Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[CH2:29][CH2:30][CH3:31])[CH:16]=2)[CH:5]=1.[OH-].[Li+]>CO.O>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:15]2[CH:16]=[C:11]([S:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:32])=[O:2])[CH:12]=[N:13][CH:14]=2)=[C:20]([CH2:29][CH2:30][CH3:31])[C:21]=1[OH:28])(=[O:27])[CH3:26]
Reactant: CCCc1c(OCc2cncc(Sc3cccc(C(=O)OC)c3)c2)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1c(OCc2cncc(Sc3cccc(C(=O)O)c3)c2)ccc(C(C)=O)c1O
Reaction time: 12 h

Procedure:
Dissolve 3-[5-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-pyridin-3-ylsulfanyl]-benzoic acid methyl ester (379 mg, 0.84 mmol) in methanol (2 mL) and water (0.5 mL). Add 2N aqueous lithium hydroxide solution (0.42 mL, 0.84 mmol). After 12 hours, concentrate under reduced pressure and dissolve residue in 4N hydrochloric acid in dioxane. Add water until white precipitate forms, and collect by filtration. Triturate in ethyl acetate, then methanol. Collect the title compound by filtration as a white solid (317 mg, 0.73 mmol): 1H NMR (DMSO-d6) δ 0.76 (t, 3H), 1.37 (m, 2H), 2.47 (m, 2H), 2.58 (s, 3H), 5.30 (s, 2H), 6.70 (d, 1H), 7.52 (t, 1H), 7.63 (m, 1H), 7.77 (m, 1H), 7.80 (m, 1H), 7.86 (m, 1H), 7.90 (d, 1H), 8.60 (m, 2H), 12.83 (s, 1H), 13.21 (br s, 1H); MS (m/z): 438 (M+1).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:21].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.Br.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O>[Br:21][CH:17]([CH2:18][CH3:19])[C:16]([C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:8][C:9]=2[CH:15]=1)=[O:20]
Reactant: [Br-]
Reactant: CCCC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCC(Br)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
400 mg (1.51 mmol) 1-(2-phenyl-benzoxazol-6-yl)-butan-1-one and 643 mg (1.81 mmol) pyridinium tribromide are dissolved in 4 ml glacial acetic acid at RT, then 1.04 ml (5.40 mmol) hydrogen bromide, dissolved 30% in glacial acetic acid, are added and the mixture is stirred for 1 h at RT. Then the reaction mixture is mixed with water and adjusted to pH 8 with 5% potassium carbonate solution, then it is extracted with DCM, the org. phase is dried on magnesium sulphate and the solv. is eliminated completely in vacuo. The residue is separated through silica gel (eluant cyclohexane/EA).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2oc3ccccc3c2n1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2oc3ccccc3c2n1
Temperature: 25 °C

Procedure:
2,4-dichlorobenzofuro[3,2-d]pyrimidine (61 mg, 0.255 mmol, 1.0 eq) was dissolved in MeOH (2 mL) and morpholine (49.1 mL, 562 μmol, 2.2 eq) was added. The reaction mixture was hated to reflux for 30 minutes and then cooled to room temperature. Solvents were removed in vacuo and the residue was purified by silica gel chromatography (gradient from 100% hexane in EtOAc to 50% hexane) and a colorless solid was obtained (59.4 mg, 80%).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH2:10]([O:17][C:18](=[O:30])[C@@H:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]I)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.I[C:32]1[CH:37]=[CH:36][C:35]([N:38]2[S:42](=[O:44])(=[O:43])[N:41]([CH2:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)[C:40](=[O:54])[CH2:39]2)=[CH:34][CH:33]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl-].[NH4+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:10]([O:17][C:18](=[O:30])[C@@H:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][C:32]1[CH:33]=[CH:34][C:35]([N:38]2[CH2:39][C:40](=[O:54])[N:41]([CH2:45][C:46]3[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=3)[S:42]2(=[O:44])=[O:43])=[CH:36][CH:37]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(I)cc3)S2(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CI)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: BrCCBr
Solvent: O
Product: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc4ccccc4)cc3)S2(=O)=O)cc1
Temperature: 50 °C
Reaction time: 0.42 h

Procedure:
Onto zinc foil (99.9% Aldrich 35, 602-6, 775 mg, 11.85 mmol) cut in small pieces is added DMF (freshly distilled from CaH2 under argon, 4.5 mL) and 1,2-dibromoethane (0.033 mL, 0.38 mmol) under argon. The mixture is heated at 50° C. for 10 min, then allowed to cool and trimethylsilyl chloride (0.19 mL, 0.153 mmol) is added. The reaction is stirred for 25 min and a solution of (R)-2-t-butoxycarbonylamino-3-iodo-propionic acid benzyl ester (Fluka, 2.18 g, 5.37 mmol) in DMF (10 mL) is added. After 15 min, the mixture is decanted into a solution of the title A compound, 5-(4-iodo-phenyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (1.75 g, 3.82 mmol), tri-o-tolylphosphine (232.5 mg, 0.764 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (175 mg, 0.191 mmol) in DMF (13 mL). After stirring for 1.5 h, the resulting reaction mixture is poured onto a mixture of saturated aqueous ammonium chloride (200 mL) and water (200 mL) and extracted with EtOAc (2×250 mL). The organic solution is washed with water (1×200 mL) and brine (1×200 mL), then filtered through celite to removed a strong gray precipitate. The filtrate is dried over anhydrous Na2SO4, filtered and concentrated to give a dark red brown oil. This is chromatographed on a 110 g silica gel RediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 0:100 (EtOAc:CH2Cl2) to 10:90 over 25 min. Fractions containing product are combined and concentrated to yield (S)-2-t-butoxycarbonylamino-3-(4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester as a white solid after tritruration with Et2O: [M+NH4]+=627.0, [M−HCO2]−=654.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10](OCC)=[O:11])[CH:5]=[CH:6][CH:7]=1.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl>[OH:11][CH2:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCc1cccc(O)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: OCCCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 94.1 %

Procedure:
To a solution of ethyl 3-(3-hydroxyphenyl)propanoate (54.5 g) in DCM (926 mL) was added dropwise 1.0 M DIBAL in DCM (926 mL) at 0° C. over 1 hour under N2 gas atmosphere. 30% Rochelle salt aqueous solution (1.34 L) was added to the reaction mixture with dropping funnel at the same temperature. The resulting mixture was stirred for 7 hours at ambient temperature and the organic layer was separated. The aqueous layer was stand for 2 days and extracted with chloroform(1.5 L) 4 times. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo to afford 3-(3-hydroxypropyl)phenol (40.2 g) as a yellow oil.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]2=[O:27])[S:5]([CH3:8])(=[O:7])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>C(Cl)Cl>[Br:48][CH2:2][CH2:3][N:4]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]2=[O:27])[S:5]([CH3:8])(=[O:7])=[O:6]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N(CCO)S(C)(=O)=O)cc2C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N(CCBr)S(C)(=O)=O)cc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a stirred solution of tert-butyl 2-(5-(N-(2-hydroxyethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (as obtained from Example 38, step 1, 1.12 g, 2.81 mmol) in DCM (20 ml), triphenylphosphine (0.958 g, 3.65 mmol) was added. After 10 minutes at room temperature under stirring, CBr4 (1.212 g, 3.65 mmol) was added, and the mixture was stirred at the same temperature for additional 14 hours. The volatiles were removed under vacuum and the crude was purified by chromatography on silica gel column (petroleum ether:ethyl acetate=7:3) affording tert-butyl 2-(5-(N-(2-bromoethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate that crystallized on standing (0.980 g, 2.124 mmol, 76% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][OH:29])[O:22][C@@H:13]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>N1C=CC=CC=1.ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][O:29][S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])[O:22][C@@H:13]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1[C@@H](OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@H](OCc3ccccc3)[C@H](NC(=O)OCc3ccccc3)[C@@H](O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 30 g of benzyl 2-benzyloxycarbonylamino-2-desoxy-a-D-glucopyranoside (Heyns and Paulsen, Chem. Ber. 88, 188 (1955)) in 116 ml of pyridine was treated at 0° C. with a solution of 19.85 g of p-tolylsulfonyl chloride in 30 ml of dichloromethane and stirred at room temperature for 4 hours. Then, the mixture was poured into ice-cold 2N sulfuric acid and extracted with dichloromethane. The organic phases were washed with aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated. The residue was chromatographed over silica gel with hexane/ethyl acetate and gave benzyl 2-benzyloxycarbonylamino-2-desoxy-6-O-(p-tolylsulfonyl)-a-D-glucopyranoside, [a]+101.8° (c 0.5; dioxan), MS: m/z 580 ([M+Na]+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.[C:12]([NH2:20])(=[S:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>>[CH3:11][C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:3]1[N:20]=[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[S:19][CH:2]=1
Reactant: Cc1ccncc1C(=O)CBr
Reactant: NC(=S)c1cccnc1
Product: Cc1ccncc1-c1csc(-c2cccnc2)n1
Yield: 39.5 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-methylpyridin-3-yl)ethanone hydrobromate (432 mg) and thionicotinamide (152 mg), the title compound (110 mg) was obtained as colorless powder crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:21][CH2:20]1>>[CH2:26]([CH:25]([N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:2]2[N:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:20][CH2:21]1)[CH2:28][CH3:29])[CH3:27]
Reactant: CCC(CC)N1CCC(N)CC1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(Cl)nn2)cc1
Product: CCC(CC)N1CCC(Nc2ccc(-c3ccc(S(C)(=O)=O)cc3)nn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(4-methanesulfonylphenyl)pyridazine and 4-amino-1-(1-ethylpropyl)piperidine.
Reaction SMILES: COCCOC[O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]([N:20]([CH2:22][C:23]1[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH:36]4[S:40][C:39](=[O:41])[NH:38][C:37]4=[O:42])=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=1)[CH3:21])=[O:19])[CH:12]=[CH:11]2.S(=O)(=O)(O)O.O>O1CCCC1.CO>[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]([N:20]([CH2:22][C:23]1[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH:36]4[S:40][C:39](=[O:41])[NH:38][C:37]4=[O:42])=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=1)[CH3:21])=[O:19])[CH:12]=[CH:11]2
Reactant: COCCOCOc1ccc2cc(C(=O)N(C)Cc3cccc(-c4ccc(CC5SC(=O)NC5=O)cc4)c3)ccc2c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
1.5 g (2.5 mmol) of 6-(2-methoxyethoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide (obtained in Example 16) in 10 ml of tetrahydrofuran and 10 ml of methanol are introduced into a round-bottomed flask. 500 μl of concentrated sulphuric acid are added and the medium is stirred for 2 hours at room temperature. Water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and then evaporated off. The residue is purified by chromatography on a silica column eluted with a heptane and ethyl acetate (30/70) mixture. 1.26 g (99%) of 6-hydroxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide are obtained in the form of a white powder having a melting point of 218° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH:8]=[CH:7]2.Cl[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH:27][C:21]=2[N:20]=1>>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:19]3[NH:23][C:22]4[CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH:27][C:21]=4[N:20]=3)[CH2:14][CH2:13]1)[CH:8]=[CH:7]2
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Reactant: Oc1cccc2ccc(N3CCNCC3)nc12
Product: Oc1cccc2ccc(N3CCN(c4nc5ccc(C(F)(F)F)cc5[nH]4)CC3)nc12

Procedure:
The piperazine from step (b) above (0.329 g, 1.67 mmol) and 2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.370 g, 1.67 mmol, Example 1c) reacted under the conditions of Example 3c to give the title compound. M.p. 191-193° C. MS (ESI, pos. ion) m/z: 414 (M+1).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[N+:11]([C:14]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][C:15]=1[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[O:17])([O-])=O>C1COCC1>[CH:1]([NH:11][C:14]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][C:15]=1[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[O:17])=[O:2]
Reactant: O=CO
Reactant: CC(C)NC(=O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC(C)NC(=O)c1cc(Oc2ccccc2)ccc1NC=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.3 %

Procedure:
A solution of formic acid (0.02 mL, 0.56 mmol) and acetic anhydride (0.05 mL, 0.56 mmol) was heated to 50° C. for 2 hours under an argon atmosphere. The resulting mixture was diluted with THF (0.2 mL) and added dropwise to a solution of 34B (50 mg, 0.19 mmol) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The resulting solution was concentrated to dryness and purified by chromatography (SiO2, 40% EtOAc in hexane) to afford 44A (58 mg, 100%).
Reaction SMILES: [CH:1]1([C:7]2[N:8]3[C:36]4[CH:35]=[C:34]([C:37]([O:39]C)=[O:38])[CH:33]=[CH:32][C:31]=4[CH2:30][CH:9]3[C:10]3[C:22](=O)[CH:21]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH2:20][C:19](=O)[C:11]=3[CH2:12][N:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(C)C.[OH-].[Na+]>C1COCC1>[CH:1]1([C:7]2[N:8]3[C:36]4[CH:35]=[C:34]([C:37]([OH:39])=[O:38])[CH:33]=[CH:32][C:31]=4[CH2:30][CH:9]3[C:10]3[CH2:22][CH:21]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH2:20][CH2:19][C:11]=3[CH2:12][N:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(c1)N1C(C3CCCCC3)=C3C=NC=CN3CC3=C(C(=O)C(CCN(C)C)CC3=O)C1C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CSC
Product: CN(C)CCC1CCC2=C(C1)C1Cc3ccc(C(=O)O)cc3N1C(C1CCCCC1)=C1C=NC=CN1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
To a solution of methyl 11-cyclohexyl-2-[2-(dimethylamino)ethyl]-1,4-dioxo -1,2,3,4,17,17a-hexahydro-6H-indolo[2,1-a]pyrazino[2,1-d][2,5]benzodiazocine-14-carboxylate in THF (0.15 M), 20 eq of BH3.Me2S (2 M solution in THF) were added and the mixture was stirred overnight at RT. The solution was carefully quenched by adding 1.25 N HCl in MeOH until effervescence subsided. Then the volatiles were driven off by boiling the mixture to dryness. The crude residue was dissolved in MeOH (0.06 M) and 10 eq of 1N NaOH (aq) were added. The solution was stirred at 60° C. for 5 h. The solvent was evaporated in vacuo. The crude was then purified by prep RP-HPLC (stationary phase: column WATERS X-TERRA prep. C18, 5 microns. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (8% yield from dimethyl 14-cyclohexyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-7,11-dicarboxylate). 1H NMR (400 MHz, DMSO-d6+TFA, 330 K) δ 8.15 (s, 1H), 7.93 (d, J 8.4, 1H), 7.90-7.85 (m, 1H), 7.76 (d, J 8.4, 1H), 7.70-7.60 (m, 2H), 7.59-7.49 (m, 1H), 4.50-4.40 (m, 1H), 4.30-4.20 (m, 1H), 4.00-3.80 (m, 2H), 3.80-3.70 (m, 1H), 3.70-3.50 (m, 2H), 3.40-3.20 (m, 5H), 2.79 (s, 6H), 2.80-2.70 (m, 2H), 2.70-2.60 (m, 2H), 2.00-1.80 (m, 3H), 1.80-1.60 (m, 2H), 1.60-1.50 (m, 1H), 1.40-1.10 (m, 4H); MS (ES+) m/z 501 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH3:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:22]([CH3:35])[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: CI
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(C(F)(F)F)cc4)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)Cc4ccc(C(F)(F)F)cc4)cc3)c2)o1

Procedure:
2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(4-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(4trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.75,(3H, m), 7.59-7.46,(7H, m), 4.79-4.65,(2H, m), 2.94,(3H, s), 2.55,(3H, s), 2.32,(3H, s). LCMS; retention time 3.67 min, MH+ 466.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:4][CH:3]=1.CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1.O>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]4[CH:11]([C:12](=[O:15])[NH:13][N:14]=3)[CH2:10]4)=[CH:6][CH:7]=2)[CH:18]=[CH:22][CH:21]=[CH:20]1
Reactant: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: O
Product: O=C1NN=C(c2ccc(-n3cccc3)cc2)C2CC12
Yield: 41 %

Procedure:
10.0 g (49.7 millimoles) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one (see Example 8a), 6.6 g (49.9 millimoles) of 2,5-dimethoxytetrahydrofuran and 100 ml of acetic acid are refluxed for 4 hours. The product is filtered off at 10° C. and recrystallized from a dimethylformamide/water mixture. 5.2 g (41% of theory) of 2-[p-(pyrrol-1-yl)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one, hydrated with one mole of water per four moles of compound, are obtained as beige crystals, of melting point 230°-231° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH:20]=[CH2:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([N:29]([CH2:35]OC)[CH2:30][Si](C)(C)C)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:22]([N:29]1[CH2:35][CH2:21][CH:20]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[CH:11][C:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])=[CH:19]3)[CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=Cc1cccc2cc(S(=O)(=O)c3ccccc3)cnc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)c1cnc2c(C3CCN(Cc4ccccc4)C3)cccc2c1
Yield: 32.9 %

Procedure:
3-(Phenylsulfonyl)-8-vinylquinoline (210 mg, 0.71 mmol, prepared according to WO2007039219) was reacted with benzyl methoxymethyl trimethylsilylmethyl amine (253 mg, 1.07 mmol) in dichloromethane (2 ml) in the presence of trifluoroacetic acid for 20 minutes. The solution was washed with a saturated aqueous solution of NaHCO3 solution, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography (100% dichloromethane) to give the title compound as a colourless oil (100 mg, 33%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.C([O:18][C:19]([C:21]1[C:22]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][O:38]C(=O)CCCCC)[N:32]=3)=[CH:26][C:23]=2[S:24][CH:25]=1)=O)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:19]([C:21]2[C:22]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][OH:38])[N:32]=4)=[CH:26][C:23]=3[S:24][CH:25]=2)=[O:18])[CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: CCCCCC(=O)OCc1nccc(Oc2ccc3c(C(=O)OCC)csc3c2)n1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cccc(NC(=O)c2csc3cc(Oc4ccnc(CO)n4)ccc23)c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
In a dried vessel, 82 mg (0.55 mMol) 3-tert-butyl-aniline are dissolved in 8 ml toluene and cooled in an ice bath. Then 825 μl Me3Al (2 M in toluene; 1.65 mMol) are added via syringe. After 1¼ h at rt, a solution of 107 mg (0.25 mMol) 6-(2-hexanoyloxymethyl-pyrimidin-4-yloxy)-benzo[b]thiophene-3-carboxylic acid ethyl ester (Step 17.5) in 1 ml THF is added and the solution is stirred for 1 h in an oil bath of 110° C. The solution is cooled in an icebath and hydrolyzed with 16 ml of a sat. NH4Cl solution. After 15 min stirring, the mixture is diluted with EtOAc and water, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; hexane/EtOAc 9:1→1:1→EtOAc) gives the title compound: Anal. (+0.3H2O): C,H,N,S; MS: [M+1]+=434; TLC(hexane/EtOAc 1:2): Rf=0.31; 1H MNR (DMSO-d6): δ ppm 10.32 (s, HN), 8.67 (d, 1H), 8.58 (s, 1H), 8.46 (d, 1H), 8.03 (s, 1H), 7.76 (s, 1H), 7.68 (d, 1H), 7.35 (d, 1H), 7.28 (t, 1H), 7.15 (d, 1H), 6.98 (d, 1H), 5.18 (sb, HO), 4.41 (s, CH2), 1.31 (s, 9H).