Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:3]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:4]=[C:5]([C:7]([NH:9][C@H:10]([C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:8])[N:6]=1.[C:40]([NH:46][C:47]1[N:48]=[C:49]([OH:59])[C:50]2[CH:56]=[C:55]([C:57]#[CH:58])[CH:54]=[N:53][C:51]=2[N:52]=1)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42].C(N(CC)CC)C>C(#N)C>[C:40]([NH:46][C:47]1[N:48]=[C:49]([OH:59])[C:50]2[CH:56]=[C:55]([C:57]#[C:58][C:2]3[N:3]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:4]=[C:5]([C:7]([NH:9][C@H:10]([C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:8])[N:6]=3)[CH:54]=[N:53][C:51]=2[N:52]=1)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42]
Reactant: COC(=O)CC[C@H](NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1)C(=O)OC
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@H](NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)n1)C(=O)OC
Yield: 66 %

Procedure:
Following the procedure of Example 1, dimethyl N-(2-iodo-1-triphenylmethylimidazol-4-ylcarbonyl)-L-glutamate (638 mg, 1.0 mmol), 2-pivaloylamino4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine (541 mg, 2.0 mmol), Pd(PPh)2Cl2 (35 mg, 0.05 mmol), cuprous iodide (19 mg, 0.1 mmol), triethylamine (0.7 mL), and acetonitrile (50 mL) yield dimethyl N-(2-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethynyl]-1-triphenylmethylimidazol-4-ylcarbonyl}-L-glutamate [515 mg, 66% after flash column chromatography (ethyl acetate:hexanes, 2:1), mp 93-95° C]: 1H NMR (CDCl3) δ 12.05 (br s, 1H), 8.43 (br s, 1H), 8.26 (s, 1H), 7.93 (d, 1H, J=2.2 Hz), 7.61 (s, 1H), 7.54 (d, 1H, J=7.6 Hz), 7.33-7.28 (m, 9H), 7.18-7.12 (m, 6H), 4.77 (m, 1H), 3.74 (s, 3H), 3.65 (s, 3H), 2.45 (m, 2H), 2.32 (m, 1H), 2.05 (m, 1H), 1.30 (s, 9H). HRMS calcd for C44H41N7O7 779.3067, found 779.3088.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])[CH:12]=[CH:13][CH:14]=1>CO>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:16](=[O:17])[NH:7][CH:5]=[N:6][C:21]2=[O:22])[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc(Cl)c1
Reactant: N=CN
Solvent: CC(=O)O
Solvent: CO
Product: O=C1N=CNC(=O)C1c1cccc(Cl)c1
Reaction time: 2.5 h

Procedure:
5.97 g of formamidine acetate were added to a solution of 3.96 g of Na and 100 ml of absolute methanol. After cooling, the solution to 10° C. 15.51 g of diethyl (m-chlorophenyl)malonate were added in portions. After 2.5 hours, the solvent was evaporated under reduced pressure. The residue was dissolved in water and the solution was adjusted to pH 5.0 with glacial acetic acid. The resulting precipitate was removed by filtration under suction, washed with water, ethanol and ether and dried at 70° C. under reduced pressure. There was obtained 5-(m-chlorophenyl)-4,6(1H,5H)-pyrimidinedione which was used directly in the next step.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[C:14]2=[O:31])=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>ClCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH:17]=[CH:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[C:14]2=[O:31])=[CH:11][CH:12]=1
Reactant: COc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1n(-c2ccc(O)cc2)ccn1-c1ccc(Oc2ccccc2)cc1
Reaction time: 3 h

Procedure:
Boron tribromide (2.5 ml) was added to a solution of 1-(4-methoxyphenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (6.0 g) in dichloromethane (75 ml) at 0° C. After 3 hours, saturated sodium bicarbonate solution was added and the organic phase was washed with saturated brine. The organic phase was dried over magnesium sulfate and concentrated, and the residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol 9:1). The product with the molecular weight of 344.37 (C21H16N2O3); MS (ESI): 345 ([M+H]+), was obtained in this way.
Reaction SMILES: [F:1]/[C:2](=[C:4]1\[CH2:5][CH2:6][C@@H:7]2[C@:21]\1([CH3:22])[CH2:20][CH2:19][C@H:18]1[C@H:8]2[CH2:9][CH:10]=[C:11]2[C@:16]1([CH3:17])[CH2:15][CH2:14][C@H:13]([OH:23])[CH2:12]2)/[CH3:3].CC([Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC/C/2=C(\F)/C)C1)(C)C>>[F:1]/[C:2](=[C:4]1/[CH2:5][CH2:6][C@@H:7]2[C@:21]/1([CH3:22])[CH2:20][CH2:19][C@H:18]1[C@H:8]2[CH2:9][CH:10]=[C:11]2[C@:16]1([CH3:17])[CH2:15][CH2:14][C@H:13]([OH:23])[CH2:12]2)/[CH3:3]
Reactant: C/C(F)=C1/CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C/C(F)=C1/CC[C@H]2[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Product: C/C(F)=C1\CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Prepare A11 from A10 in a manner analogous to the preparation of A8 from A7 to give A11 (204 mg, 64%) as a white crystalline solid, after crystallization from methanol: mp 153-155° C. TLC Rf 0.27, ethyl acetate/hexane (1:3); 1H NMR δ 5.37-5.33 (m, 1H), 3.59-3.46 (m, 1H), 3.49 (s, 0.6H, MeOH solvate), 179 (dt, 3H, J=17.2, 1.4 Hz, 21-Me), 1.02 (s, 3H, 19-Me), 0.89 (s, 3H,); 19F NMR δ −110.27 (q of q, J=17.2, 2.0 Hz); MS (CI, CH4) m/z (rel intensity) 319 (MH+, 7), 318 (15), 317 (28), 301 (100), 299 (39), 281 (8). Analysis. Calculated for C21H31OF. 0.2 MeOH: C, 78.38; H, 9.87. Found: C, 78.40; H, 9.82.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:13]C=O)([CH3:12])[CH3:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH2:13])([CH3:11])[CH3:12])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(CC(C)(C)NC=O)c1
Agent: Cl
Product: Cc1cc(C)cc(CC(C)(C)N)c1

Procedure:
By reacting 6.00 g (34 mmol) of 1-(3,5-dimethylphenyl)-2-methylpropanol-2-ol and 2.00 g (41 mmol) of sodium cyanide in a Ritter reaction, 2.40 g of 2-(3,5-dimethylphenyl)-1,1-dimethylethylformamide (35% yield) is obtained. To liberate the amine, the formamide (2.40 g, 11.7 mmol) is treated with hydrochloric acid. The method and working up are analogous to the method for Example 10(c). Oil. Yield: 1.70 g (82%); mass spectroscopy: [M+H]+=178.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>O1CCCC1>[O:10]=[C:8]([N:27]1[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]1)[CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)Cc1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN1CCN(C(=O)Cc2ccncc2)CC1
Reaction time: 8 h
Yield: 28 %

Procedure:
A solution is prepared of 3 g (17.3 mM) of (4-pyridinyl)acetic acid in 50 ml of tetrahydrofuran (THF) and, at ambient temperature, a solution of 3.4 g (20.7 mM) of carbonyldiimidazole in solution in 50 ml of THF, is added dropwise. The reaction mixture is agitated for 8 hours, and a solution of 1.73 g (17.3 mM) of N-methylpiperazine in 20 ml of THF is then added. The reaction mixture is heated under reflux of the solvent for 2 hours, and then concentrated under reduced pressure. The residue from evaporation is taken up with 80 ml of 3N sodium hydroxide and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated under reduced pressure. The crude product is purified by silica gel chromatography in eluting with the aid of a dichloromethane/methanol mixture (99/1; v/v). The product sought after is obtained as a colourless oil (yield=28%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:52][CH:53]1[CH2:61][C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:54]1>C(OCC)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:52][CH:53]3[CH2:61][C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[CH2:54]3)=[O:26])[CH2:20][CH2:19]2)=[O:17])=[CH:27][CH:28]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: NC1Cc2ccccc2C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(NC1Cc2ccccc2C1)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
The following was added sequentially to DCM (2 mL): 1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (50 mg, 0.126 mmol), DIPEA (0.07 mL, 0.378 mmol), EDC (30 mg, 0.151 mmol), HOBT (24 mg, 0.151 mmol), and 2-aminoindane (0.020 mL, 0.151 mmol). The mixture was stirred for 36 h at rt, at which time the solution diluted with a 1:1 solution of ethyl acetate:diethyl ether and washed with 1M HCl (1×), 10% aq. sodium carbonate (1×) and brine (1×), which resulted in a precipitate that failed to go into either phase. The precipitate was collected and washed with water and diethyl ether to afford the title compound as a white solid. (Yield: 52 mg, 0.102 mmol, 81%) 1H NMR (400 MHz, CDCl3) 7.64, 7.33-7.14, 7.03, 6.64, 5.62, 5.51, 4.76, 4.4, 3.33, 2.84-2.75, 2.21, 1.75
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5](C#N)[C:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([CH3:9])[CH:7]=[CH2:8])C.[OH-].[K+].Cl.O>C(O)CO>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:6]([CH3:9])([CH:7]=[CH2:8])[CH2:5][C:4]([OH:21])=[O:3])=[CH:12][CH:13]=1
Reactant: C=CC(C)(Cc1ccc(OC)cc1)C(C#N)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: C=CC(C)(CC(=O)O)Cc1ccc(OC)cc1
Temperature: 25 °C

Procedure:
A mixture of the product prepared in STEP 2 (5.8 g), ethylene glycol (15 mg) and KOH (5.6 g) was heated at 150 degrees for two days under nitrogen. The solution was cooled to room temperature and poured into 1% hydrochloric acid/water (200 ml). The aqueous portion was extracted well with ethyl acetate and the combined organic extract was washed with water, brine and dried over MgSO4. Solvent was removed to give the crude product that was used without further purification. The 1H NMR was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[F:35]>CC(C)=O>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1[CH2:27][O:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COC(=O)c1cc(C(=O)N2CCOCC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccc(F)cc1F
Temperature: 50 °C

Procedure:
To a stirred solution of methyl 2-hydroxy-5-(4-morpholinylcarbonyl)benzoate (may be prepared as described in Description 108, 270 mg, 1.02 mmol) in acetone (3 ml) was added cesium carbonate (663 mg, 2.04 mmol) and 1-(bromomethyl)-2,4-difluorobenzene (0.17 ml, 1.32 mmol). The mixture was heated at 50° C. for 2 hours, cooled and the solvent removed in vacuo. The residue was partitioned between water (5 ml) and ethyl acetate (10 ml). The organic layer was dried (MgSO4) and the solvent removed in vacuo to give a residue. Purification by column chromatography (silicon, 4:1 ethyl acetate/cyclohexane) yielded the title compound as a yellow gum. 100 mg.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH2:8][N:9]([CH2:27][CH2:28][NH:29][C:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:10]([NH:19]C(OC(C)(C)C)=O)=[N:11]C(OC(C)(C)C)=O.[C:49]1([C:55](Cl)([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:7][N:6]1[C:2]([NH:1][C:55]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:3]([CH2:8][N:9]([CH2:27][CH2:28][NH:29][C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:10]([NH2:19])=[NH:11])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(CN(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cn1ncc(CN(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=N)N)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
To a solution of N-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-N′,N″-bis(tert-butoxycarbonyl)-N-[2-(tritylamino)ethyl]guanidine (1.84 g) in pyridine (10 ml) was added triphenylmethyl chloride (0.94 g), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added chloroform (50 ml). The mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 3% methanol/chloroform to give N′,N″-bis(tert-butoxycarbonyl{-N-([1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]methyl}-N-[2-(tritylamino)ethyl]guanidine (1.60 g) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[CH:16]=[CH:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[C:17]3[CH:16]=[CH:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[N:11]=[CH:10]2)=[CH:3][C:2]=1[C:22]1[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=1
Reactant: Cn1ccc2c(ncn2-c2ccc(F)c(Br)c2)c1=O
Reactant: OB(O)c1cccnc1
Product: Cn1ccc2c(ncn2-c2ccc(F)c(-c3cccnc3)c2)c1=O
Yield: 32 %

Procedure:
1-(3-Bromo-4-fluorophenyl)-5-methyl-1,5-dihydroimidazo[4,5-c]pyridin-4-one was coupled to 3-pyridylboronic acid, in the same way as in Example 1, to give 1-[4-fluoro-3-(pyridin-3-yl)phenyl]-5-methyl-1,5-dihydro-imidazo[4,5-c]pyridin-4-one as an off-white solid (50 mg, 32%): δH (400 MHz, CDCl3) 3.69 (3H, s), 6.38 (1H, d, J 7), 7.22 (1H, d, J 7), 7.40-7.49 (3H, m), 7.54 (1H, dd, J 7 and 3), 7.90-7.94 (2H, m), 8.70 (1H, dd, J 5 and 2), 8.84 (1H, s); m/z (ES+) 321 [MH+].
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1([C:6]([O:8]C(C)(C)C)=[O:7])[CH2:5][CH2:4]1.[OH-].[Na+]>C1COCC1.CO.Cl>[OH:1][CH:2]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:3]1([C:6]([OH:8])=[O:7])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)C1(C(O)c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(C(O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.8 %

Procedure:
To a solution of tert-butyl 1-(hydroxy(phenyl)methyl)cyclopropanecarboxylate (0.56 g, 2.255 mmol) in THF (4 mL) and MeOH (1 mL) was added 10 N sodium hydroxide (3 mL, 30.0 mmol). The reaction mixture was stirred at rt for 12 h. The reaction was diluted with 1 N HCl, extracted with 2×EtOAc, and the combined organic phase was washed with sat. NaCl, dried (anhydrous Na2SO4), filtered and concentrated to yield 1-(hydroxy(phenyl)methyl)cyclopropanecarboxylic acid (0.35 g, 81% yield) as Cap N-11. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.48-7.26 (m, 5H), 4.94 (s, 1H), 1.46 (ddd, J=9.8, 7.0, 4.3 Hz, 1H), 1.38-1.30 (m, 1H), 1.08 (ddd, J=9.5, 7.1, 4.3 Hz, 1H), 0.93-0.84 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1.[H-].[Li+].[CH2:23](I)[CH2:24][CH2:25][CH3:26]>>[CH2:23]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:7][C:6]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCI
Reactant: COc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Agent: [H-]
Agent: [Li+]
Product: CCCCn1c(=Nc2ccc(OC)cc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 428 mg of 2-(4-methoxyanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 14 mg of lithium hydride and 0.17 ml of butyl iodide were used. As a result, 295 mg of 3-butyl-2-[(4-methoxyphenyl)imino]-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a low polarity substance, and 55 mg of 2-[N-butyl-N-(4-methoxyphenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a high polarity substance.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH:18]([CH:20]1[O:24][C:23]([N:25]([CH3:27])[CH3:26])=[N:22][C:21]1=[O:28])[CH3:19])=[CH:12][NH:13]2)C1C=CC=CC=1>C(O)C.O1CCCC1.[C].[Pd]>[CH3:27][N:25]([CH3:26])[C:23]1[O:24][CH:20]([CH:18]([C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[OH:8])[NH:13][CH:12]=2)[CH3:19])[C:21](=[O:28])[N:22]=1
Reactant: CC(c1c[nH]c2cccc(OCc3ccccc3)c12)C1OC(N(C)C)=NC1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(c1c[nH]c2cccc(O)c12)C1OC(N(C)C)=NC1=O
Reaction time: 5 h
Yield: 61.3 %

Procedure:
5-[1-(4-benzyloxyindol-3-yl)ethyl]-2-dimethylamino-2-oxazolin-4-one (268 mg) was dissolved in a mixture of ethanol and tetrahydrofuran (7:3.10 ml). 10% palladium-carbon (80 mg) was added and the whole was hydrogenated for 5 hours at room temperature under normal pressure. The catalyst was removed from the mixture and 10% palladium-carbon (80 mg) was added again. The whole was hydrogenated for additional 24 hours at room temperature under normal pressure. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated to give 2-dimethylamino-5-[1-(4-hydroxyindol-3-yl)ethyl]-2-oxazolin-4-one (125 mg).
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.[W]>[Br:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:10]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)N(S(C)(=O)=O)CCO2
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)N1CCOc2ccc(CBr)cc21
Temperature: 25 °C
Yield: 98.7 %

Procedure:
4-Methanesulfonyl-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (2.0 g, 8.8 mmol) and N-bromosuccinimide (1.88 g, 10.6 mmol) were dissolved in carbon tetrachloride (100 mL) and the mixture heated at reflux under a 250 W tungsten lamp. After 2 h the mixture was cooled to ambient temperature and filtered through Kieselguhr. The combined filtrate and washings were evaporated to dryness under reduced pressure to give the title compound (2.66 g, 100%) as a brown oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH3:21][Li].[Cl-].[NH4+]>CN(C=O)C.[Cu](I)I.C(OCC)(=O)C.CO.C1COCC1.C(OCC)C>[C:14]([C@@H:11]1[CH2:10][CH2:9][C@H:8]([C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH2:13][CH2:12]1)(=[O:16])[CH3:21]
Reactant: CCCCOC(=O)[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: [Li]C
Agent: I[Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: CCCCOC(=O)[C@H]1CC[C@@H](C(C)=O)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a mixture of cis-4-(butoxycarbonyl)cyclohexane carboxylic acid (3.3 g) and thionyl chloride (13 mL) was added DMF (2 drops), followed by stirring at 50° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene to obtain a residue. A mixture of copper iodide (5.2 g) and THF (13 mL) was stirred at an internal temperature of −40° C. under an argon atmosphere. To the reaction mixture was added dropwise a diethyl ether solution (1.1 M, 55 mL) of methyl lithium at an internal temperature of −30 to −40° C. over about 15 minutes, followed by stirring at the same temperature for 1 hour. The reaction mixture was cooled to an internal temperature of −60° C., and the THF solution (10 mL) of the above-described residue was added dropwise thereto at an internal temperature of −50 to −60° C. over about 5 minutes. The mixture was stirred at the same temperature for 0.5 hours, and methanol (15 mL) was added dropwise thereto, followed by warming to room temperature. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The organic layer was combined, washed with a saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain butyl cis-4-acetylcyclohexane carboxylate (2.2 g).
Reaction SMILES: S(=O)(=O)(O)O.Cl.[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15]N)=[CH:11][CH:10]=1)[CH3:8].[CH3:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O>O1CCOCC1>[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]2[NH:15][C:21]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][C:20]=3[C:11]=2[CH:10]=1)[CH3:8]
Reactant: CN1CCCCC1=O
Reactant: CCc1ccc(NN)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CCc1ccc2[nH]c3c(c2c1)CN(C)CC3
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sulfuric acid is added to a solution of 4-ethyl phenyl hydrazine hydrochloride (1 equiv.) in dioxane, and stirred for 5 min. at RT. N-Methyl piperidone (0.76-1.4 equiv.) is added and the mixture is heated at 80° C. for 3 h. After completion, as monitored by TLC, the reaction mixture is concentrated under reduced pressure and basified to pH 10 using 10% aqueous KOH solution, extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to provide the desired compound.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH3:14].CON(C)[C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1>C1COCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:12]2[C:7]([Cl:6])=[C:8]([CH3:14])[CH:9]=[CH:10][C:11]=2[Cl:13])=[O:26])=[CH:20][CH:21]=1
Reactant: Cc1ccc(Cl)cc1Cl
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(C(=O)c2ccc(Cl)cc2)c1Cl
Reaction time: 1 h
Yield: 55.1 %

Procedure:
n-BuLi (1.6M, 76 ml) was added dropwise to a solution of 2,4-dichlorotoluene (16.7 ml, 121 mmol) in dry THF (125 ml) at -78° C. under a nitrogen atmosphere. After 1 h a solution of N-methoxy-N-methyl-4-chlorobenzamide (24.26 g, 1 eq.) in dry THF (50 ml) was added slowly to the reaction mixture and the stirring was continued for an additional 1 h. The reaction was then quenched with 1M NH4Cl, and allowed to room temperature. The solvent was removed in vacuo and the resulting mixture was diluted with ether. The organic layer was separated, washed with 1M NH4Cl, water, and brine, and dried over MgSO4. The solvent was removed in vacuo to give an oil, which upon crystallization from hexanes gave 3-(4-chlorobenzoyl)-2,4-dichlorotoluene (19.98 g) as white crystals, mp 132.0°-135.8° C.