Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1
Reactant: COCCOCCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOCOc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 40 h
Yield: 79.7 %

Procedure:
2-Methoxyethoxymethyl chloride (5.10 mL, 45.0 mmol) was slowly added to a mixture of 4-hydroxybenzaldehyde (5.00 g, 40.9 mmol) and K2CO3 (6.20 g, 45.0 mmol) in acetone (70 mL) cooled at 0° C. The mixture was allowed to reach room temperature and stirred for 40 h. After removal of the solvent, the crude residue was dissolved in EtOAc (50 mL) and consecutively washed with water (50 mL) and NaOH (10% aqueous solution, 2×20 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. After removal of the solvent, 6.85 g of 4-((2-methoxyethoxy)methoxy)benzaldehyde were obtained [Rf=0.6 (50% AcOEt/Hexanes), colorless oil, 80% yield], that were used without further purification.
Reaction SMILES: [C:1]([O:20]C(C)C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]CCCCCCCCC.[CH2:24](O)CCCCCCCCCCCCCCC>>[CH3:24][C@@H:1]([OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(C)C
Product: CCCCCCCC[C@@H](C)O
Temperature: 90 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
To the distillation residue, i.e., a mixture of (R)-(-)-2-decanol stearic acid ester and unreacted isopropyl stearate, were added 200 g of palmityl alcohol and 3 g of Lipase PL. After the particle size of the enzyme was regulated by ultrasonication in the same manner as described above, the mixture was stirred at 90° C. and 250 rpm under reduced pressure of 2 mmHg for 24 hours to carry out interesterification while recovering the distillate to obtain free (R)-(-)-2-decanol with high purity (yield: 72%; chemical purity: 99.6%; optical purity: 95% ee).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19]>CN(C=O)C>[CH2:18]([N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][CH2:3]1)[CH3:19]
Reactant: c1ccc2c(c1)NCCO2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCOc2ccccc21
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
To a stirred solution of 3,4-dihydro-2H-benzo[1,4]oxazine (4.0 g, 29.6 mmol) in DMF (20 mL) was added potassium carbonate (10.22 g, 74.0 mmol). After stirring for five min. Iodo-ethane (3.5 mL, 44.4 mmol) was added and heated to 60° C. for overnight. Reaction mixture was cooled to room temperature, quenched by the addition of water (20 mL), extracted with ethyl acetate (3×25 mL). The organic layer was washed with water (30 mL), brine (30 mL), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 4-ethyl-3,4-dihydro-2H-benzo[1,4]oxazine (2.7 g).
Reaction SMILES: [C:1](O)(=O)C.[CH3:5][S:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3[CH:19]=[C:20]([C:23]([NH:25][NH2:26])=[O:24])[CH:21]=[CH:22][C:17]=3[N:16]=[CH:15]2)=[CH:10][CH:9]=1)=[O:7].CN(C)C=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O1CCCC1.N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:5][S:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3[CH:19]=[C:20]([C:23]4[O:24][CH:1]=[N:26][N:25]=4)[CH:21]=[CH:22][C:17]=3[N:16]=[CH:15]2)=[CH:10][CH:9]=1)=[O:7]
Reactant: CC(=O)O
Reactant: CS(=O)c1ccc(-n2cnc3ccc(C(=O)NN)cc32)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CS(=O)c1ccc(-n2cnc3ccc(-c4nnco4)cc32)cc1
Reaction time: 8 h
Yield: 3.7 %

Procedure:
A solution of acetic acid (57 μl, 1.00 mmol) and N,N′-carbonyldiimidazole (195 mg, 1.20 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature for 1 hr. To this reaction mixture were added 1-[4-(methylsulfinyl)phenyl]-1H-benzimidazole-6-carbohydrazide (314 mg, 1.00 mmol) and N,N-dimethylformamide (5 mL), and the resulting mixture was stirred overnight. To this reaction mixture was added a solution of p-toluenesulfonyl chloride (381 mg, 2.00 mmol) in pyridine (5 mL), and the resulting mixture was stirred at 80° C. for 24 hr. After cooling, the reaction mixture was diluted with chloroform, washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=4/1-0/1) and recrystallized from hexane/ethyl acetate to give the title compound (12 mg, yield 3.8%) as colorless crystals.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:15])[CH3:14])[CH:3]=[CH2:4].ClC1C=CC=C(C(OO)=[O:24])C=1>>[O:24]1[CH2:4][CH:3]1[CH:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:15])[CH3:14])[CH3:1]
Reactant: C=CC(C)Oc1ccccc1NC(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC(=O)Nc1ccccc1OC(C)C1CO1

Procedure:
The compound was prepared from N-{2-[(1-Methyl-2-propenyl)oxy]phenyl}acetamide (549 mg, 2.67 mmol) and m-chloroperbenzoic acid (80%, 923 mg, 4.28 mmol) analogously to that described in Example 8 (ii). Purification wag done on silica gel with petroleum ether/ethyl acetate 10/15 as eluent. This gave separation of the two diastereomeric pairs.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[O:11][C:10]([CH2:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][CH:31]3[S:35][C:34](=N)[NH:33][C:32]3=[O:37])=[CH:28][CH:27]=1)([CH3:23])[CH2:9][C:8]2=[O:40])(=O)C.Cl.C[O:43]CCO>O>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:21])([CH3:22])[CH2:16][C:17]([CH3:19])([CH3:18])[CH3:20])[O:11][C:10]([CH2:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][CH:31]3[S:35][C:34](=[O:43])[NH:33][C:32]3=[O:37])=[CH:28][CH:27]=1)([CH3:23])[CH2:9][C:8]2=[O:40]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc(CC3SC(=N)NC3=O)cc1)CC2=O
Reactant: COCCO
Agent: Cl
Solvent: O
Product: CC(C)(C)CC(C)(C)c1cc2c(cc1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
A mixture of 5.2 g of 5-{4-[6-acetoxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl) chroman-2-ylmethoxy]-benzyl}-2-iminothiazolidin-4-one prepared as described in Preparation 26), 16 ml of 2N hydrochloric acid and 25 ml of ethylene glycol monomethyl ether was heated for 6 hours at 85°-90° C. under a nitrogen atmosphere. The reaction mixture was then poured into water and extracted with benzene. The benzene extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography, eluted with a 4:1 by volume mixture of benzene and ethyl acetate, to give the title compound as a slightly yellow foamy solid, softening at 100°-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10]1(=O)[C:20]2=[C:21]3[C:16](=[CH:17][CH:18]=[CH:19]2)[CH:15]=[CH:14][CH:13]=[C:12]3[C:11]1=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[C:10]1[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:21]=3[C:12]([C:11]1=[N:9]2)=[CH:13][CH:14]=[CH:15]4
Reactant: O=C1C(=O)c2cccc3cccc1c23
Reactant: Nc1ccc(Cl)cc1N
Product: Clc1ccc2nc3c(nc2c1)-c1cccc2cccc-3c12
Yield: 90 %

Procedure:
When 0.05 mole each of 4-chloro-o-phenylenediamine and acenaphthenequinone were reacted by the method of Example 7(A), 13 g. (90 percent yield) of 9-chloroacenaphtho[1,2-b]quinoxaline, mp = 224°-225° C., were obtained
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][NH:5][N:4]=1)#[N:2].[CH2:8]=[O:9]>CC(C)=O>[OH:9][CH2:8][N:5]1[CH:6]=[CH:7][C:3]([C:1]#[N:2])=[N:4]1
Reactant: C=O
Reactant: N#Cc1cc[nH]n1
Solvent: CC(C)=O
Product: N#Cc1ccn(CO)n1
Temperature: 130 °C
Reaction time: 7 h
Yield: 78.2 %

Procedure:
The mixture of 0.86 g of 3-cyano-1H-pyrazole and 0.55 g of paraformaldehyde was stirred at 130° C. for 7 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. After the mixture was filtered, the filterate was concentrated under reduced pressure to obtain 0.89 g of 1-(hydroxymethyl)-3-cyano-1H-pyrazole.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH:6]([CH:8]=O)[CH2:5][CH2:4][O:3]1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][CH:6](/[CH:8]=[CH:11]/[C:12]([OH:14])=[O:13])[CH2:5][CH2:4][O:3]1
Reactant: O=C(O)CC(=O)O
Reactant: C[C@H]1CC(C=O)CCO1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C[C@H]1CC(/C=C/C(=O)O)CCO1
Temperature: 100 °C

Procedure:
A mixture of (2S)-2-methyltetrahydro-2H-pyran-4-carboxaldehyde (4.0), malonic acid (6.495 g) and piperidine (0.1 ml) in pyridine (10 ml) was heated to 100° C. for 4 hours. The reaction mixture was concentrated and partitioned between ethyl acetate (100 ml) and 1N HCl. The organic layer was dried, evaporated and recrystallised form toluene to give the title compound. Yield 2.48 g. NMR CDCl3 1.2 (m, 4H), 1.5 (m, 1H), 1.7 (m, 2H), 2.45 (m, 1H), 3.5 (m, 2H), 4.05 (m, 1H), 5.8 (d, 1H), 7.0 (dd, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15][NH:14]1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:35])[O:33][CH3:34]>ClCCl>[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15][N:14]1[C:32]([O:33][CH3:34])=[O:35]
Reactant: COC(=O)C1CCNC(c2ccc(C(F)(F)F)cc2C)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)cc2C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
Methyl 2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-4-carboxylate hydrochloride (8.2 g, 24.28 mmol) and DIPEA (10.60 mL, 60.69 mmol) were dissolved in dichloromethane (100 mL). Methyl carbonochloridate (2.257 mL, 29.13 mmol) was added and the reaction stirred at room temperature for 1 h. DCM (100 mL) was added. The organic phase was washed twice with 1 M HCl and water, dried over Na2SO4 and evaporated to yield dimethyl 2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1,4-dicarboxylate (8.9 g, quant.). MS m/z 360 (M+H)+
Reaction SMILES: IC.[H-].[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([CH3:22])[NH:15][C:14]([O:23][CH3:24])=[N:13]2)=[CH:8][CH:7]=1.[CH3:25]COC(C)=O>CN(C=O)C.O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[N:13]([CH3:25])[C:14]([O:23][CH3:24])=[N:15][C:16]([CH3:22])=[C:17]2[C:18]([O:20][CH3:21])=[O:19])=[CH:8][CH:7]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)C1=C(C)NC(OC)=NC1c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)C1=C(C)N=C(OC)N(C)C1c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
Iodomethane (0.314 mL, 5.04 mmol, 1.1 equiv) and sodium hydride (60% in mineral oil, 202 mg, 5.04 mmol, 1.1 equiv) were combined in DMF (10 mL) and cooled to 0° C. The product of Step (b) (1.275 g, 4.59 mmol, 1 equiv) was added slowly as a solution in DMF (11 mL). Following the addition, the reaction was warmed to room temperature and stirred for two hours. The reaction mixture was diluted with water and poured into EtOAc. The phases were separated and the aqueous phase was extracted with an additional portion of EtOAc. The combined organic phases were washed with water, 15% aq. Na2S2O4, and satd. NaCl, then dried over sodium sulfate. The suspension was filtered and the filtrate was concentrated en vacuo to afford a mixture of two regioisomeric products. The isomers were separated by flash chromatography (3→5% Et2O/CH2Cl2), and regiochemistry of the desired product was confirmed by NOE analysis. 550 mg (41%) of the title compound was isolated as a yellow solid. 1H NMR (400 MHz, CDCl3) 7.30-7.27 (m, 2H), 7.02-6.97 (m, 2H), 5.21 (s, 1H), 3.91 (s, 3H), 3.63 (s, 3H), 2.84 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH:18](OC)[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[OH-].[NH4+]>C(Cl)Cl>[CH:1]([N:14]1[CH2:15][CH:16]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=3)[NH:21][CH:20]=2)[CH2:17]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(c1c[nH]c2ccc(C#N)cc12)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC[SiH](CC)CC
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2[nH]cc(CC3CN(C(c4ccccc4)c4ccccc4)C3)c2c1
Yield: 86 %

Procedure:
A solution of 3-[(1 -benzhydryl-azetidin-3-yl)-methoxy-methyl]-1H-indole-5-carbonitrile, triethylsilane (5.5 ml, 34 mmol) and trifluoroacetic acid (6.6 mL, 86 mmol) in methylene chloride (40 mL) was refluxed overnight. The reaction was poured into ice and neutralized with concentrated ammonium hydroxide. The mixture was extracted with methylene chloride (3×100 mL). The organic layer was washed with water (3×80 mL), dried over anhydrous sodium sulfate, filtered and solvent removed under vacuum. The crude oil was column chromatographed on a Biotage (40% ethyl acetate-hexane/hexane). The product-containing fractions were concentrated under vacuum to give 0.56 g (86%) of the title compound as a clear oil. MS ES m/e 378 (M+H)+; 1H NMR (500 MHz, DMSO-D6): 2.74–2.78 δ (M, 3H), 2.96 δ (d, J=6.7 Hz, 2H), 3.21 δ (t, J=6.4 Hz, 2H), 4.4 δ (s, 1H), 7.15–7.17 δ (m, 2H), 7.24–7.29 δ (m, 5H), 7.38–7.418 δ (m, 5H), 7.47 δ (d, J=8.4 Hz, 1H), 8.07 δ (s, 1H), 11.37 δ (br, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]3N=N[N:19]=[C:9]3[C:8]=2[N:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:19])[C:8]=2[N:20]=1
Reactant: COCCc1nc2c(c3ccccc3n3nnnc23)n1CCOCCCc1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCCc1cccnc1
Yield: 27.7 %

Procedure:
5-(2-methoxyethyl)-6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H-imidazo[4,5-c]tetraazolo[1,5-a]quinoline (0.35 g, 0.80 mmol) was treated with triphenylphosphine (0.28 g, 1.20 mmol) using the general procedure described in Part B of example 35. The crude product was crystallized from ether to yield 90 mg of 2-(2-methoxyethyl)-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine as off-white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10].[Br].[N:30]#[C:31]C#N>C(O)C>[NH2:30][C:31]1[N:5]([CH2:6][CH2:7][NH:8][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH2:4][C:3]2[C:2](=[CH:20][CH:19]=[C:18]([C:21](=[O:28])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:17]=2)[N:1]=1
Reactant: N#CC#N
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1CNCCNC(=O)C1CCCCC1
Agent: [Br]
Solvent: CCO
Product: NC1=Nc2ccc(C(=O)c3ccccc3)cc2CN1CCNC(=O)C1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of cyclohexanecarboxylic acid [2-(2-amino-5-benzoyl-benzylamino)-ethyl]-amide (0.0032 mol) in ethanol (30 mL) was stirred at room temperature. Cyanogen bromine (0.0048 mol) was added. The reaction mixture was stirred and refluxed for 2 hours, then cooled and stirred overnight at room temperature resulting in a precipitate. The precipitate was filtered off, washed with diisopropyl ether and dried to yield the title compound as a residue.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([N:20]=[C:21]=[S:22])(=O)C1C=CC=CC=1>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][NH:11][C:21]([NH2:20])=[S:22])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCN
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCNC(N)=S
Yield: 84.9 %

Procedure:
To a solution of 2-((tert-butyldimethylsilyl)oxy)ethanamine (WO 0007985: 24.4 g) in THF (300 mL) was added benzoyl isothiocyanate (22.7 g), and the mixture was mixed for 2 hours. The reaction solution was concentrated, and the residue was dissolved in methanol (150 mL). To the resulting solution were added potassium carbonate (5.0 g) and water (50 mL), and the mixture was mixed for 2 hours. The insolubles were filtered off, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, sequentially washed with 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (27.7 g) as a colorless oily matter.
Reaction SMILES: [Si]([N:8]1[CH2:11][CH2:10][C:9]1=[O:12])(C(C)(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[CH2:21]([O:24][C:25]([N:27]1[CH2:31][C@@H:30]([S:32][C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:29][C@H:28]1[CH2:52]I)=[O:26])[CH:22]=[CH2:23]>>[CH2:21]([O:24][C:25]([N:27]1[CH2:31][C@@H:30]([S:32][C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:29][C@H:28]1[CH2:52][CH:10]1[CH2:11][NH:8][C:9]1=[O:12])=[O:26])[CH:22]=[CH2:23]
Reactant: CC(C)(C)[Si](C)(C)N1CCC1=O
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC1CNC1=O
Yield: 24.5 %

Procedure:
The same procedure as in Reference Example 22-1 was carried out by using N-tert-butyldimethylsilyl-2-oxoazetidine (650 mg, 3.5 mmol), lithium diisopropylamide (2.1M tetrahydrofuran solution, 3.34 ml, 7.0 mmol), and (2S,4S)-N-allyloxycarbonyl-2-iodomethyl-4-tritylthiopyrrolidine (1 g, 1.75 mmol) to obtain (2R,4S)-N-allyloxycarbonyl-2-(2-oxoazetidin-3-ylmethyl)-4-tritylthiopyrrolidine (220 mg, yield: 24%).
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:4]=2[O:3]1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][NH2:24])[CH:19]=[CH:20][CH:21]=1.[BH4-].[Na+]>>[F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][NH:24][CH2:23][CH2:22][C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:14])([F:25])[F:26])[CH:17]=3)=[CH:10][C:4]=2[O:3]1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Reactant: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: FC1(F)Oc2ccc(CNCCc3cccc(C(F)(F)F)c3)cc2O1

Procedure:
(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine was synthesized in analogy to the above procedure using 100 mg of 2,2-difluoro-1,3-benzodioxole-5-carbaldehyde (0.54 mmol), 102 mg of 2-(3-trifluoromethylphenyl)-ethylamine (0.54 mmol) and 31 mg of sodium borohydride (0.81 mmol). The isolated colorless semisolid (110 mg, 57%) was used in the following step without further purification. MS (ISP) 360.0 (M+H)+.
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[CH3:26])=[CH:3][C:4]=3[O:24][CH3:25])=[O:7])[CH2:9][C:10]=12
Reactant: Cc1ccccc1B(O)O
Reactant: COc1cc(I)ccc1C(=O)N1Cc2cccn2Cc2ccccc21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(-c2ccccc2C)ccc1C(=O)N1Cc2cccn2Cc2ccccc21
Temperature: 100 °C
Yield: 89.6 %

Procedure:
A mixture of 10-(4-iodo-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step C (1.8 g, 4.1 mmol), 2-methylphenyl boronic acid (0.55 g, 4.1 mmol) and sodium carbonate (1.9 g, 17.9 mmol) in toluene:ethanol: water (20 mL:10 mL:10 mL) was purged with nitrogen for 1 hour. After addition of the tetrakis(triphenylphosphine) palladium(0) catalyst (0.24 g, 0.21 mmol), the reaction mixture was heated at 100° C. overnight. After cooling, the reaction was filtered through Celite and the cake washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by flash chromatography on silica gel using a solvent system of 20% ethyl acetate in hexane provided 1.5 g of title product as a white foam, which was redissolved in dichloromethane and evaporated to dryness in vacuo prior to use in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]2[S:8][C:9]([Cl:12])=[CH:10][CH:11]=2)=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:7]2[S:8][C:9]([Cl:12])=[CH:10][CH:11]=2)=[N:4][N:5]([CH2:20][C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:22])[CH:6]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: Clc1ccc(-c2n[nH]cc2Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1cc(Cl)c(-c2ccc(Cl)s2)n1)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 4-Chloro-3-(5-chloro-thiophen-2-yl)-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as yellow solid. 1H NMR (400 MHz, CDCl3): 7.58 (s, 1H), 7.38–7.42 (d, 1H), 6.94–7.1 (m, 2H), 6.84–6.88 (dd, 2H), 4.96 (s, 2H), 3.62–3.81 (m, 4H), 3.02–3.14 (m, 4H). 13C NMR (400 MHz, CDCl3): 165, 158.8, 156.8, 142.4, 131, 126.8, 124.8, 119, 116, 115.6, 54, 52, 51.6, 46, 42.6.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]>>[NH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([F:54])[C:40]([OH:55])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 36.5 %

Procedure:
Following general procedure D, (R)-tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.17 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (71 mg, 0.26 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (33 mg, 37% over 2 steps) as an orange-yellow solid 1H NMR (500 MHz, MeOD+TFA-d) δ 9.41 (s, 1H), 8.28-8.14 (m, 2H), 8.05 (br s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.65 (dd, J=9.1, 2.8 Hz, 1H), 7.16-7.04 (m, 3H), 4.53 (d, J=11.6 Hz, 1H), 3.99 (dt, J=13.7, 4.0 Hz, 1H), 3.40-3.21 (m, 3H), 2.86 (br s, 3H), 2.23-2.15 (m, 1H), 1.98-1.89 (m, 1H), 1.79-1.65 (m, 2H), 1.27-1.16 (m, 4H). ESI MS m/z 532 [C29H27ClFN5O2+H]+ HPLC>99.0% (AUC), tR=10.77 min.