Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[C:14]([F:15])=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:6]=1[C:7](OC)=[O:8]>CCO>[F:15][C:14]1[CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=[C:6]2[C:5]=1[NH:3][N:2]=[C:7]2[OH:8]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(F)c1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(F)c2[nH]nc(O)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Hydrazine monohydrate (1.91 ml) was added to an EtOH (40 ml) solution containing methyl 2,3-difluoro-5-nitrobenzoate (1.71 g) obtained in the 2nd step, followed by stirring at room temperature for 10 minutes. An insoluble precipitate was removed by filtration and washed with EtOH. 7-Fluoro-5-nitro-1H-indazol-3-ol (956 mg) was thus obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][N:4]=1.[SH:13][C:14]1[NH:18][C:17]2[CH:19]=[C:20]3[C:24](=[CH:25][C:16]=2[N:15]=1)[C:23]([CH3:27])([CH3:26])[C:22](=[O:28])[C:21]3([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:29][C:21]1([CH3:30])[C:20]2[C:24](=[CH:25][C:16]3[NH:15][C:14]([S:13][CH2:2][C:3]4[C:8]([CH3:9])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][N:4]=4)=[N:18][C:17]=3[CH:19]=2)[C:23]([CH3:27])([CH3:26])[C:22]1=[O:28]
Reactant: Cc1c([N+](=O)[O-])ccnc1CCl
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c([N+](=O)[O-])ccnc1CSc1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)C3(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 11.5 g of 2-chloromethyl-3-methyl-4-nitropyridine and 16 g of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one in 200 ml of absolute acetone was treated with 13 g of finely ground potassium carbonate and the mixture was stirred at room temperature under argon for 18 hours. 100 ml of acetone were distilled off in vacuo, whereupon the residue was poured on to ice. The product which crystallized out was filtered off and dissolved in methylene chloride; the solution obtained was washed with water, dried and concentrated. By recrystallization from ethyl acetate/ether there was obtained 5,7-dihydro-5,5,7,7-tetramethyl-2-[[(3-methyl-4-nitro-2-pyridyl)methyl]thio]indeno[5,6-d]imidazol-6(1H)-one of melting point 181°-183° (decomposition).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)/[C:12]([OH:14])=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[OH-].[NH4+:36]>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)/[C:12]([NH2:36])=[O:14])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccccc1[N+](=O)[O-]
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(N)=O)n1Cc1ccccc1[N+](=O)[O-]

Procedure:
(E)-3-[2-n-Butyl-1-{(2-nitrophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid, prepared in Example 55, was treated with thionyl chloride and then ammonium hydroxide, as described in Example 54, to give the title compound; mp 183°-185° C.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38]S(C3C=CC(C)=CC=3)(=O)=O)[N:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=4)([CH3:14])[C:4]([OH:24])=[O:3])=[CH:12][CH:11]=3)[N:35]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)c(C)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(C4CCCCC4)oc3C)cc2)C(=O)O)cc1C

Procedure:
The representative parallel synthesis procedure (B) was used to prepare the title compound from 2-(3,4-dimethylphenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 7.18 (d, 2H, J=8.4 Hz), 6.99 (d, 1H, J=8.4 Hz), 6.79 (d, 2H, J=8.4 Hz), 6.71 (d, 1H, J=2.4 Hz), 6.64 (dd, 1H, J=8.4, 2.4 Hz), 4.16 (t, 2H, J=6.0 Hz), 3.21 and 3.11 (d of Abq, 2H, J=14.0 Hz), 2.98 (t, 2H, J=6.0 Hz), 2.91 (tt, 1H, J=11.4, 3.2 Hz), 2.31 (s, 3H), 2.20 (s, 3H), 2.19 (s, 3H), 2.06-2.02 (m, 2H), 1.85-1.79 (m, 2H), 1.73-1.68 (m, 1H), 1.62-1.51 (m, 2H), 1.42-1.22 (m, 3H), 1.39 (s, 3H). IR (KBr) 3500, 2935, 1735, 1612, 1513, 1249, 1178 cm−1. HRMS (ES+) m/z exact mass calcd for C30H38NO5 492.2750, found 492.2751.
Reaction SMILES: O[C:2]1C=CC=C[C:3]=1N1C=CC=C1.ClC1C=CC(O)=C(N2C=CC=C2)C=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]2[O:35][C:34]([CH3:39])([C:36]([OH:38])=[O:37])[C:33]3=[CH:40][CH:41]=[CH:42][N:32]3[C:31]=2[CH:43]=1>>[CH2:2]([O:37][C:36]([C:34]1([CH3:39])[C:33]2=[CH:40][CH:41]=[CH:42][N:32]2[C:31]2[CH:43]=[C:27]([Cl:26])[CH:28]=[CH:29][C:30]=2[O:35]1)=[O:38])[CH3:3]
Reactant: CC1(C(=O)O)Oc2ccc(Cl)cc2-n2cccc21
Reactant: Oc1ccccc1-n1cccc1
Agent: Oc1ccc(Cl)cc1-n1cccc1
Product: CCOC(=O)C1(C)Oc2ccc(Cl)cc2-n2cccc21

Procedure:
In the same manner but replacing N-(2-hydroxyphenyl)-pyrrole with an equivalent amount of N-(5-chloro-2-hydroxyphenyl)-pyrrole, 8-chloro-4-methyl-4H-pyrrolo[2,1-c][1,4]benzoxazine-4-carboxylic acid, m.p. 153° - 154° C (dec), νmaxCHCl3 1,725, 1,510, 1,330cm-1, is obtained via the intermediate ester, 8-chloro-4-methyl-4H-pyrrolo-[2,1-c][1,4]benzoxazine-4-carboxylic acid ethyl ester, νmaxCHCl3 1,735 cm-1.
Reaction SMILES: [N:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([N:15](CC)CC)C.[C:20]([N:27]1C=CN=C1)(N1C=CN=C1)=[S:21].O.NN.[Cl-].[Na+]>O1CCCC1>[NH:27]([C:20]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH2:3]1)=[S:21])[NH2:15]
Reactant: CCOC(=O)CN1CCNCC1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCN(CC)CC
Agent: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCN(C(=S)NN)CC1
Reaction time: 2 h
Yield: 115 %

Procedure:
Ethyl piperazine-1-acetate (680 mg, 3.71 mmol) in tetrahydrofuran (8.0 mL) was mixed with triethylamine (0.776 mL, 5.57 mmol) and thiocarbonyldiimidazole (992 mg, 5.57 mmol) at room temperature and stirred at room temperate for 2 hours and then stirred with hydrazine monohydrate (0.272 mL, 5.57 mmol) for another 2 hours. The reaction solution was mixed with saturated aqueous sodium chloride and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated to give the crude preparation of the desired product (115% yield).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=O)=[CH:5][CH:4]=1.[S:15]1[C:19]2[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:18]=2[N:17]=[CH:16]1>>[S:15]1[C:19]2[CH:20]=[C:21]([NH:24][CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=3)[CH:22]=[CH:23][C:18]=2[N:17]=[CH:16]1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc2ncsc2c1
Product: FC(F)(F)c1ccc(CCNc2ccc3ncsc3c2)cc1

Procedure:
In analogy to example 33, step 1, (4-trifluoromethyl-phenyl)-acetic acid (commercially available) was coupled with benzothiazol-6-ylamine (commercially available) to give the title compound.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:20])=[O:19]
Reactant: NCCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 106.4 %

Procedure:
To a 10° C. solution of phenethylamine (12.1 g, 0.100 mol) and triethylamine (11.1 g, 0.110 mol) in CH2Cl2 (50 mL) was added methanesulfonyl chloride (12.6 g, 0.110 mol) dropwise over 10 min. The solution was stirred at room temperature for 1.5 h and was then washed with 1N HCl (5×20 mL). The organic phase was directly concentrated to provide the intermediate title compound, (methylsulfonyl)(2-phenylethyl)amine, (21.2 g, 93.3%) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)([O-:3])=[O:2].Br[C:19]1[S:20][CH:21]=[CH:22][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>O>[N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[NH:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: Brc1nccs1
Reactant: Nc1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Nc2nccs2)cc1

Procedure:
2-Nitro-N-(4-aminophenyl)aniline (5.0 g, 21.8 mmol), 2-bromothiazole (3.58 g, 21.8 mmol) and potassium carbonate (3.01 g, 21.8 mmol) was stirred at 150° C. for 24 h. Water (250 ml) was added and the mixture was extracted with ethyl acetate (250 ml).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])[O:8][CH:7]([C:17]([F:20])([F:19])[F:18])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2.[H-].[Na+].I[CH3:29].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([CH3:15])([CH3:16])[CH2:13][O:14][CH3:29])[O:8][CH:7]([C:17]([F:20])([F:19])[F:18])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(C(C)(C)CO)cc2OC1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=Cc2cc(Cl)c(C(C)(C)COC)cc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 6-chloro-7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (205 mg, 0.584 mmole) in 8 mL of dry DMF was added 86 mg of 60% NaH, and 0.5 mL of iodomethane. The mixture was stirred overnight at room temperature. Water was added, the mixture extracted with DCM, the combined organic extracts dried over Na2SO4, filtered, and evaporated. Chromatography of the residue over silica gel using DCM as eluent gave the title compound, 49 mg, as an oil.
Reaction SMILES: [CH2:1]([C@:3]1([CH:21]([CH3:25])[C:22](O)=[O:23])[C@@H:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH3:20])[C:11]=32)[CH2:6][CH2:5][CH2:4]1)[CH3:2].CN1CCOCC1.ClC(OCC)=O.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[CH2:39]([NH:46][C:22](=[O:23])[CH:21]([C@@:3]1([CH2:4][CH3:5])[C@@H:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH3:20])[C:11]=32)[CH2:6][CH2:2][CH2:1]1)[CH3:25])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC[C@@]1(C(C)C(=O)O)CCCN2CCc3c(n(C)c4ccccc34)[C@@H]21
Reactant: NCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC[C@@]1(C(C)C(=O)NCc2ccccc2)CCCN2CCc3c(n(C)c4ccccc34)[C@@H]21
Temperature: -5 °C
Yield: 78 %

Procedure:
3.40 g. (0.01 moles) of (-)-(1S,12bS)-1-ethyl-12-methyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-1-yl-propionic acid are added to a solution containing 2.04 g. (0.02 moles) of N-methylmorpholine (redistilled from sodium) in 20 ml. of dry tetrahydrofuran while stirring under nitrogen, then the solution is cooled to -5° C. and 1.10 g. (0.01 mole) of ethyl chloroformate are rapidly dropped in while stirring vigorously and keeping the inner temperature at or lower than 0° C. The mixture is stirred at 0° C. for 30 minutes, whereupon a solution containing 1.18 g. (0.011 moles) of benzylamine in 10 ml. of dry tetrahydrofuran is dropwise added at a temperature between -5° C. and 0° C. during 10 minutes. The mixture is stirred at 0° C. for 30 minutes, then during an additional stirring for 4 hours the mixture is allowed to warm to room temperature. The mixture is evaporated on a rotating evaporator and after shaking thoroughly the residue with 50 ml. of dichloromethane and 20 ml. of water, the phases are separated. The dichloromethane layer is washed at first with 20 ml. of 5% sodium carbonate solution, then three times with 20 ml. of water each, dried over anhydrous magnesium sulphate and evaporated. The residue which is the crude product, is purified by column chromatography on silica gel by using toluene containing 10% of diethylamine to give 3.36 g. (78% yield) of the title compound as an oily product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][N+]([O-])=O)[CH:3]=1.ClC1C=CN=C(N[N+]([O-])=[O:21])C=1>>[NH2:8][C:4]1[C:3]([OH:21])=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=1
Reactant: O=[N+]([O-])Nc1cc(Br)ccn1
Reactant: O=[N+]([O-])Nc1cc(Cl)ccn1
Product: Nc1nccc(Br)c1O

Procedure:
By substituting 4-bromo-2-nitraminopyridine for the 4-chloro-2-nitraminopyridine in Example I-5, there is obtained 2-amino-4-bromo-3-pyridinol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:16])[CH:4]=1.C1C(=O)N([Br:24])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)Cl>CC#N.O>[Br:24][CH2:16][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1CBr
Temperature: 70 °C

Procedure:
A mixture of methyl 4-methoxy-2-methyl-5-nitrobenzoate (994 mg, 4.41 mmol) and NBS (943 mg, 5.3 mmol) in MeCN (20 mL) was degassed and then AIBN (15 mg, 0.09 mmol) was added. The mixture was heated to 70° C. for 18 h. Further AIBN (15 mg, 0.09 mmol) was added and the mixture was heated to 70° C. for 24 h. Further AIBN (15 mg, 0.09 mmol) and NBS (300 mg, 1.7 mmol) were added and the mixture heated to 70° C. for 24 h. Further AIBN (15 mg, 0.09 mmol) was added and the mixture was heated to 70° C. for 24 h. DCM (50 mL) and water (50 mL) were added and the organic phase was passed through a hydrophobic frit. The solvent was removed in vacuo to give crude methyl 2-(bromomethyl)-4-methoxy-5-nitrobenzoate that was used directly in the next reaction without any purification.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@H:23]([OH:32])[CH2:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)([OH:8])=[O:7].[C:33](=O)([O-])O.[Na+].[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40]>CO.CCOCC>[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40].[CH3:33][O:7][C:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C@H:23]([OH:32])[CH2:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C([O-])O
Reactant: O=C(O)c1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Temperature: 25 °C

Procedure:
Concentrated sulfuric acid (2.5 ml) was added to a suspension of (2R)-1-(3'-carboxybiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.5 g) in methanol (50 ml). The mixture was heated at reflux for 10 hours. The mixture was cooled to room temperature and made basic by addition of aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:methanol (19:1) to give an oil which was converted to the oxalate salt upon treatment with oxalic acid (excess) in ether to give the title compound as a solid (0.482 g).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[C:16]([F:22])([F:21])C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH:16]([F:22])[F:21])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(F)(F)Cl
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2cc(OC(F)F)c(Br)cc21
Reaction time: 3 h

Procedure:
1-Acetyl-6-bromo-5-hydroxyindoline (2 g, 7.8 mmol), methyl 2-chloro-2,2-difluoroacetate (0.82 ml, 7.8 mmol) and potassium carbonate (1.08 g, 7.8 mmol) were suspended in N,N-dimethylformamide (20 mL) under an argon atmosphere and placed in a 65° C. oil bath. After 3 hr, additional methyl 2-chloro-2,2-difluoroacetate (0.3 ml, 2.8 mmol) and potassium carbonate (0.3 g, 2.2 mmol) was added and heated for 18 hr. The solvent was then removed in vacuo and the residue was partitioned between cold 3N HCl and ether. The aqueous layer was extracted three times with ether, the combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated. The solid was purified by flash chromatography (2% MeOH/CH2Cl2) to provide the title compound as a white solid
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:8][C:7]=2[CH:31]=1)#[N:2].CI.[Li+].[CH3:35][Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH3:35])=[N:8][C:7]=2[CH:31]=1)#[N:2]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1Cc1nc2cc(C#N)ccc2o1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)c1nc2cc(C#N)ccc2o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 4-((5-cyanobenzo[d]oxazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 144-A) (277 mg, 0.664 mmol) in THF (3.3 mL) was added MeI (0.050 mL, 0.796 mmol) at −78° C. At this point, LHMDS (0.730 mL, 0.730 mmol) was added at the same temperature and the reaction was allowed to warm up to rt over one hour and stirred at rt for 16 hrs. The reaction mixture was quenched at −78° C. with a saturated ammonium chloride (aq.) solution, diluted with water and DCM, passed through a phase separator, concentrated and purified via FCC (12 g column): Heptane/AcOEt:100/0 to 50/50 to obtain the title compound. MS (ESI+) m/z 432.4 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[C:20]1([C:26]2[N:27]=[C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:28]3[S:29][CH:30]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:27]=3)[CH2:32][CH2:33]2)=[O:19])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(NC(=O)OCC(Cl)(Cl)Cl)c1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)c1
Yield: 33.6 %

Procedure:
A solution of 2,2,2-trichloroethyl [3-(acetylamino)phenyl]carbamate (200 mg, 0.614 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (150 mg, 0.614 mmol), diisopropylethylamine (0.107 ml, 0.614 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from chloroform to obtain the desired product (87.0 mg, 33.6%) as a solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C1COCC1.[Li+].CC([N-]C(C)C)C.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>CN(P(N(C)C)(N(C)C)=O)C>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])([CH3:4])[CH3:3]
Reactant: BrCCCCBr
Reactant: CCOC(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(C)(C)CCCCBr
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
In a 1-L 3-neck round-bottomed flask fitted with condenser, dropping funnel pressure equalizer and magnetic stirrer, purged with argon and maintained under argon, were added ethyl isobutyrate (84 ml, 0.63 mol) and THF (120 ml). The mixture was cooled to −78° C., when a solution of LDA (300 ml, 2.0 M in THF/heptane) was added dropwise with a syringe. After the addition was complete, the reaction mixture was stirred at −78° C. for 1 hr. To this mixture, 1,4-dibromobutane (105 ml, 0.84 mol) was added at −78° C., followed by HMPA (90 ml). The reaction mixture was stirred for 30 min at −78° C., then the cooling was stopped. The reaction was left to warm to room temperature, and was quenched with a saturated NH4Cl solution (1.8 L). The aqueous layer was extracted with ethyl acetate (3×100 ml), the organic extracts combined were washed with brine (100 ml), 5% HCl (100 ml) and saturated NaHCO3 (100 ml). The organic phase was dried (MgSO4) and the solvent was evaporated under vacuum. The residue was distilled under reduced pressure to provide the above-titled compound (105.2 g, 70%) (bp 65° C./0.15 mmHg). 1H NMR CDCl3, δ (ppm): 4.15 (q, J=4 Hz, 2H), 3.41 (t, J=5.3 Hz, 2H), 1.85 (qv, J=4 Hz, 2H), 1.60-1.45 (m, 2H), 1.40-1.30 (m, 2H), 1.28 (t, J=4 Hz, 3H), 1.20 (s, 6H); 13C NMR CDCl3, δ (ppm): 177.3, 60.0, 41.8; 39.4, 33.2, 32.9, 24.9, 23.34, 14.02.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][NH:30][CH2:31]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][N:30]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]=1[F:16])[CH2:31]2
Reactant: COc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(NCCO)c2c1=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cccc2c1CN(c1c(F)c(NCCO)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 46.4 %

Procedure:
205 mg of 1-cyclopropyl-5-(2-hydroxyethylamino)-6,7,8- trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 150 mg of 4-methoxyisoindoline, 182 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 131 mg of the target compound.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].[CH:10](=[O:14])[CH2:11][CH2:12][CH3:13]>C(O)C>[CH2:1]([CH:2]1[CH:2]2[C:1](=[O:7])[CH:6]([CH2:5][CH2:4][CH2:3]2)[C:10]2([OH:14])[CH:3]1[CH2:4][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH3:5]
Reactant: O=C1CCCCC1
Reactant: CCCC=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCC1C2CCCC(C2=O)C2(O)CCCCC12
Temperature: 72.5 °C
Reaction time: 15 h

Procedure:
Into a three-neck 500 mL round bottom flask equipped with magnetic stirrer and an oil bath under nitrogen was added 250 parts of cyclohexanone. The oil bath temperature was maintained at 70-75° C. with stirring. A solution of 2.5 parts of potassium hydroxide dissolved in 25 mL of absolute ethyl alcohol was added to the reaction flask in one portion. Thirty parts of butyraldehyde was dissolved in 35 mL of absolute ethyl alcohol and added dropwise to the reaction flask over a period of 6 hours. The reaction mixture was stirred at 70-75° C. for the 15 hours. After the reaction mixture was cooled to room temperature and refrigerated for 15 hours. The inside surface of the flask was scratched with a glass rod to precipitate out the white material and the flask was refrigerated for additional 4-5 hours. The white solid material was filtered and washed with 50 mL of cold water and then with 50 mL cold ether. The recovered solid was dried at room temperature and the yield was 35 parts. The solid showed a single spot on silica gel TLC plate eluted with 10% ethyl acetate/hexane. The structure of the material was confirmed on the basis of 1H NMR. This reaction proceded as follows: