Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[BH4-].[Na+].C(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: OC(c1ccc(Br)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To 4′-bromo-2,2,2-trifluoroacetophenone (5.0 g, 19.76 mmol) in THF (50 mls) at 0° C. was added NaBH4 (1.5 g, 39.52 mmol). The mixture was warmed to room temperature and stirred for 1 hour. The reaction was complete by TLC (CH2Cl2). The mixture was quenched with H2O, rotary evaporated to remove most of the THF, and extracted 2 times with CH2Cl2. The organics were combined, washed with brine, concentrated to a small volume and filtered through a plug of silica gel. The silica was washed with CH2Cl2 to elute the product, and the resulting solution was concentrated to give 4.65 g of 1-(4-bromophenyl)-2,2,2-trifluoroethanol. Yield: 92%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20][C:21]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:22]=2[C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)=[O:24])[CH2:16][CH2:15]1>C(Cl)(Cl)Cl>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][NH:25][C:23](=[O:24])[C:22]1[CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=[CH:40][C:21]=1[NH:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([NH:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:19][CH2:18]1
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](N)CC2)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](NS(C)(=O)=O)CC2)cc1OC
Temperature: 25 °C

Procedure:
Methanesulfonyl chloride (54 mg) and triethylamine (48 mg) were added to a solution of 2-(trans-4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (134 mg) in chloroform (2 mL). The mixture was stirred for an hour at ambient temperature. Methanesulfonyl chloride (54 mg) and triethylamine (48 mg) were added to the reaction mixture. After stirring for an hour at ambient temperature, the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and 3.6% hydrochloric acid. The separated organic layer was washed with an saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residual crystals were suspended in hot ethanol and cooled with stirring. The resultant was collected by filtration and washed with ethanol to give N-(3,4-dimethoxybenzyl)-2-[trans-4-(methanesulfonylamino)cyclohexylamino]-5-nitrobenzamide (142 mg) as yellow crystals.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH:25][C:27](=[O:34])[C:28]5[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: C[C@H](Nc1cncc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Agent: Cl
Product: C[C@H](Nc1cncc(-n2cnc3cc(NC(=O)c4ccncc4)ccc32)n1)c1ccccc1
Yield: 23 %

Procedure:
In a procedure analogous to example 32, reaction of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-amine (33 mg, 0.10 mmol) and isonicotinoyl chloride hydrochloride (20 mg, 0.11 mmol) furnished the product (10 mg, 23%) after chromatography.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[CH:14]1C=CC=C[CH:15]=1.C(O)C.S(=O)(=O)(O)O>O>[Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH2:14][CH3:15])=[O:10])=[CH:7][CH:6]=1
Reactant: c1ccccc1
Reactant: O=C(O)c1ccc(CCCBr)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(CCCBr)cc1
Reaction time: 23 h

Procedure:
A mixture of p-(3-bromopropyl)benzoic acid (100.8 g.; 0.41 mole), benzene (290 ml.), ethanol (60 ml.) and concentrated sulfuric acid (1.4 ml.) is heated under reflux under a Dean and Stark constant water separator until the evolution of water ceases. The time required is 23 hours.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:38]([N:40]1[CH2:45][CH2:44][N:43]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:42][CH2:41]1)[CH3:39]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:49]3[CH2:50][CH2:51][CH:46]([N:43]4[CH2:44][CH2:45][N:40]([CH2:38][CH3:39])[CH2:41][CH2:42]4)[CH2:47][CH2:48]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN1CCN(C2CCNCC2)CC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCN(CC)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-ethyl-4-piperidin-4-yl-piperazine (Matrix) to give the title compound. HR-MS (ES, m/z) calculated for C40H53Cl2N6O2 [(M+H)+] 719.3602, observed 719.3606.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23](OCC)=[O:24])[N:22]=2)[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23]([NH:12][CH2:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:24])[N:22]=2)[CH:19]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: COc1ccc(CN)cc1OC
Product: COc1ccc(CNC(=O)c2cn3cc(Br)ccc3n2)cc1OC

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (3,4-dimethoxyphenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:9](=[O:11])[CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)Cc1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)Cc3ccccn3)nc12

Procedure:
From 2-pyridylacetic acid hydrochloride, HATU and N-ethyldiisopropylamine in THF, then treatment with (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. ES-MS m/e (%): 386 (M+H+, 100).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]
Reactant: COc1ccc([N+](=O)[O-])cc1CN1C(=O)c2ccccc2C1=O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Cc1cc([N+](=O)[O-])ccc1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of the compound (937 mg) obtained in Example 117 in anhydrous methylene chloride (30 ml), a solution of boron tribromide in methylene chloride (1.0 M, 9 ml) was added dropwise at −78° C. in a nitrogen atmosphere and the mixture was stirred at −78° C. for 1 h, then stirred at room temperature for 21 h. Water was added to the reaction mixture, which was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1) to give 743 mg of the titled compound (yield, 83%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](O)[CH:8]=[C:7]([CH:12]2[CH2:14][CH2:13]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:17]>C1(C)C=CC=CC=1.CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([Cl:17])[CH:8]=[C:7]([CH:12]2[CH2:14][CH2:13]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1nc(O)cc(C2CC2)n1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc(Cl)cc(C2CC2)n1
Yield: 104.9 %

Procedure:
14.8 g 2-tert-butyl-4-hydroxy-6-cyclopropyl-pyrimidine (76.9 mmol) were dissolved in 100 ml of toluene and 3 ml of dimethylformamide. 23.6 ml of POCl3 (153.7 mmol) were added dropwise at 10° C. After stirring overnight at room temperature most of the toluene was evaporated. The mixture was cooled with ice and 20 ml of water were added cautiously. Subsequently, an additional 200 ml of water were added and the aqueous phase was extracted four times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and then concentrated to dryness to yield 17 g of a yellowish oil (quant.).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[C-:22]#[N:23].[Na+].O>CCO>[C:22]([CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4])#[N:23]
Reactant: [C-]#N
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCC(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 10.1 %

Procedure:
To a solution of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (276 mg, 0.93 mmol) in EtOH (8 mL), NaCN (50 mg, 1.02 mmol) was added and the reaction mixture was heated at reflux for 21 hrs. After cooling to room temperature, water (10 mL) was added and the reaction mixture was extracted with ethyl acetate (20 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, and the residue was purified by flash chromatography (Flash Master, 5 g Isolute Silica column, gradient 0 to 5 min hexane, then ethyl acetate up to 50% over 20 min). The isolated solid was triturated with Et2O (10 mL) and filtered to afford 2-cyano-N-[3-(quinoxalin-2-yl)phenyl]acetamide as a light-yellow solid (27 mg, 10% yield). LCMS calculated for C17H12N4O (M+H): 289.30. found 289.00. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.55 (1H, br. S), 9.52 (1H, s), 8.48 (1H, m), 8.20-8.12 (2H, m), 8.10 (1H, d, J=7 Hz), 7.98-7.80 (3H, m), 7.58 (1H, m), 3.95 (2H, s).
Reaction SMILES: [C:1]([NH2:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:13]([S:15]Cl)=[O:14]>C(Cl)(Cl)Cl>[C:4]1(/[CH:3]=[CH:2]/[C:1]2[O:10][C:13](=[O:14])[S:15][N:11]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)C=Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=c1oc(/C=C/c2ccccc2)ns1
Yield: 72.3 %

Procedure:
Cinnamamide (1.9 g, 13 mmol) was mixed with chlorocarbonylsulphenylchloride (1.0 mL, 13 mmol) in chloroform and heated to reflux for 18 h. The reaction mixture was concentrated in vacuo and the resultant material was taken up in boiling hexane (100 mL). The solvent was decanted from the remaining solid, the volume of this solution was reduced by half, and the solution was allowed to cool. The crystalline solids which formed were collected and washed with hexane to afford 5-[(E)-2-phenylethenyl]-1,3,4-oxathiazol-2-one (1.93 g, 72% yield) as pale yellow needles. M.p. 105–106° C. 1H NMR (DMSO-d6, 300 MHz) δ 7.52 (m, 3H), 7.46 (s, 0.5H), 7.41 (m, 2.5H), 6.63 (d, J=16 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6](O)([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=1)=O)[C:7](OCC)=[O:8])=[O:5])C.O.[NH2:25][NH2:26].[OH-].[Na+].Cl>C(O)(C)C>[C:4]([C:6]1[C:7](=[O:8])[NH:25][N:26]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=2)[CH:12]=1)([OH:3])=[O:5]
Reactant: NN
Reactant: CCOC(=O)C(O)(CC(=O)c1ccc(C)c(F)c1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(-c2cc(C(=O)O)c(=O)[nH]n2)cc1F
Reaction time: 6 h

Procedure:
To a solution of ethyl 2-ethoxycarbonyl-4-(3-fluoro-4-methylphenyl)-2-hydroxy-4-oxobutanoate (8.41 9, 25.8 mmol) in isopropanol (100 mL) was added hydrazine monohydrate (2.84 g, 56.8 mmol), and the mixture was heated under stirring at 100 for 6 hours. Then, 2 mol/L sodium hydroxide was added, and the mixture was stirred further at the same temperature for 4 hours. The reaction mixture was ice-cooled, and concentrated hydrochloric acid was added to acidify the system. The precipitate was collected by filtration, thoroughly washed with water and dried to yield the title compound as a slightly yellow crystalline powder (5.67 g, 87.7%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][S:5][CH2:4][C:3]1=[O:8].C([Li])CCC.CCCCCC.[C:20]([C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]=1[OH:35])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1.[Ag]=O>[CH3:23][C:20]([C:24]1[CH:29]=[C:28]([CH2:30][CH:4]2[S:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]2=[O:8])[CH:27]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]=1[OH:35])([CH3:21])[CH3:22]
Reactant: CN1CCSCC1=O
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=[Ag]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCSC(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
4-methyl-3-thiomorpholinone (1.88 g, 14.3 mmol) dissolved in tetrahydrofuran (72 ml) was cooled to 0° C. and treated with 1.37M n-butyl lithium in hexane (20.9 ml, 28.7 mmol). After five minutes, the cold bath was removed. Ten minutes later a solution of 2,6-di-t-butyl-quinone methide, prepared by adding silver oxide (33.2 g, 143 mmol) to 2,6-di-t-butyl-4-methyl-phenol (BHT) (3.16 g, 14.3 mmol) in tetrahydrofuran (72 ml) stirring for 30 minutes and filtering, was added dropwise over 20 min. The reaction was stirred for three hours, quenched with 1N hydrochloric acid, and evaporated to an aqueous suspension. The crude product was extracted into ethyl acetate, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel eluting with 8 L of a 0-50% ethyl acetate in hexane gradient yielded desired product (2.0 g, 40%):
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[C:29]([C:35](O)=[O:36])=[CH:28]2>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:35]([C:29]2[N:30]([CH3:34])[C:31]3[C:27]([CH:28]=2)=[CH:26][C:25]([F:24])=[CH:33][CH:32]=3)=[O:36])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: Cn1c(C(=O)O)cc2cc(F)ccc21
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc3cc(F)ccc3n2C)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 5-Fluoro-1-methyl-1H-indole-2-carboxylic acid. LC-MS (basic): tR=0.99 min; [M+H]+=523.2.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13]1[NH:14][C:15]3[C:20]([C:21]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7]2.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:12][C:11]1[CH:10]=[CH:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:13]3[NH:14][C:15]4[C:20]([C:21]=3[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:7]=2)[C:2]=1[Br:1]
Reactant: CCCCCc1c(-c2ccc3c(Br)c(O)ccc3c2)[nH]c2ccccc12
Reactant: COC(=O)CBr
Product: CCCCCc1c(-c2ccc3c(Br)c(OCC(=O)OC)ccc3c2)[nH]c2ccccc12

Procedure:
The title compound was prepared as a solid (0.410 g, 58%) from 2-(5-bromo--6-hydroxy-2-naphthyl)-3-pentyl-1H-indole using methyl bromoacetate and the procedure from step 3 of Example 2; 1H NMR (DMSO-d6) δ 0.82 (t, J=7.0 Hz, 3H), 1.27-1.39 (m, 4H), 1.64-1.74 (m, 2H), 2.93 (t, J=7.3 Hz, 2H), 3.73 (s, 3H), 5.12 (s, 2H), 7.02 (t, J=7.5 Hz, 1H), 7.12 (t, J=7.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.48 (d, J=9.2 Hz, 1H),7.57 (d, J=7.9 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 8.03 (d, J=9.0 Hz, 1H), 8.14 (d, J=1.6 Hz, 1H), 8.22 (d, J=8.9 Hz, 1H), 11.26 (s, 1H); mass spectrum [(+) ESI], m/z 480/482 (M+H)+ and [(−) ESI], m/z 478/480 (M−H)−.
Reaction SMILES: CC1C=C(C2C(F)=C(F)C3C(=O)C([C:23]([OH:25])=[O:24])=CN4C(C)COC=2C=34)C=C(C)N=1.Br[C:30]1[C:35]([F:36])=[C:34]([F:37])[C:33]([Br:38])=[C:32]([F:39])[C:31]=1[F:40].C([Li])CCC.C(=O)=O>>[Br:38][C:33]1[C:34]([F:37])=[C:35]([F:36])[C:30]([C:23]([OH:25])=[O:24])=[C:31]([F:40])[C:32]=1[F:39]
Reactant: Cc1cc(-c2c(F)c(F)c3c(=O)c(C(=O)O)cn4c3c2OCC4C)cc(C)n1
Reactant: Fc1c(F)c(Br)c(F)c(F)c1Br
Agent: O=C=O
Agent: [Li]CCCC
Product: O=C(O)c1c(F)c(F)c(Br)c(F)c1F

Procedure:
The above Flow Sheet A illustrates the preparation of 10-(2,6-dimethyl-4-pyridinyl)-8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine6-carboxylic acid. 1,4-Dibromo-2,3,5,6-tetrafluorobenzene (III) is metalated with butyllithium and then caused to react with carbon dioxide to give 4-bromo-2,3,5,6-tetrafluorobenzoic acid (IV). The latter is converted to its acid chloride (V) which reacts with a half ester of malonic acid in the presence of butyllithium to afford an alkyl 4-bromo-2,3,5,6-tetrafluorobenzoylacetate (VI). The benzoylacetate (VI) is then treated with molar equivalent amounts of dimethylformamide (DMF) dimethyl acetal and 2-amino-1-alkanol to produce an alkyl N-(1-hydroxy-2-alkyl)-3-amino-2-(4-bromo-2,3,5,6-tetrafluorobenzoyl)propenoate (VII). The latter is then cyclized by heating with a base, preferably potassium carbonate, to give a compound of Formula II (R'=F). The alkyl 10-bromo-8,9-difluoro-3-alkyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate (II) is then caused to react with a 2,6-dimethyl-4-(trialkylstannyl)pyridine in the presence of a palladium complex catalyst thereby producing a compound of Formula I where R'=F and X=O. The latter can then be converted to the free acid (I; R=H, R'=F, X=O) by a conventional hydrolysis reaction with base or acid.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([NH:20][C:21](=O)OC(C)(C)C)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35](C=O)=[CH:34][C:33]=2[CH:39]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35]([CH:21]=[N:20][N:17]3[CH2:16][CH2:15][N:14]([CH2:13][C@:2]4([CH3:1])[O:6][C:5]5=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]5[CH2:3]4)[CH2:19][CH2:18]3)=[CH:34][C:33]=2[CH:39]=1
Reactant: CC(C)(C)OC(=O)NN1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=Cc1cc2cc(Cl)ccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(CN2CCN(N=Cc3cc4cc(Cl)ccc4o3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
To a mixture of tert-butyl (S)-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]carbamate prepared in Example 503 (0.20 g, 0.523 mmol) and 5-chlorobenzofuran-2-carbaldehyde (0.113 g, 0.628 mmol) and methylene chloride (4 ml), trifluoroacetic acid (0.4 ml) was added followed by stirring at room temperature for 2 hours. To the reaction mixture, a saturated sodium hydrogencarbonate solution was added followed by extraction with methylene chloride. The organic phase was washed with a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=4/1) to afford (S)-N-(5-chlorobenzofuran-2-ylmethylene)-N-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]amine (0.137 g, yield 59%) as a light yellow powder.
Reaction SMILES: [I: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.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([NH:35][NH2:36])=[O:34])=[CH:29][CH:28]=3)=[O:25])=[CH:21][C:16]=2[O:15][CH2:14]1>C(O)(=O)C>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([NH:35][N:36]=[C:5]4[C:4]5[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=5)[NH:7][C:6]4=[O:11])=[O:34])=[CH:29][CH:28]=3)=[O:25])=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: NNC(=O)c1ccc(NC(=O)CCc2ccc3c(c2)OCO3)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C(CCc1ccc2c(c1)OCO2)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 76 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 3-(1,3-benzodioxol-5-yl)-N-[4-(hydrazinocarbonyl)phenyl]propanamide. 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 97 mg of the title compound (76%) as a yellow solid in 98.8% purity by HPLC (Rt: 4.33, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]([OH:22])=O)[CH:16]=2)[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[C:27]=1[OH:33])=[O:25].N1C=CC=CC=1>C(Cl)(=O)C(Cl)=O.C(Cl)Cl>[C:24]([C:26]1[C:27]([OH:33])=[C:28]([NH:32][C:20]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[O:11][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:19][CH2:18]3)=[O:22])[CH:29]=[CH:30][CH:31]=1)(=[O:25])[CH3:23]
Reactant: CC(=O)c1cccc(N)c1O
Reactant: O=C(O)c1ccc2c(c1)CCC(COCc1ccccc1)O2
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1cccc(NC(=O)c2ccc3c(c2)CCC(COCc2ccccc2)O3)c1O
Temperature: 75 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
A suspension of 2-(benzyloxymethyl)-6-chromanecarboxylic acid (0.700 g, 2.35 mmol) in oxalyl chloride (5.98 ml) was heated at 75° C. for 35 minutes. The oxalyl chloride excess was evaporated off in a nitrogen stream and the resulting residue was dissolved in the minimum amount of dry methylene chloride. This solution was added at 0° C. and under inert atmosphere to a solution of 3-amino-2-hydroxyacetophenone (0.550 g, 2.37 mmol), pyridine (7 ml) and dry methylene chloride (40 ml). The resulting mixture was left under stirring at room temperature for 18 h, then diluted with methylene chloride (40 ml), washed successively with 1M HCl and a sodium chloride saturated solution, dried and the solvent was evaporated off under reduced pressure. A crude was obtained which was purified by chromatography through a silica gel column, eluting with petroleum ether:chloroform mixtures of increasing polarity. At a 40% chloroform proportion, 0.732 g of the title compound were eluted (72% yield).