Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([N+]#C)S(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].I[CH2:27][CH2:28][CH2:29][CH2:30][C:31]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:34][CH2:33][CH2:32]1.CC([O-:44])(C)C.[K+]>Cl>[CH2:38]([O:37][C:35]([C:31]1([CH2:30][CH2:29][CH2:28][CH2:27][C:10](=[O:44])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:23])([CH3:24])[C:4]([O:3][CH2:1][CH3:2])=[O:25])[CH2:34][CH2:33][CH2:32]1)=[O:36])[CH3:39]
Reactant: C#[N+]C(CCCCC(C)(C)C(=O)OCC)S(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C1(CCCCI)CCC1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: CCOC(=O)C(C)(C)CCCCC(=O)CCCCC1(C(=O)OCC)CCC1

Procedure:
Compound 106e was prepared likewise Method C starting from 108a (11.01 g, 30.1 mmol), 105b (10.28 g, 33.1 mmol) and KOtBu (4.06 g, 36.2 mmol) to give, after purification by column chromatography (silica, heptane:EtOAc=6:1; a layer of NaHCO3 was put on the base of the column), ethyl 1-[11-ethoxy-5-isocyano-10,10-dimethyl-5-[(4-methylphenyl)sulfonyl]-11-oxoundecyl]-1-cyclobutanecarboxylate (14.11 g) as a colorless oil. Part of this oil (13.86 g, 25.3 mmol) was treated with conc aqueous HCl (50 mL), as described for 106d, to give crude 106e, which was stirred up in heptane (50 mL) and the resulting precipitate was filtered off and washed with heptane (3×50 mL). The combined filtrates were washed with aqueous NaOH (1M, 2×50 mL) and brine (50 mL) and dried to give 106e (9.44 g, >90% pure by 1H NMR, 75%) as a slightly yellow oil. 1H NMR: δ 4.12 (q, J=7.1 Hz, 2H), 4.09 (q, J=7.1 Hz, 2H), 2.50-2.29 (m, 2H), 2.37 (t, J=7.4 Hz, 4H), 1.95-1.70 (m, 6H), 1.61-1.44 (m, 6H), 1.30-1.09 (m, 4H), 1.25 (t, J=7.1 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H), 1.14 (s, 6H). 13C NMR: δ 210.1, 177.3, 176.6, 60.1 (2×), 47.5, 42.57 (2×), 42.1, 40.4, 37.8, 30.0 (2×), 25.2 (2×), 24.7, 24.6, 24.2, 24.1, 15.7, 14.4, 14.3.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[NH2:18].C(O)(=O)C>O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[NH:18][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 40 °C

Procedure:
Acetic anhydride (8.0 mL) was added dropwise over a period of 10 minutes to a mixture of 2-fluoro-5-nitrophenylamine (7.8 g) and acetic acid (50 mL) at reflux. The resulting mixture was heated at reflux for 30 minutes and cooled to 40° C. The mixture was poured into cold water (800 mL) and the resulting precipitate collected by filtration, washed with 1.0 M aqueous hydrochloric acid and water and dried to give title compound as a light brown solid, 9.2 g.
Reaction SMILES: IC1C=CC(C2NC([C@@H](N3[C:21](=[O:22])[C@@H](CCC(O)=O)NC3=O)C(C)C)=NC=2)=CC=1.ClN1C(=O)CCC1=O.C(OC(=O)N[C@H](C1NC(C2C=CC=CC=2F)=CN=1)[C@H](C1C=CC=CC=1)C)(C)(C)C.C(OC(N[C@H](C1C=CC(OCC(=O)N(C)C)=CC=1)C(O)=O)=O)(C)(C)C.[NH2:91][C@H:92]([C:118]1[CH:123]=[CH:122][C:121]([O:124][CH2:125][C@H:126]([OH:129])[CH2:127][OH:128])=[CH:120][CH:119]=1)[C:93]([NH:95][C@H:96]([C:105]1[NH:106][C:107]([C:110]2[CH:115]=[CH:114][C:113]([I:116])=[CH:112][C:111]=2[F:117])=[CH:108][N:109]=1)[C@H:97]([C:99]1[CH:104]=[CH:103][CH:102]=[CH:101][CH:100]=1)[CH3:98])=[O:94]>>[OH:129][C@H:126]([CH2:127][OH:128])[CH2:125][O:124][C:121]1[CH:122]=[CH:123][C:118]([C@H:92]2[NH:91][C:21](=[O:22])[N:95]([C@H:96]([C:105]3[NH:106][C:107]([C:110]4[CH:115]=[CH:114][C:113]([I:116])=[CH:112][C:111]=4[F:117])=[CH:108][N:109]=3)[C@H:97]([C:99]3[CH:100]=[CH:101][CH:102]=[CH:103][CH:104]=3)[CH3:98])[C:93]2=[O:94])=[CH:119][CH:120]=1
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OC[C@H](O)CO)cc1)c1ncc(-c2ccc(I)cc2F)[nH]1
Reactant: CC(C)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CCC(=O)O)C1=O
Agent: CN(C)C(=O)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccccc2F)[nH]1
Agent: O=C1CCC(=O)N1Cl
Product: C[C@@H](c1ccccc1)[C@@H](c1ncc(-c2ccc(I)cc2F)[nH]1)N1C(=O)N[C@H](c2ccc(OC[C@H](O)CO)cc2)C1=O

Procedure:
Prepared by the same method as described in example 1 except that (i) chlorination of the 5-position of the imidazole ring with N-chlorosuccinimide in step F was omitted; (ii) (R)-tert-butoxycarbonylamino-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-acetic acid (prepared as described in example 33) was used in place of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid in step 36-G, and (iii) cyclization of (R)-2-amino-2-[4-((R)-2,3-dihydroxy-propoxy)-phenyl]-N-{(1S,2S)-1-[5-(2-fluoro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-acetamide in step 36-H was performed as described in example 34. HR-MS: calcd for C30H28FlN4O5 [M+H+] 671.1161. Found 671.1156.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[CH2:9][C:10](Cl)=[O:11])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH3:14])([CH3:13])[CH2:9][C:10]2=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(CC(=O)Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CC(=O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.7 %

Procedure:
A solution of 3-(4-fluorophenyl)-3-methylbutyryl chloride (19.0 g, 0.0815 mol) in dichloromethane (100 ml) was added dropwise over 2.5 h to a stirring mixture of aluminum chloride (13.57 g, 0.102 mol, Aldrich) in dichloromethane (200 ml) while protected from moisture by a nitrogen atmosphere. After stirring 18 h at 25° C., the reaction solution was poured over ice (400 g) and the resulting solution was extracted with dichloromethane (2×200 ml). The dichloromethane layers were combined, washed with deionized water (50 ml), and concentrated by spin evaporation in vacuo. The residue was dissolved in ethyl acetate and washed through a pad of silica gel. The pad was washed with additional ethyl acetate. Removal of the volatiles from the combined washes by spin evaporation in vacuo gave 15.2 g (99%) of 6-fluoro-3,3-dimethyl-1-indanone as a light yellow oil which crystallized on standing, m.p., 57-62° C.:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:19]([O:21]CC)=[O:20])=[C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[N:6]=1.[Li+].[OH-].[OH-].[Na+].C(OCC)C>O1CCCC1>[Cl:1][C:2]1[S:3][C:4]([C:19]([OH:21])=[O:20])=[C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:17])([F:16])[F:18])[N:6]=1
Reactant: CCOC(=O)c1sc(Cl)nc1OCc1ccccc1C(F)(F)F
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1sc(Cl)nc1OCc1ccccc1C(F)(F)F
Yield: 84.8 %

Procedure:
Ethyl 2-chloro-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-1,3-thiazole-5-carboxylate (0.535 g, 1.46 mmol) was dissolved in 15 mL of tetrahydrofuran with stirring, and 15 mL of 1N LiOH solution was added via pipet. The mixture was stirred for 18 hours, and poured into 0.1 N NaOH and diethyl ether. The layers were separated, and the aqueous layer was acidified to pH 2 with concentrated HCl. The mixture was filtered and the white solid was washed with water. The solid was air dried, collected, and dried further under vacuum to yield 0.418 g (85%) of 2-chloro-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-1,3-thiazole-5-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 13.22 (br s, 1H), 7.83-7.70 (m, 3H), 7.58 (m, 1H), 5.59 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][N:33]([C:36](=[O:38])[CH3:37])[CH2:32][CH2:31]2)=[CH:26][C:25]=1Br.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][C:12]([C:25]2[CH:26]=[C:27]([CH:30]3[CH2:35][CH2:34][N:33]([C:36](=[O:38])[CH3:37])[CH2:32][CH2:31]3)[CH:28]=[CH:29][C:24]=2[NH2:23])=[CH:11][CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC=C(B2OC(C)(C)C(C)(C)O2)C1
Reactant: CC(=O)N1CCC(c2ccc(N)c(Br)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)N1CCC(c2ccc(N)c(C3=CCCN(C(=O)OC(C)(C)C)C3)c2)CC1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 93 %

Procedure:
A solution of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared in Example 46, step (b), 0.62 g, 2.02 mmol) and 1-[4-(4-amino-3-bromo-phenyl)-piperidin-1-yl]-ethanone (as prepared in the previous step, 0.20 g, 0.67 mmol) in toluene:EtOH (2:1, 9 mL) was treated with 2.0 M aqueous Na2CO3 (2.7 mL, 5.38 mmol) and was degassed with sonication under Ar. The mixture was heated to 80° C., treated with Pd(PPh3)4 (54 mg, 0.05 mmol), and stirred at 80° C. for 4.5 h. The reaction was cooled to room temperature, diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.25 g, 93%) as an off-white solid. LC-MS (ESI, m/z): Calcd. for C23H33N3O3 422.2 (M+Na), found 422.0.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(Cl)Cl.Cl.[OH:12][C:13]1[CH:36]=[CH:35][C:34]([O:37][CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:33][C:14]=1[C:15]([NH:17][C:18]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])=[O:16]>N1C=CC=CC=1>[C:1]([N:41]1[CH2:40][CH2:39][CH:38]([O:37][C:34]2[CH:35]=[CH:36][C:13]([OH:12])=[C:14]([CH:33]=2)[C:15]([NH:17][C:18]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=[O:21])=[O:16])[CH2:43][CH2:42]1)(=[O:3])[CH3:2]
Reactant: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(OC2CCNCC2)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCC(Oc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, pyridine (0.30 mL) and acetic anhydride (6.7 μL) were sequentially added to a methylene chloride (1 mL) suspension of 2-(2-hydroxy-5-(piperidin-4-yloxy)benzamido)-4-phenylbenzoic acid hydrochloride (0.030 g), followed by stirring at room temperature for 1 hour. Pyridine (0.20 mL) and acetic anhydride (5.4 μL) were sequentially added to the reaction mixture, followed by stirring at room temperature for 1 hour and 30 minutes. The solvent was evaporated under reduced pressure, and methanol (0.5 mL) and a 2 mol/L aqueous solution of sodium hydroxide (0.19 mL) were added to the residue, followed by stirring at room temperature for 1 hour. To the reaction mixture, 1 mol/L hydrochloric acid (5 mL) and ethyl acetate were added. The organic layer was separated, washed with 1 mol/L hydrochloric acid, water, and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Dioxane (0.5 mL), methanol (0.5 mL), and a 2 mol/L aqueous solution of sodium hydroxide (0.32 mL) were added to the obtained residue, followed by stirring at 70° C. for 30 minutes. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure, and water was added to the obtained residue. After adjusting the pH to 3 with 6 mol/L hydrochloric acid, the solid substance was collected by filtration to obtain 0.022 g of 2-(5-(1-acetylpiperidin-4-yloxy)-2-hydroxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH:29]1[CH:35]=O>C1COCC1>[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH:29](/[CH:35]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:30][CH2:31][CH2:32][C:33]1=[O:34]
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Reactant: COC(=O)CCCCCCN1C(=O)CCCC1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCCCCCN1C(=O)CCCC1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
Sodium hydride (60% dispersion in oil, 12 mg, 0.32 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (70 mg, 0.29 mmol) in THF (1.5 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 50 min at rt, the solution was recooled to 0° C. and 7-(2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester (crude, prepared in accordance with example 11, step 2, ˜0.32 mmol) in THF (1.5 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with acetic acid (50% aqueous, 20 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (30 mL) and brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 66 mg (59%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5]C=1N.C([O-])([O-])=O.[K+].[K+].CI.[CH3:26][N:27]([CH:29]=O)[CH3:28]>>[F:1][C:2]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:29]=1[N:27]([CH3:26])[CH3:28]
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CN(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
The mixture of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (474 mg, 2 mmol), K2CO3 (828 mg, 6 mmol), and MeI (710 mg, 5 mmol) in DMF (10 mL), was stirred at 100° C. overnight. Then it was cooled and extracted by EA/H2O, the organic layer was combined, washed by brine, dried over anhydrous Na2SO4, and concentrated to give the crude compound in 93% yield. MS (m/z): 266 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.CC(O)=O.N[C@@H:15]([CH2:17][OH:18])[CH3:16]>O>[OH:18][CH2:17][C@H:15]([NH:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1)[CH3:16]
Reactant: C[C@@H](N)CO
Reactant: Nc1cc(O)nc(S)n1
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](CO)Nc1cc(O)nc(S)n1
Temperature: 50 °C

Procedure:
6-Amino-2-mercapto-4-pyrimidinol (16.1 g), AcOH (14.3 ml) and (R)-Alaninol (39 ml) were heated at 170° C. for 5 h. The mixture was cooled to approximately 50° C., diluted with water (500 ml) and cooled at 0° C. for 20 h. The resulting solid was filtered, washed with water and dried in vacuo to yield a mixture of subtitle product and starting material (2:1) as a cream coloured solid. Yield 7.2 g.
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][S:5](OC1C=CC=CC=1)(=[O:7])=[O:6].[OH-].[K+].O.Cl>C1COCC1>[CH3:15][C:2]1([CH3:16])[CH2:3][CH2:4][S:5](=[O:7])(=[O:6])[NH:1]1
Reactant: CC(C)(N)CCS(=O)(=O)Oc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCS(=O)(=O)N1
Yield: 53.8 %

Procedure:
11.58 g of phenyl 3-amino-3-methylbutane-1-sulfonate and 5.34 g of KOH were boiled under reflux in 240 ml of THF/95 ml of water for 7 hours. Then a further 2.7 g of KOH, 50 ml of water and 120 ml of THF were added, and the mixture was again boiled under reflux for 7 hour. Then a further 5.34 g of KOH were added, and the mixture was again boiled under reflux for 3 hours. It was allowed to cool and then 300 ml of a 2N aqueous HCl solution were added, and the mixture was extracted 5 times with 250 ml of EA each time. After drying over Na2SO4, the solvent was removed in vacuo. Chromatography on silica gel with EA/HEP 1:1 afforded 3.82 g of white crystals, mp 72° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:4][CH:5]=[CH:6][CH:7]=1.CC([O-])=O.[Na+].[N:28]#[C:29]Br.O>CO>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:29]#[N:28])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CBr
Reactant: Cc1cccnc1CN(CCCCN)Cc1ncccc1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cccnc1CN(CCCCNC#N)Cc1ncccc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.4 %

Procedure:
To a 0° C. solution of N1,N1-bis-(3-methyl-pyridin-2-ylmethyl)-butane-1,4-diamine (237 mg, 0.80 mmol) in MeOH (10 mL) was added NaOAc (200 mg, 2.39 mmol) and cyanogen bromide (94 mg, 1.03 mmol) and stirred at room temperature for 17 hours. Water (10 mL) was added and the reaction mixture was extracted with CH2Cl2 (4×40 mL). The extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to provide pure COMPOUND 198 as a beige solid (190 mg, 74%). 1H NMR (CDCl3) δ 1.45-1.51 (m, 2H), 1.65-1.63 (m, 2H), 2.12 (s, 6H), 2.61-2.65 (m, 2H), 2.83-2.89 (m, 2H), 3.68 (s, 4H), 7.08 (dd, 2H, J=4.2, 7.8 Hz), 7.38 (d, 2H, J=7.8 Hz), 7.57 (br s, 1H), 8.37 (d, 2H, J=4.2 Hz). 13C NMR (CDCl3) δ 18.5, 21.1, 28.3, 44.4, 53.6, 58.2, 118.9, 122.9, 133.4, 138.6, 146.6, 156.7. ES-MS m/z 324 (M+H). Anal. Calcd. for C19H25N5.0.4 CH2Cl2.0.1CH4O: C, 64.95; H, 7.32; N, 19.42. Found: C, 64.65; H, 7.22; N, 19.27.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[Cl:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:16][N:15]=[C:14]2[N:24]([CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[N:25]=[C:26](I)[C:13]=12>>[Cl:11][C:12]1[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:16][N:15]=[C:14]2[N:24]([CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[N:25]=[C:26]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:13]=12
Reactant: OB(O)c1ccccc1F
Reactant: O=C(Cn1nc(I)c2c(Cl)c(-c3ccccc3)nnc21)N1CCCC1
Product: O=C(Cn1nc(-c2ccccc2F)c2c(Cl)c(-c3ccccc3)nnc21)N1CCCC1

Procedure:
Compound 6 was synthesised according to Example 1, but using 2-fluorophenylboronic acid instead of 4-fluorophenylboronic acid and 2-(4-chloro-3-iodo-5-phenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)-1-(pyrrolidin-1-yl)ethanone instead of 2-(4-chloro-3-iodo-5-phenyl-pyrazolo[3,4-c]pyridazin-1-yl)-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanone in Step 8.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[CH:21][C:22]([N:24]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([Cl:32])[N:27]=3)[CH3:25])=[CH:23][C:16]=2[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:45])=[C:39]([S:41]([NH2:44])(=[O:43])=[O:42])[CH:40]=1>>[ClH:32].[C:1]([O:5][C:6](=[O:33])[N:7]([C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[CH:21][C:22]([N:24]([CH3:25])[C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([CH3:45])=[C:39]([S:41](=[O:43])(=[O:42])[NH2:44])[CH:40]=4)[N:27]=3)=[CH:23][C:16]=2[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Reactant: CN(c1ccc2c(c1)nc(N(C(=O)OC(C)(C)C)c1ccccc1)n2C)c1ccnc(Cl)n1
Product: Cc1ccc(Nc2nccc(N(C)c3ccc4c(c3)nc(N(C(=O)OC(C)(C)C)c3ccccc3)n4C)n2)cc1S(N)(=O)=O
Product: Cl

Procedure:
The title compound was prepared following the procedure of example 60 using {5-[(2-Chloro-pyrimidin-4-yl)-methyl-amino]-1-methyl-1H-benzoimidazol-2-yl}-phenyl-carbamic acid tert-butyl ester (100 mg, 0.22 mmol) and 5-amino-2-methyl-benzenesulfonamide (41 mg, 0.22 mmol) to give the desired product as a white solid. 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.48 (s, 1H), 8.54 (s, 1H), 7.79 (d, J=6.3 Hz, 1H), 7.66-7.71 (M, 2H), 7.56 (d, J=1.5 Hz, 1H), 7.38 (m, 4H), 7.23-7.29 (m, 4H), 7.12 (m, 1H), 5.68 (d, J=6.0 Hz, 1H), 3.78 (s, 3H), 3.48 (s, 3H), 2.49 (s, 3H), 1.42 (s, 9H). MS (ESI) m/z=615 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: BrCc1ccccc1
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with Bromomethyl-benzene using the conditions described in Example 10C to provide 4-Benzyloxy-1-chloro-2-nitro-benzene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][CH3:12])=[O:10])[CH2:3]1.C1(C[NH2:20])C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.[H][H]>[Pd].CO>[NH2:20][CH:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH:2]1[CH3:1]
Reactant: [H][H]
Reactant: COC(=O)N1CCC(=O)C(C)C1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)N1CCC(N)C(C)C1
Reaction time: 0.08 h

Procedure:
To a stirred mixture of 85.6 parts of methyl 3-methyl-4-oxo-1-piperidinecarboxylate and 240 parts of methanol are added 54.6 parts of benzenemethanamine (exothermic reaction). After stirring for 5 minutes, there are added 0.2 parts of 4-methylbenzenesulfonic acid and the whole is hydrogenated at normal pressure and at normal temperature with 10 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, (about 20 hours), the catalyst is filtered off and the filtrate is evaporated. The residue is distilled, yielding methyl 4-amino-3-methyl-1-piperidinecarboxylate; bp. 136°-140° C. (water-jet).
Reaction SMILES: I[C:2]1[C:10](=[O:11])[N:9]2[C:5]([N:6]([CH3:16])[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=32)=[N:4][C:3]=1[CH3:17].[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O>[CH3:17][C:3]1[N:4]=[C:5]2[N:9]([C:10](=[O:11])[C:2]=1[C:24]1[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=1)[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[N:6]2[CH3:16]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1nc2n(C)c3ccccc3n2c(=O)c1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc2n(C)c3ccccc3n2c(=O)c1-c1ccc(OC(F)(F)F)cc1

Procedure:
A solution of Step 3 intermediate (1.2 g, 3.512 mmol), 4-trifluoromethoxyphenyl boronic acid (0.864 g, 4.212 mmol), Pd[(C6H5)3P]4 (0.161 g, 1.420 mmol), Na2CO3 (2.32 g) was reacted together in a mixture of toluene (20 ml), ethanol (5 ml) and water (5 ml) according to the procedure outlined in Step 3, Intermediate 3 to afford the desired compound: 1H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 3H), 3.78 (s, 3H), 7.33-7.46 (m, 4H), 7.52-7.57 (m, 1H), 7.68-7.71 (m, 1H), 8.40-8.43 (s, 1H); ESI-MS (m/z) 374.62 (M+H)+.