Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]4)[N:18]=2)[CH:14]=[CH:13][S:12]3)=[CH:5][C:4]=1[O:30][CH3:31].CCN(C(C)C)C(C)C.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=1>C(Cl)Cl>[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([S:48]([N:26]2[CH2:27][CH2:28][CH2:29][C@@H:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[N:15]5[C:11]([S:12][CH:13]=[CH:14]5)=[N:10][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([F:2])=[C:4]([O:30][CH3:31])[CH:5]=4)[CH:22]=[CH:21][N:20]=3)[CH2:25]2)(=[O:50])=[O:49])=[CH:44][CH:43]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1cc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)ccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
The 4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine hydrochloride (0.25 g, 0.50 mmol) in methylene chloride (DCM) (12 ml) was cooled to 0° C. and was treated with Hunig's base (440 μl, 2.5 mmol). The mixture was kept at 0° C. for 30 minutes then the 4-chlorophenylsulfonyl chloride (0.128 g, 0.60 mmol) was added. The reaction mixture was stirred at room temperature for one hour. The mixture was diluted with methylene chloride (10 ml) and was washed water (2×10 ml) and a saturated aqueous sodium chloride solution (10 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient (ethyl acetate/hexanes, 50-75%), affording 0.281 g (94%) of the title compound as a pale yellow solid. M.p.: 142-143° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.71 (br. s, 1H), 8.15 (d, J=5.5 Hz, 1H), 7.80-7.74 (m, 2H), 7.70-7.64 (m, 2H), 7.42 (d, J=4.5 Hz, 1H), 7.36 (dd, J=8.6, 2.3 Hz, 1H), 7.27 (dd, J=11.3, 8.2 Hz, 1H), 7.19-7.12 (m, 2H), 6.43 (d, J=5.5 Hz, 1H), 4.00-3.90 (m, 1H), 3.84 (s, 3H), 3.77-3.70 (m, 1H), 3.52-3.44 (m, 1H), 2.56-2.42 (m, 1H), 2.34 (t, J=10.0 Hz, 1H), 1.95-1.80 (m, 2H), 1.66-1.52 (m, 1H), 1.45-1.33 (m, 1H). LCMS: 599 [M+H]. Calc. for C27H24N6O3S2FCl.0.16 water.0.74 diethyl ether: C, 53.94; H, 4.57; N, 12.60. Found C, 53.94; H, 4.19; N, 12.59.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10].C(N(CC)C(C)C)(C)C.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>ClCCl>[Cl:14][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)c1cc(CN)ccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(CNC(=O)C(C)(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a thermally controlled reactor, add methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride (700 g, 3.51 mol, 1.0 equiv), dichloromethane (4.9 L), and N,N-diisopropylethylamine (1.71 L, 9.82 mol, 2.8 equiv). Add pivaloyl chloride (515 mL, 4.21 mol, 1.2 equiv) dropwise at such a rate that the internal temperature does not exceed 21° C. Upon completion of the addition, stir the reaction mixture at room temperature for one hour. Quench the reaction mixture with saturated aqueous sodium bicarbonate (10 L). Extract the mixture with dichloromethane (2×1 L), combine the organic extracts, dry over sodium sulfate, filter, and concentrate under reduced pressure to give an oil, (1.1 kg) carried on crude without further purification. MS (m/z) (35Cl/37Cl) 284/286 (M+1)
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1>[Rh].O>[ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:4][CH2:3]1
Reactant: O=C(O)CCCc1ccncc1
Agent: [Rh]
Agent: Cl
Solvent: O
Product: O=C(O)CCCC1CCNCC1
Reaction time: 8 h
Yield: 97 %

Procedure:
The same procedure as in Example 1 was repeated except the following. The same reactor as used in Example 1 was charged with 13.5 g (0.067 mole) of a γ-(4-pyridyl)butyric acid hydrochloride with a purity of at least 99%, 27.0 g of water and 0.67 g of 5% Rh/C [0.25% by weight in terms of Rh based on the γ-(4-pyridyl)butyric acid hydrochloride]. The reaction was conducted at 60° C. for 8 hours. A γ-(4-piperidyl)butyric acid hydrochloride was produced in a yield of 97%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[CH3:17][C:18]1[NH:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>>[CH3:17][C:18]1[N:22]([C:2]2[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:5]=[N:4][CH:3]=2)[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1ccccc1
Product: Cc1nc2ccccc2n1-c1cncc(N[C@@H](C)c2ccccc2)n1
Yield: 10.7 %

Procedure:
In a procedure analogous to example 12, reaction of 6-chloro-N-[(1S)-1-phenylethyl]pyrazin-2-amine (120 mg, 0.51 mmol) and 2-methyl-benzimidazole (75 mg, 0.57 mmol) furnished the product (18 mg, 11%).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:10]([CH3:12])=O)=[C:7]([CH3:9])[N:8]=1)[CH2:2][CH3:3].[C:13](OCC)(=[O:16])[NH:14][NH2:15]>C(O)(=O)C.C(O)CCC>[CH3:12][C:10]1[C:6]2[N:5]([C:4]([CH2:1][CH2:2][CH3:3])=[N:8][C:7]=2[CH3:9])[C:13](=[O:16])[NH:14][N:15]=1
Reactant: CCCc1nc(C)c(C(C)=O)[nH]1
Reactant: CCOC(=O)NN
Solvent: CC(=O)O
Solvent: CCCCO
Product: CCCc1nc(C)c2c(C)n[nH]c(=O)n12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 59.7 g. of methyl 2-n-propyl-4--methyl-5-imidazolyl ketone, 41.14 g. of ethyl carbazate, 200 ml. of n-butanol and 4 drops of glacial acetic acid is warmed until solution is complete and then heated under reflux for 5 hours. The solution is concentrated in vacuo to an oily residue, 250 ml. of diphenyl ether are added and the resulting solution is heated with stirring in an oil bath for 30 minutes after the start of gas evolution. The temperature is maintained as closely as possible to the point at which gas evolution starts (150°-250° C.). The reaction is removed from the oil bath, cooled to 50° C. and diluted with 1-2 volumes hexane. The product is collected, washed with petroleum ether and then dissolved in 200 ml. of chloroform. This solution is filtered through 250 ml. of Magnesol® followed by an 800 ml. chloroform wash. The filtrate is concentrated in vacuo and the residue is recrystallized from 250 ml. of ethyl acetate, giving 48.2 g. of the desired product as off-white crystals, m.p. 154°-155° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([P:33]([CH3:36])([CH3:35])=[O:34])=[CH:29][C:28]=2[S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[N:4][C:5]([NH:8]C2OC(N3CCN(C4C=CC=CN=4)CC3)=NN=2)=[N:6][CH:7]=1.[CH2:43](N)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:43]([NH:8][C:5]1[N:4]=[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([P:33]([CH3:36])([CH3:35])=[O:34])=[CH:29][C:28]=2[S:37]([CH:40]([CH3:41])[CH3:42])(=[O:39])=[O:38])[C:2]([Cl:1])=[CH:7][N:6]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NCc1ccccc1
Reactant: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(Nc2nnc(N3CCN(c4ccccn4)CC3)o2)ncc1Cl
Product: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(NCc2ccccc2)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as described in Example 53) with benzylamine.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=1)[CH2:10][CH:11]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[O:14]C(=O)[NH:12]1)[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+]>C(O)C.O>[NH2:12][CH:11]([CH2:10][C:9]1[CH:24]=[CH:25][CH:26]=[C:7]([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[CH:8]=1)[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[OH:14]
Reactant: CC(C)(C)COc1cccc(CC2NC(=O)OC2c2cccc(Cl)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)COc1cccc(CC(N)C(O)c2cccc(Cl)c2)c1
Yield: 79.3 %

Procedure:
To a solution of (4RS,5SR)-4-[3-(neopentyloxy)benzyl]-5-(3-chlorophenyl)-1,3-oxazolidin-2-one (4.0 g, 10.7 mmol) in ethanol (80 ml) was added 8N aqueous sodium hydroxide solution (6.7 ml, 53.5 mmol), and the mixture was heated under reflux for 5 hrs. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give (1RS,2SR)-2-amino-3-[3-(neopentyloxy)phenyl]-1-(3-chlorophenyl)-1-propanol (2.95 g, 79%) as colorless crystals.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:31]=[CH:30][C:24]([CH:25]([N:27]=[C:28]=[S:29])[CH3:26])=[CH:23][CH:22]=1>CN(C)C=O>[CH2:1]([C:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:28]([NH:27][CH:25]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:31][CH:30]=3)[CH3:26])=[S:29])=[CH:17][CH:18]=2)=[N:10][O:11][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2nocc2Cc2ccccc2)cc1
Reactant: CC(N=C=S)c1ccc(F)cc1
Solvent: CN(C)C=O
Product: CC(NC(=S)Nc1ccc(-c2nocc2Cc2ccccc2)cc1)c1ccc(F)cc1

Procedure:
A solution of 4-(4-benzyl-isoxazol-3-yl)-phenylamine and 4-fluoro-α-methyl-benzyl isothiocyanate in dimethylformamide (5 mL) is stirred for 12 hours at room temperature. The reaction mixture is then partitioned between ethyl acetate and water. The organic layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.4 g crude product as a yellow solid. The latter is recrystallized from ethyl acetate/hexane to give 0.9 g product as a yellow solid. MS: m/z 433 (M+H)+.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:22])[CH2:20][CH3:21])=[CH:15][CH:14]=1>C1COCC1>[CH2:20]([C:19]1([C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=2)[CH2:8][O:22]1)[CH3:21]
Reactant: CCC(=O)c1ccc(F)cc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCC1(c2ccc(F)cc2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(4-fluorophenyl)propan-1-one (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: C(OC(=O)C)(=O)C.[N:8]1([CH2:17][CH:18]([OH:35])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.C(=O)([O-])O.[Na+].[Na+].[Cl-]>CS(C)=O>[N:8]1([CH2:17][C:18](=[O:35])[CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:25][CH:26]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: CCCCCCCCc1ccc(OCC(O)Cn2ccc3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: CCCCCCCCc1ccc(OCC(=O)Cn2ccc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.77 g (17.3 mmol) acetic anhydride are mixed with 10 ml absolute DMSO, stirred at room temperature for 10 min and added drop-wise to a solution of 0.164 g (0.432 mmol) 1-(indol-1-yl)-3-(4-octylphenoxy)propan-2-ol in 10 ml absolute DMSO. Having stirred for six hours, the solution is poured into a mixture of 5% sodium hydrogen carbonate solution and saturated NaCl solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions with diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellow oil which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 95:5) and recrystallized from petroleum ether and yields the product as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([C:28]2[N:29]([CH3:37])[C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:22][C:19]=1[CH:20]=O>>[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([C:28]2[N:29]([CH3:37])[C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:22][C:19]=1/[CH:20]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH3:14])[CH3:15])(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(S(=O)(=O)N(C)C)cc1
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=O
Product: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1/C=C/C(=O)c1ccc(S(=O)(=O)N(C)C)cc1
Yield: 64 %

Procedure:
The title compound was prepared in an analogous manner as Ex-1 using 4-acetyl-N,N-dimethyl-benzenesulfonamide (Ex-31A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 64% yield, yellow solid, mp 120–122° C. 1H-NMR (300 MHz, CDCl3) δ 8.18 (d, J=16 Hz, 1H), 8.12 (d, J=8 Hz, 2H), 7.88 (d, J=8 Hz, 2H), 7.69 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.48 (d, J=16 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 7.22–7.27 (m, 1H), 7.11–7.16 (m, 1H), 6.59 (s, 1H), 6.50 (s, 1H), 4.11 (s, 3H), 3.90 (s, 3H), 3.59 (s, 3H), 2.74 (s, 6H). HRMS (ESI) Calcd. for C28H28N2O5S: 505.1797 (M+H)+; Found: 505.1797.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C:15]2[N:16]=[C:17]([CH2:20][N:21]3[CH:25]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:23]=[N:22]3)[S:18][CH:19]=2)[CH:6]=[C:7]([C:9]#[C:10][Si](C)(C)C)[CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[C:9]([C:7]1[CH:6]=[C:5]([C:15]2[N:16]=[C:17]([CH2:20][N:21]3[CH:25]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:23]=[N:22]3)[S:18][CH:19]=2)[CH:4]=[C:3]([C:2]([F:31])([F:32])[F:1])[CH:8]=1)#[CH:10]
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cc(C#C[Si](C)(C)C)cc(C(F)(F)F)c3)cs2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cc(-c2csc(Cn3cc(C(=O)OCC)cn3)n2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (20 mL) of the compound (2.1 g, 4.4 mmol) obtained in Example 98a in tetrahydrofuran was added tetrabutylammonium fluoride (1M tetrahydrofuran solution, 6.5 mL, 6.5 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=70/30) to give the title compound (940 mg, 53%) as orange crystals.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:26][N:27]([CH3:43])[C:28]1[CH:37]=[C:36]2[C:31]([C:32]([CH3:42])=[CH:33][C:34](=[O:41])[N:35]2[CH2:38][CH:39]=O)=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:39][CH2:38][N:35]4[C:36]5[C:31](=[CH:30][CH:29]=[C:28]([N:27]([CH3:43])[CH3:26])[CH:37]=5)[C:32]([CH3:42])=[CH:33][C:34]4=[O:41])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Cc1cc(=O)n(CC=O)c2cc(N(C)C)ccc12
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(N(C)C)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To 2 mL of a chloroform solution containing 0.21 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.15 g of (7-dimethylamino-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde, 10 μL of acetic acid and 0.20 g of sodium triacetoxyborohydride were added, and stirred at room temperature overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate: 8 mol/L ammonia/methanol=50:1], to give 0.14 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-dimethylamino-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow foam.
Reaction SMILES: O.Cl.[C:3]([NH2:11])(=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na].[CH3:13][O:14][C:15](=[O:24])[C:16]([CH:19](OC)OC)=[CH:17]O.O>CN(C=O)C>[CH3:13][O:14][C:15]([C:16]1[CH:17]=[N:10][C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:11][CH:19]=1)=[O:24]
Reactant: COC(=O)C(=CO)C(OC)OC
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(-c2ccccc2)nc1
Temperature: 100 °C
Yield: 74.7 %

Procedure:
To a solution of benzamidine hydrochloride hydrate (2 mmol) in anhydrous DMF (4 mL) is added sodium salt of 2-dimethoxymethyl-3-hydroxy-acrylicacid methyl ester (0.46 g, 2.32 mmol) and the reaction mixture heated at 100° C. under N2 for 1 hour. The reaction is cooled to rt and water (15 mL) is added. After addition of water, immediate precipitation of the product is observed. The solids are collected by filtration, washed with water (2.5 mL) and vacuum dried to yield 2-phenyl-pyrimidine-5-carboxylic acid methyl ester (0.32 g, 74%). (see: P. Zhichkin, D. J. Fairfax, S. A. Eisenbeis, Synthesis, 2002, 720-722.)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:13]([Cu])#[N:14].Cl.O>CN(C=O)C.[Fe](Cl)(Cl)Cl>[C:13]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1)#[N:14]
Reactant: O=C(c1ccc(Br)cc1)C1CC1
Reactant: N#C[Cu]
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)C2CC2)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
22.5 g of 4-bromophenylcyclopropylmethanone (100 mmol) and 10.3 g of CuCN (100 mmol) are dissolved in 15 ml of DMF and heated under reflux, with stirring, for 4 hours. The suspension is allowed to cool down to 70° C. and is then poured into a solution consisting of 40 g of iron(III) chloride, 10 ml of conc. HCl and 60 ml of water. The mixture is stirred at 70° C. for 20 minutes. It is then extracted three times with 90 ml of toluene on each occasion. The combined organic phases are washed with 250 ml of 2N hydrochloric acid and with 250 ml of 2N sodium hydroxide solution, and then concentrated. The solid residue is triturated with petroleum ether and filtered off with suction.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16].Cl.CN.[CH2:21]([N:23](CC)CC)C>CN(C)C=O>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:23][CH3:21])=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (0.65 ml) was added to a solution containing 4-chloro-3-nitrobenzoic acid (1.50 g) in N,N-dimethylformamide (15 ml) and stirred for 30 minutes at room temperature. Methylamine hydrochloride (1.21 g) and triethylamine (3.11 ml) were added to the reaction mixture. After being stirred for 1 hour at room temperature, the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with water, 1N sodium hydroxide aqueous solution, 1N hydrochloric acid aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The yellow solid residue was purified by silica gel column chromatography (silica gel 10 g, chloroform:methanol=1:0-10:1), thereby yielding the entitled compound (0.97 g) as pale yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[F:19][C:20]([F:30])([F:29])[CH2:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:26][C:25]3[CH:27]=[CH:28][C:22]([CH2:21][C:20]([F:19])([F:29])[F:30])=[CH:23][CH:24]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: Nc1ccc(CC(F)(F)F)cc1
Agent: Cl
Product: FC(F)(F)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 42.8 %

Procedure:
Following General Procedure A2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.075 g, 0.25 mmol) was reacted with 4-(2,2,2-trifluoroethyl)aniline (0.066 g, 0.37 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.047 g, 62%) as an off-white solid. MW=439.30. 1H NMR (DMSO-d6, 500 MHz) δ 14.07 (s, 1H), 9.77 (s, 1H), 7.91 (t, J=1.8 Hz, 1H), 7.75-7.70 (m, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.46 (q, J=7.9 Hz, 4H), 7.08 (s, 1H), 3.70 (q, J=11.6 Hz, 2H), 3.16 (t, J=7.6 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 2.29-2.19 (m, 2H); APCI MS m/z 403 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:31])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH:19]=2)=[CH:10][CH:9]=1.ClC1C=CC=C(C(OO)=[O:40])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:40][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:31])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH:19]=2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(Cc4ccccn4)cc3)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(Cc4cccc[n+]4[O-])cc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.3 %

Procedure:
To a solution of (E)-N-[4-(2-pyridylmethyl)phenyl]-3-(4-methylphenyl)cinnamamide (302 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.27 g) at 0° C., and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give (E)-N-[4-(1-oxidopyridin-2-ylmethyl)phenyl]-3-(4-methylphenyl)cinnamamide (Compound 191) (180 mg) as pale yellow crystals.