Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH2:21][CH:22]([O:24][CH3:25])[CH3:23])[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.C([Sn](CCCC)(CCCC)[C:31]([O:33][CH2:34][CH3:35])=[CH2:32])CCC.[Li+].[Cl-].[F-].[K+]>C1COCC1.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>[CH2:34]([O:33][C:31]([C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH2:21][CH:22]([O:24][CH3:25])[CH3:23])[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2)=[CH2:32])[CH3:35]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(C)Cn1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: C=C(OCC)c1ccc2c(c1)OCCn1cc(-c3ncnn3CC(C)OC)nc1-2
Temperature: 70 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
A mixture of 12-bromo-4-[1-(2-methoxypropyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (290 mg, 0.720 mmol), tributyl(1-ethoxyvinyl)stannane (0.5 mL), Pd(PPh3)4 (27 mg, 0.023 mmol), and LiCl (97 mg, 2.3 mmol) in dry THF (10 mL) was stirred at 70° C. for 48 h under nitrogen atmosphere. KF (40 mL, 0.16 M) was added and the mixture was further stirred at room temperature for 1 h. The solid was filtered off. The filtrate was concentrated to give the crude product, which was purified by reverse phase Combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to afford 12-(1-ethoxyethenyl)-4-[1-(2-methoxypropyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (195 mg, 66% yield). LCMS (ESI) m/z: 396.3 [M+H+].
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][OH:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:16]1([NH:19][C:20]([C:22]2[S:35][C:25]3=[N:26][C:27](S(C)=O)=[C:28]([Cl:31])[C:29]([CH3:30])=[C:24]3[C:23]=2[NH2:36])=[O:21])[CH2:18][CH2:17]1>C1COCC1>[CH:16]1([NH:19][C:20]([C:22]2[S:35][C:25]3=[N:26][C:27]([O:5][CH2:4][CH2:3][S:2][CH3:1])=[C:28]([Cl:31])[C:29]([CH3:30])=[C:24]3[C:23]=2[NH2:36])=[O:21])[CH2:18][CH2:17]1
Reactant: CSCCO
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSCCOc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 54.6 %

Procedure:
To a solution of 2-(methylthio)ethanol (1.060 g, 11.50 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0M in hexanes)(3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 80° C. in a sealed tube for 1.5 hours, cooled to room temperature, and then quenched by the addition of water (15 ml). Ice is added to the reaction mixture and, while stirring, a yellow precipitate is formed. This solid is collected by filtration and placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.203 g, 55%). Mass (m/z): 372.1 (M++1), 370.1 (M+−1).
Reaction SMILES: C[C:2]1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1C=CC=CC=1.[C:17]1(=[O:31])[N:21]([CH2:22]C(Cl)=O)[C:20](=[O:26])[C:19]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:18]12.Cl>ClCCl>[O:5]=[C:4]([CH2:22][N:21]1[C:20](=[O:26])[C:19]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:18]2[C:17]1=[O:31])[CH2:6][C:7]([O:9][CH3:2])=[O:8]
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
To a solution of Meldrum's acid (14.4 g, 0.10 mol) and pyridine (15.8 g, 0.20 mol) in dichloromethane (100 mL) was added dropwise at 0° C., taking 10 minutes, a solution of phthalimidoacetyl chloride (24.6 g,. 0.11 mol) in dichloromethane (50 mL). The mixture was stirred for 30 minutes at the same temperature and for 30 minutes at room temperature. To the reaction mixture was added 1N HCl (200 mL), then insoluble material was filtered off. The aqueous layer was separated, and the organic layer was washed with water, dried over magnesium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was suspended in methanol (200 mL), which was refluxed for 1.5 hour. The reaction mixture was left standing for cooling. Crystalline precipitate was collected by filtration and washed with methanol to give the object compound (18.4 g, 70%), m.p.139°-140° C.
Reaction SMILES: [C:1]([C:4](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1)[C:5]([O:7][CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:6])(=O)[CH3:2].[N+](C1C=C(C=CC=1)C=O)([O-])=O.C(OC(C1C=CC=CC=1)CN1CCCCC1)(=O)CC(C)=O.[NH2:64][C:65]1[NH:66][CH:67]=[CH:68][N:69]=1.S(O)(O)(=O)=O.NC1NC=CN=1.[OH-].[Na+]>C(O)C>[CH3:2][C:1]1[NH:64][C:65]2[N:66]([CH:67]=[CH:68][N:69]=2)[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:4]=1[C:5]([O:7][CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:6]
Reactant: Nc1ncc[nH]1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC(CN1CCCCC1)c1ccccc1
Agent: CC(=O)CC(=O)OC(CN1CCCCC1)c1ccccc1
Agent: O=Cc1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC1=C(C(=O)OC(CN2CCCCC2)c2ccccc2)C(c2cccc([N+](=O)[O-])c2)n2ccnc2N1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To the crude 1-phenyl-2-piperidinoethyl α-acetyl-3-nitrocinnamate, which was synthesized by reacting 30 g of 3-nitrobenzaldehyde with 67 g of 1-phenyl-2-piperidinoethyl acetoacetate, is added 500 ml of ethanol solution of 2-aminoimidazole prepared from 26.4 g of 2-aminoimidazole sulfate and sodium hydroxide, and then stirred at 50° C. for 5 hours. After cooling, the precipitated crystals are collected by filtration and recrystallized from ethanol to give 9.7 g of 1-phenyl-2-piperidinoethyl 7-methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine-6-carboxylate, melting at 205°-206° C. as one diastereomer (α-form). Then, the filtrate is concentrated under reduced pressure, and the residue is purified by column chromatography on silica gel with chloroform-ethyl acetate-ethanol eluents. The crystals thus obtained are recrystallized from a mixture of chloroform and ethanol to give 4.8 g of 1-phenyl-2-piperidinoethyl 7-methyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine-6-carboxylate, melting at 216° -217° C. with decomposition as the other diastereomer (β-form).
Reaction SMILES: O[C:2]1([C:8]#[C:9][C:10]2[CH:29]=[CH:28][C:13]3[N:14]=[C:15]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[CH2:16][C:17](=[O:19])[NH:18][C:12]=3[CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:2]1([C:8]#[C:9][C:10]2[CH:29]=[CH:28][C:13]3[N:14]=[C:15]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[CH2:16][C:17](=[O:19])[NH:18][C:12]=3[CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: N#Cc1cccc(C2=Nc3ccc(C#CC4(O)CCCCC4)cc3NC(=O)C2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(C#CC4=CCCCC4)cc3NC(=O)C2)c1
Yield: 46.3 %

Procedure:
Prepared from 3-[7-(1-hydroxy-cyclohexylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile (Example 135) (50 mg, 0.13 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (22 mg).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([CH:11]=[O:12])[CH2:9][C@H:8]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:6]12[CH3:7])[C:21]1[CH:20]=[CH:19][C:18]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:17][C:16]=1[CH2:15][CH2:14]3)(=[O:3])[CH3:2].CC(C)=[O:35].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.CO.O>[CH2:26]([O:25][C:18]1[CH:19]=[CH:20][C:21]2[C@@H:22]3[C@H:13]([C@H:8]4[C@@:6]([CH2:24][CH2:23]3)([CH3:7])[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:10]([C:11]([OH:35])=[O:12])[CH2:9]4)[CH2:14][CH2:15][C:16]=2[CH:17]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(=O)O[C@H]1[C@H](C=O)C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@@]21C
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: CC(=O)O[C@H]1[C@H](C(=O)O)C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@@]21C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of 824 mg (1.90 mmol) of 5 in 120 mL of acetone was cooled to 0° C. and 710 μL of Jones reagent solution (8 M solution of CrO3 in aqueous H2SO4)37 was added. The reaction mixture was stirred at 0° C. for 30 min, diluted with MeOH (20 mL) and H2O (20 mL), concentrated to about 30 mL, and extracted with CH2Cl2 (3×, 70 mL). Combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification of the residue by flash chromatography on a 2×17 cm column of silica gel using EtOH/CH2Cl2 (5:95) gave 784.4 mg (92%) of 6 as a white foam. Data for 6: TLC, T-4, Rf0.78. 1H NMR (500 MHz, CDCl3) δ 0.87 (s, 3H, H-18), 2.10 (s, 3H, OAc), 5.02 (d, 1H, J=7.1 Hz, H-17α), 5.04(s, 2H, benzylic), 6.72 (d, 1H, J=2.8 Hz, H-4), 6.79 (dd, 1H, J=8.5, 2.8 Hz, H-2), 7.20 (d, 1H, J=8.5 Hz, H-1), 7.31-7.44 (m, 5H, Ar—H); HRMS (ES) calcd for C28H32O5Na (M+Na+) m/e 471.2147, found m/e 471.2146.
Reaction SMILES: [F:1][C:2]([F:23])([CH:12]([F:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]>O1CCCC1.CO.[C].[Pd]>[NH2:19][C:15]1[CH:14]=[C:13]([CH:12]([F:22])[C:2]([F:23])([F:1])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:8])[CH3:9])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCC(F)(F)C(F)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(F)(F)C(F)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.8 %

Procedure:
To 10% palladium-carbon (40 mg), a solution of tert-butyl (2,2,3-trifluoro-3-(3-nitrophenyl)propyl)carbamate (C35, 80 mg) in tetrahydrofuran (5 mL) and methanol (5 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure to obtain tert-butyl (3-(3-aminophenyl)-2,2,3-trifluoropropyl)carbamate (C36, 88 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:25]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:18])([CH3:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[N:9]2[CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(C#N)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1c2ccc(C#N)cc2C(C)(C)CC1c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a stirred solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (4.2 g, 12.4 mmol) in N,N-dimethylformamide (15 mL) was added a 60% dispersion of sodium hydride in mineral oil (1.5 g, 37.2 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 30 min and then iodomethane (2.4 mL, 37.2 mmol) was added to above mixture dropwise at 0° C. The solution was stirred at 0° C. for 2 h and then extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The yellowish residue was purified by ISCO combi-flash chromatography (gradient elution, 10% ethyl acetate/hexane) to afford 2-(3-bromo-phenyl)-1,4,4-trimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (1.1 g, 70%) as a yellow oil: MS obsd. (ESI+) [(M+H)+] 355.0 & 357.0.
Reaction SMILES: ONC([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([C:20]([NH:22][OH:23])=[NH:21])[CH:17]=[CH:16][C:14]=3[CH:15]=2)=[CH:7][CH:6]=1)=N.Cl>>[OH:23][NH:22][C:20]([C:10]1[CH:9]=[C:8]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([C:20]([NH:22][OH:23])=[NH:21])[CH:17]=[CH:16][C:14]=3[CH:15]=2)[CH:7]=[CH:6][CH:5]=1)=[NH:21]
Reactant: N=C(NO)c1ccc(-c2cc3ccc(C(=N)NO)cc3o2)cc1
Agent: Cl
Product: N=C(NO)c1cccc(-c2cc3ccc(C(=N)NO)cc3o2)c1

Procedure:
2-(4-(N-Hydroxycarbamimidoyl)phenyl)-N-hydroxybenzofuran-6-carboxamidine (181) White solid (0.78 g, 83%): mp 210° C. (dec) (aq HCl). 1H NMR (DMSO-d6) δ10.00-8.50 (br m, 6H), 8.19 (d, J=8.2 Hz, 2H), 8.15 (s, 1H), 7.95 (s, 1H), 7.94 (d, J=8.2 Hz, 2H), 7.88 (s, 1H), 7.69 (dd, J=8.2, 1.7 Hz, 1H). HPLC (method A) tR 4.33 min (100.0 area %). Anal. (C16H14N4O3.2HCl.1.2H2O) C, H, N, Cl.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:12]2[O:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.[Br:19]Br>ClCCl>[Br:19][C:10]1[O:11][C:12]2[C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrBr
Reactant: OCCc1cccc2c(-c3ccccc3)coc12
Solvent: ClCCl
Product: OCCc1cccc2c(-c3ccccc3)c(Br)oc12
Reaction time: 0.08 h

Procedure:
To a solution of 3.0 g. (0.0126 mole) of 7-(2-hydroxyethyl)-3-phenylbenzofuran in 50 ml. of dichloromethane is added dropwise 2.1 g. of bromine. After stirring for five minutes the mixture is evaporated, benzene is added to the residue and it is evaporated again. The residue is mixed with petroleum ether and crystallizes. Recrystallization from hexane gives 2-bromo-7-(2-hydroxyethyl)-3-phenylbenzofuran, m.p. 108°-112° C.
Reaction SMILES: [NH:1]([C:20]([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[C@@H:2]([C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14](O)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:62][C@H:63]([C:71]([NH2:73])=[O:72])[CH2:64][CH2:65][CH2:66][NH:67][C:68](=[NH:70])[NH2:69].CN1CCOCC1>CN(C=O)C.CC(O)=O>[C:20]([NH:1][C@@H:2]([C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([NH:62][C@H:63]([C:71]([NH2:73])=[O:72])[CH2:64][CH2:65][CH2:66][NH:67][C:68](=[NH:69])[NH2:70])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([O:22][CH2:23][CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:21]
Reactant: N=C(N)NCCC[C@H](N)C(N)=O
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.45 g of Fmoc-D-Phe-Pro (3 mmol) and 405 mg of HOBt were dissolved in 40 ml of DMF and, at 0oC, 630 mg of DCC were added, and then the mixture was stirred at 0oC for 30 minutes and at room temperature for 30 min. Then 880 mg of Arg-NH2 × 2 CH3COOH and 630 pl of NMM were added. After 12 hours, insolubles were filtered off, the DMF was evaporated off, and the oily residue was taken up chloroform. The organic phase was extracted by shaking three times with saturated sodium bicarbonate solution and three times with saturated sodium chloride solution, and was dried over sodium sulfate. After the chloroform had been evaporated off, a pure product was obtained.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:26]([OH:27])=[CH:25][C:24]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=4[CH:18]=3)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:35][O:27][C:26]4[CH:25]=[C:24]5[C:19](=[CH:18][C:17]3=4)[CH2:20][CH2:21][CH2:22][CH2:23]5)[C:9]2=[O:28])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1C(c2cc3c(cc2O)CCCC3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)CCCC3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1′H)-one was obtained (81%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.37-7.32 (m, 10H), 7.17-7.14 (m, 1H), 7.07 (s, 1H), 7.05-6.94 (m, 2H), 6.67 (s, 1H), 6.52 (d, J=7.6 Hz, 1H), 6.33 (s, 1H), 4.96 (d, J=8.9 Hz, 1H), 4.69 (d, J=8.9 Hz, 1H), 2.73 (br s, 2H), 2.54 (br s, 1H), 1.72-1.70 (m, 4H); MS (ES+) m/z 457.9 (M+1).
Reaction SMILES: [C@@H:1]([NH:5][C:6]1[C:7]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=3[CH:24]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].[H-].[Na+].[CH3:32]I>C1COCC1>[C@@H:1]([N:5]([CH3:32])[C:6]1[C:7]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=3[CH:24]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1cc2cc(F)ccc2o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H](C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a solution of (S)-methyl 3-(sec-butylamino)-2-(5-fluorobenzofuran-2-yl)quinoxaline-6-carboxylate (130 mg, 0.33 mmol) in THF (20 mL) was added NaH (52 mg, 1.32 mmol) and CH3I (188 mg, 1.32 mmol). The resulting solution was stirred overnight at room temperature and then the reaction mixture was poured into water/ice solution (20 mL). The mixture was evaporated until about 10 mL of water remained and adjusted to pH 5 with hydrochloric acid (1N). The product was collected by filtration to afford (S)-3-(sec-butyl(methyl)amino)-2-(5-fluorobenzofuran-2-yl)quinoxaline-6-carboxylic acid as a yellow solid (34.4 mg, 27%).
Reaction SMILES: [Cl:1][N:2]1[C:6]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]1[NH:12][CH:13]([CH3:15])[CH3:14].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[C@H:44]1[O:56][C@@H:55]([CH2:57][O:58][C:59](=[O:61])[CH3:60])[C@H:50]([O:51][C:52](=[O:54])[CH3:53])[C@@H:45]1[O:46][C:47](=[O:49])[CH3:48])(=O)C>ClCCCl>[Cl:1][N:2]1[C:6]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C@H:44]2[O:56][C@@H:55]([CH2:57][O:58][C:59](=[O:61])[CH3:60])[C@H:50]([O:51][C:52](=[O:54])[CH3:53])[C@@H:45]2[O:46][C:47](=[O:49])[CH3:48])[CH:3]1[NH:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)NC1Nc2cccc(Cl)c2N1Cl
Reactant: CC(=O)OC[C@@H]1O[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Product: CC(=O)OC[C@@H]1O[C@H](N2c3cccc(Cl)c3N(Cl)C2NC(C)C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 56.4 %

Procedure:
3,4-Dichloro-2-(isopropylamino)-1H-benzimidazole (2.01 g, 7.31 mmol), N,O-bis(trimethylsilyl)acetamide (2.0 mL, 1.65 g, 8.09 mmol), trimethylsilyl trifluoromethanesulfonate (0.9 mL, 1.06 g, 4.50 mmol), 1,2,3,5-tetra-O-acetyl-beta-L-ribofuranose (3.03 g, 9.52 mmol) and 1,2-dichloroethane (35 mL) were used according to general procedure II. The product was purified by silica gel chromatography using 95:5 dichloromethane/acetonitrile to afford 2.08 g (56%) of a yellow foam. MS (EI): m/z 502.0 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1>ClCCl.C(N(CC)CC)C>[O:16]([CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([CH2:7][NH:6][C:1](=[O:4])[CH2:2][CH3:3])[CH2:9][CH2:10]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCC(=O)Cl
Reactant: NCC1CCN(CCOc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCC1CCN(CCOc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A solution of propionyl chloride (2.37 g) in dichloromethane (10 ml) was added dropwise to a solution of 4-aminomethyl-1-(2-phenoxyethyl)piperidine (6.0 g) in dichloromethane (50 ml) and triethylamine (3.9 ml) at 0° C. The solution was allowed to warm up to ambient temperature with stirring and then stirred at this temperature for a further 2 hours. More propionyl chloride (0.3 ml) was added at ambient temperature and the solution stirred for a further half-hour. Further propionyl chloride (0.3 ml) was added and the mixture stirred for 1 hour. The mixture was extracted with 2M hydrochloric acid. The combined acidic extracts were washed with ethyl acetate, then basified with sodium hydroxide solution and extracted with dichloromethane to give an oil which solidified on standing to give N-[1-(2-phenoxyethyl)piperid-4-ylmethyl]propionamide, m.p. 85°-86° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:26]2[C:4]=1[CH2:5][C:6]1[C:7]3[CH:8]2[CH2:9][N:10](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:11][C:12]=3[CH:13]=[CH:14][CH:15]=1.CO.P([O-])([O-])(O)=O.[Na+].[Na+]>O>[CH3:1][O:2][C:3]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:26]2[C:4]=1[CH2:5][C:6]1[C:7]3[CH:8]2[CH2:9][NH:10][CH2:11][C:12]=3[CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc2c(c1OC)Cc1cccc3c1C2CN(S(=O)(=O)c1ccc(C)cc1)C3
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1OC)Cc1cccc3c1C2CNC3
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of compound 14 (440 mg, 1.01 mmol), dry methanol (10 mL) and disodium hydrogen phosphate (574 mg, 4.04 mmol) was stirred under nitrogen at room temperature. To this mixture was added 6.20 g of 6% Na-Hg in three portions and the reaction was heated at ref lux for 2 h. After cooling, water (200 mL) was added and the mixture was extracted with ether (3×200 mL). The ether layers were combined, dried (MgSO4), filtered (Celite), and evaporated to give an oil that solidified under vacuum. After rotary chromatography 142 mg (50%) of compound 15 was obtained as an oil. The oil quickly darkened on exposure to air and was used immediately for the next step. A small portion of the oil was treated with ethereal HCl and the hydrochloride salt of compound 15 was recrystallized from ethanol-ether: mp (HCl salt) 190° C. (dec); 1H NMR (CDCl3, base) δ 3.13 (dd, 1 H, J=10.8, 12 Hz, H-1a), 3.50 (dd, 1 H, J=3.4, 17.4 Hz, H-1b), 3.70 (m, 1 H, H-11b), 3.839 (s, 3 H, OCH3), 3.842 (s, 3 H, OCH3), 4.03 (dd, 1 H, J=6, 12 Hz, H-7a), 4.08 (s, 2 H, H-3), 4.33 (d, 1 H, J=17.4 Hz, H-7b), 6.78 (d, 1 H, J=8.24 Hz, ArH), 6.92 (m, 3 H, ArH), 7.11 (t, 1 H, J=7.5 Hz, ArH), 7.18 (d, 1 H, J=7.5 Hz, ArH); MS (CI) m/z 282 (100); HRCIMS Calculated for C18H19NO2: 282.1494; Found 282.1497.