Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([S:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(S)c([N+](=O)[O-])c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(SCc2ccccc2)c([N+](=O)[O-])c1
Yield: 81.6 %

Procedure:
Following General Procedure A, the title compound (580 mg, 82%) was prepared from 4-mercapto-3-nitrobenzonitrile (473 mg, 2.63 mmol), (bromomethyl)benzene (449 mg, 2.63 mmol), K2CO3 (1.81 g, 13.14 mmol) in DMF (10 ml).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:16]([O:15][C:11](=[O:14])[CH:12]=[CH:13][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])[CH3:17]
Reactant: O=C(O)c1cccc(I)c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CCOC(=O)C=Cc1cccc(C(=O)O)c1
Temperature: 100 °C
Yield: 88 %

Procedure:
A 104 mg portion of palladium acetate and 5 ml of TEA were added one by one to 50 ml of acetonitrile solution containing 7.44 g of 3-iodobenzoic acid and 3.9 ml of ethyl acrylate, and the mixture was sealed in a tube and heated at 100° C. for about 12 hours. After spontaneous cooling, the catalyst was removed by filtration while washing with appropriate amounts of methanol and ethyl acetate, and the filtrate was evaporated under a reduced pressure. The thus formed crude crystals were recrystallized from a small amount of ethanol to obtain 5.82 g (88%) of 3-(3-ethoxy-3-oxoprop-1-en-1-yl)benzoic acid as white crystals. FA: 221
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:12])[CH:11]=1)[C:5](OC)=[O:6].CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:9]=[C:10]([I:12])[CH:11]=1
Reactant: COC(=O)c1cc(Cl)cc(I)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1cc(Cl)cc(I)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Methyl 3-chloro-5-iodobenzoate was dissolved in anhydrous THF and cooled to 0° C. 1M DIBAL in toluene (13 mL) was added slowly to the reaction solution at that temperature. The reaction mixture was stirred overnight at room temperature. Next morning, another 10 mL of 1M DIBAL in toluene was added and stirred for additional 4 h. When the reaction was complete, the reaction mixture was quenched with saturated solution of potassium sodium tartrate. The reaction mixture wad then extracted with ethyl acetate (×3). The combined organic extracts were dried over Na2SO4 and concentrated to afford the desired (3-chloro-5-iodo-phenyl)-methanol (2.7 g, 98%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11]C(OC)=O)=[CH:6][C:5]=1[N+:16]([O-:18])=[O:17]>CO>[F:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[CH:6][C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(F)c([N+](=O)[O-])cc1O
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
The starting material 2-fluoro-5-hydroxy-4-methylnitrobenzene, was obtained by adding 2M aqueous sodium hydroxide solution (13.1 ml), dropwise, to a solution of 2-fluoro-5-methoxycarbonyloxy-4-methylnitrobenzene (6 g, 26 mmol), (prepared as described in European Patent Publication No. 307777), in methanol (70 ml) cooled at 0° C. After stirring for 30 minutes, the mixture was concentrated by evaporation. After dilution with water, the solution was adjusted to pH2 and extracted with ethyl acetate. The organic layer was washed with water and then brine, dried (MgSO4) and the solvent evaporated to give 2-fluoro-5-hydroxy-4-methylnitrobenzene as a yellow solid (4 g, 90%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:31]=[C:30]3[C:25]([N:26]=[CH:27][C:28]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[N:29]3)=[CH:24][CH:23]=2)=[CH:18][C:17]=1[N+:38]([O-:40])=[O:39]>CN(C=O)C.CCOC(C)=O>[CH2:1]([NH:8][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:31]=[C:30]3[C:25](=[CH:24][CH:23]=2)[N:26]=[CH:27][C:28]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:29]3)=[CH:18][C:17]=1[N+:38]([O-:40])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1cc(-c2ccc3ncc(N4CCOCC4)nc3c2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2ccc3ncc(N4CCOCC4)nc3c2)ccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.3 %

Procedure:
Benzylamine (336 mg, 3.1 mmol) and potassium carbonate (865 mg, 6.2 mmol) were added to a solution of 7-(4-fluoro-3-nitrophenyl)-2-(morpholin-4-yl)quinoxalin (1.1 g, 3.1 mmol) in DMF (100 mL). The mixture was stirred 24 h at room temperature and then diluted with EtOAc. The organic phase was washed with water and saturated aqueous sodium chloride solution, then dried over sodium sulphate. After filtration and subsequent removal of solvent, the residue was purified by chromatography (silica gel, Hexane/EtOAc: 20%->100% EtOAc) giving rise to 1.29 g (93%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][NH2:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:13]1[N:18]=[C:17](Cl)[C:16]2[N:20]=[CH:21][N:22]([C@@H:23]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]3[OH:31])[C:15]=2[N:14]=1.C(N(CC)CC)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:11][NH:12][C:17]3[C:16]4[N:20]=[CH:21][N:22]([C:15]=4[N:14]=[CH:13][N:18]=3)[C@@H:23]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]3[OH:31])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCC1(c2ccc(Cl)cc2)CC1
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4(c5ccc(Cl)cc5)CC4)ncnc32)[C@H](O)[C@@H]1O
Yield: 46.6 %

Procedure:
Reaction of the above amine (1.48 g, 8 mmol) with 6-chloropurine riboside (2.09 g, 7.3 mmol) and triethylamine (1.1 mL, 8 mmol) as prepared in Example 1 and 7 gives N6-((1-(4-chlorophenyl)cyclopropyl)methyl)adenosine (1.47 g, 47%) as a cream colored solid m.p. 132°-8° C. Found: C, 56.16; H, 5.22; N, 15.54; Cl, 9.12%. C20H22N5O4Cl calculated requires: C, 55.62; H, 5.10; N, 16.22; Cl, 8.23%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@@H:11]([C@@H:14]([OH:28])[CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[N:24]=3)[N:19]=[CH:18][CH:17]=2)[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.N1C(=O)CC[C@H]1C(O)=O>CS(C)=O>[C:1]([O:5][C:6](=[O:29])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@@H:11]([C:14](=[O:28])[CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[N:24]=3)[N:19]=[CH:18][CH:17]=2)[O:10][CH2:9]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccc2nccc(C[C@H](O)[C@@H]3CC[C@@H](NC(=O)OC(C)(C)C)CO3)c2n1
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nccc(CC(=O)[C@@H]3CC[C@@H](NC(=O)OC(C)(C)C)CO3)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of {(3R,6S)-6-[(1S)-1-hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester (prepared as described in WO 2006/032466, 0.78 g, 1.73 mmol) cooled to −10° C. was added dropwise DIPEA (1.03 mL, 5.90 mmol). A solution of Pyr.SO3 (0.684 g, 48%, 1.1 eq.) in DMSO (2 mL) was added dropwise. The reaction mixture was stirred for 1 h 45 at 0° C. The volatiles were removed under reduced pressure and water (20 mL) was added. The resulting precipitate was filtered and further dried under HV to give a yellow solid (0.518 g, 66% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:17]([NH:18][C:19](=[O:28])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16](=[O:29])[N:7]2[C:8]=1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[C:30]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P(Br)(Br)Br.C=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:21]([CH2:20][C:19]([NH:18][C@@H:17]1[C:16](=[O:29])[N:7]2[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:3]([CH:2]=[CH2:30])[CH2:4][S:5][C@H:6]12)=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)C1=C(CBr)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: BrP(Br)Br
Agent: C=O
Agent: O=C([O-])O
Solvent: ClCCl
Product: C=CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of t-butyl 3-bromomethyl-7β-phenoxyacetamidoceph-3-em-4-carboxylate, 1β-oxide (24.97 g, 50.5 mmole) and triphenylphosphine (16.4 g, 1.25 equiv.) in dry methylene chloride (300 ml) was stirred at ca. 20° for 16 hours and then cooled to --20°. A solution of phosphorus tribromide (7.34 ml, 1.5 equiv.) in dry methylene chloride (100 ml) was added with stirring over a period of 30 minutes with the reaction temperature being maintained at -20°; the mixture was then stirred at this temperature for a further hour. 40%-Formaldehyde solution (190 ml) and saturated aqueous sodium hydrogen carbonate solution (750 ml) were added in one portion, and the two-phase mixture was stirred vigorously while its temperature was allowed to reach 20° and then held at this temperature for a further hour. The organic phase was washed with water, dried (MgSO4), and evaporated, and the residue was chromatographed on Kieselgel G (Merck, 0.05 to 0.2 mm, 800 g), eluting with benzene-ethyl acetate (15:1) and (10:1) (2 liters of each). Appropriate fractions were combined and evaporated to give the title ester as a pale-yellow foam (13.53 g, 63%), [α]D - 44° (C 1.00; Me2SO), λmax (EtOH) 292.5 nm (ε 15,300), inflexions at 269.5 and 276.5 nm (ε 10,000 and 12,400), having a p.m.r. spectrum (Me2SO-d6) similar to that described in Example A (iii) 11(a)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11](I)=[N:10][C:9]=1[C:14]([O:16][CH3:17])=[O:15].[CH3:18][C:19]1[C:20]([Sn](C)(C)C)=[CH:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[N:23][CH:24]=1.[Cl-].[Li+]>O1CCOCC1.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.[Cu]I>[C:26]([NH:25][C:22]1[CH:21]=[C:20]([C:11]2[O:12][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[C:9]([C:14]([O:16][CH3:17])=[O:15])[N:10]=2)[C:19]([CH3:18])=[CH:24][N:23]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)c(C)cn1
Reactant: COC(=O)c1nc(I)oc1-c1ccccc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: COC(=O)c1nc(-c2cc(NC(C)=O)ncc2C)oc1-c1ccccc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
A mixture of methyl 5-(2-chlorophenyl)-2-iodo-1,3-oxazole-4-carboxylate (3.0 g, 8.3 mmol), N-[5-methyl-4-(trimethylstannyl)pyridine-2-yl]acetamide (2.8 g, 9.1 mmol), tetrakis(triphenylphosphine)palladium(0) (0.48 g, 0.41 mmol), copper(I) iodide (0.47 g, 2.5 mmol) and lithium chloride (1.1 g, 24.8 mmol) in 1,4-dioxane (80 mL) was degassed with argon three times. The mixture was allowed to stir at 100° C. under an atmosphere of argon for 2 h and then filtered while hot. The reaction mixture was concentrated to a small volume and then 10% aqueous ammonia (150 mL) was added. The mixture was filtered and the solid was washed with diethyl ether to give methyl 2-[2-(acetylamino)-5-methylpyridin-4-yl]-5-(2-chlorophenyl)-1,3-oxazole-4-carboxylate (2.3 g, 72%) which was used without further purification.
Reaction SMILES: C([S:4][CH:5]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:6]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([NH:19]C(OC(C)(C)C)=O)=[CH:17][CH:18]=1)[C:7]([O:9]CC)=[O:8])(=O)C>Cl>[NH2:19][C:16]1[N:15]=[CH:14][C:13]([CH2:12][CH:6]([CH:5]([SH:4])[CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:7]([OH:9])=[O:8])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(CCc1ccccc1)SC(C)=O
Agent: Cl
Product: Nc1ccc(CC(C(=O)O)C(S)CCc2ccccc2)cn1

Procedure:
Ethyl 3-(acetylsulfanyl)-2-({6-[(tert-butoxycarbonyl)amino]-3-pyridinyl}methyl)-5-phenylpentanoate (9 mg, 18.5 μmol) was dissolved in conc. HCl (1 mL) under argon. The solution was heated to reflux for 4.5 h. Concentration under reduced pressure yielded the title compound as the hydrochloride salt (6.4 mg, 98%) as a diastereomeric mixture 1:1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([CH2:29][O:30][C:31]2[C:35](/[CH:36]=[CH:37]/[C:38]3[N:39]=[C:40]([CH3:43])[S:41][CH:42]=3)=[CH:34][N:33]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:32]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([CH2:29][O:30][C:31]2[C:35](/[CH:36]=[CH:37]/[C:38]3[N:39]=[C:40]([CH3:43])[S:41][CH:42]=3)=[CH:34][N:33]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:32]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(C)n4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2csc(C)n2)ccc1OCc1nc(-c2ccc(CC(=O)O)cc2)oc1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a mixture of ethyl {4-[4-({2-methoxy-4-[({4-[(E)-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (0.48 g), tetrahydrofuran (12 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 50° C. for 2 hrs. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water, and the precipitated crystals were collected by filtration to give {4-[4-({2-methoxy-4-[({4-[(E)-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as crystals (0.44 g, yield 96%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 181-182° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[OH-:11].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([OH:11])[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1nc(Cl)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a solution of 2,4,5,6-tetrachloropyrimidine (5 g, 22.9 mmol) in THF (50 mL) was added 1N NaOH (31 mL, 31.2 mmol) dropwise, and the mixture was stirred overnight at RT. The solution was acidified with 1N HCl and extracted with DCM (3×). The organics were combined, dried, and concentrated in vacuo. The solids were slurried in Et2O for 30 min at RT, filtered, washed with Et2O, and dried to give 3.0 g (66%) of the title compound. [M+H] Calc'd for C4HCl3N2O, 201. Found, 201.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16](O)=[O:17].CO>C1COCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[CH2:16][OH:17]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
LiAlH4 (1.0 m in THF, 5.0 mL, 5.0 mmol) was slowly added to a solution of indole-2-carboxylic acid (403 mg, 2.5 mmol) in dry THF (18 mL) at 0° C. The resultant yellow solution was warmed to room temperature and stirred for 18 hours. MeOH (0.5 mL) was added and the solution concentrated under reduced pressure (3×). The resultant orange syrup was partially dissolved in CHCl3 (150 mL) and washed consecutively with H2O (10 mL) and NH4Cl (10 mL). The aqueous layer was extracted with CHCl3 (2×25 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by column chromatography on silica gel (100% CH2Cl2) afforded the desired alcohol (250 mg, 68%) as a yellow solid. 1H NMR (CDCl3) δ 4.84 (s, 2H), 6.42 (d, 1H, J=0.9 Hz), 7.11–7.20 (m, 2H), 7.36 (d, 1H, J=7.5 Hz), 7.59 (d, 1H, J=7.5 Hz), 8.31 (br s, 1H).
Reaction SMILES: [CH2:1]([P:4]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3C2CCCCO2)=[CH:11][CH:10]=1)([CH2:6][CH2:7][CH3:8])=[O:5])[CH2:2][CH3:3].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH2:1]([P:4]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][NH:20]3)=[CH:11][CH:10]=1)([CH2:6][CH2:7][CH3:8])=[O:5])[CH2:2][CH3:3]
Reactant: CCCP(=O)(CCC)c1ccc(Nc2nc(C(C)C)nc3c2ncn3C2CCCCO2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCP(=O)(CCC)c1ccc(Nc2nc(C(C)C)nc3[nH]cnc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-(4-(Dipropylphosphoryl)phenyl)-2-isopropyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (0.23 g) was added 50%/50% TFA/DCM (6 mL) and the resulting solution was stirred at rt for 15 min. HPLC showed the completion of the reaction. Solvent was removed on a rotavapor. The residue was dissolved in 30 mL ethyl acetate and the organic solution was washed 5% NaHCO3 (10 mL), brine (10 mL) and dried over anhydrous Na2SO4. The final product was obtained by flash column chromatography on silica gel (10% MeOH/DCM).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)CO)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f8) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10](=[CH:14][NH:15][C:16](=[O:18])[CH3:17])[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH3:25])[CH3:21]>C1(C)C=CC=CC=1>[CH2:20]([O:22][C:23]1([O:26][CH2:27][CH3:28])[C@@H:24]([CH3:25])[C@H:14]([NH:15][C:16](=[O:18])[CH3:17])[C:10]([C:9](=[O:19])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:11]([CH3:12])[O:13]1)[CH3:21]
Reactant: CC(=O)NC=C(C(C)=O)C(=O)Nc1ccc(Cl)cc1
Reactant: CC=C(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOC1(OCC)OC(C)=C(C(=O)Nc2ccc(Cl)cc2)[C@@H](NC(C)=O)[C@@H]1C
Temperature: 100 °C

Procedure:
N-(4'-chlorophenyl)-2-(acetylaminomethylene)-3-oxobutanamide (83 g) in toluene (200 ml) was treated with 1,1-diethoxyprop-1-ene (60 ml) and heated at 100° C. for 6 hours. The mixture was evaporated and the residue was triturated with toluene to give trans-2,2-diethoxy-3,6-dimethyl-4-(acetylamino)-5-(4'-chlorophenylcarbamoyl)-3,4-dihydro-2H-pyran (80.5 g) m.p. 199°-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[C:10]([CH3:18])=[C:11]([C:13]([O:15]CC)=O)[N:12]=2)=[CH:4][CH:3]=1.[Li+].[OH-].O=S(Cl)[Cl:31]>O.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[C:10]([CH3:18])=[C:11]([C:13]([Cl:31])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)Cl)nc(-c2ccc(Cl)cc2)n1-c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Part B: Ethyl 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylate (0.250 gram, 0.61 mmol) and LiOH (0.052 gram, 2.17 mmol) are dissolved in H2O/THF (1:1 (v/v); 50 mL) and stirred at 50° C. for one hour. The mixture is concentrated to give crude 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylic acid. To this mixture is added SOCl2 (50 mL) and the resulting mixture is heated at reflux temperature for 1 hour. The mixture is concentrated to give 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carbonyl chloride.
Reaction SMILES: [N:1]1([C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[C:18]1[CH:30]=[CH:29][C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:20]=2[CH:19]=1.N1C=CC=CC=1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I>[N:1]1([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][C:18]2[CH:30]=[CH:29][C:28]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[C:20]=3[CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: Brc1ccc2c3ccccc3n(-c3ccccn3)c2c1
Reactant: Oc1cccc(-n2ncc3ccccc32)c1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Product: c1ccc(-n2c3ccccc3c3ccc(Oc4cccc(-n5ncc6ccccc65)c4)cc32)nc1
Temperature: 95 °C
Reaction time: 72 h
Yield: 88 %

Procedure:
To a dry Shlenck tube equipped with a magnetic stir bar was added 3-(1H-indazol-1-yl)phenol 2 (630 mg, 3.0 mmol, 1.0 eq), 2-bromo-9-(pyridin-2-yl)-9H-carbazole (1163 mg, 3.6 mmol, 1.2 eq), CuI (57 mg, 0.3 mmol, 0.1 eq), picolinic acid (74 mg, 0.6 mmol, 0.2 eq) and K3PO4 (1273 mg, 6.0 mmol, 2.0 eq). The tube was evacuated and backfilled with nitrogen. The evacuation and backfill procedure was repeated for another twice. Then solvent DMSO (9 mL) was added under the protection of nitrogen. The mixture was stirred in an oil bath at a temperature of 90-100° C. for 3 days and then cooled down to ambient temperature. Water was added to dissolve the solid. The mixture was extracted with ethyl acetate three times. The combined organic layer was washed with water three time, dried over sodium sulfate, and then filtered. The solvent was removed under reduced pressure, and the residue was purified through column chromatography on silica gel using hexane/ethyl acetate (10:1-5:1-3:1) as eluent to obtain the desired product Ligand ON12 as a colorless solid 1200 mg in 88% yield. 1H NMR (DMSO-d6, 400 MHz): δ 7.05-7.08 (m, 1H), 7.15 (dd, J=8.4, 2.0 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 7.32-7.36 (m, 2H), 7.42-7.47 (m, 3H), 7.52-7.59 (m, 2H), 7.61 (d, J=2.0 Hz, 1H), 7.77-7.83 (m, 3H), 7.86 (d, J=8.0 Hz, 1H), 8.07 (td, J=7.6, 2.0 Hz, 1H), 8.23 (d, J=7.6 Hz, 1H), 8.29 (d, J=7.6 Hz, 1H), 8.33 (s, 1H), 8.66 (dd, J=5.2, 1.6 Hz, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 102.73, 110.40, 111.12, 113.54, 115.66, 116.09, 119.05, 120.28, 120.22, 121.26, 121.56, 121.82, 122.12, 123.24, 125.16, 126.02, 127.64, 131.09, 136.02, 138.01, 139.35, 139.53, 139.94, 140.98, 149.52, 150.45, 154.58, 158.62.