Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[C:9](=[O:10])[NH:8][C:7]2=[C:11]3[C:16](=[N:17][C:18]4=[CH:19][CH:20]=[CH:21][C:5](=[C:6]24)[O:4]1)[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH3:2].[CH3:22]C(C)([O-])C.[K+].CI>O1CCCC1>[CH2:1]([CH:3]1[C:9](=[O:10])[N:8]([CH3:22])[C:7]2=[C:11]3[C:16](=[N:17][C:18]4=[CH:19][CH:20]=[CH:21][C:5](=[C:6]24)[O:4]1)[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH3:2]
Reactant: CCC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CCC1Oc2cccc3nc4c(c(c23)N(C)C1=O)CCCC4
Reaction time: 0.33 h
Yield: 68.4 %

Procedure:
To a suspension of 3-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (5.0 g) in dry tetrahydrofuran (150 ml) was added potassium t-butoxide (3.0 g), with stirring. After 20 mins, methyl iodide (1.66) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with saturated potassium carbonate solution, and extracted with 2-butanone. The organic extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was adhered to silica (methanol) and flash chromatographed (50% ethyl acetate/hexane). The appropriate fractions were concentrated and the residue was triturated with diethyl ether to give 3.59 g (68%) of 3-ethyl-1,3,9,10,11,12-hexahydro-1-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[C:11]1([S:17]([CH2:20][C:21]#[N:22])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(O)C>[N+:1]([C:4]1[S:5][C:6](/[CH:9]=[C:20](/[S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:18])=[O:19])\[C:21]#[N:22])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: N#CCS(=O)(=O)c1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Solvent: O
Solvent: CCO
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 50 %

Procedure:
2-Nitrothiophen-5-carboxaldehyde (0.157 g) and phenylsulfonyl acetonitrile (0.199 g) were stirred in 2 mL of ethanol containing 0.01 mL piperidine for four hours at 100 C. The mixture was cooled to room temperature and water was added for crystalization. The crude product was filtered and recrystalized from ethanol and water to give 0.16 g of (E)-3-(2-nitrothien-5-yl)-2-(phenylsulfonyl)acrylonitrile. Alternatively, the crude product was purified on a silica gel column with a mixture of ethylacetate and hexane as eluent.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[C:5]([C:13]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:14]=1[NH:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(=O)C>[C:5]([C:13]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:14]=1[NH:15][C:16](=[O:23])[C:17](=[N:1][OH:3])[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 50 g. of sodium nitrite is added dropwise to a solution of 34.6 g. of ethyl 2'-benzoyl-4'-chloro-malonanilate in 250 ml. of glacial acetic acid. After 11/2 hours stirring at room temperature, the oxime crystallizes out and is filtered off by suction, washed with water and dried in vacuum. Ethyl 2'-benzoyl-4'-chloro-mesoxalanilate 2-oxime, m.p. 98°-105° is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:34])([CH2:32][OH:33])[C@H:10]([N:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:20][CH:19]=2)[CH:14]=[N:13]1)[CH3:11].[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(N(CC)CC)C>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:34])([CH2:32][O:33][S:36]([CH3:35])(=[O:38])=[O:37])[C@H:10]([N:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:22][CH:23]=2)[CH:14]=[N:13]1)[CH3:11]
Reactant: C[C@@H](n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.5 %

Procedure:
2-[(1R,2S)-2-(2,4-Difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (8.26 g) was dissolved in 100 ml of ethyl acetate, to which 2.89 g of methanesulfonyl chloride and 2.54 g of triethylamine were added dropwise with ice cooling. After stirring at 0° C. for 30 minutes, the solution was washed with water (20 ml×2) and 20 ml of an aqueous solution of sodium chloride successively. The organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 10 g of 2-[(1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25]([O:27][C:28](=[O:41])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=1[CH2:38][CH2:39][CH3:40])C.O>C(#N)C>[CH3:25][O:27][C:28](=[O:41])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:2][C:3]2[O:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH3:18])=[CH:33][C:32]=1[CH2:38][CH2:39][CH3:40]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1CCl
Reactant: CCCc1cc(O)ccc1OCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCCc1cc(OCc2oc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)OC
Reaction time: 6 h
Yield: 77.9 %

Procedure:
To a suspension of 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (0.10 g, 0.36 mmol) and Cs2CO3 (0.24 g, 0.72 mmol) in 2 mL acetonitrile is added (4-hydroxy-2-propyl-phenoxy)-acetic acid ethyl ester (0.09 g, 0.38 mmol). The solution is stirred for 6 hrs and poured into water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organics are washed with water (10 mL) and brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product is purified using flash column chromatography (20% ethyl acetate/hexanes) to afford 0.13 g (85%) desired {4-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethoxy]-2-propyl-phenoxy}-acetic acid methyl ester. This ester is hydrolyzed in the usual way using 0.14 g ester and 3 eq. 1M LiOH in 3 mL 3:2:1 THF:MeOH:H2O to afford 0.16 g (95%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](O)(=[O:10])[CH3:9]>>[C:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])[CH3:9]
Reactant: Nc1ccccc1
Reactant: CC(=O)O
Product: CC(=O)Nc1ccccc1

Procedure:
A process according to claim 5, wherein acetic acid is reacted with aniline to produce acetanilide.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9](O)=[C:6](OC)[CH:5]=1.C[OH:16]>>[OH:16][C:2](=[CH:3][C:4]1[CH:12]=[CH:11][CH:9]=[CH:6][CH:5]=1)[C:1]([OH:14])=[O:13]
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: CO
Product: O=C(O)C(O)=Cc1ccccc1
Reaction time: 0.08 h

Procedure:
Ferulic acid determination. Enzymatic hydrolysates were dilued to ½ with methanol 100%, centrifuged at 12,000×g for 5 min and supernatants were filtered through a 0.2 μm nylon filter (Gelman Sciences, Acrodisc 13, Ann Arbor, Mich.). Filtrates were analyzed by HPLC (25 μL injected). HPLC analyses were performed at 280 nm and 30° C. on a HP1100 model (Hewlett-Packard Rockville, Md.) equipped with a variable UV/VIS detector, a 100-position autosampler-autoinjector. Separations were achieved on a Merck RP-18 reversed-phase column (Chromolith 3.5 μm, 4.6×100 mm, Merck). The flow rate was 1.4 ml/min. The mobile phase used was 1% acetic acid and 10% acetonitrile in water (A) versus acetonitrile 100% (B) for a total running time of 20 min, and the gradient changed as follows: solvent B started at 0% for 2 min, then increased to 50% in 10 min, to 100% in 3 min until the end of running. Data were processed by a HP 3365 ChemStation and quantification was performed by external standard calibration.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]([CH3:32])[S:14]([C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[NH2:11][C:9]1[N:10]=[C:3]2[C:2]([C:20]3[CH:19]=[CH:18][C:17]([S:14]([N:13]([CH3:32])[CH3:12])(=[O:15])=[O:16])=[CH:22][CH:21]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CN(C)S(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Nc1nc2c(Br)cccn2n1
Product: CN(C)S(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1

Procedure:
4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N,N-dimethyl-benzenesulfonamide was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (150.0 mg, 0.7041 mmol) and N,N-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (210.0 mg, 0.6748 mmol) in a manner analogous to Step 2c. The reaction product was isolated as a tan solid (0.074 g, 34%). MP=188-190° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.63 (d, J=6.4 Hz, 1H), 8.38 (d, J=8.2 Hz, 2H), 7.88-7.82 (m, 3H), 7.03 (t, J=6.8 Hz, 1H), 6.21 (br s, 2H), 2.66 (s, 6H). MS=318 (MH)+.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[CH2:18][CH2:17][C:16]2[C:7](=[C:8]([N:19]=CN(C)C)[C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]1=O)C.[CH3:25][NH:26]N>CCO>[NH2:19][C:8]1[C:9]2[C:14]([N:15]=[C:16]3[C:7]=1[C:6]1[N:26]([CH3:25])[N:2]=[CH:4][C:5]=1[CH2:18][CH2:17]3)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CN(C)C=Nc1c2c(nc3ccccc13)CCC(=CN(C)C)C2=O
Reactant: CNN
Solvent: CCO
Product: Cn1ncc2c1-c1c(nc3ccccc3c1N)CC2

Procedure:
3,4-Dihydro-2-[(dimethylamino)methylene]-9-[[(dimethylamino)methylene]amino]acridin-1-(2H)-one (3.0 g) was refluxed for 60 min in 150 mL of EtOH containing 8.0 g of methylhydrazine. At the end of this time the solvent was evaporated under reduced pressure and then the residue was adhered to silica with MeOH. Purification by flash chromatography (toluene:MeOH:Et3N, 19:1:1) gave 1.71 g of material which was pure to TLC. This was combined with the product of another run of smaller size and recrystallized from toluene to give analytically pure product, mp 240° (d).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([F:28])[CH:27]=1)[NH2:24]>>[F:20][C:21]1[CH:22]=[C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cc(F)cc(F)c1
Yield: 33.8 %

Procedure:
The product is prepared according to the procedure described in Example 9, using 300 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 and 780 mg of 3,5-difluoroaniline in place of the 2-fluoroaniline. 133 mg of N-(3,5-difluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH:10]([N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])=[CH2:11]>>[O:17]=[C:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH:10]([C:9]1[C:4]2[N:3]=[N:2][NH:1][C:5]=2[CH:6]=[CH:7][CH:8]=1)[CH3:11]
Reactant: C=CN1CCCC1=O
Reactant: c1ccc2[nH]nnc2c1
Product: CC(c1cccc2[nH]nnc12)N1CCCC1=O
Yield: 64 %

Procedure:
This product is synthesised, in 64% yield, from benzotriazole and 1-vinyl-2-pyrrolidinone by the same method described in Example 1. The product distils at 180°/0.05 mbar and solidifies, on standing, to yield a white solid mp 77°-9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]2[CH:18]([OH:21])[CH2:19][CH2:20][C:15]2=[N:14]1.[OH2:22]>C1C=CC=CC=1>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[CH:17]=[C:20]2[CH2:19][C@@H:18]([OH:21])[C@@H:16]([OH:22])[C:15]2=[N:14]1
Reactant: O
Reactant: OC1CCc2nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)cc21
Solvent: c1ccccc1
Product: O[C@@H]1Cc2cn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)nc2[C@@H]1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (62) (5 g) in Benzene (50 mL) p-TSA (500 mg) was added and the resulting mixture was heated at reflux for 6 hr. while water formed in the reaction was removed using a Dean-Stark Trap. The reaction mixture was allowed to cool down to room temperature and washed with water (5×50 mL). The organic layer was concentrated in vacuo to obtain an oil which was dried on a high vacuum and directly used in next step. To a solution of above product (4.8 g) in 1:1 t-BuOH/H2O (100 mL) was treated with NMO (3 g) and OsO4 (380 mg). The resulting mixture was stirred at RT for 12 hr. Aq. NaHCO3 (300 mL) and EtOAc (300 mL) were then added, and the product was extracted in to EtOAc. Organic phase was separated, and the concentrated in vacuo to obtain compounds (80) and (84) which were separated on silica (EtOAc:Hexane 2:3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>C(O)(=O)C>[C:2]1([N:1]2[C:11](=[O:12])[C:10]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]3[C:8]2=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1ccccc1

Procedure:
The reaction of aniline 3.8 g (0.041 mol) with phthalic anhydride 4.0 g (0.041) mol in 100 ml of refluxing glacial acetic acid for 3 hours, followed by precipitation from water, filtration and vacuum drying at 120° C., afforded an 8.2 g (91%) yield of product, m.p. 205°-9° C. (from ethanol). Lit. reports m.p. 210° C. ("Dict. Org. Cpds", 5, 2740(1965), Oxford Univ. Press, N.Y.). Anal. Calcd. for C14H9NO2 : C, 75.33; H, 4.06. Found: C, 75.10; H, 4.17%. Ir(KBr): 1765, 1700, and 1375 cm-1 (imide).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[S:11][CH3:12].B(Br)(Br)Br.O>C(Cl)Cl>[CH3:12][S:11][C:4]1[C:5]([OH:9])=[CH:6][CH:7]=[CH:8][C:3]=1[OH:2]
Reactant: COc1cccc(OC)c1SC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CSc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,3-dimethoxy-2-methylsulfanylbenzene (2.8 g, 15 mmol) in methylene chloride (40 mL) is added BBr3 (30 mL, 30 mmol, 1M in methylene chloride) and the mixture is stirred at RT for 18 h. Water is added and the organic phase is washed with water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound as a pink solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18].O>N1C=CC=CC=1>[NH2:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[NH:10][C:17]([C:13]1[O:12][CH:16]=[CH:15][CH:14]=1)=[O:18]
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: c1ccncc1
Solvent: O
Product: Nc1cc([N+](=O)[O-])ccc1NC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.1 %

Procedure:
To a stirred solution of 4-nitro-o-phenylene diamine (76.5 g, 0.5 mole) in 500 ml of pyridine, is added dropwise 2-furoyl chloride (65 g, 0.5 mole). After the addition is complete the reaction solution is stirred at room temperature for 15 minutes and then at reflux for 2 hr. The hot reaction solution is poured into 6 liters of water to give an oil, which solidifies upon standing overnight at room temperature to give 125 g (100 percent) of yellow intermediate. The solid is used in part B without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[CH2:11](Br)[CH:12]([CH3:14])[CH3:13]>>[CH3:11][CH:12]([CH3:14])[CH2:13][O:4][CH2:3][C:2]([CH3:10])([CH3:1])[CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CBr
Reactant: CC(C)C(O)C(C)(C)CO
Product: CC(C)COCC(C)(C)C(O)C(C)C
Yield: 88 %

Procedure:
Treatment of 2,2,4-trimethylpentan-1,3-diol with isobutyl bromide employing the alkylation reaction conditions described above provided 1-(2-methylpropyloxy)-2,2,4-trimethylpentan-3-ol in 88.0% yield (355.5 g, b.p.=81–82 C./2.5 mmHg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:16][CH3:17])=[C:6]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:7]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:16]([CH3:17])=[O:26])=[C:6]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(F)cc1C(=O)Cn1cccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CS(=O)c1ccc(F)cc1C(=O)Cn1cccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 54.5 %

Procedure:
To a stirred cooled solution of 1-[5-Fluoro-2-(methylthio)phenyl]-2-(pyrrol-1-yl)ethanone (22c) (1.76 g, 7.06 mmol) in dichloromethane (12 ml) was added dropwise in 30 minutes a solution of m-chloroperbenzoic acid (71.5% grade, 1.70 g, 7.06 mmol) in dichloromethane (10 ml). After stirring for 45 minutes at 0° C., the mixture was treated with a 5% solution of sodium carbonate in water (41 ml) and was stirred for 15 minutes at room temperature. The organic phase was separated and water was extracted with dichloromethane (3×10 ml). The organic layers were dried and evaporated, the residue was chromatographed (10% dichloromethane in ethyl acetate) to afford 1.02 g of 23c as white crystals that darkened rapidly (64% yield). 1H NMR (CDCl3) δ8.42-8.35 (m, 1H); 7.61-7.51 (m, 2H); 6.68-6.62 (m, 2H); 6.26-6.24 (m, 2H); 5.41-5.17 (q, 2H, J=31.32, 17.87 Hz); 2.77 (s, 3H).
Reaction SMILES: [ClH:1].[C:2](=[NH:9])(OCC)[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[CH2:17]([O:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([NH:24][NH2:25])=[O:23])[CH3:18].C(=N)(OCC)CCC.Cl>C(O)(C)C>[ClH:1].[NH:9]=[C:2]([NH:25][NH:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=1[O:19][CH2:17][CH3:18])[CH2:3][CH2:4][CH3:5]
Reactant: CCOc1ccccc1C(=O)NN
Reactant: CCCC(=N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCC(=N)NNC(=O)c1ccccc1OCC
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Ethyl butyrimidate hydrochloride from Example B (71.5 g, 472 mmol) is introduced into triethylamine (65 ml, 472 mmol) and cooled to 0° C. 2-Ethoxybenzohydrazide from Example A (85 g, 472 mmol) is suspended in 250 ml of isopropanol and added to the ethyl butyrimidate mixture. The reaction mixture is stirred at room temperature for 48 hours, the solid (triethylamine hydrochloride) is removed, and 25% strength hydrochloric acid (150 ml, 1.18 mol) is slowly added dropwise to the mother liquor at 0° C. to 5° C. The suspension of crystals is then stirred at 0° C. to 5° C. for 1 hour and the crystals are filtered with suction through a sintered funnel, washed with 100 ml of cold isopropanol and dried in a vacuum oven at 30° C. and 300 mbar overnight.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:3]=1.[CH:31]1([C:34]2[NH:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)[CH2:33][CH2:32]1>>[CH:31]1([C:34]2[N:35]([C:2]3[N:10]=[C:9]4[C:5]([N:6]=[C:7]([CH2:12][N:13]5[CH2:18][CH2:17][N:16]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]5)[N:8]4[CH3:11])=[C:4]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[N:3]=3)[C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)[CH2:33][CH2:32]1
Reactant: Cn1c(CN2CCN(C(C)(C)C(N)=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: c1ccc2[nH]c(C3CC3)nc2c1
Product: Cn1c(CN2CCN(C(C)(C)C(N)=O)CC2)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21

Procedure:
2-(4-((2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-2-methylpropanamide (75 mg) was reacted with 2-cyclopropylbenzimidazole via General Procedure I for Buchwald coupling to give 38.7 mg 438 following reverse phase purification. MS (Q1) 559.1 (M)+
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]1[N:11]=[CH:10][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:8]=1)(=[O:3])[CH3:2].Cl.CO>C1COCC1>[C:1]([S:4][CH2:5][CH2:6][C:7]1[N:11]=[CH:10][NH:9][N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)SCCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)SCCc1nc[nH]n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-(2-Acetylthioethyl)-1-triphenylmethyl-1,2,4-triazole (0.50) was dissolved in THF (2.5 ml). To the solution were added 10% hydrochloric acid (0.5 ml) and methanol (10 ml). The mixture was stirred for 1.5 hour at 25° C. The reaction mixture was concentrated, to which was added NaHCO3, to make the solution to be weakly basic, followed by extraction three times with THF-ethyl acetate (1:1, 10 ml). Organic layers were combined and dried over anhydrous magnesium sulfate, followed by concentration. The concentrate was purified by means of a column chromatography (carrier: silica gel, 20 g, developing solvent: acetone) to afford the title compound (134 mg) as a crystalline product, m.p.84-86° C.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[CH2:28]([N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCN(CCc2ccccc2)C3)nc1
Temperature: 75 °C
Yield: 29 %

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Part E, 112.9 mg, 0.40 mmol), K2CO3 (110.1 mg, 0.80 mmol), and phenethyl bromide (82 uL 0.60 mmol) in DMF (2.0 mL). Heat at 70-80° C. overnight. Remove DMF azeotropically with xylenes. Purify by flash chromatography, eluting with 75:19:6 EtOAc/CH2Cl2/2.0 M NH3 in MeOH and then with 60:30:10 EtOAc/hexanes/2.0 M NH3 in MeOH. Purify by reverse phase chromatography, eluting with 0-99% 0.1% TFA/acetonitrile and 0.1% TFA/water to give the title compound (44.9 mg, 27% from Step D): MS ES+ 284.0 (M−H)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=9.85 min, 100% purity; Anal. Calcd for C24H25N3O2.0.1H2O.0.1MeOH: C, 73.75; H, 6.57; N, 10.71. Found: C, 73.45; H, 6.62; N, 10.72.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][C:23]1[C:24]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:25][C:26]2[O:31][CH:30]=[C:29]([C:32](O)=[O:33])[O:28][C:27]=2[CH:35]=1>>[OH:22][C:23]1[C:24]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:25][C:26]2[O:31][CH:30]=[C:29]([C:32]([N:12]3[CH2:11][CH2:10][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)=[O:33])[O:28][C:27]=2[CH:35]=1
Reactant: CC(C)(C)c1cc2c(cc1O)OC(C(=O)O)=CO2
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Product: CC(C)(C)c1cc2c(cc1O)OC(C(=O)N1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)=CO2
Yield: 72 %

Procedure:
That compound is obtained in a yield of 72% starting from 1-[bis(4-fluorophenyl)methyl]piperazine and 7-hydroxy-6-tert-butyl-1,4-benzodioxin-2-carboxylic acid.