Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C@@H:5]([N:17]1[CH2:25][C:24]2[C:19](=[C:20]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:21]=[CH:22][C:23]=2[Cl:26])[C:18]1=[O:33])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1.[OH-].[Na+].O>C1COCC1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([NH:27][C:28]([CH:30]2[CH2:31][CH2:32]2)=[O:29])=[C:19]2[C:24]=1[CH2:25][N:17]([C@@H:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1)[CH2:4][C:3]([OH:34])=[O:2])[C:18]2=[O:33]
Reactant: CCOc1cc([C@@H](CC(=O)OC)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc([C@@H](CC(=O)O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of (3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid methyl ester (3.0 g, 6.2 mmol) in THF (60 ml) was added NaOH (10N, 1.2 ml, 12 mmol). The mixture was stirred at room temperature overnight. To it was added water (50 ml). The mixture was extracted with EtOAc (50 ml×2). The aqueous layer was acidified by conc. HCl until pH=6. The resulted cloudy mixture was extracted with EtOAc (50 ml×2). The organice layer was washed with water (30 ml×2), brine (30 ml), dried over Na2SO4, filtered and concentrated in vacuo to give (3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid as a white solid (2.8 g, 99%): mp, 118-120° C.; 1H NMR (CDCl3) δ 0.86-0.91 (m, 2H, c-CH2), 1.05-1.11 (m, 2H, c-CH2), 1.45 (t, J=7.0 Hz, 3H, OCH2CH3), 1.65-1.70 (m, 1H, c-CH), 3.13 (dd, J=6, 15 Hz, 1H, CHH), 3.23 (dd, J=10, 15 Hz, 1H, CHH), 3.86 (s, 3H, OCH3), 4.00-4.11(m, 3H, NCHH+OCH2CH3), 4.32 (d, J=18 Hz, 1H, NCHH), 5.80-5.86 (m, 1H, CHN), 6.83-6.92 (m, 3H, Ar), 7.35 (d, J=9 Hz, 1H, Ar), 8.41 (d, J=9 Hz, 1H, Ar), 10.39 (s, 1H, NHCO). 13CNMR (CDCl3): δ 8.4, 8.5, 14.7, 16.1, 36.7, 45.9, 51.8, 55.9, 64.6, 111.5, 112.4, 118.9, 119.0, 1198, 121.9, 130.1, 132.9, 136.7, 139.0, 148.7, 149.5, 168.7, 172.8, 173.8; Anal Calcd for C24H25ClN2O6+0.37H2O: C, 60.11; H, 5.41; N, 5.84. Found: C, 60.11; H, 5.25; N, 5.64, H2O, 1.40.
Reaction SMILES: OC1C=C(CN/C=C2\C(=O)NC(=O)C3C\2=CC(I)=CC=3)C=CC=1NC(=O)C1C=CC=CC=1.[NH2:33][C:34]1[CH:55]=[CH:54][C:37]([CH2:38][NH:39]/[CH:40]=[C:41]2\[C:42](=[O:53])[NH:43][C:44](=[O:52])[C:45]3[C:50]\2=[CH:49][C:48]([Br:51])=[CH:47][CH:46]=3)=[CH:36][C:35]=1[O:56][Si](C(C)C)(C(C)C)C(C)C.[Cl:67][CH:68]([Cl:72])[C:69](Cl)=[O:70]>>[Br:51][C:48]1[CH:49]=[C:50]2[C:45](=[CH:46][CH:47]=1)[C:44](=[O:52])[NH:43][C:42](=[O:53])/[C:41]/2=[CH:40]\[NH:39][CH2:38][C:37]1[CH:54]=[CH:55][C:34]([NH:33][C:69](=[O:70])[CH:68]([Cl:72])[Cl:67])=[C:35]([OH:56])[CH:36]=1
Reactant: CC(C)[Si](Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)ccc1N)(C(C)C)C(C)C
Reactant: O=C(Cl)C(Cl)Cl
Agent: O=C1NC(=O)c2ccc(I)cc2/C1=C/NCc1ccc(NC(=O)c2ccccc2)c(O)c1
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccc(NC(=O)C(Cl)Cl)c(O)c1

Procedure:
Following the acetylation and desilylation procedure employed for the preparation of N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]benzamide, (4Z)-4-[({4-amino-3-[(triisopropylsilyl)oxy]benzyl}amino)methylene]-6-bromoisoquinoline-1,3(2H,4H)-dione (60 mg, 0.11 mmol) is reacted with dichloroacetyl chloride (110 μL, 1.1 mmol). Following desilylation and precipitation, N-[4-({[(Z)-(6-bromo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)-2-hydroxyphenyl]-2,2-dichloroacetamide is obtained 8.8 mg, 16%).
Reaction SMILES: [N+]([O-])(O)=O.N([O-])=O.[Na+].[OH:9][C:10]1([CH:23]=[CH:22][CH:21]=[CH:20][CH:19]1[C:24]([F:27])([F:26])[F:25])[CH2:11][C:12]1[N:13]([CH3:18])[C:14](S)=[N:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:9][C:10]1([CH:23]=[CH:22][CH:21]=[CH:20][CH:19]1[C:24]([F:27])([F:26])[F:25])[CH2:11][C:12]1[N:13]([CH3:18])[CH:14]=[N:15][CH:16]=1
Reactant: Cn1c(CC2(O)C=CC=CC2C(F)(F)F)cnc1S
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: Cn1cncc1CC1(O)C=CC=CC1C(F)(F)F
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a well stirred solution of nitric acid (8 ml) and water (8 ml) was added sodium nitrite (0.93 g). The reaction vessel was cooled externally with a water bath. 4-(1-hydroxy-2'-trifluoromethylbenzyl)-2-mercapto-3-methylimidazole (4.0 g) was added over 5 minutes to the greenish solution. After 1 hour, more sodium nitrite (3.0 g) was added and stirring was continued overnight. Sodium carbonate was added to saturate the mixture. Ethyl acetate was added to dissolve all organic solids. The remaining solid was removed by filtration. Water was added to the filtrate. The layers were separated after being shaken. Removal of water under reduced pressure gave 4-(1-hydroxy-2'-trifluoromethylbenzyl)-3-methylimidazole (2.8 g).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[N:21]=[CH:22][C:23]([C:26](=[NH:28])[NH2:27])=[N:24][CH:25]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[OH-].[Na+]>CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[N:21]=[CH:22][C:23]([C:26](=[NH:27])[NH2:28])=[N:24][CH:25]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1cnc(C(=N)N)cn1)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(CNc2cnc(C(=N)N)cn2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21
Yield: 11 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(2-amidinopyrazin-5-yl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 11% of theory, C23H23N9O3 (473.5); Rf value: 0.55 (Reversed Phase silica gel RP-8; 5% saline solution/methanol=6:4); EKA mass spectrum: (M+H)+=474; (M+H+Na)+=496.6.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[CH2:12]([N+:19](C)(C)C)[C:13]1C=CC=C[CH:14]=1.C(#N)C=C>C(O)(C)(C)C>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:14][CH2:13][C:12]#[N:19]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: Sc1nc2ccccc2s1
Agent: [OH-]
Solvent: C=CC#N
Solvent: CC(C)(C)O
Product: N#CCCSc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
2-Mercaptobenzothiazole (25.0 g; 0.15 moles) was mixed with t-butanol (125 ml) and benzyltrimethylammonium hydroxide (40% in methanol; 3 ml). Acrylonitrile (15.9 g; 0.30 moles) was added dropwise and the mixture stirred at room temperature for 7 days. The product was removed by filtration and recrystallized from benzene.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O:19]C(C)C)=[O:18])[C:12]2=[CH:11][C:10]=1[CH3:23])=[O:8].CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[CH:11][C:10]=1[CH3:23])=[O:8]
Reactant: Cc1cc2n(c1C(=O)c1cccn1C)CCC2C(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc2n(c1C(=O)c1cccn1C)CCC2C(=O)O

Procedure:
A solution of 500 mg. of isopropyl 5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylate in 15 ml. of methanol is treated with a solution of 1.05 g. of potassium carbonate in 8 ml. of water. The reaction mixture is refluxed under nitrogen atmosphere for 30 minutes, cooled, and evaporated to dryness. The residue is taken up in 10 ml. of 10% aqueous hydrochloric acid and 50 ml. of water and the resultant mixture extracted with ethyl acetate (3 × 50 ml.). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, to give 5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid [(A), R and R1 = CH3 ].
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[CH2:3][CH2:4][O:5][C:6]([C:8]1([C:31]([O:33]CCC(C)C)=[O:32])[O:12][C:11]2[CH:13]=[CH:14][C:15]([CH2:17][C@H:18]([NH:20][CH2:21][C@@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[OH:23])[CH3:19])=[CH:16][C:10]=2[O:9]1)=[O:7]>C(Cl)(Cl)Cl>[CH3:1][CH:2]([CH3:39])[CH2:3][CH2:4][O:5][C:6]([C:8]1([C:31]([OH:33])=[O:32])[O:12][C:11]2[CH:13]=[CH:14][C:15]([CH2:17][C@H:18]([NH:20][CH2:21][C@@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[OH:23])[CH3:19])=[CH:16][C:10]=2[O:9]1)=[O:7]
Reactant: CC(C)CCOC(=O)C1(C(=O)OCCC(C)C)Oc2ccc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)cc2O1
Solvent: ClC(Cl)Cl
Product: CC(C)CCOC(=O)C1(C(=O)O)Oc2ccc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)cc2O1

Procedure:
The title compound was prepared from 5-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3-methylbutyl)ester according to the procedure of Example 22 as an off-white solid; 1H NMR (DMSO) δ 0.80-0.85 (m, 6H), 1.02-1.09 (m, 3H), 1.45 (q, 2H), 1.55-1.70 (m, 1H), 3.01-3.05 (m, 2H), 3.15-3.25 (m, 1H), 3.26-3.40 (m, 2H), 4.15 (t, 2H), 5.00-5.08 (m, 1H), 6.45 (bs, 1H), 6.55-6.65 (m, 1H), 6.75-6.90 (m, 2H), 7.45-7.49 (m, 5H), 7.51 (s, 1H); IR (Kbr): 3394 cm-1 (--OH), 1651 cm-1 (C=O); MS (ES) m/z 492.0 (MH+); [α]D25 -22° (c, 1.0, CHCl3). Anal. Calcd. for C25H30ClNO7 : C, 61.04; H, 6.15; N, 2.85; Cl, 7.20. Found: C, 59.80; H, 6.10; N, 2.89; Cl, 7.10.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:15]Br>C(Cl)Cl>[Br:15][C:10]1[N:9]=[C:8]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=12
Reactant: BrBr
Reactant: Clc1nccn2c(C3CCC3)ncc12
Solvent: ClCCl
Product: Clc1nccn2c(C3CCC3)nc(Br)c12
Reaction time: 0.17 h

Procedure:
To a clear, vigorously stirred and cooled (0° C.) solution of 8-chloro-3-cyclobutylimidazo[1,5-a]pyrazine (0.75 g, 3.6 mmol) in DCM (90 mL) was added Br2 (0.28 mL, 5.4 mmol) in DCM (90 mL) over 34 min. The reaction became a light orange suspension towards the end of the addition. Stirring was continued at the temperature for 10 min then concentrated under reduced pressure at rt. The mixture was diluted with H2O (˜20 mL), basified with 2 M aq NaOH to ˜pH 7-9 and extracted with DCM (3×80 mL). The organic layers were washed (satd aq NaHCO3, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (50 g cartridge, 100% DCM) yielded the title compound as an off-white solid; 1H NMR (400 MHz, CD2Cl2) δ 7.41 (d, J=5.2 Hz, 1H), 7.16 (d, J=5.2 Hz, 1H), 3.70 (qud, J=1.2 Hz, 8.4 Hz, 1H), 2.48-2.33 (m, 4H), 2.13-2.02 (m, 1H), 1.98-1.88 (m, 1H); MS (ES+): m/z 286.1 (90), 288.0 (100) [MH+]; HPLC: tR=3.33 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[C:6]([CH3:22])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH:19]([CH3:21])[CH3:20])[CH:10]=1.[I-:24].[K+].II>C(O)C.CN.O>[CH3:1][C:2]1[C:3]([I:24])=[C:4]([OH:23])[CH:5]=[C:6]([CH3:22])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH:19]([CH3:20])[CH3:21])[CH:10]=1
Reactant: COCOc1ccc(Cc2c(C)cc(O)cc2C)cc1C(C)C
Reactant: [I-]
Agent: CN
Agent: II
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COCOc1ccc(Cc2c(C)cc(O)c(I)c2C)cc1C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 3,5-dimethyl-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)phenol (1.0 g, 3.18 mmol, Chiellini et al., Bioorg. Med. Chem. Lett. 10:2607 (2000)) in C2H5OH (30.0 mL) and 40% aqueous methylamine (6.20 mL) at 0° C. was added a solution of potassium iodide (2.5 g, 15.0 mmol) and iodine (0.98 g, 3.82 mmol) in H2O (6.20 mL). The reaction mixture was stirred at 0° C. for 1 h, quenched with water and extracted with ethyl acetate (2×30 mL). The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 20% ethyl acetate in hexanes to afford 3,5-dimethyl-2-iodo-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)phenol as white solid: 1H NMR (300 MHz, CD3OD): δ 6.93 (m, 2 H), 6.65 (m, 2 H), 5.18 (s, 2 H), 4.05 (s, 2 H), 3.48 (s, 3 H), 3.30 (m, 1 H), 2.41 (s, 3 H), 2.19 (s, 3 H), 1.18 (d, J=6.6 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:5); Rf=0.60.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[Cl:11].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([N:10]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)[CH:7]=[CH:6][C:5]=1[Cl:11]
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)c1cc(N)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N=Cc2cccc(Br)c2)ccc1Cl
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture solution of 5-amino-2-chloro-benzoic acid methyl ester (21 g, 113.2 mmol), 3-bromo-benzaldehyde (21 g, 113.2 mmol) and p-toluenesulfonic acid (431 mg, 2.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 5-[(3-bromo-benzylidene)-amino]-2-chloro-benzoic acid methyl ester (39.8 g, quant.) as a pale-white solid: MS calcd. for C18H11BrClNO2 353.62, obsd. (ESI+) [(M+H)+]351.9 & 353.9.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:34]=[C:35]([Cl:40])[CH:36]=[C:37]([Cl:39])[CH:38]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
1.21 g (2.01 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 0.305 mg (8.06 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR33## is obtained as white foam; TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.37; FD-MS: M+ =503.
Reaction SMILES: BrCCCS(Cl)(=O)=O.NCC[CH2:12][CH2:13][S:14]([NH:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:41])[CH:25]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:16])=[O:15].[CH2:42]([N:44](CC)CC)C>ClCCl>[NH2:44][CH2:42][CH2:12][CH2:13][S:14]([NH:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:41])[CH:25]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:15])=[O:16]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1CCCC1CNS(=O)(=O)CCCCN
Reactant: CCN(CC)CC
Agent: O=S(=O)(Cl)CCCBr
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1CCCC1CNS(=O)(=O)CCCN
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 72 %

Procedure:
A solution of Part A 3-bromopropyl sulfonyl chloride (1.06 g, 4.8 mmol) in dichloromethane (5 mL) was added dropwise to a cooled (-10° C.) stirred solution of Example 6a, Part B amine (1.05 g, 3.02 mmol) and triethyl amine (1.44 mL, 9.6 mmol) in dichloromethane (15 mL), After a few minutes, a precipitate formed. The suspension was stirred at -10° C. for 2.5 hours, diluted with dichloromethane (35 mL) and washed with 1N HCl solution (2×15 mL). The dichloromethane solution was dried (MgSO4), filtered and the solvent was removed in vacuo. The crude oil was purified on silica gel (Merck, 150 mL) eluting with 50% ethyl acetate in hexane to give title compound as a white foam (1.160 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:22]3[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][N:23]=3)=[O:26])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1ccc(Cl)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-chloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a crystalline white solid. MS (ISP): m/z=381.2 [M+H]+.
Reaction SMILES: C([N:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]2([C:25]3[C:20](=[CH:21][C:22]([Br:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH:5]1[C:28]1([CH3:31])[CH2:30][CH2:29]1)C=C.[CH3:32][O:33][CH:34]([Si:36]([CH3:39])([CH3:38])[CH3:37])[CH3:35].C[N+]1([O-])CCOCC1.[CH3:48][C:49]([CH3:51])=[O:50]>O.O=[Os](=O)(=O)=O>[Br:26][C:22]1[CH:21]=[C:20]2[NH:19][C:18](=[O:27])[C:6]3([CH:7]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=4)[CH2:8][C:9](=[O:10])[N:4]([CH2:48][CH:49]([OH:50])[CH2:51][OH:33])[CH:5]3[C:28]3([CH3:31])[CH2:30][CH2:29]3)[C:25]2=[CH:24][CH:23]=1.[CH3:32][O:33][CH:34]([Si:36]([CH3:39])([CH3:38])[CH3:37])[CH3:35]
Reactant: C=CCN1C(=O)CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Br)ccc32)C1C1(C)CC1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: COC(C)[Si](C)(C)C
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Product: CC1(C2N(CC(O)CO)C(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Br)ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a mixture of racemic (2′R,3R,4′S)-1′-allyl-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (100 mg, 0.16 mmol), N-methylmorpholine N-oxide (30 mg, 0.22 mmol) and 3 drops of water in acetone (3 mL) was added OsO4 (10 mg, 0.04 mmol). The mixture was stirred at room temperature for 1 h, then purified by Prep-HPLC to give the title compound as a white solid (40 mg, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].N1C=CC=CC=1.[CH2:16]([O:18][CH:19]=[CH:20][C:21](Cl)=[O:22])[CH3:17].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:21](=[O:22])/[CH:20]=[CH:19]/[O:18][CH2:16][CH3:17]
Reactant: CCOC=CC(=O)Cl
Reactant: Cc1cccc(Cl)c1N
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CCO/C=C/C(=O)Nc1c(C)cccc1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a cold stirring solution of 2-chloro-6-methylaniline (59.5 g 0.42 mol) and pyridine (68 ml, 0.63 mol) in THF (600 mL) was added 3-ethoxyacryloyl chloride (84.7 g, 0.63 mol) slowly keeping the temp at 0-5° C. The mixture was then warmed and stirred for 2 h. at 20° C. Hydrochloric acid (1N, 115 mL) was added at 0-10° C. The mixture was diluted with water (310 mL) and the resulting solution was concentrated under vacuum to a thick slurry. The slurry was diluted with toluene (275 mL) and stirred for 15 min. at 20-22° C. then 1 h. at 0° C. The solid was collected by vacuum filtration, washed with water (2×75 mL) and dried to give 74.1 g (73.6% yield) of (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide). 1H NMR (400 Hz, DMSO-d6) δ 1.26 (t, 3H, J=7 Hz), 2.15 (s, 3H), 3.94 (q, 2H, J=7 Hz), 5.58 (d, 1H, J=12.4 Hz), 7.10-7.27 (m, 2H, J=7.5 Hz), 7.27-7.37 (d, 1H, J=7.5 Hz), 7.45(d, 1H, J=12.4 Hz), 9.28 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 14.57, 18.96, 67.17, 97.99, 126.80, 127.44, 129.07, 131.32, 132.89, 138.25, 161.09, 165.36.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(NC(C)C)(C)C.C[Si](C[Li])(C)C.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[C:8]([B:26]([OH:27])[OH:25])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ccccn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ncccc1B(O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
A mixture of 2-methoxypyridine (23.2 g) and diisopropylamine (1.35 mL) in THF (223 mL) was added to (trimethylsilylmethyl)lithium (218 mL, 13.8 weight percent in hexanes) at −20° C. The lithiation was 84% complete after 7 hours. Tri-isopropylborate (40.8 g) was added at −20° C. over 40 minutes. The mixture was stirred overnight at ambient temperature. 5 percent NaOH (aq, 225 mL) was added. The aqueous layer was removed and brought to pH 5 by adding 10% HCl (aq). The resulting white precipitate was isolated by filtration. After drying, 22.23 g of 2-methoxypyridine-3-boronic acid was obtained (68% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[N:21]=2)=[CH:16][CH:15]=1)=[C:12]=[S:13]>>[OH:4][CH2:3][C@H:2]([NH:1][C:12]([NH:11][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:27][CH:26]=3)[N:21]=2)=[CH:18][CH:19]=1)=[S:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: N[C@@H](CO)c1ccccc1
Product: OC[C@H](NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccccc1

Procedure:
The title compound was prepared with (R)-2-amino-2-phenylethanol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole (Lambert, W.; et al., WO 2011017513) and isolated as an off-white solid (0.285 g, 69%): mp 98-101° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.37 (s, 1H), 8.40 (d, J=7.9 Hz, 1H), 8.07-8.01 (m, 4H), 7.73 (d, J=7.7 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.38-7.24 (m, 5H), 5.42 (s, 1H), 5.12 (s, 1H), 3.73 (s, 2H); ESIMS m/z 500 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@H:11]([NH2:12])[CH2:10][CH2:9][N:8]([CH2:13][CH2:14][S:15][C:16]2[CH:25]=[N:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[N:17]=2)[CH2:7]1)=[O:5])[CH3:2].[O:28]=[C:29]1[NH:34][C:33]2[CH:35]=[C:36]([C:39](O)=[O:40])[CH:37]=[CH:38][C:32]=2[S:31][CH2:30]1>>[CH2:1]([O:3][C:4]([C@@H:6]1[C@H:11]([NH:12][C:39]([C:36]2[CH:37]=[CH:38][C:32]3[S:31][CH2:30][C:29](=[O:28])[NH:34][C:33]=3[CH:35]=2)=[O:40])[CH2:10][CH2:9][N:8]([CH2:13][CH2:14][S:15][C:16]2[CH:25]=[N:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[N:17]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CN(CCSc2cnc3ccc(OC)cc3n2)CC[C@H]1N
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: CCOC(=O)[C@H]1CN(CCSc2cnc3ccc(OC)cc3n2)CC[C@H]1NC(=O)c1ccc2c(c1)NC(=O)CS2

Procedure:
The title compound is prepared as an orange semisolid (280 mg, 87% yield) following Scheme 3 and in analogy to Example 35 using (3S,4R)-4-amino-1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidine-3-carboxylic acid ethyl ester (216 mg, 0.50 mmol, 1.0 eq) and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (113 mg, 0.50 mmol, 1.0 eq) as starting material.