Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.BrC1C=C2C=CNC2=NC=1.[F:29][CH:30]([F:49])[CH2:31][N:32]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([NH:43][CH2:44][CH2:45][C:46]#[N:47])[N:38]=2)[C:34](I)=[N:33]1.[F-].[Cs+].ClCCl>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:49][CH:30]([F:29])[CH2:31][N:32]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([NH:43][CH2:44][CH2:45][C:46]#[N:47])[N:38]=2)[C:34]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)=[N:33]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: N#CCCNc1nccc(-c2cn(CC(F)F)nc2I)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Brc1cnc2[nH]ccc2c1
Solvent: COCCOC
Solvent: ClCCl
Product: N#CCCNc1nccc(-c2cn(CC(F)F)nc2-c2cnc3[nH]ccc3c2)n1
Temperature: 80 °C

Procedure:
A mixture of the 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine B-33-4, which was prepared from 5-bromo-1H-pyrrolo[2,3-b]pyridine according to known literature methods, (145 mg, 0.594 mmol), 3-({4-[1-(2,2-difluoroethyl)-3-iodo-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile (200 mg, 0.495 mmol), and cesium fluoride (1.48 mL of a 1M aqueous solution) in 3 mL of DME was deoxygenated with a nitrogen bubbler for 5 min and then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (41 mg, 0.05 mmol) was added. The mixture was then heated in a microwave reactor at 80° C. for 2.5 hours. The reaction was degassed and fresh catalyst (20 mg) was added. The mixture was heated in the microwave at 80° C. for 4 more hours. The resulting dark mixture was partitioned between ethyl acetate and brine. The aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with brine, dried over Magnesium sulfate and reduced to minimum volume. The residue was purified on silica gel using a gradient of 0-8% methanol (containing 10% ammonium hydroxide) in a mixture of tert-butyl methyl ether and dichloromethane (1:1) to give the desired product as a pale orange solid. This material was triturated twice with tert-butyl methyl ether to give 82 mg (42%) of analytically pure 3-({4-[1-(2,2-difluoroethyl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile as an off white solid. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 9.73 (br. s., 1H), 8.37 (d, J=2.02 Hz, 1H), 8.22 (s, 1H), 8.10 (d, J=5.31 Hz, 1H), 8.08 (d, J=1.52 Hz, 1H), 7.35-7.46 (m, 1H), 6.54 (d, J=3.79 Hz, 1H), 6.51 (dd, J=3.54, 2.02 Hz, 1H), 6.30 (tt, J=55.04, 3.82 Hz, 1H), 5.91 (br. t, J=6.82 Hz, 1H), 4.62 (td, J=14.65, 3.79 Hz, 2H), 3.39 (br. s., 2H), 2.40 (br. s., 2H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([NH:5][CH2:6][C:7]1[C:8]([O:19][CH3:20])=[CH:9][C:10]([Cl:18])=[C:11]([CH:17]=1)[C:12]([N:14]=[C:15]=[O:16])=O)=[O:4].[F:23][C:24]([F:41])([F:40])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH:32]C(OC(C)(C)C)=O)=[CH:27][CH:26]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:18][C:10]1[C:11]([C:12]2[NH:14][C:15](=[O:16])[N:31]([C:28]3[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:41])[F:40])=[CH:26][CH:27]=3)[N:32]=2)=[CH:17][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:22])([F:21])[F:1])=[C:8]([O:19][CH3:20])[CH:9]=1
Reactant: COc1cc(Cl)c(C(=O)N=C=O)cc1CNC(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)cc1CNC(=O)C(F)(F)F
Yield: 24.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-methoxybenzoyl isocyanate (0.500 g), tert-butyl 2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 0.450 g), DCM (20 mL), and trifluoro acetic acid (5.0 mL) to afford 0.180 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:29]([N:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:38][CH:37]1[CH2:49]Cl)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:49][CH:37]2[CH2:38][N:39]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:40][CH2:41][N:36]2[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Product: O=C1OC2(CCN(C(=O)c3cn(CC4CN(Cc5ccccc5)CCN4Cc4ccccc4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with 1,4-dibenzyl-2-chloromethyl-piperazine (described in Journal of Medicinal Chemistry 1999, 42(9), 1587-1603) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][C:11](=[O:19])[NH:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]([OH:19])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)C1CC(=O)NN1c1ncc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(O)nn1-c1ncc(Cl)cc1Cl
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
To a 100 mL flask, ethyl 2-(3,5-dichloropyridin-2-yl)-5-oxopyrazolidine-3-carboxylate (4.00 g, 13.15 mmol), acetonitrile (50 mL) and 98% sulfuric acid (2.63 g, 26 mmol) were added. The mixture was stirred for 10 minutes, and then potassium persulfate (5.69 g, 21.04 mmol) was added. The reaction mixture was heated to reflux for 5 hours. The warm (50-65° C.) reaction mixture was filtered, a cake is obtained after filtration. The cake was washed with acetonitrile (10 mL). The filtrate was concentrated to about 10 mL on rotary evaporator. Then water (50 mL) was added. The solid product was isolated by filtration, washed with 25% aqueous solution of acetonitrile (3×15 mL) and dried to give the product (3.0 g) as an orange solid in 76% yield. Melting point: 164-167° C. 1H NMR (300 MHz, CDCl3): 8.445 (d, 1H), 7.912 (d, 1H), 6.546 (s, 1H), 4.262 (q, 2H), 1.236 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Br:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2)([O-])=O.Cl[Sn]Cl>C(O)C.CS(C)=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Br:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2
Reactant: O=c1[nH]c2cc(Br)c([N+](=O)[O-])cc2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CS(C)=O
Solvent: CCO
Product: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1Br
Temperature: 90 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To a stirred mixture of 6-nitro-7-bromo-1,4-dihydro-2,3-quinoxalinedione (87 mg, 0.30 mMol) in ethanol (3 mL) and DMSO (0.5 mL) was added SnCl2 ·2H2O (343 mg, 1.50 mMol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) with stirring for 1 h to form a clear solution which was refluxed for another 1 h. It was then cooled to room temperature and the yellow precipitate was collected by filtration, followed by washing with cold ethanol (2×1 mL) to give 50 mg (67%) of crude title compound (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 21 mg of pure as bright yellow needles, mp:>300° C. (dec. from 315° C.), changed color from 300° C. NMR (1H, DMSO-d6): d 5.257 (s, 2H); 6.558 (s, 1H); 7.087 (s, 1H); 11.599 (s, 1H); 11.792 (s, 1H). HRMS: calcd for C8H6N3O2Br (M+) m/z: 254.9642; found 254.9630. Potency relative to DCK: 7.1%.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>>[NH2:1][C@H:2]([C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[F:34][C:33]([C:31]([OH:37])=[O:32])([F:36])[F:35]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
Boc-L-Ile-L-Pro-OBzl (1.63 g, 3.38 mmol) was dissolved in TFA (5 ml) and left with standing on ice for 30 minutes. On completion of the reaction, TFA was removed by evaporation, and the residue was vacuum-dried to obtain H-L-Ile-L-Pro-OBzl-TFA. The compound was dissolved in DMF (8 ml), and Boc-D-Tyr(Me)-OH (1.50 g, 5.07 mmol) was then added. HBTU (1.92 g, 5.07 mmol), HOBt.H2O (518 mg, 3.38 mmol), and triethylamine (2.37 ml, 16.9 mmol) were further added and stirred for three hours under ice-cooling. The reaction solution was concentrated, dissolved in ethyl acetate, and successively washed with an aqueous 10% citric acid solution, an aqueous 4% sodium bicarbonate solution, and saturated saline. The product was dried over MgSO4 and concentrated, and the resulting foam substance was purified by flash silica gel chromatography (4×30 cm, 1% methanol/chloroform) to obtain the foam title compound (1.44 g, 2.42 mmol, 72% yield). TLC: Rf=(CHCl3/MeOH=9/1).
Reaction SMILES: [OH:1][CH2:2][CH:3](CO)O.CC(OCC(O)CO)=O.[CH3:16][C:17]([O:19][CH2:20][CH:21]([O:24][C:25]([CH3:27])=[O:26])[CH2:22][OH:23])=[O:18]>O>[CH3:16][C:17](=[O:18])[O:19][CH2:20][CH:21]([CH2:22][O:23][C:2](=[O:1])[CH3:3])[O:24][C:25](=[O:26])[CH3:27]
Reactant: CC(=O)OCC(CO)OC(C)=O
Reactant: OCC(O)CO
Agent: CC(=O)OCC(O)CO
Solvent: O
Product: CC(=O)OCC(COC(C)=O)OC(C)=O

Procedure:
When the reaction is performed correctly, the reaction product contains only traces of glycerol, monoacetin, diacetin and water, so that the OH number normally lies below 1. Pure triacetin can be obtained readily by distillation in a rectification column of the obtained crude product, since, at atmospheric pressure, acetic acid boils at about 118° C., acetic acid anhydride boils at about 140° C., and glyceryl triacetate (triacetin) boils at about 258° C. Any catalyst that may still be present remains in the distillation residue.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1.CCN=C=NCCCN(C)C.[CH2:31](O)[CH2:32][CH2:33][CH3:34]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14][CH2:31][CH2:32][CH2:33][CH3:34])=[O:13])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)O)C1
Reactant: CCCCO
Agent: CCN=C=NCCCN(C)C
Product: CCCCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reaction time: 16 h

Procedure:
2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetic acid was mixed with EDCI and 1-butanol and the reaction mixture was stirred for 16 h to obtain butyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [NH:1]([C:3]([C@H:5]1[N:15]2[C@@H:9]([S:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]2=[O:16])[CH2:8][CH2:7][CH2:6]1)=[O:4])[NH2:2].[CH3:25]OC(OC)OC>>[O:4]1[CH:25]=[N:2][N:1]=[C:3]1[C@H:5]1[N:15]2[C@@H:9]([S:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:14]2=[O:16])[CH2:8][CH2:7][CH2:6]1
Reactant: COC(OC)OC
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)NN)N2C1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](c3nnco3)N2C1=O
Temperature: 70 °C
Reaction time: 18 h
Yield: 74.3 %

Procedure:
To a round bottom flask was added tert-butyl (4S,7S,10aS)-7-(hydrazinecarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (0.13 g, 0.35 mmol) and trimethoxymethane (2.50 mL, 22.9 mmol). The reaction was heated at 70° C. for 5 hr. and then at 95° C. for 18 hr. The reaction was concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-60% EtOAc/Hex to give tert-butyl (4S,7S,10aS)-7-(1,3,4-oxadiazol-2-yl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (94 mg, 0.26 mmol, 73% yield) as a white solid. Anal. Calcd. for C16H24N4O4S m/z 368.4. found: 369.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:5].Cl.[CH2:31]([O:33][C:34](=[O:37])[CH2:35][NH2:36])[CH3:32]>>[CH2:31]([O:33][C:34](=[O:37])[CH2:35][NH:36][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([S:13](=[O:14])(=[O:15])[NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:4](=[O:5])[C:3]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:2]=2[Cl:1])=[CH:24][CH:23]=1)[CH3:32]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccc(Cl)cc2Cl)cc1
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccc(Cl)cc2Cl)cc1

Procedure:
The title compound was prepared from 4-[2-(2,4-dichloro-benzoyl)-phenylsulfamoyl]-benzoic acid and glycine ethyl ester hydrochloride according to the method described in Example 1.1/d. MS (EI) 536.1 (MH+).
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH:12]([CH3:19])[C:13]2=[O:18]>C1COCC1.C(O)C>[C:3]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH:12]([CH3:19])[CH:13]2[OH:18]
Reactant: CC1Cc2c(cccc2-c2ccccc2-c2ccccc2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1Cc2c(-c3ccccc3-c3ccccc3)cccc2C1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
Sodium borohydride (2.34 g, 61.76 mmol, 1.5 equiv) was added in portions to a cold solution (0° C.) of compound 17 (12.27 g, 41.17 mmol, 1.0 equiv) in THF (125 mL) and ethanol (125 mL). The reaction mixture was stirred at room temperature for 2 hours when LC/MS indicated that the reaction was complete. The mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (300 mL). 1 M HCl was added dropwise to quench the reaction. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated brine (500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 18 (13.0 g, >99% yield) as a pale-yellow oil. This material was used subsequently.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:4][CH:5]=[CH:6][CH:7]=1.CC([O-])=O.[Na+].[N:28]#[C:29]Br.O>CO>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:29]#[N:28])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CBr
Reactant: Cc1cccnc1CN(CCCCN)Cc1ncccc1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cccnc1CN(CCCCNC#N)Cc1ncccc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.4 %

Procedure:
To a 0° C. solution of N1,N1-bis-(3-methyl-pyridin-2-ylmethyl)-butane-1,4-diamine (237 mg, 0.80 mmol) in MeOH (10 mL) was added NaOAc (200 mg, 2.39 mmol) and cyanogen bromide (94 mg, 1.03 mmol) and stirred at room temperature for 17 hours. Water (10 mL) was added and the reaction mixture was extracted with CH2Cl2 (4×40 mL). The extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to provide pure COMPOUND 198 as a beige solid (190 mg, 74%). 1H NMR (CDCl3) δ 1.45-1.51 (m, 2H), 1.65-1.63 (m, 2H), 2.12 (s, 6H), 2.61-2.65 (m, 2H), 2.83-2.89 (m, 2H), 3.68 (s, 4H), 7.08 (dd, 2H, J=4.2, 7.8 Hz), 7.38 (d, 2H, J=7.8 Hz), 7.57 (br s, 1H), 8.37 (d, 2H, J=4.2 Hz). 3C NMR (CDCl3) δ 18.5, 21.1, 28.3, 44.4, 53.6, 58.2, 118.9, 122.9, 133.4, 138.6, 146.6, 156.7. ES-MS m/z 324 (M+H). Anal. Calcd. for C19H25N5.0.4 CH2Cl2O.0.1CH40: C, 64.95; H, 7.32; N, 19.42. Found: C, 64.65; H, 7.22; N, 19.27.
Reaction SMILES: C([C@](O)(C(O)=O)[C@@](CC)(O)C(O)=O)C.C([C@@H]([C@H](C(OCC)=O)O)O)(OCC)=O.N([C@@H]([C@@H](O)C(OCC)=O)C(OCC)=O)=[N+]=[N-].[N:45]([C@@H:48]([C@@H:54]1[CH2:58][O:57][C:56]([CH3:60])([CH3:59])[O:55]1)[C:49](OCC)=[O:50])=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1.C(OCC)C.O>[NH2:45][C@@H:48]([C@@H:54]1[CH2:58][O:57][C:56]([CH3:60])([CH3:59])[O:55]1)[CH2:49][OH:50]
Reactant: CCOC(=O)[C@@H](N=[N+]=[N-])[C@@H]1COC(C)(C)O1
Agent: CCOC(=O)[C@@H](N=[N+]=[N-])[C@@H](O)C(=O)OCC
Agent: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Agent: CC[C@](O)(C(=O)O)[C@](O)(CC)C(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC1(C)OC[C@@H]([C@H](N)CO)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Diethyl L-tartrate [(2R,3R)-diethyl 2,3-dihydroxysuccinate] was converted to (2S,3R)-diethyl 2-azido-3-hydroxysuccinate according to the literature method (A. Breuning, R. Vicik and T. Schirmeister, Tetrahedron: Asymm., 2003, 14, 3301) and then into (S)-ethyl 2-azido-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)acetate according to the method described by S. Saito, T. Ishikawa, A. Kuroda, K. Koga and T. Moriwake, Tetrahedron, 1992, 48, 4067. This latter compound (1.8 g, 7.85 mmol) was dissolved in dry THF (12 ml) and cooled in an ice-bath. Lithium aluminium hydride (31.4 ml, 31.4 mmol, 1M in diethyl ether) was added and the mixture warmed to rt and stirred for 30 mins., then heated under reflux for 3 h. The mixture was cooled in an ice bath and water (1.2 ml), 15% aq. NaOH (1.2 ml), and water (4 ml) added successively. The mixture was diluted with diethyl ether, filtered through Celite and the Celite washed with hot CHCl3 (3×). The combined filtrates were dried (MgSO4), filtered and the solvent evaporated to a colourless oil. The oil was chromatographed on silica gel (CH2Cl2-MeOH-28% aq. NH4OH, 96:4:0.5 then 9:1:0.05) to give a pale yellow oil which was distilled on a Kugelrohr apparatus at 120° C./0.1 mmHg to afford (R)-2-amino-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (0.415 g, 61%) as a colourless oil. 1H NMR (CDCl3, referenced to the centre line of CDCl3 at 77.0 ppm) δ 4.10-3.98 (m, 2H), 3.87 (dd, J=7.4, 5.7 Hz, 1H), 3.71 (dd, J=10.9, 4.4 Hz, 1H), 3.54 (dd, J=10.9, 5.7 Hz, 1H), 2.95 (m, 1H), 1.94 (brs, 3H, exchanged to D2O), 1.42 (s, 3H), 1.35 (s, 3H). 13C NMR (CDCl3) δ 109.0, 77.8, 66.5, 64.4, 54.6, 26.5, 25.2. +ESMS Found 162.1130 (M+H)+ C7H16NO3 requires 162.1130. [α]D20 −9.5 (c, 1.47, CHCl3). Lit., [α]D −10.5, c 1.5, CHCl3 for the product made from D-ascorbic acid according to M. Banwell, C. De Savi, D. Hockless and K. Watson, Chem. Commun., 1998, 645.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:20])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+]>O.CO>[CH3:20][N:7]1[C:8]2[C:13](=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc2c(c1)cc(C(=O)OCC)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(C(=O)O)cc2cc(C(=O)O)ccc21
Reaction time: 4 h
Yield: 89.1 %

Procedure:
Solution of 1-methyl-indole-2,5-dicarboxylic acid diethyl ester 17 (675 mg, 2.5 mmole) and NaOH (5.00 mmole) in a mixture of water/MeOH (1/4) (20 ml) was stirred at 50 C. for 4 h and then overnight at ambient temperature. The reaction mixture was evaporated in vacuo to dryness and the residue was dissolved in water (20 ml) and acidified with 1M HCl up to pH=3. The precipitate was collected on the filter and washed with water (3×5 ml) and dried over phosphorus pentoxide in dessicator to give 488 mg (89%) of 1-methyl-indole-2,5-dicarboxylic acid 18 as white crystalline material. MS: 218.2 (M−H). 1—NMR (DMSO-d6): 8.35 (m, 1H, H-4, indole); 7.90 (m, 1H, H-6, indole); 7.41 (d, 1H, H-7, indole); 7.32 (s, 1H, H-3, indole); 4.05 (s, 3H, NCH3, indole).
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][N:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH2:30][CH2:31][CH2:32][CH2:33][N:34]([CH2:38][CH2:39][CH3:40])[CH2:35][CH2:36][CH3:37])[CH3:29])=[CH:23][CH:22]=1)[CH2:13][C:14]1[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=1)C.Cl>O1CCOCC1>[CH2:38]([N:34]([CH2:35][CH2:36][CH3:37])[CH2:33][CH2:32][CH2:31][CH2:30][N:28]([CH2:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:12]([CH2:11][C:7]2[N:6]([CH2:5][C:4]([OH:41])=[O:3])[CH:10]=[CH:9][N:8]=2)[CH2:13][C:14]2[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=2)=[CH:26][CH:25]=1)[CH3:29])[CH2:39][CH3:40]
Reactant: CCCN(CCC)CCCCN(C)Cc1ccc(CN(Cc2nccn2C)Cc2nccn2CC(=O)OCC)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCN(CCC)CCCCN(C)Cc1ccc(CN(Cc2nccn2C)Cc2nccn2CC(=O)O)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 199.1 %

Procedure:
The compound (41.6 mg) obtained in Example 87-1 was dissolved in dioxane (0.80 ml) and added with concentrated hydrochloric acid (800 μl) at room temperature and the whole was stirred at an outside temperature of 100° C. for 5 hours. After completion of the reaction, the resultant was concentrated and evaporated to dryness under reduced pressure, thereby obtaining a hydrochloride (78.7 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CS(O)(=O)=O.[N-:21]=[N+]=[N-].[Na+].[OH-].[Na+]>ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:15])[NH:21][CH2:10][CH2:11][O:12][C:13]=2[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(c1)OCCC2=O
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)OCCNC2=O
Temperature: 0 °C

Procedure:
7-tert-Butyl-chroman-4-one (1.3 g, 6.36 mmol) was taken up in dichloromethane (11.25 mL) and methane sulfonic acid (7.5 mL) and cooled to 0° C. With stirring at 0° C. was added sodium azide (827 mg, 2 eq) portion-wise. The resulting mixture was stirred at 0° C. for 3 hours and by TLC analysis there was no more starting material remaining, so the reaction mixture was poured into a 20% solution of NaOH(aq) (25 mL) at 0° C. This solution was stirred for 10 minutes and then it was extracted with dichloromethane (3×50 mL) and the combined dichloromethane layers were washed with brine (1×50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography on silica gel eluting with a gradient of 5% ethyl acetate in hexanes to 100% ethyl acetate afforded the title compound as a white solid (1.304 ) (M+H)+=220.