Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][CH2:20][C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:27]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][CH2:20][C:19]2[N+:18]([O-:27])=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCc2ncccc2C1)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCc2c(ccc[n+]2[O-])C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.2 %

Procedure:
To a stirred solution of 6-benzyloxycarbonylamino-5,6,7,8-tetrahydroquinoline (1.66 g, 5.87 mmol) in chloroform (13 mL) at 0° C. under nitrogen was added 3-chloroperoxybenzoic acid (1.06 g net, 6.16 mmol). The reaction mixture was then slowly warmed to room temperature. After 1 d, the reaction mixture was chromatographed on basic alumina (eluted with a 0–3% step-wise gradient of methanol in methylene chloride). The title compound (1.16 g, 66.5%) was obtained as a light yellow solid. 13C NMR (400 MHz, CDCl3) δ 155.7, 147.2, 137.3, 136.3, 133.5, 128.5, 128.1, 128.0, 126.5, 122.6, 66.8, 45.4, 36.7, 27.3, 22.9. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=6.2 Hz, 1H), 7.31 (m, 5H), 7.00 (m, 2H), 5.07 (s, 2H), 3.98 (br s, 1H), 3.12 (m, 2H), 2.95 (m, 1H), 2.70 (dd, J=7.9, 16.0 Hz, 1H), 2.11 (m, 1H), 1.86 (br s, 1H). HPLC/MS [M+H]+, 299.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:5]([C:3]([OH:2])=[O:4])[C:6]=4[CH:7]=[CH:8]3)=[CH:16][CH:17]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cccc2c1ccn2Cc1ccc([N+](=O)[O-])cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cn3ccc4c(C(=O)O)cccc43)cc2)cc1

Procedure:
The title compound was prepared from 1-(4-nitro-benzyl)-1H-indole-4-carboxylic acid methyl ester and 4-tert-butylbenzenesulfonyl chloride followed the procedure of Example 3 Step 2 as a pale pink solid: 1H NMR (DMSO-d6) δ 1.24 (s, 9H), 5.35 (s, 2H), 6.96 (d, J=3.1 Hz, 1H), 7.03 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 7.15 (t, J=7.8 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.57 (d, J=3.2 Hz, 1H), 7.62-7.68 (m, 3H), 7.70 (dd, J=7.5, 0.9 Hz, 1H), 10.26 (br s, 1H), 12.59 (br s, 1H); MS (ESI) m/z 463 (MH+), 461 ([M−H]−); HRMS calcd for C26H27N2O4S: 463.1690; found (ESI+): 463.1674.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([Cl:18])=[C:12]([F:17])[CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH:7]=1)=[O:5])C>C(O)(=O)C.Cl>[Cl:18][C:11]1[CH:10]=[C:9]2[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[CH:13][C:12]=1[F:17]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2cc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(Cl)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 25 h

Procedure:
A mixture of 2.0 g of 7-chloro-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (5.23 mmol) in 16 ml acetic acid and 16 ml HCl 37% was stirred 25 hrs at 90° C., and evaporated.
Reaction SMILES: C(#N)C.[CH3:4][S:5]([OH:8])(=[O:7])=[O:6].[F:9]F.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:4][S:5]([O-:8])(=[O:7])=[O:6].[F:9][N+:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)O
Reactant: c1ccncc1
Reactant: FF
Solvent: CC#N
Product: CS(=O)(=O)[O-]
Product: F[n+]1ccccc1
Temperature: -20 °C

Procedure:
To 40 ml of acetonitrile were added 1.655 g (20.923 mmol) of pyridine and 1,961 g (20.406 mmol) of methanesulfonic acid (i.e., the amount of pyridine was 1,025 times that of methanesulfonic acid in a molar ratio), and the mixture was cooled to -20° C. A mixed gas of fluorine and nitrogen in a volumetric ratio of 1:4 was then introduced to the mixture at a rate of 50 ml/min under stirring. The amount of fluorine gas introduced was 40.0 mmol. After completion of the reaction, the solvent was distilled off, and 3,691 g ¢19.103 mmol) N-fluoropyridinium methanesulfonate was obtained by crystallizing with ether. The yield was
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][C:14]([C:17]([NH:19][C@@H:20]3[CH:25]4[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]4)[CH2:21]3)=[O:18])=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[CH:28]1([C:32]([Cl:34])=[O:33])[CH2:31][CH2:30][CH2:29]1.C(N(CC)CC)C>C1COCC1.CN(C=O)C>[ClH:34].[N:22]12[CH2:23][CH2:24][CH:25]([CH2:26][CH2:27]1)[C@@H:20]([NH:19][C:17]([C:14]1[O:15][C:16]3[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[NH:1][C:32]([CH:28]4[CH2:31][CH2:30][CH2:29]4)=[O:33])=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]=1)=[O:18])[CH2:21]2
Reactant: O=C(Cl)C1CCC1
Reactant: Nc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)oc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccccc3NC(=O)C3CCC3)c2o1

Procedure:
60 mg (0.15 mmol) of 7-(2-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (Example 132), 26 mg (0.22 mmol) of cyclobutanecarbonyl chloride and 0.06 ml (0.44 mmol) of triethylamine are shaken in 2 ml of THF/DMF (1:1) at RT overnight. The solvent is removed under reduced pressure. Purification takes place by preparative HPLC. The product is dissolved in methanol, and an excess of 1N hydrochloric acid is added. The solvent is removed under reduced pressure. Drying under high vacuum results in 39 mg (56% of theory) of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[OH-].[K+].[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.Cl>O>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])=[O:15])=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: C[C@H](N)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(NC(=O)c1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a solution of L-Alanine (2.67 g, 30.0 mmol) and KOH (3.90 g, 69.5 mmol) in water (50.0 mL) was added 4-chlorobenzoyl chloride (5.25 g, 30.0 mmol). After stirring at RT for 16H, the reaction mixture was cooled to 0° C., acidified to pH=2 with 10 M HCl and extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated and air dried under vacuum to afford 5.80 g (85% yield) of the title compound as a white solid that was carried forward without further purification: 1H NMR (500 MHz, DMSO-d6) δ 12.62 (1H, br. s.), 8.76 (1H, d, J=7.15 Hz), 7.90 (2H, d, J=8.25 Hz), 7.55 (2H, d, J=8.25 Hz), 4.40 (1H, qd, J=7.33, 7.15 Hz), 1.38 (3H, d, J=7.15 Hz); HPLC retention time: 2.223 min; LCMS (ES): m/z 228 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.C(N(C(C)C)CC)(C)C.[CH3:43][CH:44]([CH3:49])[CH2:45][C:46](Cl)=[O:47]>ClCCl>[CH3:43][CH:44]([CH3:49])[CH2:45][C:46]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1)=[O:47]
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(=O)Nc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reaction time: 0.25 h

Procedure:
2-(2-Aminophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 626, 30 mg, 0.069 mmol) and diisopropylethylamine (30 μL, 0.17 mmol, 2.5 equiv) were combined in dichloromethane (1 mL) and treated with 3-methylbutanoyl chloride (9.2 mg, 0.076 mmol, 1.1 equiv). After 15 minutes at ambient temperature, the mixture was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC (eluting 80:20 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the title compound; 1H-NMR (400 MHz, d6-DMSO) δ 9.72 (1H, br s), 9.33 (1H, s), 8.47 (1H, d, J=2.3 Hz), 8.28 (1H, d, J=7.7 Hz), 7.93 (1H, d, 8.0 Hz), 7.84 (1H, d, J=8.9 Hz), 7.83 (2H, d, J=8.5 Hz), 7.72 (1H, br s), 7.69-7.64 (2H, m), 7.59 (1H, t, J=7.3 Hz), 7.47 (2H, d, J=8.4 Hz), 7.37 (1H, t, J=7.5 Hz), 7.27 (1H, t, J=7.5 Hz), 6.53 (1H, m), 5.83 (2H, s), 2.15 (2H, d, J=7.3 Hz), 2.09-1.94 (1H, m), 0.86 (6H, d, J=6.6 Hz) ppm; high resolution mass spectrometry (ES+) m/z 517.2391 [(M+H)+; calculated for C31H29N6O2: 517.2347].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[CH3:13].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].N1CC[CH2:24][CH2:23]1>CN(C=O)C>[Br:1][C:2]1[C:3](/[CH:13]=[CH:19]/[N:17]2[CH2:16][CH2:24][CH2:23][CH2:18]2)=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: COc1ccc(Br)c(C)c1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(/C=C/N2CCCC2)c1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
To a solution of 1-bromo-4-methoxy-2-methyl-3-nitrobenzene (1.400 g, 5.68 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.884 mL, 6.657 mmol) in DMF (10.0 mL) was added pyrrolidine (0.555 mL, 6.656 mmol) and the mixture was heated to at 110° C. for 4 h. The DMF was removed and the residue was recrystallized from DCM:methanol (1:6) mixture to afford 1-[(E)-2-(6-bromo-3-methoxy-2-nitrophenyl)vinyl]pyrrolidine.
Reaction SMILES: Cl.NCC[C:5]1[C:10]([CH2:11][C:12]([OH:14])=O)=[CH:9][CH:8]=[C:7]2[O:15][CH2:16][O:17][C:6]=12.[CH:18]1([N:24]=C=NCCN2CCOCC2)CCCC[CH2:19]1>O>[CH2:16]1[O:17][C:6]2[C:7](=[CH:8][C:9]3[CH2:19][CH2:18][NH:24][C:12](=[O:14])[CH2:11][C:10]=3[CH:5]=2)[O:15]1
Reactant: C(=NCCN1CCOCC1)=NC1CCCCC1
Reactant: NCCc1c(CC(=O)O)ccc2c1OCO2
Agent: Cl
Solvent: O
Product: O=C1Cc2cc3c(cc2CCN1)OCO3

Procedure:
Similarly, 0.005 moles (1.3 grams) of 6-(2-aminoethyl)-4,5-methylenedioxy phenyl-acetic acid hydrochloride were dissolved in 15 ml of water and to this solution was added 2.12 grams of 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide methotoluenesulfonate in 20 ml of water. After 2 hours at room temperature the precipitate that had formed was filtered off, washed and dried to yield 1,3,4,5-tetrahydro-7,8-methylenedioxy-2H-3-benzazepin-2-one, m.p. 236°-237°. After recrystallization from ether the product melted at 238°-239°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[Cl:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][CH:21]=[N:22]2)=[C:18]([Cl:25])[N:17]=1>>[Cl:15][C:16]1[N:24]=[C:23]2[C:19]([N:20]=[CH:21][N:22]2[C@@H:12]([C@@:9]2([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH2:11][O:10]2)[CH3:13])=[C:18]([Cl:25])[N:17]=1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Product: C[C@@H](n1cnc2c(Cl)nc(Cl)nc21)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 17.5 %

Procedure:
Using (1S)-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl] ethanol (578 mg) and 2,6-dichloropurine (490 mg), (2S)-2-[(1R)-1-[2,6-dichloro-9(9 H)-purinyl]ethyl]-2-(2,4-difluorophenyl)oxirane (168 mg) was obtained by the same way as in Reference Example 2.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[C:25]([Cl:26])=[CH:24][C:6]2[N:7]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:8](=[O:10])[NH:9][C:5]=2[CH:4]=1.Cl>ClCCl>[ClH:26].[F:27][C:2]([F:1])([F:28])[C:3]1[C:25]([Cl:26])=[CH:24][C:6]2[N:7]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:8](=[O:10])[NH:9][C:5]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(C(F)(F)F)c(Cl)cc32)CC1
Agent: Cl
Solvent: ClCCl
Product: O=c1[nH]c2cc(C(F)(F)F)c(Cl)cc2n1C1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1,1-Dimethylethyl 4-(5-trifluoromethyl-6-chloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate (D63, 1.0 g) was dissolved in dichloromethane (10 ml) and HCl (4M in 1,4-dioxane, 2.5 ml) was added at room temperature. The mixture was stirred at room temperature for 4 h then evaporated to give the subtitle compound, 850 mg.
Reaction SMILES: [C:1]1([NH:11][C:12]2[C:20]3[C:19]4[CH2:21][NH:22][CH2:23][CH2:24][C:18]=4[NH:17][C:16]=3[N:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>ClCCCl>[C:1]1([NH:11][C:12]2[C:20]3[C:19]4[CH2:21][N:22]([C:25](=[O:27])[CH3:26])[CH2:23][CH2:24][C:18]=4[NH:17][C:16]=3[N:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(Nc3ccnc4[nH]c5c(c34)CNCC5)cccc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4cccc5ccccc45)c3c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.6 %

Procedure:
Naphthalen-1-yl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (40 mg, 0.13 mmol), acetic anhydride (12 μL, 0.13 mmol), and triethylamine (53 μL, 0.38 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred for 3 h at room temperature. The reaction mixture was added directly to a Biotage column. The crude product was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 57 (10 mg, 22% yield) as a tan powder. LC-MS (M+H=357, obsd.=357).
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10]C(=O)C2C=CC=CC=2)=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC(=S)NC1CCCCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=S)NC1CCCCC1
Yield: 94.5 %

Procedure:
To a solution of N-(cyclohexylcarbamothioyl)benzamide (17.1 g, 65.5 mmol) in ethanol was added aqueous potassium carbonate (18.2 g, 132.2 mmol). The mixture was stirred at reflux temperature for 4 h. The organic layer was concentrated to a small volume, after which the product could be collected by filtration, then washed with petroleum ether and dried in vacuo to give the title compound as a white solid (9.8 g, 95% two steps).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[I-].[K+].Br[CH2:9][CH2:10][CH2:11][C:12]([CH2:14][CH2:15][CH2:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20]Br)=[O:13]>C(OC(=O)C)(=O)C.CCOC(C)=O>[C:1]([O:4][CH2:9][CH2:10][CH2:11][C:12]([CH2:14][CH2:15][CH2:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][O:4][C:1](=[O:3])[CH3:2])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: O=C(CCCBr)CCCC(=O)CCCBr
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)OCCCC(=O)CCCC(=O)CCCOC(C)=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.3 %

Procedure:
A solution of 20.6 g potassium acetate and 3.49 g potassium iodide in 306 ml acetic anhydride was stirred and the product (VII) of Ex. 1 added. The reaction mixture was refluxed with stirring for 12-16 hrs, then cooled to 25° C. and diluted with 100 ml EtOAc. The reaction mixture was filtered, and the filtrate concentrated in vacuo. Ethyl acetate (400 ml) was added and the resultant solution was washed with 2×200 ml of 50% aq. NaHCl3. The organic layer was isolated, dried (MgSO4 an.), filtered and concentrated in vacuo. Purification by flash chromatography yielded product (VIII) in 66.3% yield as a viscous light yellow oil (93% pure).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15](=[O:28])[CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22])[NH2:14]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15](=[O:28])[CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: COC(=O)c1cccc(OCC(=O)NN)c1
Solvent: CC(=O)O
Product: COC(=O)c1cccc(OCC(=O)NN=C2C(=O)Nc3ccc(Br)cc32)c1
Temperature: 100 °C
Yield: 34 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-bromo-1H-indole-2,3dione in acetic acid was added methyl 3-(2-hydrazino-2-oxoethoxy)benzoate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 39 mg of the title compound (34%) as a orange powder in 97.5% purity by HPLC (Rt: 4.26, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:18]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:23]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CCCC4)nc23)CC1
Yield: 83.6 %

Procedure:
Beginning with 0.080 gm (0.348 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.093 mL (0.766 mMol) cyclopentanecarbonyl chloride, 0.095 gm (84%) of the title compound was recovered as an amorphous solid essentially by the procedure described in Example 4.
Reaction SMILES: C(O[C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:11][C:10]=1[O:22][CH3:23])(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.C1(OC(=O)[NH:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:51][CH:50]=2)C=CC=CC=1>C(Cl)Cl>[C:55]([C:52]1[CH:51]=[CH:50][C:49]([CH2:48][NH:47][C:6](=[O:24])[NH:7][CH2:8][C:9]2[C:10]([O:22][CH3:23])=[CH:11][C:12]([NH:17][S:18]([CH3:21])(=[O:19])=[O:20])=[C:13]([CH:15]=[CH2:16])[CH:14]=2)=[CH:54][CH:53]=1)([CH3:58])([CH3:56])[CH3:57]
Reactant: CC(C)(C)c1ccc(CNC(=O)Oc2ccccc2)cc1
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)c(OC)cc1NS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1cc(CNC(=O)NCc2ccc(C(C)(C)C)cc2)c(OC)cc1NS(C)(=O)=O
Temperature: 0 °C
Yield: 6.2 %

Procedure:
To a ice-cooled solution of (4-methanesulfonylamino-2-methoxy-5-vinyl-benzyl)-carbamic acid tert-butyl ester (220 mg, 0.73 mmol) in methylene chloride was treated with trifluoroacetic acid (100 mg, 0.88 mmol)) for 1 hr, and then concentrated under reduced pressure. The part of crude residue (100 mg, 0.27 mmol) was suspended in methylene chloride and treated with triethylamine followed by (4-tert-butyl-benzyl)-carbamic acid phenyl ester (92 mg, 0.32 mmol). The resulting mixture was heated with reflux for 3 days and concentrated under reduced pressure. The crude residue was column-chromatographed (hexane/ethylacetate=1/2) to yield a white solid (8.8 mg, 7.0%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[O:7].[N+:17]([CH2:20][CH3:21])([O-:19])=[O:18].[OH-].[Na+].C(O)(=O)C>CCO>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH:20]([N+:17]([O-:19])=[O:18])[CH3:21])[CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A stirred solution of 3,5-bis(trifluoromethyl)benzaldehyde (1.00 g, 4.13 mmol) and nitroethane (1.13 g, 1.08 mL, 15.1 mmol) in absolute EtOH (20 mL) at 0° C. was treated with 10% aq. NaOH (m/v) (1.73 mL, 4.34 mmol), stirred for 1 h and treated with 2% aq. acetic acid (m/v) (13.0 mL, 4.32 mmol). The reaction was stirred for 1 h at room temperature then partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic extracts were washed with saturated NaHCO3 (50 mL) and brine (50 mL), dried (Na2SO4) and concentrated in vacuo to afford a 1.5:1 mixture of threo- and erythro-1-[3,5-bis(trifluoromethyl)phenyl]-2-nitropropan-1-ol as a colorless oil. 1H NMR (CDCl3, 500 MHz) threo-diastereoisomer: δ 7.88 (br s, 1H), 7.86 (br s, 2H), 5.22 (d, J=8.4 Hz, 1H), 4.77 (dq, J=8.4, 6.9 Hz, 1H), 3.03 (br s 1H), 1.42 (d, J=6.9 Hz, 3H), erythro-diastereoisomer: δ 7.90 (br s, 1H), 7.86 (br s, 2H), 5.59 (d, J=3.2 Hz, 1H), 4.72 (dq, J=3.2, 6.9 Hz, 1H), 3.03 (br s 1H), 1.50 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[CH:23]=[C:24]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH2:28][CH2:27][C:26]2[CH:35]=[CH:36][CH:37]=[CH:38][C:25]1=2>>[CH:35]1[C:26]2[CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:24](=[CH:23][C:3]3[CH:4]=[C:5]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:6]=[CH:7][C:2]=3[CH3:1])[C:25]=2[CH:38]=[CH:37][CH:36]=1
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Reactant: Cc1ccc(NS(C)(=O)=O)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(NS(C)(=O)=O)cc1C=C1c2ccccc2CCc2ccccc21
Yield: 60.7 %

Procedure:
Following the procedures essentially as described in Example 219, below, and using N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamide (120 mg, 0.386 mmol) and 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (100 mg, 0.351 mmol) affords 83 mg (61%) of the title compound as a yellow solid. MS (ES) 407 (M+NH4), 388 (M−H); HPLC shows 91% purity.
Reaction SMILES: C(OC([NH:8][C@H:9]([C@@H:17]([OH:23])[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C@H:9]([C@@H:17]([OH:23])[CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC[C@H](O)[C@@H](N)CC1CCCCC1
Yield: 98.9 %

Procedure:
A solution of 2(S)-t-butoxycarbonylamino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (600 mg) in trifluoroacetic acid (10 ml) was stirred at 0° C. for 30 minutes. After evaporation of the solvent, the residue was dissolved in ethyl acetate (20 ml). The solution was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and evaporated in vacuo to give 2(S)-amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (412 mg) as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Br[CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH3:52].BrCC1OC(C(F)(F)F)=CC=1>>[CH3:52][O:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: COCCOCCBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COCCOCCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 1-bromo-2-(2-methoxyethoxy)ethane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (65%) as a colorless solid: mp 90-91° C.; 1H NMR (300 MHz, CDCl3) δ 7.32-7.20 (m, 1H), 7.14-7.09 (m, 1H), 7.05-6.97 (m, 2H), 6.46 (s, 1H), 6.21 (s, 1H), 4.73 (ABq, 2H), 4.19-4.12 (m, 2H), 4.12-4.05 (m, 2H), 4.05-3.96 (m, 1H), 3.94-3.83 (m, 1H), 3.64-3.57 (m, 2H), 3.51-3.44 (m, 2H), 3.32 (s, 3H); 13C NMR (75 MHz, CDCl3 δ 177.6, 155.2, 144.5, 142.5, 138.3, 132.3, 128.7, 123.7, 123.2, 121.2, 111.6, 109.2, 99.3, 80.0, 71.9, 70.4, 68.2, 64.5, 63.9, 59.0, 58.0, 402; MS (ES+) m/z 397.9 (M+1).