Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27](O)=[O:28])=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[OH:30][CH2:31][C:32]([NH:35][S:36]([C:39]1[S:43][C:42]([NH2:44])=[N:41][C:40]=1[CH3:45])(=[O:38])=[O:37])([CH3:34])[CH3:33]>>[OH:30][CH2:31][C:32]([NH:35][S:36]([C:39]1[S:43][C:42]([NH:44][C:27]([C:26]2[CH:25]=[N:24][N:17]3[C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:14]([C:6]4[CH:7]=[CH:8][C:9]([C:10]([F:13])([F:12])[F:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)=[N:15][C:16]=23)=[O:28])=[N:41][C:40]=1[CH3:45])(=[O:38])=[O:37])([CH3:34])[CH3:33]
Reactant: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4nc(C)c(S(=O)(=O)NC(C)(C)CO)s4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II. Light yellow solid. MS (ISP) 665.2 [(M−H)−]; mp 276° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:14])[C:6]([OH:13])=[N:7]2.[CH3:15][C:16](=O)[C:17](=O)[CH3:18]>O>[OH:14][C:5]1[C:6]([OH:13])=[N:7][C:8]2[C:3]([N:4]=1)=[C:2]1[C:11](=[CH:10][CH:9]=2)[N:12]=[C:17]([CH3:18])[C:16]([CH3:15])=[N:1]1
Reactant: CC(=O)C(C)=O
Reactant: Nc1ccc2nc(O)c(O)nc2c1N
Solvent: O
Product: Cc1nc2ccc3nc(O)c(O)nc3c2nc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
A mixture of 0,5 g (2,6 mmol) 5,6-diamino-2,3-dihydroxyquinoxaline and 10 ml water was at 50° C. added a solution of 0,45 g (5,2 mmol) 2,3-butanedione in 5 ml water. The reaction mixture was stirred at 50° for 4 h. After cooling to 25° C., the precipitate was filtered off and washed with water. The crude product was dissolved in 2N sodium hydroxide and reprecipitated with 2N hydrochloric acid to pH 6-7 to give 0,4 g (64%) 2,3-dihydroxy-8,9-dimethylpyrazino(2,3-f)quinoxaline, m.p.>300° C. NMR (DMSO-d6): 7.27 (1H,d), 6.93 (1H,d), 2.07 (6H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[C:32]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:32]([N:40]1[CH2:45][CH2:44][N:43]([C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:29])([F:31])[F:30])[C:9]=4[CH:17]=3)[CH:19]=2)=[O:23])[CH2:42][CH2:41]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1ccccc1)N1CCN(C(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-benzoylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z=619.98 (M+H+); retention time=0.82 minutes.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:10][CH:9]([O:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][NH:7]1)=[O:5].[C:22]([O:26][C:27]([NH:29][CH:30]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:2][O:3][C:4]([CH:6]1[CH2:10][CH:9]([O:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][N:7]1[C:31](=[O:32])[CH:30]([NH:29][C:27]([O:26][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:28])[CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:5]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C1CCOCC1
Reactant: COC(=O)C1CC(OS(=O)(=O)c2ccc(Br)cc2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CC(OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)C(NC(=O)OC(C)(C)C)C1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.2 %

Procedure:
To a solution of 4-(4-bromo-benzenesulfonyloxy)-pyrrolidine-2-carboxylic acid methyl ester HCl salt (4 g, 10 mmol) in DCM (50 mL) was added tert-butoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (2.86 g, 11 mmol), HATU (5.7 g, 15 mmol) and DIPEA (7 mL, 40 mmol). The solution was stirred at room temperature for 16 h. The solution was diluted with DCM and washed twice with aq NH4Cl and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The desired product was purified by silica gel column chromatography from hexane/EtOAc to provide 4-(4-bromo-benzenesulfonyloxy)-1-[2-tert-butoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidine-2-carboxylic acid methyl ester (4.25 g 70% yield). LCMS found 606 ([M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].[S:11]1[C:15]([S:16](Cl)(=[O:18])=[O:17])=[CH:14][C:13]2[CH:20]=[CH:21][CH:22]=[CH:23][C:12]1=2>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][S:16]([C:15]2[S:11][C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[CH:14]=2)(=[O:18])=[O:17])=[C:4]([NH:10][S:16]([C:15]2[S:11][C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[CH:14]=2)(=[O:17])=[O:18])[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Product: O=S(=O)(Nc1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cc2ccccc2s1)c1cc2ccccc2s1
Yield: 63.8 %

Procedure:
N,N′-(4,5-Dichloro-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide) (120 mg) was prepared by using 4,5-dichloro-benzene-1,2-diamine (0.06 g, 0.33 mmol) and Benzo[b]thiophene-2-sulfonyl chloride (0.157 g, 0.67 mmol), following procedure as in Example 32.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=NC2CCCCC2)CCCCC1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][C:33]([OH:35])=O)=[CH:17]1.CNC>CN(C=O)C.C(#N)C>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][C:33]([N:7]([CH3:8])[CH3:1])=[O:35])=[CH:17]1
Reactant: O=C(O)Cc1ccccc1Sc1c[nH]c2ccccc12
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN(C)C(=O)Cc1ccccc1Sc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.8 %

Procedure:
N,N′-Dicyclohexylcarbodiimide (875 mg, 4.2 mmol) is added to [2-(1H-Indol-3-ylsulfanyl)-phenyl]-acetic acid (600 mg, 2.1 mmol) in 3 mL dry DMF and 7 mL acetonitril and stirred for 10 minutes at room temperature. 5.3 mL dimethyl amine (2M in THF, 10.6 mmol) is added and the reaction mixture is stirred 16 hours at room temperature. The reaction mixture is concentrated in vacuo. The residue is extracted with ethyl acetate (3 times). The combined orgnic phases are washed with brine, dried with MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate/heptane) gives 116 mg (18%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH2:27])[CH2:26][O:25][CH2:24]3)=[O:22])[CH3:19])=[C:14]([F:28])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4].[F:29][C:30]([F:36])([F:35])[CH2:31][C:32](O)=[O:33]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH:27][C:32](=[O:33])[CH2:31][C:30]([F:36])([F:35])[F:29])[CH2:24][O:25][CH2:26]3)=[O:22])[CH3:19])=[C:14]([F:28])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4]
Reactant: O=C(O)CC(F)(F)F
Reactant: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(N)COC2)c(F)c1
Product: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(NC(=O)CC(F)(F)F)COC2)c(F)c1

Procedure:
The title compound was prepared in analogy to example 1 using intermediate 4 instead of intermediate 1 and 3,3,3-trifluoropropionic acid instead of 3-fluoro-5-(trifluoromethyl)benzoic acid and was obtained as white solid. 515.2 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[NH2:11].[C:14](OC(=O)C)(=[O:16])[CH3:15]>CCO>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:12])[F:13])=[C:5]([NH:11][C:14](=[O:16])[CH3:15])[CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Br)ccc1OC(F)(F)F
Solvent: CCO
Product: CC(=O)Nc1cc(Br)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a solution of 2-trifluoromethoxy-5-bromo-phenylamine (5.12 g, 20 mmol) in EtOH (50 mL) at 0° C. was added a solution of acetic anhydride (4.7 mL, 50 mmol) in EtOH (10 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated to dryness and the solid was tritured with diethyl ether and filtered to give 5.64 g (95% yield) of N-(5-bromo-2-trifluoromethoxy-phenyl)-acetamide.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([C:5]1[CH:17]=[C:16]([O:18]CC2C=CC=CC=2)[C:8]2[N:9]=[C:10]([CH3:15])[N:11]([CH2:12][O:13][CH3:14])[C:7]=2[CH:6]=1)=[O:4].C(O)(=O)C>C(O)C.[Pd]>[CH3:26][N:2]([CH3:1])[C:3]([C:5]1[CH:17]=[C:16]([OH:18])[C:8]2[N:9]=[C:10]([CH3:15])[N:11]([CH2:12][O:13][CH3:14])[C:7]=2[CH:6]=1)=[O:4]
Reactant: COCn1c(C)nc2c(OCc3ccccc3)cc(C(=O)N(C)C)cc21
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COCn1c(C)nc2c(O)cc(C(=O)N(C)C)cc21
Yield: 60.8 %

Procedure:
A solution of 1.8 g (5.0 mmol) 7-benzyloxy-3-methoxymethyl-2-methyl-3H-benzimidazole-5-carboxylic acid dimethylamide and 270 μl acetic acid in 150 ml ethanol was hydrogenated over 240 mg 10% Pd/C in autoclave (5 bar H2) at 50° C. for 18 h. The catalyst was filtered off and the filtrate was concentrated in vacuo and crystallized from ethyl acetate-petroleum ether to afford 0.8 g (62%) of the title compound as a white solid. m.p. 173°-183° C.
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1.[CH2:11]([OH:14])[CH:12]=[CH2:13].C(N(CC)CC)C.C1(C)C=CC=CC=1>CS(C)=O.O>[CH2:11]([O:14][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1)[CH:12]=[CH2:13]
Reactant: N#Cc1nc(F)cnc1F
Reactant: C=CCO
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCOc1ncc(F)nc1C#N
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
In 30 mL of dimethyl sulfoxide was dissolved 10.0 g of 3,6-difluoro-2-pyrazinecarbonitrile. After adding 50 mL of allyl alcohol and 14.8 mL of triethylamine successively, the mixture thus obtained was stirred at 60° C. for 40 minutes. The reaction mixture was cooled to room temperature and poured into a mixture of 50 mL of toluene and 50 mL of water, and the organic layer was separated. The organic layer thus obtained was washed successively with ten 50 mL portions of water and then with saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=10:1] to obtain 11.5 g of 3-(allyloxy)-6-fluoro-2-pyrazinecarbonitrile as a light yellow-colored oily product.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:14][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(NCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
4-Benzylamino-benzonitrile (472 mg, 2.27 mmol) described in Preparation Example 89 was dissolved at 0° C. in tetrahydrofuran (20 mL), and lithium aluminum hydride (430 mg, 11.3 mmol) was added thereto. The solution was stirred overnight at room temperature, then, at 0° C., water (430 μl ), an aqueous solution of 5N sodium hydroxide (430 μl ) and water (1.29 mL) were sequentially added to the solution. The reaction solution was filtered through Celite pad, the solvent was then evaporated in vacuo, (4-aminomethyl-phenyl)-benzylamine (475 mg, 2.24 mmol, 99%) was obtained as an oil.
Reaction SMILES: [ClH:1].Cl.N[C:4]1[C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:8]=2[C:7]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:5]=1.Cl.N([O-])=O.[Na+]>O>[Cl:1][C:4]1[C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:8]=2[C:7]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:5]=1
Reactant: CN1CCc2c(N)ccc(Sc3ccccc3)c2CC1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CN1CCc2c(Cl)ccc(Sc3ccccc3)c2CC1
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 17.9 g. (0.05 mole) of 9-amino-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine dihydrochloride in 50 ml. of water and 50 ml. of concentrated hydrochloric acid at 0°-5° C. is added dropwise a solution of 4.2 g. (0.06 mole) of sodium nitrite in 25 ml. of water. After being stirred at 0°-5° C. for 30 minutes, the resulting diazonium solution is added to a solution of 6.0 g. (0.06 mole) of cuprous chloride in 25 ml. of concentrated hydrochloric acid. The mixture is stirred for 16 hours at 25° C., then it is warmed to 60°-80° C. for 1 hour. After being cooled to 15°-20° C., the mixture is made alkaline and extracted with ether. The ether extract is dried over magnesium sulfate and concentrated to leave 9-chloro-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine which is purified by chromatography or by recrystallization of appropriate acid addition salts; hydrochloride salt m.p. 231°-232° C.
Reaction SMILES: [CH:1]1([S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:15]([S:17](Cl)(=[O:19])=[O:18])[CH3:16].Cl>N1C=CC=CC=1>[CH:1]1([S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH:10][S:17]([CH2:15][CH3:16])(=[O:19])=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1SC1CCCCC1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccccc1SC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
In 10 ml of pyridine was dissolved 2.0 g of 2-(cyclohexylthio)aniline obtained in Example 2 (2), 1.2 g of ethanesulfonyl chloride was added dropwise under ice cooling, and then the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water, made acidic with dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed, in turn, with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent:n-hexaneethyl acetate=10:1) to give 2.7 g of N-[2-(cyclohexylthio)phenyl]ethanesulfonamide as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH2:15][C:16]1[C:21]2[CH2:22][CH2:23][O:24][C:20]=2[C:19]([C:25](Cl)=[O:26])=[CH:18][C:17]=1[Cl:28]>CN(C)C1C=CN=CC=1.ClCCl>[NH2:15][C:16]1[C:21]2[CH2:22][CH2:23][O:24][C:20]=2[C:19]([C:25]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[O:26])=[CH:18][C:17]=1[Cl:28]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Nc1c(Cl)cc(C(=O)Cl)c2c1CCO2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)c2cc(Cl)c(N)c3c2OCC3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
A solution of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (4.02 g) and N,N-dimethyl-4-pyridinamine (3.7 g) in dichloromethane (200 ml) was stirred at room temperature. A solution of intermediate (7) (4.8 g) in CH2Cl2 (200 ml) was poured into the solution. The reaction mixture was stirred for 3 hours at room temperature. The mixture was washed with water, a 5% NaOH solution and again water. The organic layer was separated, dried over MgSO4, filtered and the solvent was evaporated. The residue (7.4 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 4.7 g of 1,1-dimethylethyl 4-[[(4-amino-5-chloro-2,3-dihydro-7-benzofuranyl)carbonyl]oxy]-1-piperidinecarboxylate (59%) (intermediate 8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH2:29][N+:30]([O-:32])=O)[CH2:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH:35](Br)=[CH2:36].C1(N=C=O)C=CC(N=C=O)=CC=1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15]([C:29]3[CH:36]=[CH:35][O:32][N:30]=3)[CH2:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[O:18])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COC(=O)CC(C[N+](=O)[O-])c2ccc(OCc3ccc(OC)cc3)cc2)cc1
Reactant: C=CBr
Agent: O=C=Nc1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)CC(c2ccc(OCc3ccc(OC)cc3)cc2)c2ccon2)cc1
Temperature: 85 °C
Yield: 40.2 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged with 3 mL of triethyl amine. To this, added 4-methoxybenzyl 3-{4-[(4-methoxybenzyl)oxy]phenyl}-4-nitrobutanoate (0.25 g, 0.537 mmol) and followed by addition of vinyl bromide (4 ml), 1,4-phenylene diisocyanate (0.3 g, 1.87 mmol), refluxed at 85° C. for 8 h. The RM was cooled to RT, solid was precipitated. The solid was removed by filtration and the filtrate was evaporated under reduced pressure. The product obtained as a brown color gummy material (0.1 g, yield: 40.2%). 1H NMR (300 MHz, CDCl3): δ 8.17-8.18 (d, 1H), 7.25-7.28 (d, 2H), 7.05-7.11 (t, 4H), 6.75-6.85 (m, 6H), 5.97-5.98 (d, 1H), 4.92 (s, 2H), 4.86 (s, 2H), 4.46-4.52 (t, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 3.18-3.26 (q, 1H), 2.85-2.93 (q, 1H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:27])[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([CH:25]=O)[C:18]=2[O:17]1.CO.[BH4-].[Na+]>C(O)=O>[CH3:15][C:16]1([CH3:27])[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([CH2:25][NH:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:18]=2[O:17]1
Reactant: CC1(C)Cc2cccc(C=O)c2O1
Reactant: Nc1ccccc1Oc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Product: CC1(C)Cc2cccc(CNc3ccccc3Oc3ccccc3)c2O1
Temperature: 90 °C
Reaction time: 24 h
Yield: 85.8 %

Procedure:
A mixture of 2-phenoxy-phenylamine (350 mg, 1.89 mmol) and 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbaldehyde (500 mg, 2.83 mmol) was heated at 90° C. for 2 h under nitrogen. The reaction was cooled to 0° C. and MeOH (4 mL) was added, followed by NaBH4 (216 mg, 5.70 mmol) in portions over 20 min. The mixture was stirred at room temperature for 24 h. Formic acid (0.4 mL was added and the mixture stirred for 15 min. The solvents were removed in vacuo, the residue quenched with saturated aqueous NaHCO3 (50 mL), extracted with DCM (2×30 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with petroleum spirit (A) and ethyl acetate (B) (5-10% B, 80 g, 3 CV, 60 mL/min) to afford 560 mg (86%) of N-(2,2,-Dimethyl-2,3-dihydrobenzofuran-7-ylmethyl)-N-(2-phenoxy phenyl)amine as a colourless oil.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([NH2:12])[NH:10][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:13][CH:14]([CH:17]=O)[CH:15]=O>>[Br:13][C:14]1[CH:15]=[N:12][C:9]2[N:10]([N:11]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:17]=1
Reactant: O=CC(Br)C=O
Reactant: Nc1nc(N2CCOCC2)n[nH]1
Product: Brc1cnc2nc(N3CCOCC3)nn2c1

Procedure:
The title compound, a light yellow solid, MS: m/e=284.2/286.1 (M+H+), can be prepared in accordance with the general method of example 42, step 1 from 5-morpholin-4-yl-2H-[1,2,4]triazol-3-ylamine (CAS 51420-46-3) and 2-bromomalonaldehyde.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[H][H]>[Pd]>[CH2:2]([OH:1])[C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: [H][H]
Agent: [Pd]
Product: OC[C@@H](O)C(O)[C@H](O)CO
Reaction time: 0.42 h

Procedure:
Another aliquot of the arabinose solution obtained from Example 2 above is subjected to hydrogenation, in that hydrogen is passed into the solution after adding 10% palladium on charcoal thereto as a catalyst. After about 25 minutes the reaction is completed, and arabinitol is obtained by evaporation in vacuo in the form of white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:21])=[CH:12][C:13]=1[C:14]1[C:15]([CH3:20])=[N:16][CH:17]=[CH:18][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:22])[N:7]([C:8]1[CH:9]=[N:10][C:11]([Cl:21])=[CH:12][C:13]=1[C:14]1[C:15]([CH3:20])=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: Cc1ncccc1-c1cc(Cl)ncc1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncccc1-c1cc(Cl)ncc1N(C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a solution of 0.16 g (0.50 mmol) (6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-carbamic acid tert-butyl ester in 5 ml DMF were added 25 mg (0.50 mmol) sodium hydride (50% suspension in mineral oil) under nitrogen at room temperature. After stirring for 30 min 0.034 ml (0.52 mmol) methyl iodide were added. The reaction mixture was stirred for 1 h. Quenching with water was followed by extraction with three portions of dichloromethane. The combined organic layers were washed with water. The combined aqueous layers were extracted with dichloromethane. The combined organic layers were dried with sodium sulfate and concentrated. Residual DMF was removed by Kugelrohr distillation. Flash chromatography gave 0.14 g (84%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CCBr
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CCOc1ccccc1Br
Temperature: 80 °C

Procedure:
A round-bottomed flask was charged with commercially available 2-bromophenol (43 g, 0.25 mol), 1-bromo-3-methylbutane (41 mL, 0.33 mol), potassium carbonate (0.38 mol), and 200 mL of CH3CN. The resulting slurry was heated to 80° C. for 18 h. Upon completion, the mixture was cooled down to the room temperature, filtered, and concentrated down under reduced pressure. Vacuum distillation of the residue resulted in 1-bromo-2-(isopentyloxy)benzene (56 g, 93%, b.p. 82° C. at 10 mm Hg) as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ 7.55 (d, 1H), 7.25 (t, 1H), 6.90 (d, 1H), 6.80 (t, 1H), 4.05 (t, 2H), 1.97-1.85 (m, 1H), 1.78-1.70 (m, 2H), 0.98 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(=O)O)c(OC)c1
Agent: O=S(=O)(O)O
Product: COc1cc(OC)c([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(Alternative method) A 2.00 g portion of 2,4-dimethoxybenzoic acid was dissolved in 30 ml of sulfuric acid, and 0.49 ml of concentrated nitric acid was added under ice-cooling. After 3 hours of stirring at room temperature, this was poured into 100 g of ice water, and the thus formed crystals were collected by filtration, washed with water-methanol and then dried under a reduced pressure to give 1.41 g of 2,4-dimethoxy-5-nitrobenzoic acid. The physicochemical properties were identical to those of the compound obtained by the former method.