Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:25]1[N:30]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29](=[O:38])[C:28]2=[CH:39][CH:40]=[C:41]([Cl:42])[N:27]2[N:26]=1)[CH:22]1[CH2:24][CH2:23]1)[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(C)(C)C.Cl.O1CCOCC1>CCOCC>[ClH:42].[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:25]1[N:30]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:29](=[O:38])[C:28]2=[CH:39][CH:40]=[C:41]([Cl:42])[N:27]2[N:26]=1)[CH:22]1[CH2:24][CH2:23]1)[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nn3c(Cl)ccc3c(=O)n2Cc2ccccc2)C2CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1ccc(C(=O)N(CCCN)C(c2nn3c(Cl)ccc3c(=O)n2Cc2ccccc2)C2CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 132.8 %

Procedure:
A mixture of {3-[[(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-cyclopropyl-methyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester (0.24 g, 0.39 mmol) and 4 N HCl in dioxane (10 mL, 16 mmol) in Et2O (10 mL) was stirred at rt for two days. After concentration, the residue was diluted with water, washed with Et2O twice and lyophilized to obtain the title compound (0.14 g, 66%): 13C NMR (D2O) δ 174.1, 155.5, 148.4, 141.0, 136.3, 132.1, 129.7, 129.5, 128.9, 127.7, 126.1, 117.7, 117.2, 111.0, 108.8, 71.7, 70.9, 60.4, 43.4, 42.4, 36.9, 28.1, 20.7, 13.3; MS (ESI+) 504.17, 506.25 (M++H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=1[C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=1)[CH:21]=[CH:22][C:23]([O:25]C)=[O:24].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=1[C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=1)[CH:21]=[CH:22][C:23]([OH:25])=[O:24]
Reactant: CCCCCOc1cc(-c2cccc(C=CC(=O)OC)c2)c(Br)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCOc1cc(-c2cccc(C=CC(=O)O)c2)c(Br)c2ccccc12
Yield: 78.8 %

Procedure:
Methyl 3-(1-bromo-4-pentyloxynaphthalene-2-yl)cinnamate (588 mg, 1.56 mmol), ethanol (4 ml) and a 1N aqueous sodium hydroxide solution (4 ml) were mixed, and this solution was refluxed under heating for 1 hour. Ethanol was evaporated under reduced pressure and conc. hydrochloric acid was added to make the reaction mixture acidic. THF (5 ml) and ethyl acetate (20 ml) were added to dissolve the precipitated crystals. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate (20 ml). The organic layers were combined, washed 3 times with saturated brine (20 ml), and dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by washing with hexane to give 3-(1-bromo4-pentyloxynaphthalene-2-yl)cinnamic acid (540 mg, 95%) as pale-yellow crystals.
Reaction SMILES: [OH-].[NH4+:2].[C:3]([NH:7][S:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(OCC)(=O)C>[C:3]([NH:7][S:8]([C:11]1[CH:12]=[C:13]([S:17]([NH2:2])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1cccc(S(N)(=O)=O)c1
Reaction time: 8 h

Procedure:
20 ml of concentrated ammonium hydroxide was added to a solution of 1 gram (3.2 mmole) 3-tert-butylsulfamoyl-benzenesulfonyl chloride in ethyl acetate. It was stirred vigorously for 8 hours. The ethyl acetate layer was separated dried over magnesium sulfate in vacuo to give 320 mg of the titled compound as a white solid. m.p. 151-154° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]3)=[CH:23][N:24]=2)[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F-].C([N+:47]([CH2:56][CH2:57][CH2:58][CH3:59])([CH2:52][CH2:53][CH2:54][CH3:55])CCCC)CCC>O1CCOCC1.O.Cl[Pd]C1C=CC=CC=1C1C=CC=CC=1N(C)C.[C@H]12C[C@H](CC1)CC2PC1C[C@H]2C[C@@H]1CC2>[CH3:33][C@H:28]1[O:29][C@@H:30]([CH3:32])[CH2:31][N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:59]4[CH:55]=[CH:54][CH:53]=[C:52]5[C:58]=4[CH:57]=[CH:56][NH:47]5)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][NH:8]4)=[N:24][CH:23]=2)[CH2:27]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C[C@@H]1CN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@H](C)O1
Agent: CN(C)c1ccccc1-c1ccccc1[Pd]Cl
Agent: C1C[C@@H]2C[C@H]1CC2PC1C[C@@H]2CC[C@H]1C2
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CN(Cc2cnc(-c3cc(-c4cccc5[nH]ccc45)cc4[nH]ncc34)o2)C[C@H](C)O1
Temperature: 100 °C
Reaction time: 18 h
Yield: 31.8 %

Procedure:
To a solution of 6-chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (50 mg, 0.103 mmol) in 1,4-dioxane (1.5 ml) and water (0.15 ml) was added {1-[1,1,-dimethylethyl)(dimethyl)silyl]1-H-indol-4-yl}boronic acid (37 mg, 0.133 mmol), chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (5.75 mg, 10.27 μmol) and potassium phosphate tribasic (65 mg, 0.308 mmol). The reaction mixture was heated under microwave irradiation at 100° C. for 40 min. The solvent was removed and the residue dissolved in 10% methanol in dichloromethane (2 ml) and purified by silica gel chromatography, eluting with a gradient of cyclohexane and ethyl acetate. The appropriate fractions were concentrated to give a brown gum which was treated directly with tetra-n-butylammonium fluoride (0.2 ml, 0.2 mmol, 1M in tetrahydrofuran) and allowed to stand at 20° C. for 18 h. The solvent was removed and the residue dissolved in 1,4-dioxane (1 ml) and treated with 2M sodium hydroxide (1 ml) and allowed to stand at 20° C. for 48 h. The solvent was removed and the residue triturated with 10% methanol in dichloromethane then purified by silica gel chromatography, eluting with a gradient of dichloromethane and methanol to give a pale brown solid which was further purified by SCX SPE (1 g), eluting with 0.5M ammonia in 1,4-dioxane. The solvent was removed and the residue further purified by MDAP to give the title compound as a white solid (14 mg). LCMS (Method A): Rt 0.70 mins, MH+ 428.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C@H:6]([CH3:8])[C@@H:5]([C:9]([OH:11])=O)[CH2:4][CH:3]=1.C(Cl)(C(Cl)=O)=O.[CH3:18][C:19]([CH3:39])([CH3:38])[C:20]#[C:21][C:22]1[S:26][CH:25]=[C:24]([NH:27][CH:28]2[CH2:37][CH2:36][C:31]3([O:35][CH2:34][CH2:33][O:32]3)[CH2:30][CH2:29]2)[CH:23]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.ClCCCl.CN(C=O)C>[CH3:18][C:19]([CH3:39])([CH3:38])[C:20]#[C:21][C:22]1[S:26][CH:25]=[C:24]([N:27]([CH:28]2[CH2:37][CH2:36][C:31]3([O:32][CH2:33][CH2:34][O:35]3)[CH2:30][CH2:29]2)[C:9]([C@@H:5]2[C@@H:6]([CH3:8])[CH2:7][C:2]([CH3:1])=[CH:3][CH2:4]2)=[O:11])[CH:23]=1
Reactant: CC1=CC[C@H](C(=O)O)[C@@H](C)C1
Reactant: CC(C)(C)C#Cc1cc(NC2CCC3(CC2)OCCO3)cs1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1=CC[C@H](C(=O)N(c2csc(C#CC(C)(C)C)c2)C2CCC3(CC2)OCCO3)[C@@H](C)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
(1S,6S)-4,6-dimethyl-cyclohex-3-ene-carboxylic acid (3.04 g, 19.7 mmol) was dissolved in CH2Cl2 (30 mL) and DMF (20 μL) was added. The solution was cooled to 0° C. and (COCl)2 (3.7 mL, 39 mmol) was added slowly. The reaction was stirred in an ice bath for 2 hours and then concentrated. The residue was taken up in hexanes and concentrated; this hexanes coevaporation was repeated once more. To the residue was added [5-(3,3-Dimethyl-but-1-ynyl)-thiophen-3-yl]-(1,4-dioxa-spiro[4.5]dec-8-yl)-amine (4.16 g, 13 mmol), diisopropylethylamine (4.5 mL, 26 mmol), and 1,2-dichloroethane (40 mL) at 0° C. The solution was warmed to room temperature and stirred overnight. The reaction was diluted with CH2Cl2, twice washed with saturated NH4Cl(aq), dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography, eluting with a mixture of 0-75% EtOAc/hexanes, to give (1S,6S)-4,6-dimethyl-cyclohex-3-ene-carboxylic acid [5-(3,3-dimethyl-but-1-ynyl)-thiophen-3-yl]-(1,4-dioxa-spiro[4.5]dec-8-yl)-amide (5.6 g, 12 mmol) as a single isomer.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]([NH:23][C:24]([CH:26]3[CH2:28][CH2:27]3)=[O:25])[CH3:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[I:8][C:5]1[CH:4]=[N:3][C:2]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([C@@H:21]([NH:23][C:24]([CH:26]4[CH2:27][CH2:28]4)=[O:25])[CH3:22])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[N:7][CH:6]=1
Reactant: C[C@H](NC(=O)C1CC1)c1ccc(C2CCNCC2)cc1
Reactant: Clc1ncc(I)cn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H](NC(=O)C1CC1)c1ccc(C2CCN(c3ncc(I)cn3)CC2)cc1
Temperature: 25 °C

Procedure:
633 mg (2.5 mmol) 2-Chloro-5-iodopyrimidine, 757 mg (2.5 mmol) (S)-cyclopropanecarboxylic acid [1-(4-piperidin-4-yl-phenyl)ethyl]-amide (V.4) and 0.855 mL (5.0 mmol) DIPEA in 10 mL NMP are stirred for 2 h at 130° C. After cooling to rt the mixture is treated with water and the precipitate is collected by filtration and triturated with ether to yield the desired compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:24]([O:25][CH3:26])=[CH:23][C:13]2[O:14][C:15](=[O:22])[C:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:12]=2[CH:11]=1)(=O)=O.[C:27]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])(=O)/C=C/C([O-])=O.C(O)C>CC(C)=O>[CH3:26][O:25][C:24]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:36]2[CH2:37][CH2:38][CH:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][CH2:35]2)=[CH:11][C:12]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[C:15](=[O:22])[O:14][C:13]=2[CH:23]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCOS(C)(=O)=O)CCCC3
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCC(c2ccccc2)CC1)CCCC3
Yield: 100 %

Procedure:
Method B (20 h at 50° C.); starting materials: 7,8,9,10-tetrahydro-2-[3-(methanesulfonyloxy)propoxy]-3-methoxy-6H-dibenzo[b,d]pyran-6-one (example 80) and 4-phenylpiperidine; yield 100% (raw). Fumarate: method E; yield 72% on the basis of the methanesulfonyl compound; fusion point 184°-186° C. (from ethanol and acetone).
Reaction SMILES: CO[C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[CH3:30][O:31][CH2:32][CH2:33][NH2:34]>>[CH2:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3](=[O:29])[NH:34][CH2:33][CH2:32][O:31][CH3:30])=[CH:5][N:6]=3)=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[CH:21][CH:22]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: COCCN
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NCC(C)C)CC2)nc1
Product: COCCNC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NCC(C)C)CC2)nc1
Yield: 65 %

Procedure:
By the same procedure as described in the example 25, the synthesis was carried out starting with 6-[1-[3-(isobutylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester and using 2-methoxyethylamine. And then, the product was recrystallized with isopropanol to give a desired compound.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>ClC(Cl)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C(Nc1ccc2oc3c(c2c1)CCCCCC3)c1ccncc1
Yield: 44.1 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.20 g, 0.92 mmol), isonicotinoyl chloride hydrochloride (0.20 g, 1.1 mmol), and poly(vinylpyridine) (0.5 g) in dichloroethane (12 mL) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)isonicotinamide (0.13 g). MS (ESI) m/z 321 ([M+H]+); MS (ESI) m/z 319 ([M−H]−).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][CH:12]=1)(=O)=O.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].[Al]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[F:14][C:13]([F:16])([F:15])[C:10]1[N:9]=[CH:8][C:7]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:12][N:11]=1
Reactant: O=S(=O)(Oc1cnc(C(F)(F)F)nc1)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Al]
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(C(F)(F)F)nc1
Reaction time: 5 h
Yield: 95.5 %

Procedure:
2-(Trifluoromethyl)pyrimidine-5-yl trifluoromethanesulfonate (0.45 g, 1.5 mmol) and dry triethylamine (1.0 mL) were mixed in a screw-cap vial. The solution was purged with dry argon for 10 minutes. Trimethylsilylacetylene (0.43 mL, 3.0 mmol), finely ground CuI (0.010 g, 0.05 mmol) and PdCl2(PPh3)2 (0.020 g, 0.030 mmol) were added. The vial was sealed and heated in an aluminum block at 80° C. After stirring for 5 hours the volatiles were evaporated at room temperature (the product sublimes at 35-40° C./10 mbar). The black residue was taken up in EtOAc (20 mL) and concentrated with silica (about 5 to 10 g) to dryness. Flash chromatography on silica with EtOAc/heptane (1:30) afforded 2-(trifluoromethyl)-5-[(trimethylsilyl)ethynyl]pyrimidine as a white solid (0.35 g, 95%), m.p. 75.5-76.0° C.
Reaction SMILES: [Br:1][C@@H:2]([CH2:5][CH2:6][OH:7])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[Br:1][C@@H:2]([CH2:5][CH2:6][O:7][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:3][O:4][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCC[C@H](Br)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC[C@H](Br)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
A solution of 70 g (0.414 mol) (S)-2-bromo -1,4-butanediol in 1.5 liters methylene chloride was cooled in ice and 173 ml (1.24 mol) triethylamine (dried over potassium hydroxide) was added to give a clear solution. To this was added dropwise over 80 minutes at 5° to 15° C., 96 ml (1.24 mol) methanesulfonyl chloride. The mixture was then stirred at room temperature for 2.5 hours, washed 2×750 ml with water and 1×750 ml brine, dried (MgSO4), and the solvent evaporated to give an amber oil which was purified by chromatography on a 140 mm×25 cm silica gel column, eluting with 9:1 chloroform:ethyl acetate. The product fractions were combined and solvent evaporated to give 105 g (97%) of the title compound as a waxy white solid; [alpha]D=- 34.49° (c=5 in CHCl3).
Reaction SMILES: [OH-].[Na+].[CH3:3]I.[CH2:5]([O:8][C:9]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[C:18]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][C:41]([O:43][CH2:44][CH:45]=[CH2:46])=[O:42])=[C:36]([Cl:47])[CH:35]=3)=[CH:30][CH:29]=2)[C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH2:7]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH2:5]([O:8][C:9]1[C:21]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:19]=[C:18]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH:40]([C:41]([O:43][CH2:44][CH:45]=[CH2:46])=[O:42])[CH3:3])=[C:36]([Cl:47])[CH:35]=3)=[CH:30][CH:29]=2)[C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH2:7]
Reactant: CI
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C(=O)OC(C)(C)C)cc2)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOC(=O)C(C)c1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C(=O)OC(C)(C)C)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.3 %

Procedure:
tetra-n-Butylammonium hydrogensulfate (21 mg, 0.062 mmol), a 2N aqueous sodium hydroxide solution (0.06 ml, 0.12 mmol) and methyl iodide (10 μl, 0.16 mmol) were added to a solution of tert-butyl 2-(allyloxy)-6-{[(4′-{[(allyloxy)carbonyl]methyl}-3′-chloro-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoate (19 mg, 0.03 mmol) obtained in Example (18-3) in dichloromethane (0.4 ml), and the mixture was stirred at room temperature for 1.5 hours. A 2N aqueous sodium hydroxide solution (0.03 ml, 0.06 mmol) and methyl iodide (7 μl, 0.11 mmol) were added to the reaction mixture and the mixture was further stirred for 1 hour. The residue obtained by removing the solvent under reduced pressure was purified by silica gel preparative thin layer chromatography (developing solvent: hexane/ethyl acetate=5/1) to give tert-butyl 2-(allyloxy)-6-{[(4′-{1-[(allyloxy)carbonyl]ethyl}-3′-chloro-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoate (8 mg, yield: 42%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br:20]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([CH:8]1[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]1)[CH2:12][CH2:13]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)CCN2C1CCC2(CC1)OCCO2
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)CCN2C1CCC2(CC1)OCCO2
Reaction time: 3.5 h
Yield: 90 %

Procedure:
A solution of compound 3 (3.45 g, 13.30 mmol) in dry DMF (30 mL) was treated with N-bromosuccinimide (2.36 g, 13.30 mmol) in DMF (20 mL) at 0° C. over a period of 30 min. The reaction was stirred at same temperature for 3.5 h. The reaction was diluted with water (200 mL) and product was extracted into ethyl acetate (3×25 mL). The combined ethyl acetate layer was washed with water (2×50 mL), brine (25 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified by column chromatography on silica gel (ethyl acetate:hexanes, 1:4) to obtain compound 4 (4.05 g, 90%) as a syrup. 1H NMR (CDCl3) δ 7.12-7.10 (m, 2H), 6.25 (d, J=9.0 Hz, 1H), 3.95 (s, 4H), 3.38 (t, J=16.8 Hz, 3H), 2.91 (t, J=16.8 Hz, 2H), 1.86-1.57 (m, 8H). MS-ESI (m/z, %): 340 (98), 338 (M+, 100), 198 (18).
Reaction SMILES: O=S(Cl)Cl.[Br:5][C:6]1[C:7]([Cl:15])=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([OH:13])=O.CCN(C(C)C)C(C)C.[F:25][C:26]([F:36])([F:35])[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.Cl>C1(C)C=CC=CC=1.C1COCC1.CN(C=O)C>[Br:5][C:6]1[C:7]([Cl:15])=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][C:26]([F:25])([F:35])[F:36])=[CH:29][CH:30]=1)=[O:13]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
SOCl2 (1.089 mL, 14.92 mmol) and DMF (0.01 mL) were added dropwise to a suspension of 5-bromo-6-chloronicotinic acid (1.176 g, 4.97 mmol) in toluene (10 mL) and the RM was stirred at 85° C. for 2 h. The solvent was evaporated off under reduced pressure and the residue was diluted with THF (10 mL). DIPEA (1.74 mL, 9.95 mmol) was added and the mixture was cooled to −15° C. under argon atmosphere, treated with a solution of 4-trifluoromethoxyaniline (0.701 mL, 5.22 mmol) in THF (10 mL) and stirred at RT for 1 h. The solvent was off under reduced pressure and the residue was treated with aq. 1M HCl (50 mL), and extracted with TBME/EtOAc (4:1). The combined extracts were washed with aq. 1 M HCl, sat. aq. Na2CO3 and brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give the crude product was purified by flash chromatography (Biotage Silica gel column, 50 g, cyclohexane/EtOAc from 5% to 25% EtOAc) to afford the title compound as an off-white solid. UPLC-MS (Condition 1) tR=3.09 min, m/z=394.9/396.8 [M+H]+, m/z=393.0/394.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.40 (d, J=8.6 Hz, 2H) 7.86 (d, J=9.0 Hz, 2H) 8.73 (d, J=2.2 Hz, 1H) 8.92 (d, J=2.0 Hz, 1H) 10.69 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][F:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>N1CCCCC1.C(#N)C.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.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:29]#[C:28][C:26]([C:21]4[N:20]=[CH:25][CH:24]=[CH:23][N:22]=4)([OH:30])[CH3:27])[CH:10]=3)[C:6]([CH2:18][F:19])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: C#CC(C)(O)c1ncccn1
Reactant: Nc1nccc(-n2nc(CF)c3ccc(Br)cc32)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CC#N
Product: CC(O)(C#Cc1ccc2c(CF)nn(-c3ccnc(N)n3)c2c1)c1ncccn1
Temperature: 66 °C

Procedure:
To a solution of 4-[6-bromo-3-(fluoromethyl)-1H-indazol-1-yl]pyrimidin-2-amine (49 mg, 0.12 mmol) in piperidine (2 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (11.5 mg, 0.01 mmol), copper(I) iodide (1.9 mg, 0.01 mmol) and 2-(pyrimidin-2-yl)but-3-yn-2-ol (39 mg, 0.25 mmol). The reaction mixture was warmed to 66° C. for 2 hr. After cooling to RT, the reaction mixture was concentrated in vacuo, DCM (10 mL) was added and the solution re-evaporated to dryness in vacuo (re-evaporation process repeated twice). Purification of the residue by column chromatography (Biotage, DCM containing a 0-10% gradient of methanol) furnished a brown oil which was suspended in acetonitrile and concentrated in vacuo. The residue was re-suspended in acetonitrile (1 mL), whereupon a brown solid precipitated and was collected by filtration to furnish the title compound as a brown solid: 1H NMR (500 MHz, METHANOL-d4) delta 1.99 (3H, s), 5.75 (2H, d, J=47.92 Hz), 7.23 (1H, d, J=5.36 Hz), 7.42 (1H, dd, J=8.28, 1.02 Hz), 7.48 (1H, t, J=4.89 Hz), 7.85 (1H, d, J=8.20 Hz), 8.25 (1H, d, J=4.73 Hz), 8.88 (2H, d, J=4.89 Hz), 9.06 (1H, s); LC-MS: m/z=+390.05 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:23](=[O:39])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[C:34]2[CH3:38])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N:33]4[CH:37]=[CH:36][N:35]=[C:34]4[CH3:38])[CH:28]=3)[CH2:24][C:23](=[O:39])[NH:22][C:9]=2[CH:10]=1
Reactant: Cc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccc(F)cc3F)ccc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nccn1-c1cccc(C2=Nc3ccc(-c4ccc(F)cc4F)cc3NC(=O)C2)c1

Procedure:
Prepared from (2′,4′-difluoro-3-{3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K89) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light brown solid (71 mg).