Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]([CH3:61])=[C:20]([CH2:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][NH:53]C(=O)OC(C)(C)C)=[CH:28][CH:27]=3)(=[O:25])=[O:24])[N:21]=2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl>FC(F)(F)C(O)=O>[NH2:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][O:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([CH2:22][C:20]2[N:21]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])=[CH:16][CH:15]=3)[O:18][C:19]=2[CH3:61])(=[O:24])=[O:25])=[CH:27][CH:28]=1
Reactant: Cc1oc(-c2ccc(C(=O)NCc3ccccc3)cc2)nc1CS(=O)(=O)c1ccc(CCCOCCOCCOCCOCCOCCOCCNC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1oc(-c2ccc(C(=O)NCc3ccccc3)cc2)nc1CS(=O)(=O)c1ccc(CCCOCCOCCOCCOCCOCCOCCN)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A solution of carbamate 62 (55 mg, 0.064 mmol) in a mixture of trifluoroacetic acid (2 mL) and anhydrous DCM (8 mL) was stirred at 20° C. for 1 h. The solvent was evaporated and the residue was purified by column chromatography, eluting with 10% MeOH/DCM containing 1% aqueous NH3, to give the amine 63 (38 mg, 78%) as a white gum: 1H NMR δ 9.18 (t, J=5.9 Hz, 1H, CONH), 8.01 (br d, J=8.6 Hz, 2H, H-2, H-6), 7.89 (br d, J=8.6 Hz, 2H, H-3, H-5), 7.79 (br d, J=8.5 Hz, 2H, H-2″, H-6″), 7.68 (br d, J=8.5 Hz, 2H, H-3″, H-5″), 7.33-7.34 (m, 4H, H-2′, H-3′, H-5′, H-6′), 7.22-7.28 (m, 1H, H-4′), 4.74 (s, 2H, CH2SO2), 4.49 (d, J=5.9 Hz, 2H, CH2NH), 4.45 (s, 2H, CH2C≡C), 3.62-3.65 (m, 2H, CH2O), 3.56-3.59 (m, 2H, CH2O), 3.50-3.52 (m, 16H, CH2O), 3.38 (t, J=5.7H, 2H, CH2O), 2.69 (t, J=5.5 Hz, 2H, H-21′″), 2.17 (s, 3H, CH3), NH2 not observed; 13C NMR δ 165.4, 158.1, 150.1, 139.5, 138.2, 135.7, 132.0 (2), 128.7, 128.6, 128.3 (2), 128.1 (2), 127.4, 127.2 (2), 126.8 (2), 125.7, 125.4 (2), 90.1, 84.1, 71.7, 69.8 (6), 69.7, 69.6, 69.5, 68.8, 58.0, 52.7, 42.7, 40.8, 9.7; HRMS calcd for C40H50N3O10S (MH+): m/z 764.3211. found m/z 769.3227.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:45])[CH3:44])[CH2:38]2)[C:31]2[N:36]=[N:35][NH:34][C:32]=2[N:33]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[Cl:54]>>[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:45])[CH3:44])[CH2:38]2)[C:31]2[C:32](=[N:34][N:35]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[Cl:54])[N:36]=2)[N:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(=O)N[C@H]1CCN(c2nc(NC(C)(C)C)nc3[nH]nnc23)C1
Reactant: Clc1ccccc1CBr
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(=O)N[C@H]1CCN(c2nc(NC(C)(C)C)nc3nn(Cc4ccccc4Cl)nc23)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from N—[(S)-1-(5-tert-Butylamino-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl]-acetamide and 1-(bromomethyl)-2-chlorobenzene. MS (m/e): 443.4 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:22]=[C:23]([N:31]4[CH2:35][CH2:34][CH2:33][C@H:32]4[CH2:36][NH2:37])[C:24]4[S:29](=[O:30])[CH2:28][CH2:27][C:25]=4[N:26]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.[C:38]1([N:44]=[C:45]=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[N:22]=[C:23]([N:31]4[CH2:35][CH2:34][CH2:33][C@H:32]4[CH2:36][NH:37][C:45]([NH:44][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:46])[C:24]4[S:29](=[O:30])[CH2:28][CH2:27][C:25]=4[N:26]=3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC[C@@H]1CCCN1c1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@@H]1CCCN1c1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg C-((S)-1-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl}-pyrrolidin-2-yl)-methylamine trifluoroacetate, Diastereomer 2 (Example 226) (see scheme 3, 3.17.2) are placed in 2 ml dichloromethane and 30 μl phenylisocyanate are added. The reaction mixture is stirred for 4 hours at ambient temperature and then evaporated to dryness. The product is purified by preparative HPLC (method A). 64 mg of the product are obtained as a powder. Analytical HPLC-MS (method D): RT=1.33 min.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[C:29]([C:30](O)=[O:31])=[CH:28][C:27]([CH3:33])=[N:26]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:30]([C:29]2[N:25]([CH3:24])[N:26]=[C:27]([CH3:33])[CH:28]=2)=[O:31])=[O:10])[N:12]=1
Reactant: Cc1cc(C(=O)O)n(C)n1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc(C)nn2C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=0.84 min; [M+H]+=450.3.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH:26][C@@H:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Product: c1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
3-Phenoxybenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][CH2:7][CH2:8][CH:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[C:10]1([CH:9]2[N:3]3[CH2:4][CH2:5][N:1]=[C:2]3[NH:6][CH2:7][CH2:8]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OC(CCNC1=NCCN1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(C2CCNC3=NCCN32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 8 parts of α-{2-[N-(2-imidazolin-2-yl)amino]ethyl} benzylalcohol from the preceding step and 36 parts of sulfuric acid 80% is stirred for 3 hours at room temperature. The reaction mixture is poured onto crushed ice and the resulting solution is allowed to stand overnight at room temperature. It is then alkalized with sodium hydroxide solution and the product is extracted with toluene. The extract is dried, filtered and evaporated. The residue is triturated in acetone. The solid product is filtered off and crystallized from acetone, yielding 2,3,5,6,7,8-hexahydro-5-phenylimidazo[1,2-a]pyrimidine; m.p. 145.5°C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]1)=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:11]([O:14][C:15]([N:17]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCOC(=O)N1CCC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1CCC(=O)C1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A methylene chloride solution (375 ml) of dimethyl sulfoxide (21.8 ml) was cooled to -70° C. and a methylene chloride solution (125 ml) of oxalyl chloride (13.4 ml) was added thereto below -50° C. After completion of the addition, the mixture was stirred for 30 minutes, at the end of which time a solution of 1-allyloxycarbonyl-3-hydroxypyrrolidine (25 g) in methylene chloride (125 ml) was added below -50° C. The mixture was stirred at the same temperature for 1 hour and, then, triethylamine (101 ml) was added at a temperature below -50° C. The mixture was further stirred at that temperature for 1 hour. Thereafter, the temperature was allowed to rise gradually to room temperature and the reaction mixture was diluted with water and allowed to stand. The aqueous layer was then separated and extracted with 2 portions of methylene chloride. The organic layers were combined, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, water and aqueous sodium chloride solution successively, and dried over anhydrous magnesium sulfate. Finally the solvent was distilled off under reduced pressure to give 1-allyloxycarbonyl-3-oxopyrrolidine (24.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:10][CH2:11][OH:12])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:40]([O:42][C:43](=[O:56])[C@@H:44]([O:53][CH2:54][CH3:55])[CH2:45][C:46]1[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=1)[CH3:41].CCOC(/N=N/C(OCC)=O)=O>>[CH2:40]([O:42][C:43](=[O:56])[C@@H:44]([O:53][CH2:54][CH3:55])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:12][CH2:11][CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:48][CH:47]=1)[CH3:41]
Reactant: COc1ccc(C(=CCO)c2ccc(OC)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OCC=C(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1)OCC
Yield: 17.7 %

Procedure:
Reaction of 3,3-bis-(4-methoxyphenyl)-prop-2-en-1-ol (1.62 g, 5.99 mmol), triphenylphosphine (2.88 g, 10.98 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (1.19 g, 4.99 mmol) and diethy lazodicarboxylate (1.92 g, 11.04 mmol) in an identical manner to example 1 gave the title compound (0.434 g, 17%).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[C:24]([C:26]4[CH:41]=[CH:40][C:29]([O:30][CH2:31][CH2:32][N:33]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:28][CH:27]=4)([CH3:25])[O:23][C:22]4[CH:21]=[C:20]([O:42][Si](C(C)(C)C)(C)C)[CH:19]=[CH:18][C:17]=4[C:12]=3[CH2:13][O:14][C:15]=2[CH:16]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH4+].[Cl-].C(OCC)(=O)C>C1COCC1>[N:33]1([CH2:32][CH2:31][O:30][C:29]2[CH:28]=[CH:27][C:26]([C:24]3([CH3:25])[C:11]4[C:10]5[CH:9]=[CH:8][C:7]([OH:6])=[CH:16][C:15]=5[O:14][CH2:13][C:12]=4[C:17]4[CH:18]=[CH:19][C:20]([OH:42])=[CH:21][C:22]=4[O:23]3)=[CH:41][CH:40]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CC1(c2ccc(OCCN3CCCCCC3)cc2)Oc2cc(O[Si](C)(C)C(C)(C)C)ccc2C2=C1c1ccc(O[Si](C)(C)C(C)(C)C)cc1OC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccc(OCCN3CCCCCC3)cc2)Oc2cc(O)ccc2C2=C1c1ccc(O)cc1OC2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 1-(2-{4-[2,8-bis-(tert-butyl-dimethyl-silyloxy)-5-methyl-5,11-dihydro-chromeno[4,3-c]chromen-5-yl]-phenoxy}-ethyl)-azepane (77.5 mg, 0.11 mmol) in THF (7 mL) was added tetrabutylammonium fluoride (1M in THF, 213 μL, 0.21 mmol). The mixture was stirred at room temperature for 40 min. Saturated NH4Cl was then added followed by addition of ethyl acetate. The resulting layers were separated, organic layer was washed with brine, and dried over MgSO4. The remaining solvent was evaporated and the residue dried under vacuum for 2 h at room temperature to yield the title compound, which was carried on to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[N:3]=1
Reactant: Cc1cccc(Cl)n1
Reactant: C1CCNCC1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(CN2CCCCC2)n1
Yield: 41 %

Procedure:
To 2-chloro-6-methylpyridine (50.0 g, 0.392 mole) in 393 mL of carbon tetrachloride was added N-bromosuccinicide (87.2 g, 0.49 mole) and 1.0 g of benzoyl peroxide. The mixture was stirred at reflux for 22 hours, cooled to 10° and filtered. The chilled filtrate then was treated slowly with piperidine (83.5 g, 0.98 mole) and allowed to stir at ambient temperature for 18 hours. After removal of the piperidine hydrobromide by filtration, the filtrate was concentrated to about half volume and extracted with 6N HCl (65 mL) and 3N HCl (40 mL). The acid extracts were made basic with 40% sodium hydroxide and the product was extracted into methylene chloride. The solvent was evaporated and the residue distilled to yield 41% of the title compound as a colorless oil, b.p. 101°-103°/0.45 mm Hg.
Reaction SMILES: [NH2:1][CH:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH2:9][S:10][C:11]3[N:16]4[N:17]=[C:18]([CH2:20][OH:21])[N:19]=[C:15]4[N:14]=[C:13]([CH3:22])[CH:12]=3)[CH2:7][S:8][C@H:3]12.[OH-].[Na+].[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36](Cl)=[O:37]>O.CCOCC>[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36]([NH:1][CH:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH2:9][S:10][C:11]3[N:16]4[N:17]=[C:18]([CH2:20][OH:21])[N:19]=[C:15]4[N:14]=[C:13]([CH3:22])[CH:12]=3)[CH2:7][S:8][C@H:3]12)=[O:37]
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n2nc(CO)nc2n1
Reactant: O=C(Cl)Cc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)n2nc(CO)nc2n1
Yield: 80.2 %

Procedure:
In 100 ml of water was suspended 4.6 g of 7-amino-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylic acid obtained in Example 2, and a 2N aqueous sodium hydroxide solution was added to the suspension and the mixture was dissolved at a pH 7. To this solution was while stirring under ice-cooling added dropwise a solution of 1.93 g of 2-thienyl acetyl chloride in 20 ml of ether over one hour. During this time, a pH of the mixture was maintained to 7 to 7.5 by addition of a 2N aqueous sodium hydroxide. After stirring for further one hour, the reaction mixture was washed with ethyl acetate. The reaction mixture was adjusted to pH 2.5 with a 2N hydrochloric acid under ice-cooling and stirring, and precipitated crystals were collected by filtration, washed with water and dried to obtain 4.81 g of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([O:16][CH3:17])[C:9]([O:14][CH3:15])=[C:10]([CH:13]=1)[C:11]#[N:12].CON(C)[C:21](=[O:37])[CH:22]([O:35][CH3:36])[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31]([CH3:34])=[N:32][N:33]=2)=[CH:25][CH:24]=1>>[CH3:15][O:14][C:9]1[C:8]([O:16][CH3:17])=[CH:7][C:6]([C:2]2[O:1][C:5]([C:21](=[O:37])[CH:22]([O:35][CH3:36])[C:23]3[CH:24]=[CH:25][C:26]([C:29]4[O:30][C:31]([CH3:34])=[N:32][N:33]=4)=[CH:27][CH:28]=3)=[CH:4][CH:3]=2)=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Reactant: COc1cc(-c2ccco2)cc(C#N)c1OC
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)o4)cc3)o2)cc(C#N)c1OC
Temperature: 25 °C
Yield: 13 %

Procedure:
The method used for the final coupling step of Example 12 was followed for the reaction of 5-(furan-2-yl)-2,3-dimethoxybenzonitrile and N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide except that the reaction was performed at −40 to −25° C. then warmed to room temperature. Purification by chromatography (20-100% EtOAc-hexanes) provided 2,3-dimethoxy-5-(5-(2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetyl)furan-2-yl)benzonitrile (0.040 g, 13% yield). MS: m/z 460.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>CC(C)=O>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)=[CH:16][CH:15]=1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: Nc1ccc(Br)cc1
Solvent: CC(C)=O
Product: O=S1(=O)N=C(Nc2ccc(Br)cc2)c2ccccc21
Reaction time: 0.25 h
Yield: 94.2 %

Procedure:
To a solution of 3-chloro-1H-1λ6-benzo[d]isothiazole-1,1-dione (1.0 g, 0.00496 mol) in acetone (20 mL), 4-bromoaniline (1.71 g, 0.00992 mol) was added at once and the mixture was stirred for 15 min. The mixture was concentrated under reduced pressure and the residue was suspended in water (100 mL). The precipitate was collected by filtration, thoroughly washed with water and dried to yield 3-(4-bromoanilino)-1H-1λ6-benzo[d]isothiazole-1,1-dione (1.57 g, 0.00467 mol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[C:22]2[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=2[C:20]2[C:19]3[CH:18]=[C:17]([O:28]C)[CH:16]=[CH:15][C:14]=3[N:13]([CH2:30][CH2:31][OH:32])[C:12]=2[CH:11]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].B(Br)(Br)Br.COC1C=CC2NC3C=C(C(OCC4C=CC=CC=4)=O)C4C(=O)NC(=O)C=4C=3C=2C=1>>[CH3:33][S:34]([O:32][CH2:31][CH2:30][N:13]1[C:12]2[CH:11]=[C:10]([C:3]3[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:22]3[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=3[C:20]=2[C:19]2[CH:18]=[C:17]([OH:28])[CH:16]=[CH:15][C:14]1=2)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(c1)c1c3c(c(-c4c(Cl)cccc4OC)cc1n2CCO)C(=O)NC3=O
Agent: BrB(Br)Br
Agent: COc1ccc2[nH]c3cc(C(=O)OCc4ccccc4)c4c(c3c2c1)C(=O)NC4=O
Product: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCOS(C)(=O)=O

Procedure:
Reaction of 4-(2-Chloro-6-methoxyphenyl)-6-(2-hydroxyethyl)-9-methoxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (V; Ar=2-chloro-6-methoxyphenyl, R10═CH2CH2OH) (111) prepared as described in example 63 with methanesulphonyl chloride, followed by reaction with BBr3 using the procedure described in example 170 of Scheme 3 gave 2-(4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-1,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol-6 (1H)-yl)ethyl methanesulfonate (VII; Ar=2-chloro-6-methoxyphenyl, n=2, mesylate) (114), as a yellow solid, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7](=[CH:23][N:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:25]=3)[C:8]([CH2:12][CH2:13][NH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[N:9][C:10]=2[CH:11]=1.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7](=[CH:23][N:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:25]=3)[C:8]([CH2:12][CH2:13][N:14]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[C:39]([NH:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:40])=[N:9][C:10]=2[CH:11]=1
Reactant: O=C=Nc1ccccc1
Reactant: N#Cc1ccc(NCCc2nc3cc(Cl)ccc3c3nn(-c4ccccc4)cc23)cc1
Solvent: ClCCl
Product: N#Cc1ccc(N(CCc2nc3cc(Cl)ccc3c3nn(-c4ccccc4)cc23)C(=O)Nc2ccccc2)cc1
Yield: 67.5 %

Procedure:
A solution of 100 mg (0.24 mmol) of the compound of Example 1, 150 mg (1.26 mmol) of phenylisocyanate, and 8 ml of methylene chloride is stirred at ambient temperature for four days. The resulting precipitate is collected and triturated with ether to afford 88 mg (68%) of title compound: IR (KBr) 3440, 2240, 1670, 1605, 1520, 1510, and 1440 cm-1 ; NMR (DMSO-d6) δ 9.56 (s, 1H), 8.72 (s, 1H, exchangeable), 8.48-6.96 (complex m, 17H), 4.46 (t, 2H), and 3.5 (t, 2H).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:11]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC(OCC)OCC)C>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[O:8][CH:11]=[N:10][N:9]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NNC(=O)c1ccncc1
Solvent: CCOC(OCC)OCC
Product: c1cc(-c2nnco2)ccn1
Temperature: 130 °C
Yield: 57738.3 %

Procedure:
A mixture of the isonicotinic hydrazide (13.7 g, 100 mmol), triethylorthoformate (60 ml) and p-toluenesulfonic acid (30 mg) was heated at 130° C. for 12 hours. Excess triethylorthoformate was removed under vacuum. The residue was crystallized from ethyl acetate to give 2-(4-pyridyl)-[1,3,4]oxadiazole (14.8 g); H1 NMR [(CD3)2SO]: δ 9.46 (1H, s), 8.8 (2H, dd), 7.9 (2H, dd).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]([NH2:18])([CH3:17])[CH3:16].[BH4-].[Na+].O>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:18][CH:15]([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: CC(C)NC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.6 %

Procedure:
1.9 mL (6 mmol) of titanium isopropoxide and 1 g (5 mmol) of (S)-1-tert-butoxycarbonyl-pyrrolidine-2-carbaldehyde are added to a solution of 886 mg (15 mmol) of isopropylamine in 10 mL of anhydrous methanol. The solution is stirred for 5 hours at room temperature then 227 mg (6 mmol) of sodium borohydride is added. Stirring is continued for a further 2 hours then 2 mL of water is added. The reaction mixture is filtered then the solvents are evaporated. Water is added and the compound is extracted with diethyl ether. The organic phases are dried over magnesium sulfate, filtered and evaporated to give 1.05 g (86%) of (S)-1-tert-butoxycarbonyl-2-isopropylaminomethyl-pyrrolidine in the form of a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([O:21][CH2:22][CH3:23])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH3:2]>CO.[Rh]>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1)OCC
Agent: [Rh]
Solvent: CO
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Yield: 10.2 %

Procedure:
3-(4-Benzyloxyphenyl)-2-ethoxyacrylic acid ethyl ester (described in Example 38a) (0.5 g; 1.5 mmole) was hydrogenated at atmospheric pressure using rhodium on charcoal (5%; 50 mg) as catalyst in methanol (20 ml). The crude product was purified by chromatography using heptane:ethyl acetate (5:1) as eluant to give 50 mg (yield 10%) of 3-(4-benzyloxyphenyl)-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:25](=[O:27])[CH3:26])[C:10]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23]Br)=[CH:11][CH:12]=2)[CH:7]=1.[OH:29][C:30]1[C:35]([CH2:36][CH2:37][CH3:38])=[C:34]([OH:39])[CH:33]=[CH:32][C:31]=1[C:40](=[O:42])[CH3:41].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:25](=[O:27])[CH3:26])[C:10]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][O:39][C:34]3[CH:33]=[CH:32][C:31]([C:40](=[O:42])[CH3:41])=[C:30]([OH:29])[C:35]=3[CH2:36][CH2:37][CH3:38])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COC(=O)COc1ccc2ccc(OCCCOCCCBr)c(C(C)=O)c2c1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOCCCOc2ccc3ccc(OCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 55.5 %

Procedure:
A mixture of 1.73 g of [[8-acetyl-7-[3-(3-bromopropoxy)propoxy]-2-naphthalenyl]oxy]acetic acid methyl ester, 0.89 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone and 0.79 g of anhydrous potassium carbonate in 33 ml of anhydrous acetone and 11 ml of anhydrous dimethylformamide was stirred at reflux for 18 hours. The mixture was filtered and filtrate was concentrated in vacuo to an oil. Purification by high pressure liquid chromatography (10% ethyl acetate-toluene) gave 1.2 g (56%) of [[8-acetyl-7-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-naphthalenyl]oxy]acetic acid methyl ester.