Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:47])[C@@H:13]([NH:25][C:26]([C:28]2[CH:32]=[C:31]([O:33][CH2:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[N:30]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:29]=2)=[O:27])[CH2:14][NH:15][C:16]2[C:19](=[O:20])[C:18](=[O:21])[C:17]=2[O:22]CC)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH-].[Na+].Cl>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:47])[C@@H:13]([NH:25][C:26]([C:28]2[CH:32]=[C:31]([O:33][CH2:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[N:30]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:29]=2)=[O:27])[CH2:14][NH:15][C:16]2[C:17](=[O:22])[C:18](=[O:21])[C:19]=2[OH:20])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CNc2c(OCC)c(=O)c2=O)NC(=O)c2cc(OCC(=O)C(C)(C)C)n(-c3ccccc3)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CNc2c(O)c(=O)c2=O)NC(=O)c2cc(OCC(=O)C(C)(C)C)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 40 mg 4-[(S)-2-{[5-(3,3-Dimethyl-2-oxo-butoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-propionyl]-piperazine-1-carboxylic acid ethyl ester in 2 ml of THF, 0.2 ml of a 1 M aqueous NaOH solution was added. After stirring for 5 h at RT the reaction was acidified to pH 1 with diluted aqueous hydrochloric acid and extracted with DCM (3×50 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The product was dissolved in water and lyophilized to yield a white solid.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CSC.B.CO.Cl>C1COCC1.C(OCC)C>[Cl:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[Cl:23])[NH:16][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:26][CH:25]=2)[CH2:8][CH2:9]1
Reactant: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc(Cl)c(Cl)c1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: Fc1ccc(CC2CCN(CCNc3ccc(Cl)c(Cl)c3)CC2)cc1
Yield: 90 %

Procedure:
To a solution of 2-[4-(4-fluorobenzyl)-1-piperidinyl]-N-(3,4-dichlorophenyl)acetamide (Reference Example 70-2, 3.95 g, 10.0 mmol) in THF (30 mL) was added dropwise borane dimethyl sulfide (3.0 mL) at room temperature with stirring. The mixture was stirred for 3 hours under reflux. To the mixture was added dropwise methanol (10 mL) at room temperature, and the mixture was stirred at the same temperature for 18 hours. To the mixture was added a solution of 1N-hydrogen chloride in diethyl ether (30 mL), and the mixture was concentrated under reduced pressure. To the mixture was added methanol (30 mL), and the mixture was concentrated under reduced pressure. To the concentrate was added ethyl acetate and resulting precipitates were collected by filtration. The precipitates were washed with ethyl acetate, and dried under reduced pressure to give the titled compound (4.07 g, 9.0 mmol, 90%) as white crystals.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.COCC(OC1C=C(C=C(OC2C=CC(C3OC(C)=NN=3)=CC=2)C=1)C(O)=O)C.[CH3:41][C:42]1[O:46][C:45]([C:47]2[CH:70]=[CH:69][C:50]([O:51][C:52]3[CH:53]=[C:54]([CH:58]=[C:59]([O:61][CH:62]4[CH2:66][CH2:65][N:64]([CH3:67])[C:63]4=[O:68])[CH:60]=3)[C:55](O)=[O:56])=[CH:49][CH:48]=2)=[N:44][N:43]=1.[NH2:71][C:72]1[S:73][CH:74]=[C:75]([CH3:77])[N:76]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:41][C:42]1[O:46][C:45]([C:47]2[CH:48]=[CH:49][C:50]([O:51][C:52]3[CH:53]=[C:54]([CH:58]=[C:59]([O:61][CH:62]4[CH2:66][CH2:65][N:64]([CH3:67])[C:63]4=[O:68])[CH:60]=3)[C:55]([NH:71][C:72]3[S:73][CH:74]=[C:75]([CH3:77])[N:76]=3)=[O:56])=[CH:69][CH:70]=2)=[N:44][N:43]=1
Reactant: Cc1nnc(-c2ccc(Oc3cc(OC4CCN(C)C4=O)cc(C(=O)O)c3)cc2)o1
Reactant: Cc1csc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: COCC(C)Oc1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(C(=O)O)c1
Solvent: ClCCl
Product: Cc1csc(NC(=O)c2cc(Oc3ccc(-c4nnc(C)o4)cc3)cc(OC3CCN(C)C3=O)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(Dimethylamino)pyridine (DMAP) (0.149 g), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI.HCl) (0.524 g) were added to a solution of 3-(1-Methoxypropan-2-yloxy)-5-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)benzoic acid (0.5 g) (Intermediate 1) in dry DCM under nitrogen at 0-5° C. 2-amino-4-methyl thiazole (0.134 g) was added and the mixture was stirred for 16 h at room temperature. It was diluted with commercially available DCM. Organic phase was washed with dil HCl, saturated solution of NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated in vacuo to get the crude residue. The residue was chromatographed to yield pure titled compound (0.3 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[BH4-].[Na+].[Si]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1)(C(C)(C)C)(C)C.O>CN(C)C=O>[OH:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:9]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(Nc2ccc(C#N)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N(Cc2ccc(O)cc2)c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
224 mg of 4-[N(4-methoxyphenyl)amino]benzonitrile was dissolved in 1.2 ml of N,N-dimethylformamide, and 48 mg of sodium borohydride was added thereto under cooling with ice, followed by stirring at room temperature for 30 minutes. The previously prepared 4-(t-butyldimethylsilyloxy)benzyl chloride was dissolved in 1.2 ml of N,N- dimethylformamide and added to the reaction mixture under cooling with ice, followed by stirring at room temperature for 2 days. After water was added to the reaction mixture, the product was extracted with ethyl acetate. After the extract was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 1.2 ml of tetrahydrofuran, and 1.2 ml of a 1 M tetrahydrofuran solution of tetrabutylammonium fluoride was added thereto, followed by stirring at room temperature for 15 minutes. After a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, the product was extracted with ethyl acetate. After the extract was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (using ethyl acetate as the eluent) to obtain 229 mg of 4-[N-(4-hydroxybenzyl)-N-(4-methoxyphenyl)amino]benzonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH3:15])=[N:12][C:11]=2[CH2:16][OH:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26].Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:25]([O:17][CH2:16][C:11]1[N:12]=[C:13]([CH3:15])[NH:14][C:10]=1[S:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C)cc(Sc2[nH]c(C)nc2CO)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1nc(C)[nH]c1Sc1cc(C)cc(C)c1
Yield: 78 %

Procedure:
In dry methylene chloride (85 ml) was dissolved 1.7 g (6.8 mmol) of [5-(3,5-dimethylphenylthio)-2-methyl-1H-imidazol-4-yl]methanol (41d), followed by addition of 2.10 g (20.8 mmol) of triethylamine. To this solution, acetyl chloride was added dropwise with stirring under ice-cooling. At the same temperature, the mixture was stirred for 30 minutes, then, 8.3 ml of 6N hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution to neutralize, and extracted with methylene chloride. The extract was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate) to obtain 1.55 g of [5-(3,5-dimethylphenylthio)-2-methyl-1H-imidazol-4-yl]methyl acetate (41b) as oil (yield 78%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:36]2[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=2)=[N:8]1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2-c1c(F)cccc1F
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (80 mg) in DMF (2 mL)/water (0.20 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (83.0 mg), tetrakis(triphenylphosphine)palladium(0) (22.6 mg) and potassium carbonate (54.0 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (46.2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH3:15])[C:10]=1[NH:16]C(=O)[O-].ClC1C=C(F)C=CC=1C1N(C)N=C(C)C=1NC(=O)OC.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH3:15])[C:10]=1[NH2:16]
Reactant: Cc1nn(C)c(-c2ccc(F)cc2Cl)c1NC(=O)[O-]
Agent: COC(=O)Nc1c(C)nn(C)c1-c1ccc(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nn(C)c(-c2ccc(F)cc2Cl)c1N

Procedure:
A mixture of N-[5-(2-chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-4-yl]carbamate (i.e. the product of Step E) (7.07 g, 23.8 mmol) and aqueous sodium hydroxide (1 N, 70 mL) in methanol (70 mL) was heated at reflux for 20 h. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate (2×30 mL). The combined organic layers were extracted with hydrochloric acid (1 N, 2×30 mL), and the pH of the combined aqueous extracts was adjusted to 10 with the addition of sodium hydroxide (1 N). The aqueous mixture was extracted with ethyl acetate (2×40 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a viscous yellow oil (4.36 g).
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=[O:3])[CH3:2].[H-].[Na+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CS(C)=O.C(O)(=O)C>[C:1]([NH:4][C:5]1([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=[O:3])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CC(=O)NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)NC1(Cc2ccccc2)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 28.1 %

Procedure:
To a suspension of 1.4 g of 10-acetamido-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 35 ml of anhydrous dimethyl sulphoxide, maintained at 20° C. under a nitrogen atmosphere, is added 0.36 g of 80% sodium hydride and the mixture is stirred for 20 minutes. A solution of 0.7 g of benzyl chloride in 1 ml of anhydrous dimethyl sulphoxide is then added dropwise over 5 minutes at the same temperature and, after stirring for 3 hours, the reaction mixture is poured into a mixture of 200 ml of distilled water, 80 g of ice and 6 ml of acetic acid. The insoluble material formed is removed by centrifugation and the supernatant solution is stored for 15 hours at a temperature in the region of 20° C. The insoluble product formed is isolated by filtration, washed twice with 10 ml in total of distilled water and with 5 ml of acetone, and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 80° C. 0.52 g of 10-acetamido-10-benzyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained, melting at 325° C. (decomposition) (Analysis, % calculated C: 71.34, H: 4.90, N: 15.13, O: 8.64, % found C: 71.2, H: 4.5, N: 15.0).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][C:4]=1[CH:12]=[C:13]([Cl:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:1])=[O:11])=[CH:5][C:4]=1[CH:12]=[C:13]([Cl:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(Cl)=Cc1cc(N=C=O)ccc1Cl
Reactant: N
Solvent: C1CCOC1
Product: CCOC(=O)C(Cl)=Cc1cc(NC(N)=O)ccc1Cl
Reaction time: 1 h

Procedure:
Gaseous ammonia was passed into a solution of 14.3 g of 4-chloro-3-(2-chloro-2-ethoxycarbonylethenyl)-phenyl isocyanate in 200 ml of tetrahydrofuran at 20° C. in the course of 1.5 hours until saturation had been reached, and stirring was carried out for 1 hour. The precipitate was removed and washed with ether. The filtrate was evaporated down, the residue was stirred with ether and the product was removed. The solids were combined.
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:38]=[CH:37][CH:36]=[CH:35][C:8]=2[CH2:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]([NH:27]C(=O)OC(C)(C)C)[CH3:26])=[CH:21][CH:20]=3)[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][CH:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:13]2[N:12]=[C:11]([CH2:10][CH2:9][C:8]3[CH:35]=[CH:36][CH:37]=[CH:38][C:7]=3[C:4]3([C:1]([NH2:2])=[O:3])[CH2:6][CH2:5]3)[C:16]([CH3:17])=[CH:15][N:14]=2)=[CH:20][CH:21]=1)[CH3:26]
Reactant: Cc1cnc(Nc2ccc(C(C)NC(=O)OC(C)(C)C)cc2)nc1CCc1ccccc1C1(C(N)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2ccc(C(C)N)cc2)nc1CCc1ccccc1C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 42 %

Procedure:
A solution of tert-butyl (1-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)ethyl)carbamate A47 (0.110 g, 0.213 mmol) in DCM (10 mL) was treated with TFA (0.33 mL, 4.3 mmol) and stirred for 6 hours at room temperature. The volatiles were evaporated in vacuo before aq. NaOH (2 M, 30 mL) was added to the residue. The aqueous phase was extracted with EtOAc (3×30 mL) and the combined organics were washed with brine and dried over MgSO4. The solvent was removed in vacuo to give an off-white solid that still contained starting material. The solid was taken up in DCM (20 mL) and treated with TFA (0.17 mL, 2.2 mmol). The mixture was stirred at room temperature for 24 hours before the volatiles were removed in vacuo. Aq. NaOH (2 M, 30 mL) was added and the aqueous phase was extracted with EtOAc (3×30 mL). The organics were combined, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The resultant white solid was dissolved in DCM and the desired product was precipitated by the addition of cyclohexane. The precipitate was isolated by vacuum filtration to give the title compound 50 (0.037 g, 42%) as a white solid. LCMS-A: rt 2.98 min; m/z 399 [M-NH2]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][O:16][C:17]=2[N:18]=1.Cl.C(OCC)(=O)C.[OH-].[Na+]>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]=2[N:18]=1
Reactant: CC1CCCCN1c1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC1CCCCN1c1ccc2c(n1)OCCNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
A mixture of the compound (0.09 g) obtained in step 1 and 4N hydrogen chloride/ethyl acetate (3 mL) was stirred at room temperature for 3 hr. An aqueous sodium hydroxide solution was added until the aqueous layer became alkaline. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (solvent gradient; 10→40% ethyl acetate/hexane) to give 8-(2-methylpiperidin-1-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.034 g, 52%) as a pale-yellow powder.
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([OH:15])[CH:6]=1)=[O:4].[CH2:16]([CH2:18][NH2:19])[OH:17]>C(Cl)(Cl)Cl>[OH:17][CH2:16][CH2:18][NH:19][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([OH:15])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(O)nc2ccccc12
Reactant: NCCO
Solvent: ClC(Cl)Cl
Product: O=C(NCCO)c1cc(O)nc2ccccc12

Procedure:
A solution of 4-methoxycarbonyl-2-hydroxyquinoline (40 mg) and ethanolamine (0.1 ml) in chloroform (5 ml) was stirred at 60° C. for 48 hours. After cooling the colourless product was isolated by filtration.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH2:20][CH2:21][N:22]1[C:26]([CH:27]=[O:28])=[CH:25][N:24]=[CH:23]1)=[O:6])[CH:2]=[CH2:3].[BH4-].[Na+].Cl>O1CCCC1.CO>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH2:20][CH2:21][N:22]1[C:26]([CH2:27][OH:28])=[CH:25][N:24]=[CH:23]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCn1cncc1C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCn1cncc1CO
Yield: 80.5 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-{2-(5-formylimidazol-1-yl)ethyl}pyrrolidine (12.65 g) in a mixture of tetrahydrofuran (60 ml) and methanol (60 ml) was portionwise added sodium borohydride (1.17 g) with stirring under ice-cooling. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was adjusted to pH 8 with 6N hydrochloric acid at the same condition. The resulting precipitates were filtered off and the filtrate was evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (250 g) eluting with a mixture of chloroform and methanol (9:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-{2-(5-hydroxymethylimidazol-1-yl)ethyl}pyrrolidine (10.23 g).
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:47])[C@H:41]([CH2:43][CH:44]([CH3:46])[CH3:45])[NH2:42])[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:49]([O:51][CH3:52])=[O:50].C(N(CC)CC)C>ClCCl>[CH3:52][O:51][C:49](=[O:50])[NH:42][C@@H:41]([CH2:43][CH:44]([CH3:45])[CH3:46])[C:40](=[O:47])[NH:39][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([OH:38])[CH2:10][C@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29](=[O:30])[O:31][CH3:32]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(C)C)C(C)(C)C
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Yield: 58.5 %

Procedure:
A solution of Example 167B (11.2 mg, 0.017 mmol) in dichloromethane (0.25 mL) was treated with methyl chloroformate (2 μL, 0.026 mmol), and triethylamine (4.8 μL, 0.034 mmol) at 25° C. for 1 h. The solvents were evaporated, and the crude residue was purified by silica gel chromatography eluting with a gradient of dichloromethane, 100% ethyl acetate, and 95% ethyl acetate/7% methanol to give the title compound (7 mg, 57%). 1H NMR (300 MHz, CDCl3)δ ppm 0.87-0.84(s, 15H), 1.34-1.29(m, 2H), 1.65-1.51(m, 3H), 2.67-2.60(m, 2H), 2.86-2.83(d, J=7.72 Hz, 2H), 2.95-2.87(m, 1H), 3.52(s, 3H), 3.65(s, 3H), 3.78-3.73(m, 1H), 3.81(s, 1H), 4.08-4.03(m, 1H), 4.24-4.19(m, 1H), 4.33(m, 1H), 7.17-7.12(m, 1H), 7.26-7.20(m, H), 7.29-7.26(d, J=8.46 Hz, 2H), 7.35-7.30(m, 1H), 7.81-7.77(m, 3H), 7.90-7.84(m, 1H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O.C(OCC)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:11][CH:10]=1
Reactant: Oc1ccc(CCCCCCCBr)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: BrCCCCCCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
To a stirred solution of 9.1 (0.9 g, 3.32 mmol) in anhydrous acetone (40 mL), was added anhydrous K2CO3 (1.38 g, 10 mmol) and benzyl bromide (0.624 g, 3.65 mmol) and the mixture was refluxed for 6 h. The reaction mixture was cooled to room temperature, diluted with acetone and solid materials were filtered off. The filtrate was evaporated under reduced pressure and the residue obtained was dissolved in diethyl ether (50 mL). The ethereal solution was washed with water and brine, dried (MgSO4) and evaporated. Purification by flash column chromatography on silica gel (5% Et2O-hexane) afforded 10.1 (0.938 g, 78% yield) as a white solid (m p 32-34° C.).
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([OH:10])[CH2:2]1.[Br:12][CH2:13][C:14](O)=[O:15].O>C1(C)C=CC=CC=1>[Br:12][CH2:13][C:14]([O:10][CH:3]1[CH:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][CH:1]([CH3:11])[CH2:2]1)=[O:15]
Reactant: O=C(O)CBr
Reactant: CC1CCC(C(C)C)C(O)C1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CCC(C(C)C)C(OC(=O)CBr)C1

Procedure:
For the first stage, a solution of (−)-menthol (1.56 g, 10 mmol), 2-bromoacetic acid (1.39 g, 10 mmol) and monohydrated p-toluenesulphonic acid (0.5 g, 2.6 mmol) was brought to reflux for 3 h in 100 ml toluene. The water given off during the reaction is separated by azeotropic distillation. 100 ml toluene is added, and the mixture is washed 3 times with 10 ml of a 5% NaOH solution, then twice with 100 ml of brine, the organic solvent is dried on Na2SO4 and the solvent evaporated under vacuum. The menthyl 2-bromoacetate obtained (2.45 g, 89%) is used in the next step without purification.