Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:14][CH2:15][CH3:16])(OCC)[CH2:9][CH3:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[O:23](C(C(F)(F)F)=O)[C:24]([C:26]([F:29])([F:28])[F:27])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:14][CH2:15][CH3:16])=[C:9]([CH3:10])[C:24](=[O:23])[C:26]([F:29])([F:28])[F:27])=[CH:6][CH:7]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(CC)(OCC)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=C(C)C(=O)C(F)(F)F)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A solution of 2.0 g of 1-chloro-4-(1,1-diethoxypropyl)benzene and 2.5 mL of CH2Cl2 was treated with 1.45 mL of pyridine. The solution was cooled to 0° C. and treated with 5.5 mL of (CF3CO)2O in 2.5 mL of CH2Cl2. After heating overnight at reflux, the reaction mixture was cooled, diluted with CH2Cl2 and 12 mL of ice cold water was added. The organic layer was seperated and washed with 20 mL of 1N HCl, followed by a washing with 20 mL of 10% Na2CO3 and two washings with 20 mL of water. The organic layer was dried over Na2SO4 and concd in vacuo to yield 1.69 g of a dark brown oil. Chromatographic purification (silica, 10% ethyl acetate in hexanes) yielded 1.0 g of a yellow oil. Bulb to bulb distillation gave 0.45 g of a very pure light yellow oil: μ(23,D) 1.5137; major geometric isomer: 1HNMR (CDCl3) δ 1.22 (t, 3H, 7.0 Hz), 1.70 (s, 3H), 3.64 (q, 2H, 7.0 Hz), 7.30 (d, 2H, 8.3 Hz), 7.46 (d, 2H, 8.4 Hz). 19FNMR (CDCl3) δ -74.68 (CF3). Anal. Calcd for C13H12 O2F3Cl: C, 53.35; H, 4.13. Found: C, 53.44; H, 4.10.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)=[O:9])[CH:4]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(F)cc1)c1cccnc1
Reaction time: 8 h

Procedure:
To a stirred and cooled (ice-bath) mixture of 88 parts of nicotinoyl chloride hydrochloride in 400 parts of fluorobenzene are added portionwise 165 parts of aluminium chloride at a temperature between 5° and 10° C. Upon completion, the cooling-bath is removed and the mixture is stirred and refluxed for 6 hours. The reaction mixture is allowed to stand overnight at room temperature and is then poured onto a mixture of crushed ice and hydrochloric acid. After cooling, the layers are separated. The aqueous phase is extracted three times with ether. The combined organic layers are discarded and the aqueous phase is alkalized with a 40% sodium hydroxide solution. The product is extracted several times with chloroform. The extracts are washed twice with water, dried and evaporated. The residue is dissolved in ether. The solution is filtered from insoluble matter and the filtrate is allowed to crystallize upon dilution with petroleumether at -20° C, yielding p-fluorophenyl 3-pyridyl ketone; mp. 74.5° C.
Reaction SMILES: Cl.C[O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[CH2:15]([C:19]1([CH3:36])[NH:23][C:22]([Cl:24])=[C:21]([CH2:25][C:26](O)=[O:27])[N:20]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[CH2:16][CH2:17][CH3:18].ClC1C=CC=CC=1CN1C(C(O)=O)=CN=C1SCCC>>[CH2:15]([C:19]1([CH3:36])[NH:23][C:22]([Cl:24])=[C:21]([CH2:25][C:26]([NH:6][C@H:5]([C:4]([OH:3])=[O:14])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:27])[N:20]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC1(C)NC(Cl)=C(CC(=O)O)N1c1ccccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CCCSc1ncc(C(=O)O)n1Cc1ccccc1Cl
Agent: Cl
Product: CCCCC1(C)NC(Cl)=C(CC(=O)N[C@@H](Cc2ccccc2)C(=O)O)N1c1ccccc1Cl

Procedure:
The title compound is prepared following the procedure of Example 1-(iii-iv) using phenylalanine methyl ester hydrochloride in place of glycine methyl ester hydrochloride and using 2-[n-butyl-1-(2-chlorophenyl)-methyl-4-chloro-1H-imidazol-5-yl]acetic acid (prepared as in U.S. Pat. No. 4,340,598) in place of 1-(2-chlorophenyl)methyl-2 propylthio-1H-imidazole-5-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[N:18]1([C:24]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:25]=2[C:26](Cl)=[O:27])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([C:26]([C:25]3[CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=[CH:32][C:24]=3[N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:27])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: Fc1cc(N2CCNCC2)ccc1C(F)(F)F
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccc(C(F)(F)F)c(F)c2)CC1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 1-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine and 2-Morpholin-4-yl-5-nitro-benzoyl chloride (62%, yellow solid, MS (m/e): 483.2 (M+H, 100%)
Reaction SMILES: [C:1]([N:11]([CH3:45])[C@H:12]([C:22]([NH:24][CH:25]([CH3:44])[CH:26]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:27][O:28][Si](C(C)(C)C)(C)C)=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]>CC(O)=O>[C:1]([N:11]([CH3:45])[C@H:12]([C:22]([NH:24][CH:25]([CH3:44])[CH:26]([NH:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:27][OH:28])=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: COc1ccc(C[C@@H](C(=O)NC(C)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)N(C)C(=O)OCc2ccccc2)cc1
Solvent: CC(=O)O
Product: COc1ccc(C[C@@H](C(=O)NC(C)C(CO)NC(=O)OC(C)(C)C)N(C)C(=O)OCc2ccccc2)cc1
Yield: 24.2 %

Procedure:
A solution of 111 (15 mg, 0.086 mmol) in AcOH (1 mL) was stirred 15 h. at room temperature. The reaction was concentrated to yield 112 (11 mg, 90%) as a colorless oil. The crude residue was used with further purification in the next step. 1H-NMR (500 MHz, CDCl3): 1.04 (d, J=6.9 Hz, 3H), 1.45 (s, 9H), 2.81 (s, 3H), 2.88-2.92 (m, 1H), 3.02-3.09 (m, 1H), 3.29-3.33 (m, 1H), 3.51-3.62 (m, 1H), 3.70-3.79 (m, 1H), 3.78 (s, 3H), 4.02-4.08 (m, 1H), 4.43-4.47 (m, 1H), 4.51-4.55 (m, 1H), 5.05-5.18 (m, 2H), 5.22 (s, 2H), 5.98-5.99 (m, 1H), 6.72 ((d, J=7.9 Hz, 2H), 6.90-7.01 (m, 2H), 7.22-7.38 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[N:33]=[C:34]([N:37]2[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]2)[S:35][CH:36]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[N:33]=[C:34]([N:37]2[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]2)[S:35][CH:36]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: Cc1cn(-c2nc(C(=O)CC(=O)OC(C)(C)C)cs2)cn1
Product: Cc1cn(-c2nc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)cs2)cn1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (151 mg, 0.5 mmol) and 3-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-3-oxo-propionic acid tert.-butyl ester (Example H20) (154 mg, 0.5 mmol) according to the general procedure K. Obtained as a yellow amorphous substance (157 mg).
Reaction SMILES: C(O)(=O)C.[N:5]1[C:14]2[CH:13]=[CH:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Na+].[OH-].[Na+]>CO.O>[C:16]1([NH:15][CH:12]2[CH2:13][C:14]3[N:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:10][CH2:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: C1=Cc2ncccc2CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: c1ccc(NC2CCc3cccnc3C2)cc1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
Glacial acetic acid (1.2 ml, 20 mmol) was added dropwise to a stirred solution of 5,6-dihydroquinoline (1.31 g, 10 mmol) and aniline (1.86 g, 20 mmol) in methanol (4 ml). The solution was heated under reflux for 21h, cooled to room temperature, poured onto a mixture of saturated aqueous sodium chloride (25 ml) and water (25 ml), and the mixture was basified with 10N-NaOH and extracted with ether (3×25 ml). The extracts were concentrated in vacuo to give a dark orange oil which was chromatographed [alumina; ethyl acetate-toluene (1:24 to 1:4)] to give a solid. Recrystallisation from di-isopropyl ether gave the product (1.50 g), mp 102°-103°. (Found: C, 80.4; H, 76.2; N, 12.5. C15H16N2 requires C, 80.3; H, 7.2; N, 12.5%)
Reaction SMILES: [S:1]1[C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:13]([CH3:14])[C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C:5]2[S:1][C:2]3[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=3[CH:4]=2)=[CH:12][CH:11]=1
Reactant: CN(C)c1ccc(C(O)c2cc3ccccc3s2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1ccc(Cc2cc3ccccc3s2)cc1

Procedure:
2-(4-dimethylaminobenzyl)benzo[b]thiophene was prepared by the method of Example 47B with a-(2-benzo[b]thienyl)-4-dimethylaminobenzyl alcohol (7.5 mmoles, 2.1 g), triethylsilane (2.8 mmoles, 1.3 ml), CH2Cl2 (50 ml) and TFA (11.2 mmoles, 0.9 ml). Flash chromatography (10% ethyl acetate/hexanes) provided 1.5 g (73%—for two steps) of a white solid.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:31]([OH:33])=[O:32])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C([O-])=O.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1>>[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([S:58]([NH:8][C@H:9]([C:31]([OH:33])=[O:32])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:15])(=[O:60])=[O:59])=[CH:54][CH:53]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 33 %

Procedure:
Nα-tert-butoxycarbonyl-Nδ-(9-fluorenylmethoxycarbonyl)-L-ornithine was deprotected at the α position by treatment with TFA/CH2Cl2 as described in the procedure outlined in example 24 and the resulting trifluoroacetate salt was alkylated with 4-chlorobenzenesulfonyl chloride as described in example 2, affording the title compound in 33% yield.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:28]C1C=CC=CC=1B(O)O.O1C2C=CC(C3(C(NC4C=NC(Br)=CC=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[Cl:28])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Nc1ccc(-c2ccccc2)nc1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: OB(O)c1ccccc1Cl
Agent: O=C(Nc1ccc(Br)nc1)C1(c2ccc3c(c2)OCO3)CC1
Product: O=C(Nc1ccc(-c2ccccc2Cl)nc1)C1(c2ccc3c(c2)OCO3)CC1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-(2-chlorophenyl)pyridin-3-yl)cyclopropanecarboxamide was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-phenylpyridin-3-yl)cyclopropanecarboxamide from 2-chlorophenylboronic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-3-yl)cyclopropanecarboxamide.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH2:13][S:14][CH3:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](O)[CH:20]([CH3:22])[CH3:21].C(Cl)CCl>O1CCOCC1.CN(C1C=CN=CC=1)C>[CH2:19]([O:17][C:16](=[O:18])[C@H:11]([CH2:12][CH2:13][S:14][CH3:15])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CSCC[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: CC(C)CO
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: ClCCCl
Product: CSCC[C@H](NC(=O)Cc1ccccc1)C(=O)OCC(C)C
Temperature: 23 °C
Reaction time: 17 h

Procedure:
N-phenylacetyl-L-methionine (0.1285 g, 0.447 mmol) was dissolved in 3.0 mL dioxane and iso-butyl alcohol (0.2 mL) and treated with EDC (0.094 g, 0.492 mmol), and catalytic DMAP (0.015 g). After stirring for 17 hours at 23° C., the mixture was evaporated at reduced pressure to an oil, the residue was diluted in EtOAc and washed with 0.1 N HCl and saturated sodium bicarbonate. Chromatography on silica gel using 98:2 CHCl3/MeOH as eluant provided the pure product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[K+]>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[OH:15][CH2:14][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[CH:3][C:2](/[CH:18]=[CH:17]/[C:16]([O:20][CH3:21])=[O:19])=[CH:7][N:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: OCc1cccc(-c2ncc(Br)cn2)c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/c1cnc(-c2cccc(CO)c2)nc1
Temperature: 80 °C

Procedure:
100 mg (0.38 mmol) of [3-(5-bromopyrimidin-2-yl)phenyl]methanol and 51 μl (0.56 mmol) of methyl acrylate are suspended in 2 ml of DMF, and 20 mg (0.075 mmol) of triphenylphosphine, 222 mg (2.26 mmol) of potassium acetate and 157 mg (0.57 mmol) of tetra-n-butylammonium chloride are added. The reaction mixture is degassed, flushed with argon, and 17 mg (0.075 mmol) of palladium(II) acetate are added under an argon atmosphere. The mixture is heated at 80° C. for 2 h. After cooling, water is added, during which a pale-grey precipitate forms. This is filtered off with suction, washed with water and dried in vacuo. The product is reacted further without further purification; yield: 111 mg; HPLC: Rt.=2.42 min (method A); LC-MS: 271 (M+H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH2:20][CH2:21]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[CH:27]([C:29]1[N:30]=[CH:31][NH:32][CH:33]=1)=[O:28].CC(C)([O-])C.[K+]>CN(C)C=O.C(OCC)(=O)C.O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[CH2:9][C@H:8]1[CH2:20][CH2:21][N:30]1[C:29]([CH:27]=[O:28])=[CH:33][N:32]=[CH:31]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCOS(C)(=O)=O
Reactant: O=Cc1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCn1cncc1C=O
Temperature: 45 °C
Reaction time: 2 h
Yield: 23.7 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-(2-methanesulfonyloxyethyl)pyrrolidine (63 g) and 4-formylimidazole (17.8 g) in N,N-dimethylformamide (300 ml) was added potassium tert-butoxide (20.8 g) by portions. Then, the mixture was stirred at 45° C. for 2 hours. Evaporation of the solvent gave a residue, which was dissolved in a mixture of ethyl acetate (1.5 l) and water (200 ml). The organic layer was separated, washed in turn with 1N hydrochloric acid (100 ml) and brine (300 ml×3), and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (2 l) eluting with a mixture of hexane and ethyl acetate (1:1 to 1:2 to 0:1). The former active fractions were collected and concentrated in vacuo to give (2R,4R)-1-allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-{2-(5-formylimidazol-1-yl)ethyl}pyrrolidine (14.9 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=3[Cl:18])[NH2:14])=[N:8][C:5]2=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[C:13]([NH:14][C:26](=[O:27])[O:28][CH:29]([CH3:31])[CH3:30])[CH:15]=[CH:16][C:17]=3[Cl:18])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ccc(Cl)c(-c2nc3ncc(Br)cc3[nH]2)c1
Reactant: CC(C)OC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1ccc(Cl)c(-c2nc3ncc(Br)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-[6-bromo-1H-imidazo[4,5-b]pyridin-2-yl]-4-chloroaniline (I-2b) (1 g, 3.08 mmol, 1.00 equiv) in DMF (10 mL) at 0° C. was added 0.5 ml of pyridine followed by isopropyl chloroformate (solution 1M in toluene) (3.85 ml, 3.85 mmol, 1.25 equiv). The reaction mixture was stirred overnight at room temperature and then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate and the combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography (0 to 100% Ethyl acetate/Hexanes) to afford the title compound I-11. 1H NMR (400 MHz, DMSO) δ 9.95 (s, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 8.02 (s, 1H), 7.63 (s, 1H), 7.57 (d, J=8.8, 1H), 4.97 4.80 (m, 1H), 1.26 (d, J=6.2, 6H); MS M/Z=409.0 (M+1). RT=1.77: Method B.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(Cl)[C:11]1[CH:16]=[CH:15]C=[CH:13][CH:12]=1.O.C(OC(C)C)(C)C>CC1C=CC(C)=CC=1>[CH2:2]([O:3][CH2:4][C@H:5]([OH:6])[CH2:7][OH:8])[C:9]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: ClCc1ccccc1
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: Cc1ccc(C)cc1
Product: OC[C@@H](O)COCc1ccccc1

Procedure:
To this end, 1,2-isopropylidene-sn-glycerol is dissolved in p-xylene and stirred with the addition of potassium-tert.-butylate and benzyl chloride. Upon completion of the reaction, water and diisopropyl ether are added in equal parts; and a phase separation is carried out. The 3-benzyl-sn-glycerol in the upper phase is obtained by evaporation and subjected to additional cleaning steps.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([F:24])[CH:23]=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.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1>>[F:24][C:22]1[CH:23]=[C:18]([C:8]2([C:16]3[CH:11]=[CH:12][CH:13]=[C:14]([C:29]4[CH:30]=[N:25][CH:26]=[N:27][CH:28]=4)[CH:15]=3)[C:4]3[C:3](=[CH:2][CH:7]=[CH:6][CH:5]=3)[C:10]([NH2:17])=[N:9]2)[CH:19]=[N:20][CH:21]=1
Reactant: OB(O)c1cncnc1
Reactant: NC1=NC(c2cncc(F)c2)(c2cccc(Br)c2)c2ccccc21
Product: NC1=NC(c2cncc(F)c2)(c2cccc(-c3cncnc3)c2)c2ccccc21
Yield: 41 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(5-fluoropyridin-3-yl)-1H-isoindol-3-amine (Example 123) as described in Example 67 Scheme #10, D in 41% yield using pyrimidine-5-boronic acid. 1H NMR (DMSO-d6) δ 9.18 (s, 1 H), 9.04 (s, 2 H), 8.49 (t, J=1.77 Hz, 1 H), 8.45 (d, J=2.53 Hz, 1 H), 8.08-8.02 (m, 1 H), 7.90-7.80 (m, 1 H), 7.74-7.64 (m, 2 H), 7.62-7.43 (m, 5 H), 6.98 (br s, 2 H); MS (ESI) m/z 382 [M+1]+.
Reaction SMILES: S(Cl)([Cl:3])=O.O[C:6]1[C:11]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:10][C:9]([N+:17]([O-:19])=[O:18])=[CH:8][N:7]=1>CN(C=O)C>[Cl:3][C:6]1[C:11]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:10][C:9]([N+:17]([O-:19])=[O:18])=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(-n2cccn2)c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(Cl)c(-n2cccn2)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Thionyl chloride (6 ml) and DMF (0.1 ml) were added to 2-hydroxy-5-nitro-3-(1H-pyrazol-1-yl)pyridine (1.37 g), followed by stirring at 80° C. for 2.5 hours. The reaction solution was adjusted to room temperature and slowly added to ice water, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1 to 3:1), and a yellow solid of 2-chloro-5-nitro-3-(1H-pyrazol-1-yl)pyridine (0.12 g) was thus obtained.
Reaction SMILES: C(OC(=O)[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[N+:16]([O-:18])=[O:17])(C)(C)C.C(OCC)(=O)C.Cl>C(OCC)(=O)C>[CH3:15][O:14][C:10]1[C:9]([N+:16]([O-:18])=[O:17])=[C:8]([CH:13]=[CH:12][CH:11]=1)[NH:7][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24]
Reactant: COCCCCN(C(=O)OC(C)(C)C)c1cccc(OC)c1[N+](=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCNc1cccc(OC)c1[N+](=O)[O-]
Reaction time: 12 h
Yield: 99.1 %

Procedure:
tert-Butyl(4-methoxybutyl)(3-methoxy-2-nitrophenyl)carbamate (2.11 g) was dissolved in ethyl acetate (30 ml), 4M hydrogen chloride-ethyl acetate (15 ml) was added, and the mixture was stirred for 12 hr. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentration under reduced pressure to give the object product (1.50 g).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(N(CC)CC)C>C(Cl)Cl>[C:15]([Si:12]([CH3:14])([CH3:13])[O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH:2]2[CH2:3][O:1]2)=[CH:6][CH:7]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(CC2CO2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC2CO2)cc1
Reaction time: 22 h
Yield: 81.8 %

Procedure:
(RS)-4-Oxiranylmethyl-phenol (1 g, 6.66 mmol) was dissolved in CH2Cl2 (50 ml) and stirred at room temperature in the presence of tert-butyldimethylsilyl chloride (1.3 g, 8.66 mmol), 4-dimethyl-aminopyridine (0.018 g, 0.15 mmol) and triethylamine (1.2 ml, 8.66 mmol). After 22 hours at room temperature, the reaction mixture was washed with H2O (2×100 ml) and the resulting aqueous phases were extracted with CH2Cl2 (100 ml). The combined organic phases were dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1) to provide (RS)-tert-Butyl-dimethyl-(4-oxiranylmethyl-phenoxy)-silane (1.44 g, 82%) as yellow oil, MS: m/e=264 (M+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=1.[CH3:21][O:22]C=O>C1COCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Br:20])[C:19]=1[CH:21]=[O:22]
Reactant: COC=O
Reactant: Brc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1c(Br)cncc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (6.6 mL, 46.43 mmol) in THF (40 mL) at 0° C. was treated with n-butyllithium in hexanes (2.50 M solution, 18.6 miL, 46.43 mmol) over 15 minutes, stirred at 0° C. for 30 minutes, diluted with THF (200 mL), cooled to −78° C., treated with 3,5-dibromopyridine (10 g, 42.21 mmol) in THF (110 mL) over 95 minutes, stirred at −78° C. for 30 minutes, treated dropwise with methylformate (5.2 mL, 84.42 mmol), stirred at −78° C. for 2 hours, transferred to ice-cold saturated NaHCO3 solution, stirred for 15 minutes, and extracted with diethyl ether. The extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 10% acetone/hexane to provide the title compound. MS (DCI/NH3) m/z 266 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 2H), 10.09 (s, 1H).