Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([O-:14])=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CN1C(=O)CCC1>[C:24]([O:23][C:21]([N:15]1[CH2:20][CH2:19][N:18]([C:9]2[C:8]([C:12]([OH:14])=[O:13])=[CH:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:10]=2)[CH2:17][CH2:16]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)c1ncc(C(=O)[O-])c(Cl)n1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(C(C)(C)C)ncc2C(=O)O)CC1
Yield: 80 %

Procedure:
Using a procedure analogous to Example B27, 2-tert-butyl-4-chloropyrimidine-5-carboxylate from Example B27 (0.30 g, 1.24 mmol) and tert-butyl piperazine-1-carboxylate (1.15 g, 6.18 mmol) in presence of NMP (catalytic amount) were combined to afford 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-tert-butylpyrimidine-5-carboxylic acid (0.36 g, 80% yield). MS (ESI) m/z: 365.0 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[N:16]=[C:15]([C:17]4[S:21][C:20]([C:22]([C@H:26]5[CH2:31][CH2:30][C@H:29]([C:32](O)=[O:33])[CH2:28][CH2:27]5)([OH:25])[CH2:23][CH3:24])=[N:19][CH:18]=4)[CH:14]=[C:13]([CH3:35])[CH:12]=3)[CH:5]=2)[CH2:3][CH2:2]1.C[N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)C(C)C)(C)C>CO.CN(C=O)C>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[N:16]=[C:15]([C:17]4[S:21][C:20]([C:22]([C@H:26]5[CH2:27][CH2:28][C@H:29]([C:32]([NH2:37])=[O:33])[CH2:30][CH2:31]5)([OH:25])[CH2:23][CH3:24])=[N:19][CH:18]=4)[CH:14]=[C:13]([CH3:35])[CH:12]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCC(O)(c1ncc(-c2cc(C)cc(Nc3cc(C4CC4)ccn3)n2)s1)[C@H]1CC[C@H](C(=O)O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCC(O)(c1ncc(-c2cc(C)cc(Nc3cc(C4CC4)ccn3)n2)s1)[C@H]1CC[C@H](C(N)=O)CC1
Reaction time: 2 h

Procedure:
To a flask containing racemic trans-4-[1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxylic acid (25 mg, 0.051 mmol) was added 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25.1 mg, 0.066 mmol) and ammonium chloride (10.9 mg, 0.203 mmol). DMF (1 mL) and N,N-diisopropylethylamine (0.089 mL, 0.507 mmol) were added and the reaction was sealed and stirred for 2 hours. Methanol (0.1 mL) was then added to quench the reaction and the resulting solution was filtered. The filtrate was purified by reversed phase HPLC (10-100% acetonitrile/water with 0.1% TFA). The fractions containing desired product were pooled, frozen and concentrated to dryness on a lyophilizer to afford trans-4-[1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxamide. MS ESI calc'd. for C27H34N5O2S [M+H]+ 492. found 492. 1H NMR (500 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.49 (s, 1H), 8.30 (d, J=6.4 Hz, 1H), 7.53 (s, 1H), 7.38 (s, 1H), 7.15 (s, 1H), 7.04 (d, J=6.4 Hz, 1H), 6.94 (s, 1H), 6.68 (s, 1H), 5.84-5.30 (m, 1H), 2.43 (s, 3H), 2.30-2.15 (m, 1H), 2.07-1.87 (m, 4H), 1.87-1.67 (m, 3H), 1.54-1.42 (m, 1H), 1.42-1.18 (m, 6H), 1.12-0.93 (m, 3H), 0.79 (t, J=7.3 Hz, 3H) ppm. rhSyk=+++.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[C:19]([Br:24])[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:27]N(C=O)C>>[CH3:27][N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[C:19]([Br:24])[CH:18]=2)[CH2:14][CH2:15]1)=[O:9]
Reactant: CN(C)C=O
Reactant: O=C(Nc1ccccc1)N1CCN(Cc2ccc(Br)c(Br)c2)CC1
Agent: [H-]
Agent: [Na+]
Product: CN(C(=O)N1CCN(Cc2ccc(Br)c(Br)c2)CC1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3,4-dibromo-benzyl)-piperazine-1-carboxylic acid phenylamide (0.02 g) in DMF (0.6 mL) was added NaH (60% dispersion in oil; 3 mg) in one portion. The resulting mixture was allowed to stir for 30 min, then was treated with Mel (0.005 mL), and was stirred at rt for 12 h. The mixture was concentrated and the residue was purified by column chromatography (5% MeOH/DCM), giving the product as a white solid (0.015 g). 1H NMR (400 MHz, CDCl3): 7.54-7.50 (m, 2H), 7.33-7.31 (m, 2H), 7.12-7.05 (m, 4H), 3.34 (s, 2H), 3.22-3.20 (m, 6H), 2.23-2.21 (m, 4H), 1.63 (s, 3H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][C:12](=[O:19])[C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:22]=[C:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:24](OCC)=[O:25]>O1CCCC1>[CH2:1]([S:8][C:9]1[N:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH:13]([C:24](=[O:25])[C:23]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:22])[C:12](=[O:19])[C:11]=2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: O=C1CCCc2cnc(SCc3ccccc3)nc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C(=O)C1CCc2cnc(SCc3ccccc3)nc2C1=O)c1ccccc1
Yield: 68 %

Procedure:
To a solution of 0.22 g (0.81 mmol) of 2-(benzylthio)-6,7-dihydroquinazolin-8(5H)-one in 5 mL of dry tetrahydrofuran cooled to −50° C., 0.10 g of sodium hydride 60% in mineral oil were added. The resulting suspension was maintained at the same temperature for 30 minutes and then 0.59 mL of ethyl α-oxobenzeneacetate (PhCOCOOEt) were added and the reaction mixture allowed to come to room temperature. After 16 hours the mixture was partitioned between water and ethyl acetate and the organic layer was dried over Na2SO4 and evaporated to dryness. The residue was purified by chromatography on a silica gel column (eluant hexane/ethyl acetate 7/3) giving 0.22 g (68% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[C:13]12([CH2:23][NH2:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.C(C(CC)CN)C>>[C:13]12([CH2:23][NH:24][C:2]3[N:12]=[CH:11][CH:10]=[CH:9][C:3]=3[C:4]([OH:6])=[O:5])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)c1cccnc1Cl
Agent: CCC(CC)CN
Product: O=C(O)c1cccnc1NCC12CC3CC(CC(C3)C1)C2

Procedure:
The title compound was prepared according to the procedure of Example 3A substituting 2-chloronicotinic acid for ethyl 2-chloronicotinate and 1-adamantanemethylamine for 2-ethylbutylamine (0.185 g, 79%). MS (ESI+) m/z 287.1 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.74 (m, 12H), 2.00 (s, 3H), 3.31 (m, 2H), 6.60 (dd, J=7.35, 5.52 Hz, 1H), 7.96 (dd, J=5.33, 2.02 Hz, 1H), 8.26 (dd, J=7.35, 1.84 Hz, 1H).
Reaction SMILES: [CH3:1][CH:2]([C:8](=[O:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OCC)(=O)CC(C)=O>>[CH3:1][CH:2]([CH:8]([OH:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)C(C)=O
Solvent: CCOC(=O)CC(C)=O
Product: CCOC(=O)C(C)C(C)O
Yield: 60 %

Procedure:
Ethyl 2-methyl-3-hydroxybutyrate was prepared following the procedure as described in step 1) of Preparation Example 2, except for that ethyl 2-methyl-3-oxo-butyrate was used to replace for ethyl acetoacetate. Yield 60%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH3:22]I.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:22])[C:14](=[O:19])[C:15]([F:17])([F:18])[F:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CI
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1OC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(CCN(C)C(=O)C(F)(F)F)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add 20.0 9 (0.07 mol) of N-[2-(3,4-dimethoxyphenyl)ethyl]trifluoroacetamide to a suspension of 3.17 g (0.08 mol) of 60% sodium hydride in 50 mL of dry tetrahydrofuran. Stir this suspension for 30 minutes at room temperature. After 30 minutes, add 6.72 mL (0.11 mol) of methyl iodide and stir at room temperature for one h. After one h, filter reaction mixture and make basic (pH=14) with 4N sodium hydroxide. Wash this mixture with 2×100 mL of water. Extract the combined aqueous washes with 2×100 mL of methylene chloride. Wash the combined organic extracts with 6N hydrochloric acid, then with 100 mL of water. Dry the organic layer over anhydrous sodium sulfate. Filter the drying agent and remove the solvent in vacuo to provide the title compound.
Reaction SMILES: C(OC([N:6]1[CH:14]2[CH:9]([CH:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)=O)C.[OH-:23].[Na+]>CO>[Cl:22][C:17]1[CH:16]=[C:15]([C:10]2([OH:23])[CH2:11][CH2:12][CH2:13][CH:14]3[CH:9]2[CH2:8][CH2:7][NH:6]3)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: [OH-]
Reactant: CCOC(=O)N1CCC2C(c3ccc(Cl)c(Cl)c3)CCCC21
Agent: [Na+]
Solvent: CO
Product: OC1(c2ccc(Cl)c(Cl)c2)CCCC2NCCC21

Procedure:
24.9 g (3aRS,4SR,7aRS)-4-(3,4-dichlorophenyl)hexahydro-1-indoline carboxylic acid ethyl ester in 240 ml methanol are treated with 240 ml 10N sodium hydroxide and refluxed for 15 hours. The cooled resulting mixture is repeatedly extracted with methylene chloride. The organic phase is extracted with 2N tartaric acid. The acidic phase is made alkaline and extracted with methylene chloride. The methylene chloride phases are dried over magnesium sulphate, and evaporated to give the title compound, in crude free base form, as an oil which is converted, by the addition of an equivalent amount of maleic acid, into the hydrogen maleate. M.Pt. 190°-191°.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([OH:10])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([NH:22][C:23]1[CH:44]=[CH:43][CH:42]=[C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]3[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]4[CH2:40][CH2:41]4)=[O:38])[N:35]=3)[CH:32]=2)[CH:24]=1)=[O:10]
Reactant: Cn1ncc(C(=O)O)c1Cl
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cn1ncc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c1Cl
Yield: 8.6 %

Procedure:
In the same manner as in Example 18-4 and using 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (291 mg, 1.81 mmol), tetrahydrofuran (10 mL), oxalyl chloride (236 μL, 2.72 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.647 mmol), N,N-dimethylformamide (2 drops) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (25.0 mg, 9%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH2:14][CH2:15][CH:16]=[CH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:10]=[C:9]([Cl:25])[CH:8]=2)=[O:4].C1C(=O)N([Br:33])C(=O)C1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[Br:33])=[C:11]([CH2:14][CH2:15][CH:16]=[CH:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH:10]=[C:9]([Cl:25])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2c(CCC=CC(=O)OC(C)(C)C)cc(Cl)cc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]c2cc(Cl)cc(CCC=CC(=O)OC(C)(C)C)c2c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 6-chloro-4-(4-tert-butoxycarbonyl-3-butenyl)indole-2-carboxylic acid methyl ester (12.0 g, 33 mmol) in DMF (120 mL) was added slowly a solution of NBS (5.87 g, 33 mmol) in DMF (60 mL) at 0° C. The mixture was stirred for 1 h at 0° C., diluted with aqueous NaHCO3, and extracted with 2:1 ethyl acetate/toluene. The extract was washed with water and brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography with 8:1 to 5:1 hexane/ethyl acetate to give 13.3 g of the title compound (91%): 1H NMR (CDCl3) δ9.15 (bs, 1H), 7.28 (d, 1H, J=1.8 Hz), 6.97 (dt, 1H, J=15.8, 6.9 Hz), 6.93 (d, 1H, J=1.8 Hz), 5.83 (dt, 1H, J=15.8, 1.7 Hz), 3.99 (s, 3H), 3.32 (dd, 2H, J=8.3, 7.9 Hz), 2.57 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)O)=[CH:9][N:10]=2)[N:7]=1.II.[PH2](=O)O.ClC1C=CC2N(C(C(C3C(F)=C4C(=CC=3F)N(C)N=C4)C)=CN=2)N=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:13]3[C:14]([F:24])=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)=[CH:9][N:10]=2)[N:7]=1
Reactant: Cn1ncc2c(F)c(C(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Agent: CC(c1c(F)cc2c(cnn2C)c1F)c1cnc2ccc(Cl)nn12
Agent: II
Agent: O=[PH2]O
Product: Cn1ncc2c(F)c(Cc3cnc4ccc(Cl)nn34)c(F)cc21
Yield: 77.6 %

Procedure:
The title compound as a light yellow solid (370 mg, 1.109 mmol, 78%) was synthesized from (6-chloroimidazo[1,2-b]pyridazin-3-yl)(4,6-difluoro-1-methyl-1H-indazol-5-yl)methanol (500 mg, 1.43 mmol), Iodine (907 mg, 3.57 mmol) and phosphinic acid (50%, 0.55 mL) using the same procedure as described in the synthesis of compound 31.2. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.07 (s, 1H), 8.01 (d, 1H), 7.44 (s, 1H), 7.29 (d, 1H), 7.27 (d, 1H), 4.46 (s, 2H), 4.04 (s, 3H). LCMS (method B): [MH]+=333.9, tR=2.68 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:26]([C:27](O)=[O:28])=[C:25]([CH3:30])[O:24][N:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:26]3[C:22]([CH3:21])=[N:23][O:24][C:25]=3[CH3:30])=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: Cc1noc(C)c1C(=O)O
Product: Cc1noc(C)c1C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 3,5-dimethyl-4-isoxazolecarboxylic acid, as starting materials, MS (LC/MS): 426.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([CH2:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:20][CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(CCNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-nitrophenyl)ethan-1-one (1 eq) and phenylmethylamine (1 eq) in methanol was added sodium triacetoxyborohydride (1.2 eq). The resulting mixture was stirred at ambient temperature for 16 h. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative purification yielded [(4-nitrophenyl)ethyl]benzylamine. MS: MH+=256.
Reaction SMILES: [C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]1C=CC(C(C2N(C)C(CC(OCC)=O)=CC=2C)=O)=CC=1>>[C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH:15]([CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccccc2)n1C
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Product: CCOC(=O)C(C)c1cc(C)c(C(=O)c2ccccc2)n1C

Procedure:
The methylation procedure of Example 77A is repeated, except that an equivalent quantity of ethyl 5-benzoyl-1,4-dimethylpyrrole-2-acetate (from Example 86) is methylated instead of the ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A, to yield ethyl 5-benzoyl-1,4,α-trimethylpyrrole-2-acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[N:4]=[C:5]([S:37][CH3:38])[C:6]([C:20]1[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[C:22]([O:28][Si](C(C)(C)C)(C)C)[C:21]=1[F:36])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(OCC)(=O)C.O>C1COCC1>[CH3:1][O:2][C:3](=[O:39])[N:4]=[C:5]([S:37][CH3:38])[C:6]([C:20]1[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[C:22]([OH:28])[C:21]=1[F:36])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(O)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.5 %

Procedure:
To a solution of 0.76 g of {2-[3-(t-butyldimethylsilanyloxy)-5-ethyl-2-fluorophenyl]-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 30 ml of THF there was added 1.6 ml of TBAF (1.0 M, THF solution) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 hours, and then 200 ml of ethyl acetate and 100 ml of water were added. The organic layer was washed twice with 100 ml of water and once with 100 ml of saturated aqueous sodium chloride in that order and dried over anhydrous magnesium sulfate, the desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (0.41 g) as a white solid.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH2:7]([CH:10]1[CH2:18][CH2:17][C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]1=[O:19])[CH:8]=C.[OH2:20]>[Os](=O)(=O)(=O)=O.O1CCOCC1>[O:19]=[C:11]1[C:12]2[CH:16]=[CH:15][S:14][C:13]=2[CH2:17][CH2:18][CH:10]1[CH2:7][CH:8]=[O:20]
Reactant: C=CCC1CCc2sccc2C1=O
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=CCC1CCc2sccc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 4.20 g of sodium periodate was added gradually to a mixture of 1.80 g of 5-allyl-4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene, 25 mg of osmium tetraoxide, 15 ml of water and 45 ml of dioxane, while keeping the reaction mixture at 24 to 26° C., and then the mixture was stirred at room temperature for 3 hours. After extraction of the reaction mixture with ethyl acetate, the organic layers were combined, washed with 2% sodium thiosulfate aqueous solution, water and brine in that order and then dried with anhydrous magnesium sulfate. After removal of the drying agent, the solvent was concentrated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography to give 1.33 g of (4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophen-5-yl)acetaldehyde. A 1.32 g of the aldehyde compound and 1.39 g of N-acetylethylenediamine were dissolved in 50 ml of toluene. Then, 10 mg of camphorsulfonic acid was added, and the mixture was heated under reflux for 3 hours while removing the produced water. After cooling, the reaction solution was poured into ice-cooled saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layers were combined, the drying agent was removed by filtration and then the solvent was concentrated under a reduced pressure to give 1.38 g of N-(2-(4,5-dihydro-1H-thieno[2,3-g]indol-1-yl)ethyl]acetaamide. From this compound, N-[2-(1H-thieno[2,3-g]indol-1-yl)ethyl]acetamide was obtained in the similar manner as described in Reference Example 60.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:8](=O)(=[O:11])([OH:10])[OH:9].O.[OH-].[Na+]>ClC1C=CC=CC=1Cl>[S:8]([OH:11])(=[O:10])([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Nc1ccc(S(=O)(=O)O)cc1
Temperature: 200 °C

Procedure:
651.7 g (7.0 mol) of aniline in 1400 ml of o-dichlorobenzene were introduced into a 4 enamel stirring autoclave and 686.7 g (7.0 mol) of 100% sulphuric acid were added with stirring. The autoclave was then closed and the reaction mixture was heated to 200° C. with stirring. After 21/2 hours reaction time, the reaction mixture was cooled, poured into 1000 ml of water with stirring and neutralized with sodium hydroxide solution. Two liquid phases were obtained. After replenishing the aniline to the abovementioned value, the organic phase was added to a further batch. Pure p-sulphanilic acid was obtained from the aqueous phase by acidification using sulphuric acid. The yield amounted to 64.2%.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:43])[CH2:17][CH2:18][N:19]([CH2:24][CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[C:33]([O:35]CC1C=CC=CC=1)=[O:34])=[O:27])[CH2:20][CH:21]1[CH2:23][CH2:22]1)=[O:10])C1C=CC=CC=1.[H][H]>C(O)(C)C.[Pd]>[C:33]([C@H:29]1[CH2:30][CH2:31][CH2:32][N:28]1[C:26](=[O:27])[CH2:25][CH2:24][N:19]([CH2:20][CH:21]1[CH2:22][CH2:23]1)[CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:43])([OH:35])=[O:34]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)CCN(CCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)CC1CC1
Agent: [Pd]
Solvent: CC(C)O
Product: O=C(O)[C@H]1CCCN1C(=O)CCN(CCC(=O)N1CCC[C@@H]1C(=O)O)CC1CC1
Yield: 101 %

Procedure:
A solution of 220 mg (0.37 mmol) (R)-1-[3-[[3-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-cyclopropylmethyl-amino]-propionyl]-pyrrolidine-2-carboxylic acid benzyl ester in 20 ml isopropanol was stirred with 10 mg 10% palladium on charcoal under 1 atm of hydrogen for 16 h at room temperature. After filtration to remove the catalyst, concentration in vacuo afforded 153 mg (100%) of the title compound as a yellow solid. MS m/e (%): 408 ([M−H]−, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11]1([CH3:20])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.[F-].[Cs+].O>O1CCOCC1.CC(OC)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH3:20])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: O=Cc1cc(Br)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1-c1ccc(Br)cc1C=O
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-2-iodobenzaldehyde (3B Scientific Corp., 5.83 g, 18.8 mmol), o-tolylboronic acid (2.55 g, 18.8 mmol), cesium fluoride (8.55 g, 56.4 mmol) and bis(triphenylphosphine)palladium(II) chloride (263 mg, 0.38 mmol) was prepared in dioxane (60 mL) and water (25 mL) under nitrogen atmosphere and was heated at 50° C. for 16 hours. The reaction mixture was cooled at RT, diluted with MTBE (250 mL) and the layers were separated. The organic layer was washed with water (100 mL) and brine (100 mL). The aqueous layers were extracted with MTBE (150 mL). The organic layers were combined, dried (Na2SO4) and concentrated under vacuum. After purification by flash chromatography (silica, hexane/EtOAc), the title compound was obtained as a pale yellow solid (4.63 g, 90%). HPLC (Method A) Rt 5.6 min (Purity: 93%). 1H NMR (DMSO-d6, 300 MHz) δ 9.57 (s, 1H), 8.02 (s, 1H), 7.94 (m, 1H), 7.39-7.27 (m, 4H), 7.20 (m, 1H), 2.06 (s, 3H).