Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:70][Si:71]([C:74]([CH3:77])([CH3:76])[CH3:75])([CH3:73])[CH3:72])[CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:69]=[CH:68][C:28]([O:29][CH2:30][CH2:31][N:32]([CH3:67])[C:33]([C:35]3[CH:36]=[C:37]([S:41]([C:44]4[CH:45]=[C:46]5[C:51](=[C:52]([CH3:54])[CH:53]=4)[N:50]=[CH:49][C:48]([C:55]([NH2:57])=[O:56])=[C:47]5[NH:58][C:59]4[CH:64]=[CH:63][CH:62]=[C:61]([O:65][CH3:66])[CH:60]=4)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=3)=[O:34])=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1>CO>[Si:71]([O:70][C@H:20]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[CH2:21][NH:22][CH2:23][CH2:24][C:25]1[CH:69]=[CH:68][C:28]([O:29][CH2:30][CH2:31][N:32]([CH3:67])[C:33]([C:35]2[CH:36]=[C:37]([S:41]([C:44]3[CH:45]=[C:46]4[C:51](=[C:52]([CH3:54])[CH:53]=3)[N:50]=[CH:49][C:48]([C:55]([NH2:57])=[O:56])=[C:47]4[NH:58][C:59]3[CH:64]=[CH:63][CH:62]=[C:61]([O:65][CH3:66])[CH:60]=3)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=2)=[O:34])=[CH:27][CH:26]=1)([C:74]([CH3:77])([CH3:75])[CH3:76])([CH3:72])[CH3:73]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCOc5ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(OCc7ccccc7)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Solvent: CO
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCOc5ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Temperature: 0 °C
Reaction time: 72 h
Yield: 44.9 %

Procedure:
A solution of Intermediate 141 (0.3769 g, 0.3505 mmol) in MeOH (7 mL) was degassed by bubbling N2 through the solution for approximately 10 minutes. The solution was cooled to 0° C. and Pd/C (0.3850 g of 10 wt %) was added slowly. The reaction flask was purged and filled with H2 3× before stirring under H2 (1 atm, balloon). The reaction mixture was warmed to room temperature and reaction progress was monitored by LC-MS. After 72 h, the reaction mixture was filtered through a pad of Celite. The filter cake was washed with 1:1 DCM/MeOH. The filtrate was concentrated and the residue was dissolved in 3:1 MeOH/EtOAc. The solution was degassed and cooled as described above; Pd/C (0.311 g of 10 wt %) was added and the mixture was placed under H2 atmosphere as described above. Reaction progress was monitored by LC-MS. After 24 h, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient elution 1:19 to 1:3 MeOH/DCM) to yield the title compound (0.155 g, 45%) as a yellow solid. ES/MS calcd for C53H61N6O9SSi+ 985.4. Found m/z=985.5 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[N:4][C:5]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.CS(O)(=O)=O>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:13])=[N:4][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][O:14]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2nc[nH]n2)ccc1Br
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: Cc1nc(-c2ncn(C3CCCCO3)n2)ccc1Br
Temperature: 65 °C
Reaction time: 6 h
Yield: 85.1 %

Procedure:
To a suspension of 3-bromo-2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridine (96.0 g, 0.4 mol) in tetrahydrofuran (780 mL) was added 3,4-dihydro-2H-pyran (72.5 mL, 0.8 mol) and methanesulfonic acid (3.2 mL). The mixture was heated to 65° C. and the resulting yellow solution was allowed to stir at 65° C. for 6 h. The mixture was cooled to ambient temperature, quenched with triethylamine (23 mL), concentrated under reduced pressure and further dried in a high vacuum for 1 h. The resulting oil was dissolved in acetonitrile (250 mL) and the solution was added into water (750 mL) while stirring vigorously. More acetonitrile (80 mL) was added and the mixture was allowed to stir for 1 h. The resulting solids were filtered, washed with 1:4 acetonitrile/water (800 mL) and dried in a vacuum oven for 48 h to afford the product (110 g, 85% yield) as a white solid. The product was further purified by silica gel plug purification (1:1 hexanes/ethyl acetate) to give 88 g of the pure product as a white solid and 16.2 g of less pure product. MS (ESI) m/z 239.1 [M]+, 241.1 [M+2]+.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][C:15]3C=NC=[CH:19][CH:20]=3)[CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)(=[O:30])=[O:29])[CH2:9][C:8]=2[CH:36]=1)#[N:3].[Cl:37]CCCC1OCCO1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][CH2:15][CH2:20][CH2:19][Cl:37])[CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)(=[O:30])=[O:29])[CH2:9][C:8]=2[CH:36]=1)#[N:3]
Reactant: ClCCCC1OCCO1
Reactant: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1cccnc1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2CCCCCl
Reaction time: 1 h

Procedure:
To a solution of Compound B of Example 23 (410 mg, 1 mmol) dissolved in CH2Cl2 (10 mL) was added 2(chloropropyl)-1,3-dioxolane(0.53 mL, 4 mmol) followed by trifluoroacetic acid (10 mL) and triethylsilane (0.64 mL, 4 mmol). Stirring was continued for 1 hr and the solvent was removed under vacuum. The residue was neutralized with saturated aqueous Na2CO3, diluted with CH2Cl2, washed with brine and evaporated to a yellow solid (500 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5]CN.N[C@H:12](C(O)=O)CS>>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:12]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: N[C@@H](CS)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
1.3 (1), Lys:5.7 (6), Cys:-(2).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[N:6][C:5]([Cl:10])=[C:4]([Cl:11])[N:3]=1.[CH3:12]COCC.C[Mg]Br.[Cl-].[NH4+]>O1CCCC1>[NH2:1][C:2]1[C:7]([CH:8]([OH:9])[CH3:12])=[N:6][C:5]([Cl:10])=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1nc(Cl)c(Cl)nc1C=O
Reactant: CCOCC
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nc(Cl)c(Cl)nc1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In 3 ml of tetrahydrofuran there was dissolved 2-amino-5,6-dichloro-3-formylpyrazine (144 mg; 0.75 mM) prepared as in Example 1, Step B above, and then 2 ml of ether was added. The reaction mixture was cooled in a dry ice/acetone bath, and methyl magnesium bromide (0.75 ml of 11% solution in ether; 0.75 mM) was then added dropwise over 10 minutes. The reaction mixture was stirred for 0.25 hour at the cooled temperature, allowed to gradually warm to room temperature, and then stirred an additional 0.5 hour. Ammonium chloride solution was then added with stirring for 0.25 hour, followed by addition of more ether. Layers separated; the organic layer was washed with water; the aqueous layer extracted three times with ether, washed with water. The solvent was evaporated and the residue dried, then passed through a silica gel column, eluting first with dichloromethane, then 5% ethyl acetate in dichloromethane. Product yield was 98 mg.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:10][C@H:9]2[C@H:4]([C@@H:5]([CH2:16][OH:17])[O:6][C@@H:7]3[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@@H:8]32)[O:3]1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1/[CH:26]=[C:27]1\[C:28](=[O:39])[N:29]([C:36](Cl)=[O:37])[C:30]2[C:35]\1=[CH:34][CH:33]=[CH:32][CH:31]=2>N1C=CC=CC=1.C1COCC1>[CH3:15][C:12]1([CH3:14])[O:13][C@H:7]2[O:6][CH:5]([CH2:16][O:17][C:36]([N:29]3[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)/[C:27](=[CH:26]/[C:21]4[NH:22][C:23]([CH3:25])=[CH:24][C:20]=4[CH3:19])/[C:28]3=[O:39])=[O:37])[C@@H:4]3[O:3][C:2]([CH3:18])([CH3:1])[O:10][C@@H:9]3[C@H:8]2[O:11]1
Reactant: CC1(C)O[C@H]2[C@@H](O1)[C@@H](CO)O[C@@H]1OC(C)(C)O[C@@H]12
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC3O[C@@H]4OC(C)(C)O[C@@H]4[C@H]4OC(C)(C)O[C@@H]34)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
To a solution of 1,2,3,4-di-O-isopropylidene-D-galactopyranose (650 mg, 2.5 mmol) in 1.0 mL of pyridine and 2.0 mL of THF was added a suspension of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (150 mg, 0.5 mmol) at 0° C. The reaction mixture was then gradually warmed to room temperature, stirred for 4 h, and concentrated. The residue was triturated with water and washed with ether to give 170 mg (65%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid (3aR, 5aS, 8aS, 8bR)-2,2,7,7-tetramethyl-tetrahydro-bis[1,3]dioxolo[4,5-b;4′,5′-d]pyran-5-ylmethyl ester.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:19]1([CH:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:26]2[CH2:29][C:28](=[O:30])[CH2:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>C1COCC1.CCOCC.O>[C:31]1([CH:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:26]2[CH2:29][C:28]([CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3])([OH:30])[CH2:27]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 85.7 %

Procedure:
A solution of tert-butyl acetate (566 μL, 4.2 mmol) in THF (10 mL) was cooled to −78° C. To the solution was added LHMDS (5.25 mL of a 1.0 M solution in hexanes, 5.25 mmol), and the resulting mixture was stirred for 20 min at −78° C. To the solution was added 1-(diphenylmethyl)azetidin-3-one (500 mg, 2.1 mmol), prepared using procedures similar to those described in Example 15. After stirring for 1 h, saturated aqueous ammonium chloride was added, and the mixture was warmed to rt. Water and ether were added, and the resulting biphasic mixture was partitioned. The aqueous phase was extracted once with ether. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (80% hexanes: 20% ethyl acetate) to provide 1,1-dimethylethyl [1-(diphenylmethyl)-3-hydroxyazetidin-3-yl]acetate as a pale yellow solid (644 mg, 1.8 mmol, 87% yield). 1H NMR (400 MHz, CDCl3): δ 7.40 (m, 4H), 7.26 (m, 4H), 7.19 (m, 2H), 4.40 (s, 1H), 4.02 (s, 1H), 3.15 (m, 2H), 3.05 (m, 2H), 2.83 (s, 2H), 1.45 (s, 9H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH3:14])[NH:12][C:11](=[O:15])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:25][C:19]1[CH:18]=[C:17]([N:12]2[C@@H:13]([CH3:14])[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][C:11]2=[O:15])[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: C[C@@H]1NC(=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using (4S,5S)-4-(tert-butyldimethylsilyloxy)-5-methylpyrrolidin-2-one (1.06 g), 4-bromo-2-chlorobenzonitrile (1.0 g), cesium carbonate (2.25 g), tris(dibenzylideneacetone)dipalladium(0) (210 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (399 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 1.2 g, 71%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])[NH:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[NH:7][C:6]=2[N:19]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CCOC(C)=O>O1CCOCC1.O.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]>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:42])=[O:43])[C:37]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[O:11])[NH:9][CH:8]([C:12]6[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=6)[NH:7][C:6]=5[N:19]=4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=C1NC(c2cccc(F)c2)Nc2nc(Cl)ccc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)NC(c3cccc(F)c3)NC4=O)cc12
Temperature: 100 °C
Yield: 48.8 %

Procedure:
To a solution of 7-chloro-2-(3-fluorophenyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (66 mg, 0.237 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (100 mg, 0.199 mmol) and K3PO4.3H2O (106 mg, 0.398 mmol) in 1 mL of dioxane and 0.1 mL of water were added X-phos (10 mg) and Pd2(dba)3 (10 mg) under nitrogen. The mixture was heated at 100° C. for 6 h, concentrated in vacuo and the residue was suspended in water. The mixture was extracted with EtOAc and the organic phase was washed with brine, then dried over sodium sulfate. 2-(4-fluorophenyl)-5-(2-(3-fluorophenyl)-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-7-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (60 mg, yield: 49%) was obtained by the prep-TLC (PE:EtOAc=1:2). 1H-NMR (CD3OD, 400 MHz) δ 8.06 (d, J=7.6 Hz, 1H), 7.91˜7.95 (m, 2H), 7.81 (s, 1H), 7.77 (s, 1H), 7.37˜7.40 (m, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.21˜7.27 (m, 3H), 7.02˜7.08 (m, 2H), 5.96 (s, 1H), 3.27 (d, J=6.0 Hz, 3H), 2.90 (s, 3H), 2.80 (s, 3H). MS (M+H)+: 618.
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=2[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]=O.O>C(Cl)Cl>[C:20]1([C:10]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]=2/[N:9]=[CH:32]/[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccn1
Reactant: Nc1c(-c2ccccc2)cc(-c2ccccc2)cc1-c1ccccc1
Solvent: O
Solvent: ClCCl
Product: C(=N/c1c(-c2ccccc2)cc(-c2ccccc2)cc1-c1ccccc1)\c1ccccn1
Yield: 95.8 %

Procedure:
In air, to a solution of 2,4,6-triphenylaniline (0.964 g, 3.00 mmol, 1.00 equiv) in CH2Cl2 (10 mL) was added 2-pyridinecarboxaldehyde (0.326 g, 0.290 mL, 3.05 mmol, 1.02 equiv). After heating at reflux for 20 h with azeotropic removal of water using a Dean-Stark trap, the reaction mixture was concentrated under reduced pressure. The residue was purified by trituration with hexanes and dried in vacuo to give the title compound as a yellow solid (1.18 g, 96% yield).
Reaction SMILES: C(OC1C=CC=CC=1C([O:9][C:10]1[C:11]([CH3:31])=[C:12]([CH3:30])[C:13]2[O:17][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24]C(=O)C)[S:15][C:14]=2[C:28]=1[CH3:29])=O)(=O)C.[OH-].[Na+]>CO>[OH:9][C:10]1[C:11]([CH3:31])=[C:12]([CH3:30])[C:13]2[O:17][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[OH:24])[S:15][C:14]=2[C:28]=1[CH3:29]
Reactant: CC(=O)Oc1ccccc1C(=O)Oc1c(C)c(C)c2c(c1C)SC(c1ccccc1OC(C)=O)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)SC(c1ccccc1O)O2
Yield: 63.4 %

Procedure:
A mixture of 700 mg of 5-(o-acetoxybenzoyloxy)-2-(o-acetoxyphenyl)-4,6,7-trimethyl-1,3-benzoxathiole, 0.5 g of sodium hydroxide and 10 ml of methanol was heated under reflux for 1.5 hours. Subsequent treatment and purification of the reaction mixture were conducted in the same manner as in Example 52. From the fraction eluted with a 50:1 by volume mixture of benzene and ethyl acetate were obtained 260 mg of the title compound, melting at 175°-176° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([O:17][CH3:18])=[CH:15][C:14]([OH:19])=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:27])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>CC#N.[Cl-].[Na+].O>[Cl:27][C:13]1[C:11]2[CH:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[C:16]([O:17][CH3:18])=[CH:15][C:14]=1[OH:19]
Reactant: COc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Product: COc1cc(O)c(Cl)c2cc(-c3ccc(O)cc3)oc12
Yield: 22.9 %

Procedure:
Compound 62 (0.1 g, 0.39 mmol) in CH3CN (10 mL) was treated with portionwise addition of NCS (0.033 g, 0.24 mmol). After addition, 10% Na2SO3 aq was added followed by NaHCO3 and brine. The EtOAc layer was dried over MgSO4, filtered, concentrated and chromatographed on silica gel (3:7 EtOAc/hexanes) to yield 0.016 g of the product: Mp=176–177° C.; 1H NMR (DMSO-d6) δ 9.89 (br s, 2 H), 7.74 (d, 2 H, J=8.6 Hz), 7.10 (s, 1 H), 6.87 (d, 2 H, J=8.7 Hz), 6.55 (s, 1 H), 3.91 (s, 3 H); MS 291 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.C[O:24][C:25](=[O:72])[C@@H:26]([NH:42][C:43]([C@@H:45]1[CH2:54][C:53]2[CH:52]=[C:51]3[O:55][CH2:56][C@H:57]([C:59]4[CH:64]=[CH:63][CH:62]=[C:61]([O:65][CH2:66][CH:67]5[CH2:71][CH2:70][CH2:69][CH2:68]5)[CH:60]=4)[O:58][C:50]3=[CH:49][C:48]=2[CH2:47][NH:46]1)=[O:44])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[C:35]=2[CH3:41])=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCN=C=NCCCN(C)C.Cl.CCOC(C)=O.CO>[CH:67]1([CH2:66][O:65][C:61]2[CH:60]=[C:59]([C@H:57]3[CH2:56][O:55][C:51]4=[CH:52][C:53]5[CH2:54][C@@H:45]([C:43]([NH:42][C@@H:26]([CH2:27][C:28]6[CH:33]=[CH:32][C:31]([C:34]7[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[C:35]=7[CH3:41])=[CH:30][CH:29]=6)[C:25]([OH:72])=[O:24])=[O:44])[N:46]([C:7]([C:5]6[N:6]=[C:2]([CH3:1])[O:3][C:4]=6[CH3:10])=[O:9])[CH2:47][C:48]=5[CH:49]=[C:50]4[O:58]3)[CH:64]=[CH:63][CH:62]=2)[CH2:71][CH2:70][CH2:69][CH2:68]1
Reactant: Cc1nc(C(=O)O)c(C)o1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1cccc(OCC2CCCC2)c1)CO3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2cccc(OCC3CCCC3)c2)O4)c(C)o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
2,5-Dimethyl-oxazole-4-carboxylic acid (6 mg) was taken in 1 mL of anhydrous DCM and EDCl (9 mg), HOBT (7 mg) and (S)-2-{[(3S,8S)-3-(3-cyclopentylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (22 mg) and stirred for 5 minutes. The reaction mixture was cooled to 0° C. and DIEA (25 mg) was added and reaction was stirred at room temperature for 2 hours. After the reaction completed, the reaction mixture was loaded onto a silica gel column (1:3 EtOAc:hexanes to 4% MeOH in 1:1 EtOAc:hexanes) to get purified (S)-2-{[(3S,8S)-3-(3-cyclopentylmethoxy-phenyl)-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (20 mg). This was hydrolyzed according to General Procedure B to get the title compound (16 mg). LCMS (m/z): 786.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[NH2:9][C@H:10]1[C@@H:15]2[C@@H:13]([C@H:14]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C@:12]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C@@H:11]1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:4][CH2:5][C:6]([NH:9][C@H:10]1[C@@H:15]2[C@@H:13]([C@H:14]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C@:12]([NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C@@H:11]1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H]2[C@H](N)[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@H]12
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@@H]2[C@H](NC(=O)COC(C)=O)[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@H]12
Reaction time: 2.5 h
Yield: 76.4 %

Procedure:
Add acetoxyacetyl chloride (0.116 mL, 1.08 mmol) to a solution of diethyl (1S,2R,3R,4S,5R,6S)-4-amino-2-(tert-butoxycarbonylamino)-3-[(3,4-dichlorophenyl)methoxy]bicyclo[3.1.0]hexane-2,6-dicarboxylate (0.47 g, 0.89 mmol) and diisoproylethylamine (0.32 mL, 1.83 mmol) in dichloromethane (9 mL) at room temperature. After 2.5 hours, wash the solution with saturated NaHCO3 (2×), brine (1×), dry over MgSO4, filter, and conc. under reduced pressure. Purify by flash chromatography eluting with a gradient of 0 to 100% ethyl acetate in hexanes over 30 min. to yield the title compound as a white solid (0.43 g, 0.68 mmol, 76%). MS (m/z): 531 (M+H-BOC).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9]([O:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[C:8]3[NH:21][C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][C:27]=4[C:7]3=[CH:6][C:5]2=1.[Br:29]Br.C(Cl)Cl>CN(C=O)C>[Br:29][C:6]1[C:7]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[NH:21][C:8]=2[C:9]([O:15][CH2:16][CH2:17][N:18]([CH3:19])[CH3:20])=[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:2]([F:1])=[CH:3][C:4]=3[C:5]=12
Reactant: BrBr
Reactant: CN(C)CCOc1c2[nH]c3ccc(F)cc3c2cc2c1[nH]c1ccc(F)cc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)CCOc1c2[nH]c3ccc(F)cc3c2c(Br)c2c1[nH]c1ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 2-(2,10-difluoro-5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)-N,N-dimethylethanamine (213.9 mg, 0.5638 mmol) in DMF (20 mL) at 0° C. was added Br2 in CH2Cl2 (50 mg/mL, 1.982 mL, 0.6201 mmol). The reaction was warmed to room temperature and stirred for two hours. DMF was removed via vacuum pump. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated aq. NaCO3. The organic layers was concentrated and subjected to flash chromatography to provide the title compound (188.4 mg, 73%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.89 (br s, 2H), 8.39 (dd, J=10.0, 2.4 Hz, 2H), 7.55 (dd, J=8.8, 4.4 Hz, 2H), 7.31 (td, J=8.8, 2.4 Hz, 2H), 4.34 (t, J=5.2 Hz, 2H), 2.74 (t, J=5.6 Hz, 2H), 2.36 (s, 6H); MS (ESI) m/z 456.1 (M−H)−; MS (ESI) m/z 458.0 (M+H)+