Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:32]=[CH:31][C:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20]C)=[CH:17][CH:18]=3)[O:13][C:12](=[O:22])[C:11]=2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[CH:7][CH:6]=1.[Al+3].[Cl-].[Cl-].[Cl-].CCS.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:32]=[CH:31][C:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[O:13][C:12](=[O:22])[C:11]=2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[CH:7][CH:6]=1
Reactant: COc1ccc2c(Cc3ccc(OCCBr)cc3)c(-c3ccc(Cl)cc3Cl)c(=O)oc2c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: O=c1oc2cc(O)ccc2c(Cc2ccc(OCCBr)cc2)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 4-(4-(2-bromoethoxy)-benzyl)-3-(2,4-dichlorophenyl)-7-methoxy-chromen-2-one (4.0 g, 7.49 mmol), AlCl3 (5.89 g, 44.2 mmol), and EtSH (2.77 mL, 37.4 mmol) in CH2Cl2 (200 mL) was stirred at room temperature for 2.5 h. The mixture was slowly poured into CH2Cl2/sat. aq NaHCO3. The resultant layers were separated, and the aqueous phase was further extracted with CH2Cl2 (3×). The aqueous layer was raised to pH 10 with aqueous 2M NaOH and extracted with AcOEt (3×). Each organic layer was washed with brine and dried (MgSO4), and the combined organic phases were concentrated in vacuo. The resultant residue was purified using flash chromatography (250 g silica gel, 95:5→9:1 CH2Cl2:AcOEt) to afford the title compound, which was isolated as an off-white solid (3.454 g, 89%). 1H NMR (300 MHz, CDCl3) δ 7.50 (d, J=2.0 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.25 (dd, J=2.0, 8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.99 (d, J=2.0 Hz, 1H), 6.94 (d, J=8.5 Hz, 2H), 6.78 (d, J=8.5 Hz, 2H), 6.73 (dd, J=2.0, 8.8 Hz, 1H), 6.61–6.49 (br signal, 1H), 4.23 (t, J=6.0 Hz, 2H), 4.04 (d, J=15.5 Hz, 1H), 3.78 (d, J=15.5 Hz, 1H), 3.61 (t, J=6.0 Hz, 2H); MS (ESI) m/z 516.9 (M−H)−; HPLC tR 7.41 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=[CH:10]1.[Br:19]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:19][C:12]1[N:11]=[CH:10][N:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cncn1-c1ccc(C)cc1C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Br)ncn1-c1ccc(C)cc1C
Temperature: 75 °C
Yield: 27.8 %

Procedure:
To 5.0 g (21 mmol) of ethyl 1-(2,4-dimethylphenyl)-1H-imidazole-5-carboxylate in 40 mL of DMF was added 7.3 g (41 mmol) of N-bromosuccinimide and the resulting solution was heated to 75° C. for 75 min. The reaction was cooled to room temperature, diluted with 400 mL of water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate, filtered and the resulting filtrate was concentrated to an oil. The oil was purified by flash chromatography eluting with a 17-20% ethyl acetate/hexanes gradient mixture to give 1.89 g (29%) of the title compound as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]2)[CH:7]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1>>[F:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]([C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=2)=[O:28])=[CH:7][C:6]=1[C@:8]1([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC1(C)C[C@@](C)(c2cc(N)ccc2F)NC(=S)CO1
Product: CC1(C)C[C@@](C)(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)NC(=S)CO1
Yield: 72 %

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (S)-5-(5-amino-2-fluoro-phenyl)-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A17A) (132 mg, 0.47 mmol) and commercially available 5-chloro-pyridine-2-carboxylic acid [CAS No. 86873-60-1] (92 mg, 0.58 mmol). The compound was obtained as white foam (177 mg, 72%). MS (ISP): m/z=422.1 [(M+H)+] and 424.1 [(M+2+H)+].
Reaction SMILES: FC(F)(F)C([O-])=O.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]3[CH2:20][NH:21][CH2:22][CH2:23][C:18]=3[NH2+:17][N:16]=2)=[CH:11][CH:10]=1.CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]3[CH2:20][N:21]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:22][CH2:23][C:18]=3[NH:17][N:16]=2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1ccc(C2=N[NH2+]C3=C2CNCC3)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCc2[nH]nc(-c3ccc(Br)cc3)c2C1
Reaction time: 2.5 h
Yield: 50.8 %

Procedure:
To a stirred solution of 3.11 g (11.1 mmol) of 3-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinium trifluoroacetate and 4.71 mL (33.5 mmol) of Et3N in DMF (55 mL) was slowly added 1.21 mL (15.6 mmol) of methanesulfonyl chloride. After 2.5 h, the solvent was removed under reduced pressure and the residue was diluted with CH2Cl2 (100 mL) and saturated NaHCO3 (100 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (2×30 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure. Purification by column chromatography (silica, 0-5% MeOH/CH2Cl2) afforded 2.01 g (50%) of the title compound. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.3. MS (electrospray): m/z calculated for C13H14BrN3O2S [M++H] 356.00, observed 356.0.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[O:20][C:9]2=[C:10]3[C:15](=[C:16]([CH3:18])[CH:17]=[C:8]2[CH2:7]1)[NH:14][C:13](=[O:19])[CH:12]=[CH:11]3)(=[O:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(O)(=O)C>[C:1]([NH:4][CH2:5][C:6]1[O:20][C:9]2=[C:10]3[C:15](=[C:16]([CH3:18])[CH:17]=[C:8]2[CH:7]=1)[NH:14][C:13](=[O:19])[CH:12]=[CH:11]3)(=[O:3])[CH3:2]
Reactant: CC(=O)NCC1Cc2cc(C)c3[nH]c(=O)ccc3c2O1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(=O)O
Product: CC(=O)NCc1cc2cc(C)c3[nH]c(=O)ccc3c2o1
Temperature: 60 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
2-(N-Acetylaminomethyl)-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (750 mg) was suspended in acetic acid (15 ml), to which 2,3-dichloro-5,6-dicyano -1,4-benzoquinone (782 mg) was added. The mixture was stirred at 60° C. for 1 hour. The solvent was distilled off under reduced pressure. To the residue, aqueous 1N NaOH solution (50 ml) was added. Precipitated crystals were collected. As a result, 553 mg of 2-(N-acetylaminomethyl) -6,7-dihydro-5-methylfuro[2,3-f]quinoline-7-one (74.3%) was obtained.
Reaction SMILES: Br[C:2]1(Br)[C:6]2[CH:7]=[N:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]1=[O:19]>C(O)(=O)C.[Pd].[Zn]>[CH3:12][O:11][C:9]1[N:8]=[CH:7][C:6]2[CH2:2][C:3](=[O:19])[N:4]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:5]=2[CH:10]=1
Reactant: COc1cc2c(cn1)C(Br)(Br)C(=O)N2c1ccccc1
Agent: [Pd]
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1cc2c(cn1)CC(=O)N2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
To a solution of 8.73 g of the compound of step 2 in acetic acid (180 ml) was added zinc, and the suspension was stirred at room temperature overnight. The mixture was extracted with EA, the organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The resulting solid was dissolved in ethanol (245 ml), and palladium on activated carbon (1.75 g, 1.64 mmol, 10%) was added. The reaction mixture was hydrogenated (5.2 bar H2) at room temperature overnight. The mixture was filtered over celite, the solvent was removed under reduced pressure and the solid was purified by silica gel chromatography (EA (10 to 70%)/HEP). 870 mg of the title compound were obtained.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([OH:32])=[C:25]([CH:31]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])#[CH:20].C(N(CC)CC)C.Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O1CCCC1>[OH:32][C:24]1[CH:23]=[CH:22][C:21]([C:19]#[C:20][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=3)(=[O:10])=[O:9])[CH:3]=2)=[CH:31][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: C#Cc1ccc(O)c(C(=O)OCC)c1
Reactant: Cc1cccnc1NS(=O)(=O)c1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C#Cc2cccc(S(=O)(=O)Nc3ncccc3C)c2)ccc1O

Procedure:
3-Iodo-N-(3-methyl-2-pyridinyl)benzenesulfonamide (18.7 g, 50 mmol), ethyl 5-ethynyl-2-hydroxybenzoate (9.5 g, 50 mmol), triethylamine (65 ml) and tetrahydrofuran (65 ml) were stirred at 60° C. Dichlorobis(triphenylphosphine)palladium (250 mg, 0.36 mmol) and copper(I)iodide (140 mg, 0.7 mmol) were added with stirring. After 1 h the solution was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried, treated with activated carbon and the solvent evaporated. The residue was recrystallized from methanol, then from toluene and finally from acetic acid. Yield 12.7 g 58%.
Reaction SMILES: [Mg].C(I)C.C([C:7]1([OH:21])[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[S:10][C:9]2[S:18][CH:19]=[CH:20][C:8]1=2)C>CCOCC>[S:18]1[C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH2:13][C:7](=[O:21])[C:8]=2[CH:20]=[CH:19]1
Reactant: CCC1(O)Cc2ccccc2Sc2sccc21
Agent: [Mg]
Solvent: CCI
Solvent: CCOCC
Product: O=C1Cc2ccccc2Sc2sccc21

Procedure:
From 4.9 g (0.2 mole) of magnesium, 31.2 g (0.2 mole) of ethyl iodide in abs. ether and 23.2 g (0.1 mole) of benzo[f]thieno[2,3-b]thiepin-4(5H)-one, there is obtained 4-ethyl-4,5-dihydro-benzo[f]thieno[2,3-b]thiepin-4-ol as an oily crude product.
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[C:9](=[O:11])[CH3:10])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[BH4-].[Na+].Cl>CO>[OH:11][CH:9]([CH3:10])/[CH:8]=[C:2](\[CH3:1])/[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)/C(C)=C/C(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)/C(C)=C/C(C)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
28 (ethyl (2E)-2-methyl-4-oxopent-2-enoate) (HPLC: ˜84 area %, 16.73 g, 90 mmol) is dissolved in MeOH (500 ml) and cooled to 0° C. To the resulting solution is added NaBH4 (1.04 g, 27.5 mmol) in portions over 30 min. After 3 hours additional stirring at 0° C., the pH is adjusted to 5 with 2 M HCl (12 ml). The reaction mixture is concentrated under reduced pressure at room temperature. H2O (100 ml) is added. After acidification with 2 M HCl to pH 1, extraction with tBuOMe (1 and 0.5 l) follows. The organic phases are washed with H2O (100 ml) and brine (2×100 ml) successively. The combined organic phases are dried with Na2SO4 and evaporated under reduced pressure at 40° C. The residue is purified by flash chromatography (AcOiPr:heptane fraction 20:80 to 40:60) and yields 29 (rac-Ethyl (2E)-4-hydroxy-2-methylpent-2-enoate) (11.26 g, 79%) as a yellowish oil.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[C:16](I)[N:15]=2)=[N:6]1.[Cu][C:31]#[N:32]>N1C=CC=CC=1>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[C:16]([C:31]#[N:32])[N:15]=2)=[N:6]1
Reactant: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: N#C[Cu]
Solvent: c1ccncc1
Product: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(C#N)c21
Yield: 19.4 %

Procedure:
200 mg (0.399 mmol) of the compound obtained in example 107 in pyridine (3 ml) were admixed with 37 mg (0.419 mmol) of copper(I) cyanide and heated to reflux overnight. After cooling, the reaction mixture was filtered and concentrated, and the residue was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 31 mg of the title compound were obtained (18% of theory).
Reaction SMILES: [C:1]1([C:7](=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].CNCCNC.I[C:32]1[CH:33]=[C:34]([CH:40]=[CH:41][CH:42]=1)[C:35]([O:37][CH2:38][CH3:39])=[O:36]>[Cu]I.C(#N)C>[CH2:38]([O:37][C:35](=[O:36])[C:34]1[CH:40]=[CH:41][CH:42]=[C:32]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9](=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])[C:10]2=[O:18])[CH:33]=1)[CH3:39]
Reactant: CC(=C1C(=O)Nc2ccccc21)c1ccccc1
Reactant: CCOC(=O)c1cccc(I)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CCOC(=O)c1cccc(N2C(=O)C(=C(C)c3ccccc3)c3ccccc32)c1
Temperature: 80 °C
Reaction time: 23 h
Yield: 88.8 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), 3-(1-phenyl-ethylidene)-1,3-dihydro-indol-2-one (352.7 mg, 1.5 mmol), and K2CO3 (276 mg, 2.0 mmol), evacuated, and backfilled with argon. N,N′-dimethylethylenediamine (11 uL, 0.10 mmol, 10 mol %), ethyl 3-iodobenzoate (278.8 mg, 1.01 mmol), and acetonitrile (1.5 ml) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 80° C. for 23 h. The reaction was monitored by HPLC. When the reaction was finished, the solvent was removed under reduced pressure. The residue was separated by flash chromatography column (gradient elution, 5-10% ethyl acetate in petroleum ether) to give 3-[2-oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-benzoic acid ethyl ester as yellow powder (344 mg, 90%). 1H NMR (400 MHz, CDCl3) δppm 1.42 (t, J=7.20 Hz, 3H) 2.87 (s, 3H) 4.42 (q, J=7.07 Hz, 2H) 6.25 (d, J=7.58 Hz, 1H) 6.68-6.78 (m, 2H) 7.09 (t, J=7.71 Hz, 1H) 7.34-7.40 (m, 2H) 7.47-7.58 (m, 3H) 7.62-7.72 (m, 2H) 8.11-8.19 (m, 2H). MS calcd. for C25H21NO3 383, obsd. (ESI+) [(M+H)+] 383.9.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:10][CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[C:5]([O:10][CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ncccc2[N+](=O)[O-])C1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(Oc2ncccc2N)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
Palladium hydroxide on carbon (20%, 0.071 g, 0.51 mmol) was added into a solution of tert-butyl 3-(3-nitropyridin-2-yloxy)azetidine-1-carboxylate (3.0 g, 10.2 mmol) and ammonium formate (3.20 g, 50.8 mmol) in ethanol (100 mL). The solution was stirred at ambient temperature for 18 hours, filtered through Celite and concentrated in vacuo. The crude product was extracted with chloroform (×3) and the combined organic fractions concentrated in vacuo to yield pale brown solid (2.48 g, 92%).
Reaction SMILES: [O:1]=[C:2]1[C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.Cl[CH2:23][CH:24]1[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+].[I-].[K+].[BrH:34]>CN(C)C=O.CCOCC.O.C(Cl)(Cl)Cl>[BrH:34].[CH:24]1([CH2:23][N:15]2[CH2:14][CH2:13][C:12]3([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[O:5][C:4]4[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=4[C:2]3=[O:1])[CH2:17][CH2:16]2)[CH2:26][CH2:25]1
Reactant: O=C1c2ccccc2Oc2ccccc2C12CCNCC2
Reactant: ClCC1CC1
Agent: Br
Agent: O=C([O-])O
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2Oc2ccccc2C12CCN(CC1CC1)CC2
Reaction time: 16 h

Procedure:
A mixture of 2.0 g of 10,11-dihydro-11-oxospiro-[dibenz(b,f)-oxepin-10,4'-piperidine], free base of Example 3, 0.74 g of chloromethylcyclopropane, 1.8 g of sodium bicarbonate and 1.8 g of potassium iodide in 15 ml of dimethylformamide is stirred at 70°-80° C. for 16 hours. The resulting suspension is permitted to cool before being diluted with ether and water. The organic phase is successively dried, filtered and concentrated under vacuum, leaving a viscous oil. The oil is dissolved in chloroform and the chloroform solution is passed through an alumina column, with ether as an eluant. The purified oil is dissolved in ether where it is converted to its hydrobromic acid salt which is recrystallized from a methyl alcohol-ether mixture to provide rhombic crystals, mp 258°-259° C., (dec) of 1'-cyclopropylmethyl-10,11-dihydro-11-oxospiro[dibenz(b,f)oxepin-10,4'-piperidine]hydrobromide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:19]=[N+:20]=[N-:21])=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN=[N+]=[N-])cc1-c1ccccc1
Temperature: 75 °C
Yield: 77.1 %

Procedure:
A mixture of 4-bromomethyl-2-phenylbenzoic acid methyl ester (1.5 g, 4.9 mmol), sodium azide (1.28 g, 19.7 mmol) and tetrabutylammonium iodide (1.3 g, 4.9 mmol) in DMF (16 mL) was heated at 75° C. for 18 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (15% ethyl acetate-hexanes) to give the desired azide as a colorless oil (1.01 g).
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:13][C@@H:14]1[C@@H:18]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:17][C@@H:16]([N:28]2[CH:33]=[CH:32][C:31](=[O:34])[NH:30][C:29]2=[O:35])[C@@:15]1([OH:39])[CH2:36][CH2:37]O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].[NH4+].[Cl-]>N1C=CC=CC=1.C(Cl)Cl.CO>[CH2:21]([O:20][C@H:19]1[C@@:15]2([O:39][CH2:37][CH2:36]2)[C@H:16]([N:28]2[CH:33]=[CH:32][C:31](=[O:34])[NH:30][C:29]2=[O:35])[O:17][C@@H:18]1[CH2:14][O:13][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=c1ccn([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@]2(O)CCO)c(=O)[nH]1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=c1ccn([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@]23CCO3)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
Methanesulfonyl chloride (0.800 mL, 10.34 mmol) was added to 8 (4.32 g, 9.22 mmol) in dry pyridine (100 mL). After 1 hour and 15 minutes, 0.1 equivalents more methane-sulfonyl chloride was added and the mixture was further stirred at room temperature for 45 minutes. Then, a small amount of methanol was added and the mixture was evaporated to dryness. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated NaHCO3 (2×50 mL). The combined aqueous layer was extracted with ethyl acetate. The combined organic layer was then dried over Na2SO4 and concentrated in vacuo. The obtained residue was dissolved in dry THF and 95% NaH (932 mg, 36.9 mmol) was added at once at room temperature. After stirring for 2 hours at room temperature, the reaction mixture was poured on a saturated aqueous solution of NH4Cl (30 mL) followed by addition of CH2Cl2 (250 mL). The separated organic layer was washed with saturated aqueous NaHCO3 (2×100 mL) and the combined aqueous layer was extracted with CH2Cl2 (250 mL). The combined organic layer was dried (Na2SO4), filtered and evaporated to dryness under reduced pressure. The residue obtained was purified by column chromatography eluting first with heptane, then with ethyl acetate to afford 9 (3.27 g, 79%) as a foam. HPLC Condition A, Rt: 2.33 min, m/z=451 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 2.20-2.38 (m, 1 H) 2.38-2.52 (m, 1 H) 3.62-3.73 (m, 1 H) 3.89-4.13 (m, 3 H) 4.38-4.56 (m, 3 H) 4.56-4.68 (m, 1H) 4.70-4.88 (m, 2 H) 5.25 (d, J=8.00 Hz, 1 H) 6.25 (s, 1 H) 7.18-7.47 (m, 10 H) 7.87 (d, J=8.20 Hz, 1 H) 8.90 (br. s., 1 H)
Reaction SMILES: [OH:1][C:2]1[CH2:6][N:5]([CH2:7][C:8]([NH2:10])=[O:9])[C:4](=[O:11])[C:3]=1[C:12](OC)=O>C(#N)C.O>[OH:1][C:2]1[CH2:6][N:5]([CH2:7][C:8]([NH2:10])=[O:9])[C:4](=[O:11])[C:3]=1[C:12]1[CH2:6][N:5]([CH2:7][C:8]([NH2:10])=[O:9])[C:4](=[O:11])[CH:3]=1
Reactant: COC(=O)C1=C(O)CN(CC(N)=O)C1=O
Solvent: CC#N
Solvent: O
Product: NC(=O)CN1CC(C2=C(O)CN(CC(N)=O)C2=O)=CC1=O
Reaction time: 12 h

Procedure:
4.3 g of 2,5-dihydro-4-hydroxy-3-methoxycarbonyl-2-oxo-1H-pyrrole-1-acetamide are suspended in 50 ml of acetonitrile and 30 ml of water. Heating to 75° initiates the removal of carbon dioxide; the reaction mixture is stirred at this temperature for 12 hours. After cooling, the resulting product is filtered off, washed with water and acetone and dried under reduced pressure. 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo-[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid diamide is obtained in the form of white crystals having a melting point of 300° (decomposition). The product is identical to that described in Example 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:36])C(=O)C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(=O)OCC>C1COCC1>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)[CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][Br:36])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)NC(COCc1ccccc1CO)Cc1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(COCc1ccccc1CBr)Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 48.7 %

Procedure:
To a solution of compound 3h (4.15 g, 9.2 mmol) in dry THF (50 mL) was added NBS (4.1 g, 23 mmol) and PPh3 (6 g, 23 mmol) at 0° C. The mixture was stirred at 0° C. for 20 min. Then the mixture was stirred at rt for 2 hr. The solvent was evaporated in vacuo and purified by CC eluting with PE:EA=4:1 to give 3i as a white solid (2.3 g, 50% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1)=O)(C)(C)C.[ClH:32]>C(Cl)Cl>[ClH:32].[ClH:32].[C@H:12]12[CH2:14][C@H:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2Cc1ccc(Cc2nc3ccccc3s2)cc1
Agent: Cl
Solvent: ClCCl
Product: c1ccc2sc(Cc3ccc(CN4C[C@@H]5C[C@H]4CN5)cc3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 5-(4-benzothiazol-2-ylmethyl-benzyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.82 g, 1.9 mmol) in CH2Cl2 (19 mL) was added HCl (4.0 N in 1,4-dioxane, 7 mL) and the resulting white suspension was stirred at rt for 4 h. The reaction mixture was concentrated affording the title compound as a white solid (0.9 g, 100%). MS (ESI): mass calcd. for free amine C20H21N3S, 335.47; m/z found, 336.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 12.09-11.07 (br m, 1H), 10.16-9.71 (br m, 2H), 8.03 (d, J=8.0 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.72-7.70 (m, 2H), 7.50-7.47 (m, 3H), 7.42-7.39 (m, 1H), 4.62-4.59 (br m, 0.5H), 4.52 (br s, 2H), 4.48-4.44 (br m, 2H), 4.37-4.34 (br m, 1.5H), 3.95-3.92 (m, 1H), 3.72-3.70 (m, 1H), 3.34-3.30 (m, 2H), 2.69-2.63 (m, 0.5H), 2.48-2.43 (m, 0.5H), 2.13-2.06 (m, 1H).