Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[O:21])[CH:16]=[CH:17][CH:18]=1>CS(C)=O>[F:11][C:12]([F:22])([F:23])[C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:21])[NH:1][C:2]2[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1nccnc1C(=O)O
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CS(C)=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1nccnc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Aminopyrazine-2-carboxylic acid (0.7 g) in DMSO (10 ml) was treated with 3-trifluoromethylphenylisocyanate (0.9 ml), stirred at room temperature overnight and then quenched with water. A gummy residue separated. After decantation the residue was washed thoroughly with water, stirred with NaOH to basic pH, filtered and chromatographied on silica with CH2Cl2:MeOH:acetone (4:1:1) followed by CH2Cl2:MeOH:NH4OH (40:9:1) when the product started coming off the column. This gave 3-[3-(3-trifluoromethyl-phenyl)-ureido]-pyrazine-2-carboxylic acid. Mp.>300° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C(O[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:2]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccnc1
Product: CCOC(=O)C(=CNc1cccnc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.3 %

Procedure:
Pyridin-3-amine (9.41 g, 100 mmol) and diethyl 2-(ethoxymethylene)malonate (21.6 g, 100 mmol) were combined in a 250 mL screw capped vessel and this mixture was placed into a preheated oil bath at 80° C. and the resulting light brown solution was stirred for 15 h at which time LCMS analysis indicated the presence of a new spot. Then, the light brown solution was cooled to room temperature and as a result some solids started to form. The mixture was left at room temperature for 2 h. The solids were hard to break, but the big chunks were collected by filtration and washed with hexanes. After air drying, 25.18 g of diethyl 2-((pyridin-3-ylamino)methylene)malonate (24) (95.3% yield) was isolated as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]12[CH2:8][CH:7]1[CH2:6][N:5](CC1C=CC=CC=1)[CH2:4]2.[ClH:17]>CO.[Pd]>[ClH:17].[ClH:17].[CH3:1][N:2]([CH3:16])[C:3]12[CH2:8][CH:7]1[CH2:6][NH:5][CH2:4]2
Reactant: CN(C)C12CC1CN(Cc1ccccc1)C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)C12CNCC1C2
Yield: 102.1 %

Procedure:
To a solution of racemic N,N-dimethyl-3-(phenylmethyl)-3-azabicyclo[3.1.0]hexan-1-amine (0.5800 g, 2.681 mmol) in MeOH (13 mL) was added 1 N aq. HCl (5.4 mL, 5.4 mmol) and 10% Pd/C (50% water, 120 mg). The mixture was hydrogenated under balloon pressure overnight, and then filtered. The solution was concentrated in vacuo and azeotroped with MeOH (4×50 mL) to give crude, racemic N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine dihydrochloride (0.5453 g, >100% crude yield) as a light yellow foam. LCMS: (M+H)+: 127.2.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[CH:9])[CH3:5])[CH3:2].C([Li])CCC.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][CH:20]([C:19]1[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=1)[OH:21])[CH3:5])[CH3:2]
Reactant: C#CCOC(C)OCC
Reactant: O=Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(C)OCC#CC(O)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
A solution of 8 g (62.4 mmol) of 1 (1-ethoxyethoxy)-2-propyne in 134 ml of tetrahydrofuran was treated at -78° under argon with 39 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -40° for 30 minutes and then a solution of 6.6 ml (62 mmol) of 4-fluorobenzaldehyde in 54 ml of tetrahydrofuran was added within 10 minutes. The reaction mixture was warmed to 0° , stirred at 0° for a further 1 hour and then treated with 100 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over magnesium sulphate and concentrated. The residue was purified by chromatography on 600 g of silica gel (elution agent ether/hexane 1:1). There was obtained 4-(1-ethoxyethoxy)-1-(4-fluorophenyl)-2-butyn- 1-ol as an oil.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.C(N(CC)C(C)C)(C)C.[F:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]=[C:46]=[O:47])=[CH:41][CH:40]=1>CN(C=O)C>[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][N:26]([C:46]([NH:45][C:42]6[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=6)=[O:47])[CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Reactant: O=C=Nc1ccc(F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
To a suspension of benzothiazol-6-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine trihydrochloride (50.0 mg, 0.11 mmol) in DMF (1.5 mL) was added N,N-diisopropylethylamine (0.04 mL, 0.20 mmol). The reaction mixture stirred at −20° C. for 5 min prior to the addition of 4-fluorophenyl isocyanate (9.5 mg, 0.07 mmol) in DMF (0.5 mL). The mixture was left to stir at rt for 1 h. The mixture was concentrated in vacuo and purified via MDP, which afforded the title compound as a white solid. MS (ES+): m/z: 485.88 (100) [MH+]. HPLC: tr=2.73 min (ZQ2000: polar—5 min). 1H NMR (400 MHz, CDCl3): δ=2.52-2.56 (m, 2H), 3.31 (s, 1H), 3.70 (t, 2H), 4.20 (s, 2H), 6.94 (m, 1H), 6.86 (d, J=0.8 Hz, 1H), 7.06-7.11 (m, 2H), 7.48-7.51 (m, 2H), 7.87 (dd, J=2.4, 8.8 Hz, 1H), 8.04 (d, J=8.8 Hz, 1H), 8.35 (s, 1H), 8.59 (s, 1H), 8.92 (d, J=2.0 Hz, 1H), 9.24 (s, 1H), 9.62 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:31])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[O:23]CC2C=CC=CC=2)=[O:13])[C:8]([O:32][CH3:33])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:31])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[OH:23])=[O:13])[C:8]([O:32][CH3:33])=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cnc(C(C)(C)C)cc1NC(=O)c1cc2cccc(OCc3ccccc3)c2n1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cnc(C(C)(C)C)cc1NC(=O)c1cc2cccc(O)c2n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 108.3 %

Procedure:
Pd(OH)2 (20% on C, 24 mg) was added to a solution of the above indole (231 mg, 0.52 mmol) in ethanol/ethyl acetate (3:2, 5.0 mL) at room temperature. The solution was placed under a hydrogen atmosphere (1 atm) and stirred at room temperature for 18 h. The mixture was filtered through diatomaceous earth and concentrated in vacuo to provide 7-hydroxy-1-methyl-1H-indole-2-carboxylic acid (2-tert-butyl-5-methoxy-pyridin-4-yl)-amide (199 mg, 99%) as a pale brown solid.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([CH3:23])[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)(C)C.[Pd]>[CH3:23][C:11]1([NH2:10])[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(c2ccccn2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: CC1(N)CCN(c2ccccn2)CC1
Temperature: 150 °C

Procedure:
To a stirred solution of (4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid benzyl ester (0.06 g, 0.185 mmol ) in isopropanol (1.8 mL) at room temperature was added ammonium formate (0.047 g, 0.75 mmol) and 5 mg of 10% Pd/C under nitrogen. The reaction mixture was heated under microwave conditions at 150° C. for 30 minutes, cooled, filtered through Celite and concentrated under reduced pressure to provide the titled compound. MS (CI) m/z 192 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][C:10]1[S:14][C:13]([C:15]([NH:17][C@H:18]([C:23]([OH:25])=[O:24])[CH2:19][CH2:20][CH2:21][NH2:22])=[O:16])=[CH:12][CH:11]=1.C(O)(=O)C.[N:30]1[C:39]2[C:38](=O)[CH2:37][CH2:36][CH2:35][C:34]=2[CH:33]=[CH:32][CH:31]=1.C([BH3-])#N.[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][C:10]1[S:14][C:13]([C:15]([NH:17][C@@H:18]([CH2:19][CH2:20][CH2:21][NH:22][CH:38]2[C:39]3[N:30]=[CH:31][CH:32]=[CH:33][C:34]=3[CH2:35][CH2:36][CH2:37]2)[C:23]([OH:25])=[O:24])=[O:16])=[CH:12][CH:11]=1
Reactant: NCCC[C@H](NC(=O)c1ccc(CNCc2ccccn2)s1)C(=O)O
Reactant: O=C1CCCc2cccnc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(N[C@@H](CCCNC1CCCc2cccnc21)C(=O)O)c1ccc(CNCc2ccccn2)s1
Reaction time: 72 h
Yield: 27 %

Procedure:
The compound obtained in Example 14-4 (18.2 mg) was dissolved in methanol (0.6 ml), and acetic acid (0.06 ml), 5,6,7,8-tetrahydroquinolin-8-one (16 mg), and sodium cyanoborohydride (7 mg) were added. After 3 days, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (1 g, chloroform/methanol=5/1). 1 mol/l hydrochloric acid was added to the resulting colorless syrup, and the mixture was concentrated and dried under reduced pressure to obtain ahydrochloride of the title compound (6.7 mg) as a white solid.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1)=O.[NH2:17][C:18]1[C:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH2:25]([O:24][C:23]1[C:18]2[N:19]([C:2]([CH3:16])=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[O:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=4[CH:15]=3)[N:17]=2)[CH:20]=[CH:21][CH:22]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(Br)C(=O)c1ccc2oc(=O)n(C)c2c1
Reactant: Nc1ncccc1OCc1ccccc1
Product: Cc1c(-c2ccc3oc(=O)n(C)c3c2)nc2c(OCc3ccccc3)cccn12
Yield: 54.5 %

Procedure:
5-(8-Benzyloxy-3-methylimidazo[1,2-a]pyridin-2-yl)-3-methyl-2-benzoxazolinone (2.1 g) was prepared in substantially the same manner as that of Example 30 from 5-(2-bromopropionyl)-3-methyl-2-benzoxazolinone (2.84 g) and 2-amino-3-benzyloxypyridine (4.8 g). mp. 210° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].[NH3:21]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[CH2:2][N:21]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: N
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A mixture of paraformaldehyde (147.2 g.) and methanol (550 ml.) was stirred and heated to reflux with a steady stream of ammonia bubbling in. The crystal slurry of hexamethylenetetramine which formed was cooled to room temperature and 2-chloroacetamido-5-chlorobenzophenone (308.2 g., 1.0 mol) was added in one portion. With ammonia bubbling in, the reaction mixture was heated at reflux for 10 hours. The flow of ammonia was interrupted and the reaction mixture was cooled to room temperature, filtered, washed with methanol (2 × 125 ml.) and hot water (4 × 500 ml) and dried. There was obtained 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (220.4 g., 81.4%) melting at 212.5° to 215° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]2[O:22][C:21]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:20]=3[O:19][CH2:18]2)[CH2:12][CH2:11]1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[Cl:27][C:24]1[CH:25]=[CH:26][C:20]2[O:19][CH2:18][C@H:17]([CH2:16][N:13]3[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][S:35]([C:32]4[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=4)(=[O:37])=[O:36])[CH2:11][CH2:12]3)[O:22][C:21]=2[CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 59.3 %

Procedure:
Triethylamine (0.62 ml) was added to a solution of (S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine (0.44 g) and 4-fluorobenzenesulphonyl chloride (0.65 g) in dichloromethane (22 ml) under nitrogen and stirred for 3 hours. The reaction was left to stand for 14 hours then diluted with dichloromethane (100 ml), washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with a 19:1 mixture of dichloromethane and methanol gave a yellow oil which on trituration with diethyl ether yielded (S)-(-)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-fluorobenzene-sulphonamide as a yellow solid (0.4 g); m.p. 127-129° C., [α]D22 -41.3° (c=0.72, MeOH).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:26]=[CH:25][C:7]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([C:19]([O:21]CC)=[O:20])[C:11]=2[CH3:24])=[O:9])=[CH:6][C:5]=1[O:27][CH3:28]>O1CCOCC1>[NH2:3][C:4]1[CH:26]=[CH:25][C:7]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([C:19]([OH:21])=[O:20])[C:11]=2[CH3:24])=[O:9])=[CH:6][C:5]=1[O:27][CH3:28]
Reactant: CCOC(=O)c1c(C)c(C(=O)c2ccc(N)c(OC)c2)n2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)c2c(C)c(C(=O)O)c3ccccn23)ccc1N

Procedure:
30 ml of 2 N sodium hydroxide are added to 2.1 g (5.96 mmol) of ethyl 3-(4-amino-3-methoxybenzoyl)-2-methyl-1-indolizinecarboxylate in solution in 30 ml of dioxane, and the medium is heated under reflux for 20 hours. The reaction medium is concentrated under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[N:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>ClCCl>[C:24]([NH:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[N:8][C:4]=2[CH:3]=1)(=[O:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)c1nc2cc(N)ccc2[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2[nH]c(C(=O)OC(C)(C)C)nc2c1
Yield: 92.3 %

Procedure:
A suspension of 1,1-dimethylethyl 5-amino-1H-benzimidazole-2-carboxylate (0.147 g, 0.630 mmol) in dichloromethane (5 mL) was cooled in an ice bath. Pyridine (0.076 mL, 0.945 mmol) and acetic anhydride (0.059 mL, 0.630 mmol) were added. The reaction mixture was filtered and the collected solid was washed with dichloromethane and dried under vacuum to give the title compound (0.160 g, 92%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 13.06 (s, 1H), 10.05 (s, 1H), 8.14 (s, 1H), 7.61 (m, 1H), 7.24 (m, 1H), 2.04 (s, 3H), 1.55 (s, 9H). MS: m/z 276 (M+1).
Reaction SMILES: [C:1]1([S:7][C@@H:8]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C@H:25]([O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C@H:17]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:9]2[O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:51])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]1([S:7]([C@@H:8]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C@H:25]([O:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:30])[CH3:31])[C@H:17]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:21])[CH3:22])[C@H:9]2[O:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:14])[CH3:15])=[O:51])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H]1OC(=O)C(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](S(=O)c2ccccc2)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H]1OC(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of thioglycoside 40 (0.62 g, 1.0 mmol) in 20 mL of CH2Cl2 at -78° C. is added 67% m-CPBA (0.26 g, 1.0 mmol). The reaction mixture is stirred at -78° C. for 2 h and then allowed to slowly warm up to room temperature. Saturated NaHCO3 is added until the solution is basic. The reaction mixture is diluted with 100 mL of CH2Cl2 and washed with H2O (100 mL), saturated NaCl (100 mL), dried over Na2SO4, filtered, concentrated and purified by flash chromatography (15% EtOAc/hexane) to give 0.59 g (92%) of the title compound 41 as a mixture of diastereomers: Rf 0.38, 0.19 (20% EtOAc/hexane). FABMS C32H48O10S (MNa+) calcd 647.2866, found 647.2868.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([O:31][CH2:32][CH3:33])[C:25]=1[O:34][CH2:35][CH3:36])(=[O:3])[CH3:2].[Br:37]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[C:28]([CH2:30][Br:37])[CH:27]=[C:26]([O:31][CH2:32][CH3:33])[C:25]=1[O:34][CH2:35][CH3:36])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1cc(C)cc([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c1OCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cc(CBr)cc([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
A suspension of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(2,3-diethoxy-5-methylphenyl)-D-glucitol (500 mg) and N-bromosuccinimide (209 mg) in carbon tetrachloride (10 ml) was refluxed with heating and 2,2′-azobis(isobutyronitrile) (80 mg) was added. The mixture was stirred for 30 minutes under refluxing and the reaction mixture was allowed to be cooled to room temperature. After evaporating the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-(bromomethyl)-2,3-diethoxyphenyl]-D-glucitol (464 mg).
Reaction SMILES: C(O[CH2:5][C:6]1[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:8]2[C:13]([C:14]=1[C:15](=[O:19])[C:16]([OH:18])=[O:17])=[CH:12][C:11]([O:20][CH3:21])=[CH:10][CH:9]=2)(=O)C.[OH-].[K+].Cl>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:7]2[C:8]3[C:13](=[CH:12][C:11]([O:20][CH3:21])=[CH:10][CH:9]=3)[C:14]3[C:15](=[O:19])[C:16](=[O:17])[O:18][CH2:5][C:6]2=3)=[CH:24][CH:25]=1)([CH3:31])([CH3:32])[CH3:30]
Reactant: COc1ccc2c(c1)c(C(=O)C(=O)O)c(COC(C)=O)n2Cc1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COc1ccc2c(c1)c1c(n2Cc2ccc(C(C)(C)C)cc2)COC(=O)C1=O

Procedure:
The title compound was prepared from [2-[(acetyloxy)methyl]-1-(4-tert-butylbenzyl)-5-methoxy-1H-indol-3-yl](oxo)acetic acid and aqueous potassium hydroxide in substantially the same manner as described in step 6 of Example 1, followed by the treatment with aq HCl in substantially the same manner as described in step 7 of Example 1. The product was obtained as an off-white solid; mp: 238-239° C. Mass spectrum (ESI, [M−H]−) m/z 376. 1H NMR (400 MHz, DMSO-d6) δ 7.56 (d, 1H, J=9.01 Hz), 7.48 (d, 1H, J=2.45 Hz), 7.35 (d, 2H, J=8.40 Hz), 7.14 (d, 2H, J=8.25 Hz), 6.98 (dd, 1H, J=8.86 and 2.44 Hz), 5.87 (s, 2H), 5.42 (s, 2H), 3.81 (s, 3H), 1.22 ppm (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([OH:14])=O)[C:7]1=[O:15].CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:58][CH:59]([C:63]1[S:64][CH:65]=[CH:66][CH:67]=1)[C:60]([OH:62])=[O:61]>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:58][CH:59]([C:63]2[S:64][CH:65]=[CH:66][CH:67]=2)[C:60]([OH:62])=[O:61])=[O:14])[C:7]1=[O:15]
Reactant: NC(C(=O)O)c1cccs1
Reactant: O=C(O)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(C(=O)O)c1cccs1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (0.23 g, 0.00088 mol;) was dissolved in N,N-Dimethylformamide (9 mL, 0.1 mol;) and N,N-Diisopropylethylamine (800 uL, 0.004 mol;), and N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.37 g, 0.00097 mol;) were added. After 5 minutes preactivation Amino-thiophen-2-yl-acetic acid (0.266 g, 0.00169 mol;) was added. Workup consisted of rinsing with 5% citric acid then brine after dissolving the crude in ethyl acetate. The organic layer was then dried with magnesium sulfate and concentrated. The crude material was brought on directly to the next step. ES (+) MS m/e=404.81
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]([C:10]#[N:11])=[CH:5][CH2:6][CH:7]([CH3:9])[CH3:8].[N+]([CH3:16])([O-])=O>C(#N)C>[CH3:1][O:2][C:3]([C:4]1([C:10]#[N:11])[CH2:16][CH:5]1[CH2:6][CH:7]([CH3:9])[CH3:8])=[O:12]
Reactant: COC(=O)C(C#N)=CCC(C)C
Reactant: C[N+](=O)[O-]
Solvent: CC#N
Product: COC(=O)C1(C#N)CC1CC(C)C
Temperature: 25 °C
Yield: 68.4 %

Procedure:
To a solution of 2-cyano-5 methyl-hex-2-enoic acid methyl ester (20.2 g, 121 mmol) in dry acetonitrile (110 mL) was added nitromethane (9.8 mL, 181 mmol) and a portionwise addition of alumina-supported potassium flouride (40% wt, 39.3 g). The reaction mixture was stirred under reflux for 2 hours and cooled to room temperature. The solid was removed by filtration through a short pad of celite and washed with acetonitrile. Excess of solvent was removed in vacuo and the residue was re-dissolved in ether. The ether layer was washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography using hexanes/EtOAc (8:2) as an eluent to give 15 g (69%) of 1-cyano-2-isobutyl-cyclopropanecarboxylic acid methyl ester as colorless oil: 1H NMR (300 MHz, CDCl3) δ 0.98 (d, J=2.9 Hz, 3H), 1.00 (d, J=3.0 Hz, 3H), 1.35–1.42 (m, 2H), 1.65 (m, 1H), 1.79–1.94 (m, 3H), 3.81 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 19.3, 22.3, 22.4, 25.5, 27.9, 30.1, 39.0, 53.4, 117.3, 168.5.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5](Br)=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:37]2[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Nc1ccc(Br)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1
Product: Nc1ccc(-c2ccc(Cl)cc2)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound IH of Example 1 utilizing 1G and 4-chlorophenyl boronic acid. 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.52 (d, J=9.0 Hz, 1H), 7.45 (d, J=8.5 Hz, 2H), 7.31-7.23 (m, 6H), 7.19 (s, 1H), 6.89 (t, J=10.0 Hz, 2H), 6.65 (d, J=8.9 Hz, 1H), 6.52 (t, J=8.9 Hz, 1H), 6.26 (d, J=5.9 Hz, 2H), 5.27 (dd, J=16.5, 8.2 Hz, 1H), 3.61 (s, 2H), 3.00 (dd, J=13.6, 9.3 Hz, 1H), 2.85 (dd, J=13.7, 7.5 Hz, 1H). MS (m/z) 535.4 [M+H]+.