Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][N:3]1[CH2:16][CH:17]=O.[N:19]1([C:24]2[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=2)[NH2:27])[CH:23]=[CH:22][CH:21]=[N:20]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][N:3]1[CH2:16][CH2:17][NH:27][C:26]1[CH:28]=[CH:29][CH:30]=[C:24]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[CH:25]=1
Reactant: COC(=O)c1ccc2ccn(CC=O)c(=O)c2c1
Reactant: Nc1cccc(-n2cccn2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2ccn(CCNc3cccc(-n4cccn4)c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
A solution of methyl 1-oxo-2-(2-oxoethyl)-1,2-dihydroisoquinoline-7-carboxylate (0.15 g, 0.61 mmol) and 3-(1H-pyrazol-1-yl)aniline (0.15 g, 0.92 mmol) in methanol (2 mL) was stirred at rt for 30 mins. Then acetic acid (3.5 μL, 0.06 mmol) and sodium cyanoborohydride (96 mg, 1.5 mmol) was added and the reaction mixture was stirred at rt overnight. The mixture was diluted with water and extracted with DCM (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (20% to 70% EtOAc/hexanes) to afford methyl 1-oxo-2-(2-{[3-(1H-pyrazol-1-yl)phenyl]amino}ethyl)-1,2-dihydroisoquinoline-7-carboxylate (0.14 g, 59%). LC-MS: (FA) ES+ 389.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=1[OH:22])[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([OH:25])[CH3:24].C(OC(=O)C)(=O)C>[Fe].C(O)(=O)C>[C:23]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH3:12])=[C:14]([OH:22])[CH:15]=1)(=[O:25])[CH3:24]
Reactant: CN(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1O
Reactant: CCO
Agent: [Fe]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(N(C)C(=O)OCc2ccccc2)c(O)c1
Temperature: 80 °C

Procedure:
3.3×10-2 mole (10 g) of 2-(N-benzyloxycarbonyl -N-methylamino)-5-nitrophenol is added to 40 g of iron powder in 60 ml of 96° strength ethanol mixed with 20 ml of acetic acid brought to 80° C., the temperature being maintained at 80° C. When the addition is complete, heating is maintained for 30 minutes. The inorganic salts present in the reaction medium are removed by filtration while hot. The filtrate is diluted with 800 ml of ice-cold water. 3.7×10-2 mole (3.5 ml) of acetic anhydride is then added. The expected product crystallizes after 3 hours. After filtration and drying, the product obtained is recrystallized from a water/ethanol mixture. It then melts at 174° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C(O[C@@H:17]1[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C.[Si](S(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C>[NH2:1][C:2]1[N:3]([C@@H:17]2[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: C[Si](C)(C)S(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2c(N)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Yield: 15.5 %

Procedure:
2-Amino-5,6-dichlorobenzimidazole (4) (3 g, 16 mmole) was dissolved in dry acetonitrile (150 ml) and stirred in an inert atmosphere at 60° C. BSA (4.37 ml, 17 mmole) was added and the mixture was stirred for 10 minutes. 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (5.09 g, 16 mmole) and TMSTf (3.29 ml, 17 mmole) were added to the clear solution and the mixture was allowed to stir at 60° C. for 1 hr. The mixture was concentrated under reduced pressure and separated on a silica column to yield 1.14 g (15%) of 2-amino-5,6-dichloro-1-(2,3,5,tri-O-acetyl-β-D-ribofuranosyl) benzimidazole (43). 13C NMR (CDCl3): d 170.04 ppm, 169.56, 169.11, 154.57, 141.64, 132.53, 125.90, 1123.45, 117.72, 109.49, 85.78, 80.99, 70.95, 69.83, 62.91, 20.74, 20.54, 20.20. 1H NMR (CDCl3): d 0.96 ppm (s, 3H), 1.09 (s, 3H), 1.13 (s, 3H), 3.75 (m, 2H), 4.08 (dd, 1H), 5.00 (dd, 1H), 5.13 (t, 1H), 5.42 (s, 2H), 5.61 (d, 1H), 7.27 (s, 1H), 7.42 (s, 1H). MS (FAB) m/e 758,718, 676, 460, 426, 259, 217, 139.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[C:12]([CH3:21])([CH3:20])[CH2:11]1.Cl[C:23]([O:25][C:26]1C=C[C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=1)=O.C(N(C(C)C)CC)(C)C.[O:44]1CCC(CN)[CH2:45]1>O1CCCC1.O>[O:25]1[CH2:26][CH2:27][CH:28]([CH2:29][NH:32][C:45](=[O:44])[O:19][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:10]([CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=2)[CH2:11][C:12]3([CH3:21])[CH3:20])[CH2:23]1
Reactant: NCC1CCOC1
Reactant: CC1(C)CN(Cc2ccccn2)c2ccc(O)cc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)CN(Cc2ccccn2)c2ccc(OC(=O)NCC3CCOC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.7 %

Procedure:
To a suspension of 1-(2-pyridylmethyl)-3,3-dimethylindolin-5-ol dihydrochloride (50.0 mg, 0.15 mmol) in 1 mL of dry tetrahydrofuran was added 4-nitrophenyl chloroformate (34 mg, 0.165 mmol) and diisopropylethylamine (91 μL, 0.52 mmol) under ice-cooled conditions. After the reaction mixture was stirred at room temperature for 1 h, 3-tetrahydrofurylmethylamine (17 μL, 0.165 mmol) and diisopropylethylamine (39 μL, 0.225 mmol) was added with additional stirring overnight. After the reaction mixture was added with water (10 mL), the solution was extracted with ethyl acetate (10 mL). The extract was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50 to 10/90) to obtain the title compound (10.7 mg, 18%) as a white solid having the following characteristics.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH:9]([CH2:12][CH3:13])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1>C(O)CCC.[OH-].[Na+]>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:14](=[O:16])[C:3]3=[CH:4][NH:5][C:6]4[CH2:7][CH2:8][CH:9]([CH2:12][CH3:13])[CH2:10][C:11]=4[C:2]3=[N:27]2)=[CH:22][CH:21]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CC(CC)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CCC1CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.6 g of ethyl 4-chloro-6-ethyl-5,6,7,8 -tetrahydroquinoline-3-carboxylate in 30 ml n-butanol is treated with 1.38 g of 4-chlorophenylhydrazine at room temperature under nitrogen. After stirring at room temperature overnight, the reaction mixture is heated at reflux for 41/2 hours. The reaction mixture is cooled to room temperature, the precipitate is filtered off, washed with hexane and air-dried to yield a yellow solid. The crude product is dissolved in 30 ml 1N NaOH and extracted with ether. The aqueous layer is then treated with 1.6 g of NH4Cl. The precipitate which forms is filtered off, washed with water, and dried in a vacuum oven at 120° overnight to yield 2,3,6,7,8,9-hexahydro-2-p-chlorophenyl-8-ethylpyrazolo[4,3-c]quinolin-3-(5H)-one, m.p. 318°-320°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15](C)=[C:16](C)[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3COC)[N:9]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2C3C(C)=NSC=3[NH:39]C(=O)C3(CC3)N=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:16])=[N:39][S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]3([CH2:25][CH2:24]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1nsc2c1C(c1ccc(Cl)cc1)=NC1(CC1)C(=O)N2
Reactant: COC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12
Product: Cc1nsc2c1C(c1ccc(Cl)cc1)=NC1(CC1)c1nnc(C)n1-2

Procedure:
A procedure analogous to that set forth for Compound 202 was followed, with the exception that 4′-(4-chlorophenyl)-3′-methylspiro[cyclopropane-1,6′-isothiazolo[5,4-e][1,4]diazepin]-7′(8′H)-one was used as starting material. LRMS (M+H)+: 356 m/z. 1H NMR (400 MHz, DMSO-d6) δ 7.25-7.65 (m, 4H), 2.62 (br. s., 3H), 1.91 (s, 3H), 1.85-1.89 (m, 2H), 1.78-1.82 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[OH:33][C@H:34]1[CH2:38][NH:37][C@H:36]([C:39]([OH:41])=[O:40])[CH2:35]1>>[OH:33][CH:34]1[CH2:38][N:37]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([S:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[O:21][CH3:22])=[C:10]([C:23]([F:25])([F:24])[F:26])[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:36]([C:39]([OH:41])=[O:40])[CH2:35]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CC(O)CC3C(=O)O)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with trans-4-hydroxy-L-proline. A yellow solid 110 was obtained (0.031 g, 65%). MS (APCI) m/z 491 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[C:18]3[S:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)=[CH:23][C:17]=3[N:16]=[CH:15]2)=[CH:10][C:9]=1[O:31][CH3:32].[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[S:21][C:18]3[C:19](=[O:20])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([NH:7][S:39]([C:36]5[CH:37]=[CH:38][C:33]([CH3:43])=[CH:34][CH:35]=5)(=[O:41])=[O:40])=[C:9]([O:31][CH3:32])[CH:10]=4)[CH:15]=[N:16][C:17]=3[CH:23]=2)=[CH:25][CH:26]=1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A pyridine (1 mL) solution of 3-(4-Amino-3-methoxyphenyl)-6-(4-chloro-phenyl)thieno[3,2-d]pyrimidin-4(3H)-one (0.050 g, 0.0013 mol, the preparation of which is found in Example K13) and p-toluenesulfonyl chloride and was agitated overnight at RT, then diluted with water and filtered to give a white powder (0.056 g 81%). LCMS m/z 538 (MH+). 1H NMR (300 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.40 (s, 1H), 8.00 (s, 1H), 7.95 (d, 2H), 7.70 (d, 2H), 7.60 (d, 2H), 7.38 (d, 2H), 7.35 (d, 1H), 7.20 (s, 1H), 7.05 (d, 1H), 3.62 (s, 3H), 2.41 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18](O)=[O:19])=[O:15])=[C:6]1[CH3:25])[CH2:2][CH2:3][CH3:4].[CH3:26][N:27]([CH3:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]([CH3:36])[CH3:35])[CH:29]=1.C(OC(=O)C)(=O)C.[OH-].[Na+]>O>[CH3:35][N:34]([CH3:36])[C:30]1[CH:29]=[C:28]([N:27]([CH3:37])[CH3:26])[CH:33]=[CH:32][C:31]=1[C:14]1([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]=2[CH3:25])[C:16]2[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[O:15]1
Reactant: CCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Reactant: CN(C)c1cccc(N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCCCn1c(C)c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3.35 g (0.01 mole) of 2[(1-n-butyl-2-methyl-3-indolyl)carbonyl]benzoic acid, prepared as described in part A above, 1.80 g (0.011 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and five ml of acetic anhydride was stirred at ambient temperature for a period of approximately 18 hours The reaction mixture was then poured into a mixture of 40 ml of water, 40 ml of ligroin and 20 ml of 10 percent aqueous sodium hydroxide. The ligroin layer was separated and the white crystals which separated from the solution on standing, were collected by filtration and dried to obtain 3-[2,4-bis(dimethylamino)phenyl]-3-(1-n-butyl-2-methyl-3-indolyl)phthalide (Formula III: R°=R1 =R2 =R3 =Y1 =H; R=R5 =CH3 ; R4 =N(CH3)2 ; R6 =(CH2)3CH3) which melted at 165°-167° C. A characteristic infrared maximum appeared at 1752 cm-1 (C=O; s). A toluene solution of the product spotted on silica gel developed an intense purple-colored image.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:21])([CH3:20])[C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14]OS(C)(=O)=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C-:22]#[N:23].[Na+]>CN(C)C=O>[C:1]([SiH2:5][O:6][C:7]([CH3:21])([CH3:20])[C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][C:22]#[N:23])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CC[C@H](CC#N)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
38.2 g of crude trans-methanesulfonic acid 4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohexylmethyl ester and 16.7 g (340 mmol) of sodium cyanide dissolved in 380 ml of N,N-dimethylformamide were stirred for 2 hours at 80° C. After cooling the reaction mixture down to room temperature, it was partitioned between ether and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure and the residue then chromatographed on silica gel with a 9:1 v/v mixture of hexane and ethylacetate as the eluent giving 24.2 g (79.7% over two steps) of pure trans-[4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohexyl]-acetonitrile as colorless viscous oil, MS: 290 (MNa+).
Reaction SMILES: [CH2:1]([I:3])[CH3:2].[C:4]1([C@H:10]2[C@H:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:13][C:12](=[S:21])[NH:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[IH:3].[CH2:1]([S:21][C:12]1[NH:11][C@@H:10]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:13]=1)[CH3:2]
Reactant: S=C1N[C@@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: CCI
Solvent: CO
Product: CCSC1=N[C@@H](c2ccccc2)[C@H](c2ccccc2)N1
Product: I

Procedure:
25 ml of methanol and 1.85 g of ethyl iodide are added to 2.5 g of DL-trans-4,5-diphenyl-imidazolidine-2-thione and the mixture is refluxed for 15 hours. A further 0.4 g of ethyl iodide is then added and the mixture is refluxed for a further 5 hours. It is then evaporated to dryness. DL-trans-2-Ethylthio-4,5-diphenyl-imidazoline hydroiodide is obtained. In order to convert it to the base, this hydroiodide is suspended in 100 ml of ethyl acetate and 100 ml of water, the suspension is rendered alkaline with concentrated aqueous ammonia solution and the organic phase is separated off, dried over sodium sulfate and evaporated. DL-trans-2-Ethylthio-4,5-diphenyl-imidazoline with a melting point of 130°-132° is obtained.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])([O-:5])=[O:4].[C:13](OC(=O)C)(=[O:15])[CH3:14].O>O1CCCC1>[C:13]([NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[N+:3]([O-:5])=[O:4])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ccccc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
1.89 g of sodium hydride (60% content) was suspended in 23.76 g of tetrahydrofuran and cooled with ice. To the obtained suspension, 23.79 g of a tetrahydrofuran solution containing 3.00 g of 2nitroaniline was dropwise added over 1 hour, stirred for 10 minutes, allowed to stand at room temperature and stirred for 30 minutes. To the obtained mixture, 2.41 g of acetic anhydride was added dropwise over 1 hr at room temperature and stirred for 2 hours. Then, water was added to the reaction mixture, and extraction and separation were conducted. The obtained organic layer was analyzed by high performance liquid chromatography to find the yield of the desired product was 84%.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([OH:17])=O.[NH2:18][C:19]1[CH:20]=[C:21](O)[CH:22]=[CH:23][C:24]=1[Cl:25].IC1C=CC=CC=1>[Cu]I.CS(C)=O>[Cl:25][C:24]1[CH:23]=[CH:22][C:21]([O:17][C:15]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:20][C:19]=1[NH2:18]
Reactant: O=C(O)c1ccccn1
Reactant: Nc1cc(O)ccc1Cl
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Ic1ccccc1
Product: Nc1cc(Oc2ccccc2)ccc1Cl
Temperature: 80 °C
Reaction time: 15 h
Yield: 853 %

Procedure:
A heat gun-dried 100-mL round bottomed flask equipped with a magnetic stir bar was charged with potassium phosphate (5.91 g, 27.9 mmol), picolinic acid (0.171 g, 1.393 mmol), copper(I) iodide (0.133 g, 0.697 mmol), 3-amino-4-chlorophenol (2.0 g, 13.93 mmol), dimethylsulfoxide (27.9 mL), and iodobenzene (3.41 g, 16.72 mmol). The resulting mixture was heated to 80° C. After 15 h, the reaction mixture was subjected to an aqueous workup to afford the crude product, which was then purified by flash chromatography to afford pure 2-chloro-5-phenoxyaniline (2.61 g, 85%). MS (ESI, pos. ion) m/z 220 [M+1].
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]5[CH:27]=[CH:26][N:25](COCC[Si](C)(C)C)[C:21]=5[N:22]=[CH:23][N:24]=4)=[CH:15]3)[CH2:11]2)[CH2:6][CH2:5]1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>>[CH3:39][S:40]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]5[CH:27]=[CH:26][NH:25][C:21]=5[N:22]=[CH:23][N:24]=4)=[CH:15]3)[CH2:11]2)[CH2:6][CH2:5]1)(=[O:42])=[O:41]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3ccn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CS(=O)(=O)N1CCC(N2CC(CC#N)(n3ccc(-c4ncnc5[nH]ccc45)c3)C2)CC1

Procedure:
Reaction of {1-piperidin-4-yl-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride with methanesulfonyl chloride following the procedure described for Example 246, followed by purification with HPLC (method B) provided the title compound. LC-MS: 440.1 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 11.91 (brs, 1H), 8.55 (s, 1H), 7.76 (s, 1H), 7.43 (d, 1H), 7.01 (d, 1H), 6.88 (d, 2H), 3.52 (d, 2H), 3.47 (d, 2H), 3.30 (m, 2H), 3.27 (s, 2H), 2.80 (m, 2H), 2.75 (s, 3H), 2.27 (m, 1H), 1.65 (m, 2H), 1.23 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18](=[O:22])[C:19]([OH:21])=[O:20])([O-:10])=[O:9].C(O)=O>>[OH:22][C@@H:18]([CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N+:8]([O-:10])=[O:9])[C:19]([OH:21])=[O:20]
Reactant: O=C(O)C(=O)Cc1ccccc1[N+](=O)[O-]
Solvent: O=CO
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H](O)Cc1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 2 h
Yield: 138.1 %

Procedure:
Into 0.27 ml (19 mmol) of triethylamine was dissolved 3 mg (0.0048 mmol) of [RuCl((S,S)-TsDPEN)(p-cymene)] to prepare a solution, and to the solution were added 1.0 g (4.8 mmol) of o-nitrophenyl pyruvic acid and 0.54 ml (14 mmol) of formic acid, followed by stirring for 2 hours at a bath temperature of 40° C. Upon completion of the reaction, the solvent was distilled off under reduced pressure. Thereto was added 2 ml of water, and then 1 g of concentrated hydrochloric acid was gradually dropwise added under ice cooling, and pH of the solution was adjusted to 2. Extraction was performed twice with 10 ml of ethyl acetate, and then the organic phase was washed with 2 ml of a saturated aqueous solution of sodium chloride, followed by concentration under reduced pressure. As a result, 1.4 g (yield 97%, 95% ee) of (2S)-hydroxy-3-(o-nitrophenyl)propanoic acid was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.[F:18][C:19]1[CH:30]=[CH:29][C:22]2[NH:23][C:24]([CH:26]([NH2:28])[CH3:27])=[N:25][C:21]=2[CH:20]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CS(C)=O.C(OCC)(=O)C>[F:18][C:19]1[CH:30]=[CH:29][C:22]2[NH:23][C:24]([CH:26]([NH:28][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH3:27])=[N:25][C:21]=2[CH:20]=1
Reactant: CC(N)c1nc2cc(F)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NC(C)c2nc3cc(F)ccc3[nH]2)ccc1C(=O)N1CCCC1
Temperature: 25 °C

Procedure:
A solution of 0.10 g (0.43 mmol) of 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, 0.184 g (0.450 mmol) of 1-(5-fluoro-1H-benzimidazol-2-yl)ethylamine×2(CF3COOH) (prepared analogously to Methods 1a, 10b, 10c) and 0.35 mL (2.50 mmol) of triethylamine in 3 mL of dimethylsulfoxide is stirred at ambient temperature and combined with 0.193 g (0.600 mmol) of TBTU. The reaction mixture is stirred for 1 hour at ambient temperature, then diluted with ethyl acetate and washed successively with 10% aqueous citric acid, twice with 2 molar sodium hydroxide solution and with water. The organic phase is dried with sodium sulfate and concentrated. The crude product is taken up in ethyl acetate, precipitated with tert-butylmethylether, and dried. Yield: 83 mg (49% of theory); Rf value: 0.34 (silica gel; ethyl acetate/ethanol=9:1); C22H23FN4O2 (394.45); mass spectrum: (M+H)+=395
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl-].[Cl-].[Cl-].[Al+3].[OH2:14].CCCCCC.[C:21]([O:24][CH2:25][CH3:26])(=[O:23])[CH3:22]>ClCCl>[CH2:25]([O:24][C:21](=[O:23])[C:22]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)=[O:14])[CH3:26]
Reactant: c1ccc2c(c1)OCO2
Reactant: O
Reactant: CCOC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc2c(c1)OCO2

Procedure:
A mixture of ethyl oxalyl chloride (50 ml, 0.45 mmol) and 1,3-benzodioxole (50 g, 0.41 mmol) in dichloromethane (40 ml) was added dropwise to a stirred slurry of aluminium trichloride (71 g, 0.53 mmol) in dichloromethane (500 ml) at 0° C. under a nitrogen atmosphere. After 2 hours the mixture was poured into iced water and the organic layer was washed with further volumes of water (3×500 ml), saturated sodium bicarbonate solution (500 ml) and brine (500 ml). The organic layer was dried (magnesium sulphate) and concentrated to give an orange oil. Flash column chromatography (90% hexane, 10% ethyl acetate) gave 30 g of the subtitle compound as a pale yellow oil.