Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11](=[N:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)SC)=O)[CH:5]=[C:4]([CH3:23])[N:3]=1.[NH:24]([CH2:26][C@@H:27]([OH:30])[CH2:28][CH3:29])[NH2:25]>CC(O)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:24]([CH2:26][C@@H:27]([OH:30])[CH2:28][CH3:29])[N:25]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=3)[N:10]=2)[CH:5]=[C:4]([CH3:23])[N:3]=1
Reactant: CC[C@H](O)CNN
Reactant: CSC(=Nc1ccc(F)c(F)c1)NC(=O)c1cc(C)nc(Cl)c1
Solvent: CC(C)(C)O
Product: CC[C@H](O)Cn1nc(Nc2ccc(F)c(F)c2)nc1-c1cc(C)nc(Cl)c1

Procedure:
Intermediate D2 (1 g; 2.81 mmol) was dissolved in t-BuOH (40 ml) and, then intermediate D3 (0.44 g; 4.22 mmol) was added. The reaction mixture was stirred and refluxed for 4 hours and then the solvent was evaporated. The residue was purified by silica column chromatography (gradient: CH2Cl2/10% CH3OH in CH2Cl2 from 100/0 to 0/100). Yield: 1.1 g of intermediate D4 (S-enantiomer).
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:53]([N:60]1[C:64]2=[C:65]([N+:79]([O-:81])=[O:80])[C:66](OS(C(F)(F)F)(=O)=O)=[C:67]([CH3:70])[C:68](=[O:69])[N:63]2[CH2:62][CH2:61]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.[Br:82][C:83]1[CH:88]=[CH:87][C:86]([NH2:89])=[C:85]([F:90])[CH:84]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:53]([N:60]1[C:64]2=[C:65]([N+:79]([O-:81])=[O:80])[C:66]([NH:89][C:86]3[CH:87]=[CH:88][C:83]([Br:82])=[CH:84][C:85]=3[F:90])=[C:67]([CH3:70])[C:68](=[O:69])[N:63]2[CH2:62][CH2:61]1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c2n(c1=O)CCN2Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1c(Nc2ccc(Br)cc2F)c([N+](=O)[O-])c2n(c1=O)CCN2Cc1ccccc1
Temperature: 90 °C
Yield: 45.8 %

Procedure:
Palladium acetate (129 mg, 0.001 mol), BINAP (538 mg, 0.001 mol), cesium carbonate (2.8 g, 0.009 mol) were dissolved in toluene (20 mL) and the resulting mixture was sparged for 30 mins with nitrogen. This was followed by addition of trifluoro-methanesulfonic acid 1-benzyl-6-methyl-8-nitro-5-oxo-1,2,3,5-tetrahydro-imidazo[1,2-a]pyridin-7-yl ester (2.5 g, 0.006 mol) and 4-bromo-2-fluoro-phenylamine (1.15 g, 0.006 mol) in toluene (20 mL) and the reaction flask was again sparged for another 15 minutes. The reaction mixture was heated at 90° C. for 1 hour. The reaction was monitored by TLC (80% ethylacetate in hexane). The reaction mixture was filtered through celite bed and concentrated. Purification by column chromatography on silica gel (40% ethylacetate in hexane) afforded 1.3 g of the product (48% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.CC(C)=O.C(=O)=O.[Li]CCCC.[CH3:21][Si:22](Cl)([CH3:35])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C1COCC1.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([Si:22]([CH3:21])([CH3:35])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:3][CH:4]=1
Reactant: CCCCCCCCCCCC[Si](C)(C)Cl
Reactant: Brc1ccc(Br)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCC[Si](C)(C)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
100 mL of THF and 8.5 g (0.036 moles) of 1,4-dibromobenzene were put into a Schlenk flask which had been filled with nitrogen. Then the flask was agitated. The temperature was maintained at −78° C. by using acetone/dry ice. 22.6 mL (0.036 moles) of n-BuLi (1.6 M n-hexane solution) was slowly dropped into the reaction mixture over 10 minutes. After several minutes, a white salt began to be formed. After completion of the dropping of n-BuLi, a further agitation was carried out for about one hour. Then 10 g of dimethyldodecylsilyl chloride dissolved in 20 mL of THF was slowly dropped into the solution. Then the solution became clearer. After about three hours, the solution was put into 300 nL of water, and extracted with ethyl acetate. The extracts were dried by using anhydrous MgSO4 and filtered with a solvent, and then the solvent was evaporated. The obtained oil was either distilled in a vacuum (boiling point of 160-170° C./1.5 mmHg), or purified by a silica gel chromatography (eluent: n-hexane). Thus, 1-bromo-4-(dimethyldodecylsilyl)benzene (I) was obtained with a yield of about 90 % or above. The chemical structure of compound (I) was identified through 1H-NMR as follow: 1H-NMR (CDCl3): δ0.24 (s, 6H, Si(CH3)2), 0.72 (t, 2H, SiCH2), 0.89 (t, 3H,—CH3), 1.27 (m, 20H, (CH2)10, 7.37 and 7.49 (d, 4H, aromatic protons).
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[C:7]([C:14]([O:16]C)=[O:15])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[CH:1]1([C:4]#[C:5][C:6]2[C:7]([C:14]([OH:16])=[O:15])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1nc(SC)ncc1C#CC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1ncc(C#CC2CC2)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
Methyl 5-(cyclopropylethynyl)-2-(methylthio)pyrimidine-4-carboxylate (Preparation 183, 520 mg 2.1 mmole) was dissolved in methanol (8 mL) and 2M sodium hydroxide (1.6 mL, 3.2 mmole) was added. The reaction was stirred at room temperature for 3 hours. The reaction was cooled in ice and 2M hydrochloric acid (1.6 mL) was added. The deposited solid was filtered, washed with water and dried to afford the title compound (387 mg, 78%).
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16][C:17]([OH:19])=O.C(N(CC)CC)C.[NH2:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)Cl>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16][C:17]([NH:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:19]
Reactant: CCOC(=O)c1ccccc1N
Reactant: O=C(O)C=Cc1ccco1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1NC(=O)C=Cc1ccco1
Yield: 30.2 %

Procedure:
Under nitrogen stream, 2-chloro-1-methylpyridinium iodide (1.272 g, 4.34 mmol) was suspended in dry methylene chloride (5 ml). To the suspension a solution of 3-(2-furyl)acrylic acid (500 mg, 3.62 mmol), triethylamine (1.2 ml, 8.69 mmol), and ethyl 2-aminobenzoate (0.53 ml, 3.62 mmol) in dry methylene chloride (5 ml) was added. The mixture was heated under reflux for 40 hours. Then, the reaction mixture was diluted with methylene chloride, and washed with 10% aqueous HCl, saturated aqueous sodium chloride, 1N-aqueous NaOH, and saturated aqueous sodium chloride successively, and dried. Removal of solvent gave a viscous oil, which, on washing with n-hexane gave white solids of the title compound (312 mg, yield: 30.2%), which was recrystallized from methanol. m.p., 85°-86° C.
Reaction SMILES: C(O)C.Cl.C(=O)([O-])[O-].[Na+].[Na+].O.[Si:12]([O:19][C@@H:20]1[C@H:24]([CH2:25][O:26][Si](C(C)(C)C)(C)C)[CH2:23][C@@H:22]([O:34][C:35]2[CH:40]=[C:39]([Cl:41])[N:38]=[CH:37][N:36]=2)[CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[Si:12]([O:19][C@H:20]1[CH2:21][C@H:22]([O:34][C:35]2[CH:40]=[C:39]([Cl:41])[N:38]=[CH:37][N:36]=2)[CH2:23][C@H:24]1[CH2:25][OH:26])([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(Cl)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](Oc2cc(Cl)ncn2)C[C@H]1CO
Temperature: -45 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
In a 2 L round-bottomed flask, 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]-oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine (14) (20.5 g, 0.0433 mol was dissolved in ethanol (647.2 mL, 11.08 mol), and cooled to an internal temp of −45° C. To this was added a precooled (−20° C.) solution of 2% conc. HCl in EtOH (326 mL, 0.0516 mol, prepared by diluting 6.5 mL conc. HCl in 319.5 mL ethanol). The reaction mixture was warmed to −25° C. (to prevent pressure buildup upon capping the flask), and then capped and placed in a freezer at −35° C. The reaction was left to stand at −35° C. for 18 hours. The reaction was quenched with sodium carbonate (13.78 g, 0.1300 mol) (˜3 equiv relative to HCl) as a solution in water (40 mL, 2 mol). The volatiles were removed in vacuo, and the reaction mixture was diluted with CH2Cl2 (750 mL). The solids were filtered and set aside, and the volatiles were removed from the filtrate in vacuo. The resulting aqueous mixture with was diluted with EtOAc (500 mL) and water (200 mL) and transferred to a separatory funnel. The layers were separated, and the aqueous layer was extracted 2×250 mL with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (applied to column with ˜50 mL CH2Cl2, 400 g column, eluent 0-40% EtOAc:hexanes over 40 min to afford {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-chloropyrimidin-4-yl)oxy]cyclopentyl}methanol (11.2 g, 72%). LCMS: (FA) ES+ 359; 1H NMR (400 MHz, CDCl3) δ 8.56 (app d, J=0.6, 1H), 6.70 (app d, J=0.8, 1H), 5.62-5.54 (m, 1H), 4.56 (dd, J=5.6, 10.9, 1H), 3.86-3.78 (m, 1H), 3.70 (ddd, J=6.0, 7.6, 11.3, 1H), 2.48 (dd, J=4.6, 7.6, 1H), 2.42-2.31 (m, 1H), 2.23 (ddd, J=6.3, 9.8, 14.2, 1H), 2.15-2.09 (m, 2H), 1.89 (ddd, J=1.9, 8.0, 14.3, 1H), 0.91 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][CH:10]=[O:11].CN(C)C=O.[CH:17]1([N:20]=[C:21]=[O:22])[CH2:19][CH2:18]1.C(N(CC)CC)C>CCOCC.O>[CH:17]1([NH:20][C:21](=[O:22])[N:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH:10]=[O:11])[CH2:19][CH2:18]1
Reactant: O=C=NC1CC1
Reactant: O=CNc1cc(F)ccc1F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: O=CN(C(=O)NC1CC1)c1cc(F)ccc1F

Procedure:
A mixture of 9.9 g of 2B, 25 ml of dimethylformamide, 11 g of 1A and 2 g of triethylamine (catalyst) was heated in a steam bath for 24 hours. The resulting mixture was diluted with ether and water, and phase-separated. The ether phase was washed with water, and dried (MgSO4), and the solvent was evaporated. The residue was triturated with ether. The residual off-white solid was 2, m.p.: 118°-120° C.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.OS([O-])=O.[Na+].[CH2:18]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([NH2:35])[CH:29]=2)=[CH:24][CH:23]=1)[CH2:19][CH2:20][CH3:21].[Li+].[OH-]>CC(N(C)C)=O.CCOC(C)=O.O>[CH2:18]([C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]3[N:34]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:12])=[CH:5][CH:6]=4)[NH:35][C:30]=3[CH:29]=2)=[CH:26][CH:27]=1)[CH2:19][CH2:20][CH3:21]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCCCc1ccc(-c2ccc(N)c(N)c2)cc1
Agent: O=S([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCc1ccc(-c2ccc3nc(-c4ccc(C(=O)O)cc4)[nH]c3c2)cc1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A hot (140° C.) mixture of 4-formyl-benzoic acid methyl ester (21.0 mg, 0.129 mmol) and NaHSO3 (20.1 mg, 0.193 mmol, 1.5 eq.) in DMA (250 μL) is treated with the dropwise addition of 4′-butyl-biphenyl-3,4-diamine (31 mg, 0.129 mmol) in DMA (100 μL) over 10 minutes. The resulting mixture is stirred for 1 hour at 140° C. and is then treated with H2O (1 ml) and stirred an additional hour. The reaction is diluted with EtOAc and the phases separated. The organic phase is dried over MgSO4, filtered, and concentrated. The crude benzimidazole product is diluted with 95% Ethanol (0.5 ml) and THF (1 ml) and transferred into a Smith-Process Vial containing LiOH (15.4 mg, 0.645 mmol, 5 eq.). The reaction vessel is heated to 165° C. under microwave irradiation for 5 minutes. After concentration, the crude product is purified by preparative RP LC-MS to give 4-[6-(4-butyl-phenyl)-1H-benzoimidazol-2-yl]-benzoic acid: 1H NMR (400 MHz, CD3OD) δ 9.00 (d, J=8.2 Hz, 1H), 8.91 (d, J=8.1 Hz, 1H), 8.63 (s, 1H), 8.53 (s, 1H), 8.31 (d, J=7.6 Hz, 2H), 8.23 (d, J=8.3 Hz, 1H), 8.02 (d, J=7.7 Hz, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 3.38 (dd, J=7.8, 7.7 Hz, 1H), 2.69 (dd, J=7.8, 7.6 Hz, 1H), 2.35 (m, 1H), 2.09 (m, 1H), 1.66 (dd, J=7.4, 7.3 Hz, 3H), 1.41 (m, 1H), 0.97 (dd, J=7.3, 6.9 Hz, 2H); ESMS m/z 371.2 (M+H+).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[C:10]([NH2:25])=[N:11][CH:12]=[C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH3:24])[CH:19]=[CH:18]4)[CH:14]=2)[N:6]=[N:5]1)([CH3:3])[CH3:2].C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[C:10]([NH2:25])=[N:11][CH:12]=[C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH3:24])[CH2:19][CH2:18]4)[CH:14]=2)[N:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cc(-c2cc(-c3ccc4c(ccn4C)c3)cnc2N)nn1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1cc(-c2cc(-c3ccc4c(c3)CCN4C)cnc2N)nn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
To a solution of 3-(1-isopropyltriazol-4-yl)-5-(1-methylindol-5-yl)pyridin-2-amine (170 mg, 0.511 mmol) in TFA (5.0 mL) was added triethylsilane (0.16 mL, 1.022 mmol) at 0° C. The reaction temperature was stirred for 1 h at 0° C. The reaction mixture was poured into ice-cold water (20 mL), basified with saturated NaHCO3, extracted with EtOAc (30 mL), dried over anhydrous Na2SO4 and evaporated the solvent under reduced pressure to get crude compound. Crude compound was washed with diethyl ether to afford title compound as a yellow solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:7](O)([CH3:9])[CH3:8]>>[C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)O
Reactant: c1ccccc1
Product: CC(C)c1ccccc1

Procedure:
alkylating benzene in the presence of iso-propanol to obtain cumene;
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([F:26])([F:25])[S:21](Cl)(=[O:23])=[O:22].C(OCC)(=O)C>CN(C)C=O.CCCCCC.O.C(OCC)C>[F:19][C:20]([F:26])([F:25])[S:21]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
To a solution of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (3.456 g, 21.18 mmol) in anhydrous N,N-dimethylformamide (25 mL) was added potassium carbonate (4.146 g, 30.00 mmol), then and trifluoromethanesulfonyl chloride (5.000 g, 29.67 mmol) in N,N-dimethylformamide (5 mL) dropwise. The reaction mixture was stirred at room temperature for 24 hours, and a second portion of potassium carbonate (4.146 g, 30.00 mmol) and trifluoromethanesulfonyl chloride (5.000 g, 29.67 mmol) in N,N-dimethylformamide (5 was added slowly, and stirred for 16 hours. Evaporation of the solvent under reduced pressure gave a crude mixture to which a mixture of 15% ethyl acetate in n-hexane (20 mL) and water (50 mL) was added. Diethyl ether (5 mL) was added and the mixture sonicated, filtered, and the solid thus obtained was washed with 3M aqueous potassium carbonate (100 mL), water (200 mL), n-hexane (100 mL), 15% ethyl acetate in n-hexane (30 mL), and dried to afford 2-oxo-1,2,3,4-tetrahydroquinolin-7-yl trifluoromethanesulfonate as a yellow solid (4.311 g, 14.60 mmol, 69%). LCMS mz 295.9 (M+H), 317.9 (M+Na), anal HPLC >90% in purity, 1H NMR (400 MHz; CDCl3) δ8.17 (bs, 1H); 7.23 (d, J=8.2 Hz, 1H); 6.90 (dd, J=8.2 and 2.3 Hz, 1H); 6.71 (d, J=2.3 Hz, 1H); 3.00 (m, 2H); 2.67 (m, 2H).
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][C:15]([Br:20])=[CH:14][CH:13]=3.CO>ClCCl.[Fe](Cl)(Cl)Cl>[Br:20][C:15]1[CH:14]=[CH:13][C:12]2[N:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]3[CH:9]=[C:8]4[C:32]5[C:27]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=6[C:7]4=[CH:19][C:18]=3[C:17]=2[CH:16]=1)=[CH:28][CH:29]=[CH:30][CH:31]=5
Reactant: Brc1ccc2c(c1)c1cc(-c3ccccc3-c3ccccc3)ccc1n2-c1ccccc1
Agent: Cl[Fe](Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Brc1ccc2c(c1)c1cc3c4ccccc4c4ccccc4c3cc1n2-c1ccccc1
Reaction time: 0.17 h
Yield: 73.1 %

Procedure:
In a 3000 ml three-necked flask that had been degassed and filled with nitrogen, 19.9 g (42 mmol) of 3-(biphenyl-2-yl)-6-bromo-9-phenyl-9H-carbazole was dissolved in anhydrous dichloromethane (1000 ml), 68.2 g (420 mmol) Iron(III) chloride was then added, and the mixture was stirred 10 minutes. Methanol 300 ml were added to the mixture and the organic layer was separated and the solvent removed in vacuo. The residue was purified by column chromatography on silica(hexane-dichloromethane) afforded a white solid (14.5 g, 30.7 mmol, 73%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:27])[C@H:11]([CH2:23][CH2:24][S:25][CH3:26])[NH:12][C:13](=[O:22])[C@H:14]([CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[NH2:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OC(=O)[C@H](CCSC)NC(=O)[C@H](CC1C2C(=CC=CC=2)NC=1)N[C:42](=[O:68])[CH2:43][NH:44][C:45](=[O:67])[CH2:46][NH:47][C:48](=[O:66])[C@H:49]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([OH:65])=[CH:61][CH:60]=1)[NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])C1C=CC=CC=1>>[CH2:2]([O:9][C:10](=[O:27])[C@H:11]([CH2:23][CH2:24][S:25][CH3:26])[NH:12][C:13](=[O:22])[C@H:14]([CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[NH:15][C:42](=[O:68])[CH2:43][NH:44][C:45](=[O:67])[CH2:46][NH:47][C:48](=[O:66])[C@H:49]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([OH:65])=[CH:61][CH:60]=1)[NH:50][C:51]([O:53][C:54]([CH3:56])([CH3:57])[CH3:55])=[O:52])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CSCC[C@H](NC(=O)[C@@H](N)Cc1cccs1)C(=O)OCc1ccccc1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Product: CSCC[C@H](NC(=O)[C@H](Cc1cccs1)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When an equivalent quantity of β-(2-thienyl)-L-alanyl-L-methionine benzyl ester hydrochloride is substituted for the L-tryptophyl-L-methionine benzyl ester hydrochloride of Example 7 and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-L-tyrosylglycylglycyl β-(2-thienyl)-L-alanyl-L-methionine benzyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:7])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1cccc(Br)c1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.40 g (2.0 mmol) 3-bromobenzoic acid and 0.28 g (2.0 mmol) 5-fluoro-2,3-dihydro-1H-indole in 0.55 mL (4.0 mmol) TEA and 10 mL DCM were combined with 0.64 mg (2.0 mmol) TBTU and stirred overnight at RT. The reaction mixture was extracted with saturated sodium hydrogen carbonate solution and DCM. The combined organic phases were dried on sodium sulphate, filtered and evaporated down. The residue was suspended in MeOH, suction filtered and dried.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([OH:21])=[C:15]2[CH:14]=[N:13]1.[CH3:22][NH:23][CH3:24]>CS(C)=O>[CH3:22][N:23]([CH3:24])[C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([OH:21])=[C:15]2[CH:14]=[N:13]1
Reactant: CNC
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(O)ncnc32)c(F)c1
Solvent: CS(C)=O
Product: CN(C)c1cc(S(C)(=O)=O)ccc1-n1ncc2c(O)ncnc21
Temperature: 120 °C
Yield: 89.3 %

Procedure:
1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (0.520 g, 1.68 mmol) was dissolved in DMSO (3 mL) and dimethylamine (2M solution in THF) (4 mL, 150 mmol) was added. The mixture was heated at 120° C. for 15 h. The solvent was removed under reduced pressure and the crude was purified by HPLC, yielding 1-(2-dimethylamino-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol as an off-white solid (0.500 g, 89%). Exact mass calculated for C14H15N5O3S 333.09, found 334.4 (MH+, 100%).
Reaction SMILES: Cl[CH2:2][C@H:3]([CH3:21])[C@H:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)[CH2:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:29][NH:30][CH3:31].O>CN(C)C=O>[CH2:5]([C@@H:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)[C@@H:3]([CH3:21])[CH2:2][N:30]([CH3:31])[CH3:29])[CH3:6]
Reactant: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CCl
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CN(C)C
Yield: 90 %

Procedure:
The product of Example 42 (2.4 g, 8 mmol) was dissolved in N,N-dimethylformamide, potassium carbonate (2.7 g, 20 mmol) and dimethylamine hydrochloride (0.7 g, 8 mmol) were added therein, then it was reacted at room temperature for 12 hours. After that, the reaction solution was poured into water, the aqueous phase was extracted with dichloromethane twice, then the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated through silica gel column chromatography to give target 2.2 g, yield: 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[C:12]([F:13])=[CH:11][C:10]([S:14]([N:17](CC3C=CC(OC)=CC=3OC)[C:18]3[S:22][N:21]=[CH:20][N:19]=3)(=[O:16])=[O:15])=[C:9]([F:34])[CH:8]=2)=[C:4]([C:37]2[N:41]([CH:42]3[CH2:45][N:44](C(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:43]3)[N:40]=[CH:39][CH:38]=2)[CH:3]=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.ClC(OC(Cl)C)=O>ClCCl.CO>[NH:44]1[CH2:43][CH:42]([N:41]2[C:37]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:36]=[CH:35][C:5]=3[O:6][C:7]3[C:12]([F:13])=[CH:11][C:10]([S:14]([NH:17][C:18]4[S:22][N:21]=[CH:20][N:19]=4)(=[O:15])=[O:16])=[C:9]([F:34])[CH:8]=3)=[CH:38][CH:39]=[N:40]2)[CH2:45]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccnn3C3CN(C(c4ccccc4)c4ccccc4)C3)cc2F)c(OC)c1
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(Oc2ccc(Cl)cc2-c2ccnn2C2CNC2)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(4-chloro-2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}phenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 688, 270 mg, 0.321 mmol) was dissolved in dichloromethane (15 ml) and N,N,N′,N′-tetramethylnaphthalene-1,8-diamine (85 mg, 0.40 mmol) was added followed by 1-chloroethyl chloroformate (0.07 ml, 0.65 mmol) and the solution was stirred at room temperature for 4 hours. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate (40 ml) and 1M aqueous citric acid solution (20 ml), the ethyl acetate was washed with water, dried over anhydrous sodium sulphate, evaporated and the solvents removed in vacuo to give an oil. The oil was dissolved in methanol (15 ml) and refluxed for 5 hours. Some of the methanol was removed in vacuo to leave about 5 ml, the precipitated solid was removed by filtration and the filtrate was adsorbed onto silica gel (5 g) and dried prior to purification by column chromatography on silica gel using 10-25% v/v methanol (containing 10% v/v 0.880 aqueous ammonia) in dichloromethane. This afforded the title compound as a pinkish solid, 80 mg.