Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[C:14]([N:15]2[CH2:19][C@@H:18]([C:20]([O:22]C(C)(C)C)=[O:21])[N:17]([CH3:27])[C:16]2=[O:28])=[CH:13][CH:12]=[CH:11][N:10]=1>ClCCl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[F:8][C:9]1[C:14]([N:15]2[CH2:19][CH:18]([C:20]([OH:22])=[O:21])[N:17]([CH3:27])[C:16]2=[O:28])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CN1C(=O)N(c2cccnc2F)C[C@H]1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)N(c2cccnc2F)CC1C(=O)O
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (400 mg, 1.998 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-fluoro-3-iodopyridine (352 mg, 1.998 mmol) in 1,4-dioxane (20 ml) was added trans-N,N-dimethylcyclohexane-1,2-diamine (0.062 ml, 0.400 mmol), potassium phosphate (1272 mg, 5.99 mmol) and copper(I) iodide (38.0 mg, 0.200 mmol) and the reaction mixture was heated at reflux under argon overnight. The reaction mixture was allowed to cool and the solvent was evaporated. The residue was partitioned between dichloromethane and water. The organic layer was separated and washed with water (˜50 ml) containing 0.880 ammonia solution (˜5 ml), then brine and passed through a hydrophobic frit and the organic layer was reduced under vacuum. The residue was purified by SP4 automated silica gel chromatography eluting with 10-80% ethyl acetate in isohexane to give 1,1-dimethylethyl 1-(2-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (405 mg, 67.3% yield). LC/MS [M+H]+=296. (ii) Trifluoroacetic acid (2 ml) was added to a solution of 1,1-dimethylethyl (4S)-1-(2-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (400 mg, 1.355 mmol) in dichloromethane (5 ml) and the solution was stirred at room temperature for 36 hours. The reaction mixture was reduced under vacuum and the residue was azeotroped with toluene and dried under heated vacuum to give 1-(2-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜1.35 mmol) which was used in the next step. LC/MS [M+H]+=240.
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([CH3:13])[CH:11]([NH2:14])[CH:10]([CH3:15])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)Cl>[C:16]1([CH:9]2[CH:10]([CH3:15])[CH:11]([NH:14][C:29](=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:12]([CH3:13])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:8]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC1C(c2ccccc2)NC(c2ccccc2)C(C)C1N
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)NC1C(C)C(c2ccccc2)NC(c2ccccc2)C1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
To a stirred 0° C. solution of 12.7 g (45.3 mmol) of 2,6-diphenyl-3,5-dimethyl-4-aminopiperidine and 5.1 g (50 mmol) of triethylamine in 150 ml of methylene chloride is added dropwise a solution of 9.9 g (45.3 mmol) of lauroyl chloride. After stirring for 30 minutes at 0° C., the reaction mixture is washed with water (2×200 ml) followed by a saturated aqueous sodium bicarbonate solution (300 ml). The organic phase is separated, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting solid is recrystallized from ethanol to give 15.4 g (73% yield) of the title compound as a white solid melting at 112°-114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:26]>CN(C=O)C>[Br:26][C:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:20]3[S:21][CH:22]=[CH:23][N:24]=3)[CH:10]=2)[N:15]=[CH:14][CH:13]=1
Reactant: BrP(Br)Br
Reactant: Oc1ccnc2ccc(C(c3ccc(Cl)cc3)c3nccs3)cc12
Solvent: CN(C)C=O
Product: Clc1ccc(C(c2ccc3nccc(Br)c3c2)c2nccs2)cc1

Procedure:
6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-4-ol (500 mg, 1.417 mmol, 1 equip) was dissolved in DMF (4 mL) and phosphorus tribromide (766 mg, 2.834 mmol, 2 equip) was added dropwise. A red-brown precipitate formed immediately and was collected to yield 2-((4-bromoquinolin-6-yl)(4-chlorophenyl)methyl)thiazole which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([CH3:24])([CH3:23])[C:18]([O:20]CC)=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.[Li+].[OH-]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([CH3:24])([CH3:23])[C:18]([OH:20])=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(C)(C)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanoate (Example 59, 300 mg, 0.78 mmol) in THF (2.6 mL) and MeOH (2.6 mL) was added LiOH (54 mg, 2.25 mmol) in H2O (2.6 mL). The reaction was stirred at ambient temperature overnight. The solvents were removed under reduced pressure, 10% HCl (aq.) (5 mL) was added and the precipitate was collected and dried under vacuum, the crude product was used without further purification in the next step.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[CH3:11][O:12][C:13](=[O:32])[CH:14]1[CH:19]=[C:18]([N:20]2[CH:24]=[CH:23][CH:22]=[CH:21]2)[C:17](Cl)=[C:16]([N+:26]([O-:28])=[O:27])[C:15]1=[S:29](=[O:31])=[O:30]>C1COCC1>[CH3:11][O:12][C:13](=[O:32])[CH:14]1[CH:19]=[C:18]([N:20]2[CH:24]=[CH:23][CH:22]=[CH:21]2)[C:17]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:16]([N+:26]([O-:28])=[O:27])[C:15]1=[S:29](=[O:31])=[O:30]
Reactant: Sc1ccccc1
Reactant: COC(=O)C1C=C(n2cccc2)C(Cl)=C([N+](=O)[O-])C1=S(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1C=C(n2cccc2)C(Sc2ccccc2)=C([N+](=O)[O-])C1=S(=O)=O
Temperature: 25 °C
Yield: 45 %

Procedure:
A solution of 24.5 ml of thiophenol in 100 ml of anhydrous THF is added to a suspension of 13 g of sodium methylate in 440 ml of absolute THF whilst stirring at room temperature under nitrogen. 72 g of 4-chloro-3-nitro-5-pyrrol-1-yl-sulfonylbenzoic acid methyl ester in 220 ml of absolute THF are then added dropwise and the mixture is stirred at room temperature until the end of the reaction is reached, as ascertained by thin layer chromatography. After removing the solvent on a rotary evaporator, the residue is repeatedly extracted with hexane and then recrystallized from ethyl acetate/methanol. 3-Nitro-4-phenylthio-5-pyrrol-1-yl-sulfonyl-benzoic acid methyl ester of melting point 153°-154° C. is obtained. Yield: 45%.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:17]([CH3:18])=[N:16][N:15]([CH2:19][CH3:20])[C:9]2=[N:10][C:11]=1[O:12][CH2:13][CH3:14])=[O:5])C.[OH-].[Na+]>C(O)C>[CH2:13]([O:12][C:11]1[N:10]=[C:9]2[N:15]([CH2:19][CH3:20])[N:16]=[C:17]([CH3:18])[C:8]2=[N:7][C:6]=1[C:4]([OH:5])=[O:3])[CH3:14]
Reactant: CCOC(=O)c1nc2c(C)nn(CC)c2nc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1nc2c(nc1C(=O)O)c(C)nn2CC
Reaction time: 8 h

Procedure:
2.78 g. of 6-ethoxy-1-ethyl-3-methyl-1H-pyrazolo-[3,4-b]pyrazine-5-carboxylic acid ethyl ester (0.01 mol.) dissolved in 20 ml. of ethanol are added to 20 ml. of aqueous sodium hydroxide (2.5 N) and the solution is allowed to stand overnight. After the vacuum removal of the alcohol, the solution is acidified with concentrated hydrochloric acid, the precipitated 6-ethoxy-1-ethyl-3methyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid is filtered off, washed with water and dried at 70°, yield 2 g. (80%), m.p. 172°.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:11](Cl)(=[O:21])[C:12]1[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:14](Cl)=[O:15].C(O)(=O)C(O)=O>[N+](C1C=CC=CC=1)([O-])=O.CCO>[CH:1]1[C:6]2[C:14](=[O:15])[C:13]3[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:21])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Agent: O=C(O)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2ccccc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
7.2 g (0.2 mols) of benzene were added at ambient temperature and in a gentle stream of dry nitrogen to 26.6 g (0.2 mols) of anhydrous AlCl3 in 300 ml nitrobenzene. The mixture was heated to 100° C.; after agitation for 15 minutes at this temperature, 20.2 g (0.1 mols) of phthalic acid dichloride dissolved in 100 ml nitrobenzene were added during about 20 minutes. The volume of the solution was made up to 500 ml with nitrobenzene and the temperature was kept at 100° C. with agitation for 30 minutes, after which the reacting substance was cooled and 300 ml of saturated aqueous solution of oxalic acid was added with intense agitation. Three extractions were made, each time with 200 ml ethyl ether and the combined extracts were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the product was purified by crystallization from toluene, giving 17.7 g (85% yield) of 9,10-anthraquinone (1), m.p. 285° C. (literature: 286° C., EtOH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.[F:76][C:77]1[CH:78]=[C:79]([SH:83])[CH:80]=[CH:81][CH:82]=1>O1CCOCC1.[Cl-].[Na+].O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([S:83][C:79]3[CH:80]=[CH:81][CH:82]=[C:77]([F:76])[CH:78]=3)=[CH:15][C:14]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)ccc1-c1ccn(C(=O)OC(C)(C)C)c1
Reactant: Fc1cccc(S)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(Sc2cccc(F)c2)ccc1-c1ccn(C(=O)OC(C)(C)C)c1
Temperature: 90 °C
Yield: 53.3 %

Procedure:
3-(4-Bromo-2-ethoxycarbonyl-phenyl)-pyrrole-1-carboxylic acid tert-butyl ester (1.65 g, 4.180 mmol) was dissolved in 25 ml of dioxane. Tris(dibenzylideneacetone) dipalladium(0) (478 mg. 0.522 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (605 mg, 1.044 mmol), and DIPEA (1.82 ml, 10.45 mmol) were added followed by 3-fluorothiophenol (0.353 ml, 4.180 mmol). The mixture was heated to 90° C. overnight. The mixture was cooled to 5° C. and diluted with pH 2 buffer. Brine was added and the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered through a GF/F filter and concentrated under reduced pressure. The residue was purified by flash chromatography (Hexane/EtOAc 9/1) to give 983 mgs (53.02%) of 3-[2-Ethoxycarbonyl-4-(3-fluoro-phenylsulfanyl)-phenyl]-pyrrole-1-carboxylic acid tert-butyl ester as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:24]
Reactant: O=C(Cl)c1cccs1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccs4)nc23)CC1
Yield: 35.5 %

Procedure:
Beginning with 0.100 gm (0.43 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.056 mL (0.52 mMol) 2-thiophenecarbonyl chloride, 0.052 gm (34%) of the title compound was recovered as a crystalline solid by the procedure described in Example 4.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])=[CH:6][CH:5]=1.[CH3:19][CH:20](Br)[CH2:21][CH3:22].O>O1CCCC1.CN(C=O)C>[CH3:19][CH:20]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])=[CH:17][CH:18]=1)[CH2:21][CH3:22]
Reactant: CCC(C)Br
Reactant: CCOC(=O)NCCOc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1ccc(OC(C)CC)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To pre-washed sodium hydride (0.106 g, 4.4 mmol) in 5 ml of tetrahydrofuran (THF) and 5 ml of DMF at RT is added ethyl N-{2-(4-hydroxyphenoxy]ethyl}carbamate (1.0 g, 4.4 mmol) in 5 ml of THF. The mixture is stirred at RT for 1.5 hours and is then cooled to -5°. 1-Methylpropyl bromide (0.72 g, 5.3 mmol) in 2 ml of THF is added to the mixture, followed by addition of 5 ml of DMF. The reaction mixture is allowed to warm slowly to RT, and is then heated at 60° for 18 hours. The reaction is cooled to RT and poured into water and the mixture is extracted with ether (3×). The combined ether layers are washed with water until neutral, followed with brine, and dried over calcium sulfate. The solvent is removed in vacuo and purification by prep. TLC yields ethyl N-{2-[4-(1-methylpropoxy)phenoxy]ethyl}carbamate (compound 13, Table A).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:18][C:15]2[CH:14]=[CH:13][C:12]([CH:11]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:9](=[O:30])[CH:10]3[CH2:19][CH2:20][CH:21]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[OH:22])=[CH:17][CH:16]=2)=[CH:35][CH:34]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Reactant: BrCc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCc3ccc(CBr)cc3)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3.0 g of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-azetidin-2-one (11) 7.0 g of 1,4-bisbromomethylbenzene and 5.0 g of potassium carbonate were dissolved in 100 ml of dimethylformamide and stirred at room temperature for 90 min. After the reaction ended, the mixture was dissolved in ethyl acetate and extracted two times with water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (n-heptane/ethyl acetate). Yield 3.2 g of colorless crystals (12) of molecular weight 592.49 (C32H28BrF2NO3); MS (ESI): 592.2 (MH+).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=O)[CH2:11][CH2:10][CH2:9]3)=[N:4][N:3]=[N:2]1.Cl.[CH2:18]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([NH:34]N)[CH:29]=2)=[CH:24][CH:23]=1)[CH2:19][CH2:20][CH3:21]>>[CH2:18]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[C:30]3[C:31]([C:11]4[CH2:10][CH2:9][C:8]5[CH:7]=[C:6]([C:5]6[NH:4][N:3]=[N:2][N:1]=6)[CH:15]=[CH:14][C:13]=5[C:12]=4[NH:34]3)=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1ccc(-c2cccc(NN)c2)cc1
Reactant: O=C1CCCc2cc(-c3nnn[nH]3)ccc21
Agent: Cl
Product: CCCCc1ccc(-c2ccc3c4c([nH]c3c2)-c2ccc(-c3nnn[nH]3)cc2CC4)cc1

Procedure:
The 6-(1H-Tetrazol-5-yl)-3,4-dihydro-2H-naphthalen-1-one and (4′-Butyl-biphenyl-3-yl)-hydrazine hydrochloride (example 70, step 1) are reacted in the same manner and similar yield as example 1, step 3 except that the solid was washed with acetic acid rather than methanol. 1H NMR (400 MHz, d6-DMSO) δ 11.66 (s, 1H), 7.97 (m, 2H), 7.84 (d, J=8.9 Hz, 11H), 7.63 (m, 4H), 7.34 (d, J=8.2 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 3.13 (t, J=7.5 Hz, 2H), 2.99 (t, J=7.6 Hz, 2H), 2.63 (m, 2H), 1.60 (m, 2H), 1.35 (m, 2H), 0.93 (t, J=7.3 Hz, 3H); LC/MS calculated for [M+H]+ C27H26N5: 420.5, found: 420.1.
Reaction SMILES: C([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([N:22]([CH3:25])[CH:23]=[O:24])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([N:22]([CH3:25])[CH:23]=[O:24])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1
Reactant: CN(C=O)c1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CO
Product: CN(C=O)c1ccc2c(c1)[nH]c1cc(O)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.6 %

Procedure:
To N-(7-(benzyloxy)-9H-carbazol-2-yl)-N-methylformamide (110 mg, 0.33 mmol) in 50 mL MeOH was added Palladium on activated carbon (50 mg). The mixture was stirred at rt under H2 atmosphere for 15 h. Solid was filtered off and the filtrate was concentrated to afford N-(7-hydroxy-9H-carbazol-2-yl)-N-methylformamide as a brown solid (75 mg, 94%). This material was used directly for the next reaction without purification. MS (ESI) m/z 241 (M+H+).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH3:10].[C:11](=[O:13])=[O:12]>O1CCCC1.BrC(Br)C.BrC1C=CC(F)=CC=1C>[CH3:10][C:4]1[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: Cc1cc(F)ccc1Br
Reactant: O=C=O
Agent: CC(Br)Br
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C(=O)O
Temperature: 55 °C

Procedure:
To a flask fit with a reflux condenser and addition funnel was added magnesium (2.6 g, 106 mmol) and tetrahydrofuran (10 mL). A solution of 2-bromo-5-fluorotoluene (1.0 g, 5.3 mmol) in tetrahydrofuran (2 mL) and dibromoethane (0.04 mL) was added. The solution was warmed gently in a 55° C. oil bath until a vigorous reflux began. A solution of 2-bromo-5-fluorotoluene (9.0 g, 48 mmol) in tetrahydrofuran (18 mL) was added dropwise to maintain a gentle reflux. After addition was complete, the reaction mixture was heated in a 55° C. oil bath for 1 h. The reaction mixture was allowed to cool to room temperature and poured onto crushed dry ice (50 mL). The excess dry ice was allowed to sublime. The solution was partitioned between ethyl acetate (100 mL) and 3% HCl (50 mL). The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was removed in vacuo. to afford the title compound (8.3 g) in quantitative yield. Rf=0.34 (silica gel, 5% isopropanol/dichloromethane).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1.O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:23]=[CH:22][C:5]3[C:6]4[N:7]([CH:11]=[C:12]([C:14]5[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=5)[N:13]=4)[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)=[CH:27][CH:26]=1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccc(Cl)cc3)cc1OCC2
Yield: 21.1 %

Procedure:
To a mixture of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 (300 mg, 0.80 mmol), 4-chlorophenylboronic acid (188 mg, 1.21 mmol), Pd(dppf)Cl2 (65 mg, 0.080 mmol) and Cs2CO3 (314 mg, 0.96 mmol) in a microwave reaction tube, dioxane/H2O (5 ml) was added and argon was bubbled through. The reaction mixture was heated under microwave irradiation at 130 C for 30 min. The reaction mixture was filtered, concentrated, and purified by HPLC to give 567 (68.4 mg, 21%). 1H NMR (DMSO, 400 MHz) δ 8.46 (d, J=8.8 Hz, 1H), 7.94 (s, 1H), 7.90 (s, 1H), 7.74 (d, J=6.4 Hz, 2H), 7.51-7.46 (m, 3H), 2.34 (s, 1H), 5.95-5.84 (m, 1H), 4.53 (s, 4H), 1.46 (d, J=6.8 Hz, 6H). LCMS (ESI): m/z 406.0 (M+H+)
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:23]1([C:29]2[C:30]3[CH:31]=[CH:32][C:33]([C:50]([O:52][CH3:53])=[O:51])=[CH:34][C:35]=3[N:36]3[CH2:42][C:41]([C:43](O)=[O:44])=[CH:40][C:39]4[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=4[C:37]=23)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:65][N:66]1[CH2:72][CH:71]2[NH:73][CH:68]([CH2:69][CH2:70]2)[CH2:67]1>CN(C=O)C>[CH:23]1([C:29]2[C:30]3[CH:31]=[CH:32][C:33]([C:50]([O:52][CH3:53])=[O:51])=[CH:34][C:35]=3[N:36]3[CH2:42][C:41]([C:43]([N:73]4[CH:68]5[CH2:69][CH2:70][CH:71]4[CH2:72][N:66]([CH3:65])[CH2:67]5)=[O:44])=[CH:40][C:39]4[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=4[C:37]=23)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CN1CC2CCC(C1)N2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)O)=Cc1ccccc1-3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1C2CCC1CN(C)C2)=Cc1ccccc1-3

Procedure:
TBTU (115 mg, 0.361 mmol) was added at rt, in one portion, to a solution containing 13-cyclohexyl-10-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (100 mg, 0.241 mmol), DIEA (0.17 mL, 0.964 mmol), 3-Methyl-3,8-diaza-bicyclo[3.2.1]octane dihydrochloride (115 mg, 0.289 mmol), and DMF (2.4 mL). The solution was maintained for 18 h and concentrated. The resultant residue was charged with dichloromethane (30 mL), washed with water (4×15 mL), washed with brine (15 mL), dried (magnesium sulfate), filtered and concentrated to afford a yellow solid which was used without further purification in the next step. LCMS: retention time: 2.272 min LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode: m/z 524 (MH+). Crude 1H NMR (300 MHz, CDCl3) δ ppm: 8.19 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.77 (dd, J=8.78 Hz, J=1.46 Hz, 1H), 7.61 (m, 1H), 7.49 (m, 3H), 6.96 (s, 1H), 5.2 (s, 1H), 4.41 (s, 1H), 2.81 (m, 4H), 2.51 (s, 1H), 1.95 (m, 15H), 1.29 (m, 11H), 0.76 (m, 2H).