Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:12]2[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C@H:13]2[CH2:26]OS(C)(=O)=O)[CH:8]=[CH:9][C:10]=1[Cl:11].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:1]([CH2:26][C@H:13]1[C@H:12]([C:7]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:5]([Cl:4])[CH:6]=2)[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:14]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](COS(C)(=O)=O)C1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC#N)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Potassium cyanide (1.720 g) was added to a solution of tert-butyl (6S,7R)-7-(3,4-dichlorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate (3 g) in DMF (30 ml), and the mixture was stirred at 80° C. overnight. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (2.00 g).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])[C:3]#[N:4].[C:12]([CH2:15][C:16](=O)[CH3:17])(=[O:14])[CH3:13]>CO>[C:12]([C:15]1[C:3]([NH2:4])=[C:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:11])[NH:1][C:16]=1[CH3:17])(=[O:14])[CH3:13]
Reactant: CC(=O)CC(C)=O
Reactant: Cc1ccccc1C(N)C#N
Solvent: CO
Product: CC(=O)c1c(C)[nH]c(-c2ccccc2C)c1N

Procedure:
Starting from 2-amino-2-(o-tolyl)acetonitrile and acetylacetone, the open-chain intermediate compound is obtained, b.p. 120° C./0.2 mm Hg. The title compound is obtained in a 77% overall yield, m.p. 258° C. (from methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6](B(O)O)[CH:7]=1.Cl[C:13]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]=2)[CH:7]=1
Reactant: OB(O)c1cc(Cl)ccc1F
Reactant: Nc1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ccnc(-c2cc(Cl)ccc2F)c1
Yield: 19.7 %

Procedure:
5-Chloro-2-fluorophenylboronic acid (2.7 g, 15.48 mmol), 2-chloropyridin-4-amine (1.531 g, 11.91 mmol), sodium carbonate (5.96 ml, 11.91 mmol), and bis(triphenylphosphine) palladium chloride (0.836 g, 1.191 mmol) were combined in dioxane (54 mL) and refluxed for 3 hours. The reaction was cooled, the solvent removed in vacuo and the reaction mixture partitioned between brine and EtOAc. The organic layer was separated, dried over MgSO4 filtered and purified using NH silica column chromatography and a gradient of 5-95% EtOAc in hexanes to afford the title compound as a white solid (522 mg; 20%). ESI-MS: m/z 223.1 (M+H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C@:12]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:44])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][CH2:9][CH2:10][NH:11][C@:12]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:44])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(tert-butoxycarbonylamino)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (900 mg, 1.310 mmol) in dioxane (1 mL) was added HCl (4M in dioxane) (4.26 mL, 17.03 mmol) and the reaction mixture was stirred for 4 h at rt. The reaction mixture was concentrated under reduced pressure to provide the title compound as a brown solid (769 mg, 100%). LCMS: m/e 588.08 (M+H)+, 2.44 min (method 11).
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][C:18]2=[N:31][S:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33]>C1COCC1>[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][C:18]2([CH2:2][C:1]([O:4][CH3:5])=[O:3])[NH:31][S:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33]
Reactant: COC(C)=O
Reactant: CC(C)(C)S(=O)N=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CC1(NS(=O)C(C)(C)C)CC(c2ccccc2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
To a solution of methyl acetate (383 mg, 0.41 mL, 5.17 mmol) in anhydrous THF (10 mL) at −78° C. under N2 atmosphere is added 2 M LDA solution in THF (3.4 mL, 6.8 mmol) dropwise, and the solution is stirred another 30 min at the same temperature after the addition. To this mixture is added TiCl(OiPr)3 (1.681 g, 6.45 mmol) dropwise. The mixture is then stirred another 30 min at −78° C. To this mixture is added a solution of N-(6-bromo-2-phenylchroman-4-ylidene)-2-methylpropane-2-sulfinamide (1.050 g, 2.58 mmol) in anhydrous THF (10 mL) dropwise within 30 min. The reaction mixture is stirred another 3 h at −78° C. then quenched with sat. aq. NH4Cl. The mixture is stirred 10 min after being warmed to rt and filtered through a pad of Celite, and washed with EA (80 mL). The filtrate is transferred to separating funnel and the separated organic phase is washed with brine, and dried over anhydrous Na2SO4, filtered and concentrated, and the residue is purified through chromatography on silica gel to afford methyl 2-(6-bromo-4-(1,1-dimethylethylsulfinamido)-2-phenylchroman-4-yl)acetate 427 mg as an oil. MS ESI+ve m/z 480 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([CH3:35])=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([O:32]C)=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([CH3:35])=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([OH:32])=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2cc3c(cc2C)N(CC(C)C)CCCC(C(=O)OC)=C3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2cc3c(cc2C)N(CC(C)C)CCCC(C(=O)O)=C3)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
To methyl 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-9-methyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylate (770 mg) were added tetrahydrofuran (15 ml) and methanol (15 ml), followed by adding aqueous 1N sodium hydroxide solution (4.8 ml), and the mixture was stirred at 90° C. overnight. After cooling to 0° C., water was added and the mixture was neutralized with 1N hydrochloric acid. After extracting with ethyl acetate, the organic layer was washed with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from hexane-ethyl acetate to give 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-9-methyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylic acid (408 mg) as yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][S:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=4)(=[O:24])=[O:23])=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].[C:34](OCC)(=O)[CH3:35]>S(Cl)(Cl)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][S:22]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:30]=4)(=[O:24])=[O:23])=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(C)=O
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(NS(=O)(=O)c3ccc(C(=O)O)cc3)ccc21
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(S(=O)(=O)Nc2ccc3c(c2)nc(CCc2ccc(C#N)cc2)n3C)cc1

Procedure:
N-{2-[2-(4-Cyanophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-(4-carboxy-benzenesulphonamide) (2.0 g, 4.3 mmol) is refluxed in 10 mL thionyl chloride for 1.5 h. The mixture is diluted with 50 mL ethyl acetate, the crystalline hydrochloride of the acid chloride is filtered off and washed with ethyl acetate/diethylether. The solid is suspended in 40 mL ethanol and slowly brought to reflux temperature. Half the ethanol is distilled off, the remainder is cooled and combined with ice water and made alkaline with aqueous potassium carbonate solution with stirring. It is diluted with water, the solid is filtered off and washed with water.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH2:8][C:9]2[S:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[CH:7]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([CH2:8][C:9]2[S:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccc(Cc2cc(Br)ccc2I)s1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Clc1ccc(Cc2cc(Br)ccc2-c2ccccc2)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of the above 5-bromo-1-(5-chloro-2-thienylmethyl)-2-iodobenzene (1.0 g) in dimethoxyethane (10 ml) were added phenylboronic acid (310 mg), bis(triphenylphosphine)palladium(II)dichloride (85 mg) and 2M aqueous sodium carbonate solution (3.8 ml), and the mixture was stirred at 50° C. overnight. Added thereto was a saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 5-bromo-1-(5-chloro-2-thienylmethyl)-2-phenylbenzene (683 mg) as oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([N:21]2[CH2:22][CH2:23][CH2:24][C:19]([OH:25])([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=3)[CH2:20]2)=[O:6])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3cccc(Br)c3)C2)c1

Procedure:
The compound of Example 21 was prepared according to the general preparation protocol A from 3-bromobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[C:11](Cl)(=[O:13])[CH3:12]>>[C:9]([CH2:8][C:4]1[CH:3]=[C:2]([NH:1][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][CH:5]=1)#[N:10]
Reactant: CC(=O)Cl
Reactant: N#CCc1cccc(N)c1
Product: CC(=O)Nc1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.4 %

Procedure:
To a mixture of (3-amino-phenyl)-acetonitrile (500 mg, 3.79 mmol) and TEA (498 mg, 4.93 mmol) was added acetyl chloride (387 mg, 4.93 mmol) slowly at 0° C. The resulting mixture was stirred at room temperature for 10 min. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with DCM twice. The combined organic layers were washed with aqueous ammonia chloride and brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound (558 mg, 3.20 mmol, 85% yield) as a pale-yellow solid. MS (ESI) m/z 175.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][OH:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Br[CH2:16][CH2:17][F:18].Cl>C1(C)C=CC=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.CCOC(C)=O.CCCCCC.O>[C:1]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][O:11][CH2:16][CH2:17][F:18])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: FCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CN(CCOCCF)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 37.9 %

Procedure:
To a solution of (2-hydroxy-ethyl)-methyl-carbamic acid tert-butyl ester (CAS Nr. 57561-39-4; 2.50 g, 14.3 mmol) in toluene (35 ml) was added powered KOH (2.8 g, 50 mmol) and Bu4NHSO4 (0.97 mg, 2.86 mmol). The reaction mixture was stirred vigorously and heated to 50° C. while neat 1-bromo-2-fluoro-ethane (2.72 g, 21.4 mmol) was added slowly. The temperature was increased to 80° C. and maintained for 3-5 h. The reaction mixture was cooled to RT, water was added (50 ml) and the pH was adjusted to 7 with 1N HCl solution. Extraction with EtOAc (2×150 ml), washing with brine, drying with Na2SO4 and concentrating under vacuum yielded the crude product. The crude material was subjected to column chromatography on silica by EtOAc:hexane (10:90 to 20:80) to give the desired product as light yellow liquid (1.2 g, 38%). MS (m/z)=122.0 [M−Boc+]; 166.2 [M−tBu+].
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9]([O:11][CH3:12])[C:8]([CH:13]=O)=[C:7]([O:15][CH3:16])[N:6]=1.[CH3:17][C:18]([CH3:20])=[O:19]>O>[CH3:3][O:4][C:5]1[N:10]=[C:9]([O:11][CH3:12])[C:8]([CH:13]=[CH:17][C:18](=[O:19])[CH3:20])=[C:7]([O:15][CH3:16])[N:6]=1
Reactant: CC(C)=O
Reactant: COc1nc(OC)c(C=O)c(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1nc(OC)c(C=CC(C)=O)c(OC)n1

Procedure:
An aqueous solution of 2% sodium hydroxide (15 ml) was added to a stirred suspension of 2,4,6-trimethoxypyrimidine-5-carboxaldehyde (8 g) in acetone (15 ml) and water (15 ml). The mixture was stirred and refluxed for 4 hours, a precipitate slowly forming during this period. The suspension was diluted with water (100 ml) and extracted with chloroform (2×100 ml). The organic layer was washed with water, dried over magnesium sulphate and the solvent was removed by evaporation under reduced pressure to give 1-(2,4,6-trimethoxy-5-pyrimidyl)but-1-en-3-one as a pale yellow solid (8.0 g), mp 98°-99° C.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=1)[C:3](=O)[CH3:4].[C:17]([NH:20][C:21]([NH2:23])=[S:22])(=[O:19])[CH3:18].O.C(OCC)(=O)C>C(O)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:22][C:21]([NH:20][C:17](=[O:19])[CH3:18])=[N:23][C:3]=2[CH3:4])=[CH:7][C:8]=1[S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: CC(=O)C(Br)c1ccc(F)c(S(C)(=O)=O)c1
Reactant: CC(=O)NC(N)=S
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)Nc1nc(C)c(-c2ccc(F)c(S(C)(=O)=O)c2)s1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
A mixture of 1-bromo-1-(4-fluoro-3-methanesulfonyl-phenyl)-propan-2-one (Example 47c) (0.17 g, 0.55 mmol) and N-acetylthiourea (0.065 g, 0.55 mmol) in ethanol is heated at 70° C. for 3 hours then at room temperature over two days. The reaction mixture is poured into water (200 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford a viscous solid. This solid in a minimum amount of ethyl acetate is sonicated to give a suspension which is then heated until all solid has dissolved then left to cool to room temperature overnight. The white crystalline solid is filtered off to afford the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:9]2[C:10]([CH:24]=O)=[CH:11][C:12]([O:14][CH2:15][C:16]3[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[CH:13][C:8]=2[S:7][CH:6]=1.C1COCC1.O.[NH2:33]OS(O)(=O)=O>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:9]2[C:10]([C:24]#[N:33])=[CH:11][C:12]([O:14][CH2:15][C:16]3[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: COC(=O)Cc1csc2cc(OCc3ccc(C)nc3C)cc(C=O)c12
Reactant: NOS(=O)(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1csc2cc(OCc3ccc(C)nc3C)cc(C#N)c12
Yield: 96.8 %

Procedure:
To a mixture of methyl(6-((2,6-dimethylpyridin-3-yl)methoxy)-4-formyl-1-benzothiophen-3-yl)acetate (100 mg), THF (5 mL) and water (5 mL) was added hydroxylamine-O-sulfonic acid (45.9 mg) at room temperature, and the mixture was refluxed for 48 h. The suspension was diluted with EtOAc, and TEA (1 mL) was added to the mixture. The mixture was refluxed for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (96 mg).
Reaction SMILES: [CH3:1][C:2]1(C)OC(=O)[C:5](=[C:9]([OH:30])[CH:10]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][N:11]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:4](=[O:31])[O:3]1.[O-]CC.[Na+]>C(O)C>[CH2:2]([O:3][C:4](=[O:31])[CH2:5][C:9]([CH:10]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][N:11]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:30])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(O)=C2C(=O)OC(C)(C)OC2=O)C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Yield: 46.6 %

Procedure:
To a solution of bis(1,1-dimethylethyl) 2-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)(hydroxy)methyl]-1,4-piperazinedicarboxylate (may be prepared as described in Intermediate 2; 8.32 g) in ethanol (250 mL) under argon, cooled to 0° C., was added dropwise a 21% weight solution of sodium ethoxide (118 mL). After completion of addition, the reaction was heated to reflux for 18 hours. The reaction mixture was evaporated and the residue partitioned between 2× ethyl acetate and water. The combined organic phases were washed with brine, dried through a hydrophobic frit, then evaporated to an orange oil. An attempt was made to dissolve in DCM for purification but a solid formed. This was evaporated and then triturated in ether. The resulting cream solid was collected by filtration, but was an impurity. The liquors were evaporated and then purified by silica column (SP4-40M) eluting with 0-40% ethyl acetate in iso-hexane over 12 CV. The clean fractions were combined and evaporated to give the title compound as a yellow oil (3.40 g).
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.[C:12]([CH:15]([N:25]1[C:29]2[N:30]=[C:31]([CH2:35][C:36]3[CH:41]=[CH:40][C:39](Br)=[CH:38][CH:37]=3)[NH:32][C:33](=[O:34])[C:28]=2[CH:27]=[N:26]1)[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:14])[CH3:13].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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>[C:12]([CH:15]([N:25]1[C:29]2[N:30]=[C:31]([CH2:35][C:36]3[CH:37]=[CH:38][C:39]([C:4]4[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=4)=[CH:40][CH:41]=3)[NH:32][C:33](=[O:34])[C:28]=2[CH:27]=[N:26]1)[CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)C(CCCc1ccccc1)n1ncc2c(=O)[nH]c(Cc3ccc(Br)cc3)nc21
Reactant: CCB(CC)c1cccnc1
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: C1CCOC1
Product: CC(=O)C(CCCc1ccccc1)n1ncc2c(=O)[nH]c(Cc3ccc(-c4cccnc4)cc3)nc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
71 mg (0.48 mmol) of diethyl-(3-pyridyl)-borane and 16 mg of tetrakistriphenylphosphine-palladium are added under argon to a solution of 177 mg (0.37 mmol) of 1-(1-acetyl-4-phenyl-butyl)-6-(4-bromo-benzyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one in 4 ml of THF, and the mixture is stirred for one hour at 70° C. After 0.522 ml of 2 N Na2CO3 solution have been added, the mixture is stirred for a further 4 hours at 70° C., a further 27 mg (0.185 mmol) of diethyl-(3-pyridyl)-borane and 16 mg of tetrakistriphenylphosphine-palladium are added, and the mixture is stirred for 14 hours under reflux. The solvent is removed in vacuo and the residue taken up in CH2Cl2. The mixture is extracted with 2N HCl, and the aqueous phase is rendered alkaline with 1N NaOH and extracted twice with CH2Cl2. After the mixture has been dried over Na2SO4, the solvent is removed in vacuo. Purification by chromatography (toluene/ethyl/acetate=4:1) gives 110 mg (6.4%) of a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:3]2[NH:7][C:6]([C:8](C3C=C(C(C)(C)C)C=C(C(C)(C)C)C=3)=[C:9]3[N:40]=[C:12]([C:13](Br)=[C:14]4[NH:38][C:17](=[C:18](C5C=C(C(C)(C)C)C=C(C(C)(C)C)C=5)[C:19]5[CH:20]=[CH:21][C:22]=1[N:23]=5)[CH:16]=[CH:15]4)[CH:11]=[CH:10]3)=[CH:5][CH:4]=2.C([C@@H]1COC(=O)N1)C1C=CC=CC=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[C:3]12[CH:2]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:17]3[NH:38][C:14]([CH:15]=[CH:16]3)=[CH:13][C:12]3=[N:40][C:9]([CH:10]=[CH:11]3)=[CH:8][C:6]([NH:7]1)=[CH:5][CH:4]=2
Reactant: CC(C)(C)c1cc(-c2c3nc(c(Br)c4ccc([nH]4)c(-c4cc(C(C)(C)C)cc(C(C)(C)C)c4)c4nc(c(Br)c5ccc2[nH]5)C=C4)C=C3)cc(C(C)(C)C)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
The general procedure was used to couple 5,15-dibromo-10,20-di(3′,5′-di-tert-butylphenyl)porphyrin (0.043 g, 0.05 mmol) with (R)-(+)-4-benzyl-2-oxazolidinone (0.0708 g, 0.4 mmol), using Pd2(dba)3 (0.0023 g, 0.0025 mmol) and Xantphos (0.0058 g, 0.01 mmol) in the presence of Cs2CO3 (0.0652 g, 0.2 mmol). The reaction was conducted in THF (5 mL) at 80° C. for 22 h. The title compound was isolated by flash column chromatography (silica gel, ethyl acetate:hexanes (v/v)=1:3) as purple mixture of two atropic isomers (0.039 g, 79%, α,α/α,β=50%/50%). 1H NMR (300 MHz, CDCl3): δ 9.48 (d, J=4.8 Hz, 2H), 9.46 (d, J=4.8 Hz, 2H), 9.27 (d, J=4.8 Hz, 2H), 9.25 (d, J=4.8 Hz, 2H), 9.08 (d, J=4.8 Hz, 2H), 9.04 (d, J=4.8 Hz, 2H), 9.02 (d, J=4.8 Hz, 2H), 9.00 (d, J=4.8 Hz, 2H), 8.24 (s, 2H), 8.12 (d, J=0.9 Hz, 2H), 8.07 (d, J=0.9 Hz, 2H), 7.93 (s, 2H), 7.86 (s, 4H), 7.08 (m, 12H), 6.88 (m, 8H), 5.40 (m, 2H), 5.27 (m, 2H), 5.03 (q, J=9.0 Hz, 4H), 4.84 (q, J=7.8 Hz, 4H), 3.27 (m, 4H), 3.00 (m, 2H), 2.77 (m, 2H), 1.61 (s, 18H), 1.59 (s, 18H), 1.56 (s, 18H), 1.53 (s, 18H), −2.76 (s, 2H), −2.81 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 159.5, 159.4, 149.3, 149.1, 149.0, 140.2, 140.0, 135.1, 130.1, 130.1, 129.8, 129.8, 128.8, 128.7, 127.1, 127.0, 122.9, 121.5, 111.4, 111.2, 68.9, 68.8, 66.3, 40.5, 40.4, 35.1, 31.8, 31.7. UV-vis (CHCl3, λmax, nm): 419, 514, 549, 591, 646. HRMS-MALDI ([M+H]+): calcd for C68H73N6O4, 1037.5688; found: 1037.5677 with an isotope distribution pattern that is the same as calculated one.