Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:21]([CH3:29])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([O:41][CH2:42][CH3:43])=[CH:33][N:32]=1.CC([O-])(C)C.[K+]>CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([C@H:21]([CH3:29])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:10]([N:12]1[CH2:16][C@H:15]([O:17][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]([O:41][CH2:42][CH3:43])=[CH:33][N:32]=2)[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CCOc1cnc(Cl)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc2ncc(OCC)c3ccccc23)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.2 %

Procedure:
To a solution of (2S,4R)-1-((3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (700 mg, 1.6 mmole) in DMSO was added 1-chloro-4-ethoxyisoquinoline (420 mg, 2.0 mmole), prepared above, followed by t-BuOK (1M sol. in THF, 8 mL, 8 mmole) at room temperature under nitrogen atmosphere. The reaction mass was stirred at room temperature for 4 h. The reaction mass was quenched with aqueous citric acid solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound. The crude compound was purified by combiflash to get desired product (2S,4R)-1-((3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-((4-ethoxyisoquinolin-1-yl)oxy)pyrrolidine-2-carboxylic acid (600 mg, 64%) as off-white solid. MS: MS m/z 585.1 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]([C:32](=[O:56])[NH:33][CH2:34][C:35](=[O:55])[NH:36][CH2:37][C@@H:38]([C:50]([O:52][CH2:53][CH3:54])=[O:51])[NH:39]C(=O)OCC2C=CC=CC=2)[CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.NC[C@H](N[S:67]([CH2:70][C:71]12[C:77]([CH3:79])([CH3:78])[CH:74]([CH2:75][CH2:76]1)[CH2:73][C:72]2=[O:80])(=[O:69])=[O:68])C(OCC)=O.C(OC(N1CCC(CCC(CCC2CCN(C(OC(C)(C)C)=O)CC2)C(NCC(O)=O)=O)CC1)=O)(C)(C)C>>[C:28]([O:27][C:25]([N:22]1[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17][CH:16]([C:32](=[O:56])[NH:33][CH2:34][C:35](=[O:55])[NH:36][CH2:37][C@@H:38]([C:50]([O:52][CH2:53][CH3:54])=[O:51])[NH:39][S:67](=[O:68])(=[O:69])[CH2:70][C:71]23[C:77]([CH3:79])([CH3:78])[CH:74]([CH2:75][CH2:76]2)[CH2:73][C:72]3=[O:80])[CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[CH2:24][CH2:23]1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCOC(=O)[C@H](CN)NS(=O)(=O)CC12CCC(CC1=O)C2(C)C
Reactant: CCOC(=O)[C@H](CNC(=O)CNC(=O)C(CCC1CCN(C(=O)OC(C)(C)C)CC1)CCC1CCN(C(=O)OC(C)(C)C)CC1)NC(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC(CCC(CCC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)NCC(=O)O)CC1
Agent: Cl
Product: CCOC(=O)[C@H](CNC(=O)CNC(=O)C(CCC1CCN(C(=O)OC(C)(C)C)CC1)CCC1CCN(C(=O)OC(C)(C)C)CC1)NS(=O)(=O)CC12CCC(CC1=O)C2(C)C

Procedure:
According to the procedure described for compound 29, starting with ethyl (2S)-3-amino-2-({[(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methyl]sulphonyl}amino)propanoate hydrochloride and compound 4.
Reaction SMILES: [CH:1]([C@H:4]1[C:17](=[O:18])[N:7]2[C@@H](C3C=CC=CC=3)[O:9][CH2:10][C@@H:6]2[CH2:5]1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[OH:9][CH2:10][C@H:6]1[NH:7][C:17](=[O:18])[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:5]1
Reactant: CC(C)[C@@H]1C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H]1C[C@@H](CO)NC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 16.5 g of (3R,6S,7aS)-6-isopropyl-3-phenyltetrahydro-pyrrolo[1,2-c]oxazol-5-one in 175 mL of dichloromethane is treated with 15.35 g of trifluoroacetic acid at room temperature. The resulting solution is stirred for 24 hours at room temperature and a further 14 g of trifluoroacetic acid added. Stirring is continued for a further 24 hours and the solvent removed in vacuum. The residue is treated with 50 mL of water and 100 mL of dichloromethane and the pH of the two-phase mixture adjusted to 12 with concentrated sodium hydroxide solution. Solid sodium chloride is added and the mixture stirred. The organic layer is removed under reduced pressure to give (3S,5S)-5-hydroxymethyl-3-isopropyl-pyrrolidin-2-one as a semi-solid. mp. 55.9° C., [α]D=+47.9° (1% in MeOH)
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:6][CH2:7][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH2:10])[CH:4]=[CH2:5].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[C:26]([O:1][CH2:2][CH:3]([O:6][CH2:7][C@@H:8]([NH:11][C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18])[CH:9]=[CH2:10])[CH:4]=[CH2:5])(=[O:28])[CH3:27]
Reactant: C=CC(CO)OC[C@H](C=C)NC(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(COC(C)=O)OC[C@H](C=C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a mixture of tert-butyl [(1S)-1-({[1-(hydroxymethyl)prop-2-en-1-yl]oxy}methyl)prop-2-en-1-yl]carbamate (268 mg, 1.04 mmol) in methylene chloride (10 mL) was added with triethylamine (435 μL, 3.12 mmol). The mixture was cooled to 0° C., and acetyl chloride (150 μL, 2.1 mmol) was added drop wise. The reaction was stirred at room temperature for 2 h, then quenched with water. The organic layer was concentrated and the resultant residue purified on silica gel (eluting with 20% ethyl acetate/hexanes) to give the desired product (0.26 g, 85%). LCMS calculated for C10H18NO3 (M−100+H)+: m/z=200.1. Found: 200.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[N:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:14]2=[CH:13][C:12]=1[C:20]([OH:22])=O.[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:23]([O:25][CH2:26][CH2:27][O:28][NH:29][C:20]([C:12]1[CH:13]=[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]2[C:11]=1[NH:10][C:3]1[CH:4]=[CH:5][C:6]([S:8][CH3:9])=[CH:7][C:2]=1[F:1])=[O:22])=[CH2:24]
Reactant: CSc1ccc(Nc2c(C(=O)O)cc3ccncn23)c(F)c1
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1cc2ccncn2c1Nc1ccc(SC)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
7-(2-Fluoro-4-methylsulfanyl-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (200 mg, 0.63 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (106 mg, 0.69 mmol), HOBt (94 mg, 0.69 mmol), EDCI hydrochloride (132 mg, 0.69 mmol) and DIPEA (118 μL, 0.69 mmol) were dissolved in DMF (5 mL). The reaction was stirred at room temperature for 16 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethylacetate in cyclohexane) to yield the title compound as a brown solid (139 mg, 55%). LCMS (Method B): RT=3.35 min, M+H+=403.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]1(C)C=CC(S(O)(=O)=O)=C[CH:13]=1>C(O)C>[N+:1]([C:4]1[O:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc([N+](=O)[O-])o1

Procedure:
To a solution of 39 g. of 5-nitro-2-furancarboxylic acid in 200 ml. of ethanol is added 2 ml. of p-toluenesulfonic acid. The reaction is heated for 48 hours. The reaction mixture is evaporated and methylene chloride is added to the residue. The solution is extracted with 10% sodium bicarbonate and dried over anhydrous sodium sulfate. The solution is concentrated and then filtered through Magnesol. The product is obtained by recrystallization from methylene chloride and hexane.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)[Br:17]>ClCCl>[Br:17][CH2:2][C:3]1[CH:4]=[C:5]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: BrB(Br)Br
Reactant: CCOC(=O)COc1cccc(CO)c1
Solvent: ClCCl
Product: CCOC(=O)COc1cccc(CBr)c1
Reaction time: 1 h

Procedure:
To a solution of 3-hydroxymethyl-1-ethoxycarbonylmethoxybenzene (1 g) in dichloromethane (10 ml) was added BBr3 (0.45 ml). After 1 hour, the solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with NaHCO3 and brine. The dried solvent was evaporated in vacuo to give 3-bromomethyl-1-ethoxycarbonylmethoxybenzene (0.76 g). NMR (CDCl3, δ): 1.29 (3H, t, J=7 Hz), 4.24 (2H, d, J=7 Hz), 4.61 (2H, s), 5.00 (1H, d, J=3.0 Hz), 5.05 (1H, d, J=3.0 Hz), 6.7-7.1 (3H, m), 7.2-7.3 (1H, m)
Reaction SMILES: [OH:1][C:2]([CH3:27])([CH:9]=[CH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[Br:28]Br.C(=O)([O-])O.[Na+]>CO>[OH:1][C:2]1([CH3:27])[CH:9]([Br:28])[CH:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: BrBr
Reactant: CCOC(=O)CC(C)(O)C=CCCc1ccccc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC1(O)CC(=O)OC(CCc2ccccc2OCc2ccccc2)C1Br

Procedure:
The carboxylic acid (2.15 g) prepared by hydrolyzing ethyl 3-hydroxy-3-methyl-7-(o-benzyloxyphenyl)-4-heptenoate was treated with 1.6 g of bromine in an aqueous methanol solution of sodium hydrogen carbonate and the reaction mixture was worked up according to the method described in Example 1 (b). The product was recrystallized from ether to give 2.3 g of the desired compound melting at 122°-125° C.
Reaction SMILES: I[C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19](C(F)(F)F)[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1.C1COCC1.[F:36][C:37](I)([F:39])[F:38]>[Zn].CN(P(N(C)C)(N(C)C)=O)C>[CH2:28]([N:3]1[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:37]([F:39])([F:38])[F:36])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=[C:2]1[C:37]([F:39])([F:38])[F:36])[CH2:29][CH3:30]
Reactant: CCCn1c(I)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Reactant: FC(F)(F)I
Agent: [Zn]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCn1c(C(F)(F)F)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
A mixture of 2-Iodo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (36 mg, 0.068 mmol), Zn dust (10 mg, 0.136 mmol) and THF (2 ml) was stirred for 2 hours at room temperature. Trifluoromethyl iodide gas was passed through the reaction mixture and HMPA (2 ml) was added and heated at 120° C. for 18 hours. The reaction mixture was cooled to room temperature, organic volatile solvent was evaporated and the residue was extracted with DCM (2×10 ml). The organic layer was washed with brine (10 ml), dried over Na2SO4, evaporated and purified by preparative HPLC to get 1-Propyl-2-trifluoromethyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one as pale yellow solid (4.5 mg, 14%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28]OS(C)(=O)=O)[CH:25]=[C:24]([Br:34])[CH:23]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2].[C-:43]#[N:44].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][C:43]#[N:44])[CH:25]=[C:24]([Br:34])[CH:23]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(COS(C)(=O)=O)c2)c1CCC(=O)OCC
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(CC#N)c2)c1CCC(=O)OCC
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To a solution of 4-[3-[6-(3-bromo-5-methanesulfonyloxymethyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.51 g, 3.74 mmol) in DMF (40 mL), KCN (292 mg, 4.48 mmol) was added and stirred a 60° C. overnight. The reaction was diluted with EtOAc (250 mL) washed with water (100 mL×2), brine (50 mL), dried with Na2SO4. Concentration under reduced pressure provided an oil. Flash column chromatography (30% EtOAc/Hex) provided a light yellow oil (1.19 g, 53% yield). 1H NMR (CDCl3): δ 7.08 (t, 1H), 7.04 (s, 1H), 6.99 (s, 1H), 6.79 (s, 1H), 6.77 (d, 1H), 6.68 (d, 1H), 4.17-4.06 (m, 4H), 4.01-3.91 (m, 4H), 3.68 (s, 2H), 2.97 (dd, 2H), 2.63 (dd, 2H), 2.56-2.46 (m, 4H), 2.17-0.89 (m, 16H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[C:28](Cl)(=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[O:6]=[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:28](=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]/[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:24][CH:25]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:27]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(N)cc1)Cc1ccc(C(F)(F)F)cc1
Reactant: CCCCC=CCCCCCCCC(=O)Cl
Product: CCCC/C=C/CCCCCCCC(=O)Nc1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)C(=O)OCC)cc1
Yield: 81 %

Procedure:
The same procedure as employed in the preparation of Example 15, step d using ethyl{(4-aminobenzyl)[4-(trifluoromethyl)benzyl]amino}(oxo)acetate and tetradec-9-enoyl chloride gave the title compound as a colorless oil (81%). M−(LC/MS(ESI)): 588.0. HPLC (Condition A), Rt: 7.3 min (HPLC purity: 96.9%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[CH:19]1[CH:25]=[CH:24][NH:23][C:21](=[S:22])[CH:20]=1>>[CH3:18][C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:22][C:21]3[CH:20]=[CH:19][CH:25]=[CH:24][N:23]=3)=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: S=c1cccc[nH]1
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Product: CC1=NNC(=O)/C1=C1/C=C(Sc2ccccn2)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and 2-thiopyridine using the procedure described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.31 (s, 3H) 7.40 (dd, J=7.20, 4.93 Hz, 1H) 7.55 (t, J=7.58 Hz, 2H) 7.73 (s, 1H) 7.77-7.87 (m, 2H) 7.96 (d, J=8.59 Hz, 1H) 8.06 (d, J=8.08 Hz, 1H) 8.58 (d, J=3.79 Hz, 1H); ESI-MS: m/z calc'd for C18H14N4OS 334.09. found 335.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+]>CO>[CH3:12][NH:13][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of indole-3-carboxaldehyde (5.4 g, 34.1 mmole) in MeOH (30 mL) was added a solution of 2.0 M CH3NH2 in MeOH (51.3 mL, 102.6 mmole). The reaction was stirred at RT overnight, then was concentrated to a light yellow oil. This oil was dissolved in EtOH (40 nL), and NaBH4 (1.3 g, 34.1 mmole) was added. After 16 hrs the reaction was concentrated to a slurry and dissolved in 10% Na2CO3(100 mL). The aqueous solution was extracted with EtOAc (2×200 mL) and the combined organic fractions were dried over Na2SO4 and concentrated. Drying in high vacuum left the title compound (5.2 g, 94%) as a faintly yellow oil: MS (ES) m/e 161 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[CH3:9][O-:10].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:10][CH3:9])[CH:7]=1
Reactant: C[O-]
Reactant: Brc1cncc(Br)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cncc(Br)c1
Temperature: 25 °C

Procedure:
3,5-Dibromopyridine (30.0 g) was added to a stirred solution of sodium methoxide (prepared from 11.6 g of sodium) in methanol (120 ml) and heated to reflux for 70 hours under an atmosphere of nitrogen. The mixture was cooled to ambient temperature, poured into water (1000 ml), extracted with diethyl ether and the extracts combined, washed with water and dried over magnesium sulphate. The solvent was evaporated to give 3-bromo-5-methoxypyridine as a colourless liquid, which slowly crystallised on storing (19.3 g).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:12]1[CH2:21][CH2:20][CH:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[N:12]1[CH2:21][CH2:20][CH:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13]1
Reactant: COC(=O)C1CCNCC1
Reactant: O=[N+]([O-])c1cccc(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C1CCN(c2c(F)cccc2[N+](=O)[O-])CC1
Temperature: 80 °C

Procedure:
A mixture of difluoronitrobenzene (0.34 mL, 3.10 mmol), methyl isonipecotate (0.51 mL, 3.78 mmol), and diisopropylethylamine (1.08 mL, 6.20 mmol) in acetonitrile (15 mL) was heated at 80° C. overnight. The solvents were removed in vacuo. Chromatographic purification (20% ethyl acetate:hexane) of the residue gave Int-20a (0.85 g, 97%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Cl)cc1
Reactant: O=Cc1ccc(Cl)cc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Yield: 80 %

Procedure:
A solution of 4-chlorobenzyl sulfonylacetic acid (0.01 mol) and 4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 80% yield.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12]C)=O)[C:4]=2[CH:3]=[CH:2]1.[CH3:14][O:15][C:16]1[CH:26]=[CH:25][C:19]([CH:20]=[CH:21][N+:22]([O-])=O)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:26]=[CH:25][C:19]([CH:20]2[C:3]3=[CH:2][NH:1][C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([C:4]=43)[C:10](=[O:12])[NH:22][CH2:21]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1
Product: COc1ccc(C2CNC(=O)c3cccc4[nH]cc2c34)cc1

Procedure:
In a manner similar to that described for the preparation of Example Q, methyl indole4-carboxylate and p-methoxy nitrostyrene were condensed and the resulting nitro alkane was reduced/cyclized to give, after recrystallization (CH2Cl2/MeOH/hexanes), (rac)-3-(4-methoxyphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one, 16.9 mh (50%) as a white solid: m.p. 221-223° C.; 1H NMR (300 MHz, d4-MeOH) 3.57 (br m, 5H), 5.15 (br s, 1H) 6.62 (m, 2H), 6.86 (m, 2H),7.08 (app t, J=7.8 Hz, 1H), 7.11 (s, 1H),7.37 (d, J=7.9 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H). Anal. (C19H16N2O2.0.25 H2O) C, H, N.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:11][CH3:12])[O:9][CH3:10])=[CH:4][CH:3]=1.[C:13]1([CH2:19][CH:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-].C(OCC)(=O)C>C1COCC1>[CH3:10][O:9][CH:8]([O:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([CH:20]([OH:21])[CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1
Reactant: O=CCc1ccccc1
Reactant: COC(OC)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(OC)c1ccc(C(O)Cc2ccccc2)cc1

Procedure:
A mixture of Mg turnings 2.4 g (0.1 mol) and 2 mL 1-bromo-4-(dimethoxymethyl)benzene (0.012 mol) in THF (100 mL) was heated under nitrogen atmosphere until the reaction starts. Subsequently additional 1-bromo-4-(dimethoxymethyl)benzene 14.71 mL (0.088 mol) dissolved in 30 mL THF was added slowly and the reaction refluxed for 1 h mixture to complete formation of the Gringnard reagent. A solution of 11.70 mL phenylacetaldehyde (0.1 mol) in 100 mL THF was added at to 0° C. and the reaction refluxed for 2 h upon completion of the addition. The mixture was worked up by pouring into saturated aqueous NH4Cl and extraction with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and the solvents were evaporated under reduced pressure. The brown-black oily product was used for the next step without purification.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[C:7]2[C:8]([O:10][C:11](=[O:12])[C:6]=12)=O)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26].CC([O-])=O.[Na+]>C(O)(=O)C>[O:10]=[C:8]1[C:7]2[C:6](=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:15]=[CH:14][CH:13]=2)[C:11](=[O:12])[N:23]1[CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]
Reactant: NC1CCC(=O)NC1=O
Reactant: CC(=O)Oc1cccc2c1C(=O)OC2=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC(=O)Oc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 57 %

Procedure:
1,3-Dioxo-2-(2,6-dioxopiperidin-3-yl)-4-acetoxyisoindoline was prepared and isolated as follows. A mixture of 3-acetoxyphthalic anhydride (40 mg), aminoglutarimide trifluoroacetate (47 mg), and NaOAc (32 mg) in acetic acid (2 mL) was refluxed for 5 h. The solvent was evaporated, water (10 mL) was added, and the resulting solution was stirred for several minutes. The solid was filtered out and recrystallized from ethyl acetate to give 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-acetoxyisoindoline as pale yellow crystals (35 mg, 66%): 1H NMR (DMSO) δ 11.16 (s, 1H), 11.07 (s, 1H), 7.64 (t, J=7.2 Hz, 1H), 7.22-7.31 (m, 2H), 5.05 (dd, J=5.4 Hz, J=12.5 Hz, 1H), 2.87-2.92 (m, 2H), 2.48 (s, 3H), 2.08-2.00 (m, 2H).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:7].[CH2:8]([O:10][C:11](=[O:14])[CH2:12][NH2:13])[CH3:9].C([BH3-])#N.[Na+]>CO>[ClH:7].[CH2:8]([O:10][C:11](=[O:14])[CH2:12][NH:13][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:9]
Reactant: O=C1CCCC1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CNC1CCCC1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
Cyclopentanone (10 g) and glycine ethyl ester hydrochloride (21.6 g) are dissolved in 200 ml of methanol, and 7.48 g of sodium cyanoborohydride is added in small portions with stirring at room temperature. The mixture is further stirred at room temperature for 3 hours and the reaction mixture is concentrated under reduced pressure. To the residue is added 500 ml of water and the mixture is adjusted to pH 10 with diluted sodium hydroxide solution and extracted with 300 ml of ethyl acetate. The extract is washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solvent is then distilled off under reduced pressure and the resulting oily product is dissolved in 200 ml of ether, followed by addition of 10 ml of 10% alcoholic hydrochloride, whereupon crystals immediately separates out. The crystals are collected by filtration to give 12.7 g of N-cyclopentylglycine ethyl ester hydrochloride as colorless needles melting at 174°-175° C.