Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8].[OH-].[Na+].[CH3:27][NH:28][C:29](=[O:34])C(Cl)(Cl)Cl>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH:21][C:29]([NH:28][CH3:27])=[O:34])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8]
Reactant: CNC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(N)(=O)=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CNC(=O)NS(=O)(=O)N1CCC(CCNC(=O)c2cc(Cl)ccc2OC)CC1
Yield: 5.8 %

Procedure:
376 mg (1 mmol) of 4-(2-(5-chloro-2-methoxybenzamido)ethyl)piperidine-1-sulfonamide and 80 mg (2 mmol) of sodium hydroxide were heated in 5 ml of N-methyl-2-pyrrolidone with 180 mg (1 mmol) of N-methyltrichloroacetamide at 80° C. for 10 minutes. The reaction mixture was poured onto ice/2 M hydrochloric acid, and the precipitated solid was filtered off with suction and washed with water until neutral. Purification by chromatography (silica gel; toluene/ethanol/ethyl acetate 8/1/1) resulted in 25 mg (6%) of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:18])[NH:11][NH:12][C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[C:28]([O:36][C@@H:37]3[O:54][C@H:53]([CH2:55][O:56][C:57](=[O:59])[CH3:58])[C@@H:48]([O:49][C:50](=[O:52])[CH3:51])[C@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@H:38]3[O:39][C:40](=[O:42])[CH3:41])=[N:29][NH:30][C:31]=2[C:32]([F:35])([F:34])[F:33])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[C:28]([O:36][C@@H:37]3[O:54][C@H:53]([CH2:55][O:56][C:57](=[O:59])[CH3:58])[C@@H:48]([O:49][C:50](=[O:52])[CH3:51])[C@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@H:38]3[O:39][C:40](=[O:42])[CH3:41])=[N:29][NH:30][C:31]=2[C:32]([F:34])([F:33])[F:35])=[CH:22][CH:21]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([O:18][C@@H:37]3[O:54][C@H:53]([CH2:55][OH:56])[C@@H:48]([OH:49])[C@H:43]([OH:44])[C@H:38]3[OH:39])=[N:11][NH:12][C:13]=2[C:14]([F:16])([F:15])[F:17])=[CH:4][CH:3]=1
Reactant: O=c1[nH][nH]c(C(F)(F)F)c1Cc1ccc(Cl)cc1
Agent: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)F)c2Cc2ccc(Cl)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)F)c2Cc2ccc(Cl)cc2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
4-[(4-Chlorophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole was prepared in a similar manner to that described in Reference Example 28 using 4-[(4-chlorophenyl)methyl]-1,2-dihydro-5-trifluoromethyl-3H-pyrazol-3-one instead of 1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one. Then, the title compound was prepared in a similar manner to that described in Reference Example 37 using 4-[(4-chlorophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole instead of 4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12](O)=[O:13])=[CH:9]2)=[CH:4][C:3]=1[O:15][CH3:16]>O1CCCC1>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][OH:13])=[CH:9]2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc2ccc(C(=O)O)cc2cc1N
Solvent: C1CCOC1
Product: COc1cc2ccc(CO)cc2cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Borane tetrahydrofuran complex (1 mL, 0.92 mmol) was added, at 0° C., to a suspension of 7-amino-6-methoxy-naphthalene-2-carboxylic acid (0.1 g, 0.46 mmol) in anhydrous tetrahydrofuran (2 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched by addition of methanol and then was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure, partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford (7-amino-6-methoxy-naphthalen-2-yl)-methanol without further purifications. MS=204 [M+H]+.
Reaction SMILES: [O-2].[La+3:2].[O-2].[O-2].[La+3].O.[N+:7]([O-:10])([OH:9])=[O:8]>>[N+:7]([O-:10])([O-:9])=[O:8].[La+3:2].[N+:7]([O-:10])([O-:9])=[O:8].[N+:7]([O-:10])([O-:9])=[O:8]
Reactant: O=[N+]([O-])O
Agent: [La+3]
Agent: [O-2]
Solvent: O
Product: O=[N+]([O-])[O-]

Procedure:
Lanthanum oxide (La2O3) (212 g, 0.065 mole) was completely dissolved in an aqueous nitric acid solution, after which the solution was concentrated by heating to prepare lanthanum nitrate, to which was added water to give 400 cc of an aqueous lanthanum nitrate solution.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:11]=[C:10]([CH3:26])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:27]([NH:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH3:25])[CH:15]=4)[CH:11]=[C:10]([CH3:26])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1cc(-c2cc(C)nc(-c3ccnc(Cl)c3)c2)ccc1C(F)(F)F
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: COc1cc(-c2cc(C)nc(-c3ccnc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)c3)c2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2′-chloro-4-(3-methoxy-4-trifluoromethyl-phenyl)-6-methyl-[2,4′]bipyridinyl (example E.99) (0.378 g, 1.0 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.283 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.390 g, 70%). MS (ISP) 556.5 [(M+H)+]; mp 189° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH2:11][CH3:12])=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C>[O:1]([CH2:2][C:3]1[C:4]([CH2:11][CH3:12])=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1nc(SC)ncc1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCc1nc(SC)ncc1CO[Si](C)(C)C(C)(C)C
Yield: 94 %

Procedure:
A solution of 5-hydroxymethyl-4-ethyl-2-methylthiopyrimidine (0.50 g, 2.72 mmol), t-butyldimethylsilylchloride (0.49 g, 3.26 mmol), and imidazole (0.20 g, 2.99 mmol) in DMF (5 mL) was stirred overnight and concentrated to give of 5-t-butyldimethylsiloxymethyl-4-ethyl-2-methylthiopyrimidine in a 94% yield (0.76 g); GC/MS calcd for C14H26N2OSSi (M+) 299, found 299. The title compound was then prepared by (a) oxidation of 5-t-butyldimethylsiloxymethyl-4-ethyl-2-methylthiopyrimidine (0.30 g, 1.0 mmol) with mCPBA (0.35 g, 2.0 mmol) as described for Example 67, (b) reaction with methyl hydrazine (0.16 mL, 3.0 mmol) followed by citraconic anhydride (0.11 g, 1.0 mmol) also described in Example 67; (c) reaction of 2-[N-(1'-aminocitraconamido)]-5-t-butyldimethylsiloxymethyl-4-ethylpyrimidine; (0.08 g, 0.21 mmol) and concentrated HCl (0.5 mL) in EtOH (20 mL) for 1 hour, concentration and chromatography (Hexanes/EtOAc, 2:1) to provide the title compound in 76% yield (0.043 g) from 2-[N-(1'-aminocitraconamido)]-5-t-butyldimethylsiloxymethyl-4-ethylpyrimidine; m.p. 108-110° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:22][CH3:23])([O:20][CH3:21])[CH:17]([OH:19])[CH3:18])=[CH:12][CH:11]=1)[CH:7]([CH3:9])[CH3:8].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([O:19][CH:17]([CH3:18])[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:6][CH:7]([CH3:9])[CH3:8])=[CH:11][CH:12]=1)([O:22][CH3:23])[O:20][CH3:21])(=[O:4])=[O:3]
Reactant: COC(OC)(c1ccc(CC(C)C)cc1)C(C)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(OC)(c1ccc(CC(C)C)cc1)C(C)OS(C)(=O)=O
Reaction time: 1.5 h

Procedure:
A solution of 6.25 g of methanesulfonyl chloride in 20 ml of dry methylene chloride is added dropwise to a mixture of 12.37 g of 1-(4-isobutylphenyl)-1,1-dimethoxypropan-2-ol and 80 ml of dry methylene chloride containing 6.5 g of dry triethylamine at 5°-10° C. The addition takes place over about 40 minutes and the reaction mixture is stirred for an additional 1.5 hours at 5°-10° C. after that addition is completed. After that time, an additional 0.6 g of methanesulfonyl chloride is added at 5°-10° C. and stirring is continued for an additional 50 minutes. An additional 1.5 g of triethylamine is added to the reaction mixture and then the reaction mixture is poured into 50 ml of water. The aqeuous and organic phases are separated and the aqueous phase is extracted with methylene chloride. The combined methylene chloride layers then are washed with 50 ml of saturated aqueous sodium chloride and the methylene chloride layer is dried over sodium sulfate. After filtration to remove the sodium sulfate, the methylene chloride is evaporated on a rotary evaporator under reduced pressure to afford 1-(4-isobutylphenyl)-1,1-dimethoxyprop-2-yl methanesulfonate [which is characterized by an NMR spectra in deuterochloroform of τ=9.10 (doublet, J=2.2), 8.8 (doublet, J=2.1), 8.12 (septet, J=2.1), 7.48 (doublet, J=2.3), 6.88, 6.75, 6.67, 4.92 (quartet, J=2.1) and 2.5-2.9 (aromatic AB pattern)].
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(CN2C(=O)C3=CC=CC=C3C2=O)C(=O)N(CC(C)C)N=1.[C:32]([C:35]1[C:36](=[O:58])[N:37]([CH2:49][CH:50]=[CH:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[N:38]=[C:39]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[C:43]([CH3:48])[CH:42]=2)[CH:40]=1)(O)=[O:33]>>[CH2:49]([N:37]1[C:36](=[O:58])[C:35]([CH2:32][OH:33])=[CH:40][C:39]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[C:43]([CH3:48])[CH:42]=2)=[N:38]1)[CH:50]=[CH:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: Cc1cc(-c2cc(C(=O)O)c(=O)n(CC=Cc3ccccc3)n2)ccc1F
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2C(=O)c3ccccc3C2=O)c1=O
Product: Cc1cc(-c2cc(CO)c(=O)n(CC=Cc3ccccc3)n2)ccc1F

Procedure:
Following the procedure of Example 1 (8), 4-carboxy-2-cinnamyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as slightly yellow needles (yield: 20.1%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:34])=[C:4]([CH:29]=[CH:30][C:31]=1[C:32]#[N:33])[C:5]([NH:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:27])([C:23]([F:26])([F:25])[F:24])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[Cl:28])=[O:6].[H-].[Na+].C(C1C=CC(C(NC2C(Br)=CC(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)=CC=2Br)=O)=CC=1N[C:70](=[O:80])[C:71]1[CH:76]=[CH:75][C:74]([C:77]#[N:78])=[CH:73][C:72]=1[CH3:79])#N.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[C:32]([C:31]1[CH:30]=[CH:29][C:4]([C:5]([NH:7][C:8]2[C:9]([Cl:28])=[CH:10][C:11]([C:15]([F:27])([C:23]([F:24])([F:25])[F:26])[C:16]([F:21])([F:22])[C:17]([F:18])([F:19])[F:20])=[CH:12][C:13]=2[Cl:14])=[O:6])=[C:3]([F:34])[C:2]=1[NH:1][C:70](=[O:80])[C:71]1[CH:76]=[CH:75][C:74]([C:77]#[N:78])=[CH:73][C:72]=1[CH3:79])#[N:33]
Reactant: N#Cc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc2Cl)c(F)c1N
Reactant: Cc1cc(C#N)ccc1C(=O)Nc1cc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc2Br)ccc1C#N
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C#N)ccc1C(=O)Nc1c(C#N)ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc2Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a suspension of 3-amino-4-cyano-N-[2,6-dichloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)phenyl]-2-fluorobenzamide (Example 1.7) (0.054 g, 0.10 mmol) in N,N-dimethylacetamide (“DMA”) (1 ml) was added sodium hydride (55% w/v) (0.018 g, 0.40 mmol). The reaction mixture was stirred for 30 minutes at ambient temperature and then 4-cyano-2-methylbenzoyl chloride (see first part of Example 2.1) (0.10 mmol) was added. The reaction mixture was stirred at ambient temperature for 16 hours. Satruated aqueous sodium hydrogen carbonate (30 ml) was added and the organic phase extracted twice with ethyl acetate (2×20 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent:cyclohexane/ethyl acetate 7:3) to give Compound No. A18 of Table A (0.010 g, 15% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH:19]2[CH:24]3[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]3)[CH2:20]2)=[O:17])[C:5]2[O:10][CH:9]([CH2:11][CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[CH:15]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH+:18]([O-:35])[CH:19]2[CH:24]3[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]3)[CH2:20]2)=[O:17])[C:5]2[O:10][CH:9]([CH2:11][CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC1Oc2c(C(=O)NC3CN4CCC3CC4)cc(Cl)cc2N(C)C1=O
Solvent: ClC(Cl)Cl
Product: CCC1Oc2c(C(=O)[NH+]([O-])C3CN4CCC3CC4)cc(Cl)cc2N(C)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of 2.6 g of 6-chloro-2-ethyl-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide in 100 ml of chloroform is added portionwise 1.9 g of metachloroperbenzoic acid under cooling and stirring. After 0.5 hour, ammonia gas is bubbled through the reaction solution under stirring and the precipitate is filtered off. The mother liquor is distilled off under reduced pressure followed by recrystallizing the residue from ethanol-isopropyl ether to give 6-chloro-2-ethyl-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4- benzoxazine-8-carboxamide N-oxide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:9]([C:10]([N:12]([O:14]C(C)(C)C)[CH3:13])=[O:11])[N:8]=[C:7]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[S:6]1.C(O)(C(F)(F)F)=O>>[NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:9]([C:10]([N:12]([OH:14])[CH3:13])=[O:11])[N:8]=[C:7]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[S:6]1
Reactant: CN(OC(C)(C)C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(O)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN)c1ccccc1
Reaction time: 18 h
Yield: 49.2 %

Procedure:
To 2-(3-aminopropyl)-N-tert-butoxy-5-(2,5-difluorophenyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide (0.023 g, 0.05 mmol) was added TFA (2 mL). After stirring for 18 hours, the mixture was concentrated and chromatographed (10:1:0.2 dichloromethane/methanol/30% NH4OH) to provide the product (0.01 g, 49%). MS ESI (+) m/z 407 (M+1) detected; 1H NMR (400 MHz, CDCl3)δ 7.45 (d, 2H), 7.36 (m, 3H), 7.29 (m, 1H), 7.11 (m, 2H), 3.28 (s, 3H), 3.12 (m, 1H), 2.90 (m, 1H), 2.78 (m, 1H), 2.24 (m, 1H), 1.98 (m, 1H), 1.62 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.Cl[Sn:13]([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[CH3:1][N:2]1[C:6]([Sn:13]([CH3:16])([CH3:15])[CH3:14])=[CH:5][N:4]=[N:3]1
Reactant: Cn1ccnn1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nncc1[Sn](C)(C)C
Temperature: -30 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a stirred solution of 1-methyl-1H-1,2,3-triazole (0.5 g, 6.0 mmol) in anhydrous tetrahydrofuran (50 mL) at −78° C. under an atmosphere of nitrogen was added n-butyllithium (2.5M solution in hexanes, 2.6 mL, 6.6 mmol) dropwise over ten minutes. On complete addition the reaction was allowed to warm to −30° C. and stirred for 2 h. A solution of chlorotrimethylstannane (1.3 g, 6.6 mmol) in tetrahydrofuran (2 mL) was added dropwise over 10 minutes then the reaction mixture was allowed to warm to room temperature over 2 h. The reaction was quenched by the addition of saturated ammonium chloride solution (5 mL) then diluted with water (20 mL). The solvent was evaporated in vacuo and the aqueous phase extracted with ethyl acetate (2×30 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to afford a pale yellow oil (1.4 g, 90%). 1H NMR (DMSO-D6, 400 MHz): 7.61 (s, 1H), 4.04 (s, 3H), 0.40 (s, 9H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:27])([CH3:26])[CH2:20]/[CH:21]=[CH:22]/[C:23](O)=[O:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN(C)C(=O)[C@H](NC)CC1C=CC=CC=1.[CH3:65][N:66]([CH3:95])[C:67]([C@H:69]([N:77]([CH3:94])[C:78](=[O:93])[CH:79]([NH:91][CH3:92])[CH2:80][C:81]1[CH:90]=[CH:89][C:88]2[C:83](=[CH:84][CH:85]=[CH:86][CH:87]=2)[CH:82]=1)[CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)=[O:68]>ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C:19]([CH3:26])([CH3:27])[CH2:20]/[CH:21]=[CH:22]/[C:23](=[O:24])[N:91]([C@@H:79]([C:78](=[O:93])[N:77]([C@@H:69]([C:67](=[O:68])[N:66]([CH3:65])[CH3:95])[CH2:70][C:71]3[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=3)[CH3:94])[CH2:80][C:81]3[CH:90]=[CH:89][C:88]4[C:83](=[CH:84][CH:85]=[CH:86][CH:87]=4)[CH:82]=3)[CH3:92])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CNC(Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN[C@H](Cc1ccccc1)C(=O)N(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a solution of (2E)-5-(((9H-flouren-9-yl)methoxy)- carbonylamino)-5-methylhex-2-enoic acid (280 mg, 0.77 mmol) in dichloromethane (5 ml) were added 1-hydroxy-7-azabenzotriazole (126 mg, 0.92 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (207 mg, 1.08 mmol) and the mixture was stirred for 30 min. Then 2R)-N-((1R)-1-dimethylcarbamoyl-2-phenylethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide (386 mg, 0.92 mmol) in dichloromethane (5 ml) and diisoprbpylethylamine (0.17 ml, 1.00 mmol) were added and the mixture was stirred overnight at room temperature. The mixture was washed with water (20 ml), saturated aqueous sodium bicarbonate (20 ml), water (2×20 ml), brine (20 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (400 g) with ethyl acetate/heptan 1:1 to give 401 mg of ((3E)-4-(N-((1R)-1-(N-((1R)-1-dimethylcarbamoyl-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid 9H-flouren-9-ylmethyl ester. The obtained product was dissolved in 20% piperidine in dimethylformamide (10 ml) and stirred for 30 min. The mixture was chromatographed on silica (20 g) with dichloromethane/methanol/ammonia 89:10:1 to give 228 mg of (2E)-5-amino-5-methylhex-2-enoic acid N-((1R)-1-(N-((1R)-1-(dimethylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide as an oil. The product was redissolved in water (30 ml) and acetic acid (2 ml) was added and the mixture was lyophilized to give 645 mg of the acetate salt of the title compound as an amorphous powder.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16](I)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.CC1(C)C(C)(C)OB([C:49]2[CH:50]=[N:51][N:52]([CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=3)[CH:53]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[N:56]1[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=1[CH2:54][N:52]1[CH:53]=[C:49]([C:16]2[C:10]3[C:11](=[N:12][CH:13]=[C:8]([C:6]4[CH:7]=[CH:2][C:3]([CH:28]5[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35])[CH2:32][CH2:33]5)=[CH:4][CH:5]=4)[CH:9]=3)[N:14]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:19])=[O:20])[CH:15]=2)[CH:50]=[N:51]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(Cc3ccccn3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccn4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 39.1 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (intermediate 67B) (150 mg, 0.52 mmol) was coupled with 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridine (intermediate 64H) (180 mg, 0.63 mmol) using Pd(PPh3)2Cl2 (18 mg, 0.026 mol) and sodium carbonate (165 mg, 1.56 mmol) in toluene/ethanol/water (10/10/2 ml) to afford 140 mg (97.2% yield) of the titled compound. MS: m/z=688.4 (M+1).
Reaction SMILES: OC1C=CC(CNC(=O)C2C=CC(NC3C4N(C=CN=4)C(C4C=NNC=4)=CN=3)=CC=2)=CC=1.[Br:33][C:34]1[N:39]2[CH:40]=[CH:41][N:42]=[C:38]2[C:37](Br)=[N:36][CH:35]=1.[N:44]1([C:49]2[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=2)[CH:48]=[CH:47][N:46]=[CH:45]1.CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Br:33][C:34]1[N:39]2[CH:40]=[CH:41][N:42]=[C:38]2[C:37]([NH:55][C:52]2[CH:51]=[CH:50][C:49]([N:44]3[CH:48]=[CH:47][N:46]=[CH:45]3)=[CH:54][CH:53]=2)=[N:36][CH:35]=1
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: Brc1ncc(Br)n2ccnc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Brc1cnc(Nc2ccc(-n3ccnc3)cc2)c2nccn12

Procedure:
In the same way as described for Compound 90, step 1, using 5,8-dibromoimidazo[1,2-a]pyrazine (203.8 mg, 0.736 mmol), 4-imidazol-1-yl-phenylamine (117.7 g, 0.739 mmol), NaOtBu (99 mg, 1.03 mmol), Pd2(dba)3 (27.0 mg, 0.0295 mmol), Xantphos (34.1 mg, 0.0589 mmol) and toluene (10 mL). The crude material is purified by Isolute FlashSilicaII cartridge chromatography eluting with 99:1 DCM:NH3 (7M in MeOH), followed by 97:3 DCM/NH3 (7M in MeOH). The title compound is isolated, after a second column chromatography purification using a 5:5:1 mixture EtOAc-petroleum ether-MeOH, as a yellow solid (104 mg, 40%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:36]=[CH:37][CH:38]=1)[O:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([N:27]=[C:28]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[N:29]=2)[CH:26]=1>O1CCCC1.CN(C)C=O.O>[CH:33]1([C:31]([NH:30][C:28]2[N:29]=[C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]4[CH:18]=[C:17]([NH:16][C:7]([C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=5)=[O:9])[CH:38]=[CH:37][CH:36]=4)=[CH:26][N:25]3[N:27]=2)=[O:32])[CH2:34][CH2:35]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cn1cccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cccc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
To a solution of 1-methyl-1H-pyrrole-2-carboxylic acid (121 mg, 0.970 mmol) in tetrahydrofuran (5 mL) were added oxalyl chloride (169 μL, 1.94 mmol) and N,N-dimethylformamide (1 drop), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (3 mL). N-[6-(3-Aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.323 mmol) was added thereto with stirring under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate to give the title compound (56.0 mg, 14%) as a white solid.