Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][S:6]([CH3:9])(=[O:8])=[O:7])(=O)=O.O[C:11]1[CH:20]=[C:19]2[C:14]([N:15]=[CH:16][C:17]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([NH:30][C:31]([C:33]4[CH:34]=[CH:35][C:36]5[S:41][CH2:40][C:39](=[O:42])[NH:38][C:37]=5[CH:43]=4)=[O:32])[CH2:26][CH2:25]3)=[N:18]2)=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C=O>[O:42]=[C:39]1[NH:38][C:37]2[CH:43]=[C:33]([C:31]([NH:30][CH:27]3[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][O:21][C:17]4[CH:16]=[N:15][C:14]5[C:19]([N:18]=4)=[CH:20][C:11]([O:5][S:6]([CH3:9])(=[O:7])=[O:8])=[CH:12][CH:13]=5)[CH2:29][CH2:28]3)=[O:32])[CH:34]=[CH:35][C:36]=2[S:41][CH2:40]1
Reactant: O=C1CSc2ccc(C(=O)NC3CCN(CCOc4cnc5ccc(O)cc5n4)CC3)cc2N1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)Oc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
Methanesulfonic anhydride (519 mg, 2.92 mmol, 20.0 eq) is added at 0° C. to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (70 mg, 0.15 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed by triethylamine (610.4 μL, 4.38 mmol, 30.0 eq). After 30 minutes stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×5 mL) and water (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford methanesulfonic acid 3-(2-{4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidin-1-yl}-ethoxy)-quinoxalin-6-yl ester as an off-white powder (25 mg, 26% yield).
Reaction SMILES: NC1C=CC([C:8]2[NH:9][C:10]3[CH:16]=[CH:15][C:14](N)=[CH:13][C:11]=3[N:12]=2)=CC=1.[C:18]1([C@@H:24]2[CH2:26][C@H:25]2[C:27](Cl)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C@@H:24]2[CH2:26][C@H:25]2[C:27]([C:8]2[NH:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: Nc1ccc(-c2nc3cc(N)ccc3[nH]2)cc1
Product: O=C(c1nc2ccccc2[nH]1)[C@@H]1C[C@H]1c1ccccc1

Procedure:
Bis-trans-2-phenyl-cyclopropanecarbonyl benzimidazole was prepared by method C from 2-(4-aminophenyl)-6-amino-benzimidazole (0.500 g, 2.23 mmole) and trans-2-phenyl-1-cyclopropanecarbonyl chloride (0.831 ml, 0.966 g, 5.35 mmole). The resulting solid was purified on silica gel (5% MeOH in CH2Cl2). HPLC showed the product was 95.5% pure.
Reaction SMILES: [CH2:1]([NH:19][CH2:20][C:21]([NH:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:25]=1[O:34][CH3:35])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1.[K+].[Br-]>C(OCC)(=O)C>[CH3:53][C:43]1[CH:48]=[CH:47][C:46]([S:49]([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][C:21]([NH:23][C:24]2[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:25]=2[O:34][CH3:35])=[O:22])(=[O:51])=[O:50])=[CH:45][CH:44]=1
Reactant: CCCCCCCC/C=C\CCCCCCCCNCC(=O)Nc1c(OC)cc(OC)cc1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCC/C=C\CCCCCCCCN(CC(=O)Nc1c(OC)cc(OC)cc1OC)S(=O)(=O)c1ccc(C)cc1
Reaction time: 72 h

Procedure:
To a mixture of 0.50 g of the product of Example 7, excess triethylamine, and ethyl acetate at room temperature was added 0.25 g p-toluene sulfonyl chloride and this was allowed to sit 3 days at room temperature. The reaction mixture was then washed with H3PO4, NaHCO3, and NaCl solutions, dried over MgSO4, filtered, and stripped to an oil. This oil was purified by chromatography on silica gel (70-230 mesh) using 1/1 hexane/EtoAc as eluant. The product was obtained as a viscous oil. 0.28 g (42%). NMR (CDCl3) δ 0.88 (3H, z), δ 1.26 (24H, m), δ 1.66 (2H, m), δ 2.01 (4H, m), δ 2.44 (3H, s), δ 3.21 (2H, m), δ 3.79-3.88 (9H, m), δ 5.34 (2H, m), δ 6.15 (2H, s), δ 7.26-7.75 (5H, m). IR (KBr) 3019, 2925, 1599, 1466, 1206 cm-1.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:5][N:6]=1.[NH2:23][C:24]1[CH:25]=[C:26]([NH:30][S:31]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=1>CC(O)C>[C:35]1([CH2:34][S:31]([NH:30][C:26]2[CH:25]=[C:24]([NH:23][C:2]3[O:3][C:4]([C:7]4[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]5[C:14]([CH:15]=4)=[CH:13][CH:12]=[CH:11][CH:10]=5)=[CH:5][N:6]=3)[CH:29]=[CH:28][CH:27]=2)(=[O:32])=[O:33])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Nc1cccc(NS(=O)(=O)Cc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Cl)o2)cc2ccccc21
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(NS(=O)(=O)Cc4ccccc4)c3)o2)cc2ccccc21
Temperature: 80 °C
Yield: 45.2 %

Procedure:
A mixture of tert-butyl 2-(2-chlorooxazol-5-yl)-1H-indole-1-carboxylate 21 (0.31 g, 0.974 mmol) and N-(3-aminophenyl)-1-phenylmethanesulfonamide 26 (3.1 g, 1.948 mmol) in 2-propanol (20 mL) was heated to 80° C. for 14 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide tert-butyl 2-(2-((3-(phenylmethylsulfonamido)phenyl)amino)oxazol-5-yl)-1H-indole-1-carboxylate 28 (0.24 g, 45% yield) as solid. MS (ES) m/z 545 (M+H+).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)=[C:2]=[S:3].C(N(C(C)C)CC)(C)C.Cl.[NH:23]([CH2:25][C:26](OCC)=[O:27])[NH2:24]>ClCCl>[NH2:24][N:23]1[CH2:25][C:26](=[O:27])[N:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)[C:2]1=[S:3]
Reactant: CCOC(=O)CNN
Reactant: O=C(O)c1ccc(N=C=S)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NN1CC(=O)N(c2ccc(C(=O)O)cc2)C1=S
Yield: 52.5 %

Procedure:
179 mg (1 mmol) of 4-isothiocyanatobenzoic acid and 523 μl (3 mmol) of diisopropylethylamine were stirred in 8 ml of dichloromethane and then with 155 mg (1 mmol) of ethyl hydrazinoacetate hydrochloride at room temperature for 96 hours. After the solvent was concentrated, the mixture was partitioned between ethyl acetate and 30% acetic acid. The aqueous layer was extracted with ethyl acetate again, and the organic layers were combined, washed with water and then with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The resulting solid was mixed with a 190:10:0.8 liquid mixture of ethyl acetate, methanol and acetic acid, and the insoluble was dried to obtain 132 mg of the desired product (yield 53%).
Reaction SMILES: CO[C:3]([C:5]1[CH2:6][CH2:7][N:8]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:9][CH:10]=1)=[O:4].Cl.[CH3:18][NH:19][O:20][CH3:21].C([Mg]Cl)(C)C>C1COCC1>[CH3:21][O:20][N:19]([CH3:18])[C:3]([C:5]1[CH2:6][CH2:7][N:8]([C:11]2[N:12]=[CH:13][CH:14]=[CH:15][N:16]=2)[CH2:9][CH:10]=1)=[O:4]
Reactant: COC(=O)C1=CCN(c2ncccn2)CC1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)C1=CCN(c2ncccn2)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a suspension of 1-pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridin-4-carboxylic acid methyl ester (73.8 mg, 0.337 mmol) and N-methyl-O-methyl hydroxylamine hydrochloride (51.0 mg, 0.552 mmol) in THF (3 ml), was added isopropyl magnesium chloride (2.0 M in THF, 0.505 ml) at −20° C. over 15 minute-period. The mixture was stirred at −10° C. for another 30 minutes before it was quenched with the addition of saturated ammonium chloride (10 ml). The mixture was extracted with EtOAc (2×15 ml). The combined organic layers were washed with brine (15 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (4% MeOH/CH2Cl2) to give 1-pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridin-4-carboxylic acid methoxy-methyl amide (48 mg, 58%) as white crystals: 1H NMR (CDCl3, 400 MHz) δ 8.35 (d, J=6.4 Hz, 2H), 6.53 (t, J=6.4 Hz, 1H), 6.43 (m, 1H), 4.35 (m, 2H), 3.99 (t, J=5.6 Hz, 2H), 3.66 (s, 3H), 3.27 (s, 3H), 2.55 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>C1COCC1.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[C:2]1=[O:10]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: O=C1Cc2cccnc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(C3C(=O)Nc4ncccc43)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.2 %

Procedure:
A solution of 7-azaoxindole (284 mg, 2.1 mmol), (prepared as described for the starting material in Example 2), in THF (10 mn) was added to a suspension of sodium hydride (112 mg, 2.8 mmol, prewashed with petroleum ether) in THF (6 ml). After stirring for 20 minutes at ambient temperature, a solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (238 mg, 0.7 mmol) in a mixture of THF (3 ml) and DMF (1 ml) was added. After stirring for 1 hour at 65° C., the volatiles were removed by evaporation. The residue was partitioned between water and ether. The aqueous layer was separated and adjusted to pH7 with 2M hydrochloric acid. After evaporation of water, the precipitate was triturated with ether, collected by filtration, washed with ether, and dried under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (9515 followed by 90110). After evaporation of the solvent, the residue was suspended in methylene chloride/methanol (1/1) and 3M hydrogen chloride in ether was added. After removal of the solvent by evaporation, the solid was collected by filtration, washed with ether and dried under vacuum to give 4-(7-azaoxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (150 mg, 51%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[O:22][C:16]3=[CH:17][N:18]=[C:19](Cl)[CH:20]=[C:15]3[CH2:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:23][S:24]([N:27]1[CH2:32][CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH2:29][CH2:28]1)(=[O:26])=[O:25]>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[O:22][C:16]3=[CH:17][N:18]=[C:19]([C:30]4[CH2:31][CH2:32][N:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:28][CH:29]=4)[CH:20]=[C:15]3[CH2:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid isopropyl ester and 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine following a procedure analogous to that described in Example 28. LC (method 7): tR=1.03 min; Mass spectrum (ESI+): m/z=450 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[NH:17][CH3:18].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([N:17]([C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:14][CH3:13])[CH3:18])=[O:9]
Reactant: CNc1ccccc1OC
Reactant: O=C(O)c1cc(Br)c(Cl)cc1O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Product: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1O
Temperature: 60 °C
Yield: 44.7 %

Procedure:
Alternatively, a mixture of 5-bromo-4-chloro-2-hydroxybenzoic acid (5 g, 19.9 mmol), 2-methoxy-N-methylaniline (3.13 g, 22.9 mmol) and P2O5 (5.36 g, 37.8 mmol) in anhydrous xylene was heated at 60° C. for 2 hrs and then refluxed for 17 hrs. The mixture was concentrated and purified via silica gel flash column chromatography eluted with ethyl acetate in hexane (20%) to give 5-bromo-4-chloro-2-hydroxy-N-(2-methoxy-phenyl)-N-methyl-benzamide (3.3 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20]C)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.I[Si](C)(C)C.C(=O)(O)O.[CH2:31]([O:35][C:36]([NH:38][CH:39]1[CH2:43][CH2:42][NH:41][CH2:40]1)=[O:37])[CH2:32][CH2:33][CH3:34]>ClCCl.C(#N)C>[CH2:31]([O:35][C:36]([NH:38][CH:39]1[CH2:43][CH2:42][N:41]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:40]1)=[O:37])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOC(=O)NC1CCNC1
Reactant: COC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: C[Si](C)(C)I
Agent: O=C(O)O
Solvent: ClCCl
Solvent: CC#N
Product: CCCCOC(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
To a solution of 1.0 g (3.4 mmole) of methyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 25 ml dichloromethane was added 0.6 ml (0.8 g, 4.2 mmole) of iodotrimethylsilane while stirring at room temperature under a nitrogen atmosphere. The mixture was warmed to reflux and stirred overnight. The reaction was cooled to room temperature, concentrated, and the residue taken up in 25 ml acetonitrile. To the resulting suspension was added a solution of 1.6 g (8.5 mmole) of 3-butoxycarbonylaminopyrrolidine bicarbonate in 10 ml acetonitrile while under nitrogen. The reaction was warmed to reflux for four hours, then cooled to room temperature. The formed precipitate was filtered, washed with acetonitrile and ether, yielding 1.26 g (82%) of 7-[3-(butoxycarbonyl)amino-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 228°-230° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:27][O:28][Si](C(C)(C)C)(C)C)[C@@H:10]([NH:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([Cl:19])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.C1C=CN=CC=1.F>C1COCC1>[Si:1]([O:8][C@H:9]([CH2:27][OH:28])[C@@H:10]([NH:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([Cl:19])[CH:13]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[S@](=O)N[C@@H](Cc1cc(F)cc(Cl)c1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: *CC(*)C
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](Cc1cc(F)cc(Cl)c1)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 50 mL polypropylene bottle containing (S)—N-((2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-(3-chloro-5-fluorophenyl)butan-2-yl)-2-methylpropane-2-sulfinamide (350.00 mg, 618 μmol) was added THF (10 mL) and the mixture was allowed to stir at 0° C. for 5 minutes. At this time, PYRIDINE (2699 μl, 33371 μmol) was added via syringe before the addition of HF-Pyridine, 70% HF 30% pyr (1782 μl, 19775 μmol) via a syringe. The reaction was allowed to stir at this temp for 2 h and then quenched by pouring into sodium bicarbonate (sat 150 ml). The aq. layer was extracted with EtOAc 94×75 mL). The combined organics were washed with HCl (0.1 N, 3×100 mL), bicarbonate (sat, 100 mL), brine and dried with sodium sulfate. The dried solution was filtered and concentrated to give a yellow oil which was purified on a 40 g ISCO column to give the title compound.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]([CH2:23][C@H:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[C:36]([N:26]1[CH2:27][CH2:28][C@H:24]([CH2:23][C@H:13]([C:10]2[CH:9]=[CH:8][C:7]([S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:5])=[O:6])=[CH:12][CH:11]=2)[C:14]([NH:16][C:17]2[S:18][C:19]([F:22])=[CH:20][N:21]=2)=[O:15])[CH2:25]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: O=C(Nc1ncc(F)s1)[C@H](C[C@H]1CCNC1)c1ccc(S(=O)(=O)C2CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC[C@H](C[C@@H](C(=O)Nc2ncc(F)s2)c2ccc(S(=O)(=O)C3CC3)cc2)C1
Reaction time: 0.33 h
Yield: 76 %

Procedure:
The (R)-2-(4-(cyclopropylsulfonyl)phenyl)-N-(5-fluorothiazol-2-yl)-3-((S)-pyrrolidin-3-yl)propanamide (1.17 g, 2.77 mmol) obtained in Step 1 of Example 2 was dissolved in dichloromethane (27 mL), and thereafter, triethylamine (0.806 mL, 5.81 mmol) and acetyl chloride (0.207 mL, 2.91 mmol) were added to the above obtained solution under ice-cold condition. The obtained mixture was stirred for 20 minutes. Thereafter, the reaction solution was washed with a 1 M aqueous solution of hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate. The resultant was dried over anhydrous sodium sulfate, and was then concentrated in vacuo. The obtained residue was purified by silica gel chromatography (chloroform/methanol=1%→15%) to obtain the captioned compound (980 mg, 76%) in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:24])[N:16]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:33][OH:34].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:24])[N:16]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:17]=2)=[N:33]\[OH:34])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(CCCC(=O)O)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(CCCC(=O)O)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 4-{5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-2-oxo-2H-pyridin-1-yl}-butyric acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI−): m/z=495.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH:12]([C:15]([O:17]CC)=O)[C:11]([CH3:20])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[Cl:29])[NH2:25]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH:12]([C:15](=[O:17])[NH:25][C:24]3[CH:26]=[CH:27][C:28]([Cl:29])=[C:22]([Cl:21])[CH:23]=3)[C:11]([CH3:20])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C1C(=O)N(c2ccc(Cl)c(Cl)c2)N=C1C
Solvent: Cc1ccccc1C
Product: CC1=NN(c2ccc(Cl)c(Cl)c2)C(=O)C1C(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
The mixture of 0.6 g of 1-(3,4-dichlorophenyl)-3-methyl-4-carbethoxy-2-pyrazolin-5-one, 0.31 g of 3,4-dichloroaniline and 40 ml of xylene is distilled for a few minutes, refluxed 20 minutes and distilled again a few minutes. The cooled solution deposits crystals, which are collected, washed with benzene and recrystallized from ethyl acetate to yield the 1-(3,4-dichlorophenyl)-3-methyl-4-(3,4-dichlorophenylcarbamoyl)-2-pyrazolin-5-one, melting at 255°-257° (dec.).
Reaction SMILES: S(=O)(=O)(O)O.C([NH2:8])=O.[Cl:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([O:16][CH:17]([C:23](=O)[CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=O)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]2[O:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:23]([CH3:24])[N:8]=2)=[CH:12][CH:11]=1
Reactant: NC=O
Reactant: CCOC(=O)C(OC(=O)c1ccc(Cl)cc1)C(C)=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1oc(-c2ccc(Cl)cc2)nc1C
Temperature: 140 °C
Yield: 55.6 %

Procedure:
19.6 g (0.2 mol) of concentrated sulphuric acid were added dropwise during 10 minutes to 90 g (2 mol) of formamide, the temperature of the solution being held below 10° C. by external cooling, 26.8 g (0.09 mol) of ethyl 2-(4-chlorobenzoyloxy)-3-oxo-butyrate were added and the stirred solution was heated at 140° C. for 2 hours. The cooled suspension was partitioned between 400 ml of water and 300 ml of diethyl ether. The organic phase was washed twice with 200 ml of 1N hydrochloric acid each time and once with 200 ml of water and then filtered to remove suspended solids. The organic phase was dried over magnesium sulphate, filtered and evaporated. The residue was purified by chromatography on silica gel using 20% by volume ethyl acetate in hexane for the elution. After evaporation of the eluate there were obtained 13.3 g (50%) of ethyl 2-(4-chlorophenyl)-4-methyl-5-oxazolecarboxylate of melting point 80°-81° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31]C)=[C:6]([C:8]([CH3:30])([CH3:29])[CH2:9][C:10]([OH:28])([C:24]([F:27])([F:26])[F:25])[CH:11]=[N:12][C:13]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]3[C:14]=2[CH2:15][NH:16][C:17]3=[O:23])[CH:7]=1.B(Br)(Br)Br.CO.ClCCl>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:31])=[C:6]2[C:7]=1[CH:11]([NH:12][C:13]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]3[C:14]=1[CH2:15][NH:16][C:17]3=[O:23])[C:10]([OH:28])([C:24]([F:27])([F:26])[F:25])[CH2:9][C:8]2([CH3:30])[CH3:29]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cc(F)cc2c1CNC2=O)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cc(F)cc3c2CNC3=O)c2c(F)ccc(O)c21
Reaction time: 1 h
Yield: 2.5 %

Procedure:
380 mg (0.832 mmol) of 4-{[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}6-fluoro-2,3-dihydroisoindol-1-one is mixed at room temperature with 8.3 ml of a 1 M solution of BBr3 in dichloromethane and stirred for one hour at ice bath temperature. The working-up of the batch is carried out as described in Example 4. After chromatography of the crude product on a Flashmaster (amine phase; mobile solvent:methanol/dichloromethane), 9.2 mg (2.7%) of the desired compound is obtained.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH3:5][C:6]([CH3:14])([CH3:13])[C:7]#[C:8][C:9]#[C:10][CH2:11]Br>C(O)C>[CH3:5][C:6]([CH3:14])([CH3:13])[C:7]#[C:8][C:9]#[C:10][CH2:11][NH:3][CH2:2][CH2:1][NH2:4]
Reactant: NCCN
Reactant: CC(C)(C)C#CC#CCBr
Solvent: CCO
Product: CC(C)(C)C#CC#CCNCCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
In 20 ml of ethanol was dissolved 1.5 g of ethylenediamine. Then 1.24 g of 6,6-dimethyl-2,4-heptadiynyl bromide was added to the solution followed by stirring at room temperature overnight. The solvent was distilled off under reduced pressure and the residue was extracted with ethyl ether and saturated sodium bicarbonate aqueous solution. After the organic layer was taken by fractionation, the aqueous layer was further extracted with ethyl ether. The procedure was repeated 5 times and the ethereal layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was then removed under reduced pressure to give 695 mg (yield: 63%) of N-(6,6-dimethyl-2,4-heptadiynyl)ethylenediamine as light yellow oil.