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cc1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
To a solution of (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)acrylic acid (103 mg) in DMF (2 mL) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (35.8 mg), HOBt (48.8 mg), and EDCI (56.1 mg) and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution, sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1) to give (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (76 mg) as pale yellow form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(NCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine (35 mg, 0.125 mmol) from Example 5 step 3 was dissolved in DMF (0.62 mL), cesium carbonate (203 mg, 0.62 mmol) was added, stirred at room temperature for 10 minutes. 2-bromo-5-(methylsulfonyl)pyridine (32.4 mg, 0.137 mmol) was added. Reaction was run at room temperature for 1 hour, then heated to 50° C. for 5 hours. Water (10 mL) was added, extracted with EtOAc (10 mL×2), second wash with brine (10 mL). The organic phase was dried by magnesium sulfate, filter, concentrated and purified by preparative-TLC (Analtech Silica Gel GF 1500 μM, 20×20 cm) using 30% acetone/hexane to give the title compound as a white solid.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]([C:16]1[CH:48]=[CH:47][C:19]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([C:27]([C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][CH:39]4[CH2:44][CH2:43][S:42](=[O:45])[CH2:41][CH2:40]4)=[O:37])=[C:31]([F:46])[CH:30]=3)=[O:28])[CH2:23][CH2:22]2)=[CH:18][CH:17]=1)([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9])(C)(C)C.[F-].[K+]>O1CCCC1>[F:46][C:31]1[CH:30]=[C:29]([C:27]([N:24]2[CH2:25][CH2:26][N:21]([CH2:20][C:19]3[CH:47]=[CH:48][C:16]([C:7]([OH:6])([C:8]([F:11])([F:9])[F:10])[C:12]([F:13])([F:14])[F:15])=[CH:17][CH:18]=3)[CH2:22][CH2:23]2)=[O:28])[CH:34]=[CH:33][C:32]=1[NH:35][C:36]([NH:38][CH:39]1[CH2:44][CH2:43][S:42](=[O:45])[CH2:41][CH2:40]1)=[O:37]
Reactant: CC(C)(C)[Si](C)(C)OC(c1ccc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCS(=O)CC4)c(F)c3)CC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F)NC1CCS(=O)CC1
Temperature: 80 °C
Yield: 18.1 %

Procedure:
To a stirring solution of 1-[4-(4-{4-[1-(tert-butyl-dimethyl-silanyloxy)-2,2,2-trifluoro-1-trifluoromethyl-ethyl]-benzyl}-piperazine-1-carbonyl)-2-fluoro-phenyl]-3-(1-oxo-tetrahydro-thiopyran-4-yl)-urea (0.173 mmol, 130 mg) in tetrahydrofuran (1 mL) was added potassium fluoride (50% wt on celite) (1.727 mmol, 201 mg). The resulting suspension was heated to 80° C. for 48 hours. The reaction mixture was filtered through celite and purified by SCX chromatography to afford the title compound (20 mg). MS (ESI) m/z 639.0 [M+H]+
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[N:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](Cl)=[O:16])=[CH:10][CH:9]=1)(=[O:7])[CH3:6].O>[N+](C1C=CC=CC=1)([O-])=O>[C:5]([C:8]1[CH:23]=[CH:22][C:11]2[O:12][C:13]3=[N:21][CH:20]=[CH:19][CH:18]=[C:14]3[C:15](=[O:16])[C:10]=2[CH:9]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)c1ccc(Oc2ncccc2C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CC(=O)c1ccc2oc3ncccc3c(=O)c2c1
Temperature: 80 °C

Procedure:
1.68 g of powdered anhydrous aluminum chloride is added to a solution of 1.15 g of 2-(p-acetylphenoxy)nicotinoyl chloride in 5 ml of nitrobenzene at 20°-30°C, and the mixture is heated at 80°C for 3.5 hours. After cooling, water is added to the reaction mixture to decompose the aluminum chloride. After removing the nitrobenzene by distillation, the mixture is extracted with chloroform, and the extract is concentrated. The residue is recrystallized from toluene to give 7-acetyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine melting at 195-196°C.
Reaction SMILES: [CH3:1][C@@H:2]([NH2+:11][CH3:12])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH3:1][C@H:2]([NH:11][CH3:12])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[NH2+][C@H](C)[C@@H](O)c1ccccc1
Solvent: CCO
Product: CN[C@@H](C)[C@H](O)c1ccccc1
Temperature: 25 °C
Yield: 90 %

Procedure:
(R,S)-2-methoxy-2-(2-methoxyphenyl)acetic acid (20.75 g, 105.9 mM) was dissolved in hot ethanol (53 mL) and added quickly to a vigorously stirred, hot solution of (1S,2R)-(+)-ephedrine (17.5 g, 105.9 mM) in ethanol (50 mL). The mixture was allowed to cool to ambient temperature. The white solid obtained was collected by filtration and recrystallised from ethanol to give a crystalline ephedrine salt (15.65 g). This salt was dissolved in water (150 mL). The solution was acidified by adding 1 equivalent of M hydrochloric acid (43 mL) and then extracted with ethyl acetate (2×100 mL). The extracts were washed with water, then with saturated sodium chloride solution, dried (MgSO4) and the solvent evaporated to give (+)-2-methoxy-2-(2-methoxyphenyl)acetic acid as an oil, which slowly crystallised to give solid (8.0 g), 21 [α]D =+151.8° (c=1, Et0H); optical purity 97.6% e.e. [by NMR analysis using the NMR shift reagent (R)-(-)-TFAE].
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH:9]=[CH:8][C@H:7]2[S:11][C:12]([NH2:14])=[N:13][C@@H:6]12)=[O:4].C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][CH2:10][CH:9]=[CH:8][C:7]1[S:11][C:12](=[NH:14])[NH:13][CH:6]=1
Reactant: COC(=O)N1CC=C[C@H]2SC(N)=N[C@H]21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)NCC=Cc1c[nH]c(=N)s1
Temperature: 25 °C
Yield: 28.1 %

Procedure:
Compound 6 (0.070 g, 0.32 mmol) is heated in DMSO (5 ml) at 175° C. for 2 h. After cooling to ambient temperature, the reaction mixture is poured onto ice-cold water (100 ml), basified (5% Na2CO3) to a pH of greater than 10 and then extracted with DCM (3×150 ml). The organic phases are combined, washed with saturated NaCl solution, dried (MgSO4) and then evaporated to dryness. The crude product obtained (0.06 g) is then purified by chromatography on thick layers of silica gel (DCM, sat. NH3/MeOH, 95:5). The product (Rf=0.49, DCM/MeOH/NH3 vap., 95:5) is obtained in the form of a brown semisolid (20 mg, 0.09 mmol, 28%), an inseparable mixture of E/Z (9:1) isomers according to 1H NMR.