Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC(C)=O>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([C:10](=[C:4]2[CH2:3][C:2]([CH3:25])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[C:11]2[CH:12]=[CH:13][C:14]([O:17][C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:15][CH:16]=2)=[CH:23][CH:22]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(O)cc2)CC(C)(C)C1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Yield: 34.7 %

Procedure:
The O-alkylation procedure described for 190 was employed. To a suspension of 4,4′-[(3,3,5,5-tetramethylcyclohexylidene)methanediyl]diphenol (219) (0.500 g, 1.74 mmol), K2CO3 (0.257 g, 1.86 mmol), and acetone (75 mL) was added ethyl 2-bromo-2-methylpropanoate (0.33 mL, 2.3 mmol) at RT. The reaction mixture was refluxed for 48 h, and filtered. The filtrate was concentrated and purified to afford 0.272 g (40%) of compound 227 as a white foam. In addition, 0.200 g of unreacted SM was recovered. 1H NMR (300 MHz, CDCl3): δ 7.04 (d, J=1.8 Hz, 2H), 7.01 (d, J=1.8 Hz, 2H), 6.76 (d, J=1.5 Hz, 2H), 6.77 (d, J=2.7 Hz, 2H), 6.74 (d, J=2.4 Hz, 2H), 4.75 (br s, 1H), 4.24 (q, J=7.2 Hz, 2H), 1.96 (d, J=6.9 Hz, 4H), 1.60 (s, 6H), 1.29 (s, 2H), 1.23 (t, J=7.2 Hz, 3H), 0.934 (s, 6H), 0.92 (s, 6H). LCMS (ESI): m/z 449 (M−H)−.
Reaction SMILES: [Na].[H-].[Na+].[CH3:4][SH:5].[Cl:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9](Cl)[N:8]=1>C1C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([S:5][CH3:4])[N:8]=1
Reactant: CS
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: c1ccccc1
Product: CSc1cncc(Cl)n1

Procedure:
A mixture of 0.13 mole of sodium methylmercaptide (prepared from 3.12 g. sodium hydride and excess methyl mercaptan), 20 g. (0.13 mole) of 2,6-dichloropyrazine and 200 ml. benzene is heated at reflux for 24 hours, cooled and washed twice with 50 ml. water. The benzene layer is separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Distillation of the residue gives 2-chloro-6-methylthiopyrazine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(N(CC)CC)C.C(OCC)(=O)C.[Cu]I>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1cccc(Br)c1
Reactant: C#CCCCCCCCCCC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC#Cc1cccc(C=O)c1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a solution of 3-bromobenzaldehyde (26.5 g) and (25.0 g) 1-dodecyne in triethylamine (105 ml) was added bis(triphenylphosphine)palladium(I)chloride (1.73 g) followed by copper(I) iodide (0.24 g). The resultant mixture was stirred in the dark at 55° C. for 7 hrs, under nitrogen. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 37.7 g 3-(1-dodecynyl)benzaldehyde. The filtrate was an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][CH2:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[CH2:23][CH3:24].[CH:25]1([CH:31]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:8]=[C:9]([N:13]([CH2:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:14][CH:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[CH2:23][CH3:24]
Reactant: O=CC1CCCCC1
Reactant: CCc1cc(Oc2cccc(NCC(O)C(F)(F)F)c2)ccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1cc(Oc2cccc(N(CC3CCCCC3)CC(O)C(F)(F)F)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
The 3-[[3-(4-chloro-3-ethylphenoxy)phenyl]amino]-1,1,1-trifluoro-2-propanol product from EX-18C was dissolved in 12 mL of tetrahydrofuran. To this stirred solution was added cyclohexanecarboxaldehyde (0.032 g, 0.285 mmol), followed by sodium tri-acetoxyborohydride (0.079 g, 0.370 mmol and concentrated acetic acid (0.020 g, 0.325 mmol). The resulting mixture was stirred at room temperature for 18 h. Additional cyclohexanecarboxaldehyde (0.032 g, 0.285 mmol) was added and the mixture was allowed to stir at room temperature for another 18 h. The reaction was quenched with saturated sodium bicarbonate and extracted with methylene chloride. The organic layers were combined, dried over MgSO4 and concentrated to an orange/brown oil. The crude product was purified by flash column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to give 0.080 g (61%) of the desired 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][3-cyclohexylmethyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow-orange oil (>95% pure by HPLC). HRMS calcd.: 456.1917 [M+H]+, found: 456.1942. 1H NMR (CDCl3) δ 0.82-1.01 (m, 2H), 1.22-1.27 (m, 3H), 1.73-1.76 (m, 5H), 2.74 (dd, 2H), 3.15 (dd, 2H), 3.23 (dd, 1H), 3.52 (m, 1H), 3.80 (dd, 1H), 4.28 (m, 1H), 6.34 (d, 2H), 6.42 (d, 1H), 6.83 (dd, 1H), 6.98 (d, 1H), 7.19 (t, 1H), 7.29 (d, 1H). 19F NMR (CDCl3) δ−79.06 (d, 3F).
Reaction SMILES: [C:1]1([CH:7]([O:37]C(=O)C)[C:8](=[O:36])[NH:9][C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=5)[N:23]=[CH:22][N:21]=4)[C:13]=3[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:37][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([NH:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[C:24]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=4)[N:23]=[CH:22][N:21]=3)[C:13]=2[N:14]=1)=[O:36]
Reactant: CC(=O)OC(C(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1)C(O)c1ccccc1

Procedure:
This material was prepared according to the procedure described in Example 68(b) using acetic acid phenyl-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylcarbamoyl}-methyl ester, (Example 79), (0.44 g, 0.78 mmol) and potassium carbonate (0.22 g, 1.6 mmol) in MeOH (8 mL). Purification by silica gel chromatography (1:2 of EtOAc/hexanes) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 523 (M+1). Mp: 197.7-205.4° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:30])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:17][CH2:16]2)=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[CH:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.B.[Na]>C(O)C>[CH2:31]([NH:1][C:2]1[CH:3]=[C:4]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:30])[CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:17][CH2:16]2)=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN(CCc1ccccc1)C1CCN(C(=O)c2cc(N)c3c(c2)CCC(=O)N3)CC1
Reactant: O=Cc1ccccc1
Agent: B
Agent: [Na]
Solvent: CCO
Product: CN(CCc1ccccc1)C1CCN(C(=O)c2cc3c(c(NCc4ccccc4)c2)NC(=O)CC3)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.5 %

Procedure:
In 10 ml of ethanol was dissolved 1 g of 8-amino-6-{4-[N-methyl-N-(2-phenylethyl)amino]-1-piperidinylcarbonyl}-3,4-dihydrocarbostyril. Thereto was added 0.3 g of benzaldehyde. The mixture was refluxed by heating, for 4 hours in an oil bath. The reaction mixture was allowed to cool and then mixed with 0.15 g of sodium boron hydride. The mixture was stirred at room temperature for 4 hours and subjected to distillation under reduced pressure to remove the solvent. The residue was mixed with water. The mixture was extracted with methylene chloride. The extract was dried with anhydrous sodium sulfate and subjected to distillation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: methylene chloride/methanol=100/1~50/1~20/1). The eluate was subjected to distillation to remove the solvent. The residue was recrystallized from ethanol-n-hexane to obtain 0.8 g of 8-benzylamino-6-{4-[N-methyl-N-(2-phenylethyl)amino]-1-piperidinylcarbonyl}-3,4-dihydrocarbostyril as a light yellow powder having a melting point of 144.5°-145.5° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[N:13].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[C:12]([C:14](=[C:9]([CH3:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:15]([O:17][CH3:18])=[O:16])#[N:13]
Reactant: COC(=O)CC#N
Reactant: CC(=O)CCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C#N)=C(C)CCc1ccccc1
Yield: 87.3 %

Procedure:
A mixture of 4-phenyl-2-butanone (1 g), methyl cyanoacetate (0.77 g), acetic acid (0.29 mL), ammonium acetate (0.11 g) and toluene (10 mL) was heated for reflux overnight removing the generated water. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1) to give methyl 2-cyano-3-methyl-5-phenyl-2-pentenate (1.35 g). To this material were added methanol (10 mL) and N,N-dimethylformamide dimethyl acetal (0.95 mL), and the mixture was heated for reflux overnight. The reaction mixture was concentrated under reduced pressure. To the residue were added acetic acid (8 mL) and a solution of 30% hydrobromic acid in acetic acid (5.9 g), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into ice water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice, a saturated aqueous sodium hydrogen carbonate solution twice, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1) to give the title compound (1.7 g)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10](Cl)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[NH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1.N1C=CC=CC=1>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Nc1nccs1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
3-Cyano-4-fluorobenzenesulfonyl chloride (10 g, 45.53 mmol) was added portion wise to a solution of 2-aminothiazole (5 g, 50.13 mmol) in dichloromethane (50 mL) and pyridine (18.4 mL, 228 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature. After 1 hour a precipitate was observed. The mixture was stirred for 18 hours at room temperature. The mixture was sonicated for 2.5 hours until the solid had dissolved, then left to stir at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and azeotropically dried with toluene (2×100 mL). The residue was diluted carefully with a 1M aqueous solution of hydrogen chloride and stirred for 1 hour at room temperature whereupon a precipitate formed. The brown solid was collected by filtration and triturated with dichloromethane to afford the title compound as a brown solid (7.8 g, 60%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]([NH:19][CH:20]=[C:21]2[C:26](=[O:27])OC(C)(C)OC2=O)[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:16]([C:26](=[O:27])[CH:21]=[CH:20][NH:19]2)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OCc1ccccc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
After adding Dowtherm A (160 ml) to methyl 2-(benzyloxy)-4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)benzoate (15.477 g, 37.6 mmol), the mixture was stirred at 200° C. for 1 hour. Upon cooling to room temperature, the precipitated crystals were filtered, washed with diethyl ether and blow-dried to obtain the title compound (7.19 g, 23.2 mmol, 61.80).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].CC1C=CC(S(O[CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[C:25]2[CH2:29][CH2:30][CH3:31])(=O)=O)=CC=1>CO>[CH2:29]([C:25]1[N:24]([CH2:23][CH2:22][S:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:28]=[CH:27][N:26]=1)[CH2:30][CH3:31]
Reactant: CCCc1nccn1CCOS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1nccn1CCSc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.5 %

Procedure:
4-aminothiophenol (1.0 g) was dissolved in methanol (20 ml), 3N sodium hydroxide (8.0 ml) was added to the mixture, and 2-(2-propylimidazol-1-yl)ethyl 4-methylbenzene sulfonate (3.7 g) was added to the mixture. The mixture was stirred for 20 hours at room temperature, and the solvent was removed under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/ethanol=15/1→6/1), to give 4-[[2-(2-propylimidazol-1-yl)ethyl]sulfanyl]aniline (1.2 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:7]([CH2:10][C:11]([OH:13])=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH3:46][O:47][C:48](=[O:51])[CH2:49][NH2:50].C(N(CC)CC)C>C(Cl)Cl>[CH3:46][O:47][C:48](=[O:51])[CH2:49][NH:50][C:11]([CH2:10][C:7]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][CH:8]=1)=[O:13]
Reactant: CCCCc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Reactant: COC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1ncc(CC(=O)NCC(=O)OC)n1Cc1ccccc1Cl
Yield: 53.6 %

Procedure:
The procedure of Example 1-(iii) was followed using 0.5 g (1.63 mmol) of 2-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]acetic acid, 0.21 g (1.79 mmol) of N-hydroxysuccinimide, 0.37 g (1.79 mmol) of dicyclohexylcarbodiimide, 0.27 g (2.12 mmol) of glycine methyl ester hydrochloride, triethylamine (0.3 mL, 2.12 mmol) and methylene chloride (15 mL), there was obtained 0.33 g (53%) of N-[{2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl}methylcarbonyl]glycine methyl ester as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH:28]([NH2:31])([CH3:30])[CH3:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:31][CH:28]([CH3:30])[CH3:29])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (150 mg, 0.41 mmol), sodium hydride (15 mg, 0.6 mmol), N-phenyl(trifluoromethylsulfon)imide (208 mg, 0.58 mmol), and isopropylamine (0.14 mL, 1.65 mmol) are treated according to method E yielding the title product.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH3:15][N:14]1[C:10]([CH2:9][CH2:8][NH2:7])=[N:11][N:12]=[N:13]1
Reactant: Cn1nnnc1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1nnnc1CCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[2-(1-Methyl-1H-tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester (0.204 g, 0.9 mmol) is dissolved in DCM (3.5 ml). To this solution is added 4M HCl in dioxane (0.9 ml, 3.6 mmol) and the reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo to afford the title compound as the hydrochloride salt.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[CH:4]/[C@:5]1([CH3:29])[S:11][C@H:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[C@H:6]1[C:13]([O:15][CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].[Cl:30][CH2:31][C:32]([N:34]=[C:35]=[O:36])=[O:33]>O1CCCC1>[Cl:30][CH2:31][C:32]([NH:34][C:35]([O:1][CH2:2]/[CH:3]=[CH:4]/[C@:5]1([CH3:29])[S:11][C@H:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[C@H:6]1[C:13]([O:15][CH:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14])=[O:36])=[O:33]
Reactant: O=C=NC(=O)CCl
Reactant: C[C@@]1(/C=C/CO)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C[C@@]1(/C=C/COC(=O)NC(=O)CCl)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
300 mg (0.73 mmol) of benzhydryl (E)-(2S,3S,5R)-3-(3-hydroxy- propenyl)-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate were dissolved in 10 ml of tetrahydrofuran under argon and treated with 90 μl (1.05 mmol) of chloroacetyl isocyanate. The mixture was stirred for 3 hours, evaporated and chromatography was carried out over silica gel (particle size 0.040-0.063 mm) with ethyl acetate:n-hexane (9:16) as the eluent. Yield: 300 mg (77%) of colorless foam IR (KBr): 3300(br), 1779, 1753, 1730, 1495, 1203 cm-1MS: (M+NH4)+ 546.4
Reaction SMILES: Cl[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:13]=[N:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:11][C:12]1[CH:13]=[N:14][N:15]([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=2)[CH:16]=1
Reactant: OCc1ccc(CCl)cc1
Reactant: Clc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: OCc1ccc(Cn2cc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
A mixture of 4-(chloromethyl)benzyl alcohol (0.500 g, 3.19 mmol), 4-chloro-1H-pyrazole (0.753 g, 7.34 mmol), and potassium carbonate (0.908 g, 7.02 mmol) in acetonitrile (40 mL) was stirred at rt overnight. After this time, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.375 g, 75%) as a white solid. MW=222.67. 1H NMR (CDCl3, 500 MHz) δ 7.45 (s, 1H), 7.37 (s, 1H), 7.35 (s, 1H), 7.33 (s, 1H), 7.23 (s, 1H), 7.22 (s, 1H), 5.24 (s, 2H), 4.70 (d, J=5.9 Hz, 2H), 1.68 (t, J=5.9 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:20]([CH3:19])(=[O:22])=[O:21])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(O)ccc1-c1nc2ncccc2[nH]1
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ncccc2[nH]1

Procedure:
Prepared analogously to Example 1 from 2-(2'-methoxy-4'-hydroxyphenyl)-imidazo[4,5-b]pyridine and methanesulfonic acid chloride.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:20]I>O1CCCC1.O>[CH3:20][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNc2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(C(=O)OC(C)(C)C)c2ccccc21
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl 3,4-dihydroquinoxaline-1(2H)-carboxylate obtained in Reference Example 28 (1.06 g) in tetrahydrofuran (20 ml), sodium hydride (60% suspension in oil, 181 mg) was added and stirred for 5 minutes, followed by addition of methyl iodide (281 μl). After stirring at room temperature for 1 hour, sodium hydride (60% suspension in oil, 181 mg) was further added and stirred for 30 minutes, followed by addition of methyl iodide (281 μl). After stirring overnight at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=10:1 to 5:1) to give tert-butyl 4-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (331 mg) as a brown powder. To a solution of tert-butyl 4-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate thus obtained (331 mg) in ethyl acetate (2 ml), 4N hydrochloric acid (in ethyl acetate, 1.1 ml) was added and stirred overnight at room temperature. The reaction mixture was diluted with 8M aqueous sodium hydroxide and then extracted with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to give the titled compound, i.e., 1-methyl-1,2,3,4-tetrahydroquinoxaline (179 mg) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12](=[O:14])[CH3:13])=[N:7][N:6]=[CH:5]2.[CH3:15][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])([CH3:15])[CH3:13])=[N:7][N:6]=[CH:5]2
Reactant: CC(=O)c1nncc2cc(Cl)ccc12
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(O)c1nncc2cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
A solution of 1-(6-chlorophthalazin-1-yl)ethanone (350 mg, 1.69 mmol) in 20 mL of THF at 0° C. was treated with 0.8 mL MeMgBr (3.16 M in Et2O) and stirred at 0° C. for 1 h. The mixture was quenched with saturated NH4Cl, and extracted 2×20 mL EtOAc. The combined EtOAc layers were dried over MgSO4, filtered and concentrated. Purification on an ISCO (12 g column, 15-50% EtOAc:Hexanes) afforded 2-(6-chlorophthalazin-1-yl)propan-2-ol (172 mg, 46% yield) as a pale yellow amorphous solid. MS (ESI, pos. ion) m/z: 223.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][B:30]([CH2:32][CH3:33])[O:29][C@@H:28]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27]1>>[CH2:32]([B:30]1[O:29][C@@H:28]([CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:27][C@@H:26]([CH2:25][CH2:24][N:23]2[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:31]1)[CH3:33]
Reactant: CCB1O[C@H](CCN)C[C@H](CC(=O)OC(C)(C)C)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: CCB1O[C@H](CCn2c(C(C)C)cc(-c3ccccc3)c2-c2ccc(F)cc2)C[C@H](CC(=O)OC(C)(C)C)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and t-butyl 2-((4R,6R)-6-(2-aminoethyl)-2-ethyl-1,3,2-dioxaborinan-4-yl)acetate.