Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:23]=[CH:22]2>CN(C=O)C>[Si:6]([O:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:23]=[CH:22]2)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(CNCCO)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc2cc(CNCCO[Si](C)(C)C(C)(C)C)ccc21
Yield: 86 %

Procedure:
In a similar manner to Step 1 of Reference Example 18, 5-[(2-hydroxyethyl)aminomethyl]-1-(tert-butoxycarbonyl)indole (5.40 g) was dissolved in DMF (50 mL) and the solution was treated with imidazole (940 mg, 13.8 mmol) and tert-butyl dimethylsilylchloride (2.08 g, 13.8 mmol), followed by purification by slurry using diisopropyl ether and hexane to obtain 5-{[2-(tert-butyldimethylsilyloxy)ethyl]aminomethyl}-1-(tert-butoxycarbonyl)indole (4.80 g, yield 86%, 2 steps).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[N:11]([CH2:12][CH3:13])[CH2:10][C:9](=[O:14])[NH:8][C:5]2=[N:6][CH:7]=1.[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[N:21]1[CH:25]=[N:24][N:23]=[C:22]1[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH2:12]([N:11]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([C:22]4[N:21]([CH:16]5[CH2:17][CH2:18][CH2:19][CH2:20][O:15]5)[CH:25]=[N:24][N:23]=4)=[CH:27][CH:28]=3)[N:3]=2)[NH:8][C:9](=[O:14])[CH2:10]1)[CH3:13]
Reactant: CC1(C)OB(c2ccc(-c3nncn3C3CCCCO3)cc2)OC1(C)C
Reactant: CCN1CC(=O)Nc2ncc(Br)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN1CC(=O)Nc2ncc(-c3ccc(-c4nncn4C4CCCCO4)cc3)nc21
Temperature: 120 °C
Yield: 45 %

Procedure:
6-Bromo-4-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1.1 equiv), 4-(tetrahydro-2H-pyran-2-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-1,2,4-triazole (1 equiv) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane (0.05 equiv) were combined in 1,4-dioxane followed by the addition of sodium carbonate (3 equiv) in water. The solution was heated in a Biotage Emrys Optimizer microwave reactor to 120° C. for 30 min. The solution was condensed under reduced pressure and purified using column chromatography (0-10% methanol in ethyl acetate) to afford the title compound in 45% yield. MS (ESI) m/z 406.6 [M+1]+.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=O>>[CH2:43]([N:42]([CH2:45][CH3:46])[CH2:40][CH2:39][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:6][CH:7]=1)[CH3:44]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(CC)CCOc1ccc(CCCNc2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1
Yield: 185.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (29 mg) and 2-chloro-N,N-diethylacetamide (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (27 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13](Cl)=[O:14])[N:12]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13]([N:25]([O:26][CH3:27])[CH3:24])=[O:14])[N:12]=1
Reactant: O=C(Cl)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carbonyl chloride (4.71 g, 13.4 mmol, prepared by the method described in Example 13, step 1) in 10 mL dichloromethane was added to a solution of N,O-dimethylhydroxyamine hydrochloride (1.44 g, 14.7 mmol) and triethylamine (5.6 mL, 40.2 mmol) in 60 mL dichloromethane in an ice water bath under argon with stirring. The bath was removed upon completion of addition. Stirring was continued for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated down under reduced pressure. The crude product was purified on silica gel, eluting with ethyl acetate to yield 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-methoxy-N-methyl-1H-imidazole-4-carboxamide as an off-white solid (4.20 g, 83%): Rf=0.22 (ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[H][H]>N.[Ni]>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH2:11]
Reactant: Cc1cccc(CC#N)c1C
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: Cc1cccc(CCN)c1C
Yield: 66 %

Procedure:
A mixture of 2,3-dimethylphenylacetonitrile (J. Org Chem, 51(26), 5157-60; 1986), (190 mg, 1.31 mmol) and Raney® nickel (100 mg) in 2M methanolic ammonia (5 mL) was stirred under 50 psi of hydrogen gas for 4 days. The mixture was then filtered through Arbocel® and concentrated in vacuo to afford the title compound as a solid in 66% yield, 130 mg. 1H NMR (400 MHz, CDCl3) δ: 7.02-6.94 (3H, m), 2.26-2.13 (10H, m) ppm; LRMS ESI m/z 150 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[H-].[Na+].Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[N:17]=[C:16]([CH3:30])[N:15]=1.O>CN(C)C=O>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([C:18]2[N:17]=[C:16]([CH3:30])[N:15]=[C:14]([O:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[CH:19]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: COc1ccc(-c2cc(Cl)nc(C)n2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cc(Oc3c(C)cc(C)cc3C)nc(C)n2)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
To a solution of 2,4,6-trimethylphenol (1.03 g) in N,N-dimethylformamide (20 ml) was added sodium hydride (60% in oil, 0.30 g), and stirred at ambient temperature for 5 minutes. To the solution was added 4-chloro-6-(3,4-dimethoxyphenyl)-2-methylpyrimidine (2.0 g), and the mixture was stirred at ambient temperature for 18 hours. The solution was poured into water (300 ml), and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel eluting with chloroform to give 6-(3,4-dimethoxyphenyl)-2-methyl-4-(2,4,6-trimethylphenoxy)pyrimidine (1.96 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1Br)([CH3:7])[CH3:6])[CH3:2].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:1]([O:3][C:4](=[O:24])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1-c1ccccc1

Procedure:
2-(4-Benzyloxy-2-bromo-phenoxy)-2-methyl-propionic acid ethyl ester (3.00 g, 7.63 mmol) and phenyl boronic acid (1.12 g, 9.15 mmol) were dissolved in toluene (75 mL)/ethanol (75 mL). The solution was degassed (2×), and tetrakis(triphenylphosphine)palladium (70 mg, 0.061 mmol) was added followed by aqueous 2M Na2CO3 solution (7.63 mL, 15.3 mmol). The reaction mixture was degassed (2×) and heated to reflux under argon for 16 h. The reaction mixture cooled and partitioned between ethyl acetate (200 mL) and H2O (75 mL). The organic layer was washed with brine (75 mL), dried (Na2SO4), and concentrated to a light brown oil (3.58 g). The crude product was used directly in the next reaction: 1H NMR (400 MHz, CDCl3) δ1.266 (t, 3H, J=7.1 Hz), 1.273 (s, 6H), 4.20 (q, 2H, J 7.1 Hz), 5.03 (s, 2H), 6.82 (dd, 1H, J=3.2, 9.0 Hz), 6.92 (d, 1H, J=8.8 Hz), 6.97 (d, 1H, J=3.0 Hz), 7.28-7.44 (m, 8H), 7.51-7.60 (m, 2H); MS (ES) m/e #[M+1].
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[F:25][C:26]([F:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:27][NH2:28].CCN(C(C)C)C(C)C>>[F:35][C:26]([F:25])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:27][NH:28][C:18]1[S:19]/[C:15](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][C:5]([C:23]#[N:24])=[C:4]3[O:3][CH2:1][CH3:2])/[C:16](=[O:22])[N:17]=1
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Reactant: NCC(F)(F)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NCC(F)(F)c4ccccn4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), 2,2-difluoro-2-pyridin-2-yl-ethylamine and DIEA to give 6-[2-(2,2-Difluoro-2-pyridin-2-yl-ethylamino)-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-ethoxy-quinoline-3-carbonitrile. LC-MS m/e 466 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:29][CH2:28][N:11]2[C:12](=[O:27])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:15][C:14]=3[C:23]([F:26])([F:25])[F:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:29][CH2:28][N:11]2[C:12](=[O:27])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:15][C:14]=3[C:23]([F:25])([F:26])[F:24])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)=Cc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)Cc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Reaction time: 2 h
Yield: 45.3 %

Procedure:
To a stirring degassed solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-methyl-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (60 mg, 0.15 mmol) and 10% palladium on carbon (5 mg) in MeOH (2 mL) was added hydrogen (1 atm). After 2 h, the reaction was filter and the solid was washed with methanol. The organic layers were combined and conc. in vacuo to a colorless oil. The oil was purified by flash chromatography (silica gel, 0–50% EtOAc in hexanes) to give 28 mg of the desired product as a white solid. MS (ESI) 413 (M+H).
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.Cl>CN(C)C=O.O>[CH3:10][C:2]([O:1][CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)([CH3:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)O
Reactant: BrCCCOC1CCCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)OCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution (22 mL) of tert-butyl 2-hydroxy-2-methylpropanoate (1.0 g) in N,N-dimethylformamide was added sodium hydride (250 mg) under an ice bath, and the mixture was stirred at room temperature for 1 hour. Thereafter, under an ice bath, 2-(3-bromopropoxy)tetrahydro-2H-pyran (0.88 mL) was added dropwise, and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and 1N hydrochloric acid under an ice bath, followed by extraction with t-butyl methyl ether. The organic layer was sequentially washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain the title compound having the following physical property values, as a mixture (400 mg) with tert-butyl 2-hydroxy-2-methylpropanoate.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[C:25]([O:29][C:30]([N:32]([CH3:49])[C@H:33]([C:46](O)=[O:47])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:37][CH:36]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.[C:51]1([CH2:57][CH2:58][CH2:59][NH:60][C:61](=[O:68])[C@@H:62]([CH2:64][CH2:65][S:66][CH3:67])[NH2:63])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>O1CCCC1>[C:25]([O:29][C:30]([N:32]([CH3:49])[C@H:33]([C:46]([NH:63][C@@H:62]([C:61]([NH:60][CH2:59][CH2:58][CH2:57][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:68])[CH2:64][CH2:65][S:66][CH3:67])=[O:47])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[CH:37][CH:36]=1)=[O:31])([CH3:26])([CH3:27])[CH3:28]
Reactant: CSCC[C@@H](N)C(=O)NCCCc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)O
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)N(C)C(=O)OC(C)(C)C)C(=O)NCCCc1ccccc1
Temperature: -20 °C

Procedure:
Diisopropylethylamine (0.90 ml.), then diphenylphosphinyl chloride (1.23 g.), were added to a solution of N-(tert-butyloxycarbonyl)-O-(tert-butyl)-N-methyl-L-tyrosine (1.76 g.) in tetrahydrofuran (15 ml.) maintained at -20° C., and the mixture was stirred for ten minutes. A solution of N-(3-phenylpropyl)-D-methioninamide hydrochloride (1.58 g.) and diisopropylethylamine (0.90 ml.) in tetrahydrofuran (10 ml.) was then added. The mixture was stirred for one half hour at -20°, one hour at 0° C. and overnight at room temperature, then filtered and stripped of solvent. A solution of the residue in ethyl acetate (100 ml.) was washed with water, aqueous citric acid, water again, aqueous sodium bicarbonate and water again, dried and stripped of solvent. Purification of the residue by high pressure liquid chromatography on silica gel (350 g.) using hexane-ethyl acetate (2:1) as the eluant afforded in fractions 6-7 (k'=8-14) [N-(tert-butyloxycarbonyl)-O-(tert-butyl)-N-methyl-L-tyrosyl]-N-(3-phenylpropyl)-D-methioninamide as a clear gum (2.1 g.).
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[CH:11]([CH:15]([CH3:17])[CH3:16])[CH2:10][CH:9]([O:18][CH3:19])[CH2:8][C:7]=2[S:4]1(=[O:6])=[O:5].[CH3:20][C:21]1[C:26]([C:27]([OH:29])=[O:28])=[C:25]([CH3:30])[CH:24]=[CH:23][N:22]=1>>[CH3:20][C:21]1[C:26]([C:27]([O:29][CH2:2][N:3]2[C:13](=[O:14])[C:12]3[CH:11]([CH:15]([CH3:17])[CH3:16])[CH2:10][CH:9]([O:18][CH3:19])[CH2:8][C:7]=3[S:4]2(=[O:6])=[O:5])=[O:28])=[C:25]([CH3:30])[CH:24]=[CH:23][N:22]=1
Reactant: Cc1ccnc(C)c1C(=O)O
Reactant: COC1CC2=C(C(=O)N(CCl)S2(=O)=O)C(C(C)C)C1
Product: COC1CC2=C(C(=O)N(COC(=O)c3c(C)ccnc3C)S2(=O)=O)C(C(C)C)C1

Procedure:
It is contemplated that following the procedure of Example 17, 2-chloromethyl-4-isopropyl-6-methoxy-4,5,6,7-tetrahydrosaccharin of preparation 23BJ can be coupled with 2,4-dimethyl-3-pyridinecarboxylic acid to provide 4-isopropyl-6-methoxy-4,5,6,7-tetrahydro-2-saccharinylmethyl 2,4-dimethylpyridine-3-carboxylate.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[CH2:31]([O:34][CH2:35][CH:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)[CH:32]=[CH2:33]>>[CH2:31]([O:34][CH2:35][CH:36]1[CH2:41][CH2:40][CH:39]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:38][CH2:37]1)[CH:32]=[CH2:33]
Reactant: C=CCOCC1CCC(=O)CC1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: C=CCOCC1CCC(N2CC(NC(=O)CNc3nn(C)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-allyloxymethyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:23]([CH2:36][CH2:37][CH3:38])[CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29][CH2:28]1)[CH2:21][CH3:22]>C(OCC)(=O)C>[CH2:36]([N:23]([CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH:35][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:29][CH2:28]1)[CH2:37][CH3:38]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCCN(CCC)CCCC1CCN(CCN)CC1
Solvent: CCOC(C)=O
Product: CCCN(CCC)CCCC1CCN(CCNC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 43 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-[3-(dipropylamino)propyl]-piperidin-l-yl]ethanamine in a yield of 43% of theory. Colourless crystals, m.p. 169°-170° C. (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].Cl.Cl[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>C(#N)C>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]=[CH:4]1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Clc1nc[nH]c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Clc1ncn(Cc2ccc3ccccc3n2)c1Cl

Procedure:
4,5-Dichloroimidazole (2.00 g, 14.6 mmol) was dissolved in 15 mL acetonitrile in a round bottom flask. Potassium hydroxide (0.90 g, 16.0 mmol) was added and the mixture was refluxed for 15 min. Concurrently, 2-chloromethylquinoline hydrochloride (3.13 g, 14.6 mmol) and potassium hydroxide (0.82 g, 14.6 mmol) were added to a second round bottom flask and stirred in 60 mL acetonitrile at reflux for 10 min. The contents of the second flask were added to the first, and the combined mixture was refluxed overnight, during which time a white precipitate formed. The reaction mixture was filtered hot, yielding a clear, tan filtrate. Slow evaporation and cooling of the filtrate yielded tan crystals of 1-(quinolin-2-ylmethyl)-4,5-dichloroimidazole, which were collected by a second filtration. The crystals (0.278 g, 1.0 mmol) will be dissolved in a minimum volume of DMF. Iodomethane (0.62 mL, 10.0 mmol) will be added and the mixture will be heated at 80° C. for 12 h. Removal of the volatile components under reduced pressure will yield the product.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([OH:17])[C:13]([NH:15][CH3:16])=[O:14].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:17][CH:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][O:4][C:3]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:2]=1[CH3:1])[C:13]([NH:15][CH3:16])=[O:14])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=O)C(O)c1ccccc1COc1cc(C)ccc1C
Solvent: c1ccncc1
Product: CNC(=O)C(OC(C)=O)c1ccccc1COc1cc(C)ccc1C
Yield: 81.7 %

Procedure:
A solution of 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxy-N-methylacetamide (0.57 g, 1.9 mmol) and acetic anhydride (0.43 g, 4.2 mmol) in pyridine (3 ml) was stirred at room temperature for 8 hours, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=1/1) to give the desired compound 2-acetoxy-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-N-methylacetamide (0.53 g, 82%) as colorless crystals.
Reaction SMILES: C([NH:4][CH:5]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])C(OCC)=O)(=O)C.[ClH:17]>>[ClH:17].[NH2:4][CH2:5][C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCC(=O)C(NC(C)=O)C(=O)OCC
Agent: Cl
Product: CCCCC(=O)CN

Procedure:
Ethyl 2-acetamido-3-oxoheptanoate (10.4 g) was hydrolysed by heating under reflux with 50% hydrochloric acid (80 ml) for 9 hours. The mixture was evaporated to dryness to give 1-amino-2-hexanone hydrochloride (5.8 g) as a dark red oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7]C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.[CH3:15][C:16]([CH3:18])=O>>[CH3:15][CH:16]([N:1]1[CH2:2][CH2:3][CH:4]([NH2:7])[CH2:5][CH2:6]1)[CH3:18]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(C)=O
Product: CC(C)N1CCC(N)CC1

Procedure:
Synthesized according to the method of reagent preparation 9 by using acetone and 1,1-dimethylethyl piperidin-4-ylcarbamate. MS (EI) for C8H18N2: 143 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[CH:21]=[C:20]([N:22]([CH3:24])[CH3:23])[N:19]=[C:18](S(C)=O)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[N:30]1([C:36]2[N:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>ClC1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[CH:21]=[C:20]([N:22]([CH3:24])[CH3:23])[N:19]=[C:18]([N:33]3[CH2:34][CH2:35][N:30]([C:36]4[N:37]=[CH:38][CH:39]=[CH:40][N:41]=4)[CH2:31][CH2:32]3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)c1cc(Nc2cccc(OCc3ccccc3)c2)nc(S(C)=O)n1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Solvent: Clc1ccccc1
Product: CN(C)c1cc(Nc2cccc(OCc3ccccc3)c2)nc(N2CCN(c3ncccn3)CC2)n1
Yield: 42.5 %

Procedure:
A mixture of N4-[3-(benzyloxy)phenyl]-N6,N6-dimethyl-2-(methylsulfinyl)-4,6-pyrimidinediamine (30 mg, 0.078 mmol) and 2-(1-piperazinyl)pyrimidine dihydrochloride (74 mg, 0.312 mmol) in chlorobenzene (2 mL) was heated at reflux for 15 hours. The crude product was purified by preparative thin-layer chromatography [eluent: hexane/EtOAc (7:3)], giving the desired product (16 mg, 42%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1>>[CH3:39][O:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(CBr)c1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: COc1cccc(COc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-3-methoxy-benzene following the procedure of Example 478: MS (ESI) m/z 514.