Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4](F)[C:3]=1[F:14].[OH-:15].[K+]>CS(C)=O.O>[N+:8]([C:7]1[C:2]([F:1])=[C:3]([F:14])[C:4]([OH:15])=[C:5]([F:12])[C:6]=1[F:11])([O-:10])=[O:9]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1c(F)c(F)c(O)c(F)c1F
Reaction time: 24 h
Yield: 95 %

Procedure:
21.3 g of pentafluoronitrobenzene (0.1 mol) are dissolved in 400 ml of dimethyl sulfoxide; a solution of 11.2 g of potassium hydroxide (0.2 mol) in 100 ml of water is added drop wise to this solution with vigorous stirring. After 24 hours at room temperature, the crude product is washed by shaking with 200 ml of ethyl acetate and 400 ml of water. The organic phase is washed three times with water, dried over sodium sulfate and evaporated to half in a rotary evaporator. The reaction product is then recrystallized from a mixture of ethyl acetate and n-hexane (volume ratio 1:1) and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 95%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=C(C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)C[CH2:12][O:11][CH2:10]1)C1C=CC=CC=1.[NH2:47]CC1(N(CC2C=CC=CC=2)CC2C=CC=CC=2)COC1>>[NH2:8][C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[N:47][CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:10][O:11][CH2:12]1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Product: NC1(CNc2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccncc23)COC1

Procedure:
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-1,6-naphthyridin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloro-1,6-naphthyridine) and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400 MHz, CD3OD) δ ppm 9.15 (s, 1 H), 8.28-8.80 (d, J=6.4 Hz, 1 H), 8.00-7.95 (d, J=1.2 Hz, 1 H), 7.95-7.90 (d, J=7.2 Hz, 1 H), 7.62-7.58 (t, J=0.8 Hz, 1 H), 7.50-7.40 (m, 2 H), 6.31 (s, 1 H), 5.35 (s, 2 H), 4.65-4.58 (m, 6 H), 3.80 (s, 2 H), 3.60-3.50 (t, J=2.8 Hz, 2 H).
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:17])([CH3:16])[CH2:11][C:12]2=[O:15])=[CH:8][CH:7]=1>O.F[B-](F)(F)F.[H+]>[OH:2][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:17])([CH3:16])[CH2:11][C:12]2=[O:15])=[CH:8][CH:7]=1
Reactant: O=N[O-]
Reactant: CC1(C)CC(=O)c2cc(N)ccc21
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CC1(C)CC(=O)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
A solution of sodium nitrite (14.8 g, 214 mmol) in 30 mL of water was slowly added to the solution of 6-amino-3,3-dimethyl-indan-1-one (14.0 g, 85.8 mmol) in 30 mL of 48% tetrafluoroboric acid and 30 mL of water at 0°-5° C. After being stirred for 30 min, the mixture was filtered, and the solids were washed with cold 5% tetrafluoroboric acid and dried in vacuum. The solids were then added in several portions into a boiling solution of 50 mL of sulfuric acid in 0.5 liter of water. After refluxing for 1 hour, the solution was cooled to room temperature and extracted with ethyl acetate (100 mL×3). The combined extracts were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (EtOAc:hexane=1:10 to 1:2) to give 7.60 g (50% yield) of the title compound as a solid; 1H-NMR (CDCl3) δ 1.40 (s, 6H), 2.64 (s, 2H), 7.13 (s, 1H),7.18 (d, J=8.2 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H); MS m/e 177 (MH+).
Reaction SMILES: [Cl:1][C:2]([Cl:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH3:6].Br[CH:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Ca+2].[Cl-].[Ca+2].[Cl-]>C(O)C>[C:16]([C:10]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:4]([CH:3]=[C:2]([Cl:8])[Cl:1])[C:5]1([CH3:7])[CH3:6])#[N:17]
Reactant: CC(C)=CC=C(Cl)Cl
Reactant: CCOC(=O)C(Br)C#N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C
Reaction time: 6 h
Yield: 68.7 %

Procedure:
A mixture of 1,1-dichloro-4-methylpenta-1,3-diene (30.2 parts), ethyl bromocyanoacetate (38.4 parts), calcium carbonate (20 parts), cuprous chloride (0.2 part) and calcium chloride (22.2 parts) in ethanol (100 parts by volume) is heated to reflux temperature and held at 78°-84° C. for 6 hours. The ethanol is distilled off under reduced pressure and the residue is stirred with a mixture of toluene (100 parts by volume), water (150 parts) and concentrated hydrochloric acid (100 parts by volume). The mixture is filtered from extraneous matter, the residue is washed with toluene and the filtrate and washings are combined. The toluene layer is separated and washed with water. The crude ethyl 1-cyano-3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate is isolated by removal of the toluene under reduced pressure. The product has a strength of 74.6% and a cis-cyano/trans-cyano ratio of 86.1:13.9. The yield is 68.7%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([SH:14])[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:9]=1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:4])([CH3:3])[CH3:2].[S:28](Br)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].N1C=CC=CC=1>CCOC(C)=O>[C:23]([O:22][C:20]([NH:19][C:9]1[C:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:27])=[CH:13][C:12]([S:14][S:28]([C:31]2[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[C:11]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH:10]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1cc(S)c(C(C)(C)C)cc1NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Sc2cc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)cc2C(C)(C)C)cc1

Procedure:
The title compound was prepared according to the General Method 15 using (2-tert-butoxycarbonylamino-4-tert-butyl-5-mercapto-phenyl)-carbamic acid tert-butyl ester (prepared in Example TT-2; 16.9 g, 42.8 mmol), tosyl bromide (10.04 g, 42.76 mmol), pyridine (10 mL), and EtOAc (150 mL). The crude product was purified by flash chromatography (5%-60% EtOAc in hexanes as eluents). 1 H-NMR (CDCl3): δ1.19 (s, 9 H), 1.53 (s, 18 H), 2.42 (s, 3 H), 6.42 (br s, 1 H), 7.22 (d, 2 H), 7.28 (s, 1 H), 7.5 (m, 3 H), 7.87 (br s, 1 H).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:9][CH:8]=3.[NH:25]1[CH:29]=[CH:28][C:27](B(O)O)=[N:26]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:25]1[NH:26][C:27]([C:2]2[N:6]3[C:7]4[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:5]3=[N:4][CH:3]=2)=[CH:11][C:10]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:9][CH:8]=4)=[CH:28][CH:29]=1
Reactant: OB(O)c1cc[nH]n1
Reactant: OCCCNc1nc2cc(OC(F)(F)F)ccc2n2c(Br)cnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCCCNc1nc2cc(OC(F)(F)F)ccc2n2c(-c3ccn[nH]3)cnc12
Temperature: 130 °C
Reaction time: 17 h

Procedure:
To a solution of 3-(1-bromo-7-trifluoromethoxy-imidazo[1,2-a]quinoxalin-4-ylamino)-propan-1-ol (300 mg; 0.74 mmol; 1 eq) in N,N-dimethylformamide (8 mL), pyrazoleboronic acid (166 mg, 1.48 mmol; 2 eq) is added under argon followed by sodium carbonate (314 mg; 2.96 mmol; 4 eq) and tetrakis(triphenylphosphine)palladium (257 mg; 0.22 mmol; 0.3 eq). The solution is allowed to stir for 17 hours at 130° C. until the reaction is complete on TLC. The crude mixture is cooled to room temperature, diluted with ethyl acetate (50 mL), washed once with a saturated solution of sodium hydrogenocarbonate (90 mL) and three times with brine (3×25 mL). The resulting organic phase is dried over sodium sulfate, filtered and concentrated under vacuum to afford a crude brown powder. This solid is purified by chromatography on silica gel (gradient dichloromethane/methanol 98:2→95:5) to afford the title compound as an orange powder. Recristallization of this solid from ethyl acetate at 0-5° C. afforded the pure title compound (88 mg; 0.22 mmol; 30%) after filtration, washing with diethyl ether and drying of the resulting beige powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl:12][C:13]1[CH:21]=[C:20](F)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:39])=[C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=1.Cl>O>[Cl:12][C:13]1[CH:21]=[C:20]([N:36]2[CH2:35][CH2:34][N:33]([C:31]3[CH:32]=[C:27]([F:26])[CH:28]=[CH:29][C:30]=3[CH3:39])[CH2:38][CH2:37]2)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: Cc1ccc(F)cc1N1CCNCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1N1CCN(c2cc(Cl)c(C(=O)O)cc2[N+](=O)[O-])CC1
Yield: 76.7 %

Procedure:
In a 20 ml scintillation vial equipped with a magnetic stir bar and fitted with a nitrogen inlet, the potassium carbonate (201.60 mg, 1.46 mmol) was suspended in clean, dry N,N-dimethylformamide (2.00 ml, 25.83 mmol) and the 2-chloro-4-fluoro-5-nitro-benzoic acid 1b (160.10 mg, 0.73 mmol) was added to the reaction mixture and stirred until it appeared all the organic solid was taken up into solution. The 1-(5-fluoro-2-methyl-phenyl)-piperazine 16d (170.00 mg, 0.88 mmol) was added to the reaction and the reaction mixture was allowed to stir at room temperature under a nitrogen atmosphere overnight. The reaction mixture was diluted with 10 ml of water and treated with 10 ml of 2N HCl. The product mixture was stirred until no further gas evolved and was then filtered under vacuum. The orange solid that was collected was washed with water and dried under high vacuum. The product, 2-chloro-4-[4-(5-fluoro-2-methyl-phenyl)-piperazin-1-yl]-5-nitro-benzoic acid 16e (222.30 mg, 0.56 mmol), was isolated as a yellow solid and was carried on without further purification. LCMS (m/e)=394 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([C:41]([NH2:43])=[O:42])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N[OH:45]>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:16]([C:41]([NH:43][OH:45])=[O:42])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:34])=[O:35])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NO
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(N)=O)cc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(=O)NO)cc1
Reaction time: 3 h
Yield: 18 %

Procedure:
A portion of the crude intermediate of example 58 above, (25 mg, 0.03 mmol) was added to a solution of hydroxylamine in ethanol (1M, 10 mL). The resulting solution was stirred for 3 h before evaporation of the solvent. The residue was purified by preparative HPLC to yield 4.0 mg, 18% of the desired material.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].O1CCCC1.[C@@H:10]12[O:17][CH2:16][C@@H:14]([O:15]1)[CH:13]=[CH:12][C:11]2=[O:18]>C(OCC)(=O)C>[CH:1]([C@:11]1([OH:18])[CH:12]=[CH:13][C@H:14]2[CH2:16][O:17][C@@H:10]1[O:15]2)=[CH2:2]
Reactant: C=C[Mg]Br
Reactant: O=C1C=C[C@H]2CO[C@@H]1O2
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C[C@]1(O)C=C[C@H]2CO[C@@H]1O2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
9.5 ml (1 mol) of vinyl magnesium bromide was gradually added to 50 ml of a dry tetrahydrofuran solution containing 1 g of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose under stirring at 0° C. under an inert atmosphere of nitrogen gas. 30 minutes later, the ice bath was removed, and stirring was further continued for 30 minutes at room temperature. Completion of the reaction was confirmed by thin layer chromatography, and then a small amount of water was added to inactivate any excess Grignard reagent. Then, the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in 200 ml of ethyl acetate and washed three times with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained syrup product was purified by silica gel column chromatography (ethyl acetate: hexane=1:2) to obtain 0.9 g of the desired product (Compound No. 27). The NMR analytical data of this product are as follows.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:26]1([CH2:29][NH2:30])[CH2:28][CH2:27]1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:30][CH2:29][CH:26]4[CH2:28][CH2:27]4)=[O:2])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Reactant: NCC1CC1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)NCC2CC2)cn1
Yield: 70 %

Procedure:
As described for example 117, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (144 mg, 0.4 mmol) was converted, using cyclopropanemethylamine instead of 2,2,2-trifluoroethylamine, to the title compound (111 mg, 70%) which was obtained as a white solid. MS: m/e=398.4 [M+H]+.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[C:19]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:18][CH:17]=[C:16]([O:34][CH3:35])[N:15]=1>C(#N)C>[CH3:35][O:34][C:16]1[N:15]=[C:14]2[NH:13][C:1](=[O:2])[N:20]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:23][CH2:22]3)[C:19]2=[CH:18][CH:17]=1
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: COc1ccc2c(n1)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Carbonyldiimidazole (1.6 g, 9.8 mmol) was added to a solution of 2-amino-3-[(1-t-butoxycarbonylpiperidin-4-yl)amino]-6-methoxypyridine (1.29 g, 4.00 mmol) in acetonitrile (100 mL) at room temperature. The reaction was stirred until all the starting material was consumed. Methanol was added to the reaction and the solution stirred for several hours, then the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with water and saturated brine, and then dried over magnesium sulfate. The crude product was purified by chromatography (silica gel, 2.5% to 5% methanol in methylene chloride gradient elution), which gave the title compound. MS 349 (M+1) 1H NMR (500 MHz, CDCl3) δ 8.50 (br s, 1H), 7.29 (d, J=8 Hz, 1H), 6.43 (d, J=8 Hz, 1H), 4.46 (m, 1H), 4.31 (br s, 2H), 3.90 (s, 3H), 2.85 (br s, 2H), 2.13 (m, 2H), 1.85 (d, J=12 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:21]1([C:27]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:35]3[CH:31]([CH2:32][NH:33][CH2:34]3)[C:30](=[O:36])[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([N:33]1[CH2:32][CH:31]2[CH:35]([C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29][C:30]2=[O:36])[CH2:34]1)=[O:19])[CH3:9])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)c1ccccc1CC(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)c1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
N,N'-carbonyldiimidazole (1.13 g) is added to a solution, cooled to +5° C., of [2-(N-tert-butoxycarbonyl-N-methylamino)phenyl]acetic acid (1.85 g) in dry dichloromethane (30 cc). The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenylperhydro-4-isoindolone hydrochloride (2.29 g) and triethylamine (1.9 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 2 hours, then washed with water (2×200 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063 mm, diameter 4 cm, height 50 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (30:70 by volume) and collecting 125-cc fractions. Fractions 22 to 34 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-{[2-(N-tert-butoxycarbonyl-N-methylamino)phenyl]acetyl}-7,7-diphenylperhydro-4-isoindolone (2.8 g) in the form of a white meringue-like product.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([CH3:38])[CH:32]=2)[O:28][C:29]=1[CH3:30]>>[F:37][C:34]1[CH:35]=[CH:36][C:31]([C:27]2[O:28][C:29]([CH3:30])=[C:25]([CH2:24][N:11]3[C:12]4[C:8](=[CH:7][C:6]([CH2:5][CH:4]([O:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[C:3]([OH:2])=[O:22])=[CH:14][CH:13]=4)[CH:9]=[CH:10]3)[N:26]=2)=[CH:32][C:33]=1[CH3:38]
Reactant: Cc1cc(-c2nc(CCl)c(C)o2)ccc1F
Reactant: COC(=O)C(Cc1ccc2[nH]ccc2c1)Oc1ccccc1
Product: Cc1cc(-c2nc(Cn3ccc4cc(CC(Oc5ccccc5)C(=O)O)ccc43)c(C)o2)ccc1F

Procedure:
In analogy to the procedure described in example 44, rac-3-(1H-indol-5-yl)-2-phenoxy-propionic acid methyl ester (preparation 7) was reacted with 4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole to give rac-3-{1-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-5-yl}-2-phenoxy-propionic acid off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:16].[CH3:17]O>>[ClH:16].[NH2:10][CH:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)[C:11]([O:13][CH3:17])=[O:12]
Reactant: CO
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: Cl
Product: COC(=O)C(N)Cc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of p-nitro-L-phenylalanine (12.6 g) and c.HCl (7.5 g) in methanol (150 ml) was refluxed for 1.5 hours and the solvent then evaporated in vacuo. The residue was triturated with ether and recrystallised from SVM to give the desired product as a off-white solid, [α]25 +15.3° (c=0.55, MeOH).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:21])[C:11]1[CH:16]=[C:15]([NH2:17])[C:14]([CH3:18])=[CH:13][C:12]=1[O:19][CH3:20])[CH3:2].[C:22]([NH:26][S:27](Cl)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:21])[C:11]1[CH:16]=[C:15]([NH:17][S:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:29])=[O:28])[C:14]([CH3:18])=[CH:13][C:12]=1[O:19][CH3:20])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)Cl
Reactant: CCN1CCCC1CNC(=O)c1cc(N)c(C)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CCCC1CNC(=O)c1cc(NS(=O)(=O)NC(C)(C)C)c(C)cc1OC
Yield: 68.3 %

Procedure:
To a mixture of N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-aminobenzamide (1.0 g), dry methylene chloride (20 ml), and triethylamine (693 mg) is added dropwise a mixture of t-butylaminosulfonyl chloride (707 mg) and methylene chloride (5 ml) with ice cooling and stirring. After stirring for 15 minutes, the reaction mixture is mixed with aqueous sodium hydrogencarbonate and shaken with methylene chloride. The organic layer is washed with water, dried over sodium sulfate, and evaporated to remove the solvent. The residue is chromatographed on a column of alumina and eluted with 0-2% methanol/methylene chloride. The eluate is recrystallized from ethyl acetate/isopropyl ether to give N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-t-butylaminosulfonamidobenzamide (1.0 g) as crystals melting at 167° to 168° C.
Reaction SMILES: [F:1][CH:2]([F:12])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1I.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([O:23][CH3:24])[CH:15]=1>CCCCCCC.CCOC(C)=O>[F:1][CH:2]([F:12])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][C:16]=1[O:23][CH3:24]
Reactant: FC(F)CNc1cnccc1I
Reactant: COc1cc(F)ccc1B(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1cc(F)ccc1-c1ccncc1NCC(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (2,2-difluoro-ethyl)-(4-iodo-pyridin-3-yl)-amine and 4-fluoro-2-methoxyphenylboronic acid (CAS RN 179899-07-1) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light brown solid (78%). MS (ESI): m/z=283.18 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[NH:11][C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](I)[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.[Cu]>[Br:26][C:27]1[CH:28]=[C:29]([N:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:17]=3[C:18]3[C:10]2=[CH:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:19]=3)[CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(-c2ccc3[nH]c4ccc(-c5ccccc5)cc4c3c2)cc1
Reactant: Brc1cccc(I)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Brc1cccc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)c1
Temperature: 190 °C
Yield: 86.3 %

Procedure:
3,6-Diphenylcarbazole (2.80 g, 8.77 mmol), 1-bromo-3-iodobenzene (22.18 g, 87.7 mmol), copper powder (0.279 g) and potassium carbonate (4.85 g) were mixed together, and the mixture was heated in a nitrogen atmosphere at 190° C. for 9 hours. The resultant mixture was cooled to room temperature and diluted with methylene chloride, followed by washing with water and drying, to thereby obtain a pale brown liquid. Next, the obtained liquid is purified through silica gel column chromatography using a solvent mixture of methylene chloride/hexane (2/3 by volume), to thereby obtain 3.59 g of 9-(3-bromophenyl)-3,6-diphenylcarbazole.