Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]2=[O:30])[CH2:15][CH2:14]1>C(O)(C)C>[OH:12][CH:10]([CH2:9][O:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][N:6]=1)[CH2:11][N:13]1[CH2:14][CH2:15][CH:16]([N:19]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:20]2=[O:30])[CH2:17][CH2:18]1
Reactant: Clc1nccnc1OCC1CO1
Reactant: O=C1N(c2ccccc2)CCN1C1CCNCC1
Solvent: CC(C)O
Product: O=C1N(c2ccccc2)CCN1C1CCN(CC(O)COc2nccnc2Cl)CC1

Procedure:
7.27 g of 2-chloro-3-(2,3-epoxy-propoxy)-pyrazine and 7.35 g of 1-(4-piperidyl)-3-phenyl-2-imidazolidinone in 120 ml of isopropanol are stirred for 24 hours at approx. 20° C. The reaction mixture is then concentrated in a water jet vacuum. The residue crystallises from ether and yields 1-{1-[2-hydroxy-3-(3-chloro-pyrazin-2-yloxy)-propyl]-4-piperidinyl}-3-phenyl-imidazolidin-2-one with a melting point of 122°-124° C.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[CH2:16][NH:15][CH2:14][CH2:13][CH:12]=1)(=[O:10])[NH2:9].Cl[C:18]1[C:19]2[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]([C:30]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][C:31]=3[S:39][CH3:40])[C:20]=2[N:21]=[C:22]([CH3:24])[N:23]=1.C(=O)([O-])O.[Na+]>C(O)C>[C:8]([C:11]1[CH2:16][N:15]([C:18]2[C:19]3[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]([C:30]4[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[CH:32][C:31]=4[S:39][CH3:40])[C:20]=3[N:21]=[C:22]([CH3:24])[N:23]=2)[CH2:14][CH2:13][CH:12]=1)(=[O:10])[NH2:9]
Reactant: NC(=O)C1=CCCNC1
Reactant: CSc1cc(C(C)C)ccc1-n1c(C)c(C)c2c(Cl)nc(C)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CSc1cc(C(C)C)ccc1-n1c(C)c(C)c2c(N3CCC=C(C(N)=O)C3)nc(C)nc21
Yield: 26.7 %

Procedure:
In 4 ml of ethanol, 0.27 g of 5-carbamoyl-1,2,3,6-tetrahydropyridine trifluoroacetate and 0.36 g of 4-chloro-7-(4-isopropyl-2-methylthiophenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine were dissolved, and subsequently, 0.39 g of diisopiopylethylamine was added thereto. The reaction mixture was heated under reflux for 8.5 hours, and subsequently, a saturated aqueous solution of sodium hydrogencarbonate was poured therein to. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and was then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform—methanol=60:1), followed by crystallization from a mixed solvent of ethyl acetate-diethyl ether to yield 0.12 g of 4-(5-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)-7-(4-isopropyl-2-methylthiophenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][C:14]1[C:15]2[C@H:22]([CH3:23])[CH2:21][CH:20]([OH:24])[C:16]=2[N:17]=[CH:18][N:19]=1.CCN(CC)CC.[C:32]([O-:35])(O)=[O:33].[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:24][C@@H:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([Cl:13])[C:15]=3[C@H:22]([CH3:23])[CH2:21]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][C:14]1[C:15]2[C@H:22]([CH3:23])[CH2:21][C@H:20]([C:11]3[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=3[C:32]([O-:35])=[O:33])[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H]1CC(O)c2ncnc(Cl)c21
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(Cl)c21
Product: C[C@@H]1C[C@H](c2cc([N+](=O)[O-])ccc2C(=O)[O-])c2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %
Yield: 54 %

Procedure:
Solid 4-nitrobenzoyl chloride (6.73 g, 36.3 mmol) was added to a stirred solution of (5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol (6.09 g, 33.0 mmol) and NEt3 (5.98 mL, 42.9 mmol) in DCM (165 mL) at 0° C. The reaction was warmed to room temperature and then stirred at room temperature for 3 hours. The reaction was diluted with DCM and saturated aqueous NaHCO3. The combined extracts were washed with brine, dried MgSO4, filtered, and concentrated. The crude residue was chromatographed eluting with 10-14% EtOAc/hexane several times to give (5R,7S)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (3.96 g, 36%) and (5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl-4-nitrobenzoate (5.92 g, 54%).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.O>C(#N)C>[N:20]1([CH:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: COC(=O)C(Br)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: COC(=O)C(c1ccccc1)N1CCOCC1
Reaction time: 18 h

Procedure:
Methyl α-bromophenylacetate (3.79 g, 16.5 mmol) was dissolved in 50 mL of dry ACN, to which triethylamine (3.46 mL, 24.8 mmol) and morpholine (1.73 mL, 19.8 mmol) were added and the mixture was stirred for 18 hours. The mixture was poured into water, extracted twice with EtOAc. The combined organic extracts were dried with Na2SO4, filtered and concentrated in vacuo, providing methyl morpholin-4-yl(phenyl)acetate. ESI+MS: 236.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:14]([Cu])#[N:15].[C-]#N.[K+].C(Cl)(Cl)Cl>CN(C=O)C.CCOC(C)=O>[C:14]([C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2)#[N:15]
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cc(Br)c2[nH]ccc2c1
Agent: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])cc2cc[nH]c12
Yield: 78.8 %

Procedure:
A solution of 7-bromo-5-nitroindole (2.5 g, 10.4 mmol), CuCN (3.0 g, 33.3 mmol) and KCN (3.0 g, 46.1 mmol) in 20 mL of DMF was stirred at 120° C. for 24 h. The reaction mixture was diluted with 500 mL of EtOAc and washed with brine several times. Organic layer was dried over Na2SO4 and concentrated in vacuo, yielding a brown oily residue which was subjected to column chromatography (CHCl3, neat) to provide 1.5 g (8.2 mmol, 77%) of the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[CH2:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[N:11]1([C:14]2[CH:19]=[C:18]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[CH:26]2[CH2:27][C:28]([CH3:35])([CH3:34])[CH2:29][C:30]([CH3:32])([CH3:33])[CH2:31]2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC1(C)CC(c2ccc(N3CCOCC3)cc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC(c2ccc(N3CCOCC3)cc2N2CCNCC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
A mixture of 4-[5-morpholin-4-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (103 mg, 0.212 mmol) produced in Example (81d), trifluoroacetic acid (1 mL, 13.0 mmol) and dichloromethane (2 mL) was stirred for 1 hour at room temperature. Ethyl acetate and saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 42 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:18]([O-])=O)[CH:4]=1.[H][H]>CO.O=[Pt]=O>[NH2:18][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: [H][H]
Reactant: COCCOc1cc(C(=O)OC)c([N+](=O)[O-])cc1OC
Agent: O=[Pt]=O
Solvent: CO
Product: COCCOc1cc(C(=O)OC)c(N)cc1OC
Yield: 82.8 %

Procedure:
A solution of methyl 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate (3.39 g, 11.88 mmol) in methanol (40 mL) was hydrogenated at 50 psi hydrogen gas in the presence of PtO2 (0.050 g) using a Parr hydrogenator for 24 h. The reaction mixture was filtered and concentrated to give the title compound as an oil (2.51 g, 83%).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH2:19]([O:26][C:27]1[CH:31]=[C:30]([C:32](O)=[O:33])[O:29][N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[CH2:19]([O:26][C:27]1[CH:31]=[C:30]([C:32]([N:16]2[CH2:17][CH2:18][N:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:3]([CH3:6])([CH3:4])[CH3:5])[CH2:14][CH2:15]2)=[O:33])[O:29][N:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(O)c1cc(OCc2ccccc2)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2cc(OCc3ccccc3)no2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (2.1 g, 7.2 mmol), 3-(benzyloxy)isoxazole-5-carboxylic acid (1.58 g, 7.2 mmol), triethylamine (2.79 mL, 20.0 mmol), EDCI (1.92 g, 10.0 mmol) and HOBt (1.53 g, 10.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to purify the residue by NH-silica gel column chromatography (hexane/ethyl acetate 90:10 to 50:50). Solvent was removed to obtain a solid (2.2 g, 73%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:26])=[C:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=3[O:21][C:22]([F:25])([F:24])[F:23])[CH:16]=[O:17])[CH:11]=2)[C:6]([CH3:28])([CH3:27])[CH2:5][C:4]1=[O:29])[CH3:2].[CH3:30][Mg]Br.CCOCC.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.ClCCl>[C:16]([C:15]1[CH:18]=[CH:19][C:20]([O:21][C:22]([F:23])([F:24])[F:25])=[C:13]([C:10]2[CH:11]=[C:12]3[C:7]([C:6]([CH3:28])([CH3:27])[CH2:5][C:4](=[O:29])[N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[CH3:26])[CH:14]=1)(=[O:17])[CH3:30]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OC(F)(F)F)cc21
Reactant: C[Mg]Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C(C)=O)ccc3OC(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of Compound 2A (270 mg, 0.66 mmol) in 3 mL of dry THF was cooled to −78° C. and treated with a 3M solution of methyl magnesium bromide in ether (0.24 mL, 0.73 mmol). The reaction mixture was allowed to slowly warm to room temperature where it was quenched with 10 mL of a saturated ammonium chloride solution. The reaction mixture was then passed through a 10 mL SPE (solid phase extraction) column which was further washed with dichloromethane. The eluant was collected and stripped to give crude alcohol which was then dissolved in dichloromethane and treated with Dess-Martin reagent (336 mg, 0.79 mmol) and stirred at room temperature overnight. The reaction was quenched with 4 mL of saturated sodium thiosulfate solution and 4 mL of saturated sodium bicarbonate solution, the reaction mixture was stirred until clear. The reaction mixture was passed through another SPE and eluted with dichloromethane, removal of solvent yielded crude ketone which was purified with flash chromatography (25% EtOAc/hexane) to yield 207 mg (75%) of the desired product (Compound 19A) and a white solid. MS (electrospray): mass calculated for C23H24F3NO3, 419.17; m/z found 420.2 [M+H]+.
Reaction SMILES: N[C@H:2]1[CH2:7][C@@H:6]([NH:8][C:9](=[O:17])[O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C@@H:5]([N:18]2[CH2:22][CH2:21][C@H:20]([NH:23][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[C:19]2=[O:34])[CH2:4][CH2:3]1.C(C1C(=O)C(=[O:49])C=C(C(C)(C)C)C=1)(C)(C)C.C1COCC1.C(O)(=O)C(O)=O>CO.O>[CH2:27]([O:26][C:24]([NH:23][C@H:20]1[CH2:21][CH2:22][N:18]([C@H:5]2[CH2:4][CH2:3][C:2](=[O:49])[CH2:7][C@H:6]2[NH:8][C:9](=[O:17])[O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:16])[CH3:15])[C:19]1=[O:34])=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Reactant: C[Si](C)(C)CCOC(=O)N[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOC(=O)N[C@@H]1CC(=O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Yield: 53.5 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl (1R,2S,5R)-5-amino-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)cyclohexylcarbamate (1.03 g, 2.099 mmol) in methanol (10 ml) was added 3,5-di-tert-butyl-1,2-benzoquinone (0.555 g, 2.52 mmol). This mixture was stirred for 2 hr before THF (6 mL) and water (2 mL) were added along with oxalic acid to pH 4. This mixture was concentrated. The resulting residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried (MgSO4), filtered, and concentrated. This was purified via flash chromatography to give 2-(trimethylsilyl)ethyl (1R,2S)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-oxocyclohexylcarbamate (0.550 g, 1.123 mmol, 53.5% yield). LC/MS found [M+H]+=491.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH3:12])[C:5]#[N:6].[F:13][C:14]1[CH:15]=[C:16]([N:20]2[C:24]([CH2:25][C:26](O)=O)=[CH:23][CH:22]=[N:21]2)[CH:17]=[CH:18][CH:19]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1>[CH2:11]([N:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=[C:26]1[CH2:25][C:24]1[N:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=2)[N:21]=[CH:22][CH:23]=1)[CH3:12]
Reactant: CCNc1ccc(C#N)cc1N
Reactant: O=C(O)Cc1ccnn1-c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CCn1c(Cc2ccnn2-c2cccc(F)c2)nc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
To a stirring solution of 3-amino-4-ethylaminobenzonitrile (887 mg, 5.5 mmol) and 1-(3-Fluorophenyl)-5-carboxymethylpyrazole (1.10 g, 5 mmol) in pyridine (5 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.15 g, 6 mmol). The mixture is stirred at room temperature for 17.5 h, then concentrated. The residue is cooled in an ice bath, aqueous HCl is added with stirring, the precipitate is collected by filtration, rinsed well with water and dried. The solid is added to acetic acid (75 mL) and heated at reflux for 5.5 h. The mixture is cooled, concentrated, and purified by silica gel chromatography to give 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-cyano-1H-benzimidazole. The product is converted to the mesylate salt in acetone. 1H NMR (CDCl3): δ 8.17 (s, 1H), 7.89 (d, J=8.52 Hz, 1H), 7.68-7.75 (m 1H), 7.44-7.54 (m, 2H), 7.37-7.40 (m, 1H), 7.21-7.28 (m, 1H), 6.35 (d, J=1.65 Hz, 1H), 4.65 (8, 2H), 4.29 (q, J=7.14 Hz, 2H), 2.34 (s, 3H), 1.19 (t, J=7.14 Hz, 3H). LCMS 346.0 (MH+), 344.4 (MH−)
Reaction SMILES: O1CCCC1.[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=O.[CH2:16]([NH2:19])[CH2:17][CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]1[NH:19][CH2:16][CH2:17][CH3:18]
Reactant: CCCN
Reactant: O=C1Cc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCNC1Cc2ccccc2C1
Yield: 67.6 %

Procedure:
A tetrahydrofuran (150 mL) solution of 2-indanone (11.0 g, 92 mmol), propyl amine (12 mL, 146 mmol), sodium triacetoxy borohydride (35.0 g, 165 mmol), and acetic acid (5 mL) was stirred at ambient temperature for 1 hour. The solution was then heated at reflux temperature for 2 hours. After cooling, the solvent was evaporated and the residue taken up in concentrated hydrochloric acid (40 mL). The acidic solution was washed with diethyl ether and then basified (10M sodium hydroxide). Extraction of the aqueous layer with ether, drying over anhydrous sodium carbonate and removal of the solvent yielded 10.9 g of the title compound as a yellow oil (75%).:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]1[CH:46]=[CH:45][C:29]2[NH:30][C:31]([C@@H:33]3[CH2:37][CH2:36][CH2:35][N:34]3[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[N:32][C:28]=2[CH:27]=1.O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH2:25][C:26]2[CH:46]=[CH:45][C:29]3[NH:30][C:31]([C@@H:33]4[CH2:37][CH2:36][CH2:35][N:34]4[C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])=[N:32][C:28]=3[CH:27]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:16][CH:17]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CBr)ccc2[nH]1
Reactant: O=[N+]([O-])c1ccc(CNc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CN(Cc3ccc([N+](=O)[O-])cc3)c3ccccc3)ccc2[nH]1
Reaction time: 2.5 h
Yield: 28.6 %

Procedure:
The product from Example 20A (0.530 g, 2.32 mmol) and K2CO3 (0.802 g, 5.81 mmol) were combined in dry DMF (20 mL) at room temperature, and nitrogen was bubbled through the solution for 10 min. The product from Example 7C (1.0 g, 2.63 mmol) was added in three equal portions in 20 min. intervals, and the reaction was stirred a total of 2.5 h. The mixture was poured into water, extracted into EtOAc, washed with brine. The organic was dried (MgSO4), filtered and evaporated. The product was purified by chromatography on silica gel, eluting with c 0-4% MeOH in CH2Cl2, and a second column eluting with 0-5% EtOAc in CH2Cl2 to give the title compound (0.350 g, 28.6% yield).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[N:14]=2)=[CH:6][CH:5]=1>C(O)(=O)C>[Br:1][C:12]1[S:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)=[N:14][C:13]=1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: BrBr
Reactant: O=C(O)Cc1csc(-c2ccc(Cl)cc2)n1
Solvent: CC(=O)O
Product: O=C(O)Cc1nc(-c2ccc(Cl)cc2)sc1Br
Temperature: 0 °C
Yield: 75.2 %

Procedure:
Bromine (15.9 g, 5.15 ml, 0.1 mol) was added dropwise to 2-(4-chlorophenyl) thiazol-4-yl acetic acid (24 g, 0.096mol) suspended in glacial acetic acid (200 ml) and the resulting mixture was heated at 60°-70° C. for 5 hours. The reaction mixture was cooled to 0° C. (ice bath) and the solid which separated was filtered and washed with CHCl3. The residue was then washed with cold ethanol to afford the desired product (24 g, 75%)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)=[CH:15]2)[CH3:9].C(=O)([O-])[OH:25].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].[OH2:36]>C(#N)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7]([CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)=[CH:15]2)[CH3:9])(=[O:25])=[O:36]
Reactant: O
Reactant: O=C([O-])O
Reactant: CC(Sc1nccn1C)c1cccc2cc(-c3nccs3)[nH]c12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CC(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1nccn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
To a mixed solution of 7-{1-[(1-methyl-1H-imidazol-2-yl)thio]ethyl}-2-(1,3-thiazol-2-yl)-1H-indole (0.089 g) in acetonitrile (5 mL) and water (5 mL) was added sodium carbonate-1.5 hydrogen peroxide complex (0.530 g), and the mixture was stirred at room temperature for 4 hr. Saturated aqueous sodium hydrogencarbonate solution and 1N aqueous sodium thiosulfate solution were added, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50-100:0) to give the title compound (0.077 g, yield 64%) as colorless crystals.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][C:41](=[O:49])[NH:42][C:43]([C:46]([OH:48])=O)([CH3:45])[CH3:44])=[CH:33][C:32]=2[CH3:50])=[C:28]([CH:51]([CH3:53])[CH3:52])[NH:27][N:26]=1)(=O)C.[OH:54][CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1.NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][C:41](=[O:49])[NH:42][C:43]([C:46]([N:60]4[CH2:61][CH2:62][N:57]([CH2:56][CH2:55][OH:54])[CH2:58][CH2:59]4)=[O:48])([CH3:44])[CH3:45])=[CH:33][C:32]=3[CH3:50])=[C:28]([CH:51]([CH3:52])[CH3:53])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCC(=O)NC(C)(C)C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: OCCN1CCNCC1
Agent: CC(C)(N)C(N)=O
Product: Cc1cc(OCCCC(=O)NC(C)(C)C(=O)N2CCN(CCO)CC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9](O)=[O:10])=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([CH3:19])[C:13]1=[O:20].CC1C(=O)NC(=O)C=1C.S(Cl)([Cl:32])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([Cl:32])=[O:10])=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([CH3:19])[C:13]1=[O:20]
Reactant: CC1=C(C)C(=O)N(c2cc(C(=O)O)c(Cl)cc2F)C1=O
Reactant: O=S(Cl)Cl
Agent: CC1=C(C)C(=O)NC1=O
Solvent: Cc1ccccc1
Product: CC1=C(C)C(=O)N(c2cc(C(=O)Cl)c(Cl)cc2F)C1=O

Procedure:
A mixture of 6 g of N-(2-fluoro-5-carboxy-4-chlorophenyl)-2,3-dimethylmaleic acid imide, 0.5 ml of dimethylmaleinimide, 2 ml of thionyl chloride and 50 ml of toluene is heated under reflux for 4 hours. After cooling, the whole is concentrated by evaporation in vacuo. 6 g of N-(2-fluoro-5-chlorocarbonyl-4-chlorophenyl)-2,3-dimethylmaleic acid imide having a melting point of 123°-124° are obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])=[N:2]1.Cl[S:14]([N:17]=[C:18]=[O:19])(=[O:16])=[O:15]>C1(C)C=CC=CC=1>[N:17]([S:14]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:3]1[CH:4]=[CH:5][O:1][N:2]=1)(=[O:16])=[O:15])=[C:18]=[O:19]
Reactant: Oc1ccccc1-c1ccon1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: O=C=NS(=O)(=O)Oc1ccccc1-c1ccon1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution containing 30 g of 2-(isoxazol-3-yl)phenol [prepared by the procedure of R. Beugelmans and C. Morin, J. Org. Chem., 42, 1356 (1977)] in 200 ml of dry toluene was added slowly 26.3 g of chlorosulfonyl isocyanate while maintaining the temperature at 20° to 30° C. with external cooling. The resulting suspension containing a white solid was stirred at 25° C. for 1 hour, then heated at 100° to 110° C. for 1 hour. The resulting slightly cloudy solution was cooled to 25° C., filtered, and the filtrate was concentrated in vacuo to yield 45 g of the title compound as a crude oil. The IR spectrum showed an isocyanate absorption at 2220 cm-1.