Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[C:11]([OH:13])=O.[NH:14]1[CH2:23][CH2:22][CH2:21][C@H:15]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].CCOC(OC(OCC)=O)=O.C(N(CC)CC)C>C(OCC)(=O)C.CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[C:11]([N:14]1[CH2:23][CH2:22][CH2:21][C@H:15]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13]
Reactant: O=C(O)C1=Cc2ccccc2CC1
Reactant: CCOC(=O)[C@@H]1CCCN1
Agent: CCOC(=O)OC(=O)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CCCN1C(=O)C1=Cc2ccccc2CC1
Reaction time: 48 h
Yield: 92.7 %

Procedure:
To a DMF solution (60 ml) containing 3,4-dihydro-2-naphthoic acid (9a, 7.12 g, 40.0 mmole), and (S)(-)-ethyl prolinate (6.41 g, 44.8 mmole), a DMF solution (60 ml) containing DEPC (7.17 g, 44.0 mmole) and a DMF solution (60 ml) containing triethylamine (4.05 g, 40.0 mmole) are dropwise added at 0° C. in 5 minutes. The resultant mixture is stirred at 0° C. for 2 hours and then at room temperature for 2 days. The reaction mixture is diluted with ethyl acetate (1.8 liters), and the ethyl acetate solution is washed with 5% hydrochloric acid (130 ml×2), water (130 ml×2), a saturated aqueous solution of sodium chloride (130 ml×2), a saturated aqueous solution of sodium hydrogen carbonate (130 ml×2) and water (130 ml×2) in order and then dried over anhydrous magnesium sulfate. After filtration and evaporation, a crude product (10a) is obtained as a yellow caramel (13.9 g, 116%), which is purified by column chromatography (silica gel, 300 g; solvent, ether) to obtain an almost pure product (10a) as colorless needles (11.1 g, 91%). M.P. 55°-57° C. Recrystallization from ether-hexane affords an analytical sample as colorless needles melting at 56°-57° C. [α]D20 -18.6° (c=1.03, ethanol). IRνmaxNujol cm-1 : 1750 (ester), 1650 (C=C), 1610 (CON), NMR (in CDCl3): 1.27 (3H, t, J=7 Hz, CO2CH2CH3), 1.64-2.40 (4H, m, NCH2CH2CH2), 2.40-3.20 (4H, m, CH2CH2C=), 3.72 (2H, t, J=6 Hz, N--CH2), 4.16 (2H, q, J= 7 Hz, CO2CH2CH3), 4.58 (1H, t, J=6 Hz, NCHCO2), 6.77 (1H, s, CH=C), 7.12 (4H, s, aromatic proton).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]C(=O)N(C)C)=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39]>CO.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CN(C)C(=O)Sc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CSc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
Dissolve 3-(tert-butoxycarbonyl)-7-chloro-6-(4-dimethylcarbamoylthio-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (270 mg, 0.5 mmol) in methanol (20 mL). Add potassium hydroxide (308 mg, 5.5 mmol) and heat the mixture for 3 h at 65° C. Add methyl bromoacetate (0.52 mL, 5.5 mmol) and heat at 65° C. for 3 h. Cool the mixture to room temperature and dilute with EtOAc. Wash the organic phase with water, dry over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate as an oil (203 mg, 75%).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:12]=[C:13]3[CH:30]=[C:29](/[CH:31]=[CH:32]/[C:33]4[S:34][CH:35]=[C:36]([CH:38]([CH3:40])[CH3:39])[N:37]=4)[CH:28]=[CH:27][N:14]3[C:15](=[O:26])[C:16]=2/[CH:17]=[CH:18]/[C:19]([NH:21][CH2:22][CH2:23][C:24]#[N:25])=O)[CH2:6]1)(=[O:3])[CH3:2].[N-:41]=[N+:42]=[N-:43].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])O.[Na+]>C(#N)C>[C:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:12]=[C:13]3[CH:30]=[C:29](/[CH:31]=[CH:32]/[C:33]4[S:34][CH:35]=[C:36]([CH:38]([CH3:39])[CH3:40])[N:37]=4)[CH:28]=[CH:27][N:14]3[C:15](=[O:26])[C:16]=2/[CH:17]=[CH:18]/[C:19]2[N:21]([CH2:22][CH2:23][C:24]#[N:25])[N:43]=[N:42][N:41]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC1CCCN(c2nc3cc(/C=C/c4nc(C(C)C)cs4)ccn3c(=O)c2/C=C/C(=O)NCCC#N)C1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)OC1CCCN(c2nc3cc(/C=C/c4nc(C(C)C)cs4)ccn3c(=O)c2/C=C/c2nnnn2CCC#N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
The 1-(3-{(E)-3-[(2-cyanoethyl)amino]-3-oxo-1-propenyl}-8-[(E)-2-(4-isopropyl -1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)-3-piperidyl acetate (57.3 mg, 0.102 mmol) obtained in (B) was suspended in acetonitrile (3.0 ml), added with sodium azide (13.3 mg, 0.204 mmol) and trifluoromethanesulfonic acid anhydride (25.8 μl, 0.153 mmol) under ice cooling, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was further added with sodium azide (13.3 mg, 0.204 mmol) and trifluoromethanesulfonic acid anhydride (25.8 μl, 0.153 mmol), and stirred for 3 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate and extracted with chloroform, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (hexane:ethyl acetate=1:2→1:3→0:1, v/v) to obtain the title compound (26.8 mg, 45%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 75 %

Procedure:
A mixture of 5-hydroxy-1-indanone 5.1 (available from Aldrich) (5 g, 34 mmol), 1-(bromomethyl)benzene (available from Aldrich) (4 mL, 37 mmol) and cesium carbonate (16 g, 51 mmol) in DMF (40 mL) was stirred at room temperature for 17 hours. EtOAc (400 mL) was added, and the mixture was washed with water and brine, and dried over anhydrous sodium sulfate. After removing solvent, the residue was purified by chromatography (silica gel, 1:4 EtOAc/hexane) to give 5.2 in 75% yield.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:34])/[CH:16]=[CH:17]/[C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:33])=[CH:11][C:10]=1[CH3:35])C1C=CC=CC=1>C(O)C.O1CCOCC1.[OH-].[Pd+2].[OH-]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:34])[CH2:16][CH2:17][C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:33])=[CH:11][C:10]=1[CH3:35]
Reactant: Cc1cc(C(=O)/C=C/c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1cc(C(=O)CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1O

Procedure:
To a solution of (2E)-1-[4-(benzyloxy)-3-methylphenyl]-3-{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}prop-2-en-1-one (intermediate 9, 0.77 g) in ethanol (30 ml) and 1,4-dioxane (10 ml) was added to 20% palladium hydroxide (0.31 g) and hydrogenated at 21° C. for 18 hours. The reaction was filtered through Celite and the filtrate evaporated to give material which was further purified by flash column chromatography using cyclohexane:ethyl acetate (3:1) as eluent to give the title compound as a colourless oil.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]([CH2:15][CH2:16]Br)[CH:5]1[CH3:18])(=[O:3])[CH3:2].[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]([CH2:15][CH2:16][N:28]2[CH2:29][CH2:30][CH:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)[CH:5]1[CH3:18])(=[O:3])[CH3:2]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COc1ccc2c(c1)C(CCBr)C(C)N2C(C)=O
Product: COc1ccc2c(c1)C(CCN1CCC(c3ccccc3)CC1)C(C)N2C(C)=O

Procedure:
In the manner described in Example 1, treatment of 1-acetyl-3-(2-bromoethyl)-5-methoxy-2-methylindoline with 4-phenylpiperidine gives the product as an amorphous solid.
Reaction SMILES: Br[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17]3[C:22]([CH:23]=[C:24]4[C:29]=2[CH:28]=[CH:27][CH:26]=[CH:25]4)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:30]1([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>[Cu].C1(C)C=CC=CC=1>[C:37]1([N:36]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:2]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]3[C:17]4[C:22]([CH:23]=[C:24]5[C:29]=3[CH:28]=[CH:27][CH:26]=[CH:25]5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[CH:7]3)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Brc1c2ccccc2c(-c2c3ccccc3cc3ccccc23)c2ccccc12
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(N(c2ccccc2)c2c3ccccc3c(-c3c4ccccc4cc4ccccc34)c3ccccc23)cc1
Yield: 68.1 %

Procedure:
In a flask were placed 35 g of 9,9′-bianthryl, 18.0 g of N-bromosuccinimide and 500 mL of carbon tetrachloride, and the mixture was stirred overnight. The reaction mixture was filtered, the filtrate was passed through a column filled with alumina. Carbon tetrachloride was evaporated from the solution under a reduced pressure, and then the residue was recrystallized from petroleum ether, to give 35 g(yield: 80%) of 10-bromo-9,9′-bianthryl. Then, in a 100 mL three-necked flask were placed 18.3 g of 10-bromo-9,9′-bianthryl, 10 g of diphenylamine, 8.5 g of potassium carbonate, 0.2 g of copper powder and 50 mL of nitrobenzene, and the mixture was stirred at 200° C. for 30 hours. After completion of the reaction, toluene was added to the mixture. The mixture was filtered to remove inorganics. Toluene and nitrobenzene were evaporated under a reduced pressure. The residue was purified by column chromatography on silica gel eluting with a 1:2 mixture of toluene and ligroin, to give 15 g(yield: 60%) of 10-diphenylamino-9,9′-bianthryl.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C[O:12]S([O-])(=O)=O.CC1C=CC=C2C=1N=C1C(C=CC=C1)=[NH+]2.C(O)(=O)C.O.NN>O.[Ni]>[OH:4][C:3]1[C:5]([OH:12])=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9]
Reactant: O=C(O)c1ccccc1O
Reactant: COS(=O)(=O)[O-]
Agent: [Ni]
Agent: Cc1cccc2[nH+]c3ccccc3nc12
Agent: NN
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cccc(O)c1O
Yield: 861.3 %

Procedure:
0.15 g of salicylic acid and 0.03 g of 9-methylphenazinium methylsulphate are placed into a reactor and dissolved in 100 ml of water acidified by acetic acid to the pH=3.0; then 3.0 ml of hydrazine hydrate and 0.5 g of Raney nickel are added thereto. Thereafter, the reaction mixture is maintained for 4 hours under vigorous stirring. Then nickel is filtered-off, the resulting mixture is evaporated to 10 ml and extracted with chloroform. After cooling the precipitated desired product is crystallized by a mixture of water and ethanol in the ratio of 1:1 to give 0.13 g of 2,3-dihydroxybenzoic acid (90% as calculated for the starting compound) having m.p. 203°-204° C. The composition, in %, is as follows:
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]([CH3:13])([OH:12])[CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18](=[O:21])[NH:17][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]#[N:23])[CH:8]=2)[O:3]1.[C:25]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:1][C:2]1([CH3:24])[C:11]([CH3:13])([OH:12])[CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH3:25])[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]#[N:23])[CH:8]=2)[O:3]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C(Oc2ccc(=O)[nH]n2)C1(C)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: Cn1nc(OC2c3cc(C#N)ccc3OC(C)(C)C2(C)O)ccc1=O

Procedure:
A mixture of 327 mg of 2,2,3-trimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyl-oxy)-6-cyano-chroman-3-ol, 20 ml of acetone, 400 mg of K2CO3 and 0.2 ml of dimethyl sulfate is refluxed for 2 hours. The mixture is filtered, concentrated and chromatographed on silica gel. There is obtained with ethyl-acetate/methanol (9:1) 2,2,3-trimethyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-oxy)-6-cyanochroman-3-ol, m.p. 197°-199°.
Reaction SMILES: [N:1]([C:4]1[C:13]([Cl:14])=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[Cl:23])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1)=[N+]=[N-].CCOC(C)=O>C(Cl)Cl.CC(O)=O.[Zn]>[NH2:1][C:4]1[C:13]([Cl:14])=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[Cl:23])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1
Reactant: COC(=O)c1cnc(N=[N+]=[N-])c(Cl)c1Nc1ccc(Br)cc1Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cnc(N)c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of methyl 6-azido-4-(4-bromo-2-chlorophenylamino)-5-chloronicotinate (316 mg, 0.76 mmol) in a mixture of DCM (6 ml) and AcOH (2 ml) was added Zn dust (255 mg, 3.9 mmol) in small portions. After complete addition it was furthers stirred at room temperature for 30 min. Then, the mixture was poured into EtOAc (30 ml), washed with H2O, saturated sodium bicarbonate solution and brine. The organic fractions were dried with Na2SO4 and the solvents were removed and the product was dried in oil-pump vacuo (246 mg, 83%). Rf (CHCl3/MeOH 30:1)=0.3. 1H-NMR (500 MHz, DMSO-D6): δ=9.17 (s, 1H), 8.45 (s, 1H), 7.70-7.70 (d, 1H), 7.38-7.36 (dd, 1H), 7.1 (s, 1H, br), 6.68-6.67 (d, 1H), 3.76 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH:21]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH:21]([N:34]1[CH2:39][CH2:38][N:37]([C:15](=[O:17])[CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)[CH2:36][CH2:35]1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-benzhydryl-piperazine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C29H32N2O5 [M+H]+: 489.
Reaction SMILES: [CH2:1]1[O:15][C:14]2[C:3](=[CH:4][C:5]3[O:10][CH2:9][CH:8]([CH2:11][NH2:12])[O:7][C:6]=3[CH:13]=2)[O:2]1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][CH:27]=[N:28]2)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[N:28]1[C:29]2[C:24](=[CH:23][CH:22]=[C:21]([O:20][CH2:19][CH2:18][CH2:17][NH:12][CH2:11][CH:8]3[O:7][C:6]4[CH:13]=[C:14]5[O:15][CH2:1][O:2][C:3]5=[CH:4][C:5]=4[O:10][CH2:9]3)[CH:30]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: BrCCCOc1ccc2cccnc2c1
Reactant: NCC1COc2cc3c(cc2O1)OCO3
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1cnc2cc(OCCCNCC3COc4cc5c(cc4O3)OCO5)ccc2c1
Temperature: 80 °C
Yield: 57.6 %

Procedure:
2,3-Dihydro-6,7-methylenedioxy-1,4-benzodioxin-2-methanamine (1.3 g, 6.2 mmole), 7-(3-bromopropoxy)quinoline (1.53 g, 5.5 mmole), diisopropylethylamine 2.6 g, 20 mmole) and sodium iodide (5.5 g, 37 mmole) were combined in 200 ml of DMF and heated at 80° C. for 15 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with 500 ml of dichloromethane. The mixture was washed with 250 ml each of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on 250 g of silica gel using 3% methanol/dichloromethane as eluant. The product-containing fractions were combined and concentrated in vacuum and the residue (2.25 g) recrystallized from ethanol with the addition of 6 ml of 4N isopropanolic HCl to give 1.25 g of the title compound as a yellow solid dihydrochloride salt, m.p. 224°-226° C.
Reaction SMILES: [Cu:1](I)I.[CH3:4][O:5][C:6]1[CH:7]=[C:8](C#C)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]>N.C(O)C>[C-:6]#[C-:11].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([Cu+2:1])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: I[Cu]I
Reactant: C#Cc1ccc(OC)c(OC)c1
Agent: N
Solvent: CCO
Product: COc1ccc([Cu+2])cc1OC
Product: [C-]#[C-]
Reaction time: 1 h
Yield: 48.1 %

Procedure:
In 15 ml of aqueous ammonia was dissolved 0.39 g of copper iodide, and the solution was added to a solution of 0.33 g of 3,4-dimethoxyphenylacetylene in 20 ml of ethanol at room temperature. The mixture was stirred for 1 hour, filtered, washed five times with water, once with ethanol, and once with ethyl ether, and dried under reduced pressure at 40° C. to yield 110 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8](O)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:38].CCCCCCC>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([Cl:38])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)OC(C)(C)C
Temperature: 4 °C
Reaction time: 0.75 h
Yield: 88.9 %

Procedure:
A solution of 374 g (1.48 mol) (2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in 1.6 l CH2Cl2 was treated with 680 g (2.6 mol) triphenylphosphine, cooled to 3-5° C. and treated in 10 min with 1.24 l (12.8 mol) CCl4, after 2 h at this temperature cooling was stopped, the reaction temperature raised during 2 h to 35° C. It was cooled down to 20° C. and stirred for further 45 min. After addition of 4 l of n-heptane, the reaction was evaporated to 2.9 l , cooled to 0° C., filtered, the residue was treated twice the same way, the third time by dissolving the residue again in 2 l of CH2Cl2. The solvents were evaporated and filtered through silica gel with hexane/tert.-butyl-methylether 9:1 as eluent. Evaporation of the solvents gave 347 g (89%) of (2S,4S)-4-Chloro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, MS: 246 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[Cl:13][C:14]1[CH:15]=[C:16]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:17][N:18]1[C:22]2[CH:23]=[C:24]([C:27]#[N:28])[CH:25]=[CH:26][C:21]=2[N:20]([C@H:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)[C:19]1=[O:34].O>ClCCl>[Cl:13][C:14]1[CH:15]=[C:16]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:17][N:18]1[C:22]2[CH:23]=[C:24]([C:27]#[N:28])[CH:25]=[CH:26][C:21]=2[N:20]([C@H:29]2[CH2:33][CH2:32][N:31]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:30]2)[C:19]1=[O:34]
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CCNC3)c3ccc(C#N)cc32)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cn2c(=O)n([C@H]3CCN(S(C)(=O)=O)C3)c3ccc(C#N)cc32)cc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
Methanesulfonyl chloride (27 mg) and triethylamine (24 mg) were added to a solution of 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[(S)-pyrrolidin-3-yl]-2,3-dihydro-1H-benzimidazol-2-one (75 mg) in dichloromethane (2 mL). The reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was poured into water and extracted with a mixture of chloroform and methanol (5:1). The organic layer was washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The obtained crystals were suspended in hot ethyl acetate and then cooled with stirring. The resulting precipitate was collected by filtration and washed with ethyl acetate to give 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[(S)-1-methanesulfonylpyrrolidin-3-yl]-2,3-dihydro-1H-benzimidazol-2-one (76 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=O)[CH:7]=1.CSC.B>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([CH2:8][CH2:9][N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(CC(=O)N2CCOCC2)c1
Agent: B
Solvent: Cc1ccccc1
Solvent: CSC
Product: Cc1ccc([N+](=O)[O-])c(CCN2CCOCC2)c1
Yield: 79.1 %

Procedure:
2-(5-Methyl-2-nitro-phenyl)-1-morpholino-ethanone (267 mg, 1.01 mmol) was dissolved in toluene (10 mL) and treated with borane dimethylsulfide (983 mg, 1.23 mL, 11.7 mmol) and heated at reflux for 2 h. The reaction was concentrated in vacuo then resuspended in 2 N HCl (8 mL) and heated at reflux for 30 min. The reaction was diluted with 1N HCl and washed with ethyl acetate. The solution was basified (5 N NaOH) and the product extracted into dichloromethane (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 4-[2-(5-methyl-2-nitro-phenyl)ethyl]morpholine as an oil (200 mg, 79% yield). LC/MS m/z 251.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35]([N:42]1[CH2:46][CH2:45][C@H:44]([NH2:47])[CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH2:35]([N:42]1[CH2:46][CH2:45][C@H:44]([NH:47][C:27]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[O:33])[CH2:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H]4CCN(Cc5ccccc5)C4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 28.5 %

Procedure:
Chloroform (10 ml) and triethylamine (2 ml) were added to 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) to prepare a solution. Triphosgene (110 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. (3S)-(+)-1-Benzyl-3-aminopyrrolidine (89 mg) was then added thereto, and the mixture was stirred at room temperature for 5 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (48 mg, yield 29%).