Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([O:30]CC)=O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+:34].C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:30])[NH2:34])[N:27]=2)[CH2:22]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](OC1CN(c2nc(C(N)=O)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 17 h
Yield: 91 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (5.85 g, 12.5 mmol) (obtained as described in Reference Example 2(1)) in benzene (290 ml) was added a solution of 0.67M ammonium chloride-trimethylaluminium in benzene (56.4 ml) at room temperature under an atmosphere of nitrogen. The mixture was stirred in a water bath (40° C.) for 17 hours. After checking the completion of the reaction, 10% aqueous acetic acid solution (100 ml) and ethyl acetate (50 ml) were added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 2 hours. After adding ethyl acetate thereto, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (3:1→1:2) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-carbamoyl-1,3-thiazol-2-yl)azetidine (4.97 g, yield 91%) as a pale brown solid.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([NH:11][C@H:12]([C:20]([NH2:22])=[O:21])[CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.Cl.[NH:25]([C:39]([CH3:41])=[O:40])[C@H:26]([C:36](O)=[O:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C.[N-]=[N+]=[N-]>CN(C)C=O>[NH:25]([C:39]([CH3:41])=[O:40])[C@H:26]([C:36]([NH:1][C@H:2]([C:9]([NH:11][C@H:12]([C:20]([NH2:22])=[O:21])[CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1
Reactant: NC(=O)[C@H](Cc1cccnc1)NC(=O)[C@@H](N)C1CCCCC1
Reactant: CC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Agent: Cl
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)N[C@H](C(=O)N[C@@H](Cc1cccnc1)C(N)=O)C1CCCCC1
Yield: 82.4 %

Procedure:
Stir overnight H-(L)-Chg-(L)-Pal-NH2.2HCl (1.13 g, 3 mmol), Ac-(L)Phe(4-CN)-OH (0.84 g, 3.6 mmol), diisopropylethylamine (10 mmol). and diphenylphoshoryl azide (803 μl 3.6 mmol) dimethyl formamide (30 mL) overnight. Evaporate dimethyl formamide, precipitate by ether, filter and wash by ether to give Ac-(L)-Phe(4-CN)-(L)-Chg-(L)-Pal-NH2 (1.282 g, 82%). ##STR21##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([O-:3])=[O:2].[CH3:17]OS(OC)(=O)=O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:17])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)ccc1O
Reactant: COS(=O)(=O)OC
Product: COc1ccc(-c2ccccc2)cc1[N+](=O)[O-]

Procedure:
After the 3-nitro-4-hydroxybiphenyl is formed as described above, it is then reacted with dimethylsulfate to form 3-nitro-4-methoxybiphenyl, which is then reduced to form 3-amino-4-methoxybiphenyl. The 3-amino4-methoxybiphenyl is precipitated by the addition of hydrochloric acid solution, forming the desired 3-amino-4-methoxybiphenyl hydrochloride.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:10][C:9]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[S:13][CH2:14][C:8]=2[C:7](=[O:19])[C:6]=1[CH3:20])=[O:4].[OH-].[Na+]>CO>[CH3:20][C:6]1[C:7](=[O:19])[C:8]2[CH2:14][S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:9]=2[O:10][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1oc2c(c(=O)c1C)CSc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)oc2c(c1=O)CSc1ccccc1-2

Procedure:
A mixture of 3-methyl-4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-2-carboxylic acid methyl ester (1.60 g, 5.56 mmoles, described in Example 7) in a solution of sodium hydroxide (0.5 g) in methanol (50 ml is refluxed for 2 hr and evaporated. The residue is dissolved in water, and the solution is washed with diethyl ether and added with stirring to 3 N hydrochloric acid (25 ml). The fine precipitate is collected, washed with very dilute hydrochloric acid, small amount of water and then dried (1.506 g), mp 299°-301° C. The precipitate is crystallized from dimethyl sulfoxide-water to obtain crystals of the title compound, mp 302°-303° C.
Reaction SMILES: [CH3:1][CH:2]([NH2:14])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.[NH2:15][C:16](=[O:29])[CH2:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][CH:24]2[O:26][CH2:25]2)=[CH:20][CH:19]=1>CO>[NH2:15][C:16](=[O:29])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH:24]([OH:26])[CH2:25][NH:14][CH:2]([CH3:1])[CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:7]=[CH:6]2)=[CH:27][CH:28]=1
Reactant: CC(N)CCn1cnc2ccccc21
Reactant: NC(=O)Cc1ccc(OCC2CO2)cc1
Solvent: CO
Product: CC(CCn1cnc2ccccc21)NCC(O)COc1ccc(CC(N)=O)cc1

Procedure:
A mixture of 1.65 grams of α-methyl-1H-benzimidazole-1-propanamine and 1.82 grams of 1-[4-(2-amino-2-oxoethyl)phenoxy]-2,3-epoxypropane in 6 ml. of 95 percent methanol was refluxed for 19 hours. The solvent was evaporated from the mixture and the residual solid was triturated several times with ether. The solid was then dried and chromatographed on a silica gel column using methanol. The fractions containing the desired product were determined by thin-layer chromatography and combined. The solvent was then evaporated to leave a residual oil which solidified on cooling to give N-{3-[4-(2-amino-2-oxoethyl)phenoxy]-2-hydroxypropyl}-α-methyl-1H-benzimidazole-1-propanamine melting at about 139°-142° C. This compound has the following structural formula. ##STR18##
Reaction SMILES: [CH3:1]I.[Na].[NH2:4][C:5]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([O:25][CH3:26])[C:17]=2[CH3:27])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].O>CN(C=O)C>[NH2:4][C:5]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([O:25][CH3:26])[C:17]=2[CH3:27])=[O:15])=[CH:10][C:6]=1[C:7]([O:9][CH3:1])=[O:8]
Reactant: COc1c(C)c(C(=O)c2ccc(N)c(C(=O)O)c2)n2ccccc12
Reactant: CI
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3ccccn23)ccc1N
Reaction time: 1 h

Procedure:
1.51 ml (24.26 mmol) of methyl iodide are added, under an inert atmosphere at ambient temperature, to 8 g (23.1 mmol) of the sodium salt of 2-amino-5-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]benzoic acid (described in WO 03/084956) in 130 ml of DMF. After stirring for 1 hour, water is added. The precipitate formed is filtered off, rinsed with water, and then dried under reduced pressure at 50° C. overnight. 7.17 g of a yellow solid are obtained.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]4[O:28][C:27]([CH2:29]O)=[CH:26][C:25]=4[CH:31]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(Cl)Cl.O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]4[O:28][C:27]([CH2:29][N:43]5[CH2:44][CH2:45][CH:40]([CH3:39])[CH2:41][CH2:42]5)=[CH:26][C:25]=4[CH:31]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: CC1CCNCC1
Reactant: OCc1cc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc2o1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1CCN(Cc2cc3cc(C#Cc4ccc(-c5ccc(Cl)cc5)cn4)ccc3o2)CC1
Reaction time: 1 h

Procedure:
32 μL (0.40 mmol) methanesulphonic acid chloride are added to a solution of 100 mg (0.28 mmol) {5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-benzofuran-2-yl}-methanol and 69 μL (0.50 mmol) triethylamine in 5 mL DCM at 0° C. and the reaction is stirred for 1 h at this temperature. Another 70 μL (0.89 mmol) methanesulphonic acid chloride are added and the reaction is stirred overnight at RT. Then 0.24 ml (2.00 mmol) 4-methylpiperidine is added and the reaction is stirred for 2 hours at RT. The reaction solution is diluted with water and the aqueous phase extracted twice with DCM. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (DCM/methanol 9:1).
Reaction SMILES: Cl.O=[C:3]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][CH2:13]2)[CH:4]([CH3:9])[CH2:5][C:6](O)=[O:7].O.[NH2:20][NH2:21]>C(O)C>[CH3:9][CH:4]1[C:3]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH2:14][CH2:13]3)=[N:21][NH:20][C:6](=[O:7])[CH2:5]1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc2c(c1)CCN2
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc2c(c1)CCN2

Procedure:
A solution of 27 g of 4-oxo-4-(indolin-5-yl)-3-methylbutanoic acid hydrochloride and 15 ml of hydrazine hydrate in 200 ml of ethanol was heated under reflux on a water bath for 2 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The precipitated crystals were filtered off, washed with water and recrystallized from ethanol to give 20 g of 5-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)indoline as white crystals, melting at 187°-189° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:20]2[CH2:24][CH2:23][C@@H:22]([CH3:25])[CH2:21]2)[CH2:9][C:10]([F:19])([F:18])[C:11](=[O:17])C(OCC)=O)[C:5]([N+:26]([O-])=O)=[CH:4][N:3]=1.Cl.CCOC(C)=O.CCOCC>CC(O)=O.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:26][C:11](=[O:17])[C:10]([F:19])([F:18])[CH2:9][N:8]([CH:20]3[CH2:24][CH2:23][C@@H:22]([CH3:25])[CH2:21]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)C(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CC[C@@H](C)C1
Agent: [Fe]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: C[C@@H]1CCC(N2CC(F)(F)C(=O)Nc3cnc(Cl)nc32)C1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Compound ethyl 4-((2-chloro-5-nitropyrimidin-4-yl)((3R)-3-methylcyclopentyl)amino)-3,3-difluoro-2-oxobutanoate was dissolved in AcOH and then cooled in an ice bath (sometimes this crystallizes out upon cooling). Iron powder (2 equivalents) was added followed by the slow addition of HCl (15 mL, conc.). After 10 minutes the reaction was transferred to a heat bath and left to stir at 60° C. for 5 hours. The reaction was then cooled, the stir bar and unreacted iron removed with a magnet (or by filtration through paper), and the solvent volume reduced by about 75% on a rotovap. The mixture was then diluted with ice water (150 mL) and EtOAc (1500 mL), the layers separated, the aqueous layer washed with EtOAc (2×150 mL), the organic extracts combined, washed with sat. NaHCO3 (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated to yield a brown syrup. Trituration with EtOAc (15 mL) and ether (100 mL) to coax out a tannish solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91-2.29 (m, 10 H) 3.80-4.20 (m, 2 H) 4.81-5.07 (m, 1 H) 8.12 (s, 1 H) 11.07 (br. s., 1 H). m/z 317.
Reaction SMILES: [CH2:1]([O:9][C:10]1[C:11]([F:25])=[C:12](C2C(O)=CC=CC=2F)[C:13](O)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(OC1C=CC(Br)=CC=1F)C1C=CC=CC=1.BrCCCCCCCC.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:29]2[CH:30]=[CH:31][C:32]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:27]([F:26])[CH:28]=2)=[CH:12][C:11]=1[F:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(O)c(-c2c(O)cccc2F)c1F
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1F
Agent: Fc1cc(Br)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCCCBr
Solvent: CCC(C)=O
Product: CCCCCCCCOc1ccc(-c2ccc(OCCCCCCCC)c(F)c2)cc1F
Reaction time: 20 h

Procedure:
A mixture of 4'-octyloxy-3,3'-difluorobiphenol (0.1 mol, obtained by coupling 3-fluoro-4-octyloxyphenyl boronic acid with 4-benzyloxy-3-fluoro-brombenzene followed by hydrogenolytic cleavage of the benzylic ether), 1-bromooctane (0.12 mol), potassium carbonate (30 g) and butanone (125 ml) is heated under reflux and stirred for 20 hrs. After cooling the reaction mixture is filtered and the filtrate evaporated off, distillation under reduced pressure affords the required product, m.p. 84°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Mg].C(O[CH2:21][C:22]([F:36])=[CH:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)(=O)C>O1CCCC1>[CH2:34]([O:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2([CH:23]=[C:22]([F:36])[CH2:21][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:4]=3)[CH2:25][CH2:26]2)=[CH:28][CH:29]=1)[CH3:35]
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Reactant: CCOc1ccc(C2(C=C(F)COC(C)=O)CC2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc(C2(C=C(F)Cc3ccc(F)c(Oc4ccccc4)c3)CC2)cc1
Yield: 12.4 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 4-fluoro-3-phenoxyphenyl bromide (0.246 g), tetrahydrofuran (2 ml) and magnesium (21 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-ethoxyphenyl)cyclopropane (Example 18) (0.176 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C18; solvent: methanol; flow rate: 8 ml/min) to afford 1-(4-ethoxyphenyl)-1-(2-fluoro-3-(4-fluoro-3-phenoxyphenyl)-prop-1-enyl)cyclopropane (32 mg, 12%).
Reaction SMILES: CO[C:3](=[O:18])[CH2:4][C@:5]([NH2:17])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[CH2:6][CH3:7].[CH3:19][NH:20][C:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=S>>[C:26]([O:25][C:24](=[O:30])[NH:23][C:21]1[N:20]([CH3:19])[C:3](=[O:18])[CH2:4][C@@:5]([CH2:6][CH3:7])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[N:17]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Reactant: CC[C@](N)(CC(=O)OC)c1cccc([N+](=O)[O-])c1
Product: CC[C@@]1(c2cccc([N+](=O)[O-])c2)CC(=O)N(C)C(NC(=O)OC(C)(C)C)=N1

Procedure:
Starting from (S)-3-amino-3-(3-nitro-phenyl)-pentanoic acid methyl ester (1.2 mmole) and tert-butyl [(methylamino)carbonothioyl]carbamate, the product [(S)-4-ethyl-1-methyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (372 mg) was obtained as white solid. MS (ESI): m/z=375.4 [ M−H]−.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[CH2:16](O)[CH3:17]>>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C(O)CCCCCCCBr
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCCCCCCBr
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Thionylchloride (8.15 ml, 0.112 mols) was added dropwise to an ethanol (500 ml) solution of 8-bromooctanoic acid (50.0 g, 0.224 mols) with cooling with ice, and the reaction mixture was then stirred for 12 hours at room temperature. The reaction mixture was concentrated in vacuo, and a saturated aqueous sodium bicarbonate solution was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated in vacuo. The thus-obtained crude product was purified by alumina column chromatography (hexane) to obtain the entitled compound (51.6 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:13]([OH:15])=O)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([C:13]([NH:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[O:15])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COc1nc2ccccc2nc1C(=O)O
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1nc2ccccc2nc1C(=O)Nc1nnn[nH]1

Procedure:
3Methoxy-2-quinoxalinecarboxylic acid (1.5 g) and N,N-carbonyldiimidazole (1.2 g) in tetrahydrofuran (50 ml) were heated under reflux for 15 minutes. 5-Amino-1H-tetrazole (0.7 g) in dimethylformamide (5 ml) was added and the solution was heated under reflux for 1 hour. The crystalline solid was collected and stirred with dilute hydrochloric acid (25 ml., 2N) and the solid was filtered off and dried. It had m.p. 260° (d) (45%).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=O.[Cl:15][C:16]1[N:17]=[CH:18][N:19]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH2:30])=[S:29])=[CH:23][C:22]=2[O:31][CH3:32])[CH:20]=1>C(O)C.CCOC(C)=O>[Cl:15][C:16]1[N:17]=[CH:18][N:19]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]3[S:29][C:2]4[CH2:7][CH2:6][CH2:5][CH:4]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[C:3]=4[N:30]=3)=[CH:23][C:22]=2[O:31][CH3:32])[CH:20]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(Cl)c1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-n1cnc(Cl)c1
Yield: 26 %

Procedure:
A mixture of 2-bromo-6-phenylcyclohexanone (89 mg, 0.352 mmol, from preparation AAA) and 1-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)thiourea (99 mg, 0.352 mmol, from step 4 of preparation A) was heated in ethanol (0.60 mL) at 80° C. for 3 h. The crude reaction was diluted with EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuo. The crude product was purified using preparatory TLC (60% acetone/hexanes) to give 42 mg (26% yield) of the titled compound as a white solid. LC-MS (M+H)+ 437.0. 1H NMR (400 MHz, chloroform-d) δ ppm 7.50 (d, J=1.51 Hz, 1 H) 7.45 (d, J=2.52 Hz, 1 H) 7.28-7.36 (m, 2 H) 7.14-7.23 (m, 3H) 7.08 (d, J=8.31 Hz, 1 H) 7.00 (d, J=1.51 Hz, 1 H) 6.60 (dd, J=8.44, 2.39 Hz, 1 H) 4.05 (t, J=6.30 Hz, 1H) 3.47 (s, 3 H) 2.68-2.89 (m, 2 H) 2.20-2.28 (m, 1 H) 1.98 (dd, J=7.30, 5.29 Hz, 1 H) 1.78-1.93 (m, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=C(I)C4C(=O)NC(=O)C=4[C:5]=3[C:4]=2[CH:3]=1.[Br-].[Cl:22][C:23]1[C:48]([O:49][CH3:50])=[CH:47][CH:46]=[C:45]([Cl:51])[C:24]=1[CH2:25][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].[CH3:53]C([N-]C(C)C)C>>[Cl:22][C:23]1[C:48]([O:49][CH3:50])=[CH:47][CH:46]=[C:45]([Cl:51])[C:24]=1/[CH:25]=[CH:9]/[C:10]1[NH:11][C:12]2[C:4]([CH:5]=1)=[CH:3][C:2]([O:1][CH3:53])=[CH:14][CH:13]=2
Reactant: CC(C)[N-]C(C)C
Reactant: COc1ccc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1Cl
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Agent: [Br-]
Agent: [Li+]
Product: COc1ccc2[nH]c(/C=C/c3c(Cl)ccc(OC)c3Cl)cc2c1
Reaction time: 5 h

Procedure:
The 5-methoxy-1H-indole-2-carbaldehyde (1) was reacted with (2,6-dichloro-3-methoxybenzyl)(triphenyl)phosphonium bromide (526), prepared as described in example 117, using the procedure described in example 37, except that the aldehyde was added at 0° C., the ratio of LDA:aldehyde was 1.55:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/hexane) the diene (527) as a cream solid (the pure E isomer) (76%), mp 138–140° C. 1H NMR (CDCl3) δ 8.21 (br s, 1H), 7.32 (d, J=8.9 Hz, 1H), 7.26 (d, J=8.7 Hz, 1H), 7.22 (d, J=16.8 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 6.92 (d, J=16.8 Hz, 1H), 6.87 (dd, J=8.8, 2.5 Hz, 1H), 6.80 (d, J=8.9 Hz, 1H), 6.61 (d, J=1.7 Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H). Found: C, 61.92; H, 4.52; N, 3.91. C18H15Cl2NO2 requires C, 62.09; H, 4.34; N, 4.02.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:24][C:20]1[CH:19]=[C:18]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:31]4[C:26]([F:25])=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:3]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:23]=[CH:22][N:21]=1
Reactant: NC1=NC(c2cccc(Br)c2)(c2ccnc(Cl)c2)c2ccccc21
Reactant: OB(O)c1cccnc1F
Product: NC1=NC(c2cccc(-c3cccnc3F)c2)(c2ccnc(Cl)c2)c2ccccc21
Yield: 35 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-chloropyridin-4-yl)-1H-isoindol-3-amine (Example 120) as described in Example 67 Scheme #10, D in 35% yield using 2-fluoropyridine-3-boronic acid. 1H NMR (DMSO-d6) δ 8.32 (d, J=5.31 Hz, 1 H), 8.27-8.19 (m, 1 H), 8.08-7.99 (m, 1 H), 7.96-7.81 (m, 2 H), 7.61-7.31 (m, 9 H), 7.01 (br s, 2 H); MS (ESI) m/z 415 [M+1]+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]3[C:28](=[O:29])[C:27]4=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]4[C:25]3=[O:34])=[CH:19][CH:18]=2)[C:5]1=[O:36])(=O)C.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[C:38]1([NH:37]/[C:16](=[C:6]2\[C:5](=[O:36])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:24]3[C:25](=[O:34])[C:26]4=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]4[C:28]3=[O:29])=[CH:21][CH:22]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccccc1)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1

Procedure:
Prepared analogously to Example 146 from 1-acetyl-3-[1-chloro-1-(4-phthalimidomethyl-phenyl)-methylidene]-5-nitro-2-indolinone, aniline, N-ethyl-N,N-diisopropyl-amine and DMF.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([F:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](I)[CH3:19]>CS(C)=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:18][CH3:19])=[C:4]([F:11])[CH:3]=1.[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH2:18][CH3:19])[CH:6]=2
Reactant: Fc1cc(Br)cc2[nH]ncc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCn1cc2c(F)cc(Br)cc2n1
Product: CCn1ncc2c(F)cc(Br)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %
Yield: 17 %

Procedure:
To a solution of 6-bromo-4-fluoro-1H-indazole (1000 g, 4.65 mol) in DMSO (5.0 L), was added K2CO3 (900 g, 6.51 mol), followed by addition of ethyl iodide (900 g, 5.77 mol). The reaction mixture was stirred at r.t. for 16 h. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (0-10% EtOAc in hexanes) to give 6-bromo-1-ethyl-4-fluoro-1H-indazole (595 g, 2.45 mol, 52%) as a yellow oil and 6-bromo-2-ethyl-4-fluoro-2H-indazole (278 g, 1.14 mol, yield 17%) as an orange solid. 1H NMR (600 MHz, CDCl3) δ 1.52 (t, 3H), 4.39 (q, 2H), 6.95 (dd, 1H), 7.40 (s, 1H), 8.02 (s, 1H). MS (ES+)(M+H) 243.