Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[C:26]4[N:27]=[C:28]([NH2:30])[S:29][C:25]=4[CH:24]=[CH:23][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31](OC(=O)C)(=[O:33])[CH3:32]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[C:26]4[N:27]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[S:29][C:25]=4[CH:24]=[CH:23][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(Oc3cccc4sc(N)nc34)ncn2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc2c(Oc3cc(C4=CCN(C(=O)OC(C)(C)C)CC4)ncn3)cccc2s1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
4-[6-(2-Amino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester, (Example 200), (110 mg, 0.26 mmol) was dissolved in toluene (1.0 mL) and treated with acetic anhydride (100 μL, 1.0 mmol, Aldrich) at room temperature. The reaction mixture was stirred at 90° C. for 30 min. The resulting mixture was allowed to cool to room temperature and the solvents were removed in vacuum. The residue was purified by silica gel chromatography (gradient: 0% to 4.0% MeOH/CH2Cl2) to provide the title compound as a light-yellow foam. MS (ESI, pos. ion) m/z: 468 (M+1), 466 (M−1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH2:17]O)[N:3]=1.C(N(S(F)(F)[F:25])CC)C>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH2:17][F:25])[N:3]=1
Reactant: Nc1nc(N)c(-c2cccc(Cl)c2Cl)c(CO)n1
Reactant: CCN(CC)S(F)(F)F
Product: Nc1nc(N)c(-c2cccc(Cl)c2Cl)c(CF)n1
Temperature: -10 °C

Procedure:
Fluorination of racemic 2,4-diamino-5-(2,3-dichlorophenyl)-6-hydroxymethyl pyrimidine can be effected using diethylaminosulphur trifluoride (DAST). That may be carried out in dichloromethane at, initially, -78° C. followed by warming to -10° C. for four and a half hours, to afford racemic 2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23]([N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])(C(C)(C)C)(C)C.[Si]([O:46][CH2:47][CH:48]=O)(C(C)(C)C)(C)C.[BH3-]C#N.[Na+]>CO.CC(O)=O>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:13]1[CH2:12][N:11]([C:23]([N:25]([CH:26]2[CH2:27][CH2:28][N:29]([CH2:48][CH2:47][OH:46])[CH2:30][CH2:31]2)[CH3:32])=[O:24])[C:10]([CH2:9][OH:8])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=1
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO[Si](C)(C)C(C)(C)C)c1ccccc1)C1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1)C1CCN(CCO)CC1
Reaction time: 1 h

Procedure:
To 150 mg (0.28 mmol) of amine 7-2 in MeOH was added 145 mg (0.83 mmol) of (t-butyldimethylsilyloxy) acetaldehyde and several drops of HOAc. After stirring for 1 h, 35 mg (0.55 mmol) of NaCNBH3 was added and the reaction was stirred overnight in a sealed flask. The mixture was partitioned between EtOAc and saturated NaHCO3, the layers were separated, the organic phase was washed with water, dried over MgSO4, and concentrated by rotary evaporation. The residue was dissolved in dry EtOAc, saturated with HCl(g) and stirred for 1 h. The reaction was partitioned between EtOAc and saturated NaHCO3, the layers were separated, the organic phase was washed with water, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by reverse phase HPLC, but was not of sufficient purity, so it was then purified by column chromatography on silica gel with 20:1:1 EtOH/NH4OH/H2O in EtOAc to provide 11-1 as a white solid. Data 11-1: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.4 (m, 1H), 4.8 (m, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.0 (m, 1H), 3.75 (m, 1H), 3.6 (m, 2H), 3.0 (m, 2H), 2.9 (s, 3H), 2.5 (m, 2H), 2.2 (m, 2H), 1.8 (m, 3H), 1.7 (m, 1H) ppm. HRMS (ES) calc'd M+H for C26H31F2N3O3: 472.2406. Found: 472.2386.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](Cl)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:22][S:23]([O-:25])=[O:24].[Na+].C(OCC)(=O)C.O>CS(C)=O>[CH3:1][O:2][C:3](=[O:21])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:23]([CH3:22])(=[O:25])=[O:24])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CS(=O)[O-]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 83.3 %

Procedure:
A solution of 2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-propionic acid methyl ester (1.00 g, 3.21 mmol) and sodium methanesulfinate (0.36 g, 3.53 mmol) in dimethyl sulfoxide (3 mL) was heated at 130° C. for 5 h. The black reaction mixture was then poured over ice (20 g), resulting in the formation of a brown sticky substance. The resulting mixture was then treated with ethyl acetate (50 mL) and water (50 mL), and the layers were separated. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid methyl ester (0.95 g, 84%) as a yellow gel: FAB-HRMS m/e calcd for C16H21NO6S (M+H)+ 356.1169, found 356.1175.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[NH2:6][CH2:7][C:8](=[O:21])[CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH2:6][CH2:7][C:8](=[O:21])[CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12]
Reactant: O=S(=O)([O-])[O-]
Agent: NCC(=O)CCC(=O)OCc1ccccc1
Product: O=S(=O)(O)O

Procedure:
The elemental analysis shows that the product exists as the sulfate (2:1), i.e. (benzyl 5-amino-4-oxopentanoate)
Reaction SMILES: C[N:2](C)/[C:3](/[CH3:26])=[CH:4]/[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13](=[O:25])[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)=O.O.[NH2:29]N.C(O)(=O)C>C(O)C>[CH3:26][C:3]1[NH:2][N:29]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH:12][C:13](=[O:25])[CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[CH:4]=1
Reactant: NN
Reactant: C/C(=C\C(=O)c1sccc1NC(=O)Cc1cccc2ccccc12)N(C)C
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2sccc2NC(=O)Cc2cccc3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
To a solution of (E)-N-(2-(3-(dimethylamino)but-2-enoyl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide (139 mg, 0.37 mmol) in abs. ethanol (2 mL) was added hydrazine hydrate (1 mL, 62.91 mmol) and acetic acid (0.5 mL, 8.73 mmol). The reaction mixture was stirred at room temperature overnight under N2 (g) inlet and then concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and H2O. The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, 20:80 ethyl acetate/hexane) yielded N-(2-(5-methyl-1H-pyrazol-3-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide (20 mgs, 16%). Method [7] m/z 348.1 (M+Na); retention time=6.791. 1H-NMR (CDCl3) δ 10.28 (broad s, 1H), 8.07 (d, J=5.8 Hz, 2H), 7.91 (d, J=4.5 Hz, 2H), 7.53 (d, J=5.8 Hz, 2H), 7.53 (s, 1H), 7.50 (d, J=4.5 Hz, 2H), 7.08 (d, J=5.2 Hz, 1H), 5.88 (s, 1H), 4.23 (s, 2H), 2.19 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2C1CCCCO1.CC1C(OC2C=CC=C([N+]([O-])=O)C=2)=CC=C2C=1C=NN2C1CCCCO1.[Cl:44][C:45]1[CH:46]=[C:47]([N+:52]([O-:54])=[O:53])[CH:48]=[CH:49][C:50]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(N(CC)CC)C.O>[Cl:44][C:45]1[CH:46]=[C:47]([N+:52]([O-:54])=[O:53])[CH:48]=[CH:49][C:50]=1[O:11][C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][N:5]=[CH:4]2
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Cc1c(O)ccc2c1cnn2C1CCCCO1
Agent: Cc1c(Oc2cccc([N+](=O)[O-])c2)ccc2c1cnn2C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Oc2ccc([N+](=O)[O-])cc2Cl)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 85.6 %

Procedure:
Under nitrogen, the 4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-ol (150 mg, 0.646 mmol) obtained in Example 734, (a) and 3-chloro-4-fluoronitrobenzene (125 mg, 0.710 mmol) were dissolved in N,N-dimethylformamide (2 ml), followed by adding thereto potassium carbonate (134 mg, 0.969 mmol), and the resulting mixture was stirred at 70° C. for 1.5 hours. After the reaction solution was cooled to room temperature, water was added thereto, followed by extraction with toluene/ethyl acetate=1/3. The extract layer was washed with water and then a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was suspended in methanol (10 ml), followed by adding thereto a 4N-hydrochloric acid/1,4-dioxane solution (5 ml), and the resulting mixture was stirred at room temperature for 14 hours. (The residue was once dissolved and then gave a white suspension again). The resulting mixture was made basic by adding triethylamine slowly under ice-cooling, and the solvent was distilled off under reduced pressure. Then, water was added to the residue, followed by extraction with ethyl acetate. The extract layer was washed with a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1, 2/1) to obtain 5-(2-chloro-4-nitrophenoxy)-4-methyl-1H-indazole (168 mg, yield 86%).
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[NH:9][C:8]2[C:3]1=[N:4][C:5](/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:6][CH:7]=2.N12CCN(CC1)CC2.CN(C)C=O.[N:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>O>[CH3:1][N:2]1[C:10](=[O:11])[N:9]([C:38]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:39])[C:8]2[C:3]1=[N:4][C:5](/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:6][CH:7]=2
Reactant: Cn1c(=O)[nH]c2cnc(/C=C/c3ccccc3)nc21
Reactant: O=C(Cl)N1CCCC1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C(=O)N2CCCC2)c2cnc(/C=C/c3ccccc3)nc21
Reaction time: 1 h

Procedure:
To a mixture of 9-methyl-2-[(E)-2-phenylethenyl]-7,9-dihydro-8H-purine-8-one <the compound of Reference Example 3> (100 mg), 1,4-diazabicyclo[2.2.2]octane (133 mg) and N,N-dimethylformamide (3 ml) was added dropwise 1-pyrrolidinecarbonyl chloride (106 mg) at room temperature and the mixture was stirred for 1 hour. To the reaction mixture was added water (50 ml) and the mixture was extracted with ethyl acetate (80 ml×2). The organic layer was dried over anhydrous magnesium sulfate and was filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0˜0/100) to give the title compound 56 mg.
Reaction SMILES: C(OC[N:9]1[C:13]2=[N:14][CH:15]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([C:27]#[N:28])=[CH:24][CH:25]=4)[N:20]([CH3:29])[N:19]=3)[N:17]=[C:12]2[C:11]([C:30](=[O:36])[NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:10]1)(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1>[C:32]([NH:31][C:30]([C:11]1[C:12]2[C:13](=[N:14][CH:15]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([C:27]#[N:28])=[CH:24][CH:25]=4)[N:20]([CH3:29])[N:19]=3)[N:17]=2)[NH:9][CH:10]=1)=[O:36])([CH3:35])([CH3:34])[CH3:33]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COC(=O)C(C)(C)C)c2ccc(C#N)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2ccc(C#N)cc21
Reaction time: 15 h
Yield: 73.5 %

Procedure:
To a stirred solution of (7-(tert-butylcarbamoyl)-2-(6-cyano-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl pivalate (80 mg, 0.164 mmol) in THF (5 mL) was added a 15% NaOH aqueous solution (0.5 mL) at room temperature and the reaction mixture stirred for 15 hours. The solvent was evaporated under reduced pressure. The residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 15% acetonitrile/75% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-tert-butyl-2-(6-cyano-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 74%) as white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=1.S1(=O)(=O)[N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]2[CH2:11]O1>>[I:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH2:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1
Reactant: Ic1cccc(I)c1
Reactant: O=S1(=O)OC[C@@H]2CCCCN21
Product: Ic1cccc(C[C@@H]2CCCCN2)c1

Procedure:
(S)-2-(3-Iodo-benzyl)-piperidine was prepared from 1,3-diiodobenzene and (S)-hexahydro-[1,2,3]oxathiazolo[3,4-a]pyridine 1,1-dioxide in analogy to the procedure described for Example 4 in U.S. Pat. No. 5,130,432. LC-MS B: tR=0.54 min; [M+H]+=302.07.
Reaction SMILES: [OH:1][C@H:2]1[CH2:11][N:10]2[C@H:4]([C:5](=[O:17])[NH:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9]2=[O:12])[CH2:3]1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C)C=O>[Si:23]([O:1][C@H:2]1[CH2:11][N:10]2[C@H:4]([C:5](=[O:17])[NH:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9]2=[O:12])[CH2:3]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1Nc2ccccc2C(=O)N2C[C@H](O)C[C@@H]12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2C(=O)Nc3ccccc3C(=O)N2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
To a suspension of (2R,11aS)-2-hydroxy-1,2,3,10,11,11a-hexahydro-5H-pyrrolo(2,1-c][1,4]benzodiazepin-5,11-dione (50 g) prepared in Reference Example 21 and imidazole (33.7 g) in N,N-dimethylformamide (500 ml), there was added 37.9 g of tert-butyldimethylsilyl chloride at room temperature in a nitrogen gas atmosphere and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into one liter of ice water and the crystals precipitated were recovered by filtration. The crystals were washed with water and then dried to give 72.5 g (yield 99.9%) of (2R,11aS)-2-(tert-butyldimethylsilyloxy)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-dione as white crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:4][CH2:3]1.[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:19]([NH:27][C:28]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:6][CH2:7]1)=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NC(=S)NC1CCN(Cc2ccc3ccccc3c2)CC1)c1ccccc1

Procedure:
4-Amino-1-(naphth-2-ylmethyl)piperidine (1.0 g, 0.0042m) and benzoylisothiocyanate (0.69 g, 0.0042 m) in toluene (120 cm3) was stirred at room temperature for 6 hours. The solvent was evaporated and the gum dissolved in isopropyl alcohol and acidified with ethanolic HCl. The solvent was evaporated and the residue dissolved in ethyl acetate. The title compound crystallised and was filtered and dried as the monohydrochloride quarterhydrate salt, m.p. 212°-214° C.
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[CH:21]=[CH:20][C:14]3[S:15][CH:16]=[C:17]([CH2:18][OH:19])[C:13]=3[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(OC2C=CC(SCC#C)=CC=2)(=O)=[O:29])C=CC=CC=1.Cl[O-].[Na+].S(=O)(=O)(O)O.S([O-])([O-])=O.[Na+].[Na+].Cl([O-])=O.[Na+].OO>C(#N)C.O.CC1(C)N([O])C(C)(C)CCC1>[C:1]1([S:7]([O:10][C:11]2[CH:21]=[CH:20][C:14]3[S:15][CH:16]=[C:17]([C:18]([OH:29])=[O:19])[C:13]=3[CH:12]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Oc1ccc2scc(CO)c2c1)c1ccccc1
Reactant: C#CCSc1ccc(OS(=O)(=O)c2ccccc2)cc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Reaction time: 0.25 h
Yield: 51.7 %

Procedure:
The compound (4) (51.26 g, 155 mmol) prepared in above (3) was dissolved in acetonitrile (1.54L), and TEMPO (2, 2, 6, 6-tetramethylpiperidine-1-oxyl, 250 mg, 0.01 eq.) was added thereto. To the mixture was added dropwise 0.81 N aqueous sodium hypochlorite, which had been prepared by diluting 1.63 N aqueous sodium hypochlorite (150 ml) with water (75 ml), adjusting pH 8.6 with 1 N sulfuric acid, and adjusting the total volume to 300 ml, over 15 minutes, while maintaining the inner temperature between −1° C. and 8° C. After stirring for 25 minutes at this temperature, 1 N aqueous sodium sulfite (32 ml) was added. Subsequently, 79% sodium chlorite (27.48 g, 240 mmol) and 31% aqueous hydrogen peroxide (23.26 g, 212 mmol) were added under ice-cooling. The cooling bath was removed and the mixture was stirred for 2 hours. The reaction was diluted with water (1.5L), adjusted to pH 3 with 1 N hydrochloric acid and the deposited crystals were filtered, and washed twice with water (200 ml), acetonitrile (50 ml) to provide 32.4 g of crude crystals. The crude crystals (32.4 g) were suspended in acetonitrile (224 ml), refluxed for 15 minutes and cooled on ice. The crystals were filtered and washed with acetonitrile (65 ml) to provide 26.79 g of the title compound (6). Yield: 51.7%, mp 202-203° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=1)(=[NH:4])[CH2:2][CH3:3].Br.[S:23]1[CH:27]=[CH:26][N:25]=[C:24]1[C:28](=O)[CH2:29]CC>>[CH2:2]([C:1]1[N:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=2)[CH:29]=[C:28]([C:24]2[S:23][CH:27]=[CH:26][N:25]=2)[N:4]=1)[CH3:3]
Reactant: CCC(=N)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Reactant: CCCC(=O)c1nccs1
Agent: Br
Product: CCc1nc(-c2nccs2)cn1-c1ccc(CCNC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 4 of Example 26 from tert-butyl 2-[4-(propanimidoylamino)phenyl]ethylcarbamate and 1-(1,3-thiazol-2-yl)butan-1-one hydrobromide. (Helv. Chim. Acta., 1948, 31, 1142). MS (ESI) m/z 399 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][C:16]1[CH:27]=[CH:26][C:19]2[S:20][C:21]([C:23](O)=[O:24])=[CH:22][C:18]=2[CH:17]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:23]([C:21]2[S:20][C:19]3[CH:26]=[CH:27][C:16]([Cl:15])=[CH:17][C:18]=3[CH:22]=2)=[O:24])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: O=C(O)c1cc2cc(Cl)ccc2s1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2cc3cc(Cl)ccc3s2)C1

Procedure:
66.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 5-chloro-benzo[b]thiophene-2-carboxylic acid to give (R)-3-{[(5-chloro-benzo[b]thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. White solid. MS 392.9 ([M−H]−)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:44]([O:46][C:47](=[O:70])[NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][N:56]2[C:61](=[O:62])[CH:60]=[CH:59][C:58]([C:63]3[CH:68]=[CH:67][CH:66]=[C:65]([NH2:69])[CH:64]=3)=[N:57]2)[CH:50]=1)[CH3:45]>CN(C=O)C>[CH2:44]([O:46][C:47](=[O:70])[NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][N:56]2[C:61](=[O:62])[CH:60]=[CH:59][C:58]([C:63]3[CH:68]=[CH:67][CH:66]=[C:65]([NH:69][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:64]=3)=[N:57]2)[CH:50]=1)[CH3:45]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3cccc(N)c3)ccc2=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3cccc(NC(=O)CCCNC(=O)OC(C)(C)C)c3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
138 mg (0.68 mmol) of 4-(tert-butoxycarbonylamino)butyric acid are suspended in 2 ml of DMF, 138 μl (1.23 mmol) of 4-methylmorpholine, 86 mg (0.617 mmol) of 1-hydroxybenzotriazole and 239 mg (1.23 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride are added. The reaction mixture is stirred at room temperature for 10 min, 274 mg (0.62 mmol) of ethyl{3-[3-(3-aminophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}carbamate are subsequently added, and the mixture is stirred at room temperature for 24 h.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]1[CH:13]=CC=[CH:10][CH:9]=1>CC1C=CC=CC=1C>[C:4]1(=[O:5])[O:6][C:1](=[O:7])[C:2]2=[CH:13][CH:8]=[CH:9][CH:10]=[C:3]12
Reactant: c1ccccc1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1C
Product: O=C1OC(=O)c2ccccc21

Procedure:
These objectives are realized in the present invention by employing compressed air as a propellant for the jet pumps maintaining the vacuum as hereinbefore described and by introducing this air, charged with sucked organic-containing vapors, into the gas scrubbing zone. The entire quantity of organic-containing vapors and gases withdrawn from the maleic anhydride processing stages is sucked into the vacuum lines by the jet pumps, after which a large portion of such vapors, primarily water vapor, is condensed in a surface condenser(s). The propellant air, which is admixed with the remaining sucked gases and vapors recovered from the maleic anhydride processing stages, is introduced into the gas scrubbing solution, along with those reaction gases which are being treated and which contain residual maleic anhydride. Such reaction gases can be formed, for example, in the production of maleic anhydride from benzene or C-4 hydrocarbons, preferably after partial condensation of the maleic anhydride from the gas. Such reaction gases can also be formed in the production of phthalic anhydride from o-xylene after separation of the phthalic anhydride therefrom.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[NH:21][C:22](=[O:30])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[Cl:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([NH:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(Cl)ccc1C1=CCNCC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To the solution of 4-[4-chloro-2-(3-chloro-benzoylamino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.504 g, 1.13 mmol) in dichloromethane (10 mL) is added trifluoroacetic acid (1 mL) in a dropwise fashion. The resulting reaction is allowed to stir at room temperature for 2 h. 2N NaOH aqueous solution is added to adjust the pH>12. The mixture is then extracted with dichloromethane 3×. The organic layers are combined, washed with brine 1×, dried (Na2SO4) and concentrated under vacuum to give 0.391 g of 3-chloro-N-[5-chloro-2-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide in 99% yield.