Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25].Cl>C1(C)C=CC=CC=1.CC#N.CC#N.CC#N.CC#N.F[P-](F)(F)(F)(F)F.[Cu+].C(OCC)(=O)C>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: COc1ccccc1O
Reactant: O=C(O)c1ccccc1Br
Agent: [Cu+]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccccc1Oc1ccccc1C(=O)O
Yield: 982.6 %

Procedure:
Tetrakis(acetonitrile)copper(I) hexafluorophosphate (4.62 g, 12.4 mmol), cesium carbonate (32 g, 98 mmol), 2-bromobenzoic acid (10g, 49. 7 mmol) and 2-methoxyphenol (6.17 g, 49.7 mmol) were combined in toluene (100 mL), and the mixture was heated to reflux for 15 hr. Ethyl acetate (200 mL) and 1N HCl (200 mL) were added, and the organic layer was separated. The organic layer was dried over MgSO4, filtered, and evaporated to yield 16.8 g of Compound 1a. The residue was used without further purification. MS m/z (M-H)− 243.1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[S:63](Cl)(=[O:65])=[O:64])#[N:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([S:63]([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=2[C:55]#[N:56])(=[O:65])=[O:64])[CH2:49][CH2:48]1)=[O:53]
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1S(=O)(=O)N1CCN(C(=O)COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D20, step A, using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 2-cyanobenzenesulfonyl chloride as the starting materials in 50% yield. LCMS for C30H28ClN8O4S (M+H)+: m/z=631.0.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:25][NH:26][CH2:27][CH3:28].CO>ClCCl.CC(=O)OCC.[Pd].C1COCC1>[CH2:27]([N:26]([CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([NH2:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4])[CH3:25])[CH3:28]
Reactant: CCNC
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CC2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN(C)CC(=O)N1CCc2cc(OC)c(N)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 1-(bromoacetyl)-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (4.0 g, 12.7 mmol) was dissolved in 50 mL of dichloromethane, then K2CO3 (4.4 g, 31.7 mmol) and N-methylethanamine(1.5 g, 25.4 mmol) in 10 mL dichloromethane were added and the reaction was stirred at RT for 3 hours. After filtration, the organic layers were washed with water (2×100 mL) and dried over Na2SO4. The solvent was was removed under reduced pressure and the derived residue (3.4 g, 11.59 mmol) was dissolved in 10 mL of EA, 25 mL of MeOH and 15 mL of THF, then 0.8 g 10% Pd/C was added, the reaction was stirred at RT overnight under H2 pressure (65 psi). The catalyst was removed via filteration, and the solvent was evaporated under reduced pressure to afford 1-{[ethyl(methyl)amino]acetyl}-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine as a yellow solid, 3.0 g (97%).1HNMR (400 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.14 Hz, 3H), 2.20 (s, 3H), 2.46(m, 2H), 2.94 (t, 2 H), 3.16(s, 2H), 3.68 (s, 3H), 4.06 (t, J=8.42 Hz, 2 H), 4.60 (s, 2H), 6.67 (s, 1 H), 7.52 (s, 1 H).
Reaction SMILES: [ClH:1].[C:2]1([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])=[O:18])[CH2:13][CH2:14][CH2:15][NH2:16])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH:44][C:45](=[N:48]C(OCC1C=CC=CC=1)=O)SC)(OCC1C=CC=CC=1)=O.CCN(C(C)C)C(C)C>>[ClH:1].[C:28]1([CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH3:21])=[O:18])[CH2:13][CH2:14][CH2:15][NH:16][C:45](=[NH:44])[NH2:48])=[O:10])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: C[C@@H](NC(=O)[C@H](CCCN)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1
Yield: 116.1 %

Procedure:
Prepared according to the method described in Example 4(f) above from (R)-N2 -(diphenylacetyl)-(S)-N-(1-phenylethyl)ornithine amide hydrochloride (0.50 g; 1.0 mmol; from step (c) above), N,N'-bis(Cbz)-S-methyliso-thiourea (0.40 g; 1.1 mmol) of and DiPEA (0.3 mL; 1.6 mmol), yielding 0.59 g (74%) of sub-title compound as a solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([OH:34])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=1)=[O:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:35][C:36]1[C:37]([N:44]2[C:48]3=[N:49][CH:50]=[N:51][C:52](Cl)=[C:47]3[CH:46]=[N:45]2)=[C:38]([CH:41]=[CH:42][CH:43]=1)[C:39]#[N:40]>>[Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([O:34][C:52]1[N:51]=[CH:50][N:49]=[C:48]2[N:44]([C:37]3[C:38]([C:39]#[N:40])=[CH:41][CH:42]=[CH:43][C:36]=3[Cl:35])[N:45]=[CH:46][C:47]=12)[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=1)=[O:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Reactant: Cc1ccc(NC(=O)[C@@H](O)COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1
Product: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)nc1

Procedure:
Prepared using a procedure analogous to that described with Intermediate AH7 using (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-methylpyridin-2-yl)-2-hydroxypropanamide (Intermediate AU2) and 3-chloro-2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (Intermediate AH6). m/z (ES+) (M+H)+=732; HPLC tR=3.76 min
Reaction SMILES: [OH:1][C:2]1([C:11]2[S:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)C(=O)N[C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH-].[Na+]>>[CH3:17][O:16][C:13]1[S:12][C:11]([CH:2]2[O:1][C:5](=[O:9])[NH:4][C:3]2=[O:10])=[CH:15][CH:14]=1
Reactant: COc1ccc(C2(O)C(=O)NC(=O)NC2=O)s1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C2OC(=O)NC2=O)s1
Reaction time: 1.5 h

Procedure:
5-Hydroxy-5-(5-methoxy-2-thienyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (1.1 g.) was dissolved in 10 ml. of 1 N sodium hydroxide, allowed to stand for 1.5 hours at room temperature, extracted with ether, acidified with acetic acid, diluted with 15 ml. of water and filtered to yield product [567 mg., m.p. 144°-146° C. (dec.)]. Recrystallization from acetone-hexane gave purified 5-(5-methoxy-2-thienyl)oxazolidine-2,4-dione in two crops [487 mg., m.p. 147°-148° C. (dec.)].
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[C:5]2[CH2:6][N:7]([C:10](=[O:12])[CH3:11])[CH2:8][CH2:9][N:4]2[N:3]=1.Br[C:15]1[C:16](=[O:23])[N:17]([CH3:22])[CH:18]=[C:19]([Br:21])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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].CO.CCOCC.CCOC(C)=O.O>[C:10]([N:7]1[CH2:8][CH2:9][N:4]2[N:3]=[C:2]([NH:1][C:15]3[C:16](=[O:23])[N:17]([CH3:22])[CH:18]=[C:19]([Br:21])[CH:20]=3)[CH:13]=[C:5]2[CH2:6]1)(=[O:12])[CH3:11]
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(=O)N1CCn2nc(N)cc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 41 %

Procedure:
A sealed tube was equipped with a magnetic stirrer and charged with 125f (860 mg, 4.8 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.8 g, 6.7 mmol), and cesium carbonate (3.4 g, 10.5 mmol) in 1,4-dioxane (67 mL). After bubbling nitrogen through the solution for 30 min, Xantphos (330 mg, 0.6 mmol) and tris(dibenzylideneacetone)dipalladium(0) (300 mg, 0.3 mmol) were added, and the reaction mixture was heated to 100° C. for 16 h. After this time, H2O (50 mL) and EtOAc (50 mL) were added. The aqueous layer was separated and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate. The resulting residue was purified by column chromatography eluting with a gradient of CH2Cl2 —60:35:5 CH2Cl2:Et2O:MeOH to afford a 41% yield of 125g (720 mg).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH:19]([CH2:20][OH:21])[CH2:18][NH:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].Cl[C:28]([O:30][CH3:31])=[O:29]>C(OCC)(=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH:19]([CH2:20][OH:21])[CH2:18][N:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2CNCC2CO)cc1OC1CCCC1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)N1CC(CO)C(c2ccc(OC)c(OC3CCCC3)c2)C1
Yield: 69.1 %

Procedure:
To a vigorously stirring mixture of 3-(3-cyclopentoxy-4-methoxyphenyl)-4-(hydroxymethyl)pyrrolidine (328 mg, 1.13 mmol) in 4 mL of 1:1 ethyl acetate:sat aq NaHCO3 was added methyl chloroformate (138 mg, 1.47 mmol). When TLC analysis indicated a complete reaction the mixture was diluted with ethyl acetate, and the layers were separated. The organic layer was dried over K2CO3, filtered, and concentrated under reduced pressure to provide 3-(3-cyclopentoxy-4-methoxyphenyl)-4-hydroxymethyl-1-(methoxycarbonyl)pyrrolidine as a colorless viscous oil (273 mg, 69%). Anal. Calcd for C19H27NO5 ·0.5 H2O: C, 63.67; H, 7.87; N, 3.91. Found: C, 63.30; H, 7.75; N, 3.92.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[O:11])(=[O:3])[CH3:2].[Cl-].[CH3:13][NH2+]C.C=O>>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[CH2:13])[CH:10]=[O:11])(=[O:3])[CH3:2]
Reactant: C[NH2+]C
Reactant: CC(=O)OCCCCCC=O
Agent: C=O
Agent: [Cl-]
Product: C=C(C=O)CCCCOC(C)=O

Procedure:
16 g (101.1 mmol) of 6-acetoxyhexanal, 9.2 g (113 mmol) of dimethylammonium chloride and 9.2 ml (118.3 mmol) of a 37% solution of formaldehyde are stirred for 1 hour at a bath temperature of 110° C. The mixture is allowed to cool and extracted three times with CH2Cl2. The combined organic phases are dried over Na2SO4, filtered, and concentrated by evaporation giving 6-acetoxy-2-methylene-hexanal as a slightly yellowish oil which is further reacted without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[N:12]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[CH:13]=[C:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:15]=2)=[O:10])=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[CH3:33][Si:34]([CH3:49])([CH3:48])[CH2:35][CH2:36][O:37][CH2:38][N:39]1[C:43]2[NH:44][CH2:45][CH2:46][CH2:47][C:42]=2[CH:41]=[N:40]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:14]1[N:15]=[C:11]([C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([N:44]3[CH2:45][CH2:46][CH2:47][C:42]4[CH:41]=[N:40][N:39]([CH2:38][O:37][CH2:36][CH2:35][Si:34]([CH3:49])([CH3:48])[CH3:33])[C:43]3=4)=[CH:3][CH:4]=2)[N:12]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c1NCCC2
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(N2CCCc3cnn(COCC[Si](C)(C)C)c32)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Palladium (II) acetate (13 mg, 0.06 mmol) was added to a degassed, ambient temperature solution of 2-[(4-bromophenyl)acetyl]-4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Intermediate 7) (500 mg, 1.13 mmol), sodium tert-butoxide (436 mg, 4.52 mmol), 1-{[2-(trimethylsilyl)ethoxy]methyl}-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine (574 mg, 2.26 mmol) and 2-(dicyclohexylphosphino)biphenyl (40 mg, 0.11 mmol) in 1,4-dioxane (10 mL). After stirring at 110° C. overnight, the reaction mixture was cooled, diluted with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-60% ethyl acetate/hexane afforded 4-(2,2-dimethylpropyl)-N,N-dimethyl-2-{[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)phenyl]acetyl}-1H-imidazole-1-sulfonamide.
Reaction SMILES: CO.[CH3:3][NH2:4].[CH3:5][C:6]1[CH:13]=[C:12]([O:14][CH:15]2[CH2:18][N:17]([C:19]([C:21]3[O:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:24][N:25]=3)=[O:20])[CH2:16]2)[CH:11]=[CH:10][C:7]=1[CH:8]=O.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O.C(Cl)Cl>[CH3:5][C:6]1[CH:13]=[C:12]([CH:11]=[CH:10][C:7]=1[CH2:8][NH:4][CH3:3])[O:14][CH:15]1[CH2:18][N:17]([C:19]([C:21]2[O:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:24][N:25]=2)=[O:20])[CH2:16]1
Reactant: CN
Reactant: Cc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1C=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CNCc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
Titanium(IV) isopropoxide (0.20 mL, 0.68 mmol) was added to a methanol solution of methylamine (0.75 mL 2M, 1.50 mmol). The resulting solution was added to 53C (162 mg, 0.45 mmol) and then methanol (1 mL) was added. After 60 min, DCM (5 mL) was added and the solution was stirred for 2 h. Sodium borohydride (21 mg, 0.56 mmol) was added and the mixture was stirred for 60 min. Water was added and the mixture was filtered through Celite and the solid was washed extensively with DCM. The filtrate was further filtered through a phase separator and the organic solution was evaporated. The product was purified by preparative HPLC (Kromasil, C8) eluting with a gradient of acetonitrile and a mixture of acetic acid and water (0.2%). The pure fractions were combined and freeze-dried twice. There was obtained 74 mg (44%) of 53 as a solid. 1NMR (500 MHz, CDCl3): δ 2.27 (s, 3H), 2.3-2.6 (m, 4H), 3.62 (m, 2H), 4.24 (dd, 1H), 4.56 (dd, 1H), 4.66 (dd, 1H), 4.99 (m, 1H), 5.04 (m, 1H), 6.49 (d, 1H), 6.54 (s, 1H), 7.15 (d, 1H), 7.46 (t, 2H), 7.51 (t, 1H), 8.08 (d, 2H), MS (APCI+) m/z 379 [M+H]+, LC purity: 99%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:16]=3[N:15](C(C)=C)[C:14]2=[O:27])=[CH:3]1.O.Cl>CO.C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:16]=3[NH:15][C:14]2=[O:27])=[CH:3]1
Reactant: C=C(C)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cc(C)c(C)cc21
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1cc2[nH]c(=O)n(Cc3cn(C)c4cccc(C)c34)c2cc1C
Temperature: 60 °C

Procedure:
To 1-(1,4-Dimethyl-1H-indol-3-ylmethyl)-3-isopropenyl-5,6-dimethyl-1,3-dihydro-benzimidazol-2-one (0.35 mmol) in MeOH (5 mL) was added water (5 mL) and cone. HCl (3 mL). The reaction mixture was heated to 60° C. for 2 h. The reaction mixture turned into pink in color and heterogeneous (milky solution). The TLC indicated that the reaction was complete and clean. The reaction mixture was therefore diluted with CH2Cl2 and washed with water. The organic phase remained heterogeneous (milky with fine powder). The organic phase was filtered through a fine filter to collect some of the solid which was partially soluble in DMSO-d6. 1H-NMR indicated this filtered solid being the desired product. Therefore, the organic phase was concentrated without drying with Na2SO4 to afford a pink solid. 1H-NMR of this product in DMSO-d6 matched well with the previous filtered solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][CH2:8][C@H:9]1[O:24][C:22](=[O:23])[C@H:21]([CH3:25])[C@@H:20]([O:26][C@@H:27]2[O:32][C@@H:31]([CH3:33])[C@H:30]([OH:34])[C@@:29]([O:36][CH3:37])([CH3:35])[CH2:28]2)[C@H:19]([CH3:38])[C@@H:18]([O:39][C@@H:40]2[O:45][C@H:44]([CH3:46])[CH2:43][C@H:42]([N:47]([CH3:49])[CH3:48])[C@H:41]2[OH:50])[C@:16]2([CH3:51])[O:17][C:13](=[C:14]([CH3:52])[CH2:15]2)[C@H:12]([CH3:53])[C@@H:11]([OH:54])[C@@:10]1([OH:56])[CH3:55]>>[CH3:53][CH2:12][C@@H:11]([OH:54])[C@@:10]([OH:56])([C@@H:9]1[O:24][C:22](=[O:23])[C@H:21]([CH3:25])[C@@H:20]([O:26][C@@H:27]2[O:32][C@@H:31]([CH3:33])[C@H:30]([OH:34])[C@@:29]([O:36][CH3:37])([CH3:35])[CH2:28]2)[C@H:19]([CH3:38])[C@@H:18]([O:39][C@@H:40]2[O:45][C@H:44]([CH3:46])[CH2:43][C@H:42]([N:47]([CH3:49])[CH3:48])[C@H:41]2[OH:50])[C@:16]2([CH3:51])[O:17][C:13](=[C:14]([CH3:52])[CH2:15]2)[C@@H:8]1[CH3:7])[CH3:55]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@]2(C)CC(C)=C(O2)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC[C@@H](O)[C@@](C)(O)[C@@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@]2(C)CC(C)=C(O2)[C@@H]1C
Yield: 78 %

Procedure:
Glacial acetic acid solution of erythromycin A (12.4 g, 16.9 mmol) was stirred at room temperature for 2 hours, added slowly aqueous sodium hydrogen carbonate and neutralized. The reaction mixture was extracted with chloroform, dehydrated the organic layer with sodium sulfate, filtered off the sodium sulfate and removed the solvent by distillation to obtain crude substance. The crude substance was purified with silica gel chromatography (chloroform:methanol:aqueous ammonia=10:0.5:0.01→10:1:0.05) to obtain EM201 (7.7 g, 63%). Subsequently, potassium carbonate (1.4 g, 10.6 mmol) was added to the methanol solution (100 ml) of EM 201 (7.6 g, 10.6 mmol) and refluxed for 2 hours. After distilled off the solvent, the residue was dissolved in aqueous sodium hydrogen carbonate and extracted with chloroform. The mixture was dehydrated with sodium sulfate, filtered and removed the sodium sulfate, then the obtained crude substance was purified by silica gel chromatography (chloroform:methanol:aqueous ammonia=10:0.5:0.01→10:1:0.05) to obtain EM701 (5.9 g, 78%, white powder).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[CH3:29])[N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[C:4]([CH3:30])[CH:3]=1.CN1CCOCC1.[Si](I)(C)(C)C>C(Cl)Cl>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:30])[N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[C:23]([CH3:29])[CH:24]=1
Reactant: Cc1cc(Cl)ccc1C(c1ccc(Cl)cc1C)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(Cl)ccc1C(c1ccc(Cl)cc1C)N1CCNCC1
Temperature: 0 °C

Procedure:
A round bottom flask was charged with tert-butyl 4-(bis(4-chloro-2-methylphenyl)methyl)piperazine-1-carboxylate (184 mg, 409 mmol), CH2Cl2 (5 mL), and NMM (90 μL, 0.819 mmol). Cooled to 0° C. and added TMSI (70 μL, 0.491 mmol) dropwise. After 15 min at 4° C. the reaction was quenched with sat Na2CO3 and extracted with CH2Cl2 (3×). The organics were dried (Na2SO4), filtered, and concentrated. The residue was chromatographed on a silica gel column (100% CH2Cl2 to 6% 2M NH3 in MeOH) and 1-(bis(4-chloro-2-methylphenyl)methyl)piperazine (143 mg, 70%). 1H NMR 400 MHz (CDCl3) δ 7.47 (dd, J=8.4, 1.1 Hz, 2H), 7.16-7.11 (m, 1H), 7.11-7.06 (m, 2H), 4.64 (s, 1H), 2.88-2.80 (m, 4H), 2.44-2.33 (m, 5H), 2.28 (s, 7H). LCMS (ESI, m/z): 349 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3](=[O:30])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:57]1[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:60]=[C:59](B(O)O)[CH:58]=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][S:25](=[O:28])(=[O:29])[CH2:24][CH2:23]3)=[CH:7][CH:8]=2)[C:3](=[O:30])[C:2]=1[C:59]1[CH:58]=[N:57][C:66]2[C:61]([CH:60]=1)=[CH:62][CH:63]=[CH:64][CH:65]=2
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2cnc3ccccc3c2)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Yield: 74 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-[2-(1,1-dioxothiomorpholin-4-yl)ethoxy]-1H-inden-1-one obtained in Step 1 of Example 112 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 3-quinolinylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (74%).
Reaction SMILES: [S:1]1[C:5]([NH:6][S:7]([C:10]2[C:40]([Cl:41])=[CH:39][C:13]3[N:14]([C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH:27]=4)[CH3:19])[C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)(=[O:9])=[O:8])=[N:4][CH:3]=[N:2]1.C(Cl)Cl.Cl.CCOC(C)=O>CO>[ClH:41].[Cl:41][C:40]1[C:10]([S:7]([NH:6][C:5]2[S:1][N:2]=[CH:3][N:4]=2)(=[O:9])=[O:8])=[CH:11][C:12]2[O:16][C:15](=[O:17])[N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH:27]=3)[CH3:19])[C:13]=2[CH:39]=1
Reactant: C[C@H](c1ccccc1C1=CCN(C(=O)OC(C)(C)C)CC1)n1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)c(Cl)cc21
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](c1ccccc1C1=CCNCC1)n1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)c(Cl)cc21
Temperature: 25 °C

Procedure:
To a flask containing (R)-tert-butyl 4-(2-(1-(6-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-5-chloro-2-oxobenzo[d]oxazol-3(2H)-yl)ethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (34-5) (16 mg, 0.026 mmol) (prepared by a sequence analogous to the synthesis of 16-4, vide supra) was added DCM (2 ml) & MeOH (2), then added saturated HCl in EtOAc (˜4N) (64.7 μl, 0.26 mmol). The reaction mixture was capped (not under N2) & stirred at room temperature. Followed by LC/MS. After 3 hours the reaction mixture was concentrated to yield (R)-5-chloro-2-oxo-3-(1-(2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide hydrochloride (34-6). HRMS [M+H] calculated; 518.0718, observed; 518.0706. 1H NMR (499 MHz, DMSO): δ 9.15 (d, J=33.1 Hz, 2H); 8.51 (s, 1H); 7.95 (s, 1H); 7.79 (d, J=7.7 Hz, 1H); 7.63-7.46 (m, 2H); 7.46-7.36 (m, 2H); 7.23 (s, 1H); 7.09 (d, J=7.3 Hz, 1H); 5.74-5.68 (m, 1H); 5.42 (br s, 1H); 3.65-3.54 (m, 1H); 3.35-3.23 (m, 1H); 3.18-3.09 (m, 2H); 2.67-2.55 (m 1H); 2.18-2.08 (m, 1H); 1.83 (d, J=7.1 Hz, 3H). Note: NMR peaks overlapping with solvent or water could not be accurately accounted for.