Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[O:2].N[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].C[N:24](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[OH:22][C:17]1[CH:18]=[CH:19][C:20]([NH:24][C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3]([CH:1]=[O:2])=[N:4][NH:5]3)=[CH:10][CH:9]=2)=[O:14])=[CH:21][CH:16]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1ccccc1O
Reactant: O=Cc1n[nH]c2cc(C(=O)O)ccc12
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=Cc1n[nH]c2cc(C(=O)Nc3ccc(O)cc3)ccc12
Reaction time: 2 h

Procedure:
Using the same procedure as for the synthesis of 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid in Example 53(a), step (ii), N-(4-hydroxyphenyl)-3-formyl-1H-indazole-6-carboxamide and 4,5-difluoro 1,2-phenylenediamine gave 3-(5,6-difluoro-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)1H-indazole-6-carboxamide as a tan solid. 1H NMR (DMSO-d6) δ 13.99 (1H, s), 13.27 (1H, s), 10.21 (1H, s), 9.25 (1H, s), 8.52 (1H, d, J=8.7 Hz), 8.21 (1H, s), 7.85 (1H, d, J=9.0 Hz), 7.80 (1H, t, J=9.8 Hz), 7.55 (2H, d, J=8.7 Hz), 7.47 (1H, t, J=9.8 Hz), 6.75 (2H, d, J=8.7 Hz). MS (APCI positive) 406. The starting material was prepared as follows: To a solution of 3-formyl-1H-indazole-6-carboxylic acid (1.6 g, 8.4 mmol) and 4 aminophenol (1.8 g, 16.8 mmol) in dry dimethylformamide (35 mL) was added HATU (3.8 g, 16.8 mmol) followed by triethylamine (1.4 mL, 10.1 mmol). The reaction was stirred at room and monitored by TLC and LC/MS. After two hours the reaction was complete. The solvent was removed by vacuum and the product was purified by flash column chromatography using ethyl acetate: petroleum ether 1:1 to pure ethyl acetate. N-(4-Hydroxyphenyl)-3-formyl-1H-indazole-6-carboxamide was isolated as a tan colored solid. 1H NMR (DMSO-d6) δ 6.79 (2H, d, 8.9 Hz), 759 (2H, d, 8.9 Hz), 7.94 (1H, d, 9.8 Hz), 8.24 (1H, d, 8.2 Hz), 8.31 (1H, s), 9.31 (1H, br s), 10.27 (2H, s). MS (APCI pos) 282.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH2:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH:12]1([C:15](Cl)=[O:16])[CH2:14][CH2:13]1>N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:11][C:15]([CH:12]3[CH2:14][CH2:13]3)=[O:16])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Nc1n[nH]c2cc(Br)ccc12
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2cc(Br)ccc12)C1CC1
Reaction time: 4 h

Procedure:
To a solution of 6-bromo-1H-indazol-3-amine (4.24 g, 20 mmol) in pyridine (100 mL) was added cyclopropanecarbonyl chloride (1.83 mL, 20 mmol) dropwise at 0° C. The reaction mixture was stirred at this temperature for 4 hours. Once the reaction was completed, the solvent was removed in vacuo. The residue was dissolved in DMF, and water was added dropwise. The precipitated solid was filtered off and washed three times with hexanes (15 ml each). The product was dried in vacuo and used without further purification (4.3 g).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[CH3:9].[C:10]1(B(O)O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.[CH2:23](N(CC)CC)C>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CN(C)C=O>[CH3:23][C:5]1[CH:6]=[C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[CH:2]=[C:3]([CH3:9])[CH:4]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: CCN(CC)CC
Reactant: Cc1ccc(Br)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(-c2cccc3ccccc23)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
A mixture of dimethyl-5-bromobenzene (1.85 g, 10 mmol), 1-naphthalene boronic acid (1.89 g, 11 mmol), triethylamine (2.8 mL, 20 mmol), tris-(2-tolyl)phosphine (0.125 g, 0.4 mmol), palladium (II) diacetate (0.045 g, 0.4 mmol) and anhydrous dimethylformamide (25 mL) with 5 Å molecular sieves (0.5g) was stirred at 100° C. under a nitrogen atmosphere for about 4 hours. The solvent was evaporated in vacuo and the residue was treated with 5% aqueous ammonia solution, extracted with ethyl acetate, and washed with saturated aqueous sodium chloride. After filtration to remove a black precipitate, the organic layer was dried over magnesium sulfate, filtered and evaporated. The yellowish oil residue was chromatographed on silica gel (methylene chloride;petroleum ether 1:2 as eluant) to give a colorless oil (1.7 g, 7.3 mmol) in 73% yield. This crystallized upon standing (mp 68-70° C.).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:15]=[C:14]([C:16]2[C:25]3[C:26]4[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=4[S:28][C:24]=3[C:23]([Br:33])=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[CH:21]3)[CH:13]=[C:12]([Br:34])[C:5]=1[O:6][CH2:7][C:8]([O:10]C)=[O:9]>C1COCC1.CO.O>[Br:3][C:4]1[CH:15]=[C:14]([C:16]2[C:25]3[C:26]4[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=4[S:28][C:24]=3[C:23]([Br:33])=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[CH:21]3)[CH:13]=[C:12]([Br:34])[C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: COC(=O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reaction time: 2.5 h
Yield: 91 %

Procedure:
1.0 N Aqueous potassium hydroxide (2.66 mL, 2.66 mmol) was added to a stirred suspension of [2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl )-phenoxy]-acetic acid, methyl ester (1.51 g, 2.37 mmol) in THF (13 mL) and methanol (4 mL). Dissolution occurred. After 2.5 h at ambient temperature, the reaction mixture was diluted with water and extracted with ether (100 mL). The aqueous phase was acidified with 10% aqueous HCl and filtered. The solid was washed with water and triturated with pet. ether. The solid was dried in vacuo at 70° C. to provide the title compound as a white solid (1.34 g, 91%): mp 259-261° C.: NMR (DMSO-d6): δ8.29 (dd, J=8, 1 Hz, 1 H), 8.06 (dd, J=8, 1 Hz, 1 H), 7.82 (s, 2 H), 7.79 (ddd, J=8, 6, 2 Hz, 1 H), 7.61 (m, 2 H), 7.52 (ddd, J=8, 7, 1 Hz, 1 H), 7.32 (ddd, J=8, 7, 1 Hz, 1 H), 6.73 (dd, J=8, 1 Hz, 1 H), 4.78 (s, 2 H); MS (EI): [M+], 3 bronine isotope pattern, 618 (30%), 620 (90%) 622 (100%) 624 (50%); Anal. Calc. for C24H13Br3O3S: C, 46.41, H, 2.11, N, 0.00. Found: C, 46.38, H, 1.99, N, 0.01.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[C:14]1([CH2:20][CH2:21][SH:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:11][N:7]1[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=[C:2]([S:22][CH2:21][CH2:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=[C:6]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: SCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCCn2c1cc(SCCc1ccccc1)nc2=O
Temperature: 100 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
To a solution of 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (100 mg, 0.501 mmol) and 2-phenylethanethiol (83 mg, 0.601 mmol) in dimethyl sulfoxide (DMSO) (3 mL) was added K2CO3 (208 mg, 1.503 mmol). The reaction mixture was stirred at 100° C. for 16 hr. The crude product was purified by Prep-HPLC to afford 70 mg title product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20](=[O:26])[CH2:21][O:22]COC)=[CH:11][C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]=2[F:19])=[C:4]([Cl:27])[CH:3]=1.Cl.CO.C([O-])(O)=O.[Na+]>CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20](=[O:26])[CH2:21][OH:22])=[CH:11][C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]=2[F:19])=[C:4]([Cl:27])[CH:3]=1
Reactant: COCOCC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)CO)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazol-5-yl]-2-methoxymethoxy-ethanone 10j (15 mg, 0.033 mmol), 10% aqueous HCl (0.3 mL), methanol (0.01 mL), and water (0.05 mL) is stirred for 3 days at room temperature. The reaction mixture is neutralized with saturated aqueous NaHCO3, and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (1.5% MeOH in CH2Cl2) to afford the desired prouduct (7.3 mg, 54%): MS APCI (+) m/z 412, 414 (M+, Br pattern) detected; 1H NMR (400 MHz, acetone-d6) δ 8.64 (s, 1H), 8.34 (s, 1H), 8.16 (s, 1H), 7.58 (d, 1H), 7.31 (dd, 1H), 6.59 (dd, 1H), 4.94 (s, 2H), 4.06 (s, 3H); 19F NMR (376 MHz, acetone-d6) −132.45 (s, 1F).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][C@H:9]1[C:14](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH2:25][C:26]1[CH:30]=[C:29]([Br:31])[S:28][C:27]=1[C:32]([NH2:34])=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[Br:31][C:29]1[S:28][C:27]2[C:32](=[O:33])[NH:34][C:14]([C@@H:9]3[CH2:10][CH:11]=[CH:12][CH2:13][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:25][C:26]=2[CH:30]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1CC=CC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC=CC[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
To a mixture of (2S)-1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid (1.16 g), triethylamine (1.42 mL) and tetrahydrofuran (12 mL) was added 2-methylpropyl chlorocarbonate (0.662 mL) with stirring at room temperature. After 1 hr, 3-amino-5-bromothiophene-2-carboxamide (752 mg) produced in Example 1, step D, was added, and the mixture was stirred in a microwave reactor at 100° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (10 mL), 2M aqueous sodium hydroxide solution (10.2 mL) was added, and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was ice-cooled, and 6M hydrochloric acid (3.33 mL) was added dropwise. The reaction mixture was poured into brine, and extracted with 3:1 ethyl acetate/tetrahydrofuran mixture. The extract was dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) to give the title compound (851 mg) as a white solid. The optical purity was 51.1% ee. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK IC (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 1 mL/min, column temperature: 30° C., detection 220 nm).
Reaction SMILES: CC[O:3][C:4]([CH:6]1[C:8](C)(C)[CH:7]1[CH:11]=C(C)C)=[O:5].[Mn]([O-])(=O)(=O)=[O:16].[K+].C[C:22]([CH3:24])=[O:23]>>[CH3:8][C:7]1([CH3:11])[CH:6]([C:4]([OH:3])=[O:5])[CH:24]1[C:22]([OH:16])=[O:23]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)=O
Reactant: CCOC(=O)C1C(C=C(C)C)C1(C)C
Agent: [K+]
Product: CC1(C)C(C(=O)O)C1C(=O)O
Reaction time: 2 h

Procedure:
To a solution of ethyl chrysanthemumate (163.1 g) in acetone (600 mL) at 20° C. was added potassium permanganate (KMnO4) (472.7 g) as a solid in 9 equal portions. After each addition of KMnO4, the exotherm that ensued was allowed to subside before the addition of the next portion of KMnO4. Upon completion of KMnO4 addition, the reaction mixture was stirred for another 2 hours and then filtered. The solid cake was washed with acetone (450 mL) and suction dried. The dried solid was mixed with sodium sulfite (Na2SO3) (364.3 g), and the solid mixture was added in portions to 30% sulfuric acid (H2SO4) (960 mL) while maintaining the temperature below 65° C. Ethyl acetate (EtOAc) (1000 mL) was added, and the mixture was filtered through celite. The layers were separated and the aqueous layer was washed with EtOAc (600 mL). The combined organic solutions were dried over anhydrous sodium sulfate and concentrated to an oil (158.6 g). This oil was treated with 45% sodium hydroxide solution (NaOH) (240 mL) and water (100 mL) at 85° C. for about 30 min. The reaction mixture was cooled, acidified to pH 3 with 30% sulfuric acid (about 300 mL) and further extracted three times with EtOAc (450 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give caronic acid (162.6 g) as a mixture of cis- and trans-isomers. 1H NMR (400 MHz, CD3OD); cis-isomer δ1.26 (s, 3H), 1.40 (s, 3H), 1.96 (s, 2H); trans-isomer δ1.32 (s, 6H), 2.19 (s, 2H).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]3[CH2:16][O:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:37]=[CH:36][C:23]([C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C.O.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH:1]1([CH2:4][N:5]([CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]3[CH2:16][O:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[C:33](=[O:34])[CH2:32][N:29]2[CH2:30][CH2:31][CH:26]([C:24](=[O:25])[C:23]3[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:37][CH:36]=3)[CH2:27][CH2:28]2)[CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Reactant: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)C2CCN(CC(=O)N(Cc3nc4c(c(=O)[nH]3)COCC4)CC3CC3)CC2)cc1
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a well stirred suspension of 2-[(Cyclopropylmethyl-amino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (15.66 g, 57.6 mmol) in dichloromethane (600 mL) was added 2-(4-(4-methoxybenzoyl)piperidin-1-yl)acetic acid (16.45 g, 59.3 mmol), followed by triethylamine (24 mL, 173 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (21.41 g, 140 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (13.26 g, 69.2 mmol). The resulting yellow suspension was stirred for 12 h, filtered and then washed with water three times (250 mL, 150 mL, then 50 mL). The organic layer was washed twice with brine (50 mL), dried with Na2SO4, filtered and concentrated in vacuo (33.34 g). The residue was dissolved in 750 mL dichloromethane, and washed with a pH 9 KHCO3/K2CO3 solution (2×100 mL). The organic layer was washed twice with brine (50 mL), dried with Na2SO4, filtered and concentrated in vacuo (23.4 g). The crude material was dissolved in approximately 25 mL MeOH resulting in an orange solution and placed in a freezer overnight to form a slurry. The mixture was filtered, washed with MeOH and dried in vacuo to yield 21.959 g of the title compound as a white solid. HRMS calculated for C27H34N4O5 495.2607. found (ESI, [M+H]+), 495.2607, retention time=3.717 min. CHN analysis: calculated (results). C, 65.57 (65.17), H, 6.93 (6.64), N, 11.33 (11.39).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[S:5][C:6]=1[SH:7].Cl[CH2:13][C:14]([N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1)=[O:15].S1C(SCC(N2C3C(=CC=CC=3)CCC2)=O)=CC2C=CC=CC1=2>>[N:16]1([C:14](=[O:15])[CH2:13][S:7][C:6]2[S:5][C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[C:2]=2[CH3:1])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: Cc1c(S)sc2ccccc12
Reactant: O=C(CCl)N1CCCc2ccccc21
Agent: O=C(CSc1cc2ccccc2s1)N1CCCc2ccccc21
Product: Cc1c(SCC(=O)N2CCCc3ccccc32)sc2ccccc12
Yield: 11.7 %

Procedure:
Crude compound 75 (0.55 g, 3.0 mmol) was coupled with compound 4 (0.48 g, 2.3 mmol) according to procedure used to synthesize compound 73. The product was purified by column chromatography to yield compound 76 (95 mg, 5% for two steps): MS: m/z+ 354.1 [M+H]+; Anal. Calcd (found) for C20H19NOS2.0.1H2O: C, 67.61 (67.59); H, 5.45 (5.48); N, 3.94 (3.94); S, 18.05 (17.75).
Reaction SMILES: C(C(C(C)([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)C)CCCO[Si](C(C)(C)C)(C)C)#N.[F-].[NH4+:29].[NH4+].[NH4+].[NH4+].[F-].[F-].[F-].[Cl-].[Na+].[OH2:38]>O1CCCC1>[C:20]([C:19]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)([CH:24]([CH3:25])[CH3:23])[CH2:18][CH2:17][CH2:26][OH:38])#[N:29]
Reactant: CC(C)(c1ccc2ccccc2c1)C(C#N)CCCO[Si](C)(C)C(C)(C)C
Reactant: [NH4+]
Reactant: O
Agent: [Cl-]
Agent: [F-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C(C#N)(CCCO)c1ccc2ccccc2c1

Procedure:
1.00 g (4.78 mmol) of 3-methyl-2-(2-naphthyl)butyronitrile was dissolved in 20 ml of dimethylformamide, 191 mg (4.78 mmol, 60% by weight) of sodium hydride was added thereto, and the mixture was heated. After 30 minutes; it was cooled to a room temperature, 0.93 ml (4.00 mmol) of (3-bromopropoxy)-tert-butyldimethylsilane was added thereto. After completion of the reaction, brine was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated, to give a crude product. The crude product was subjected to 50 g of silica gel (ethyl acetate:hexane=1:18), to give 1.40 g of a mixture of the objective product, a raw material and an impurity. The mixture was used for the following reaction without purification. Namely, 1.40 g of the abve-mentioned crude 4-cyano-5-methyl-5-(2-naphthyl)hexanoxy-tert-butyldimethylsilane was dissolved in 20 ml of tetrahydrofuran, and 5 ml (5 mmol) of tetraammonium fluoride was added thereto. After completion of the reaction, brine was added thereto, and the mixture was extracted withethyl acetate. Theorganiclayerwaswashedwith an aqueous saturated ammonium chloride and brine, dried over magnesium sulfate and evaporated, to give a crude product. The crude product was subjected to 50 g of silica gel (ethyl acetate:hexane=1:4), to give 590 mg (2.21 mmol, 46.2%, 2 steps) of the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:12]=[CH:13][N:14]=[C:15]([O:16][CH2:17][CH3:18])[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.Cl[C:20]1[C:29]2[CH:30]=[CH:31][N:32]=[C:33]([Cl:34])[C:28]=2[C:27]2[C:22](=[CH:23][CH:24]=[N:25][CH:26]=2)[N:21]=1.[Cl:35][C:36]1[CH:42]=[C:41]([I:43])[CH:40]=[C:39]([Cl:44])[C:37]=1[NH2:38].CC(C)([O-])C.[Na+]>C1COCC1>[Cl:34][C:33]1[C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[N:25][CH:26]=3)[N:21]=[C:20]([NH:38][C:37]3[C:36]([Cl:35])=[CH:42][C:41]([I:43])=[CH:40][C:39]=3[Cl:44])[C:29]=2[CH:30]=[CH:31][N:32]=1.[Cl:35][C:36]1[CH:42]=[C:41]([I:43])[CH:40]=[C:39]([Cl:44])[C:37]=1[NH:38][C:2]1[C:11]2[CH:12]=[CH:13][N:14]=[C:15]([O:16][CH2:17][CH3:18])[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1
Reactant: Nc1c(Cl)cc(I)cc1Cl
Reactant: CCOc1nccc2c(Cl)nc3ccncc3c12
Reactant: Clc1nc2ccncc2c2c(Cl)nccc12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1nccc2c(Nc3c(Cl)cc(I)cc3Cl)nc3ccncc3c12
Product: Clc1cc(I)cc(Cl)c1Nc1nc2ccncc2c2c(Cl)nccc12
Temperature: 85 °C

Procedure:
To a mixture of 6-chloro-10-ethoxypyrido[4,3-c]-1,6-naphthyridine (Example 133, Step 3) (200 mg, 0.770 mmol) and 6,10-dichloropyrido[4,3-c]-1,6-naphthyridine (Example 133, Step 3)(193, 0.770 mmol) in THF (12 mL) were added 2,6-dichloro-4-iodoaniline (443 mg, 1.54 mmol) and sodium tert-butoxide (444 mg, 4.62 mmol) and the mixture was heated to 85° C. for 1 hr. After cooling to room temperature, the mixture was extracted with EtOAc. The organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure. Column chromatography (100% hexane to 100% EtOAc) provided 10-chloro-N-(2,6-dichloro-4-iodophenyl)pyrido[4,3-c]-1,6-naphthyridin-6-amine and N-(2,6-dichloro-4-iodophenyl)-10-ethoxypyrido[4,3-c]-1,6-naphthyridin-6-amine. Most instances 10-chloro-N-(2,6-dichloro-4-iodophenyl)pyrido[4,3-c]-1,6-naphthyridin-6-amine and N-(2,6-dichloro-4-iodophenyl)-10-ethoxypyrido[4,3-c]-1,6-naphthyridin-6-amine were carried on as a mixture, however, the mixtures can be separated and carried on separately. This mixture (282 mg) was taken up in methanol (5 mL) and 25% sodium methoxide (3 mL) and heated at 100° C. for 1 hr. After cooling to room temperature, the solution was concentrated and then taken up in EtOAc and washed with water. The organic layers were dried with MgSO4, filtered, and concentrated to afford the title compounds.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:43][O:44][C:45](=[O:63])[C@@H:46]([NH2:62])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][N:57]=[C:56]([CH3:60])[C:55]=2[CH3:61])=[CH:50][CH:49]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:19])[NH:62][C@H:46]([C:45]([O:44][CH3:43])=[O:63])[CH2:47][C:48]2[CH:49]=[CH:50][C:51]([C:54]3[CH:59]=[CH:58][N:57]=[C:56]([CH3:60])[C:55]=3[CH3:61])=[CH:52][CH:53]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (260 mg), (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (190 mg), EDC (106 mg), and HOBt (78 mg) were suspended in 2 mL DCM and NMM (0.214 mL) added. The resulting mixture stirred at room temperature for 4 hours and loaded directly onto silica. The residue was purified by silica gel flash chromatography (hexanes to 1:1 hexanes/EtOAc to 1:1 hexanes/EtOAc+1% MeOH) to give 320 mg after drying under vacuum. LCMS: m/z 853.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].BrC#[N:35].O>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]3[CH2:21][CH2:22][N:23]([C:26]#[N:35])[CH2:24][CH2:25]3)=[N:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: N#CBr
Reactant: CN1CCN(c2nn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCN(c2nn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.9 %

Procedure:
To a stirred mixture, under N2 of 6-fluoro-1-phenylsulfonyl-3-(4-methyl-1-piperazinyl)-1H-indazole (30.0 g, 0.86 mol) of Example 31c, K2CO3 (4.7 g, 0.086 mol) and dimethyl sulfoxide (DMSO) [250 ml] was added, dropwise, BrCN (9.1 g, 0.086 mol) dissolved in DMSO (50 ml). The reaction was stirred at ambient temperature for 2 hours and water was added. The resultant solid was collected and taken up in CH2Cl2, and after washing the organic layer with H2O, drying (K2CO3) and concentrating there remained 25.3 g of the target compound. A sample (5.0 g) was removed and recrystallized from ethyl acetate (twice) to afford 2.3 g (35%) of 4-(6-fluoro-1-phenylsulfonyl-1H-indazol-3-yl)-1-piperazine carbonitrile m.p. 178°-180° C.