Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C(CS([C:11]2[NH:12][C:13]3[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:14]=3[N:15]=2)=O)=NC=CC=1.[NH2:24][CH2:25][CH2:26][SH:27].[ClH:28]>O1CCCC1>[Cl-:28].[NH2:24][CH2:25][CH2:26][S:27][S:27][CH2:26][C:25]1[C:19]([CH3:18])=[CH:13][CH:14]=[CH:16][N+:24]=1[C:11]1[NH:12][C:13]2[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:14]=2[N:15]=1
Reactant: Cl
Reactant: NCCS
Reactant: Cc1cccnc1CS(=O)c1nc2ccc(C(F)(F)F)cc2[nH]1
Solvent: C1CCOC1
Product: Cc1ccc[n+](-c2nc3ccc(C(F)(F)F)cc3[nH]2)c1CSSCCN
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.39 g of 2-[[(3-methyl-2-pyridyl)methyl]sulphinyl]-5-(trifluoromethyl)benzimidazole are dissolved in 50 ml of tetrahydrofuran and treated with 0.77 g of cysteamine. 40 ml of 3N hydrochloric acid are added at an internal temperature of 40°. After stirring at 40° for 10 minutes and at room temperature overnight the mixture is evaporated in vacuo. The residue is crystallized from tert.butyl methyl ether/ether. There is obtained 2-[[(2-aminoethyl)dithio]methyl]-3 -methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl1pyridinium chloride of melting point 95°-100°.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:43]([CH3:44])=[CH:42][C:15]2[N:16]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:21]([C:32]4[CH:33]=[C:34]5[C:38](=[CH:39][CH:40]=4)[N:37]([CH3:41])[N:36]=[CH:35]5)[CH2:20]3)[S:18][C:14]=2[C:13]=1[C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)C>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:43]([CH3:44])=[CH:42][C:15]2[N:16]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH:21]([C:32]4[CH:33]=[C:34]5[C:38](=[CH:39][CH:40]=4)[N:37]([CH3:41])[N:36]=[CH:35]5)[CH2:20]3)[S:18][C:14]=2[C:13]=1[C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCN(C(=O)OC(C)(C)C)C(c4ccc5c(cnn5C)c4)C3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc2nc(N3CCN(C(=O)OC(C)(C)C)C(c4ccc5c(cnn5C)c4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To the solution of tert-butyl 4-(6-((S)-1-tert-butoxy-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-2-(1-methyl-1H-indazol-5-yl)piperazine-1-carboxylate (5 mg) in THF/MeOH (0.5 mL/0.5 mL) was added sodium hydroxide solution (0.4 mL, 1.0 N). The mixture was heated at 50° C. for 16 hours. The mixture was cooled, and was acidified with acetic acid (60 μL). Concentration and purification with reverse phase HPLC gave (2S)-2-tert-butoxy-2-(2-(4-(tert-butoxycarbonyl)-3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)acetic acid. LCMS-ESI+: calc'd for C37H43ClN5O5S: 704.3 (M+H+); Found: 704.1 (M+H+). 1H-NMR 400 MHz, (CD3OD) δ 7.96 (s, 1H), 7.64 (m, 2H), 7.49 (m, 3H), 7.38 (m, 3H), 5.46 (m, 1H), 5.19 (s, 1H), 4.4 (m, 1H), 4.2 (m, 1H), 4.07 (s, 3H), 4.0-3.7 (m, 2H), 3.5 (m, 2H), 2.5 (s, 3H), 1.40 (s, 9H), 0.98 (s, 9H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:36])[C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19](=[O:35])[C@H:20]([CH:32]([CH3:34])[CH3:33])[NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH2:25]([O:24][C:22]([NH:21][C@H:20]([C:19]([N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[C:13]([OH:36])=[O:12])=[O:35])[CH:32]([CH3:34])[CH3:33])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Trifluoroacetic acid (200 ml) was added to a mixture of N-benzyloxycarbonyl-L-valyl-L-proline tert-butyl ester (80.0 g) in methylene chloride ((300 ml) at 0° C. over approximately 30 minutes. After stirring at 0° C. for one hour, the reaction mixture was allowed to rise to ambient temperature and stirred an additional 3 hours. The reaction mixture was then comcentrated under vacuum and reconcentrated four times from toluene to remove residual trifluoroacetic acid. The resulting viscous oil was dried under vacuum for 16 hours. The crude product was purified on by chromatography on silica gel, usimg methylene chloride as eluant, to give N-benzyloxycarbonyl-L-valyl-L-proline (A) (63.6 g) as a pale yellow viscous oil; NMR (d6 -DMSO): 0.92 (2d, 6H), 1.65-2.05 (2m, 4H), 2.25 (m, 1H), 3.60 (m, 1H), 3.80 (m, 1H), 4.05 (dd, 1H), 4.25 (m, 1H), 5.02 (2d, 2H), 7.35 (m, 5H), 7.50 (d, 1H).
Reaction SMILES: Br[C@@H:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][C:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])(=[O:16])=[O:15])=[CH:13][C:4]=2[C@H:3]1O.[H-].[Na+].[OH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.CS(C)=[O:37]>>[O:28]=[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]1[C@H:3]1[C@H:2]([OH:37])[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][C:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])(=[O:15])=[O:16])=[CH:13][C:4]1=2
Reactant: CS(C)=O
Reactant: Oc1ccccn1
Reactant: COc1ccccc1S(=O)(=O)c1ccc2c(c1)[C@@H](O)[C@H](Br)C(C)(C)O2
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1S(=O)(=O)c1ccc2c(c1)[C@@H](n1ccccc1=O)[C@H](O)C(C)(C)O2
Temperature: 60 °C
Reaction time: 3 h

Procedure:
3.5 g (0.0082 mol) of trans-3-bromo-3,4-dihydro-2,2-di-methyl-6-(2-methoxyphenylsulfonyl)-2H benzo[b]pyran-4-ol are added to a suspension of 0.6 g of NaH (80% in oil) (0.0246 mol) and 3.1 g of 2-hydroxypyridine in 50 ml of dimethyl sulfoxide. The mixture is warmed to 60° C. and stirred for 3 hours. The mixture is poured into ice water, and the white precipitate is filtered off with suction and dried in air. Chromatography on silica gel using methanol/ethyl acetate 1:10 gives the product as a white, amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:15]=3)[CH2:10][CH2:9]2)=[C:4]([F:27])[CH:3]=1.[N+:28]([C:31]1[O:35][C:34]([CH:36]=O)=[CH:33][CH:32]=1)([O-:30])=[O:29]>CC(O)=O.CO>[CH2:20]([N:16]1[N:15]=[C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:6]=[CH:7][C:2](/[N:1]=[CH:36]/[C:34]4[O:35][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=4)=[CH:3][C:4]=3[F:27])[CH2:13][CH2:12]2)[O:18][C:17]1=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc(N2CCC(c3nn(Cc4ccccc4)c(=O)o3)CC2)c(F)c1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Solvent: CC(=O)O
Solvent: CO
Product: O=c1oc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)nn1Cc1ccccc1
Yield: 88 %

Procedure:
5-[1-(4-Amino-2-fluorophenyl)-4-piperidyl]-3-benzyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7 h, 0.36 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 3-benzyl-5-[1-(2-fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]amino phenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9 h, 432 mg, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12]O)[CH:6]=[CH:7][C:8]=1[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C(Cl)Cl>[Br:33][CH2:12][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(CCCO)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CCCBr)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
Under N2, a solution of 7.33 g (40.7 mmol) of 3-(3-methoxy-4-methylphenyl)-1-propanol in 200 mL of CH2Cl2 was treated with 10.67 g (40.7 mmol) of triphenylphosphine followed in portions by 7.3 g (40.7 mmol) of recrystallized N-bromosuccinimide. The solution was stirred at room temperature for 2 hours, then filtered through flash silica gel. Removal of the solvent under reduced pressure left 8.68 g (87.9% yield) of the product as a clear oil. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:5]2[N:6]([CH2:10][CH3:11])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.[Br:15][CH2:16][C:17]#[C:18][CH2:19]Br>CCOCC>[Br-:15].[Br:15][CH2:16][C:17]#[C:18][CH2:19][N+:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[C:13]([Cl:14])=[CH:12][C:5]=2[N:6]([CH2:10][CH3:11])[C:7]=1[CH3:9]
Reactant: CCn1c(C)nc2cc(Cl)c(Cl)cc21
Reactant: BrCC#CCBr
Solvent: CCOCC
Product: CCn1c(C)[n+](CC#CCBr)c2cc(Cl)c(Cl)cc21
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5,6-Dichloro-1-ethyl-2-methylbenzimidazole (11.5 g., 0.05 moles) and 1,4-dibromo-2-butyne (31 g., 0.15 moles) were mixed together and stirred at room temperature overnight. The reaction mixture was treated with ether, the solid was collected by filtration, washed with ether and dried. It was recrystallized from acetonitrile containing 5% water (400 ml). The product was recovered in two crops. Yield 20.2 g (92%), mp. 185°-189° C.
Reaction SMILES: [OH:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6](=[O:29])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:32][N:33]1[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]1.FC(F)(F)C(O)=O.C(Cl)[Cl:54]>>[ClH:54].[ClH:54].[OH:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6](=[O:29])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([S:19]([C:22]4[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=4)(=[O:20])=[O:21])[CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c3ccccc32)cc1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(/C=C3\Oc4c(ccc(O)c4CN4CCNCC4)C3=O)c3ccccc32)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(1-tosyl-1H-indol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0400 g, 0.0635 mmol) in methylene chloride (2 mL) was added with trifluoroacetic acid (2 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and then a solution of the resulting residue in methanol (4 mL) was added with a 5% solution of hydrogen chloride in methanol (1 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the resulting solid was suspended in acetonitrile and thereby washed to obtain the objective (Z)-6-hydroxy-7-(piperazin-1-ylmethyl)-2-[(1-tosyl-1H-indol-3-yl)methylene]benzofuran-3(2H)-one dihydrochloride (0.0344 g, 89%).
Reaction SMILES: [CH:1]1[C:6](Br)=[CH:5][C:4]2[C:8]([CH2:11][CH2:12][OH:13])=[CH:9][NH:10][C:3]=2[CH:2]=1.[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.O>[N:14]1[CH:19]=[CH:18][C:17]([C:6]2[CH:5]=[C:4]3[C:3](=[CH:2][CH:1]=2)[NH:10][CH:9]=[C:8]3[CH2:11][CH2:12][OH:13])=[CH:16][CH:15]=1
Reactant: OB(O)c1ccncc1
Reactant: OCCc1c[nH]c2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1c[nH]c2ccc(-c3ccncc3)cc12

Procedure:
5-Bromotryptophol (1.05 g, 4.39 mmol; see Table 1 and 2) and pyridine-4-boronic acid (10 mg, 6.59 mmol) were suspended in tetrahydrofuran (65 ml), and Na2CO3 solution (4.65 g, 43.9 mmol) in 44 ml of H2O) were added. Bistriphenylphosphinepalladium dichloride (456.2 mg, 0.65 mmol) was then added. The reaction mixture, which was clear when hot, was boiled at 65° C. for 14 h, while stirring. The course of the reaction was monitored by TLC. For working up, the reaction solution was filtered. The filtrate comprised two phases. The organic phase was separated off. The solvent was distilled off on a rotary evaporator. The viscous residue was purified by flash chromatography [silica gel 60 (45 g); eluent: EtOAc (800 ml)].
Reaction SMILES: [CH2:1]([N:3]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][OH:21])[CH:16]=2)[O:11][C:10]([CH3:23])([CH3:22])[CH2:9]1)[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].[H-].[Na+].[CH2:26](I)[CH3:27]>CC(N(C)C)=O>[CH2:26]([O:21][CH2:20][CH2:19][O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([CH3:22])([CH3:23])[CH2:9][CH:8]2[N:3]([CH2:1][CH3:2])[S:4]([CH3:7])(=[O:5])=[O:6])[CH3:27]
Reactant: CCN(C1CC(C)(C)Oc2ccc(OCCO)cc21)S(C)(=O)=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOCCOc1ccc2c(c1)C(N(CC)S(C)(=O)=O)CC(C)(C)O2

Procedure:
2.3 g (6.7 mmol) of N-ethyl-N-[6-(2-hydroxyethoxy)-2,2-dimethylchroman-4-yl]methanesulfonamide (Example 8) were alkylated with 0.48 g (about 10 mmol) of NaH (80 percent dispersion) and 1.6 ml (about 20 mmol) of ethyl iodide in 50 ml of DMA under nitrogen. After working up and purification by column chromatography on silica gel, 1.0 g of the title compound was crystallized from corresponding fractions using petroleum ether, m.p. 73-75° C.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][Br:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1-c1cccc2ccccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccccc1-c1cccc2ccccc12
Yield: 91.2 %

Procedure:
114 g (0.52 mol) of 18 and 103 g (0.58 mol) of N-bromosuccinimide were dissolved in 2000 cm3 of tetrachloromethane at room temperature, 3 g of azobisisobutyronitrile were added, and the mixture was refluxed for 4 hours. The succinimide which precipitated was filtered off, the solvent was removed in vacuo, and the residue was purified by filtration through 1000 g of silica gel (hexane/methylene chloride 9:1), giving 141 g (82%) of 19 as a colorless lachrymatory oil.
Reaction SMILES: C1C=CC(O[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][C:10]#[N:11])=CC=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl>[O:12]([C:8](=[N:9][C:10]#[N:11])[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: N#CN=C(Oc1ccccc1)N1CCCCC1
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
a)To a stirred solution of 6 g of diphenyl cyanocarbonimidate in 50 ml of dichloromethane at room temperature were added portionwise 2.1 g of piperidine. Stirring was continued for 30 minutes at room temperature. The reaction mixture was evaporated and the residue was crystallized from 2,2'-oxybispropane. The crystals were filtered off and dried, yielding 4.6 g (80.7%) of [phenoxy(1-piperidinyl)methylene]cyanamide; mp. 85.7° C. (interm. 32).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21](OC)=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH:30]=1.C[Al](C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([N:27]([CH3:26])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH:30]=3)=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1
Reactant: CNCc1cccc(CN2CCCC2)c1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N(C)Cc3cccc(CN4CCCC4)c3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BK using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (150 mg, 0.41 mmol), methyl-(3-pyrrolidin-1-ylmethyl-benzyl)-amine (99 mg, 0.48 mmol), trimethylaluminium (2 M in toluene, 0.44 mL) and THF (15 mL).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[S:15][CH:14]3[C:16](=[O:19])[N:17]([CH3:18])[C:11]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)([C:12](=[O:21])[N:13]3[CH3:20])[S:10]2)=[CH:5][CH:4]=1.Cl[CH2:30][O:31][C:32]1C=CC=CC=1.C([Li])CCC.[CH3:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48].[Na+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[S:10][C:11]3([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:12](=[O:21])[N:13]([CH3:20])[C:14]([CH2:30][O:31][CH2:32][C:45]4[CH:44]=[CH:43][CH:48]=[CH:47][CH:46]=4)([C:16](=[O:19])[N:17]3[CH3:18])[S:15]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2SC3C(=O)N(C)C(Cc4ccccc4)(S2)C(=O)N3C)cc1
Reactant: ClCOc1ccccc1
Reactant: CCCCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C2SC3(COCc4ccccc4)C(=O)N(C)C(Cc4ccccc4)(S2)C(=O)N3C)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Crystalline 26 (144 mg, 0.35 mmol, 1 eq) and phenyl chloromethyl ether (500 μL, 455 mg, 1.75 mmol, 5 eq., 60% reagent only) was dissolved in anhydrous THF (40 mL). The solution was cooled to −78° C. and to the stirred mixture 1.54 M n-butyllithium in hexane (1.16 mL, 1.8 mmol, 1.5 eq) was added dropwise over a period of 5 min. After the mixture was stirred for 10 min at −78° C. the resulting red, cloudy solution was allowed to warm to room temperature and was stirred. Saturated NaCl solution was added into the reaction mixture and the red solution was extracted with dichloromethane. The organic phase was washed with water twice, dried under MgSO4 and concentrated under vacuum. The syrup was separated on column (hexane-ethylacetate, 8-2, Rf 0.4) to give 114 mg of 27 as a glass-like solid (62%). 1H NMR (CDCl3, TMS, ppm) δ: 7.35 (m, 5H), 7.28 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H), 5.02 (s, 1H), 4.72 (d, J=11.7 Hz, 1H), 4.58 (d, J=12.0 Hz, 1H), 4.51 (d, J=10.8 Hz, 1H), 4.20 (d, J=16.5 Hz, 1H), 3.78 (s, 3H), 3.74 (d, J=10.5 Hz, 1H), 3.25 (d, J=16.9 Hz, 1H), 3.19 (s, 3H), 3.15 (s, 3H). FAB-MS: Calcd. for C29H30N2O4S2: 534.1. Found [M+H]+: 535.0.
Reaction SMILES: [C:1]([N:9]1[CH:22]([C:23](O)=[O:24])[CH2:21][C:20]2[CH:19]=[C:18]3[C:13]([O:14][C@@H:15]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:16](=[O:26])[NH:17]3)=[CH:12][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:44][O:45][C:46](=[O:63])[C@@H:47]([NH2:62])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[CH3:44][O:45][C:46](=[O:63])[C@@H:47]([NH:62][C:23]([CH:22]1[CH2:21][C:20]2[CH:19]=[C:18]3[C:13]([O:14][C@@H:15]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:16](=[O:26])[NH:17]3)=[CH:12][C:11]=2[CH2:10][N:9]1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:24])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1
Reactant: O=C(O)C1Cc2cc3c(cc2CN1C(=O)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3

Procedure:
(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-chloro-biphenyl-4-yl)-propionic acid methyl ester (71 m g, LC/MS: m/z 878) was prepared from Intermediate D (100 mg) and (S)-2-amino-3-(4′-chloro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride according to general procedure A.
Reaction SMILES: [Br:1][C:2]1[C:14]([Cl:15])=[CH:13][C:12]([C:16](=[O:18])[NH2:17])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7](C(OCC)=O)=[CH:8][C:9]=1[NH:10]2.[CH3:24][Mg]Cl.[NH4+].[Cl-].[CH2:29]1[CH2:33][O:32]CC1>CC(C)=O>[Br:1][C:2]1[C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:33]([OH:32])([CH3:29])[CH3:24])=[CH:6][CH:5]=3)[NH:10][C:11]=2[C:12]([C:16]([NH2:17])=[O:18])=[CH:13][C:14]=1[Cl:15]
Reactant: C[Mg]Cl
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Temperature: -15 °C

Procedure:
A suspension of ethyl 5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate (58.56 g, 148 mmol) in THF (700 mL) under nitrogen was cooled to −15° C. in an acetone-dry ice bath. The mixture was treated dropwise with 3 M methylmagnesium chloride in THF (395 mL, 1.19 mol) at a rate that the internal temperature remained between −15° C. and −10° C. After 5 h the mixture was poured into 3 vessels, each containing ca. 1.5 L of crushed ice and 500 mL of saturated aqueous NH4Cl. The resulting mixtures were extracted with EtOAc, and the combined organic phases were dried and concentrated. The residue was combined with material from two additional batches, one starting from 146 mmol of ethyl 5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate and the other starting from 142 mmol of ethyl 5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate, and stirred for 1 h in acetone (250 mL). The precipitate was collected by filtration, washed with hexane and dried to provide 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide as a solid (134.56 g). The filtrate was concentrated and the residue was again stirred for 1 h in acetone, forming a precipitate which was collected by filtration, washed with hexane and dried to give additional 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide as a solid (7.36 g) for a total of 141.92 g (88% yield). The filtrate from the second filtration was combined with impure material from other batches and subjected to column chromatography on silica gel (2×1.5 kg), eluting with EtOAc-hexanes (gradient from 40-100%), providing additional product.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][N:14]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]([C:21](O)=[O:22])=[CH:15]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:21]([C:16]3[CH:17]=[CH:18][C:19](=[O:20])[N:14]([CH3:13])[CH:15]=3)=[O:22])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: Cn1cc(C(=O)O)ccc1=O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cn1cc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
TEA (0.61 mL, 4.35 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.20 g, 0.87 mmol, Example 1, Step H), 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.17 g, 1.13 mmol) and BOP-Cl (0.33 g, 1.30 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 1 hour, and then a LiOH solution (3 mL, 2N) was added. The mixture was stirred for 30 minutes, and water (10 mL) was added. The solid formed was collected by filtration, washed with DCM (10 mL) and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (0.22 g, 69% yield) as a solid.