Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]2=[N:8][C:7]=1[N:15]([CH2:25][CH2:26][CH2:27][CH3:28])[C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)=[O:5])C>CO.O1CCOCC1.O>[CH2:25]([N:15]([C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[C:7]1[N:8]=[C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2[C:6]=1[C:4]([OH:5])=[O:3])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN(C(=O)c1cccc(Cl)c1)c1nc2n(c1C(=O)OCC)CCCC2
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CCCCN(C(=O)c1cccc(Cl)c1)c1nc2n(c1C(=O)O)CCCC2
Temperature: 25 °C

Procedure:
2-[butyl-(3-chloro-benzoyl)-amino]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (11.7 mmol) was dissolved in a solution of 190 mL MeOH/dioxan/4 M NaOH in water in a ratio of 15/4/1 and the solution was stirred over night at room temperature. The solvent was removed under vacuum, EtOAc (700 mL) was added thereto and the organic phase was washed with 0.5 M KHSO4 in water (700 mL). The aqueous phase was extracted with EtOAc (300 mL) and the combined organic phases were washed with saturated aqueous NaCl solution (700 mL) and dried over sodium sulphate, and the solvent was removed under vacuum. 4.13 g (94% over two stages) of the desired product 2-[butyl-(3-chloro-benzoyl)-amino]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([S:22]C3C=CC([N+]([O-])=O)=CC=3[N+]([O-])=O)=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.O1CCCC1.[OH-].[K+].[F:42][C:43]([F:47])=[C:44]([F:46])[F:45]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([S:22][C:44]([F:46])([F:45])[CH:43]([F:47])[F:42])=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: FC(F)=C(F)F
Reactant: COc1ccc(-c2cc(Sc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])sc2-c2ccc(OC)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cc(SC(F)(F)C(F)F)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
2,3-bis(4-Methoxyphenyl)-5-(2,4-dinitrophenylthio)thiophene (4.9 g, 10 mmoles), tetrahydrofuran (60 ml), methanol/water (7.5 ml, 2.5 ml) and potassium hydroxide (1.3 g, 20 mmoles) were charged into a stainless steel bomb. The bomb was briefly evacuated, charged with tetrafluoroethylene (5 g, 50 mmoles) and agitated for 12 hours at room temperature. The reaction mixture was filtered and the filtrate concentrated to near dryness. The residue was taken up in ethyl acetate and filtered. The filtrate was washed three times with 1 N NaOH, three times with 1 N HCl, once with brine, dried and concentrated in vacuo. Crystallization from ethanol/water gave the title compound (2.4 g), m.p. 84°-7° (D). Infrared and H-NMR spectra were consistent with the assigned structure. MS 428 (M+)
Reaction SMILES: [CH3:1][CH2:2][OH:3].[H-].[Na+].F[C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]>C1COCC1>[Br:13][C:11]1[CH:10]=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:3][CH2:2][CH3:1])[CH:12]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
To a cooled (0° C.) solution of EtOH (0.07 mL, 1.193 mmol) in THF (5 mL) was added NaH (60% suspension in mineral oil, 68 mg, 1.705 mmol). The reaction mixture was stirred under nitrogen at 0° C. for 15 minutes. 2-fluoro-4-bromo-nitrobenzene (250 mg, 1.136 mmol) was added and the reaction mixture stirred for a further 18 hours, whilst warming slowly to room temperature. The reaction mixture was concentrated in vacuo. Ether (20 mL) and HCl (0.5 M, 20 mL) were added. The aqueous layer was basified with aqueous saturated NaHCO3 solution and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo, to give the title compound (270 mg, 97%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:13][CH2:14][CH3:15])[CH2:8][CH:9]([OH:12])[CH2:10][OH:11])=[O:6].[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][N:4]([N:16]=[O:17])[C:5]([N:7]([CH2:13][CH2:14][CH3:15])[CH2:8][CH:9]([OH:12])[CH2:10][OH:11])=[O:6]
Reactant: CCCN(CC(O)CO)C(=O)NCCCl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCN(CC(O)CO)C(=O)N(CCCl)N=O
Yield: 50.5 %

Procedure:
3 g 1-(2-chloroethyl)-3-n-propyl-3-(2,3-dihydroxy-n-propyl)urea are dissolved in 10 ml of acetic acid, and 1.5 g of sodium nitrite are added thereto under stirring. The mixture is stirred at the same temperature for 4 hours. After the reaction, the mixture is treated in the same manner as described in Example 62-(2). 1.7 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-(2,3-dihydroxy-n-propyl)urea are thereby obtained as a yellow oil.
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: CCS
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
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: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH2:18][CH2:17][CH2:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.CN1CCOCC1.Cl.[CH3:33][NH:34][O:35][CH3:36]>C(Cl)Cl.C1COCC1.C(Cl)Cl>[C:14]1([CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([N:34]([O:35][CH3:36])[CH3:33])=[O:12])[CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1=CCCC1)C(=O)O
Reactant: CNOC
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](CC1=CCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a flask charged with (S)-2-(tert-Butoxycarbonylamino)-3-cyclopentenylpropanoic acid (55.0 g, 214 mmol) was added THF/DCM (800 mL, 1:1). The solution was cooled to 0° C. and ethyl chloroformate (24.5 mL, 257 mmol) and NMM (28.4 mL, 257 mmol) were added dropwise sequentially. After addition, the mixture was stirred at 0° C. under nitrogen for 1 h. To the other flask charged with N,O-dimethylhydroxylamine HCl (25 g, 257 mmol) was added DCM (400 mL). The mixture was cooled to 0° C. and TEA (38.7 mL, 278 mmol) was added. The resulting mixture was transferred into the former reaction flask. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was quenched with water (500 mL) and the organic phase was washed with water (500 mL), dried over anhydrous sodium sulfate, and concentrated to afford (S)-tert-butyl (3-(cyclopent-1-en-1-yl)-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate as colorless oil (60 g, 93% yield), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17]CC)=[O:16].[OH-:20].[Na+]>O1CCOCC1>[ClH:1].[OH:20][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: [OH-]
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1Cl)OCO3
Agent: [Na+]
Solvent: C1COCCO1
Product: Cl
Product: O=C(O)c1cnc2cc3c(cc2c1O)OCO3

Procedure:
Ethyl 4-chloro-6,7-methylenedioxyquinoline-3-carboxylate (18.5 g, 66.2 mmol) was dissolved in dioxane (100 mL) and treated with 50 mL 5 N NaOH and heated at reflux for 2 hour. After this time the solution was concentrated on a rotary evaporator, cooled and extracted with dichloromethane (2×100 mL). The remaining aqueous solution was then acidified with concentrated HCl and the precipitate collected and dried to afford 7 g of crude 4-hydroxy-6,7-methylenedioxyquinoline-3-carboxylic acid hydrochloride.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[N:10][NH:9][C:8]1=[S:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([O:32][CH3:33])[CH:26]=[C:25]3[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=2)=[O:21])=[CH:16][CH:15]=1.O>C1COCC1>[Cl:40][C:36]1[CH:35]=[C:34]([C:25]2[C:24]3[C:29](=[CH:30][CH:31]=[C:22]([C:20]([C:17]4[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=4)([C:11]4[N:7]([CH3:6])[C:8]([SH:12])=[N:9][N:10]=4)[OH:21])[CH:23]=3)[N:28]=[C:27]([O:32][CH3:33])[CH:26]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Reactant: Cn1cn[nH]c1=S
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3nnc(S)n3C)ccc2n1
Temperature: -70 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
BuLi (0.233 mol) was added dropwise at −70° C. to a solution of 2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (0.0612 mol) in THF (350 ml) under N2 flow. The mixture was stirred at −70° C. for 1 hour and then brought to 0° C. The mixture was stirred at 0° C. for 45 minutes and then cooled to −70° C. A solution of intermediate (56) (0.0612 mol) in THF (150 ml) was added. The mixture was then brought to 0° C., poured out into water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: Cyclohexane/EtOAc 70/30; 15–35 μm). The pure fractions were collected and the solvent was evaporated, yielding 11.06 g (35%) of 4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(5-mercapto-4-methyl-4H-1,2,4triazol-3-yl)-2-methoxy-6-quinolinemethanol (intermediate 57), mp. >260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10](Cl)[C:9]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:8]=3[S:7][C:6]=2[CH:18]=1.[N:19]1([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:22]3[CH2:23][CH2:24][N:19]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:20][CH2:21]3)[C:9]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:8]=3[S:7][C:6]=2[CH:18]=1
Reactant: Fc1ccc2c(c1)Sc1cc(Cl)ccc1CC2Cl
Reactant: O=C1OCCN1CCN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: O=C1OCCN1CCN1CCN(C2Cc3ccc(Cl)cc3Sc3cc(F)ccc32)CC1

Procedure:
17 G. of 3,10-dichloro-7-fluoro-10,11-dihydro-dibenzo[b,f]thiepin are treated with 45.5 g. of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone and stirred at 120°-130° C. (internal temperature) for 8 minutes. The mixture is treated with 2N sodium hydroxide and extracted with ether. The ether solution is washed to neutrality and shaken out with dilute methanesulfonic acid. The acid solution is made alkaline with sodium hydroxide and extracted with methylene chloride. The organic solution is washed with water and dried over magnesium sulfate. The residue is recrystallized from acetone, whereby there is obtained 3-{2-[4-(3-chloro-7-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone (melting point 168°-170° C.) which is converted into the dimethanesulfonate (melting point 191°-193° C.) by reaction with methansulfonic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[CH2:24]([NH:26][C:27](=[O:44])[NH:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)[CH3:25].C([O-])([O-])=O.[Na+].[Na+]>COC1CCCC1.CCO.O>[CH2:24]([NH:26][C:27](=[O:44])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[N:3]=[C:4]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:5]3[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=3[N:7]=2)=[CH:31][CH:30]=1)[CH3:25]
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC1CCCC1
Solvent: CCO
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(=O)OC(C)(C)C)C3)cc1
Temperature: 130 °C
Yield: 66.7 %

Procedure:
To a solution of tert-butyl 2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 2) (300 mg, 0.88 mmol) and 4-(3-ethylureido)phenylboronic acid pinacol ester (281 mg, 0.97 mmol) in CPME/EtOH/H2O (7/2/3) (4.0 mL) was added Pd(PPh3)2(Cl)2 (31 mg, 0.04 mmol) and Na2CO3 (140 mg, 1.32 mmol). The reaction mixture was then heated by microwave at 130° C. for 0.5 h. The crude reaction mixture was then partitioned between water and EtOAc, the phases separated and the solvent removed in vacuo. The residue was purified by flash chromatography (0-40% EtOAc/Petroleum Ether 40-60) to yield an off-white solid (275 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[C:4]([O:10][CH2:11][O:12][CH3:13])[CH:3]=1.[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Cl-:1].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P+:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]([O:10][CH2:11][O:12][CH3:13])[CH:3]=1
Reactant: COCOc1cc(Cl)ccc1CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COCOc1cc(Cl)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Yield: 162.9 %

Procedure:
3.38 g of 4-chloro-2-methoxymethoxybenzyl chloride [prepared as described in step (c) above] were dissolved in 50 ml of toluene, and then 6.02 g of triphenylphosphine were added to the resulting solution. The resulting mixture was heated under reflux for 15.5 hours. At the end of this time, the reaction mixture was cooled on ice, and the crystals which precipitated were collected by filtration, and dried in vacuo, to give 6.02 g (yield 82%) of the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(Cl)Cl.[CH2:9]([O:11][C:12](=[O:16])[C:13](Cl)=[O:14])[CH3:10].[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:9]([O:11][C:12](=[O:16])[C:13]([C:20]1[CH:21]=[CH:22][C:17]([O:23][CH3:24])=[CH:18][CH:19]=1)=[O:14])[CH3:10]
Reactant: COc1ccccc1
Reactant: CCOC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C(=O)c1ccc(OC)cc1
Temperature: 5 °C
Reaction time: 0.67 h

Procedure:
Aluminum chloride (84.30 g, 632 mmol) was added to chloroform (300 ml) and chloroglyoxylic ethyl ester (60 g, 439 mmol) was added dropwise to the resulting suspension over 20 minutes at 0° C. The reaction mixture was stirred for 40 minutes at 5° C. At the same temperature, anisole (68.79 g, 636 mmol) was slowly added dropwise to the reaction solution and then stirred for 12 hours at 10° C. When the reaction is completed, the reaction solution was cooled and, after adding cooling water (100 ml), extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and then concentrated to obtain the title compound as a yellow solid (TLC identification). The resulting compound was used in the next reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1CO)([O-:3])=[O:2].[CH2:12]([N:20]=[C:21]=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].S([O-])([O-])(=O)=[O:24].[Na+].[Na+]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:5]=1)([O-:3])=[O:2].[CH2:12]([NH:20][C:21](=[O:24])[O-:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: O=S(=O)([O-])[O-]
Reactant: CCCCCCCCN=C=O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCNC(=O)[O-]
Product: O=[N+]([O-])c1ccccc1

Procedure:
100 ml of toluene, 10 g of 2-nitrobenzyl alcohol and 11.4 ml of octyl isocyanate heated to reflux for 2 hours in a nitrogen atmosphere. After being cooled, the reaction solution was washed several times with water, and the toluene solution obtained was dehydrated with sodium sulfate. The sodium sulfate was filtered out, and the solvent was removed. The solid obtained was recrystallized twice from hexane, producing 12.5 g of o-nitrobenzene-n-octylcarbamate in the form of pale yellow needle crystals. Melting point: 70 to 71° C., infrared absorption spectrum: 3331 cm-1, 1691 cm-1.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][S:14][C:15]1[N:20]=[C:19]([C:21]2[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=2)[CH:18]=[CH:17][N:16]=1>>[CH3:13][S:14][C:15]1[N:20]=[C:19]([C:21]2[S:25][C:24]([S:26]([NH:1][C:2]3[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=3)(=[O:28])=[O:27])=[CH:23][CH:22]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CSc1nccc(-c2ccc(S(=O)(=O)Cl)s2)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(-c3ccnc(SC)n3)s2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 5-[2-(methylthio)pyrimidin-4-yl]thiophene-2-sulfonyl chloride as described in the synthetic METHOD B to give a white solid (34.5 mg) with purity >90%. MS (pos) m/z 475.3.
Reaction SMILES: [Si]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=[O:24])=[CH:17]2)(C(C)(C)C)(C)C.[F-].[NH4+]>CO.O>[NH3:11].[OH:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=[O:24])=[CH:17]2
Reactant: COc1ccccc1CNC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)ccc2[nH]1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1ccccc1CNC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O)c3ccc(O)c(CO)c3)ccc2[nH]1
Product: N
Temperature: 40 °C
Yield: 137.2 %

Procedure:
A solution of 5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(2-methoxybenzyl)-1H-indole-2-carboxamide (Preparation 1, 67 mg, 0.11 mmol) in a mixture of methanol (4.0 ml) and water (2.4 ml) was treated with ammonium fluoride (40 mg, 1.08 mmol) and the resulting suspension heated at 40° C. for a period of 16 hours. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (95:5:0.5 changing to 85:15:1.5, by volume) to give the title compound as a colourless solid (38 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[S:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([NH:7][CH:11]2[CH2:12][CH2:13][S:8][CH2:9][CH2:10]2)=[N:5][N:6]=1
Reactant: Cc1nnc(N)[nH]1
Reactant: O=C1CCSCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nnc(NC2CCSCC2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.5 %

Procedure:
To a solution (50 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (2.5 g) and tetrahydro-4H-thiopyran-4-one (3.6 g) in acetic acid was added sodium cyanoborohydride (8.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (2.4 g, 48%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[N:20]2[C:21]3[C:16]([O:17][CH2:18][CH2:19]2)=[C:15]([F:22])[CH:14]=[CH:13][C:12]=3[N:11]=1)[CH3:9])(C)(C)C.FC1C=CC2=C3C=1OCCN3C(C(NC(=O)C)C)=N2.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:22][C:15]1[CH:14]=[CH:13][C:12]2=[C:21]3[C:16]=1[O:17][CH2:18][CH2:19][N:20]3[C:10]([CH:8]([NH2:7])[CH3:9])=[N:11]2
Reactant: CC(NC(=O)OC(C)(C)C)c1nc2ccc(F)c3c2n1CCO3
Agent: CC(=O)NC(C)c1nc2ccc(F)c3c2n1CCO3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(N)c1nc2ccc(F)c3c2n1CCO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To an ice-cooled solution of the mixture of [1-(6-fluoro-3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)ethyl]carbamic acid tert-butyl ester and N-[1-(6-fluoro-3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)ethyl]acetamide from the previous step in DCM (15 mL) was added TFA (3 mL) and the mixture was stirred at RT for 2 h. Toluene was added and volatiles were removed under reduced pressure, the resulting residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. Purification by column chromatography (Si—PCC, gradient 2-8% 2M NH3/MeOH in DCM) afforded the title compound as a light brown gum (185.6 mg, 65%, 2 steps). LCMS (Method B): RT 1.54 min [M+H]+ 222
Reaction SMILES: ClC1C(C(C)CC)=NC(C2C=NC=CC=2)=CN=1.[NH:18]([C:20]1[C:25]([CH:26]([CH3:29])[CH2:27][CH3:28])=[N:24][C:23]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:22][N:21]=1)[NH2:19].[C:36](OCC)(=O)[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>C(O)C.O>[CH3:29][CH:26]([C:25]1[C:20]2[N:21]([C:36]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N:19][N:18]=2)[CH:22]=[C:23]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[N:24]=1)[CH2:27][CH3:28]
Reactant: CCC(C)c1nc(-c2cccnc2)cnc1NN
Reactant: CCOC(=O)CC(=O)OCC
Agent: CCC(C)c1nc(-c2cccnc2)cnc1Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1nnc2c(C(C)CC)nc(-c3cccnc3)cn12

Procedure:
In a manner analogous to Example 1, by condensing 3-(2-amino-1,1-diethoxyethyl)pyridine with 3-methyl-2-oxopentanoic acid there is obtained rac-N-[2,2-diethoxy-2-(3-pyridyl)ethyl]-3-methyl-2-oxovaleramide as an amorphous, colorless solid. Subsequent acidic hydrolysis to rac-3-methyl-2-oxo-N-[(3-pyridylcarbonyl)methyl]valeramide hydrochloride (beige, crystalline solid, melting point 158°-159°) and ring closure gives rac-3-(1-methylpropyl)-5-(3-pyridyl)-2(1H)-pyrazinone as a yellow solid, melting point 146°-148° (from acetonitrile). The conversion into rac-2-chloro-3-(1-methylpropyl)-5-(3-pyridyl)pyrazine is also effected analogously to Example 1. Hydrazinolysis to rac-2-hydrazino-3-(1-methylpropyl)-5-(3-pyridyl)pyrazine in the form of beige crystals, melting point 166°-167° (from ethanol/water) and subsequent condensation with diethyl malonate gives ethyl rac-8-(1-methylpropyl)-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 335 (M)+, which is converted by saponification into the above acid, MS: 267 (M-CO 2)+.