Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]([C:11]1[N:12]=[CH:13][S:14][CH:15]=1)#N>O>[CH:4]1[CH:5]=[CH:6][C:1]2[N:8]=[C:9]([C:11]3[N:12]=[CH:13][S:14][CH:15]=3)[NH:7][C:2]=2[CH:3]=1
Reactant: N#Cc1cscn1
Reactant: Nc1ccccc1N
Solvent: O
Product: c1ccc2[nH]c(-c3cscn3)nc2c1
Temperature: 50 °C
Yield: 89.3 %

Procedure:
The product, thiabendazole, precipitated as it was formed in the reaction mixture. The reaction was monitored by gas chromatography and determined to be complete when the peaks corresponding to o-phenylenediamine and 4-cyanothiazole were negligible. The reaction mass was allowed to cool to 50° C. and 150 ml of 50° C. deionized water was added to thin the mixture before being vacuum filtered using a medium fritted glass filter. The solid product was washed four times with 300 ml portions of deionized water. The washed precipitate was dried overnight in a vacuum oven under 15-20" Hg and at a temperature of 80°-90° C. A total of 89.77 grams of thiabendazole were obtained which corresponds to an 89.3% yield. The color of dry thiabendazole was cream. High Performance Liquid Chromatography (HPLC) using a Hewlett-Packard Model 1090M showed that the purity was 98.77% (based on % area).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([CH3:15])=[C:4]([CH3:16])[N:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][NH2:24].Cl>C(#N)C.O1CCOCC1>[ClH:1].[CH:9]1([NH:8][C:6]2[C:5]([CH3:15])=[C:4]([CH3:16])[N:3]=[C:2]([NH:24][CH2:23][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)[N:7]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1nc(Cl)nc(NC2CCCCC2)c1C
Reactant: NCc1ccccn1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Temperature: 25 °C
Yield: 50.3 %

Procedure:
To a stirred solution of 2-chloro-N-cyclohexyl-5,6-dimethylpyrimidin-4-amine (0.1 g, 0.40 mmol) and (pyridin-2-ylmethyl)amine (0.04 g, 0.400 mmol) in acetonitrile (5 mL) was added a 3.5 M solution of hydrogen chloride in dioxane (0.2 mL). The resulting mixture was irradiated in CEM Focused Microwave™ Synthesis System at 160° C. for 120 minutes. The resulting mixture was cooled to ambient temperature. The formed precipitate was collected by filtration and dried to yield 0.07 g (48.2%) of the titled compound as the hydrochloride salt. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.99-1.03 (m, 2H), 1.13 (d, J=12.63 Hz, 1H), 1.20-1.26 (m, 2H), 1.51-1.59 (m, 2H), 1.60-1.63 (m, 3H), 1.89 (s, 3H), 2.24 (s, 3H), 3.70 (s, 1H), 4.62 (d, J=5.10 Hz, 2H), 7.24 (dd, J=7.25, 4.84 Hz, 1H), 7.31 (d, J=7.79 Hz, 1H), 7.58 (d, J=7.72 Hz, 1H, 7.74 (t, J=7.66 Hz, 1H), 8.1 (s, 1H), 8.50 (d, J=4.84 Hz, 1H); MS (ESI) m/z 312.3 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[CH:15]=[C:14]([C:16]3[C:21]([OH:22])=[CH:20][C:19]([OH:23])=[CH:18][C:17]=3[O:24][C:25]3[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=3)[O:13][N:12]=2)=[O:10])[CH2:4][CH2:3]1.[O:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1.C=O>>[OH:22][C:21]1[CH:20]=[C:19]([OH:23])[CH:18]=[C:17]([O:24][C:25]2[CH:26]=[CH:27][C:28]([NH:31][CH:35]3[CH2:36][CH2:37][O:32][CH2:33][CH2:34]3)=[CH:29][CH:30]=2)[C:16]=1[C:14]1[O:13][N:12]=[C:11]([C:9]([NH:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:10])[CH:15]=1
Reactant: CN1CCC(NC(=O)c2cc(-c3c(O)cc(O)cc3Oc3ccc(N)cc3)on2)CC1
Reactant: O=C1CCOCC1
Agent: C=O
Product: CN1CCC(NC(=O)c2cc(-c3c(O)cc(O)cc3Oc3ccc(NC4CCOCC4)cc3)on2)CC1
Yield: 53 %

Procedure:
Operating as in Example 24 Step 4, but employing N-(1-methylpiperidin-4-yl)-5-{2-[4-(amino)phenoxy]-4,6-dihydroxyphenyl}isoxazole-3-carboxamide instead of tert-butyl 4-{[(5-{2,4-bis[(2-methoxyethoxy)methoxy]-6-(4-aminophenoxy)phenyl}isoxazol-3-yl)carbonyl]amino}piperidine-1-carboxylate and tetrahydro-pyran-4-one instead formaldehyde, the title compound was obtained in 53% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22](OC)=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH:2]=1.[NH3:26]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:26])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:11][CH:12]=2)[CH:2]=1
Reactant: COC(=O)c1cccc2nc(-c3ccc(-c4cccnc4)cc3)oc12
Reactant: N
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(-c4cccnc4)cc3)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
Methyl 2-(4-(pyridin-3-yl)phenyl)benzo[d]oxazole-7-carboxylate (600 mg, 1.81 mmol) was added to ammonia in methanol (30 ml) and the mixture was stirred at room temperature for 3 days. Then the solid was filtered, washed with methanol, dried in vacuum. 550 mg 2-(4-(pyridin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 96%. LC-MS (ESI) m/z: 316 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[O:15])=[CH:11][C:10]([C:30]([CH3:33])([CH3:32])[CH3:31])=[N:9]2)=[CH:4][CH:3]=1.[CH3:34][C:35]1([CH3:42])[CH2:40][C:39](=[O:41])[O:38][C:36]1=[O:37]>C1COCC1.CCOCC>[C:30]([C:10]1[CH:11]=[C:12]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)=[CH:19][CH:18]=2)=[O:15])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:39](=[O:41])[CH2:40][C:35]([CH3:42])([CH3:34])[C:36]([OH:38])=[O:37])=[CH:3][CH:4]=2)[N:9]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(N)cc2)n1
Reactant: CC1(C)CC(=O)OC1=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(CC(=O)Nc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1)C(=O)O
Temperature: 60 °C
Yield: 84.6 %

Procedure:
A solution of 1-[2-(4-amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea (208 mg, 0.47 mmol) and 2,2-dimethylsuccinic anhydride (66 mg, 0.52 mmol, 1.1 eq) in 2 mL THF was stirred at room temperature overnight. HPLC analysis indicated that starting material was remaining. The reaction was then heated at 60° C. for 2 days, at which time HPLC analysis indicated the reaction was complete. The reaction mixture was cooled to room temperature, and the resulting suspension was diluted with Et2O. The solid was isolated by filtration to afford the desired product (227 mg, 85%). 1H-NMR (DMSO-d6) δ 12.06 (s, 1H), 10.06 (s, 1H), 9.09 (s, 1H), 8.40 (d, J=6.0 Hz, 2H), 8.31 (s, 1H), 7.69 (d, J=9.0 Hz, 2H), 7.47 (d, J=9.0 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H), 6.85 (dd, J=1.5 & 4.7 Hz, 2H), 6.33 (s, 1H), 2.59 (s, 2H), 1.26 (s, 9H), 1.21 (s, 6H); MS LC-MS [M+H]+=571.3, RT=2.49 min.
Reaction SMILES: [CH:1]([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:3])[CH3:2].O[CH2:12][C:13]#[N:14]>>[CH:5]1([N:4]([CH2:12][C:13]#[N:14])[CH:1]([CH3:3])[CH3:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: N#CCO
Reactant: CC(C)NC1CCCCC1
Product: CC(C)N(CC#N)C1CCCCC1

Procedure:
Prepared from N-isopropylcyclohexylamine and hydroxyacetonitrile by a similar method to Preparation 24.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:21](Cl)([Cl:23])=[O:22].N1C=CC=CC=1>C1COCC1>[Cl:23][C:21]([O:13][C:8]([C:9]([CH3:11])([CH3:12])[CH3:10])=[C:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][CH:19]=1)[N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)=[O:22]
Reactant: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)C(OC(=O)Cl)=C(Oc1ccc(Cl)cc1)n1cncn1
Reaction time: 72 h
Yield: 36 %

Procedure:
To a solution of 29.4 g (0.01 mole) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)-2-butanone in 250 ml of THF was added 20 ml of liquid phosgene, followed by 9 ml of pyridine. After 3 days, the mixture was filtered and the filtrate evaporated in vacuum to a residual oil. The oil was dissolved in hot 1-chlorobutane and the solution filtered to remove a little white solid. The filtrate was cooled, precipitating a white solid. The solid was isolated by filtration, providing 12.9 g (36% of theoretical) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)-1-buten-2-yl chloroformate, m.p. 159°-161°. The infrared spectrum showed absorption at ca 1800 cm-1.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[NH:16][C:17]3[C:22]([C:23]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[CH:21][C:20]([F:28])=[C:19]([CH2:29][CH3:30])[CH:18]=3)=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O.[Cu]I>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[N:16]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[C:17]3[C:22]([C:23]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[CH:21][C:20]([F:28])=[C:19]([CH2:29][CH3:30])[CH:18]=3)=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc2[nH]c(-c3ccc(S(=O)(=O)NC(C)(C)C)cn3)c(S(C)(=O)=O)c2cc1F
Reactant: Brc1ncccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc2c(cc1F)c(S(C)(=O)=O)c(-c1ccc(S(=O)(=O)NC(C)(C)C)cn1)n2-c1ncccn1
Temperature: 110 °C
Yield: 91 %

Procedure:
A mixture of N-tert-butyl-6-(6-ethyl-5-fluoro-3-(methylsulfonyl)-1H-indol-2-yl)pyridine-3-sulfonamide (115 mg, 0.25 mmol), 2-bromopyrimidine (88 mg, 0.55 mmol), CuI (28 mg, 0.15 mmol), K2CO3 (160 mg, 1.15 mmol), and DMF (0.5 mL) was heated at 110° C. for 15 hours. The reaction mixture was diluted in water and extracted into ethyl acetate. The organic layer was washed with water and then with brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (40% ethyl acetate in hexanes) yielded N-tert-butyl-6-(6-ethyl-5-fluoro-3-(methylsulfonyl)-1-(pyrimidin-2-yl)-1H-indol-2-yl)pyridine-3-sulfonamide (121 mg, 91%) as a white solid. Melting point: 244-248° C.; MS m/z 532.2 M+H+; 1H NMR (DMSO-d6, 500 MHz): δ 8.82 (d, 1H, J=2 Hz), 8.73 (d, 2H, 5.0 Hz), 8.23 (dd, 1H, J=8.0 Hz, 2 Hz), 8.05 (d, 1H, J=6.5 Hz), 7.96 (d, 1H, J=8 Hz), 7.87 (s, 1H), 7.76 (d, 1H, 10.5 Hz), 7.51 (t, 1H, J=5 Hz), 3.38 (s, 3H), 2.78 (q, 2H, J=7.5 Hz), 1.23 (t, 3H, 3.75 Hz), 1.13 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:25][CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:24]=1)[CH3:2].[OH-].[NH4+:33].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(OCC)C>ClCCl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:25][CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:12][C:11]=3[N:10]=[C:9]([NH2:33])[C:8]=2[N:24]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOCc1nc2c[n+]([O-])c3cc(N4CCOCC4)ccc3c2n1CCCOC(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(N4CCOCC4)ccc3c2n1CCCOC(C)C
Reaction time: 24 h

Procedure:
2-Ethoxymethyl-1-(3-isopropoxypropyl)-7-(morpholin-4-yl)-1H-imidazo[4,5-c]quinoline 5-oxide from Part B was dissolved in dichloromethane (4 mL). Ammonium hydroxide (2 mL) was added, followed by p-toluenesulfonyl chloride (0.074 g). The reaction was stirred for 24 hours. The layers were separated and the aqueous fraction was extracted with dichloromethane. The combined organic fractions were concentrated under reduced pressure to yield a yellow-brown oil. The oil was covered with diethyl ether and a precipitate formed. The solid was recovered by filtration and then dried to provide 0.085 g of 2-ethoxymethyl-1-(3-isopropoxypropyl)-7-(morpholin-4-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 161-162.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[Cl:11].C(N(CC)CC)C.[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])#[CH:21]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:21]#[C:20][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:6][C:5]=1[Cl:11]
Reactant: COC(=O)c1ccc(Br)cc1Cl
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1Cl
Temperature: 70 °C

Procedure:
To a degassed solution of 4-bromo-2-chloro-benzoic acid methyl ester (3.0 g, 12.0 mmol, 1.0 equiv; [CAS RN 185312-82-7]) in triethylamine (24.3 g, 33.5 mL, 240.5 mmol, 20.0 equiv; [CAS RN 121-44-8]) under Ar was added ethynyl-trimethyl-silane (1.24 g, 1.78 mL, 12.63 mmol, 1.05 equiv; [CAS RN 1066-54-2]), tetrakis(triphenylphosphine)palladium(0) (0.70 g, 0.60 mmol, 0.05 equiv; [CAS RN 14221-01-3]) and copper(I) iodide (0.23 g, 1.20 mmol, 0.1 equiv; [CAS RN 7681-65-4]) and the reaction mixture heated to 70° C. for 18 h. The crude reaction was filtered over Celite®, a sat. solution of NaCl (50 mL) added and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over Na2SO4 and the product used in the consecutive step without any further purification. Yield: 4.52 g (99%) of the title compound in ca. 70% purity as a slightly brown oil. MS (ISN): 267.0 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:7]([OH:15])[CH2:8][C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH2:11])=[O:4].[C:26]([O:30][C:31]([NH:33][C@H:34]([C:42](O)=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[OH:15][C@@H:7]([CH2:8][C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH2:11])[C@@H:6]([NH:5][C:3]([C@@H:2]([NH:1][C:42]([C@@H:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:43])[CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)=[O:4])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)C
Yield: 26.8 %

Procedure:
A mixture of 880 mg (2.5 mmol) of (S)-α-amino-N-[(1S,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]-imidazole-4-propionamide. 1.99 g (7.5 mmol) of t-butoxycarbonyl-L-phenylalanine. 1.05 ml (7.5 mmol) of triethylamine and 3.32 g (7.5 mmol) of BOP in 100 ml of acetonitrile was stirred at room temperature for 6 days. Thereafter, the solvent was evaporated and the residue was dissolved in ethyl acetate and washed in succession with 2N sodium bicarbonate solution, saturated ammonium chloride solution, again with 2N sodium bicarbonate solution and again with saturated ammonium chloride solution. The organic solution was dried over sodium sulfate and evaporated and the residue was triturated twice with hexane. The residue was chromatographed on 100 g of silica gel with a 98:2 mixture of chloroform and methanol. Recrystallization of the thus-obtained crude product from methylene chloride and hexane yielded 400 mg of t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-2-hydroxy-1-isobutyl-4 -isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate as a white powder, melting point 82°.
Reaction SMILES: S(Br)([Br:3])=O.N1C=CC=CC=1.[C:11]1([C:17]2[C:18]([O:20][C:21](=[O:23])[CH:22]=2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Br:3][C:22]1[C:21](=[O:23])[O:20][C:18](=[O:19])[C:17]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(Br)Br
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C(c2ccccc2)=C1Br
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
At 10° C., first 40.2 g (193 mmol) of thionyl bromide and then 15.3 g (193 mmol) of pyridine were added dropwise with stirring to 16.8 g (97 mmol) of phenylmaleic anhydride in 200 ml of toluene. The mixture was stirred at 10° C. for 30 min, heated at 75° C. for 30 min using a preheated heating bath and allowed to cool, and excess thionyl bromide was removed at 65° C. under reduced pressure. The mixture was then stirred with 150 ml of toluene and filtered, and the residue was washed twice with in each case 200 ml of toluene, and the filtrate was concentrated under reduced pressure. The crude product (9.3 g) still contained 25% of unreacted starting material and was used without further purification.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:24]=[C:25]([Cl:27])[N:26]=2)[C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:13])[CH2:5][CH2:4]1.[Cl:28][C:29]1[C:33]([Cl:34])=[C:32]([CH3:35])[NH:31][C:30]=1[C:36](NC1CCN(C2C=CC=C(Cl)N=2)CC1)=[O:37]>>[Cl:27][C:25]1[CH:24]=[C:11]([CH:10]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:36]([C:30]3[NH:31][C:32]([CH3:35])=[C:33]([Cl:34])[C:29]=3[Cl:28])=[O:37])[CH2:8][CH2:7]2)[N:26]=1)[C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:13]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cccc(Cl)n3)CC2)c(Cl)c1Cl
Reactant: NC1CCN(c2cc(C(=O)NCCCN3CCOCC3)cc(Cl)n2)CC1
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)NCCCN4CCOCC4)cc(Cl)n3)CC2)c(Cl)c1Cl

Procedure:
The title compound was synthesised by an analogous method to Example 99 starting from 2-(4-aminopiperidin-1-yl)-6-chloro-N-(3-morpholin-4-ylpropyl)isonicotinamide hydrochloride salt (Intermediate 219) and 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3).
Reaction SMILES: ClC(Cl)(Cl)[S:3][C:4]1[CH:22]=[CH:21][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]C(Cl)(Cl)Cl)=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1.ClC(Cl)C>C(O)C>[SH:3][C:4]1[CH:22]=[CH:21][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc(SC(Cl)(Cl)Cl)cc1)c1ccc(SC(Cl)(Cl)Cl)cc1
Solvent: CCO
Solvent: CC(Cl)Cl
Product: O=C(c1ccc(S)cc1)c1ccc(S)cc1
Reaction time: 6 h

Procedure:
10 g said 4,4′-di(trichloro methyl sulfenyl)benzophenone obtained in step 2, 30 g dichloroethane and 10 g ethanol are added into a 100 ml reaction flask. The solution is heated to react under reflux with nitrogen protection, and is cooled after reacting for 6 hours to precipitate solids. Filtering, and washing with ethanol to obtain 4.4 g white flake crystals, the yield is 85%, and the melting point is 179-182.3° C. 1H-NMR data (solvent CDCl3): δ3.6369 ppm, s, 2H, δ7.3168, 7.3435 ppm, d, 4H, δ7.6384, 7.6650 ppm, d, 4H.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[S:19][C:20]([CH2:22][O:23][CH3:24])=[CH:21][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>>[ClH:25].[CH3:24][O:23][CH2:22][C:20]1[S:19][C:18]2[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][O:16][C:17]=2[CH:21]=1
Reactant: COCc1cc2onc(C3CCN(C(=O)OC(C)(C)C)CC3)c2s1
Agent: Cl
Product: COCc1cc2onc(C3CCNCC3)c2s1
Reaction time: 8 h

Procedure:
Stir a solution of 4-(5-methoxymethyl-thieno[2,3-d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (2.21 g, 6.68 mmol, 1.00 equivalents) and hydrochloric acid (1.0 M in diethyl ether, 35 mL) overnight to form a suspension. Add additional hydrochloric acid (1.0 M in diethyl ether, 10 mL). Stir the suspension overnight, filter and wash the solid with ether. Collect the solid and dry to yield the desired product as a dark blue solid. LC/MS (ESI), m/e 253 (MH+), retention time 1.17 minutes. Condition II.
Reaction SMILES: [C:1]([C:3]1([C:14]2[C:19]3[N:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[O:22][C:18]=3[C:17]([O:26][CH3:27])=[CH:16][CH:15]=2)[CH2:8][CH:7](C(OC)=O)[C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2].[Na+].[Cl-].O>CS(C)=O>[C:1]([C:3]1([C:14]2[C:19]3[N:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[O:22][C:18]=3[C:17]([O:26][CH3:27])=[CH:16][CH:15]=2)[CH2:8][CH2:7][C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c3oc(C(C)C)nc23)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C2(C#N)CCC(=O)CC2)c2nc(C(C)C)oc12
Temperature: 140 °C
Reaction time: 8.5 h
Yield: 77.5 %

Procedure:
0.69 g (1.86 mmol) of methyl 5-cyano-5-(2-isopropyl-7-methoxybenzoxazol-4-yl)-2-oxocyclohexanecarboxylate (starting compound A8) is dissolved in 16 ml of DMSO, a solution of 0.73 g of NaCl in 2 ml of dist. water is added and the mixture is stirred at 140° C. for 8.5 h. After cooling the reaction mixture, it is diluted with 80 ml of dist. water and extracted with ethyl acetate, and the organic phase is separated off, dried over magnesium sulfate and concentrated to dryness in vacuo. After chromatography, the title compound (0.45 g) is obtained as a colorless solid. TLC, silica gel (glass plates), petroleum ether/ethyl acetate (7:3), Rf=0.56, m.p. 118° C.
Reaction SMILES: [NH2:1][N:2]1[C:13](=[O:14])[C:12]2[C:15]3[N:4]([CH:5]([CH3:18])[CH2:6][O:7][C:8]=3[C:9](F)=[C:10]([F:16])[CH:11]=2)[C:3]1=[O:19].[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>C(#N)C>[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:31][CH2:30][N:29]([C:9]2[C:8]3=[C:15]4[C:12]([C:13](=[O:14])[N:2]([NH2:1])[C:3](=[O:19])[N:4]4[CH:5]([CH3:18])[CH2:6][O:7]3)=[CH:11][C:10]=2[F:16])[CH2:28]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC1COc2c(F)c(F)cc3c(=O)n(N)c(=O)n1c23
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1COc2c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)c(F)cc3c(=O)n(N)c(=O)n1c23
Yield: 104.1 %

Procedure:
A solution of 0.2 g (0.75 mmol) of 5-amino-8,9-difluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dione (Example 24h), 0.58 g (2.0 mmol) of (S)-3-pyrrolidinylcarbamic acid tert-butyl ester (J. Med. Chem., 1992; 35:1764), 0.5 g (0.5 mmol) of triethylamine and 20 mL of acetonitrile is heated at reflux for 18 hours. The solvent is removed in vacuo and the residue is partitioned between dichloromethane-water. The organic layer is washed with water, dried (MgSO4) and concentrated in vacuo. The residue is chromatographed over flash grade silica gel (230-400 mesh) eluting with dichloromethane/ethanol (95:5) to give 0.34 g of the title compound, mp 114-116° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:4]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:32]([O:34]C)=[O:33].[OH-].[Na+].CO.Cl>O1CCCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:4]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:32]([OH:34])=[O:33]
Reactant: COC(=O)c1c(Br)c2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cccc2c1c(Br)c(C(=O)O)n2CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 126C (22 mg), NaOH (0.167 ml), methanol (1.5 ml) and tetrahydrofuran (1.500 ml) was stirred at room temperature for 36 hours, acidified with HCl and concentrated. The residue was purified by RPHPLC (mobile phase: 10%-100% acetonitrile in 0.1% TFA aqueous solution during 60 minutes) on a C18 column to provide the title compound. 1H NMR (500 MHz, dichloromethane-d2) δ 8.30-8.40 (m, 1H), 7.79-7.85 (m, 1H), 7.56 (d, J=8.54 Hz, 1H), 7.47-7.55 (m, 2H), 7.43 (d, J=8.24 Hz, 1H), 7.35 (t, J=7.93 Hz, 1H), 7.28-7.33 (m, 2H), 7.20-7.27 (m, 2H), 7.13-7.18 (m, 1H), 6.93 (d, J=7.02 Hz, 1H), 6.75 (d, J=7.63 Hz, 1H), 4.78-5.03 (m, 2H), 4.16 (t, J=5.65 Hz, 2H), 2.37-2.54 (m, 2H), 2.01 (s, 3H).