Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH:8](Br)[C:7]1=O)=[O:5])[CH3:2].[CH2:16]([O:23][CH2:24][CH2:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([CH:6]1[C:7]2[C:28]3[C:27](=[CH:32][CH:31]=[CH:30][C:29]=3[F:33])[N:26]([CH2:25][CH2:24][O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:8]=2[CH2:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: Fc1cccc(NCCOCc2ccccc2)c1
Reactant: CCN(CC)C(=O)C1CCCC(Br)C1=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: CCN(CC)C(=O)C1CCCc2c1c1c(F)cccc1n2CCOCc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 30.8 %

Procedure:
A mixture of 3-bromo-2-oxo-cyclohexanecarboxylic acid diethylamide (35; prepared according to Example 7(c)) (2.3 g, 10 mmol) and (2-benzyloxy-ethyl)-(3-fluoro-phenyl)-amine (40) (4.1 g, 17 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (10 mL) and dry zinc chloride (4.09 g, 30 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and washed with 2 N HCl (50 mL), water (2×50 mL) and aqueous potassium carbonate solution (2×50 mL) then dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (5-100% B, 100 g, 28 CV, 60 mL/min) to afford 1.3 g (30%) of 9-(2-benzyloxy-ethyl)-5-fluoro-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (41) along with the isomer 9-(2-benzyloxy-ethyl)-7-fluoro-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide as a mixture which was used in the next step without purification. The structure of 9-(2-benzyloxy-ethyl)-5-fluoro-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (41) was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.10-1.40 (6H, m, N(CH2CH3)2), 1.60-2.60 (4H, m, 2- and 3-CH2), 2.70-2.85 (2H, m, 1-CH2), 3.10-3.65 (4H, m, N(CH2CH3)2 and CH2CH2OBn), 4.00-4.30 (3H, m, CH2CH2OBn and 4-CH), 4.43 (2H, s, OCH2Ph), 6.55-6.65 (1H, m, NCCHCHCHCF), 6.90-7.05 (1H, m, NCCHCHCHCF), 7.05-7.15 (1H, m, NCCHCHCHCF), and 7.16-7.25 (5H, m, Ph).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:26].[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]cyclohexyl amino}-1,5-naphthyridin-3-yl)ethanone (20 mg, 0.055 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (27 mg, 0.10 mmol) followed by formation of the dihydrochloride salt to afford the desired product (16 mg, 52%) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.15 (s, 1H), 8.45 (d, J=9.1 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 8.02 (t, J=1.9 Hz, 1H), 7.88 (dd, J=11.5, 2.2 Hz, 1H), 5.75-5.65 (m, 1H), 3.09 (d, J=6.6 Hz, 2H), 2.94 (s, 6H), 2.76 (s, 3H), 2.45 (d, J=12.5 Hz, 2H), 2.11-2.01 (m, 3H), 1.75-1.63 (m, 2H), 1.47-1.36 (m, 2H). ESI MS m/z 471 [M+H]+; HPLC>99% (AUC), tR=9.66 min.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=1)[CH2:9][OH:10])(C)(C)C.[ClH:25]>ClCCl.O1CCOCC1>[ClH:25].[NH2:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=1)[CH2:9][OH:10]
Reactant: CCCC(C)COc1ccc([C@H](CO)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCC(C)COc1ccc([C@@H](N)CO)cc1

Procedure:
To a solution of {(R)-2-Hydroxy-1-[4-(2-methyl-pentyloxy)-phenyl]-ethyl}-carbamic acid t-butyl ester (0.70 g 2.08 mmol), in dichloromethane (10 ml) in an ice bath was added 4 M HCl in 1,4-dioxane (10 ml). The final mixture was then stirred at room temperature for 1.5 hrs. The excessive solvent was removed in vacuum to give a white solid, which was used directly for next step.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][Mg]Cl.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH3:11]
Reactant: C[Mg]Cl
Reactant: O=Cc1ccc(I)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 2-fluoro-4-iodo-benzaldehyde (17.40 g, 69.60 mmol) in anhydrous tetrahydrofuran (300 mL) at −10° C. under an atmosphere of nitrogen was added 3.0 M methylmagnesium chloride in tetrahydrofuran (27.84 mL, 83.52 mmol) via syringe at such a rate as to maintain the temperature of the reaction mixture below 0° C. The reaction was stirred for 30 minutes while warming to room temperature. Saturated aqueous ammonium chloride solution was added and the mixture was diluted with ethyl acetate (200 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic extracts were combined, washed with water (1×50 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 15 to 40% v/v ethyl acetate/hexanes to give 1-(2-fluoro-4-iodo-phenyl)-ethanol (15.50 g, 84%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([NH:20][CH3:21])=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([N:20]([CH3:21])[S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNc1ccc(OC)cc1
Product: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (0.5 g, 2.27 mmol) was treated with 4-methoxy-N-methylaniline (933 mg, 6.80 mmol) using method A to give 4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid as a yellow solid. Yield: 617 mg (85%). 1H-NMR: 8.10 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 6.98 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 3.74 (s, 3H), 3.13 (s, 3H).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[CH3:10][CH:11]([CH3:23])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=O.[C:24](#[N:28])[CH2:25][C:26]#[N:27]>C(O)(=O)C>[CH3:10][CH:11]([CH3:23])[CH2:12][C:13](=[C:25]([C:24]#[N:28])[C:26]#[N:27])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1
Reactant: N#CCC#N
Reactant: COc1cccc(C(=O)CC(C)C)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC(=O)O
Product: COc1cccc(C(CC(C)C)=C(C#N)C#N)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 88 %

Procedure:
To a stirred solution of acetic acid (14.36 mL, 251 mmol), was added hexamethyldisilazane (7.01 mL, 33.5 mmol) dropwise. The resulting solution was added to a solution of 3-methyl-1-[3-(methyloxy)phenyl]-1-butanone (4.02 g, 20.91 mmol) (Description 18) and malononitrile (2.76 g, 41.8 mmol) in acetic acid (15 mL). The mixture was stirred for 7 h at 70° C. The solution was cooled to RT and partitioned between toluene (167 mL) and water (130 mL). The aqueous layer was further extracted with toluene (70 mL). The combined organic layers were concentrated, and purified by chromatography on silica gel, eluting with DCM, to afford the title compound (4.42 g). LCMS (B) m/z: 241 [M+1]+, Rt 3.14 min.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[P:12]([O-:19])(OCC)OCC.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([PH:12](=[O:19])[C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOP([O-])OCC
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=[PH](c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 3 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
Under an argon atmosphere, a solution of magnesium (6.95 g, 1.0 equivalent) and a small amount of iodine in THF (70 mL) was stirred at room temperature for 1 hr. 1-Bromo-4-fluorobenzene (50 g, 0.286 mol) was added at 40° C., and the mixture was stirred at 3° C. for 1 hr. Then, diethyl phosphite (19.7 g, 0.50 equivalents) was added at 13 to 19° C., and the mixture was stirred at 5° C. for 1 hr. Water (45 mL) was added at 4° C., and toluene (150 mL) and 6M—HCl (45 mL) were added. The mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned, and the organic layer was washed successively with water, 5% aqueous NaHCO3 solution (50 mL), and 5% aqueous NaCl solution (50 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered by gravity, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 30 g, n-hexane/ethyl acetate=1/0→3/1) to give the title compound (12.0 g, pale-red oil). yield 35.2%.
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[CH2:6]O)/[CH2:3]O.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[CH2:20]([N:27]1[CH2:6][CH:5]=[C:2]([CH3:3])[CH2:1]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: C/C(=C\CO)CO
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1=CCN(Cc2ccccc2)C1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a solution containing 40.8 g (0.4 mol) of E-2-methyl-2-butene-1,4-diol, 83.8 g (0.8 mol) of triethylamine, and 416.6 g of ethyl acetate in a round flask reactor, methanesulfonyl chloride was added dropwise with stirring for 30 min. at about 5° C. using an ice-bath. After addition, the mixture was allowed to react with stirring for 2 hours at room temperature. To the mixture, 171.7 g (1.6 mol) of benzylamine was added continuously dropwise with stirring for 30 min. at ambient temperature. After 2 hours of stirring, the crystallized solid was removed by filtration; 42.0 g of 35% HCl (aq) was added to the filtrate, and then excess benzylamine hydrochloride was removed by filtration or extraction. After the solvent was evaporated under reduced pressure, 54.2 g of 1-benzyl-3-methyl-3-pyrroline (yield 78.2%) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:27])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=O)(=[O:10])=[O:9]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:27])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[CH2:16][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)(=[O:10])=[O:9]
Reactant: COc1cccc(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Br)c1
Solvent: C1CCOC1
Product: COc1cccc(NCc2sccc2S(=O)(=O)Nc2onc(C)c2Br)c1
Yield: 11.6 %

Procedure:
BH3 THF (15 ml, 1 M in THF) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide (Example 22) (1.0 g, 2.12 mmol) in dry THF (15 ml). The mixture was refluxed for 8 hours and cooled. THF was evaporated on a rotavap and MeOH was added to the residue. The resulting solution was concentrated. The final residue was purified by HPLC to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3-methoxyphenyl)aminomethyl]thiophene-3-sulfonamide (113 mg., 12% yield) as a grey powder, m.p. 70-73° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)C1C=CC=CC=1>[Pd].CCO>[OH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2
Reactant: c1ccc(COc2cccc3cc[nH]c23)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1cccc2cc[nH]c12

Procedure:
Furthermore, 7-benzyloxyindole (404 mg, 1.81 mmol) was hydrogenated over 10% palladium on carbon (40 mg) in EtOH (4.2 mL) at ambient temperature under atmosphere pressure for 6 h. The catalyst was filtered off and washed with EtOH. The filtrate was concentrated to give 7-hydroxyindole as pale purple crystals, which was rapidly and directly used for the next reaction.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:22]1([NH2:29])[C:23]([NH2:28])=[CH:24][CH:25]=[CH:26][CH:27]=1>ClCCl>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:29][C:7]([C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[O:9]
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Nc1ccccc1NC(=O)c1ccncc1
Reaction time: 1.42 h
Yield: 34 %

Procedure:
A stirred suspension of 4-pyridinecarboxylic acid (2.15 g, 17.5 mmol) in dichloromethane (40 ml) was treated with 1,1'-carbonyldiimidazole (3.115 g, 19.2 mmol) and the resulting solution was stirred for 85 minutes and added to 1,2-benzenediamine (3.777 g, 34.9 mmol) in dichloromethane (125 ml). After 3 hours, the precipitate formed was filtered and purified by chromatography (SiO2 ; ethyl acetate) to give the title compound as pale yellow crystals (1.267 g), m.p. 225°-235°.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:36]=[N:37][C:38]([O:44][CH3:45])=[C:39]([O:41][CH2:42][CH3:43])[CH:40]=1)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[CH2:42]([O:41][C:39]1[CH:40]=[C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:20]2[NH:19][C:18](=[O:17])[N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:36]=[N:37][C:38]=1[O:44][CH3:45])[CH3:43]
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cnc1OC
Reactant: NNc1ncccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cnc1OC
Temperature: 85 °C
Reaction time: 21 h

Procedure:
After adding 23.5 mg of 2-hydrazinopyrimidine and 0.030 ml of triethylamine to a solution of 100 mg of {2-(5-ethoxy-6-methoxypyridin-3-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 1 ml of DMF, the mixture was stirred at 85° C. for 21 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 2.0 ml of methanol and 0.1 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 23 hours. The reaction mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product of 5-{(5-ethoxy-6-methoxypyridin-3-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one. To a solution of the obtained crude product in 3 ml of a methanol:water:acetic acid=1:1:1 mixed solvent there was added 100 mg of iron powder, and the mixture was stirred at 60° C. for 11 hours and 30 minutes under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 4-{[(5-ethoxy-6-methoxypyridin-3-yl)-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}benzamidine acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([CH3:36])[C:26]=1[N:27]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[N:28]1)[O:5][CH:6]([CH:18]1[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19]1)[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=1.O1CCCC1.CO.[OH-].[Na+]>O>[CH3:36][C:25]1[CH:24]=[C:4]([CH:3]=[C:2]([CH3:1])[C:26]=1[N:27]1[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[N:28]1)[O:5][CH:6]([CH:18]1[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19]1)[C:7]1[CH:17]=[CH:16][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1ccc(C(Oc2cc(C)c(-n3cc(C(F)(F)F)cn3)c(C)c2)C2CC(C)(C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OC(c2ccc(C(=O)O)cc2)C2CC(C)(C)C2)cc(C)c1-n1cc(C(F)(F)F)cn1
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a flask containing ethyl 4-((3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)(3,3-dimethylcyclobutyl)methyl)benzoate (135 mg, 0.270 mmol) was added anhydrous tetrahydrofuran (0.680 mL), methanol (0.680 mL), water (0.680 mL) and sodium hydroxide (55.7 mg, 1.35 mmol). After 8 h, the reaction was concentrated and dissolved in ethyl acetate and water. 1 N hydrochloric acid was added to pH 3 and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 4-((3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)(3,3-dimethylcyclobutyl)methyl)benzoic acid (110 mg, 86% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J=8.2 Hz, 2H), 7.88 (s, 1H), 7.65 (s, 1H), 7.41 (d, J=8.4 Hz, 2H), 6.58 (s, 2H), 5.03 (d, J=6.8 Hz, 1H), 2.80-2.55 (m, 1H), 2.07-1.72 (m, 9H), 1.67 (dd, J=8.2, 3.5 Hz, 1H), 1.14 (s, 3H), 1.10 (s, 3H). MS (M+1): 473.5.
Reaction SMILES: C([C:5]1[N:10]=[C:9]([NH2:11])[C:8]([C:12]2[NH:24][C:15]3[CH:16]=[N:17][C:18](C(C)(C)C)=[CH:19][C:14]=3[N:13]=2)=[CH:7][N:6]=1)(C)(C)C.N[C:26]1C(C2NC3C=CC=CC=3N=2)=CC=CN=1>>[CH:7]1[C:8]2[C:12]3[N:24]([CH:26]=[N:11][C:9]=2[N:10]=[CH:5][N:6]=1)[C:15]1[C:14](=[CH:19][CH:18]=[N:17][CH:16]=1)[N:13]=3
Reactant: Nc1ncccc1-c1nc2ccccc2[nH]1
Reactant: CC(C)(C)c1cc2nc(-c3cnc(C(C)(C)C)nc3N)[nH]c2cn1
Product: c1cc2nc3c4cncnc4ncn3c2cn1

Procedure:
Preparation analogous to 7), using 32.4 g (100 mmol) of 2-(2-tert-butyl-4-aminopyrimidin-5-yl)-6-tert-butyl-3H-imidazo[4,5-c]pyridine (S56) (employed as equimolar mixture with 2,6-di-tert-butyl-3H-imidazo[4,5-c]-pyridine as obtained from synthesis 27)) instead of 100 mmol of the 2-(2-aminopyridin-3-yl)benzimidazole derivative. After crystallisation from methanol, the crude products are passed through a silica-gel column (heptane:ethyl acetate, 3:1 vv). The solids obtained in this way are freed from low-boiling components and non-volatile secondary components by sublimation (p about 1×10−5 mbar, T about 200-240° C.). Purity according to 1H-NMR typically >99.5%.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:15]([F:16])=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[C:18]=2[F:26])[N:13]=[C:12]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:11]=1/[CH:37]=[CH:38]/[Si](C)(C)C>CN(C=O)C.O>[NH2:9][C:10]1[C:15]([F:16])=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[C:18]=2[F:26])[N:13]=[C:12]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:11]=1/[CH:37]=[CH:38]/[Cl:1]
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(/C=C/[Si](C)(C)C)c(N)c2F)c1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(/C=C/Cl)c(N)c2F)c1F
Temperature: 50 °C
Reaction time: 24 h
Yield: 21.5 %

Procedure:
N-Chlorosuccinimide (NCS; 190 mg, 1.4 mmol, 2.0 equiv) was added to a stirred solution of (E)-benzyl 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-3-(2-(trimethylsilyl)vinyl)picolinate (350 mg, 0.70 mmol, 1.0 equiv) in DMF (7.0 mL) at 23° C. The homogeneous pale green solution was heated to 50° C. and stirred for 24 h. The cooled reaction mixture was diluted with water (400 mL) and extracted with Et2O (4×100 mL). The combined organic layers were dried (MgSO4), gravity filtered, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient) to afford the desired product, (E)-benzyl 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-(2-chlorovinyl)-5-fluoropicolinate as a tan powder (70 mg, 22% yield): mp 133-135° C.; IR (thin film) 3486 (s), 3345 (s), 3215 (w), 3069 (w), 3037 (w), 2953 (w), 1719 (s), 1616 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.47-7.43 (m, 2H), 7.41-7.33 (m, 3H), 7.27 (m, 2H), 6.89 (d, J=14 Hz, 1H), 6.45 (d, J=14 Hz, 1H), 5.37 (s, 2H), 4.62 (br s, 2H), 3.97 (d, J=1 Hz, 3H); ESIMS m/z 465 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.Cl[CH2:21][CH2:22][CH2:23][O:24][C:25]1[C:26]2[CH:27]=[CH:28][NH:29][C:30]=2[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]3[CH2:13][CH2:14][N:15]([CH2:21][CH2:22][CH2:23][O:24][C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)[CH2:16][CH2:17]3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: FC(F)(F)c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccc2c(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 192 from 6-trifluoromethyl-3-(piperidin-4-yl)-1H-indole (0.60 g, 2.2 mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.65 g, 2.2 mmol) and potassium carbonate (0.46 g, 3.4 mmol). The product was isolated as a white foam. Yield 165 mg (17%). mp 92°-97° C. FDMS m/e=442 (M+ of free base).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=4)[O:22][C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:21]2[O:22][C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:19]=3[N:20]=2)=[CH:28][CH:27]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3oc(-c4ccc(C(C)(C)C)cc4)nc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCNCC4)cccc3o2)cc1

Procedure:
4-[2-(4-tert-butyl-phenyl)-benzooxazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (900 mg, 2.07 mmol) was stirred in a solution of concentrated trifluoroacetic acid (20 mL) and methylene chloride (20 mL) under N2 at room temperature for 5 h. The solvent was removed in vacuo and the oil was transferred to a separatory funnel with ethyl acetate (150 mL) and washed with 1M aqueous potassium carbonate solution (100 mL×2). The aqueous washings were combined and extracted with ethyl acetate (150 mL). The organic extracts were combined and washed with brine (100 mL), dried (Na2SO4), filtered and the filtrate concentrated to give a clear oil which was concentrated in vacuo with hexane several times to give a waxy material which was placed on a drying pistol overnight to afford the product as an amber colored wax (550 mg, 79%). Mass Spectrum (+ESI): 336 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:30]([NH:33][C:34](=[O:38])[C:35](O)=[O:36])([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35](=[O:36])[C:34](=[O:38])[NH:33][CH:30]([CH3:32])[CH3:31])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)NC(=O)C(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(=O)NC(C)C)c1

Procedure:
Prepared as described in Example 76 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (53 mg, 0.14 mmol) and 2-(isopropylamino)-2-oxoacetic acid (18 mg, 0.14 mmol). Yield 42 mg (62%).