Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:5]([NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([NH:19]C(=O)C)[CH:11]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].C(O)C>O>[CH2:1]([S:5]([NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([NH2:19])[CH:11]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])c(NC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])c(N)c1
Reaction time: 3 h
Yield: 94.4 %

Procedure:
A mixture containing 6.30 g of N-1-butanesulfonyl-3-acetylamino-4-nitrobenzamide, a 10% sodium hydroxide aqueous solution, 300 ml of ethanol and 200 ml of water was stirred at room temperature for 4 hours and then at 50° C. for 3 hours. The solvent was distilled off to approximately a half volume, and the residue was adjusted to a pH of 2 with 10% hydrochloric acid. The crystals precipitated were collected, and were dried under reduced pressure to give 5.22 g of N-1-butanesulfonyl-3-amino-4-nitrobenzamide.
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([NH:11][C@@H:12]([CH3:28])[CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21](Cl)[CH:20]=3)=[N:15]2)=[O:10])[CH:5]=1)(=[O:3])[CH3:2].CN(C=O)C.[CH3:34][S-:35].[Na+]>CC#N>[C:1]([C:4]1[CH:5]=[C:6]([C:9]([NH:11][C@@H:12]([CH3:28])[CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([S:35][CH3:34])[CH:20]=3)=[N:15]2)=[O:10])[NH:7][N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n[nH]1
Reactant: C[S-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CSc1cc(-c2ccn(C[C@H](C)NC(=O)c3cc(C(C)=O)n[nH]3)n2)ccc1C#N
Temperature: 150 °C
Yield: 13.8 %

Procedure:
(S)—5-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide (64 mg, 0.16 mmol) was placed into a microwave vial. DMF (1 ml) and sodium thiomethoxide (12.4 mg, 0.18 mmol) were added and the reaction mixture was heated in microwave reactor at 150° C. Sodium thiomethoxide was added after 30, 30 and 20 min of heating (12.4 mg, 5.6 mg and 5.6 mg, respectively). After total of 90 min of heating DMF was evaporated, and the evaporation residual was taken up in DCM and washed with water. Organic phase was dried over Na2SO4, filtered and evaporated. Thus obtained crude product was suspended in MeCN. Suspension was filtered to give 9 mg (14%) of the title compound as a colourless solid. Filtrate was purified by CombiFlash (column: C-18 silica, eluent: 0-100% MeCN in water) to yield 13 mg (20%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.11-1.20 (m, 3H), 2.49 (s, 3H, overlap with DMSO) 2.57-2.64 (m, 3H), 4.20-4.55 (m, 3H), 6.91 (s, 1H), 7.31 (s, 1H), 7.62-7.89 (m, 4H), 8.47 (dd, 1H), 14.2 (d, 1H).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:38])[C:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=1)=[C:13]2[C@H:27]([CH3:37])[CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([CH3:9])[CH3:8])C>>[C:33]([O:32][C:30]([NH:29][CH2:28][C@H:27]([C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([C:7]([CH3:9])([CH3:8])[C:6]([OH:38])=[O:5])[CH:11]=2)[NH:15][C:14]=1[C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=1)[CH3:37])=[O:31])([CH3:34])([CH3:35])[CH3:36]
Reactant: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c([C@H](C)CNC(=O)OC(C)(C)C)c2c1
Agent: [K+]
Agent: [OH-]
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)O)cc3c2[C@H](C)CNC(=O)OC(C)(C)C)c1
Temperature: 94 °C
Yield: 101.8 %

Procedure:
To a stirred solution of (S)-2-[3-(2-tert-butoxycarbonylamino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid ethyl ester (2.5 g in 80 mL methanol) was added 26 mL of 2.0N potassium hydroxide and the mixture heated to 94° C. on an oil bath. After 14 hours the mixture was cooled to 0° C., acidified to pH5 and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride, dried over sodium sulfate and concentrated in vacuo to give the crude title compound (2.4 g).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[CH2:24][CH2:25][C:26]1[N:30]([CH3:31])[C:29]2[C:32]3[C:37]([CH:38]=[CH:39][C:28]=2[N:27]=1)=[CH:36][CH:35]=[CH:34][CH:33]=3>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:24][CH2:25][C:26]3[N:30]([CH3:31])[C:29]4[C:32]5[C:37]([CH:38]=[CH:39][C:28]=4[N:27]=3)=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: Cn1c(CCCl)nc2ccc3ccccc3c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1c(CCN2CCN(c3ccc(Cl)cc3)CC2)nc2ccc3ccccc3c21
Yield: 90 %

Procedure:
6.5 g (0.024 mole) of 1-(4-chlorophenyl)-piperazine dihydrochloride and 8.43 cc (0.06 mole) of triethylamine are added to a solution of 2.93 g (0.012 mole) of 2-(2-chloroethyl-1-methyl-1H-naphth[1,2-d]imidazole in 100 cc of ethanol. The reaction mixture is then heated at reflux temperature and maintained under an argon atmosphere for 23 hours. By evaporating the solvent, grinding the residue with water and filtering, a raw product is obtained, which is recrystallized from methylisopropylketone, yielding 4.36 g (90% yield) of pure compound. M.p. 213°-15° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.C(O)(=O)C>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+].[Fe]>[I:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:3]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(I)cc(N2CCOCC2)c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Nc1cc(I)cc(N2CCOCC2)c1
Yield: 81 %

Procedure:
4-(3-Iodo-5-nitrophenyl)morpholine (200 mg, 0.60 mmol, prepared according to WO 2008104754 A1 20080904) and powdered iron (142 mg, 2.54 mmol) were suspended in ethanol (2 ml) and acetic acid (240 μl, 4.20 mmol) and heated 3 h to 95° C. The reaction mixture was diluted with water, neutralised to pH=6 with sodium carbonate and extracted with ethyl acetate (×3). The organic phase was washed successively with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 179 mg (81% yield, 82% purity) of the title compound were obtained and used in the next synthetic step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:4][C:5]([NH:8]C(=O)C(C)(C)C)=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl>[Br:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CN1CCC(Nc2cc(NC(=O)C(C)(C)C)ncc2Br)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN1CCC(Nc2cc(N)ncc2Br)CC1
Yield: 71.1 %

Procedure:
A solution of N-(5-bromo-4-(1-methylpiperidin-4-ylamino)pyridin-2-yl)pivalamide (0.526, 1.42 mmol) in 6M HCl (6 mL) was heated under microwave irradiation at 105° C. for 50 min. The solution was basified with Na2CO3 and extracted with ethyl acetate (3×20 mL). The crude mixture was purified by flash chromatography on silica, eluting with methanol and dichloromethane (1/9), to give the title compound as a colourless solid (0.288 g, 70%).
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7](/[CH:19]=[CH:20]/[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16](O)=[O:17])=[CH:10]2)([CH2:3][CH3:4])[CH3:2].S(Cl)(Cl)=O.[CH2:34]([NH:36]CC)[CH3:35]>ClCCl>[CH:1]([C:5]1[CH:6]=[C:7](/[CH:19]=[CH:20]/[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16]([NH:36][CH2:34][CH3:35])=[O:17])=[CH:10]2)([CH2:3][CH3:4])[CH3:2]
Reactant: CCNCC
Reactant: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc2cc(C(=O)O)c(=O)oc12
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCNC(=O)c1cc2cc(/C=C/C(=O)c3ccc(C)cc3)cc(C(C)CC)c2oc1=O
Reaction time: 0.75 h

Procedure:
To a suspension of (E)-8-sec-butyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxylic acid of the formula (V) (0.5 g, 1.28 mmol) in dichloromethane (20 mL). added thionyl chloride (1.0 mL), was refluxed for 1.5 h. The resulting solution was evaporated to dryness under reduced pressure, and the residue was dispersed in dichloromethane (10 mL). The solvent was eliminated under reduced pressure. Dispersion in dichloromethane and solvent elimination was repeated twice. The residue was dissolved in dichloromethane (15 mL) and added with stirring to a solution of the diethyl amine (0.09 g, 1.28 mmol). After 45 min at room temperature, the solvent was removed by evaporation under reduced pressure and extracted 3-fold with CHCl3 (25 mL). The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 20% ethyl acetate in hexane to 40% ethyl acetate in hexane, which upon concentration provides (E)-8-sec-butyl-N,N-diethyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxamide (General Formula VI). (0.37 g, 65% yield). White solid, m. p. 146-147° C.; 1H NMR (CDCl3 300 MHz): δ 7.95, (d, J=8.1 Hz, 2H) 7.82-7.76 (m, 2H), 7.70 (d, J=1.8 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.51 (d, J=15.7 Hz, 1H), 7.33 (d, J=8.0 Hz, 2H), 3.58 (q, J=7.0 Hz, 2H), 3.45-3.41 (m, 1H), 3.33 (q, J=7.1 Hz, 2H), 2.45 (brs, 3H), 1.79-1.72 (m, 2H) 1.34-1.25 (m, 6H), 1.20 (t, J=7.1 Hz, 3H) 0.89 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz): δ 189.7, 164.3, 157.8, 152.7, 144.0, 142.6, 141.4, 136.7, 135.5, 131.7, 129.8, 129.5, 128.8, 126.7, 126.0, 122.9, 118.7, 43.4, 39.6, 33.5, 29.8, 21.8, 20.6, 14.3, 12.9, 12.1; ESI-MS (m/z): 446 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:11])[CH3:10].[C:12]([C:20]1[C:21](=[O:31])[N:22]([CH3:30])[C:23](=[O:29])[N:24]([CH3:28])[C:25]=1[CH2:26]Br)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(O)C>[CH3:28][N:24]1[C:25]2=[CH:26][N:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][C:9](=[O:11])[CH3:10])[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:20]2[C:21](=[O:31])[N:22]([CH3:30])[C:23]1=[O:29]
Reactant: CC(=O)Nc1ccccc1N
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)Nc1ccccc1-n1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 170 °C
Yield: 50.5 %

Procedure:
A mixture of N-(2-aminophenyl)acetamide (315 mg, 2.1 mmol), bromo-compound 4 (680 mg, 2 mmol), triethylamine (200 mg, 280 μL, 2 mmol), and ethanol (2 mL) was microwave-heated at 170° C. for 1 h (2-5 mL vial, pressure 13 bar). The shiny white crystalline mass was filtered, washed, and recrystallized from ethanol to give 5 (392 mg, 51% yield): mp>250° C.; 1H NMR (DMSO-d6): δ 9.17 (s, 1H), 7.69 (d, 1H, pyrrole CH, J=8.06 Hz), 7.33-7.14 (m, 6H), 7.10-6.94 (m, 3H), 3.31 (s, 3H), 3.17 (s, 3H), 1.87 (s, 3H). MS (ES+) (m/z): [M+1]+ calculated for C22H21N4O3, 389.43. found 389.19.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:6][CH:5]=1)([O-])=O>[C].[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CCn2cccn2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCn2cccn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.4 %

Procedure:
A mixture of 1-[2-(4-nitrophenyl)ethyl]-1H-pyrazole (0.8 g), 10% palladium carbon (80 mg) and ethanol (200 ml) was stirred under a hydrogen atmosphere at room temperature for 6 hrs. Palladium carbon was removed from the reaction mixture by filtration, and the filtrate was concentrated. Recrystallization of the residue from ethyl acetate-hexane gave 1-[2-(4-aminophenyl)ethyl]-1H-pyrazole (520 mg, 75%) as colorless prism crystals. melting point: 73-74° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=O)[CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C(O)(=O)C.O.[NH2:22][NH2:23].C([O-])(O)=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:23][N:22]=1)=[O:16])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccccc2)[nH]n1
Yield: 87.7 %

Procedure:
A solution of 2,4-dioxo-4-phenyl-butyric acid ethyl ester (1.68 g, 0.0076 mole), acetic acid (10 mL) and hydrazine hydrate (0.42 g, 0.0083 mole) was heated to reflux for 5 hours. The reaction mixture was then poured into iced water, basified with saturated aqueous NaHCO3 solution and the product was extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium and concentrated under reduced pressure. The resulting residue was purified by column chromatography using basic aluminium oxide (50% ethyl acetate in hexane) to afford 1.442 g (88%) of 5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 217.09 (M+1)+, 97.92%. To a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.4 g, 0.00667 mol) in a mixture of THF (30 mL), methanol (15 mL) and H2O (10 mL) was added LiOH.H2O (0.839 g, 0.0199 mol) at ambient temperature. The resulting mixture was stirred at 45° C. overnight. Volatiles were evaporated and the residue was diluted with water, acidified with concentrated HCl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 1.26 g (86%) of 5-phenyl-1H-pyrazole-3-carboxylic acid. LCMS: 189.06 (M+1)+, 97.7%.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:28]1([C:34]2[O:38][N:37]=[C:36]([C:39]([OH:41])=O)[CH:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:19])[C:39]([C:36]3[CH:35]=[C:34]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:38][N:37]=3)=[O:41])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3cc(-c4ccccc4)on3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 78 and 5-phenylisoxazole-3-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:13](C(OCC)=O)[C:12]2=[O:29])=[CH:2]1>CN(C)C=O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:29])[CH:13]=[C:14]([NH:16][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(NC2CCCCCC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: CN(C)C=O
Product: O=C1C=C(NC2CCCCCC2)OC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 12.4 %

Procedure:
A solution of the compound (0.040 g, 0.10 mmol) of Example 59 in N,N-dimethylformamide (2.0 mL) was refluxed for 8 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0040 g, y. 12%).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][NH:5]1)[C:2]#[CH:3].[Cl-:19].[Mn+2:20].[Cl-:21]>CO.C(O)C>[Cl:19][C:4]1([CH2:1][C:2]#[CH:3])[CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][N:5]1[Cl:21].[Mn+2:20]
Reactant: C#CCC1CNCCNCCNCCNCCN1
Reactant: [Cl-]
Agent: [Mn+2]
Solvent: CCO
Solvent: CO
Product: C#CCC1(Cl)CNCCNCCNCCNCCN1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 2-propargyl-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 29G (310 mg, 1.22 mmol) and anhydrous manganese(II) chloride (154 mg, 1.22 mol) in methanol (50 ml) were refluxed under a dry nitrogen atmosphere for 2 h and then stirred overnight at room temperature. The solution was taken to dryness, redissolved in absolute ethanol (15 ml) and filtered through celite. Concentration and recrystallization from ethanol-ether afforded 370 mg (80% yield) of white microcrystalline product: FAB mass spectrum (NBA) m/z (relative intensity) 378 (M+, 2), 343/345 ((M-Cl)+, 100/30); Anal. calcd. for C13H27Cl2 nN5 : C, 41.14; H, 7.18; N, 18.47. Found: C, 40.49; H, 6.56; N, 18.14.
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([O:8][CH2:9][CH:10]([OH:36])[CH2:11][N:12]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19][N:18]([CH2:28][C:29]([OH:31])=[O:30])[CH2:17][CH2:16][N:15]([CH2:32][C:33]([OH:35])=[O:34])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH:10]([OH:36])[CH2:11][N:12]2[CH2:13][CH2:14][N:15]([CH2:32][C:33]([OH:35])=[O:34])[CH2:16][CH2:17][N:18]([CH2:28][C:29]([OH:31])=[O:30])[CH2:19][CH2:20][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23]2)=[CH:37][CH:38]=1
Reactant: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)COc2ccc([N+](=O)[O-])cc2)CCN(CC(=O)O)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCC(O)CN2CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC2)cc1
Reaction time: 8 h

Procedure:
15 g (27.7 mmol) of 10-[3-(4-nitrophenoxy)-2-hydroxypropyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (EP 0485045 (Schering AG), Example 12a), is dissolved in 250 ml of methanol and 5 g of palladium catalyst (10% Pd on activated carbon) is added. It is hydrogenated overnight at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in a vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3=[N:12][N:13]=[C:14]([S:15][CH3:16])[N:9]3[CH:8]=[CH:7][C:6]=2[CH:17]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3=[N:12][N:13]=[C:14]([S:15]([CH3:16])=[O:26])[N:9]3[CH:8]=[CH:7][C:6]=2[CH:17]=1
Reactant: CSc1nnc2n1C=Cc1cc(Cl)ccc1C2
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CS(=O)c1nnc2n1C=Cc1cc(Cl)ccc1C2

Procedure:
By a procedure similar to that described in Example 17, 8-chloro-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine was reacted with m-chloroperbenzoic acid to obtain 8-chloro-3-methylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepine. Colorless needles (as recrystallized from methanol), m.p. 183°-185° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][CH2:10][NH:11][C@@H:12]2[C@H:16]([CH2:17][CH3:18])[CH2:15][C@H:14]([NH:19][S:20]([CH:23]3[CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH2:13]2)=[CH:6][N:5]=[C:4]2[N:26]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:27]=[CH:28][C:3]=12.CCN(C(C)C)C(C)C.[I-].[K+]>C(O)CC>[CH2:17]([C@H:16]1[C@@H:12]([N:11]2[C:2]3[C:7](=[CH:6][N:5]=[C:4]4[N:26]([S:29]([C:32]5[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=5)(=[O:31])=[O:30])[CH:27]=[CH:28][C:3]4=3)[CH2:8][CH2:9][CH2:10]2)[CH2:13][C@@H:14]([NH:19][S:20]([CH:23]2[CH2:25][CH2:24]2)(=[O:22])=[O:21])[CH2:15]1)[CH3:18]
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1NCCCc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1Cl
Agent: [I-]
Agent: [K+]
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1N1CCCc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c21
Temperature: 150 °C
Yield: 26.7 %

Procedure:
A microwave vial was charged with a solution of N-((1S,3S,4R)-3-(3-(4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.200 g, 0.345 mmol) in 1-propanol (1.70 mL). DIEA (0.180 mL, 1.04 mmol) and potassium iodide (0.057 g, 0.345 mmol) were added and the reaction mixture was heated in a Biotage® microwave at about 150° C. for about 30 min. The reaction was resubmitted to microwave heating at about 180° C. for about 1 h. The reaction was resubmitted to microwave heating at about 180° C. for about 10 h. The reaction mixture was transferred to a round bottom flask and silica gel (about 1 g) was added. The solvent was removed under reduced pressure and the resulting silica gel mixture was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to give N-((1S,3R,4S)-3-ethyl-4-(7-tosyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.050 g, 27%) as a yellow foam: LC/MS (Table 1, Method b) Rt=2.52 min; MS m/z: 543 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][CH2:7]1.[OH-].[Na+]>CCOCC.O>[CH2:1]([NH:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCNC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butylamine (9.05 g, 0.1225 mole) was dissolved in Et2O (30 ml). Succinic anhydride (5 g, finely powdered) was added portionwise. After addition was complete, the heterogeneous mixture was stirred 1 hour at room temperature. The reaction mixture was then poured into 10% NaOH in H2O (10 ml) and Et2O (30 ml). The layers were separated and the ether layer was extracted with additional 10% NaOH (10 ml). The combined aqueous layers were washed with ether (30 ml) and acidified with concentrated HCl to give a layer of oil above the water layer. This was extracted with Et2O (50 ml×2). The ether extracts were washed with saturated NaCl solution (3×30 ml) and dried (MgSO4). The solvent was removed in vacuo to give a white solid (7.5 g) which was recrystallized from benzene to give title acid as needle shaped crystals (4.83 g, 56%), m.p. 93.5°-94.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[O:6][C@H:7]([CH2:10]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:8][O:9][C:4]=2[CH:3]=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].O>CN(C=O)C>[Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[O:6][C@@H:7]([CH2:10][N:29]3[C:25](=[O:35])[C:26]4[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:28]3=[O:30])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3cc(Cl)c(Cl)cc3O2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C[C@H]1COc2cc(Cl)c(Cl)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
Toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester (8.0 g, 20.5 mmol) was combined with potassium phthalimide (6.1 g, 33 mmol) in DMF (75 mL) and heated to reflux for 1 h, cooled to room temperature and poured into vigorously stirring water (0.5 L) and then stirred 30 min. White solid was filtered and the solid was washed several times with water, 2% NaOH, and water again and then let air dry to yield (2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-isoindole-1,3-dione (6.0 g, 80%) as a white powdery solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:20]([O:24][CH2:25][CH3:26])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.O.C[C@@H](N)C1C=CC=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([C@@H:20]([O:24][CH2:25][CH3:26])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(C(=O)O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: C[C@@H](N)c1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: CCO[C@@H](C(=O)O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reaction time: 16.5 h

Procedure:
To a stirred suspension of racemic ethoxy-acid 53 (100 g, 0.27 mol) in acetone:water mixture (9:1, 900 ml) was added a solution of R-(+)-alpha methylbenzylamine (35 ml, 0.27 mol) acetone:water (9:1, 100 ml) in a dropwise manner. The resulting mixture was stirred for 16-17 hours, filtered to separate the solid and neutralise with acetic acid. The process was repeated several times to get (−)-ethoxy acid 54 (18 g, 98-99% e.e by HPLC).