Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:31]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(F)cc1F
Yield: 99.4 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 2,4-difluorocinnamic acid (2.6 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.5 g, 99%) as an oily product.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.ClC1C(C=O)=C[N:17]=[C:16]2N([Si](C(C)C)(C(C)C)C(C)C)C=CC=12.CN>COC(O)C>[CH3:16][NH:17][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12
Reactant: O=Cc1cnc2[nH]ccc2c1Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(C=O)cnc21
Agent: CN
Agent: COC(C)O
Product: CNc1c(C=O)cnc2[nH]ccc12
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde and 4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (2.0 g, from above step), methylamine (40% solution in water, 16 mL, 100 mmol) in methoxy-ethanol (4 mL) is heated at 110° C. in a sealed tube overnight. The reaction mixture is cooled to room temperature and concentrated. The residue is dissolved in HCl solution (1N, 20 mL) and heated at 50° C. After stirring for 1.5 hours at 50° C., the reaction mixture is neutralized with saturated sodium bicarbonate solution to a pH of 8. The solid is collected by filtration and washed with water, then hexanes, dried to afford the title compound as a light yellow solid: MS m/z 176.1 (M+1).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.C1(=O)CCCC1.[C-]#N.[K+].CN(C)[C:17]1([C:22]#[N:23])[CH2:21][CH2:20][CH2:19][CH2:18]1>O>[N:2]1([C:17]2([C:22]#[N:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:5][CH2:4][CH2:3]1
Reactant: CN(C)C1(C#N)CCCC1
Reactant: C1CNC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: O=C1CCCC1
Product: N#CC1(N2CCC2)CCCC1
Yield: 43 %

Procedure:
The title compound (1.29 g, 43%) was prepared from azetidine hydrochloride (1.85 g, 20 mmol), cyclopentanone (1.68 g, 20 mmol) and potassium cyanide (1.30 g, 20 mmol) in water (10 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ: 1.70-1.82 (6H, m), 1.86 (2H, m), 2.07 (2H, quin, J=7 Hz), 3.32 (4H, t, J=7 Hz).
Reaction SMILES: O=[O+][O-].[C:4]1([CH:10]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:11][CH:12]=C)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:24]=O.S(C)C>C(Cl)Cl>[O:24]=[CH:12][CH2:11][CH:10]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=O
Reactant: C=CCC(NS(=O)(=O)c1ccccc1)c1ccccc1
Agent: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: O=CCC(NS(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84 %

Procedure:
A stream of ozone was passed through a solution of the product of Step 3 (1.9 g, 6.6 mmol) in CH2Cl2 (90 mL) at −78° C. for 1 h. The solution was then purged with oxygen, Me2S (1.1 mL, 15 mmol) was added, the cooling bath removed and the mixture allowed to warm to RT. The reaction was complete after 3 days and the solvent removed under reduced pressure and the mixture purified by column chromatography on silica eluting 5–10% MeOH/CH2Cl2 to give the benzenesulfonamide as a colourless oil (1.6 g, 84%). 1H NMR (360 MHz, CDCl3) δ 2.90–3.10 (2H, m), 4.79–4.86 (1H, m), 5.45 (1H, d, J=7.4 Hz), 7.03–7.09 (2H, m), 7.13–7.18 (3H, m), 7.35–7.39 (2H, m), 7.46–7.51 (1H, m), 7.69–7.71 (2H, m), 9.64 (1H, s).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[CH3:9][C@@H:10]1[CH2:14][CH2:13][N:12]([C@@H:15]([CH3:18])[CH2:16][OH:17])[CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)CCC.[Cu]I>[I:8][C:5]1[CH:6]=[CH:7][C:2]([O:17][CH2:16][C@@H:15]([N:12]2[CH2:13][CH2:14][C@@H:10]([CH3:9])[CH2:11]2)[CH3:18])=[CH:3][CH:4]=1
Reactant: C[C@@H]1CCN([C@@H](C)CO)C1
Reactant: Ic1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Product: C[C@@H]1CCN([C@@H](C)COc2ccc(I)cc2)C1
Temperature: 125 °C
Yield: 76.2 %

Procedure:
A mixture of 1,4-diiodobenzene (2.07 g, 6.27 mmol), ((S)-2-((R)-3-methylpyrrolidin-1-yl)propan-1-ol (0.6 g, 4.18 mmol), CuI (80 mg, 0.4 mmol), cesium carbonate (1.36 g, 4.18 mmol) in butyronitrile (4 mL) was degassed and then heated at 125° C. overnight. The mixture was cooled to room temperature, filtered through celite and washed with EtOAc. The filtrate was concentrated and purified on a silica gel column using 0-10% methanol in dichloromethane to afford (R)-1-((S)-1-(4-iodophenoxy)propan-2-yl)-3-methylpyrrolidine (1.1 g, 78%). 1H NMR (400 MHz, DMSO-d6) δ: 7.57 (d, 2H), 6.79 (d, 2H), 4.04-3.99 (m, 1H), 3.89-3.78 (m, 1H), 2.94-2.85 (m, 1H), 2.66-2.56 (m, 2H), 2.56 (m, 1H), 2.15-2.05 (m, 2H), 1.90-1.86 (m, 1H), 1.24-1.22 (m, 1H), 1.10 (d, 3H), 0.96 (d, 3H). LCMS: 346 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=1[Cl:12].C(=O)([O-])[O-:15].[K+].[K+].OO>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH2:11])=[O:15])=[CH:6][C:5]=1[Cl:12]
Reactant: COC(=O)c1ccc(C#N)cc1Cl
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 498 %

Procedure:
A mixture of 2-chloro-4-cyano benzoic acid methyl ester (12.4 g, 63.4 mmol) and potassium carbonate (1.3 g, 9.4 mmol) in dimethylsulfoxide (40 mL) was treated dropwise under cooling with 30% hydrogen peroxide (7.6 mL). The mixture was allowed to warm to room temperature and stirred overnight. The solution was quenched with water and the resulting precipitate collected by filtration. The crude material was dissolved in dichloromethane and absorbed on a silica gel Merck-60 flash column. Elution with a dichloromethane-methanol gradient (from 98:2 to 90:10) provided the title compound (10 g) as a white solid, m.p. 154-156° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Br)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:9])[CH:4]=2)[CH:14]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(COc2ccc(Br)c(F)c2)c1
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-3-fluorophenol (18.34 g, 96 mmol), 3-bromomethylbenzoic acid methyl ester (20 g, 87.3 mmol), potassium carbonate (13.3 g, 96 mmol), and acetone (300 mL) was heated to reflux overnight, followed by cooling to room temperature and filtered. The filtrate was evaporated. The solid was washed with water and cold MeOH to give 3-(4-bromo-3-fluoro-phenoxymethyl)-benzoic acid methyl ester, 28 g (72%). LC-MS (ES) calculated for C15H12BrFO3, 338; obsd 339 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]O.O=S(Cl)[Cl:23].CO>C(Cl)(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][Cl:23]
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(OCc2ccc3ccccc3n2)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(2-quinolylmethoxy)benzyl alcohol 3.58 g, 13.5 mmol) in CHCl3 (100 ml) was added SOCl2 (2 ml). The mixture was stirred at room temperature for 24 hours. A small amount of methanol was added to the reaction mixture, and the solvent thereof was removed under reduced pressure, to thereby obtain the title compound as white powder.
Reaction SMILES: B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[CH2:29]([SH:32])[CH2:30][SH:31].[C:33]([NH2:37])(=[O:36])[CH:34]=[CH2:35]>O>[CH2:29]([S:32][CH2:35][CH2:34][C:33]([NH2:37])=[O:36])[CH2:30][S:31][CH2:35][CH2:34][C:33]([NH2:37])=[O:36]
Reactant: SCCS
Reactant: C=CC(N)=O
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Solvent: O
Product: NC(=O)CCSCCSCCC(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
Sodium tetraborate (1.20 g, 5.95 mmol) was dissolved in DI water (150 mL). 1,2-Ethane dithiol (5.00 mL, 59.4 mmol) was added, followed by acrylamide (9.31 g, 130 mmol), and stirred at room temperature for two hours to give a white-colored slurry. The solid was filtered off, washed with water and dried under vacuum, giving 13.1 g (93.2%) of Compound 1 as a white solid. 1H NMR (500 MHz, d6-DMSO) δ 7.33 (s, 2H), 6.82 (s, 2H), 3.37 (s, 4H), 2.69 (t, J=7.2 Hz 4H), 2.32 (t, J=7.3 Hz, 4H). 13C NMR (126 MHz, d6-DMSO) δ 172.68, 35.69, 31.35, 26.92.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1.[CH3:14]I>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[C:6]([Br:12])[C:7]([O:11][CH3:14])=[C:8]([Br:10])[CH:9]=1
Reactant: CI
Reactant: COC(=O)c1cc(Br)c(O)c(Br)c1
Product: COC(=O)c1cc(Br)c(OC)c(Br)c1

Procedure:
3,5-Dibromo-4-methoxybenzoic acid methyl ester was prepared from 3,5-dibromo-4-hydroxybenzoic acid methyl ester by following Method C using methyl iodide as an alkylating agent in quantitative yield. The product was used without further purification.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])=[CH:10][CH:9]=1>CN(C=O)C.CCOC(C)=O>[N:1]([CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])=[CH:10][CH:9]=1)=[N+:2]=[N-:3]
Reactant: CC(C)OC(=O)c1ccc(CCBr)s1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1ccc(CCN=[N+]=[N-])s1
Reaction time: 18 h
Yield: 96.5 %

Procedure:
Sodium azide (697 mg, 10.7 mmol) was added to a solution of the bromide from step 2 (2.7 g, 9.7 mmol) in DMF (39 mL) at room temperature. After 18 h at room temperature, the reaction mixture was diluted with EtOAc (300 mL) and washed with water (3×100 mL) and brine (50 mL). The organic phases was dried (Na2SO4), filtered and concentrated in vacuo to afford 2.24 g (96%) of isopropyl 5-(2-azidoethyl)thiophene-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[CH2:18][CH:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:16][C:15](=O)[C:14]=3[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:27]([NH:30][NH2:31])([NH2:29])=[NH:28].[ClH:32].Cl.O>C(O)C>[ClH:32].[NH:30]([N:31]=[C:15]1[CH2:16][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][C:19]2[N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:12]=[CH:13][C:14]1=2)[C:27]([NH2:29])=[NH:28]
Reactant: N=C(N)NN
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CC(c2ccccc2)CC3=O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2CC(c2ccccc2)CC3=NNC(=N)N)cc1
Yield: 87.8 %

Procedure:
A mixture of 1-(4-methylphenyl)sulfonyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (1.0 g), aminoguanidine hydrochloride (0.32 g), concentrated hydrochloric acid (0.14 ml), water (0.14 ml) and ethanol (50 ml) was refluxed for 20 minutes. Under reduced pressure, the solvent was evaporated, and the residue was washed with water, dried and recrystallized from ethanol to give 4-guanidinoimino-1-(4-methylphenyl)sulfonyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 19) (1.1 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([OH:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22]COCC.[N+](=C)=[N-]>COCCOC>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([OH:21])[CH2:17][C:18]([O:20][CH3:22])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@@H](O)CCCCNC(=O)OCc1ccccc1
Reactant: CCOCC
Agent: C=[N+]=[N-]
Solvent: COCCOC
Product: COC(=O)C[C@@H](O)CCCCNC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Into 4 ml of 1,2-dimethoxyethane, was dissolved 450 mg (1.52 mmoles) of (S)-7-benzyloxycarbonylamino-3-hydroxyheptanoic acid. To the solution, while being cooled in ice, was added dropwise 7 ml (4.56 mmoles) of an ether solution of diazomethane. The mixture was stirred for 30 minutes and then evaporated to dryness to yield 461 mg (98% yield) of methyl (S)-7-benzyloxycarbonylamino-3-hydroxyheptanoate. [α]D21 +1°.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:23]=[C:24]1[NH:32][C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[N:25]1[CH:33]1[CH2:38][CH2:37][N:36]([C:39]2[N:44]=[CH:43][N:42]=[C:41]([C:45]([OH:47])=O)[CH:40]=2)[CH2:35][CH2:34]1.Cl.Cl.[CH3:50][C:51]1([CH3:60])[CH2:56][NH:55][CH2:54][C:53]2[CH:57]=[N:58][NH:59][C:52]1=2.C(N(CC)CC)C>CN(C=O)C>[CH3:50][C:51]1([CH3:60])[CH2:56][N:55]([C:45]([C:41]2[N:42]=[CH:43][N:44]=[C:39]([N:36]3[CH2:37][CH2:38][CH:33]([N:25]4[C:26]5[C:27](=[N:28][CH:29]=[CH:30][CH:31]=5)[NH:32][C:24]4=[O:23])[CH2:34][CH2:35]3)[CH:40]=2)=[O:47])[CH2:54][C:53]2[CH:57]=[N:58][NH:59][C:52]1=2
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: CC1(C)CNCc2cn[nH]c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CN(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)Cc2cn[nH]c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.26 mmol) TBTU were added to 80 mg (0.24 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 70.0 mg (0.31 mmol) 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine dihydrochloride, 120.0 μL (0.86 mmol) triethylamine in 1.0 mL DMF and the mixture was stirred overnight at RT. The reaction mixture was purified by preparative HPLC, the product fractions were combined and then lyophilised.
Reaction SMILES: CC1C=CC=C(C)N=1.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18](Br)[C:19]([O:21]C)=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1.[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[CH:29]=[CH:28]2>CN(C)C=O>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18]([C:28]3[C:27]4[C:31](=[CH:32][CH:33]=[C:25]([Br:24])[CH:26]=4)[N:30]([CH3:34])[CH:29]=3)[C:19]([OH:21])=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: COC(=O)C(Br)c1ccc2c(c1)OCO2
Reactant: Cn1ccc2cc(Br)ccc21
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: Cn1cc(C(C(=O)O)c2ccc3c(c2)OCO3)c2cc(Br)ccc21
Temperature: 80 °C
Yield: 79.4 %

Procedure:
2.6-Dimethylpyridine (0.75 ml) was added to a stirred solution of methyl 2-(1,3-benzodioxol-5-yl)-2-bromoacetate (from Example 61(c), 1.75 g, 6.43 mmol) and 5-bromo-1-methylindole (from step (a), 1.35 g) in anhydrous dimethylformamide (10 ml) at ambient temperature, under a nitrogen atmosphere. The solution was heated to 80° C. for 8 hours. The reaction mixture was partitioned between diethylether and water, separated and the organic layer dried (magnesium sulphate) and evaporated in vacuo. The residue was flash chromatographed (using 50% dichloromethane and 50% hexane as eluant) to give the subtitle compound as a colourless oil (1.98 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:8])=[C:5]([N+:23]([O-:25])=[O:24])[C:4]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C1COCC1.[H-].[Na+].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>O>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][N:9]([C:7](=[O:8])[C:6]1[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[C:4]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:5]=1[N+:23]([O-:25])=[O:24])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)[CH3:45]
Reactant: CCCCCOc1c(OC)ccc(C(=O)NCCc2ccc([N+](=O)[O-])cc2)c1[N+](=O)[O-]
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCOc1c(OC)ccc(C(=O)N(CCc2ccc([N+](=O)[O-])cc2)CC(=O)OCC)c1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 68 %

Procedure:
4-Methoxy-2-nitro-N-[2-(4nitrophenyl)ethyl]-3-pentyloxybenzamide obtained in Example 2-47, THF (1 ml) and sodium hydride (13.3 mg, 0.556 mmol) were mixed, and the mixture was stirred for 5 minutes. Ethyl bromoacetate (0.0617 ml, 0.556 mmol) was added, and the mixture was stirred at 90° C. for 5.5 hours. Then, sodium hydride (6.7 mg, 0.278 mmol) and ethyl bromoacetate (6.7 mg, 0.278 mmol) were further added, and the mixture was stirred at 90° C. for 6.5 hours. To the mixture was added water (3 ml) to stop the reaction, and the organic layer was extracted 3 times with ethyl acetate (5 ml). The organic layers were combined and dried over anhydrous magnesium sulfate. The drying agent was fitered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1-2/3) to give ethyl{ (4-methoxy-2-nitro-3-pentyloxybenzoyl)-[2-(4nitrophenyl)ethyl]amino}acetate (0.137 g, 68%) as a pale-yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Br[CH2:45][C:46]1[CH:47]=[C:48]([CH:53]=[CH:54][CH:55]=1)[C:49]([O:51][CH3:52])=[O:50].BrCC1OC(C(F)(F)F)=CC=1>>[O:21]=[C:2]1[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:45][C:46]1[CH:47]=[C:48]([CH:53]=[CH:54][CH:55]=1)[C:49]([O:51][CH3:52])=[O:50]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: COC(=O)c1cccc(CBr)c1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COC(=O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one, and methyl 3-(bromomethyl)benzoate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, methyl 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate was obtained (93%) as a colorless solid: mp 97-98° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ8.04 (s, 1H), 8.02-7.96 (m, 1H), 7.58-7.52 (m, 1H), 7.49-7.42 (m, 1H), 7.25-7.17 (m, 2H), 7.09-7.00 (m, 1H), 6.78 (d, J=7.5 Hz, 1H), 6.56 (s, 1H), 6.45 (s, 1H), 5.16 (d, J=15.7 Hz, 1H), 5.02 (d, J=9.0 Hz, 1H), 4.89 (d, J=15.7 Hz, 1H), 4.74 (d, J=9.0 Hz, 1H), 4.60-4.52 (m, 2H), 3.93 (s, 3H), 3.13-2.96 (m, 2H); 13C NMR (75 MHz, CDCl3) δ178.1, 166.7, 162.0, 161.4, 141.9, 136.3, 132.8, 131.9, 130.9, 129.3, 129.2, 128.9, 128.4, 124.1, 123.7, 120.2, 120.1, 119.1, 109.2, 93.4, 80.7, 72.5, 57.9, 52.3, 43.9, 29.2; MS (ES+) m/z 428.1 (M+1).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[C:6]([C:9]1[CH:10]=[C:11]([C:17]#[N:18])[C:12](=[O:16])[NH:13][C:14]=1[CH3:15])(=[O:8])[CH3:7]>>[C:6]([C:9]1[CH:10]=[C:11]([C:17]([NH2:18])=[O:2])[C:12](=[O:16])[NH:13][C:14]=1[CH3:15])(=[O:8])[CH3:7]
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C
Reactant: O=S(=O)(O)O
Product: CC(=O)c1cc(C(N)=O)c(=O)[nH]c1C
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To 100 grams of concentrated sulfuric acid is added 10 g (0.056 mole) of 5-acetyl-1,2-dihydro-6-methyl2-oxo-3-pyridinecarbonitrile. The mixture is stirred at 60° C. for 5 hours, cooled and then poured on 1 kg ice. The resulting solid is collected, washed with water and recrystallized from ethanol to give the title compound.
Reaction SMILES: C(O[C@@H:5]1[O:20][C@H:19]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:11]([O:12][CH3:13])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[CH2:26]([SH:28])[CH3:27].B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][CH3:13])[C@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:19]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:20][C@H:5]1[S:28][CH2:26][CH3:27])(=[O:10])[CH3:9]
Reactant: CO[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@H]1OC(C)=O
Reactant: CCS
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCS[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC)[C@H]1OC(C)=O
Yield: 53438.8 %

Procedure:
1,2,4,6-Tetra-O-acetyl-3-O-methyl-β-D-glucopyranose 1 (69 g, 0.19 mmol), (B. Helferich et al., J. prakt. Chem., 132, 321 (1932)) is dissolved in toluene (580 ml). Ethanethiol (28 ml, 0.38 mmol) is added, followed by dropwise addition of a solution of trifluoroborane diethyl etherate (1 M in toluene, 190 ml). The mixture is left stirring for 1.5 hours (TLC), solid sodium hydrogen carbonate is introduced and the mixture is filtered, washed with water, dried and concentrated. Chromatography on a column of silica (3/1 cyclohexane/ethyl acetate) gives 2 (37 g, 54%) [α]D−26 (c=1. dichloromethane). 1H NMR (CDCl3). δ 5.05-4.96 (m, 2H, H-2, H-4), 4.39, (d, 1H, J=9.5 Hz, H-1), 4.18-4.12 (m, 2H, H-6, H-6′), 3.60 (m, 1H, H-5), 3.50 (dd, 1H, J=9.3 Hz, H-3), 3.41 (s, 3H, OCH3), 2.65-2.53 (m, 2H, SCH2CH3), 2.12, 2.11, 2.09 (3s, 9H, 3 Ac), 1.25 (t, 1H, SCH2CH3)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH:10](=O)[CH2:11][CH2:12][CH2:13][CH3:14].C([BH3-])#N.[Na+]>CO>[CH2:10]([NH:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH2:9])=[O:8])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC=O
Reactant: NC(=O)c1[nH]cnc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCNc1nc[nH]c1C(N)=O
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
4-Amino-1H-imidazole-5-carboxamide (13.0 g, 0.104 mol) and valeraldehyde (11 mL, 0.10 mol) were mixed in methanol (200 mL). After being stirred for 30 min, sodium cyanoborohydride (6.5 g, 0.10 mol) was added to the solution and stirring was continued overnight. The reaction mixture was concentrated under reduced pressure. The remaining residue was taken up in EtOAc and the resulting solution was washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by flash chromatography (DCM to 5% MeOH/DCM) to give the desired product (12.9 g, 63.1%). LCMS calculated for C9H16N4O (M+H): 197.1. Found: 180.1 (M+H−NH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[S:11]([NH:14][C:15]1[C:16]([F:25])=[CH:17][C:18]2[CH2:22][O:21][B:20]([OH:23])[C:19]=2[CH:24]=1)(=[O:13])=[O:12].[H][H]>O1CCOCC1.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([S:11]([NH:14][C:15]2[C:16]([F:25])=[CH:17][C:18]3[CH2:22][O:21][B:20]([OH:23])[C:19]=3[CH:24]=2)(=[O:12])=[O:13])=[C:2]([F:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2cc3c(cc2F)COB3O)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1ccc(S(=O)(=O)Nc2cc3c(cc2F)COB3O)c(F)c1
Yield: 52.1 %

Procedure:
To a solution of 2-fluoro-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-nitrobenzenesulfonamide (1.84 g, 4.97 mmol) in 50 mL of dioxane was added Pd/C (10 wt. % on activated carbon, 500 mg). The reaction mixture was hydrogenated at room temperature under 50 psi of hydrogen for 16 hours. After Pd/C was filtered through a pad of Celite, the solution was concentrated under reduced pressure to give a yellow residue. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give 0.88 g of the title compound as a white solid. MS calcd for (C13H11BF2N2O4S): 340.1. MS found (ESI negative): (M−H)−=339.1. 1H NMR (DMSO-d6) δ (ppm): 9.69 (s, 1H), 9.23 (bs, 1H), 7.58 (d, 1H), 7.10-7.21 (m, 3H), 6.67 (t, 1H), 4.83 (s, 2H).