Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:21][C:22]1[CH:30]=[C:26]([C:27]([OH:29])=[O:28])[C:25]([OH:31])=[CH:24][CH:23]=1>C(O)(=O)C>[C:27]([C:26]1[CH:30]=[C:22]([N:21]2[C:11]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[CH2:18][CH2:19][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:23]=[CH:24][C:25]=1[OH:31])([OH:29])=[O:28]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(CC1CCc2ccccc2C1=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2-c2ccccc2CC3)ccc1O

Procedure:
A mixture of 20.0 g. (0.076 mole) of 2-phenacyl-1-tetralone, 11.6 g. (0.076 mole) of 5-aminosalicylic acid, and 70 ml. of glacial acetic acid was heated under reflux for 4 hours, cooled diluted with 10 ml. of water and filtered. The filter cake was washed with water and dried to provide 15.5 g. of solid, m.p. 215°-218°. Recrystallization from benzene-cyclohexane gave 6.5 g. (22%) of yellow crystals, m.p. 245°-247°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH:5]=[CH:4][C:3]=1[C:16](=O)[CH3:17].[NH2:19][OH:20]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH:5]=[CH:4][C:3]=1[C:16](=[N:19][OH:20])[CH3:17]
Reactant: CC(=O)c1ccc(Oc2ccccc2Cl)cc1Cl
Reactant: NO
Solvent: CCO
Product: CC(=NO)c1ccc(Oc2ccccc2Cl)cc1Cl

Procedure:
A mixture of 2.4 g (8.54 mmol) of 1-[2-chloro-4-(2-chloro-phenoxy)-phenyl]-ethanone and 0.76 mL hydroxylamine solution (50% in water) in 60 mL ethanol was refluxed for 24 hours. Then the mixture was evaporated to dryness and the residue was purified by chromatography (silica gel column, methylene chloride).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([NH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:4]=1)#[N:2].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>C(OCC)(=O)C>[NH2:8][C:7]1[C:6]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:10][CH:9]=2)[N:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:18]=1[C:19](=[O:20])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)Nc1cc(C#N)ccc1C#N
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(C#N)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-cyano-2-(ethoxycarbonylamino)benzonitrile (step 1) and 2-bromoacetophenone. tlc: Rf=0.2 (25% ethyl acetate in hexanes)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13](O)[CH3:14])[CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][C:9](=[O:11])[CH3:10].S([O-])(O)(=O)=O.[K+].C(C1C=C(O)C=CC=1O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][C:9](=[O:11])[CH3:10])[CH:13]=[CH2:14]
Reactant: CC(=O)Oc1c(C)cc(C(C)O)cc1Br
Agent: CC(C)(C)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CCOCC
Product: C=Cc1cc(C)c(OC(C)=O)c(Br)c1
Temperature: 0 °C
Yield: 26 %

Procedure:
A mixture of 28 g 1-(3'-bromo-4'-acetoxy-5'-methylphenyl)ethanol and 0.5 g freshly prepared potassium hydrogen sulfate is heated under a 20 Torr vacuum to 190°-200° C. The distillate is transferred to an ice-filled reaction vessel which contains 2 g t-butylhydroquinone. After 2h, the distillate is taken up in ether, the ether phases are treated with a5% sodium carbonate solution and dried, then the solvent is distilled off under vacuum. At 0.05 Torr, 6.8 g of an impure product is obtained at a temperature of 86°to 89° C., from which 18 g of pure monomercan be obtained.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH2:26]1[CH:30]([OH:31])[CH2:29][NH:28][CH2:27]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:28]1[CH2:27][CH2:26][CH:30]([OH:31])[CH2:29]1)=[O:13])[CH2:8]2
Reactant: OC1CCNC1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1N1CCC(O)C1

Procedure:
5-(3-Hydroxy-pyrrolidin-1-y1)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and DL-3-pyrrolidinol. Mass spectrum (ES) MH+=407.
Reaction SMILES: C(O[CH:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:9]2[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:8]=2[NH:7][C:6]1=[O:24])(=O)C.[I-].[Na+].[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K]>CN(C)C=O>[C:27]1(=[O:37])[N:31]([CH:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:9]3[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:8]=3[NH:7][C:6]2=[O:24])[C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12
Reactant: CC(=O)OC1N=C(c2ccccc2F)c2cccc(Cl)c2NC1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2c(Cl)cccc2C(c2ccccc2F)=NC1N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
A mixture of (3RS)-3-acetoxy-5-(2-fluorophenyl)-9-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one (3.60 g), sodium iodide (15.59 g) and potassium phthalimide (2.89 g) in dimethylformamide (25 ml) was stirred at 100° C. for 1 hour. The reaction mixture was poured into ice-water and the resultant precipitate was collected by filtration. After washing with water several times and dried over phosphorus pentoxide under reduced pressure, the crude powder was subjected to column chromatography on silica gel eluting with a mixture of chloroform and methanol (100:1). The fractions containing the desired product were combined and evaporated in vacuo to give (3RS)-3-phthalimido-5-(2-fluorophenyl)-9-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one (0.82 g, 18.9% yield) as a crystalline powder.
Reaction SMILES: [F:1][C:2]1[C:9](I)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][CH3:12])[CH:3]=1.[Cl-].[Li+].[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17]>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.C1(C)C=CC=CC=1>[F:1][C:2]1[C:9]([CH2:17][CH:16]=[CH2:15])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(F)c(I)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1cc(C#N)c(OC)cc1F
Temperature: 115 °C

Procedure:
To a mixture of 4-fluoro-5-iodo-2-methoxybenzonitrile (2.5 g, 9.0 mmol), Pd(Ph3P)4 (1.0 g, 0.90 mmol) and lithium chloride (0.96 g, 23 mmol) under nitrogen was added anhydrous toluene (50 mL) and the mixture was flushed (3×) with nitrogen. Allyltributyltin (4.15 mL, 14 mmol) was added and the mixture was flushed again with nitrogen. The reaction was heated under nitrogen at 115° C. for 2.5 hours and then let cool to room temperature. TLC (10% ethyl acetate/Hexanes) showed several spots with a strongly charring product spot right above the starting material. The reaction was diluted with hexanes and filtered to remove insoluble material. The mother liquor was concentrated and the residue was purified on a Biotage 65+M column with a gradient elution from 0 to 40% ethyl acetate in hexanes to afford the title product which had some residual tributylstanane by-product contaminant by NMR. 1H-NMR (500 MHz, CDCl3) δ ppm 3.327 (d, J=6.5 Hz, 2H), 3.902 (s, 3H), 5.102 (2 d, J=10.0 and 17 Hz, 2H), 5.868 (m, 1H), 6.668 (d, J=11.1 Hz, 1H), 7.390 (d, J=8.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH2:11]([C@H:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)[CH3:12]>>[NH2:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[N:18]1[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:14][C@H:13]1[CH2:11][CH3:12]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1c(N)cnn1C

Procedure:
Following the procedure for Intermediate 10 starting from 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 and (R)-tert-butyl 3-ethylpiperazine-1-carboxylate gave (R)-tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-ethylpiperazine-1-carboxylate as an orange gum (118 mg, 67% over two steps). LCMS (ES+) m/z 310 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[NH2:12])C.[ClH:14]>CCOCC>[ClH:14].[NH:12]1[C:7]2[C:6](=[CH:11][CH:10]=[N:9][CH:8]=2)[CH2:5][C:4]1=[O:3]
Reactant: CCOC(=O)Cc1ccncc1N
Agent: Cl
Solvent: CCOCC
Product: O=C1Cc2ccncc2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 50-ml round-bottom flask was added 0.36 g (2.0 mmol) of 3-amino-4-pyridineacetic acid ethyl ester, 15 mL of ether and 10 mL of 10% hydrochloric acid. The resulting biphasic solution was stirred for 16 h at room temperature. The two phases were separated, and the ether phase was washed with 5 mL of water. The combined aqueous phases were evaporated to dryness to yield 0.285 g of the title compound as a brown solid. 1H NMR (DMSO-d6): δ5.93 (s, 1H), 7.59 (d, J=5.6 Hz, 1H), 8.02 (s, 1H), 8.49 (d, J=5.6 Hz, 1H), 12.54 (s, 1H), 14.0 (bs, 1H); C8H6N2O: APCI+MS: m/z 135 (M+H).
Reaction SMILES: CCN(CC)CC.[Si:8]([O:15]S(C(F)(F)F)(=O)=O)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[C:23]([C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35]=1[N:34]=[C:33]([S:36][CH3:37])[N:32]([CH3:38])[C:31]2=[O:39])(=O)[CH3:24]>C(Cl)Cl>[Si:8]([O:15][C:23]([C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35]=1[N:34]=[C:33]([S:36][CH3:37])[N:32]([CH3:38])[C:31]2=[O:39])=[CH2:24])([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:9])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CSc1nc2c(C(C)=O)cccc2c(=O)n1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2c(=O)n(C)c(SC)nc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Et3N (0.094 mL, 0.674 mmol) and TBSOTf (0.131 mL, 0.570 mmol) were sequentially added to a yellow solution of 8-acetyl-3-methyl-2-(methylthio)quinazolin-4(3H)-one (128.7 mg, 0.518 mmol) in DCM (2.7 mL) at 0° C., and the resulting light-yellow solution was stirred at 0° C. for 30 min. The mixture was partitioned between DCM (50 mL) and saturated aq. NaHCO3 (20 mL). The organic layer was separated, and the aq. layer was extracted with DCM (30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide crude 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-methyl-2-(methylthio)quinazolin-4(3H)-one as a peach-colored solid. This material was combined with 8-(1-ethoxyvinyl)-3-methyl-2-(methylthio)quinazolin-4(3H)-one (35.5 mg, 0.128 mmol), and the resulting mixture was taken up in THF (2.70 mL). Water (0.149 mL, 8.29 mmol) and NBS (115 mg, 0.648 mmol) were sequentially added at 25° C., and the resulting solution was stirred at 25° C. for 30 min. The mixture was partitioned between Et2O (50 mL) and water (30 mL). The organic layer was separated, sequentially washed with saturated aq. NaHCO3 (20 mL), water (20 mL), and brine (20 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to provide crude 8-(2-bromoacetyl)-3-methyl-2-(methylthio)quinazolin-4(3H)-one as an off-white solid. NH4OAc (200 mg, 2.59 mmol) and piperidine-2,4-dione (88 mg, 0.777 mmol) were added to this solid, and the resulting mixture was taken up in EtOH (2.70 mL) and heated under argon in a sealed flask at 40° C. for 16 h. The reaction suspension was vacuum filtered, and the collected solid was washed with MeOH (20 mL) and dried in vacuo. The residue was triturated with DMSO (2.0 mL), and the resulting suspension was vacuum filtered. The collected solid was sequentially washed with MeOH (5 mL) and DCM (5 mL) and dried in vacuo to provide 3-methyl-2-(methylthio)-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinazolin-4(3H)-one (57.1 mg, 0.168 mmol, 26% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.67 (1H, br. s.), 8.05 (1H, dd, J=7.6, 1.2 Hz), 7.95 (1H, dd, J=7.8, 1.0 Hz), 7.44 (1H, t, J=7.8 Hz), 7.03 (1H, d, J=2.3 Hz), 6.96 (1H, br. s.), 3.56 (3H, s), 3.41 (2H, td, J=6.8, 2.2 Hz), 2.85 (2H, t, J=6.9 Hz), 2.74 (3H, s). m/z (ESI, +ve) 341.1 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([OH:31])=O)[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:32][S:33]([NH2:36])(=[O:35])=[O:34]>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[C:26]([CH3:27])([CH3:28])[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:36][S:33]([CH3:32])(=[O:35])=[O:34])=[O:31])[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(-c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2cccc(C3Nc4ccc(C(=O)NS(C)(=O)=O)cc4CC3(C)C)c2)cc1
Yield: 27.7 %

Procedure:
A mixture of 2-(4′-isopropoxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (90 mg, 0.22 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (63 mg, 0.33 mmol), 4-dimethylaminopyridine (40 mg, 0.33 mmol), methane sulfonamide (63 mg, 0.66 mmol) in dichloromethane (10 mL) was refluxed for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[2-(4′-isopropoxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (30 mg, 28%) as a light yellow solid: LC/MS m/e calcd for C28H32N2O4S (M+H)+: 493.64, observed: 493.5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH2:13][CH:12]([C:14](OC)=[O:15])O[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O:21]CC)C>CO.O=[Pt]=O>[C:1]([O:5][C:6](=[O:18])[CH:7]([OH:21])[CH2:8][CH:9]1[CH2:13][CH2:12][C:14](=[O:15])[NH:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOCC
Reactant: COC(=O)C1CC(CCC(=O)OC(C)(C)C)=NO1
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)(C)OC(=O)C(O)CC1CCC(=O)N1

Procedure:
A suspension of 105 of 4,5-dihydro-5-methoxycarbonyl-3-isoxazolepropanoic acid t-butyl ester and 2.0 g of PtO2 /C in 1 L of methanol is placed under a hydrogen atmosphere with agitation. After H2 absorption is complete, the solution is filtered and the solvent removed under reduced pressure to give an oil. The oil is titurated with anhydrous diethyl ether and filtered to yield 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid t-butyl ester as a white solid with mp 110°-112° C. NMR (CDCl3) and 6.38 (s, 1H), 4.13 (m, 1H), 3.87 (m, 1H), 3.27 (d, 1H), 2.47-1.60 (m, 6H), 7.53 (s, 9H). IR (KBr) 3460, 3245, 2978, 2938, 1723, 1686, 1426, 1392, 1372, 1318, 1277, 1256, 1209.
Reaction SMILES: C[Sn](C)(C)[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.Br[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.Cl>[OH-].[K+].[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:23]1[CH:24]=[CH:25][C:20]([C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc([Sn](C)(C)C)c2ccccc12
Reactant: Brc1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Product: COC(=O)c1ccc(-c2ccncc2)c2ccccc12
Yield: 60 %

Procedure:
A stirred solution of D7 (9.06 g, 26 mmole) in dry degassed DMF (150 ml) was treated with copper (I) iodide (495 mg, 2.6 mmole), dichlorobis(triphenylphosphine)palladium(II) (1.52 g, 2.2 mmole) and 4-bromopyridine (prepared by suspending the HCl salt (6.07 g, 31 mmole) in 40% KOH solution, extracting with toluene and adding the dried toluene solution to the reaction). The mixture was heated at reflux under argon for 5 h and allowed to cool before removing the DMF under vacuum. The residue was partitioned between EtOAc and 10% NaHCO3 solution and the organics dried (Na2SO4) and chromatographed on silica gel eluting with EtOAc to afford the title compound as a white solid (4.1 g, 60%).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH2:24].CCOC(C)=O>CS(C)=O>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH:24][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2ncc(Cl)nc2c1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cnc3ccc(C)cc3n2)c(OC)c1
Yield: 97.2 %

Procedure:
2-Chloro-7-methylquinoxaline (0.51 g, 2.86 mmol), ), prepared according to J. Chem. Soc. 1948 1310-1313, and (2,4-dimethoxyphenyl)methanamine (1.29 mL, 8.57 mmol) were microwaved in DMSO (2.5 mL) for 30 min at 150° C. This was diluted into 150 mL EtOAc and extracted three times with 100 mL brine. The crude product was purified by flash chromatography on a 90 g silica gel cartridge with 20 to 80% EtOAc in hexane, 50 min, at 40 mL/min to afford N-(2,4-dimethoxybenzyl)-7-methylquinoxalin-2-amine (860 mg, 2.78 mmol, 97% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([CH3:13])([CH3:12])[C:8]([O:10]C)=[O:9].[OH-].[K+]>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([CH3:13])([CH3:12])[C:8]([OH:10])=[O:9]
Reactant: COCCOCC(C)(C)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COCCOCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.6 %

Procedure:
A suspension of methyl 3-(2-methoxyethoxy)-2,2-dimethylpropanoate (39) (1.83 g, 9.62 mmol) and KOH (2.16 g, 38.5 mmol) in water (20 mL) was stirred at RT for 3 days. The aqueous layer was washed with DCM (3×20 mL) and acidified to pH 1-2 with 6 M HCl (aq.) and extracted with DCM (3×20 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo to afford 3-(2-methoxyethoxy)-2,2-dimethylpropanoic acid (40) (1.62 g, 96%) as colourless oil: 1H NMR (400 MHz, CDCl3) δ: 3.67-3.65 (m, 2H), 3.56-3.54 (m, 2H), 3.51 (s, 2H), 3.38 (s, 3H), 1.23 (s, 6H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:16]([C:19]1[N:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)([CH3:18])[CH3:17].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:25][C:22]4[CH:23]=[N:24][C:19]([CH:16]([CH3:18])[CH3:17])=[CH:20][CH:21]=4)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)c1ccc(N)cn1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cn1
Reaction time: 3 h

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol) and 6-isopropylpyridin-3-amine (13.6 g, 0.100 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) containing triethylamine (0.042 mL, 0.300 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 39.9 mg, 0.105 mmol) was added and the solution was allowed to stir for 3 hours. The mixture was then purified by reverse phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield the pure product. ESI-MS m/z calc. 324.2, found 325.3 (M+1)+. Retention time 2.14 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][NH:20][C:19](=[O:23])[CH:18]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].Cl[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[N:34][CH:35]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][N:20]([CH2:29][C:30]4[CH:31]=[N:32][CH:33]=[N:34][CH:35]=4)[C:19](=[O:23])[CH:18]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:25])[F:26]
Reactant: ClCc1cncnc1
Reactant: O=c1cc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Product: O=c1cc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1Cc1cncnc1

Procedure:
The title compound was prepared by a procedure similar to that described for E21 starting from 4-{[(4-{[4-Chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]oxy}-2 (1H)-pyridinone and 5-(chloromethyl)pyrimidine. LC-MS (ESI): m/z 488 [M+H]+; 3.57 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Cl)cc1
Solvent: CC(C)=O
Product: CC(=O)c1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
There were weighed out p-chlorophenyl-ethanol (5, racemic compound) (78 mg, 0.05 mmol) and (S)-(−)-3,3,5,5-tetramethyl-4H-dinaphtho[2,1-c:1′,2′-e]-azepin-N-oxyl (1.8 mg, 0.05 mmol). Then, 2 ml of acetone was added to obtain a uniform solution. Added thereto was 250 mg of silica gel (product of Merck, grade 9385) and the mixture was vigorously agitated for 5 minutes. The acetone used was distilled off under reduced pressure. Added thereto was 7% aqueous solution of sodium bicarbonate (5 ml) containing 20 wt. % of sodium bromide. Then, the mixture was thoroughly stirred. Two platinum electrodes (1.5×1.0 cm) were applied to the mixture which was then subjected to electrolytic oxidation reaction for 0.68 hour while being vigorously stirred at −15° C. and maintaining the current at 30 mA (quantity of electricity being 2.2 F/mol). After completion of reaction, silica gel was filtered off from the reaction mixture, extraction was effected with 5 ml of acetone and acetone was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=7/1), giving p-chloroacetophenone (6) [39 mg, yield 100% based on the starting compound (5a)] and the starting compound (5b) (38 m, recovery percentage 97%, optical purity 83%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][N:21]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][N:14]([C:20]2[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][N:21]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2cc(C#N)ccn2)CC1
Yield: 55.9 %

Procedure:
A solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester (310 mg, 1.25 mmol, Example 30B), 2-chloro-4-cyanopyridine (250 mg, 1.8 mmol) and diisopropylethylamine (280 μL) in dioxane (6 mL) was heated in a sealed tube at 90° C. for 3 days. The reaction mixture was cooled, concentrated, and then flash chromatographed using a gradient of 5% ethyl acetate/hexane to 30% ethyl acetate/hexane to provide the titled compound (245 mg) as a colorless foam. MS (CI) m/z 350 (M+H)+; 1H NMR (300 MHz, MeOH-d4) δ 8.22 (d, 1H), 7.34 (m, 1H), 7.29 (m, 5H), 7.00 (s, 1H), 6.77 (d, 1H), 5.04 (s, 2H), 3.95-3.89 (m, 2H), 3.26 (m, 2H), 2.19-2.10 (m, 2H), 1.61-1.50 (m, 2H), 1.27 (s, 3H).