Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.[O:21]1[CH:26]2[CH:22]1[CH2:23][O:24][CH2:25]2.C(N(CC)CC)C>ClCCl>[OH:21][C@@H:22]1[CH2:23][O:24][CH2:25][C@H:26]1[O:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: C1OCC2OC12
Reactant: O=C(OCc1ccccc1)N1CCC(OCCO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(OCCO[C@@H]2COC[C@H]2O)CC1
Reaction time: 16 h
Yield: 48.8 %

Procedure:
Benzyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (6.70 g, 24.0 mmol) produced in Reference Example 1 (1b) and 3,4-epoxytetrahydrofuran (1.03 g, 12.0 mmol) were dissolved in dichloromethane (5.0 mL). To the resulting mixture, a boron trifluoride diethyl ether complex (0.34 g, 2.4 mmol) was added at room temperature, followed by stirring for 16 hours. More boron trifluoride diethyl ether complex (0.34 g, 2.4 mmol) was added, followed by further stirring for two hours. Triethylamine (1.82 g, 18.0 mmol) was then added, and the resulting reaction liquid was directly purified by basic silica gel column chromatography (hexane:ethyl acetate, 100:0-0:100, ethyl acetate:methanol, 100:0-95:5, V/V) to give the desired title compound (2.14 g, yield 49%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].[H-].[Na+].CS(O[CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=O)=O.O>CN(C=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:10]([C:12]2[CH:13]=[CH:14][N:15]([CH2:24][CH2:25][NH:26][C:27](=[O:28])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[N:16]=2)=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])#[N:7]
Reactant: N#Cc1ccc(-c2ccn[nH]2)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1ccc(-c2ccc(C#N)c([N+](=O)[O-])c2)n1

Procedure:
2-Nitro-4-(1H-pyrazol-5-yl)benzonitrile (1.0 g), DMF (10 ml) and sodium hydride (60% in oil, 0.24 g) were stirred for 30 min at RT. 2-(tert-Butoxycarbonyl-amino)ethyl methanesulfonate (1.45 g) in DMF (3.3 ml) was added and the mixture was microwaved for 30 min at 160° C. (Biotage Initiator Sixty operating at 2.45 GHz). After pouring the mixture to water, it was extracted with EtOAc. Combined organic phases were washed with water and brine, dried with Na2SO4 and evaporated. The product was triturated with IPA and filtered. Yield 0.92 g. 1H-NMR (400 MHz; d6-DMSO): δ 1.35 (s, 9H), 3.38 (m, 2H), 4.24 (t, 2H), 6.92 (m, 1H), 7.06 (d, 1H), 7.85 (d, 1H), 8.19 (d, 1H), 8.33 (dd, 1H), 8.70 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C(O)C>[CH:11]1([C:9]2[N:10]=[C:6]3[N:5]=[C:4]([CH3:14])[CH:3]=[C:2]([NH:21][C:20]4[CH:22]=[CH:23][C:17]([C:16]([F:15])([F:24])[F:25])=[CH:18][CH:19]=4)[N:7]3[N:8]=2)[CH2:13][CH2:12]1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Cl)n2nc(C3CC3)nc2n1
Solvent: CCO
Product: Cc1cc(Nc2ccc(C(F)(F)F)cc2)n2nc(C3CC3)nc2n1

Procedure:
To a suspension of Intermediate 20 (0.04 g, 0.192 mmol) in ethanol (2.5 mL), 4-(trifluoromethyl)aniline (ALDRICH, 0.031 g, 0.192 mmol) was added and the mixture was stirred under reflux for 2 h. Solvent was removed in vacuo and the crude mixture was purified by preparative HPLC (SunFire 19×150 mm, H2O 0.1% TFA-ACN 0.1% TFA gradient from 10 to 100%) to yield a beige solid which was further purified by preparative HPLC (SunFire 19×150 mm, H2O 0.1% TFA-ACN 0.1% TFA gradient from 30 to 100%) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].[CH:18]1([NH:24][C:25]([CH:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH3:28])=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:32]1[CH2:33][CH2:34][N:29]([CH:27]([C:25]([NH:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:26])[CH3:28])[CH2:30][CH2:31]1)=[O:9]
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Reactant: CC(C(=O)NC1CCCCC1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(C=CC(=O)N2CCN(C(C)C(=O)NC3CCCCC3)CC2)cc(OC)c1OC
Reaction time: 0.33 h

Procedure:
0.64 g of 3,4,5-trimethoxycinnamoyl chloride is added to a solution of 0.50 g of 1-[1-(cyclohexylaminocarbonyl)ethyl]piperazine and 0.27 g of triethylamine in 15 ml of chloroform, and the resulting solution is kept standing at room temperature for 20 minutes.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])[CH2:6]1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[SH:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])[CH2:6]1
Reactant: CC(=O)S[C@H]1C[C@@H](CN2CCNC2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NCCN1C[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (1.22 g) in methanol (20 ml) was added 28% sodium methoxide in methanol solution (0.61 ml) on ice-bath under atmospheric pressure of nitrogen and the mixture was stirred at the same condition for 30 minutes. To a reaction mixture was added acetic acid (0.17 ml) and evaporated in vacuo. The resulting residue was dissolved in ethyl acetate (50 ml) and the solution was washed twice with saturated aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 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 (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (0.76 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([O:14][C:15](=[O:23])[CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[CH3:13]>O>[CH2:12]([O:14][C:15](=[O:23])[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:19][CH2:18]1)[CH3:13]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: CCOC(=O)CC1CCNCC1
Solvent: O
Product: CCOC(=O)CC1CCN(c2ccc(Cl)cc2[N+](=O)[O-])CC1
Temperature: 105 °C
Yield: 94.4 %

Procedure:
A mixture of 0.500 g (2.60 mmol) of 2,5-dichloronitrobenzene and 1.0 mL (mmol) of 2-(piperdin-4-yl)-acetic acid ethyl ester is heated overnight at 105° C. The mixture is cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic phase is washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.803 g (94.4%) of [1-(4-chloro-2-nitro-phenyl)-piperidin-4-yl]-acetic acid ethyl ester as a red oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[C:6]([CH:11]=[O:12])=[CH:7]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1c[nH]c2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cn(Cc2ccccc2)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
6-Bromo-1H-indole-3-carbaldehyde (1 eq.) from the previous step was dissolved in DMF (0.19 M). Sodium hydride was added (1.5 eq.) and the resulting solution was stirred at RT for 20 min. Benzyl bromide (1 eq.) was then added and the reaction solution was allowed to stir at RT for 24 h. The reaction mixture was subsequently quenched with water and extracted with EtOAc. The combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 4:1 (v/v) Hex:EtOAc 3:7 (v/v) Hex:EtOAc) afforded the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH3:31])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([S:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([N+:28]([O-])=O)[CH:21]=1)[N:6]=2)[CH3:2]>ClCCl.CO.[Pd]>[NH2:28][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[CH2:19][S:18][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[C:3]([CH2:1][CH3:2])[N:4]2[CH3:31])=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=1
Reactant: CCc1nc2c(N3CCOCC3)nc(SCc3ccc(OC)c([N+](=O)[O-])c3)nc2n1C
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCc1nc2c(N3CCOCC3)nc(SCc3ccc(OC)c(N)c3)nc2n1C
Reaction time: 18 h
Yield: 71.6 %

Procedure:
8-ethyl-9-methyl-6-morpholino-2-(3-nitro-4-methoxybenzylsulfanyl)-9H-purine (4.10 g, 9.23 mmol) was dissolved in dichloromethane (50 ml) and methanol (50 ml), 1.0 g of Pd/C was added and catalytic hydrogenation was performed under normal pressure for 18 hours. Celite was used to filter off Pd/C, and the filtrate was distilled away under reduced pressure. Ether was added to the residue and the precipitated crystals were collected by filtration to obtain 2.74 g (72% yield) of 2-(3-amino-4-methoxybenzylsulfanyl)-8-ethyl-9-methyl-6-morpholino-9H-purine.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][C@H:4]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1)[C:5]([OH:7])=O.[CH2:19]([CH2:21][NH2:22])[OH:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[OH:20][CH2:19][CH2:21][NH:22][C:5]([C@@H:4]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1)[CH2:3][CH:2]([CH3:1])[CH3:18])=[O:7]
Reactant: NCCO
Reactant: Cc1cccc(C(=O)N[C@@H](CC(C)C)C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cccc(C(=O)N[C@@H](CC(C)C)C(=O)NCCO)c1
Reaction time: 2 h
Yield: 29.9 %

Procedure:
(S)-4-Methyl-2-(3-methyl-benzoylamino)-pentanoic acid (1 g. 4.0 mmol), ethanolamine (270 mg, 4.4 mmol) and HOBt (596 mg, 4.4 mmol) were treated with DCM (20 mL) followed by EDCI (845 mg, 4.4 mmol). The reaction was allowed to stir for 2 h and then purified directly by silica gel column chromatography using ethyl acetate and hexane to afford the product (350 mg, 30%) as a solid: 1H NMR (CDCl3, 400 MHz) δ 0.89-0.99 (m, 6H), 1.67-1.79 (m, 3H), 2.37 (s, 3H), 3.31-3.41 (m, 1H), 3.42-3.52 (m, 1H), 3.61 (dd, 1H, J1=2.7, J2=8.1), 7.24-7.34 (m, 2H), 7.43 (dd, 1H, J1=J2=5.3), 7.57-7.63 (m, 2H); HPLC-MS calcd. for C16H24N2O3 (M+H+) 292.18, found 292.2.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:24][C:25]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][NH:27][N:26]=1>>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:29]2[C:25]([CH3:24])=[N:26][NH:27][CH:28]=2)[N:7]=3)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1n[nH]cc1-c1ccc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)sc2n1
Yield: 11 %

Procedure:
The titled compound (yield=11%, white solid) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 1D (Example 1) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6H) 2.58 (s, 3H) 7.66 (d, J=8.59 Hz, 2H) 7.74 (d, J=8.59 Hz, 1H) 8.09 (d, J=8.59 Hz, 4H) 12.86 (s, 1H); ESI-MS: m/z 394.0 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[CH2:28]([O:35][C:36](=[O:42])[C@H:37]1[CH2:41][CH2:40][CH2:39][NH:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[N:20]1([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([N:38]1[CH2:39][CH2:40][CH2:41][C@@H:37]1[C:36]([O:35][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:42])=[O:24]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
5.75 g (30.0 mmol) of EDCl was added to 60 ml of tetrahydrofuran (THF) solution of 3.23 g (15.0 mmol) of N-Boc-L-Proline (manufactured by Tokyo Chemical Industry Co., Ltd) and 3.08 g (15.0 mmol) of D-Proline benzylester, followed by stirring for 18 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed sequentially with a diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water (one time for each), it was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1 (volume ratio)), thereby obtaining 4.55 g of the product with a yield of 75.4%.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[C:12]1([C@@H:18]2[O:9][C@H:19]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)Cc1ccccc1C=Cc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)Cc1ccccc1[C@@H]1O[C@H]1c1ccccc1
Yield: 48.6 %

Procedure:
7.8 g of m-chloroperbenzoic acid (about 50% pure) are added to a solution of 6 g of methyl 2-(2-phenylethenyl)phenylacetate (E/Z=3:1) in 50 ml of methylene chloride. The reaction mixture is refluxed for 12 hours and then the precipitate is filtered off with suction and the filtrate is washed twice with saturated sodium bicarbonate solution and water. The isolated organic phase is dried over sodium sulfate and concentrated, and the residue is recrystallized from methyl tert-butyl ether. 3.1 g (48%) of methyl trans-2-(3-phenyl-2-oxiranyl)phenylacetate are obtained of melting point 118°-119° C. Chromatography of the mother liquor on silica gel (6:1 ethyl acetate/n-hexane) yields 2.8 g (44%) of methyl 2-(3-phenyl-2-oxiranyl)phenylacetate as a 1:1 cis/trans mixture.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[CH:4][C:3]=1[CH:16]=O.[NH2:18][C:19]1[CH:20]=[C:21]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[NH2:25].OS([O-])=O.[Na+]>CC(N(C)C)=O>[NH2:1][C:2]1[C:3]([C:16]2[NH:18][C:19]3[CH:20]=[C:21]([S:26]([NH2:29])(=[O:27])=[O:28])[CH:22]=[CH:23][C:24]=3[N:25]=2)=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][CH:13]=[C:10]([C:11]#[N:12])[CH:9]=2)=[CH:6][N:7]=1
Reactant: N#Cc1cccc(-c2cnc(N)c(C=O)c2)c1
Reactant: Nc1ccc(S(N)(=O)=O)cc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: N#Cc1cccc(-c2cnc(N)c(-c3nc4ccc(S(N)(=O)=O)cc4[nH]3)c2)c1
Temperature: 200 °C
Yield: 43.6 %

Procedure:
3-(6-amino-5-formylpyridin-3-yl)benzonitrile (0.06 g, 0.27 mmol), 3,4-diaminobenzene-1-sulphonamide (0.050 g, 0.27 mmol), and NaHSO3 (0.029, 0.40 mmol) were combined in 2 mL of dimethylacetamide and heated to 200° C. in the SmithSynthesizer™ microwave instrument for 10 minutes. Upon cooling, the solvent was removed and the residue was chromatographed on silica gel eluting with hexanes/ethyl acetate (0 to 100% EtOAc over 10 minutes) to afford 2-[2-amino-5-(3-cyanophenyl)pyridin-3-yl]-1H-benzimidazole-6-sulfonamide (0.046 g) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.CCN(CC)CC.[C:23]1([CH3:35])[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:24]=1[S:31](Cl)(=[O:33])=[O:32]>C(Cl)(Cl)Cl>[CH:4]1[C:3]2[C:8](=[N:9][C:10]3[C:15]([C:2]=2[NH:1][S:31]([C:24]2[C:25]([CH3:30])=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=2[CH3:35])(=[O:33])=[O:32])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Nc1c2ccccc2nc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(S(=O)(=O)Nc2c3ccccc3nc3ccccc23)c(C)c1
Yield: 5.9 %

Procedure:
To a suspension of 4.00 g (20.6 mmol) of 9-aminoacridine 40 in 350 mL of CHCl3 was added 2.9 mL (20.8 mmol) of Et3N and 4.50 g (20.6 mmol) of mesitylenesulfonyl chloride. The reaction mixture was refluxed for 72 hr. Then the reaction mixture was filtered and the solvent was evaporated. The material was purified by column chromatography on silica gel by eluting first with 1% MeOH in CH2Cl2 and then with 5% MeOH in CH2Cl2 to yield 458.4 mg (6%) of sulfonamide 41 as an orange solid: 1H NMR (300 MHz, CDCl3, TMS) δ 9.25 (s, 1H), 8.77 (d, J=8 Hz, 2H), 7.46 (t, J=8 Hz, 2H), 7.21 (d, J=8 Hz, 2H), 7.15 (t, J=8 Hz, 2H), 7.02 (s, 2H), 2.78 (s, 6H), 2.36 (s, 3H).
Reaction SMILES: [O-]CC.[K+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[N:17]=1>C(OCC)C.C(O)C>[CH2:13]([O:12][C:5](=[O:11])[C:6](=[O:8])[CH2:25][C:18]1[N:17]=[C:16]([Cl:15])[CH:21]=[CH:20][C:19]=1[N+:22]([O-:24])=[O:23])[CH3:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of potassium ethoxide (134 mg, 1.59 mmol) in diethyl ether (5 mL) and ethanol (1 mL) was added diethyl oxalate (218 μL, 1.59 mmol) in one portion and the resulting solution was stirred for 30 min at rt. 2-Chloro-6-methyl-5-nitropyridine (Preparation 2, 250 mg, 1.45 mmol) was added as a suspension in diethyl ether (2 mL) and stirring was continued for 17 h at rt. The mixture was filtered on a sinter, washing with cold diethyl ether. The collected precipitate was dissolved in glacial acetic acid then evaporated to dryness in vacuo to give the title compound. δH (CDCl3): 1.40 (3H, t), 4.38 (2H, q), 7.33 (1H, d), 7.37 (1H, s), 8.40 (1H, d).
Reaction SMILES: Br[C:2]1[C:3]([CH:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:9][CH3:10])=[N:4][CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[H][H]>CO.[C].[Pd]>[N:6]1[CH:7]=[CH:2][C:3]([CH:8]([N:11]2[C:12](=[O:21])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]2=[O:20])[CH2:9][CH3:10])=[N:4][CH:5]=1
Reactant: [H][H]
Reactant: CCC(c1ncncc1Br)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC(c1ccncn1)N1C(=O)c2ccccc2C1=O
Yield: 66.6 %

Procedure:
2-[1-(5-Bromopyrimidin-4-yl)propyl]isoindoline-1,3-dione (568 mg, 1.64 mmol), triethylamine (0.228 mL, 1.64 mmol) and 10% palladium-carbon (50 wt %, 100 mg) were stirred in methanol (10 mL) in a hydrogen atmosphere at room temperature for 1 day. The reaction solution was filtered through celite and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) give the desired product (292 mg, 66% yield).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(Cl)Cl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(O)(=O)C>[CH3:14][C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[CH:2]=[O:1])=[O:9])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O

Procedure:
In accordance with Scheme I, N-α-t-BOC-D-proline 2a is reacted in an ether solvent such as tetrahydrofuran at a temperature ranging from -2° C. to the reflux temperature of the solvent with 10M borane-methyl sulfide complex to produce (R)-2-(hydroxymethyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 3a. Compound 3a in a chlorinated hydrocarbon solvent such as methylene chloride is treated with an oxidizing agent such as pyridinium chlorochromate, 4Å molecular sieves and glacial acetic acid to give (R)-2-formyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester 4a. Compound 4a in methylene chloride is treated with a methylene chloride solution of triphenylphosphine and carbon tetrabromide to produce (R)-2-(2,2-dibromoethenyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 5a. The dibromo compound 5a in an ether solvent such as tetrahydrofuran is reacted at -78° C. with an alkyl lithium reagent such as sec-butyllithium to give (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 6a.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:25][CH2:24][C:19]4([O:23][CH2:22][CH2:21][O:20]4)[CH2:18][CH2:17]3)[CH2:12][CH:11]=2)=[C:6]([F:26])[C:5]=1[F:27])[CH3:2].C([OH:30])C.[OH-].[Na+].OO>C1COCC1.O>[O:23]1[C:19]2([CH2:24][CH2:25][CH:16]([CH:13]3[CH2:14][CH:15]([OH:30])[CH:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([F:27])[C:6]=4[F:26])[CH2:11][CH2:12]3)[CH2:17][CH2:18]2)[O:20][CH2:21][CH2:22]1
Reactant: CCOc1ccc(C2=CCC(C3CCC4(CC3)OCCO4)CC2)c(F)c1F
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(C2CCC(C3CCC4(CC3)OCCO4)CC2O)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
550 ml (0.55 mol) of borane/THF complex (1 M solution) are added at −5° C. to a solution of 154.0 g (0.41 mol) of 8-[4-(4-ethoxy-2,3-difluorophenyl)-cyclohex-3-enyl]-1,4-dioxaspiro[4.5]decane in 1500 ml of THF, and the reaction mixture is stirred at room temperature for 3 h. 99 ml (1.7 mol) of ethanol, 250 ml (1.0 mol) of aqueous sodium hydroxide solution (16%) and 140 ml (1.6 mol) of aqueous hydrogen peroxide soln. (35%) are added successively to the batch, during which the internal temperature does not exceed 46° C. (ice bath). When the addition is complete, the mixture is refluxed for 2 h, and the solution is cooled, added to water and stirred vigorously. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product is purified by column chromatography (SiO2, toluene:ethyl acetate=8:2), giving 5-(1,4-dioxaspiro[4.5]dec-8-yl)-2-(4-ethoxy-2,3-difluorophenyl)cyclohexanol as colourless, viscous oil.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=[O:14])[CH:3]=1.[C:16](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:16][O:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=[O:14])[CH:3]=1
Reactant: O=C(O)c1cc(O)n(-c2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C(=O)O)nn1-c1ccccc1
Reaction time: 8 h
Yield: 38 %

Procedure:
600 mg (2.94 mmol) of 5-hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid were dissolved in 30 ml of DMF, 1.92 (5.9 mmol) of cesium carbonate and 1.04 g (7.35 mmol) of iodomethane were added, and the resulting mixture was heated for 4 h to 80° C. The mixture was filtrated and the solvent removed in vacuo. The residue was dissolved in 20 ml of MOH and 5.9 ml of an aqueous 1 M solution of sodium hydroxide. After stirring overnight the reaction was complete. The solvent was removed and the residue subjected to preparative HPLC to give the title compound in a yield of 38%.