Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][CH2:11][C:12]1[C:17]([F:18])=[CH:16][C:15](B(O)O)=[CH:14][C:13]=1[F:22].Br[C:24]1[CH:25]=[C:26]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:22][C:13]1[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)[CH:16]=[C:17]([F:18])[C:12]=1[CH2:11][NH:10][CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: OB(O)c1cc(F)c(CNC2Cc3ccccc3C2)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(-c2cc(F)c(CNC3Cc4ccccc4C3)c(F)c2)c1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
A mixture of {4-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3,5-difluoro-phenyl}boronic acid (740 mg, 2.44 mmol; Ex V-22), 3-bromonitrobenzene (495 mg, 2.44 mmol), PdCl2(dppf)2 (100 mg, 0.12 mmol) and Na2CO3 (4.90 mL, 2.0 M (aq)) in DME (10 mL) was stirred at 80° C. for 45 min. The mixture was diluted with EtOAc then filtered through a pad of Celite and silica gel. The filtrate was washed with H2O and brine, dried over Na2SO4 then concentrated to give N-[(3,5-difluoro-3′-nitro-4-biphenylyl)methyl]-2,3-dihydro-1H-inden-2-amine as a tan glass. LC/MS (method A) 0.62 min, (m/z) 381 (70%), 382 (100%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][CH:19]3[C:25](=[O:26])[N:24]([CH2:27][C:28]([N:30]([CH:42]([CH3:44])[CH3:43])[C:31]4[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=4)=[O:29])[C:23]4[CH:45]=[CH:46][CH:47]=[CH:48][C:22]=4[N:21]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:20]3=[O:55])=[N:7][N:8]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][CH:19]3[C:25](=[O:26])[N:24]([CH2:27][C:28]([N:30]([CH:42]([CH3:44])[CH3:43])[C:31]4[CH:32]=[CH:33][C:34]([O:37][C:38]([F:39])([F:40])[F:41])=[CH:35][CH:36]=4)=[O:29])[C:23]4[CH:45]=[CH:46][CH:47]=[CH:48][C:22]=4[N:21]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:20]3=[O:55])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3cc(F)ccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc(OC(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2n[nH]c3cc(F)ccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc(OC(F)(F)F)cc1
Reaction time: 6 h
Yield: 65.8 %

Procedure:
70 mg of 2-[3-(6-Fluoro-1-tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-trifluoromethoxy-phenyl)-acetamide, prepared as in Intermediate 70, is dissolved in 2 mL of CHCl3 and 5 mL of TFA is added. The reaction mixture is stirred for 6 h and the solvents were removed in vacuo. The residue is purified by silica gel flash column chromatography using hexane/EtOAc 40:60 as eluent to afford the 40 mg of the title compound: 1H NMR (400 MHz, DMSO-d6) δ7.73 (dd, 1H, J=8.9, 5.1), 7.41-7.18 (m, 12H), 7.08 (dd, 1H, J=7.3, 2.0), 6.97 (dd, 1H, J=8.9, 1.7), 6.92 (dd, 1H, J=7.2, 2.0), 6.84 (dd, 1H,J=9.1, 2.0), 5.01 (m, 1H), 4.22 (m, 3H), 3.75 (dd, 1H, J=16.5, 6.4), 3.56 (dd, 1H, J=16.5, 6.4), 1.06 (t, 6H, J=6.8); low resolution MS (FAB) m/e 660 (MH+); Tr =12.32 min. (HPLC Column: Dynamax C-8 2 mL/min., 50-90% Acetonitrile in aqueous TFA (0.1% v/v) over 15 min.).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3][S:2]1=[O:12].[Cl:13][C:14]([SH:17])([Cl:16])[Cl:15]>C(Cl)Cl>[Cl:13][C:14]([Cl:16])([Cl:15])[S:17][N:3]1[C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][S:2]1=[O:12]
Reactant: SC(Cl)(Cl)Cl
Reactant: O=C1NS(=O)Oc2ccccc21
Solvent: ClCCl
Product: O=C1c2ccccc2OS(=O)N1SC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
A 300-ml flask equipped with a stirrer and thermomether was charged with 5.0 g (0.03 mol) of 1,2,3-benzoxthiazin-4-(3H)-one 2-oxide, 5.3 g (0.03 mol) of perchloromethyl mercaptan, 3.1 g (0.03 mol) of thiethylamine and 150 ml of methylene chloride. The resulting mixture was stirred at ambient temperature for 1 hour. At the end of this time, the reaction mixture was filtered and washed 3 times with equal amounts of water. After drying, the solvent was removed by evaporation. The crude product was passed through a 250-g silica-gel column using hexane, 10% ether/hexane, and 20% ether/hexane, respectively. Evaporation gave 4 g of 3-(trichloromethylthio)-1,2,3-benzoxathiazin-4-(3H)-one 2-oxide having a melting point of 65°-67° C.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)([CH2:18][CH:19]=[CH2:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>O1CCCC1>[Cl:28][C:23]1[CH:22]=[C:21]([C:12]([NH:11][CH:1]=[O:2])([CH2:18][CH:19]=[CH2:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: C=CCC(N)(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: C=CCC(NC=O)(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Under cooling on ice, formic acid (140 mL) was added to acetic anhydride (255 mL), followed by stirring at 50° C. for 30 minutes. The reaction mixture was cooled with ice. Subsequently, ethyl 2-amino-2-(3,4-dichlorophenyl)-4-pentenoate (298 g) in tetrahydrofuran (1.5 L) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was neutaralized with saturated aqueous sodium bicarbonate. The resultant mixture was subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate anhydrate. The solvent was removed under reduced pressure, to thereby give the title compound (334 g). The title compound was used in the next step without further purification.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]=[CH2:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:24]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2]>C(O)C>[CH2:22]([C:20]1[CH:19]=[CH:18][C:17]2[C:11]3[N:12]([CH:24]=[C:9]([C:8]4[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]([CH3:25])[N:7]=4)[N:10]=3)[CH2:13][CH2:14][O:15][C:16]=2[CH:21]=1)[CH3:23]
Reactant: C=Cc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Solvent: CCO
Product: CCc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.7 %

Procedure:
2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-vinyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine from Example 447 (0.300 g, 0.894 mmol) was dissolved in ethanol (5 mL) and purged with N2.10% Palladium on Carbon (0.1:0.9, Palladium:carbon black, 0.0952 g) was added. The resulting suspension was placed under vacuum followed by addition of H2 at atm pressure. This process was repeated three times to saturate the catalyst. The reaction was stirred for 18 hours at room temperature. The reaction mixture was filtered and concentrated to dryness. The crude product was purified using reverse phase chromatography to give 499 (0.189 g, 62.9% yield).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[C:6]1([CH2:12][NH:13][CH2:14][CH2:15][OH:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl.C(O)C>[S:2]([OH:5])([O:16][CH2:15][CH2:14][NH:13][CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: OCCNCc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(O)OCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
Chlorosulfonic acid (13.3 mL, 0.2 mol) was added very slowly to (2-[(phenylmethyl)amino]ethanol (30.2 g, 0.2 mol) in carbon tetrachloride (100 mL) in an ice bath. The resulting thick white suspension was stirred at room temperature overnight The suspension was diluted with chloroform and ethanol, warmed to 45° C. and then cooled in an ice bath. The precipitate was collected by filtration, washed with ethanol and dried under vacuum for 16 hrs at 40° C. to afford the desired compound (34 g, 74%). MS (ES)+ m/z 232 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[C:12]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:13]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.N(C(OC(C)C)=O)=NC([O-])=O>C1(C)C=CC=CC=1.O1CCCC1.C(O)C>[CH2:12]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([NH2:11])=[C:2]([NH2:1])[CH:3]=1)[CH3:13]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CC(C)OC(=O)N=NC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N)c(N)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
3,4-Diaminobenzoic acid (2.003 g, 13.17 mmol) and triphenylphosphine (4.248 g, 16.20 mmol) were suspended in toluene (20 ml) and tetrahydrofuran (10 ml). Ethanol (2 ml) was then added, diisopropyl azodicarboxylate (2.5 ml, 9.96 mmol) was added dropwise to the obtained light brown suspension, and the mixture was stirred at room temperature for 3.5 hours. Isopropyl azodicarboxylate (1.5 ml, 5.98 mmol) was further added dropwise, the mixture was stirred at room temperature for 1 hour, and the obtained reaction mixture was extracted with 1N hydrochloric acid (100 ml×2 times), after which the aqueous layer was washed with 50 ml of ethyl acetate. After adding 2N aqueous sodium hydroxide to the aqueous layer to raise the pH to 11 or higher, the precipitate was extracted with ethyl acetate (100 ml×2 times). The organic layer was washed with saturated brine (50 ml) and dried overnight over anhydrous sodium sulfate. The desiccant was filtered out and the filtrate was concentrated to obtain 3,4-diaminobenzoic acid ethyl ester as a faint yellow solid. The compound was identified by LC-MS.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:39][CH2:40][C:41]([C:44](OC)=[O:45])([CH3:43])[CH3:42])=[C:12]([CH:14]2[C:19]3([C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH:18]([C:30]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[CH2:17][C:16](=[O:38])[NH:15]2)[CH:13]=1.O>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:39][CH2:40][C:41]([CH3:43])([CH3:42])[CH2:44][OH:45])=[C:12]([CH:14]2[C:19]3([C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH:18]([C:30]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[CH2:17][C:16](=[O:38])[NH:15]2)[CH:13]=1
Reactant: COC(=O)C(C)(C)COc1ccc(Br)cc1C1NC(=O)CC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Br)ccc2OCC(C)(C)CO)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
LiAlH4 (11.4 mg, 0.3 mmol) was suspended in THF in ice bath, then a solution of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in Example 262d (63 mg, 0.1 mmol) in THF (2 mL) was added slowly. The reaction mixture was stirred at room temperature for 10 min, water (1 mL) was added and the resulting mixture was filtered. The filtration was concentrated and the residue was purified by Prep-HPLC to give the title compound as a white solid (Yield: 31 mg).
Reaction SMILES: Br[C:2]1[C:3]([NH:22][CH2:23][CH2:24][CH2:25][OH:26])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.O>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:3]1[C:2]([C:32]2[CH:33]=[N:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCCO)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2NCCCO)cn1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-((3-hydroxypropyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 161.1, 72 mg, 0.15 mmol), (6-methoxypyridin-3-yl)boronic acid (23.1 mg, 0.15 mmol) and Na2CO3 (48 mg, 0.450 mmol) in a mixture of DME (3.2 mL), EtOH (0.43 mL) and water (0.64 mL) was flushed with argon for 5 min. Pd(PPh3)2Cl2 was added (5.3 mg, 0.0075 mmol) and the mixture subjected to MW irradiation at 125° C. for 20 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give a residue that was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge to afford the title compound. UPLC-MS (Condition 8) tR=2.33 min, m/z=463.1 [M+H]+, m/z=461.1 [M−H]−.
Reaction SMILES: [N+]([O:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)([O-])=O.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Cl.[H-].[Na+].CS(C)=O>O.C1C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][O:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: O=[N+]([O-])OC(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: ClCc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: Clc1ccc(C(Cn2cncn2)OCc2ccccc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3.2 parts of α-(2,4-dichlorophenyl)-1H-1,2,4-triazole-1-ethanol nitrate, 2.4 parts of 1-chloro-2-(chloromethyl)benzene, 1.5 parts of a sodium hydride dispersion 50%, 70 parts of dimethyl sulfoxide and 63 parts of benzene is stirred for 2.50 hours at room temperature. Water is added and the product is extracted twice with 2,2'-oxybispropane. The extract is washed twice with water and the solvent is removed in vacuo. The residue is crystallized from 2,2'-oxybispropane, yielding 3 parts of 1-{2-[(2-chlorophenyl)methoxy]-2-(2,4-dichlorophenyl)ethyl}-1H-1,2,4-triazole; mp. 106.4° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]1[C:20]([Cl:21])=[CH:19][C:11]2[N:12]=[C:13](S(O)(=O)=O)[NH:14][C:10]=2[CH:9]=1>P(Cl)(Cl)(Cl)=O>[Cl:2][C:13]1[NH:14][C:10]2[CH:9]=[C:8]([Cl:7])[C:20]([Cl:21])=[CH:19][C:11]=2[N:12]=1
Reactant: O=S(=O)(O)c1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
A modified procedure of Balli and Kersting procedure described in Balli, H. et al., Justis Liebigs Am. Chem. 1:647 (1961), was followed. A one liter three neck roundbottom flask was fitted with an over head stirrer and a reflux condenser connected to a gas scrubber. To the flask was added in order, phosphorus oxychloride (80 mL), phosphorus pentachloride (104.0 g, 0.5M) and 5,6-dichlorobenzimidazole-2-sulfonic acid (9) (66.8 g, 0.25M). The resulting mixture was carefully heated until an exothermic reaction occurred. The heat source was removed. When the reaction had subsided, the mixture was carefully heated to reflux. After all gas evolution had ceased (5 hr) the mixture was protected from moisture and allowed to cool to 25° C. The resulting thick slurry was carefully added to cold H2O (2.5 L) containing some ice. Ice was added as needed. The aqueous mixture was allowed to stand for 18 hr at 5° C. while the product precipitated. The pH of the mixture was adjusted to pH 8 with conc. NH4OH then acidffied to pH 3 with glacial AcOH. The solid was collected by filtration, washed with H2O, then dried on the filter. The material was dissolved in THF, treated with charcoal, then filtered through Celite. The solvent was removed under reduced pressure. The solid residue was dried at 60° C. under reduced pressure for 18 hr to yield 39.9 g (72%) of 2,5,6-trichlorobenzimidazole (5). MP: 212°-214° C. (eff. then solidifies). See Kawashima, E. et al., Nucleic Acid Chemistry: Improved and New Synthetic Procedures, Method and Techniques, eds. Townsend, L. B. et al., Wiley Interscience New York, N.Y., Part IV p. 96 (1991). TLC: Rf =0.89 (EtOAc; SiO2). Recrystallization from benzene-hexane raises the melting point to 223°-224° C.
Reaction SMILES: [CH:1]1([CH2:6][C:7](Cl)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C@H:10]1([NH:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:30])[CH:26]=3)[N:21]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1>C(N(CC)CC)C>[CH:1]1([CH2:6][C:7]([NH:30][C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([NH:19][C@H:10]2[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12][CH2:11]2)[CH:29]=[CH:28]3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Solvent: CCN(CC)CC
Product: O=C(CC1CCCC1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method 9 described in example 116 from cyclopentylacetyl chloride, triethylamine and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=386.7 (M+H+).
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][CH:8]([CH2:13][S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C2CCCCO2)[CH:17]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:6])=[N+:2]=[N-:3]>Cl.CO>[N:1]([CH2:4][C:5]([NH:7][CH:8]([CH2:13][S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:6])=[N+:2]=[N-:3]
Reactant: COC(=O)C(CSCc1cccc(OC2CCCCO2)c1)NC(=O)CN=[N+]=[N-]
Agent: Cl
Solvent: CO
Product: COC(=O)C(CSCc1cccc(O)c1)NC(=O)CN=[N+]=[N-]
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
Few drops of conc. HCl (5 drops) were added to the 44 (0.25 g) in methanol and stirred for 30 min until no starting material was seen by LCMS. After evaporation of methanol, brine was added to the reaction mixture and extracted with ethyl acetate, dried over MgSO4, concentrated and chromatographed (Hexanes/EtOAc) then 5% methanol/methylene chloride) to obtain the 0.2 g of 45 as colorless oil in quantitative yield.
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+]>C(OCC)(=O)C.C(#N)C>[C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCCc2c1c1cccc3c1n2C(c1ccccc1)CO3
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 80 °C
Yield: 26.4 %

Procedure:
To 1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (4.0 g, 13.19 mmol) in ethyl acetate/acetonitrile (30 mL/15 mL) is added trifluoroacetic acid (2 mL) and anhydrous cupric chloride (3.56 g, 26.4 mmol). The mixture is heated to reflux at 80° C. for 1.5 h. The mixture is concentrated. The residue is dissolved in ethyl acetate (50 mL) and filtered to remove inorganic solids. The filtrates are washed with saturated potassium carbonate solution followed by water, dried over magnesium sulfate and concentrated. The residue is dissolved in DMF (15 ml) to which is added lithium bromide (2.4 g, 27.7 mmol) and lithium carbonate (2.04 g, 27.7 mmol). The mixture is heated at 120° C. for 4.5 h then partitioned between water and CH2Cl2 with the organic layer being washed twice with brine (30 mL). Column chromatography (200 g silica gel) using EtOAc/hexanes (20/80) as eluent gave 1.05 g (26%) of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])[N:8]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24]CC4C=CC(OC)=CC=4)=[C:20]([O:34][CH3:35])[CH:19]=3)[C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[OH:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:8]2[C:5]3=[N:6][CH:7]=[C:2]([I:1])[CH:3]=[C:4]3[N:10]=[C:9]2[NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(OC)cc2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(O)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred solution of ethyl (6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (Example 3-34-2) (2.40 g, 4.08 mmol) in dichloromethane (50 mL) at 0° C. was added trifluoroacetic acid (4.47 g, 3.0 mL, 39.18 mmol). The resulting mixture was allowed to stir at 0° C. After 2 h, the mixture was treated with 2M potassium carbonate solution to adjust the pH to ˜9. The basic mixture was extracted with 1:1 methanol/dichloromethane solution (3×50 mL). The combined organic phases were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated to provide 1.30 g (70%) of ethyl (3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:40]5[CH:39]=[CH:38][CH:37]=[C:36]([F:35])[CH:41]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(F)c5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-fluorophenylboronic acid.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([CH2:12][NH:13][C:14]([C:16]([CH3:22])([CH3:21])[C:17]([F:20])([F:19])[F:18])=[O:15])[C:6]=1[F:23])C.CCO>[OH-].[Na+]>[F:23][C:6]1[C:7]([CH2:12][NH:13][C:14]([C:16]([CH3:21])([CH3:22])[C:17]([F:18])([F:19])[F:20])=[O:15])=[CH:8][CH:9]=[C:10]([Cl:11])[C:5]=1[C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)(C)C(F)(F)F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)NCc1ccc(Cl)c(C(=O)O)c1F)C(F)(F)F

Procedure:
Prepared analogously to example 45f with 2-fluoro-6-chloro-3-[(2,2,2-trifluoro-1,1-dimethylethyl)carbonylamino]methyl-benzoic acid ethylester (1.02 g; 2.76 mmol) in 1 M aq. NaOH with 25 mL EtOH. The solvent was evaporated, diluted with 4 M aq HCl and extracted with DCM, dried with Na2SO4 and concentrated i.vac to obtain the subtitle compound.