Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:19][C:18](=[O:20])[C:17]2[C:12](=[C:13]([O:21][CH3:22])[CH:14]=[CH:15][CH:16]=2)[N:11]=1)[CH3:2].Cl[S:24]([OH:27])(=O)=[O:25].S(Cl)(Cl)(=O)=O.[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:24]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)(=[O:27])=[O:25])=[CH:6][C:5]=1[C:10]1[NH:19][C:18](=[O:20])[C:17]2[C:12](=[C:13]([O:21][CH3:22])[CH:14]=[CH:15][CH:16]=2)[N:11]=1)[CH3:2]
Reactant: CCOc1ccccc1-c1nc2c(OC)cccc2c(=O)[nH]1
Reactant: C1CNCCN1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(=O)(Cl)Cl
Solvent: CCO
Product: CCOc1ccc(S(=O)(=O)N2CCNCC2)cc1-c1nc2c(OC)cccc2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
2-(2-Ethoxyphenyl)-8-methoxyquinazolin-4(3H)-one (Preparation 4; 2.1 g, 0.0071 mol) was added portionwise to stirred chlorosulphonic acid (15 ml) under a nitrogen atmosphere at 0° C. After 18 hours, the mixture was cautiously added dropwise to stirred ice/water (100 g) and the resulting mixture extracted with dichloromethane-methanol (9:1, 10×100 ml). The organic extracts were combined, dried (MgSO4) and evaporated under vacuum. A quantity (1.0 g) of the crude sulphonyl chloride was then added portionwise to a stirred solution of piperazine (2.1 g, 0.0244 mol) in ethanol (30 ml) at room temperature under a nitrogen atmosphere. After 18 hours the mixture was poured into stirred saturated aqueous sodium carbonate solution (100 ml) and the resulting mixture extracted with dichloromethane-methanol (9:1, 10×100 ml). The organic extracts were combined, dried (MgSO4) and evaporated under vacuum to give the title compound, which crystallized from ethanol as a colorless solid (0.8 g, 71%), m.p. 163-165° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].O.C(O)(=O)C>C(OCC)(=O)C.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(Nc2ncccc2N)cc1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
57 g (0.23 mol) of N-(3-fluoro-4-methylphenyl)-3-nitro-2-pyridylamine was dissolved in ethyl acetate (250 ml), and water (125 ml) and acetic acid (80 ml) were added thereto, and the solution was heated to 50° C. 77 g (1.40 mol) of iron powder was added to the reaction solution so that the temperature thereof would not exceed 60° C., and then stirred for 1 hour at 60° C. The reaction solution was cooled to room temperature, and the inorganic matter was separated by filtration. The solution was extracted with ethyl acetate, and washed with saturated brine, and then the obtained organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue thus obtained was washed with hexane to obtain 45 g (yield: 90%) of N2-(3-fluoro-4-methylphenyl)-2,3-pyridinediamine.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9]([OH:14])[C:10]([F:13])([F:12])[F:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:11][C:10]([F:13])([F:12])[CH2:9][O:14][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCC(F)(F)F)s1
Temperature: 100 °C
Reaction time: 20 h
Yield: 66.4 %

Procedure:
To a solution of 5-bromothiophene-2-carbaldehyde (909 mg, 4.76 mmol) and trifluoroethanol (0.69 mL, 9.52 mmol) in 10 mL dimethylformamide was added potassium carbonate (1.38 g, 10.00 mmol). The resulting suspension was stirred at 100° C. for 20 h before being cooled to room temperature and poured into 50 mL water. Organics were extracted with ether (3×50 mL), washed with water and brine (50 mL each), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (10-20% ethyl acetate in hexanes) to give 5-(2,2,2-trifluoroethoxyl)thiophene-2-carbaldehyde (664 mg, 66%) as an off-white solid. Used without further characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:20][S:21]([C:24]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1)(=[O:23])=[O:22].CS(N1C2C(=CC=CC=2)C=N1)(=O)=O>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:7]([CH2:9][N:26]3[C:27]4=[CH:28][N:29]=[CH:30][CH:31]=[C:32]4[C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[N:25]3)=[N:8][C:4]=2[CH:3]=1
Reactant: FC(F)(F)CCCn1c(CCl)nc2cc(Cl)ccc21
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Agent: CS(=O)(=O)n1ncc2ccccc21
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2CCCC(F)(F)F)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 4-1 by using 5-chloro-2-chloromethyl-1-(4,4,4-trifluoro-butyl)-1H-benzoimidazole and 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine instead of 5-chloro-2-chloromethyl-1-(4,4,4-trifluoro-butyl)-1H-benzoimidazole and methanesulfonyl-1H-indazole.
Reaction SMILES: [Br:1][CH2:2]/[C:3](=[CH:7]/[C:8]([OH:10])=[O:9])/[C:4]([OH:6])=O.[OH-].[Na+].C(O)CCC>O>[Br:1][CH2:2][C:3]1[C:4]([O:10][C:8](=[O:9])[CH:7]=1)=[O:6]
Reactant: O=C(O)/C=C(/CBr)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: O=C1C=C(CBr)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2[2-(4-aminophenyl)-2-thiaethyl]-maleic acid(4). 2-(Bromomethyl)-maleic anhydride (2) is prepared from compound 1 according to the method of Laursen et al. (1971) J. Med. Chem. 14:619-621 with the modification by Greenlee and Woodward (1980) Tetrahedron 36:3367-3375. This material (2 g) is hydrolyzed in water (20 mL) for about 1 hour at room temperature to 2-(bromomethyl)-maleic acid (3) and the solution is neutralized with 1 N NaOH (21.2 mL), degassed and kept under N2. The solution is added to a previously prepared solution of 4-aminothiophenol (1.51 g) that has been dissolved in degassed 1 N NaOH (11.6 mL) with gentle heating under N2 and filtered to remove the insoluble dimer. The filtrate is diluted with degassed water (12 mL) before being added to the above solution of compound 3. The final reaction solution is brought to about pH 11.0 with 1 N NaOH and stirred under N2 at room temperature overnight. The solution is then filtered to remove small amounts of bis-(4-aminophenyl)-disulfide, cooled on ice, and acidified with 1N HCl, which gives a yellow precipitate. n-Butanol is added (40 mL) and the mixture is vigorously stirred on ice for 5 minutes. This removes the fumaric acid analog of compound 4. The solid is then collected by filtration, washed successively with 0.1 N HCl and water, and finally dried in a vacuum desiccator over P2O5, to yield the neutral compound 4.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([OH:12])=O)=[CH:4]C=1.C1([NH:18]CC(O)=O)CCCC1>>[CH:5]1([NH:8][CH2:9][C:10]([NH2:18])=[O:12])[CH2:4][CH2:2][CH2:7][CH2:6]1
Reactant: O=C(O)CNC1CCCC1
Reactant: Cc1ccc(NCC(=O)O)cc1
Product: NC(=O)CNC1CCCC1

Procedure:
By replacing the p-methylphenylglycine employed in Procedure 14, Step A by an equivalent quantity of cyclopentylglycine, there is obtained cyclopentylglycinamide. Substituting this cyclopentylglycinamide for that employed in Procedure 13 and following the methods described in Steps A and B of Procedure 13, there is obtained in Step A 2-hydroxy-3-cyclopentylpyrazine and in Step B 2-chloro-3-cyclopentylpyrazine.
Reaction SMILES: [C:1]1([O-:12])[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]([Cl:9])=[C:3]([Cl:10])[C:2]=1[Cl:11].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Na+].[Br-]>>[CH2:15]([O:12][C:1]1[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]([Cl:9])=[C:3]([Cl:10])[C:2]=1[Cl:11])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCBr
Reactant: [O-]c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [Br-]
Agent: [Na+]
Product: CCCCCCOc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
170 g (0.6 mol) of sodium pentachlorophenate and 350 ml of absolute alcohol were placed in a liter conical flask. The reactants were stirred under reflux until dissolution was complete. The condenser was removed and 97 g (83 ml:0.6 mol) of 1-bromohexane were added. The mixture was then left refluxing for about 12 hours with the stirrer on maximum speed. Solid (NaBr) was gradually deposited and on allowing the flask to stand and cool three layers were formed: a lower solid layer, an oily middle layer (the product), and an upper layer of alcohol. The flask contents were next remixed and transfered as completely as possible to a liter round bottomed flask. The alcohol was removed on a rotovap (60° C. and 100 mm), and then the flask was cooled to room temperature. 500 ml of light petrol (40/60) were added, the flask was stoppered, and then shaken vigorously for a few seconds. The pressure was next cautiously released, and the process was repeated until all the solid was in free suspension. The mixture was then rapidly filtered at the pump, then the dark brown liquid was transfered to a column of alumina (about 8"×1"). It was found that a few yellow bands moved quickly down the column. These were collected in the same receiver as the bulk of the sample--the dark colouration will collect on the top 1" of the column. A small amount of petrol was then added to wash through the column.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([Cl:12])(=[O:11])=[O:10].Cl[C:14]1[CH:15]=CC(OC)=C(S(Cl)(=O)=O)[CH:19]=1.COC1C=CC=CC=1S>>[CH:14]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([Cl:12])(=[O:11])=[O:10])([CH3:15])[CH3:19]
Reactant: COc1ccccc1S(=O)(=O)Cl
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Agent: COc1ccccc1S
Product: CC(C)c1ccccc1S(=O)(=O)Cl

Procedure:
A mixture of 2-methoxybenzenesulfonyl chloride and 5-chloro-2-methoxybenzenesulfonyl chloride, which results from ring chlorination, was prepared from 2-methoxythiophenol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:40]([NH2:42])[CH3:41].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:26])([F:28])[F:27])=[N:20][C:21]([C:22](=[O:24])[NH:42][CH2:40][CH3:41])=[C:15]2[CH2:14]1)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: CCN
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (180 mg, 0.33 mmol) was dissolved in 10 mL of tetrahydrofuran, and ethylamine hydrochloride (269 mg, 3.3 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (168 mg, 0.66 mmol) and triethylamine (367 mg, 3.63 mmol) were then added to the solution. The reaction mixture was stirred at room temperature for 4 hours until thin lay chromatography showed the starting material disappeared, and then filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-ethylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 42a (190 mg, yield>100%) as a white solid.
Reaction SMILES: C[O-].[Na+].CN(C)[CH:6]=[CH:7][C:8]([C:10]1[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=1)=O.C(=O)(O)O.[C:21]1([NH:27][C:28]([NH2:30])=[NH:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(O)C>[NH:27]([C:28]1[N:30]=[C:8]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[CH:7]=[CH:6][N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)C=CC(=O)c1cncn1C
Reactant: N=C(N)Nc1ccccc1
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CC(C)O
Product: Cn1cncc1-c1ccnc(Nc2ccccc2)n1
Yield: 64 %

Procedure:
Sodium methoxide (2.63 g, 48.7 mmol) was added to a solution of 5-(3-dimethylaminoprop-2-en-1-oyl)-1-methylimidazole Method 4; 2.91 g, 16.2 mmol) and phenylguanidine hydrogen carbonate (3.52 g, 17.9 mmol) in 2-propanol (14 ml) and the reaction mixture heated at reflux for 3 hours. The reaction mixture was allowed to cool and partitioned between EtOAc and saturated aqueous sodium, hydrogen carbonate solution. The organic phase was separated, dried and the solvent removed by evaporation. The residue was purified by column chromatography eluting with DCM and 7M methanolic ammonia solution (97:3) to give the title compound 2.57 g, (64%) as a solid. M/z: 252.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[S:3]([O:6][C:7]1[CH2:8][CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][CH:12]=1)(=[O:5])=[O:4].[ClH:22]>C1COCC1>[Cl-:22].[F:21][C:2]([F:1])([F:20])[S:3]([O:6][C:7]1[CH2:12][CH2:11][NH2+:10][CH2:9][CH:8]=1)(=[O:5])=[O:4]
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Solvent: C1CCOC1
Product: O=S(=O)(OC1=CC[NH2+]CC1)C(F)(F)F
Product: [Cl-]
Reaction time: 1 h
Yield: 88 %

Procedure:
tert-Butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (3.77 g, 11.4 mmol) was mixed with THF (15 mL) and concentrated hydrochloric acid (15 mL). After 1 hour, the mixture was evaporated and dried by azeotropic evaporation with toluene and methanol to give a beige solid (88%) that could be used without further purification.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[OH-].[Na+].[N+:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)([O-:9])=[O:8].O>CC(C)=O>[CH:1]([NH:4][C:14](=[O:15])[C:13]1[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:18][CH:17]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 74 %

Procedure:
32.5 g of isopropylamine dissolved in 250 ml of acetone are added with 71 g of a 30% sodium hydroxide aqueous solution. This mixture, cooled to 0° C., is slowly added with 92.7 g of p-nitrobenzoyl chloride dissolved in 300 ml of acetone, coo ling with an ice bath to keep temperature from 0° to 5° C. Subsequently stirring is continued for 1 more hour allowing temperature to raise to 20°-30° C. Then the reaction mixture is poured into cold water. The formed precipitate is filtered, washed with water, dried and crystallized from isopropanol. 77 g of N-isopropyl-p-nitrobenzamide are obtained as a whitish solid substance with m.p. 152°-154° C.
Reaction SMILES: C(O[CH:4](OCC)[C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([F:17])[CH:8]=1)=O)C.[NH2:21][NH:22][C:23]([NH2:25])=[S:24].O.[C:27]1(C)C=CC(S(O)(=O)=O)=CC=1.CI>C(O)C>[F:17][C:9]1[CH:8]=[C:7]([C:5]2[N:21]=[N:22][C:23]([S:24][CH3:27])=[N:25][CH:4]=2)[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: NNC(N)=S
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(OCC)C(=O)c1ccc(C(=O)OC)c(F)c1
Solvent: CI
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2cnc(SC)nn2)cc1F
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Methyl 4-(diethoxyacetyl)-2-fluorobenzoate (3.0 g, 0.01 mol) was dissolved in ethanol (30 mL). Thiosemicarbazide (1.2 g, 0.013 mol) and p-toluenesulfonic acid monohydrate (100 mg) were added to the reaction mixture. The reaction mixture was heated at 90° C. for 2 h. After cooling, the reaction mixture to ambient temperature methyl iodide (3 mL, 0.05 mol) was added. The reaction mixture was stirred at RT for 2 h, and then concentrated under reduced pressure. The residue was dissolved in acetic acid (50 mL), and heated at 60° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in methanol and the precipitate was collected by filtration and dried under reduced pressure to give the desired product. (1.2 g, 41%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:29]=O)=[N:18][CH:19]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C@H:23]2[CH3:28])[N:21]=1.[CH2:31]([NH:38][CH2:39][CH2:40][OH:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:31]([N:38]([CH2:29][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C@H:23]2[CH3:28])=[CH:19][N:18]=1)[CH2:39][CH2:40][OH:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OCCNCc1ccccc1
Reactant: C[C@@H]1COCCN1c1cnc(C=O)c(Cl)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: C[C@@H]1COCCN1c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
Sodium triacetoxyborohydride (1.37 g) was added to a solution of 3-chloro-5-[(3R)-3-methylmorpholin-4-yl]pyrazine-2-carbaldehyde (1.04 g), N-benzylethanolamine (0.78 g) and acetic acid (0.74 mL) in acetonitrile (20 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by basic silica gel column chromatography (solvent gradient: 5→40% ethyl acetate/hexane) to give the title compound (1.65 g, quantitative) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16]C)=[O:15])[CH:12]=2)[CH:7]=[C:6]1[CH3:18].[OH-].[Na+].O.Cl>C(O)C>[C:14]([C:11]1[CH:12]=[C:13]2[C:8]([CH:7]=[C:6]([CH3:18])[N:5]2[CH2:4][C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=2[Cl:1])=[CH:9][CH:10]=1)([OH:16])=[O:15]
Reactant: COC(=O)c1ccc2cc(C)n(Cc3ccccc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Yield: 79.8 %

Procedure:
A mixture of 1-(2-chlorobenzyl)-6-methoxycarbonyl-2-methylindole (0.630 g), aqueous 10% sodium hydroxide solution (2.7 g), water (1.8 g) and ethanol (7.0 g) is refluxed for 2.5 hours. After cooled, this is processed with 10% HCl to have a pH of 4, and the crystal formed is taken out through filtration and dried to obtain 6-carboxy-1-(2-chlorobenzyl)-2-methylindole (31) (0.480 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[CH2:9]([O:12][C:13](OCCC)(OCCC)[O:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH3:11]>C(O)CC>[C:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[N:1]=[C:13]([O:14][CH2:15][CH2:16][CH3:17])[O:12][CH2:9][CH2:10][CH3:11])#[N:8]
Reactant: CCCOC(OCCC)(OCCC)OCCC
Reactant: N#Cc1ccsc1N
Solvent: CCCO
Product: CCCOC(=Nc1sccc1C#N)OCCC

Procedure:
In a small distillation apparatus a mixture of 12.4 g(0.1 mol) 2-amino-3-cyanothiophene and 37.2 g (0.15 mol) tetra-n-propylorthocarbonate is heated for 3 hours at 155° C. n-PrOH, which arises during the reaction is directly distilled out of the reaction flask. After completion of the reaction, excess tetra-n-propylorthocarbonate is distilled off under reduced pressure and the resulting raw material purified by column chromatography over silica gel (eluant: hexane/tert.butylmethyl ether 6:1). Yield: 10.6 g of 3-cyano-2-(1,1-dipropoxymethyleneamino)thiophene in the form of slightly brownish crystals; m.p. 65-67° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C1COCC1>[CH3:23][S:24]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12]([NH2:15])(=[O:13])=[O:14])[CH:7]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: NS(=O)(=O)c1cccc(CCCCO)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCCCc1cccc(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-(4-hydroxybutyl)benzenesulfonamide (458 mg) in dry THF (10 ml) was treated with triethylamine (0.307 ml) and the resultant solution cooled to 0° C. Methanesulfonyl chloride (0.17 ml) was added dropwise. The mixture was allowed to warm to room temperature and stirred for a further 15 minutes. The reaction mixture was partitioned between 1M HClaq and EtOAc. The aqueous phase was washed with EtOAc. The combined organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound LCMS RT=2.67 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:11]([O:13][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(Br)cc1
Reaction time: 46 h
Yield: 89.3 %

Procedure:
To a suspension of (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (5.02 g, 14.01 mmol) and NaHCO3 (3.53 g, 42.0 mmol) in DMF (20 mL) is added Benzyl bromide (5.10 mL, 42 mmol) at room temperature under nitrogen. After stirring for 46 hours, the reaction is diluted with H2O (200 mL), and then precipitated solid is collected and washed with H2O (500 mL) and then with heptane (200 ml) to give (R)-benzyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (5.61 g, 89%). HPLC retention time=1.56 minutes (condition B); MS (ES+)=392.1 (m-tBu+2); 348.1 (m-Boc+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39 (s, 9H) 2.48 (A of ABX, Jab=15.9 Hz, Jax=5.6 Hz, 1H) 2.54 (B of ABX, Jab=15.9 Hz, Jbx=5.3 Hz, 1H) 2.72-2.88 (m, 2H) 4.11 (br s, 1H) 5.02 (br s, 1H) 5.10 (A of AB, J=12.1 Hz, 1H) 5.16 (A of AB, J=12.1 Hz, 1H) 7.00 (d, J=8.1 Hz, 2H) 7.34-7.39 (m, 7H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[Li]CCCC.[I:18]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[Cl:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([I:18])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Clc1nccc2ccc(Br)cc12
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nccc2ccc(I)cc12
Reaction time: 0.25 h

Procedure:
To a stirred solution of 7-bromo-1-chloroisoquinoline (15 g, 62 mmol) in THF at −78° C., n-BuLi (123.7 mmol) was added. The resulting solution was stirred for 15 min. and, I2 (31.4 mg, 123.7 mmol) in THF was slowly added by syringe over a period of 5 min. The solution was then allowed to reach room temperature and treated with a saturated aqueous Na2S2O3 solution. The resulting mixture was extracted with diethyl ether (2×). The extracted organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified by flash chromatography to give the title compound.