Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:35][C:30]4[CH2:31][NH:32][CH2:33][CH2:34][C:29]=4[N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:36])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[BH-](OC(C)=O)(OC(C)=O)O[C:39](C)=O.[Na+].C=O>O1CCCC1>[CH:1]1([C:5]2[C:26]([C:27]3[NH:35][C:30]4[CH2:31][N:32]([CH3:39])[CH2:33][CH2:34][C:29]=4[N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:36])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CNCC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CN(C)CC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reaction time: 2 h
Yield: 15.8 %

Procedure:
To a solution of 4-(1-(4-cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile (406.3, 190 mg, 0.30 mmol, 1.00 equiv, 75%) in tetrahydrofuran (10 mL) were added NaBH(OAc)3 (252 mg, 1.13 mmol, 3.00 equiv, 95%) and HCHO (37%) (2.2 mL, 2.00 equiv). The resulting mixture was stiffed for 2 h at 40° C. in an oil bath and then concentrated under reduced pressure. The residue was diluted with dichloromethane and washed with aqueous saturated sodium bicarbonate and brine. The organic layer was dried (Na2SO4) and concentrated. The crude product (˜80 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.03% NH3H2O and CH3CN (36% CH3CN up to 48% in 8 min, up to 100% in 1 min, down to 36% in 1.5 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 23.4 mg (16%) of the title compound as a white solid. m/z (ES+) 494 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.69 (d, J=6.0 Hz, 2H), 7.48 (d, J=6.0 Hz, 2H), 7.37-7.31 (m, 1H), 7.26 & 7.15 (2 singlets, amide rotamers, Ar—H, 1H), ˜4.9 (1H partially obscured by water peak), 4.02-3.90 (m, 1H), 3.73-3.57 (m, 1H), 3.57 (s, 2H), 3.34-3.21 (m, 1H), 3.06-2.94 (m, 2H), 2.90-2.77 (m, 4H), 2.54 (s, 3H), 2.45 & 2.34 (2 singlets, amide rotamers, ArCH3, 3H), 2.11-1.86 (m, 6H), 1.86-1.54 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH3:26][CH:27]([CH3:36])[CH2:28][C:29](=O)[C:30](OCC)=[O:31].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]3[C:12](=[CH:13][CH:14]=2)[NH:15][C:30](=[O:31])[C:29]([CH2:28][CH:27]([CH3:36])[CH3:26])=[N:16]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(c2cccc(Cl)c2)n2ccnc2)cc1N
Reactant: CCOC(=O)C(=O)CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Cc1nc2cc(C(c3cccc(Cl)c3)n3ccnc3)ccc2[nH]c1=O
Reaction time: 4 h
Yield: 12.6 %

Procedure:
To a stirred and cooled (0° C.) solution of 9.1 parts of 4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1,2-benzenediamine in 80 parts of acetic acid and 20 parts of water were added portionwise 5.8 parts of ethyl 4-methyl-2-oxopentanoate. Upon completion, stirring was continued for 4 hours at room temperature. The reaction mixture was poured into 100 parts of water and the whole was neutralized with a sodium hydroxide solution 3N. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 1,1'-oxybisethane. The product was filtered off (the filtrate was set aside) and dried, yielding 1.5 parts (12.6%) of 6-[(3-chlorophenyl) (1H-imidazol-1-yl)methyl]-3-(2-methylpropyl)-2(1H)-quinoxalinone; mp. 209.7° C. (comp. 178)
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:13][C:14]([CH3:16])=[O:15].[OH-].[Na+].O>C(O)C>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:13][C:14](=[O:15])[CH:16]=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:2]([F:1])([F:11])[F:12]
Reactant: CC(C)=O
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccccc1C(F)(F)F)C=Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
2-(Trifluoromethyl)-benzaldehyde (1w, 0.75 ml, 5.7 mmol) and acetone (19, 0.21 ml, 2.8 mmol) were combined in ethanol (20 ml) and stirred for 10 min at room temperature. A solution of sodium hydroxide (0.34 g, 8.5 mmol) and water (15 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethanol to afford 0.92 g (87%) of a yellow solid: mp 131-133° C. [expected mp 131° C.]; 1H NMR: δ 6.99 (d, 2H, J=15.9 Hz), 7.48 (t, 2H, J=7.6 Hz), 7.56 (t, 2H, J=7.0 Hz), 7.70 (d, 2H, J=7.7 Hz), 7.77 (d, 2H, J=7.6 Hz), 8.07 (d, 2H, J=15.7 Hz); 13C NMR: δ 123.9, 126.2, 127.9, 128.8, 129.4, 129.7, 132.1, 133.7, 139.1, 188.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[O:19][CH3:20].[CH2:21]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH3:24]>>[CH2:21]([O:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=2[O:19][CH3:20])=[CH:30][CH:31]=1)[CH2:22][CH2:23][CH3:24]
Reactant: COc1cc(CC(OC)C(=O)O)ccc1OCCCBr
Reactant: CCCCOc1ccc(O)cc1
Product: CCCCOc1ccc(OCCCOc2ccc(CC(OC)C(=O)O)cc2OC)cc1

Procedure:
The title compound was prepared from 3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid (Example 175, Step B) and 4-Butoxy-phenol following the Standard Procedure J. MS (ES) for C24H32O7 [M+Na]+: 455.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Cl.[NH2:14][OH:15].C(O)C.C([O-])(=O)C.[Na+]>O>[OH:15][N:14]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C=NO)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a mixture of 4-methyl-3-nitrobenzaldehyde (3.00 g), hydroxylamine hydrochloride (1.64 g), ethanol (30 mL) and water (15 ml) was added sodium acetate (2.24 g) at room temperature, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5-hydroxyiminomethyl-2-methylnitrobenzene (2.77 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C@@H:10]([CH2:13][OH:14])[CH2:9][CH2:8]2.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:14][CH2:13][C@H:10]2[CH2:9][CH2:8][C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[O:11]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cccc2c1O[C@@H](CO)CC2
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CC2
Temperature: 50 °C
Yield: 72 %

Procedure:
To a solution of [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methanol (5.00 g, 25.7 mmol) in dichloromethane (250 mL) was added p-toluenesulfonyl chloride (9.82 g, 51.5 mmol), 4-(dimethylamino)pyridine (0.62 g, 5.15 mmol), and N,N-diisopropylethylamine (8.32 g, 64.4 mmol) and the reaction mixture was heated to 50° C. for 12 h. The reaction mixture was quenched by the addition of water (500 mL). The aqueous layer was separated and extracted with dichloromethane (200 mL). The combined organic extracts were washed with aqueous hydrogen chloride (1.0 M, 200 mL), water (200 mL), aqueous sodium chloride (200 mL), dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:3) gave 6.45 g (72%, 40% ee) of [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate as a white crystalline solid. [α]D25=−20.30 (c 13.1 in chloroform, 40% ee); Rf=0.71 (silica, ethyl acetate:hexanes 2:3); mp 115-117° C.; Anal. Calcd. for C18H20O5S: C, 62.05; H, 5.79. Found: C, 61.99; H, 5.81.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[NH3:18]>C(O)C>[NH2:18][CH2:3][C@H:2]([OH:1])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H]2CO2)CC1
Reactant: N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN)CC1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Tert-butyl 4-[[(2R)-oxiran-2-yl]methyl]piperazine-1-carboxylate 7b (3.55 g, 14.70 mmol) was dissolved in 40 mL of ethanol followed by the addition of 40 mL of aqueous ammonia, stirred for 12 hours. The resulting solution was heated to 50° C. and stirred for another 1 hour, then concentrated under reduced pressure to obtain the crude title compound tert-butyl 4-[(2S)-3-amino-2-hydroxy-propyl]piperazine-1-carboxylate 7c (3.40 g) as a light yellow solid, which was used in the next step without further furification.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]2[NH:11][N:10]=[C:9]([C:12]3[N:13]=[N:14][N:15]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[CH:16]=3)[CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:10]=[C:9]([C:12]3[N:13]=[N:14][N:15]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[CH:16]=3)[CH:8]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(Cn2cc(-c3cc(Cc4ccc(F)cc4)[nH]n3)nn2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(-c3cc(Cc4ccc(F)cc4)n(CC(=O)OC(C)(C)C)n3)nn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a solution of 4-[5-(4-fluorobenzyl)-1H-pyrazol-3-yl]-1-(4-methoxybenzyl)-1H-1,2,3-triazole (19.0 g, 0.052 mol) in anhydrous THF (100 mL) was added NaH (2.6 g, 0.06 mol) at 0° C. and the mixture was stirred at RT for 2 hours. tert-butyl bromoacetate (12.5 g, 0.057 mol) was then added at 0° C. and the mixture was stirred at RT for 2 hours. The mixture was evaporated and the residue was purified via column chromatography (silica gel, EtOAc/Petroleum ether 1:1) to yield the title compound (20.0 g, 76.0%) as a yellow solid.
Reaction SMILES: [OH-].[Na+].[C:3]1([CH3:15])[CH:8]=[CH:7][C:6]([N:9]2[C:13]([NH2:14])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.Cl[C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18]>O.CCOC(C)=O>[Cl:22][C:21]([Cl:24])([Cl:23])[CH2:20][O:19][C:17](=[O:18])[NH:14][C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([CH3:15])=[CH:8][CH:7]=2)[N:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1ccc(-n2nccc2N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nccc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
NaOH (107 mg, 2.67 mmol) was added to a stirred solution of 2-p-tolyl-2H-pyrazol-3-ylamine (for reference procedure see WO 2009/150614, which is incorporated herein by reference in its entirety, 346 mg, 2.00 mmol) in water (1 mL) and EtOAc (4 mL). The mixture was cooled to 0° C., and 2,2,2-trichloroethyl chloroformate (385 μL, 2.80 mmol) added. Stirring was continued for 30 min at 0° C. and then for 2 h at RT. The mixture was partitioned between water and EtOAc. The organic phase was washed with brine and concentrated to dryness in vacuo to give the title compound as an orange residue. LCMS (Method 3): Rt 3.90 min, m/z 348, 350 [MH+].
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=2[F:13])[C:7](O)=[O:8])[CH2:3][CH2:2]1.[NH3:14].C1COCC1>C1COCC1>[CH:1]1([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=2[F:13])[C:7]([NH2:14])=[O:8])[CH2:3][CH2:2]1
Reactant: N
Reactant: O=C(O)c1ccc(F)c(C2CC2)c1
Solvent: C1CCOC1
Product: NC(=O)c1ccc(F)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a solution of compound 3-cyclopropyl-4-fluoro-benzoic acid (Preparation 56, 74 g, 0.41 mol, 1 eq) in THF (800 mL) was added N,N′-carbonyldiimidazole (88 g, 0.53 mol, 1.29 eq) at room temperature. The suspension was stirred at room temperature for 3 h, and turned into a brown solution Ammonia/THF (1 L) was added to the mixture and the resulting mixture was stirred at room temperature overnight. THF was removed in vacuum and the residue was taken up with water (300 mL). The mixture was filtrated and the solid was washed with water (100 mL) and ether (200 mL). The solid was dissolved in DCM (500 mL), dried over sodium sulfate and concentrated in vacuum to title compound as a white solid (66 g, 0.368 mol, 89.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([S:12][CH3:13])=[N:10][OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C)([O-])C.[K+].[Cl:20][C:21]1[N:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH2:34]Cl)[C:23](=[O:27])[N:24]([CH3:26])[N:25]=1>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([S:12][CH3:13])=[N:10][O:11][CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:22]2[C:23](=[O:27])[N:24]([CH3:26])[N:25]=[C:21]2[Cl:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CSC(=NO)c1ccc(Cl)c(Cl)c1
Reactant: Cn1nc(Cl)n(-c2ccccc2CCl)c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CSC(=NOCc1ccccc1-n1c(Cl)nn(C)c1=O)c1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
The product from Step C (2.07 g) was dissolved in 10 mL of tetrahydrofuran and 10 mL of 1.0 M potassium t-butoxide in THF was added dropwise. After the addition was complete, the mixture was stirred 15 min, and then the title compound of Step E (2.06 g) was added. The reaction mixture was stirred at room temperature overnight, and then diluted with 20 mL of water and extracted with three 30 mL portions of ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give 3.53 g of the title compound of Step F as an oil. 1H NMR (CDCl3): δ 7.5 (m,5H), 7.25 (m,2H), 5.34 (d,1H), 5.18 (d,1H), 3.49 (s,3H), 2.08 (s,3H). The crude product contained minor amounts of impurities and solvent, but the material was not further purified before Step G.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][NH:6][C:5]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:4]=2[O:3]1.[H-].[Na+].Cl.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=1[O-:26]>CN(C)C=O.O>[CH3:1][C:2]1([CH3:15])[CH2:7][N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=2[O-:26])[C:5]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: [O-][n+]1ccccc1Br
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc2O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CN(c2cccc[n+]2[O-])c2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 2.66 g of 3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine followed by addition of 1.02 g of sodium hydride (60% in oil) and the mixture was stirred at room temperature for 30 minutes. Then, 2.77 g of 2-bromopyridine N-oxide hydrochloride was added with ice-cooling and, after the evolution of heat had subsided, the mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured in water and extracted with ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was chromatographed on a silica gel column using chloroform as the eluent to give crude 2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)pyridine N-oxide.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:11]1[S:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25]([CH3:30])=[CH:24]3)[CH:12]=1>>[CH3:30][C:25]1[NH:26][C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([NH:20][C:17]1[CH:16]=[CH:15][N:14]=[C:13]3[CH:12]=[C:11]([C:5]4[S:6][C:2]([CH3:1])=[CH:3][CH:4]=4)[S:19][C:18]=13)=[CH:29][CH:28]=2
Reactant: Cc1cc2cc(Nc3ccnc4cc(Br)sc34)ccc2[nH]1
Reactant: Cc1ccc(B(O)O)s1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5ccc(C)s5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 5-methylthiophene-2-boronic acid and (2-bromothieno[3,2-b]pyridin-7-yl)-(2-methyl-1H-indol-5-yl)-amine by the procedure analogous to example 2 above. 1H NMR (400 MHz, CD3OD) δ8.03 (d, 1H), 7.29 (m, 3H), 7.15 (s, 1H), 6.99 (m, 1H), 6.83 (d, 1H), 6.54 (d, 1H), 6.10 (s, 1H), 2.41 (s, 3H), 2.22 (s, 3H); RP18-HPLC RT: 6.08 minutes; API MS: 376 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17](=O)[NH:18][C:19]2[C:20](=[O:31])[N:21]([CH3:30])[C:22]3[C:27]([C:28]=2[NH2:29])=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>>[CH2:1]([O:8][C:9](=[O:33])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:18][C:19]3[C:20](=[O:31])[N:21]([CH3:30])[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[C:28]=3[N:29]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c(NC(=O)C2CCCC(NC(=O)OCc3ccccc3)C2)c(N)c2ccccc21
Solvent: CC(=O)O
Product: Cn1c(=O)c2[nH]c(C3CCCC(NC(=O)OCc4ccccc4)C3)nc2c2ccccc21
Yield: 92.4 %

Procedure:
As described in example 3D, [3-(4-amino-1-methyl-2-oxo-1,2-dihydro-quinolin-3-ylcarbamoyl)-cyclohexyl]-carbamic acid benzyl ester (0.22 g, 0.49 mmol) was heated in glacial acetic acid (5.30 g, 88.3 mmol) to give [3-(5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (0.195 g, 92% yield). 1H-NMR (CDCl3): δ 8.18 (m, 1H), 7.51 (m, 2H), 7.34 (m, 7H), 5.10 (s, 2H), 3.84 (s, 3H), 2.48 (m, 1H), 2.17 (m, 3H), 1.92 (m, 1H), 1.72 (m, 3H), 1.53 (m, 1H), 1.13 (m, 2H). MS: calculated for C25H26N4O3+H 431.2; found: 431.0.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].C1COCC1.C(Cl)(=O)C([Cl:26])=O>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8]([Cl:26])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)Cl)c1

Procedure:
3,5-Diacetoxybenzoic acid (15 g, 63 mM) was suspended in dichloromethane (100 mls), THF(20 mls) with oxalyl chloride (7.34 mls, 69.3 mM) and DMF(2–3 drops) added. The resultant mixture was stirred for three hours at ambient temperature in a flask fitted with a gas bubbler. This gave a pale brown solution. After concentration ‘in vacuo’ the residue was triturated with diethyl ether. This gave a colourless solid, 3,5-diacetoxybenzoyl chloride (15.95 g) which was used for the next stage without further purification.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1CCN.C(OCC)(=O)C>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[S:12]
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Reactant: COc1ccccc1CCN
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1CCNC(=S)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 38 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(2-methoxyphenyl)ethylamine (0.82 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.62 g (38%) of the titled product as a white solid:
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([O:12]CC)=[O:11])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[C:17](=[O:35])[CH:18]=CC1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1.[Br:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([Br:46])[C:44]=1[OH:45])[CH:40]=O>>[OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([OH:12])=[O:11])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[C:17](=[O:35])[CH:18]=[CH:40][C:39]1[CH:38]=[C:37]([Br:36])[C:44]([OH:45])=[C:43]([Br:46])[CH:42]=1
Reactant: CCOC(=O)c1c(C)c(C)c(C(=O)C=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(O)c1OC
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Product: COc1c(O)c(C(=O)C=Cc2cc(Br)c(O)c(Br)c2)c(C)c(C)c1C(=O)O

Procedure:
This compound was synthesized from 2′-hydroxy-4′-ethyl oxycarbonyldimethylmethyloxyacetophenone (starting material 1) and 3,5-dibromo-4-hydroxybenzaldehyde according to general method 2 described earlier.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH3:13][N:14](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]#[N:14])=[CH:3][C:4]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Nc1ccc(I)cc1C(F)(F)F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(N)c(C(F)(F)F)c1
Reaction time: 12 h
Yield: 99.28 %

Procedure:
4-Iodo-2-trifluoromethylphenylamine (50 mg, 0.17 mmol), Zn(CN)2 (0.88 eq, 0.15 mmol, 18.00 mg), and Pd(PPh3)4 (0.1 eq, 0.02 mmol, 19.64 mg) were added in DMF. Zn(CN)2 (0.88 eq, 0.15 mmol, 18.00 mg) and Pd(PPh3)4 (0.1 eq, 0.02 mmol, 19.64 mg) were added into the reaction mixture. The reaction mixture was stirred for 12 hr. The reaction mixture was purified according to step 1 of Example 8 to give a title product as a yellow solid (31.4 mg, 99.28%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11].[CH2:12]([O:14][C:15](=[O:19])[CH2:16][CH:17]=[CH2:18])[CH3:13]>O1CCCC1>[CH2:12]([O:14][C:15](=[O:19])[CH2:16][CH2:17][CH2:18][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH3:13]
Reactant: C=CCC(=O)OCC
Reactant: COCCOCCOCCO
Solvent: C1CCOC1
Product: CCOC(=O)CCCOCCOCCOCCOC
Reaction time: 4 h
Yield: 29.6 %

Procedure:
Triethylene glycol monomethyl ether (4.27 g, 0.026 mol) and But-3-enoic acid ethyl ester (1.5 g, 0.013 mol) were dissolved in tetrahydrofuran (10 mL). Then lump Na0 (0.030 g, 0.013 mol) was added and the reaction was stirred for 4 h. Crude reaction was quenched with 1M HCl (20 mL), washed ethyl acetate (3×20 mL). Organic layers were combined and washed with H2O (2×10 mL), dried MgSO4, and evaporated to dryness to afford 2 a yellowish oil (1.07 g, 30% yield).