Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[CH3:9][N+:10]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[CH:15]2.[Cl-].[NH4+]>C(O)C.C(Cl)Cl.[Zn]>[CH3:9][N:10]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]([C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2
Reactant: C[n+]1c2ccccc2c(C(=O)Oc2ccccc2)c2ccccc21
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Product: CN1c2ccccc2C(C(=O)Oc2ccccc2)c2ccccc21

Procedure:
Phenyl 10-methylacridinium-9-carboxylate trifluoromethanesulfonate (10 mg, 0.0216 mmol) was suspended in absolute ethanol (10 mL) and the mixture was refluxed for 15 min to obtain a clear solution. Ammonium chloride (88 mg, 1.6 mmol) was added by portions to the solution followed by zinc (108 mg, 1.6 mmol). Addition of zinc caused the yellow color of the solution to disappear immediately. The colorless solution was refluxed for 2 h. TLC of the reaction mixture showed complete conversion to a non polar material. The solution was filtered and precipitate was washed with ethanol (3×20 mL). The filtrate was concentrated to obtain an off-white solid which was redissolved in CH2Cl2 and washed with water (2×15 mL). The organic layer was dried over Na2SO4 and concentrated to yield the crude product which was purified by preparative TLC using (30% ethyl acetate:hexane). Pure product was obtained as an off-white solid. 1H NMR (CDCl3) δ 3.38 (s, 3H), 5.16 (s, 1H), 6.89-7.37 (m, 13H); 13C NMR (CDCl3) δ 33.29, 49.72, 112.93, 120.19, 121.36, 125.73, 128.67, 129.16, 129.26, 142.37, 151.04, 170.22.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>N1C=CC=CC=1>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][NH:21][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(CCNS(C)(=O)=O)CC1
Reaction time: 12 h
Yield: 39.3 %

Procedure:
Methanesulfonyl chloride (0.7 mL, 9.0 mmol) was added to a cooled solution of 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.33 g, 5.8 mmol) in pyridine (25.0 mL). The reaction was stirred for 12 h and partitioned between partitioned between aqueous sodium bicarbonate and methylene chloride. The organic phase was washed with 1M hydrochloric acid, aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate and concentrated. Purification of the crude residue by chromatography over silica gel using 0-5% methanol in methylene chloride gave 4-(2-methanesulfonylamino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.70 g, 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2([C:36](O)=[O:37])[CH2:35][CH2:34]2)=[O:32])=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([C:33]2([C:36]([NH:1][C:2]3[CH:22]=[CH:21][C:5]([O:6][C:7]4[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)=[O:15])[CH:8]=4)=[CH:4][CH:3]=3)=[O:37])[CH2:35][CH2:34]2)=[O:32])=[CH:28][CH:29]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1)N1CCCC1
Reaction time: 3 h
Yield: 58.8 %

Procedure:
Pyrrolidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (112 mg) and 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (87.4 mg) were dissolved in N,N-dimethylformamide (4 ml), and diisopropylethylamine (0.341 ml) and HBTU (203 mg) were added under a nitrogen atmosphere at room temperature, followed by stirring for 3 hr. The reaction mixture was partitioned after addition of ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml) and brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:7, then ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure, and to the residue (133.0 mg) were added tert-butyl methyl ether (4 ml) and heptane (4 ml) to suspend a solid. The solid was collected by filtration and dried under aeration to provide the titled compound as pale yellow powder (111.1 mg, 62.0%).
Reaction SMILES: [CH3:1][C@H:2]([NH2:10])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.C[C@@H:12](N)[C@@H:13]([OH:20])C1C=CC=CC=1>>[C:13]([NH:10][CH:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1])(=[O:20])[CH3:12]
Reactant: C[C@H](N)Cc1ccccc1
Reactant: C[C@@H](N)[C@@H](O)c1ccccc1
Product: CC(=O)NC(C)Cc1ccccc1

Procedure:
The commercially available precursor to dextroamphetamine is 1R,2S-(−)-norephedrine. Attempts were made to O-acetylate the norephedrine free base, but produced mostly N-acetylamphetamine according to an analysis of the carbonyl region of the infrared spectra. In one experiment, norephedrine free base in acetic acid was treated with 0.5 equivalents of sulfuric acid and then treated with 1.1 equivalents of acetic anhydride with heating to 63° C. to obtain a clear solution. Catalytic reduction followed by basification gave an oil that was composed of 13.96% amphetamine and 68% norephedrine, an indication that the acetylation procedure on a sulfate salt was only partially successful. In another experiment, a 10 mol portion of norephedrine hydrochloride was acetylated with a 20% excess of acetic anhydride in 2 mL acetic acid/g of salt and progress of the reaction followed fours (Table 2). The reaction mixture was diluted with 130 mL water and subjected to catalytic hydrogenation for 22 hours to obtain 10.4 g of oil. The long reaction time is attributed to the presence of acetic acid in the reduction mixture. Yield of amphetamine from norephedrine hydrochloride based on the weight of product and HPLC analysis is 66% (Experiments A and B). For these experiments, it can be seen that the best results were obtained with the salts of phenylpropylamine or norephedrine, particularly the hydrochloride salt.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:14](=O)[CH2:15][CH2:16][N:17]1[CH2:26][CH2:25]C2[C:19](=CC=CC=2)[CH2:18]1.Cl.CC1N(C2N=CC=CN=2)N=CC=1/C=C/CN1CCC2C(=CC=CC=2)C1.Cl.[F:55][C:56]([F:70])([F:69])[C:57]1[CH:58]=[C:59]([N:63]2CCNCC2)[CH:60]=[CH:61][CH:62]=1>>[ClH:1].[CH3:2][C:3]1[N:7]([C:8]2[N:9]=[CH:10][CH:11]=[CH:12][N:13]=2)[N:6]=[CH:5][C:4]=1/[CH:14]=[CH:15]/[CH2:16][N:17]1[CH2:18][CH2:19][N:63]([C:59]2[CH:60]=[CH:61][CH:62]=[C:57]([C:56]([F:55])([F:69])[F:70])[CH:58]=2)[CH2:25][CH2:26]1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Cc1c(C(=O)CCN2CCc3ccccc3C2)cnn1-c1ncccn1
Agent: Cc1c(/C=C/CN2CCc3ccccc3C2)cnn1-c1ncccn1
Agent: Cl
Product: Cc1c(/C=C/CN2CCN(c3cccc(C(F)(F)F)c3)CC2)cnn1-c1ncccn1

Procedure:
The procedures of Example 6 (1) and (2) were repeated but substituting the 1,2,3,4-tetrahydroisoquinoline hydrochloride employed in Example 6 (1) by 730 mg of 1-(3-trifluoromethylphenyl)piperazine hydrochloride. After the completion of the post treatment, 75 mg of the title compound was obtained.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[O:17]=[C:18]([CH3:29])/[CH:19]=[CH:20]/[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:18]([CH:19]1[CH2:3][N:4]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5][CH:20]1[C:21]1[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=1)(=[O:17])[CH3:29]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC(=O)/C=C/c1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)C1CN(Cc2ccccc2)CC1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.8 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (22.46 g, 94.6 mmol) in CH2Cl2 (100 mL) was added dropwise, over a 30 minutes period, to a stirred solution of 4-((E)-3-oxo-but-1-enyl)-benzonitrile (10.8 g, 63.1 mmol) and trifluoroacetic acid (0.48 mL, 6.30 mmol) in CH2Cl2 (40 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOac/Heptane 1:1) afforded 6.3 g (33%) of the title compound as a yellow oil. ES-MS m/e: 305.1 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=1)=[O:4].[N-:21]=[N+:22]=[N-:23].[Na+].O.CO>C1COCC1>[N:21]([CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=1)=[O:4])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)n1cc(C(=O)CBr)c2ccccc21
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)n1cc(C(=O)CN=[N+]=[N-])c2ccccc21

Procedure:
To a stirred solution of 3-bromoacetyl-1-(tert-butoxycarbonyl)-indole, which may be prepared as described in Step (c) above, (0.01 mol), in THF is added a solution or suspension of sodium azide (0.01 to 0.05 mol) in THF, which optionally contains from 0% to 50% water or methanol, and the mixture is stirred. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of desired product is formed, the mixture (or, optionally, the residue which is obtained after first rotary evaporating off the reaction solvent) is partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over sodium sulfate, and rotary evaporated to give 3-azidoacetyl-1-(tert-butoxycarbonyl)-indole, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: [CH:1]1([C:6]2[CH2:7][C@@H:8]3[C@H:11]([CH:12]=2)[C:10](=[CH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.P([O-])(O)(O)=O.[K+].[N+:38]([CH3:41])([O-:40])=[O:39]>>[N+:38]([CH2:41][C@@:10]1([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][C@H:8]2[C@@H:11]1[CH:12]=[C:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:7]2)([O-:40])=[O:39]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)C=C1C[C@@H]2CC(C3CCCC3)=C[C@H]12
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)C[C@]1(C[N+](=O)[O-])C[C@@H]2CC(C3CCCC3)=C[C@@H]21
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Tert-butyl(±)-[(1S,5R)-3-cyclopentylbicyclo[3.2.0]hept-3-en-6-ylidene]acetate (3.30 g, 12.0 mmol) was dissolved in nitromethane (30 mL). To the solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (2.20 g, 14.5 mmol) was added, and the mixture was stirred at 60° C. for 5 hours. The mixture was allowed to cool, and a saturated aqueous solution of potassium dihydrogen phosphate was then added thereto, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain the compound of interest as a yellow oil substance (3.50 g, 87%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([CH2:13][CH2:14][CH2:15][CH3:16])=[C:8]([Cl:17])[N:7]=1)(=O)C>Cl>[OH:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([CH2:13][CH2:14][CH2:15][CH3:16])=[C:8]([Cl:17])[N:7]=1
Reactant: CCCCc1c(Cl)cc(COC(C)=O)nc1Cl
Agent: Cl
Product: CCCCc1c(Cl)cc(CO)nc1Cl

Procedure:
40 g of 2-acetoxymethyl-4,6-dichloro-5-n-butyl-pyridine in 200 ml of 6 N hydrochloric acid are boiled for 15 hours under reflux. Thereafter the mixture is evaporated to dryness. The residue is taken up in chloroform and extracted by shaking with aqueous potassium carbonate solution. The chloroform solution is dried and evaporated. Fractional distillation yields 2-hydroxymethyl-4,6-dichloro-5-n-butyl-pyridine of boiling point 150°-160° (0.1 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:21])[CH2:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.[CH2:22]1N2CN3CN(C2)CN1C3.C(OC(=O)C)(=O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:8](=[O:21])[CH:9]([CH2:10][C:11]13[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]1)[CH2:18]3)[CH2:22]2
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CCC12CC3CC(CC(C3)C1)C2)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C1c2c(Cl)cccc2CC1CC12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Reaction time: 4 h
Yield: 70.9 %

Procedure:
78.7 g (260 mmole) 1-(2-Chloro-phenyl)-3-(1-adamantyl)-propan-1-one, 77.5 g (2.1 eq.) urotropine and 72.6 g (2.7 eq.) of acetic anhydride were placed in a 500 ml roundbottom flask and the mixture was stirred at 80° C. for 4 h. Then 100 ml water and 100 ml 2M NaOH were added and the mixture was extracted two times with 200 ml dichloromethane each. The organic layer was washed two times with 100 ml saturated aqueous ammonium chloride and dried over magnesium sulphate. The solvent amount was reduced in vacuo to a total of 150 ml volume and the solution was added dropwise over a period of 2.5 h to 660 g of hot (70-75° C.) concentrated sulphuric acid. After stirring for an additional 30 min at 75° C. the mixture was allowed to stand overnight at room temperature. The mixture was given to approx. 500 g of ice and extracted three times with 150 ml dichloromethane each. The organic layer was washed twice with 150 ml of a saturated sodium bicarbonate solution and once with 100 ml of a saturated sodium chloride solution. After drying over magnesium sulphate the solvent was removed in vacuo. The product was purified by column chromatography on silica (heptane/dichloromethane 5:1) to yield 58 g (71%) of the desired product as a slightly off-white glassy solid. 1H-NMR (400 MHz, CDCl3): δ=7.39 (t, 1H, aromatic), 7.27 (d, 1H, aromatic), 7.21 (d, 1H, aromatic), 3.37 (dd, 1H, COCH), 2.70 (m, 2H, benzylic), 1.36-1.18 (m, 17H, aliphatic) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[C:5]([Cl:11])=[CH:6][C:7]=1[N+:8]([O-])=O.Cl[Sn]Cl>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:13])[F:14])[C:5]([Cl:11])=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(Cl)c(C(F)(F)F)cc1N
Temperature: 90 °C
Yield: 70.3 %

Procedure:
To a stirred mixture of 3-amino-6-chloro-4-nitrobenzotrifluoride (300 mg, 1.25 mmol) in ethanol (5 mL) was added SnCl2 ·2H2O (1.40 g, 6.20 mmol) in one portion. The mixture was refluxed at 80° C. (oil bath, 90° C.) for 1 h and the solution was cooled to room temperature and ice water (20 g) was added. It was adjusted to pH=7 and extracted with ethyl acetate. The extract was dried over Mg2SO4 and evaporated to give 185 mg (71%) of 3,4-diamino-6-chlorobenzotrifluoride as a brown solid. 1H NMR (CDCl3): δ3.404 (s, 2H); 3.717 (s, 2H); 6.754 (s, 1H); 6.974 (s, 1H).
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:11]([O:13]C)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:25][CH2:26][C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28].Cl>CS(C)=O>[NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:11]([NH:25][CH2:26][C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: NCC(=O)NCC(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CS(C)=O
Product: O=C(O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
330 mg (1 mmole) of Z-L-Tyr-OMe, 400 mg (2.2 mmole) of H-Gly-Gly-Ome, HCl were suspended in 5 mL DMSO and 5 mL 0.1 M tris-HCl, pH 8.9. 25 mg of α-chymotrypsin were added and the reaction stirred for 30 minutes. Five volumes of ice water were added, and the precipitate collected by filtration. Yield 312 mg (70%, based on acyl-donor). Amino acid analysis: tyr1.0,gly2.1.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34](=[O:35])[N:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=1)([CH3:22])[CH3:23]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(C)c1ccc(CNc2ccc(C(C)C)cc2)cc1
Product: CC(C)c1ccc(CN(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccc(C(C)C)cc2)cc1
Yield: 21 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-isopropylphenyl)[(4-isopropylphenyl)methyl]amine (1.0 g) and 2,6-diisopropylphenyl isocyanate (0.99 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)-N-[(4-isopropylphenyl)methyl]urea (0.37 g) was obtained.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][CH:10]=[C:9](Cl)[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][NH2:8].[F:14][C:15]([F:24])([F:23])C1C=CC=CC=1O.ClC1C=CC=C(Cl)C=1O>>[F:14][C:15]([F:24])([F:23])[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][NH2:8]
Reactant: NCCCOc1c(Cl)cccc1Cl
Reactant: Oc1ccccc1C(F)(F)F
Agent: Oc1c(Cl)cccc1Cl
Product: NCCCOc1ccccc1C(F)(F)F
Yield: 80 %

Procedure:
Intermediate 10 (50 mg, 0.228 mmol, 80% yield) was prepared as a white powder following the procedure described for Intermediate 9 using 2-trifluoromethylphenol and 2.6-dichlorophenol as starting materials. LC-MS (ESI) 220 (M+H), RT=1.36 min (Method B).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[S:8](=[O:12])(=[O:11])[CH:9]=[CH:10][C:6]=2[CH:5]=1)([O-])=O>[Pd].CCO.C1COCC1>[O:11]=[S:8]1(=[O:12])[CH2:9][CH2:10][C:6]2[CH:5]=[C:4]([NH2:1])[CH:14]=[CH:13][C:7]1=2
Reactant: O=[N+]([O-])c1ccc2c(c1)C=CS2(=O)=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc2c(c1)CCS2(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
Palladium on carbon (25 mg) was placed under an inert atmosphere and suspended in 1:1 v/v EtOH/THF (10 mL). A solution of 5-nitrobenzo[b]thiophene 1,1-dioxide (250 mg, 1.18 mmol) in EtOH/THF (1:1) was then added, and the reaction mixture placed under H2 atmosphere (1 Atm pressure) and stirred at RT for 3 h. Reaction is filtered through a Celite pad and washed well with MeOH to obtain the title compound (200 mg, 92%) as a brown solid: TLC (10% MeOH/DCM w/5% NH4OH), Rf=0.40; LC MS m/z 184.1 (MH+).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([O:13][CH:14]1[CH2:23][CH:22]([CH3:24])[CH2:21][C:20]2[N:19]=[N:18][C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)=[CH:16][C:15]1=2)=[O:12])[CH3:10])=O)(C)(C)C.[ClH:35]>O1CCOCC1>[ClH:35].[ClH:35].[NH2:8][C@H:9]([C:11]([O:13][CH:14]1[CH2:23][CH:22]([CH3:24])[CH2:21][C:20]2[N:19]=[N:18][C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)=[CH:16][C:15]1=2)=[O:12])[CH3:10]
Reactant: CC1Cc2nnc(-c3cccc(C(F)(F)F)c3)cc2C(OC(=O)[C@H](C)NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC1Cc2nnc(-c3cccc(C(F)(F)F)c3)cc2C(OC(=O)[C@H](C)N)C1

Procedure:
5-(N-(tert-butoxycarbonyl)-L-alanyl)oxy-7-methyl-3-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydrocinnoline obtained in Example 31 was dissolved in dioxane (0.5 mL, followed by adding a 4N HCl solution/dioxane (0.5 mL) under ice cooling and reacting over night. The reaction liquid was concentrated to dryness to obtain an objective compound as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:21][O:20][N:19]([CH3:18])[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (9.20 g, 40.1 mmol), N,O-dimethylhydroxylamine hydrochloride (5.87 g, 60.2 mmol) and CH2Cl2 (120 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.54 g, 60.2 mmol), N,N-diisopropylethylamine (10.51 mL, 60.2 mmol) and 4-(dimethylamino)pyridine (250 mg, 2.046 mmol) before being stirred at RT overnight. After this time, the mixture was diluted with DCM (100 mL) and washed sequentially with 1 M hydrochloric acid (2×75 mL), saturated NaHCO3 (100 mL), and brine (100 mL). The organic phase was dried (MgSO4) and then concentrated in vacuo to give tert-butyl 4-(methoxy(methyl)carbamoyl)-piperidine-1-carboxylate as a colorless oil (9.9 g), which was used in the next step without any further purification.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][OH:15])=[N:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][O:15][S:23]([CH3:26])(=[O:25])=[O:24])=[N:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2cnc(CO)s2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2cnc(COS(C)(=O)=O)s2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-yl]-methanol (560 mg, 2.78 mmol) in dry CH2Cl2 (5.0 mL) was treated at 0° C. with Et3N (0.50 mL, 3.60 mmol) followed by DMAP (34 mg, 0.28 mmol) and Ms-Cl (0.28 mL, 3.51 mmol). After stirring at 0° C. for 1 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (5:1 to 2:1 hept-EA) gave the title compound as a brown oil. LC-MS-conditions 01: tR=0.77 min; [M+H]+=279.88.