Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][CH2:10][S:11][CH3:12])=[O:6])[CH:2]=[CH2:3].Cl.[C:17](=O)(O)[O-].[Na+]>CO>[CH3:17][O:14][C:13](=[O:15])[C@H:8]([CH2:9][CH2:10][S:11][CH3:12])[NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6]
Reactant: O=C([O-])O
Reactant: C=CCOC(=O)N[C@@H](CCSC)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N[C@@H](CCSC)C(=O)OC

Procedure:
A solution of 0.06 mol of N-(allyloxycarbonyl)methionine, prepared as described by H. Kunz and C. Unverzagt in Angew. Chem. Int. Ed. Engl., 1984, 23, 436-437, and 0.066 mol of HCl in 100 mL of CH3OH is stirred at reflux for 8 hours. The solution is then cooled and treated with 0.066 mol of sodium bicarbonate. The solvent is removed by rotary evaporator, and the residue is dissolved in diethyl ether, filtered, driedover MgSO4, and filtered. The solvent is removed by rotary evaporator to give N-(allyloxycarbonyl)methionine methyl ester.
Reaction SMILES: [CH3:1][C:2]([NH:14][C:15]1[C:16](=[O:41])[N:17]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[C@@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)[CH:19]=1)([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:3].C([BH3-])#N.[Na+]>C(O)(=O)C.C1COCC1>[CH3:3][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:28])([F:29])[F:30])[CH:21]=2)[N:17]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:40])[F:39])=[CH:35][CH:36]=2)[C:16]1=[O:41])([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([F:11])([F:13])[F:12])[N:5]=1)[CH3:1]
Reactant: CC(C)(NC1=C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1ccnc(C(F)(F)F)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(N[C@@H]1C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1ccnc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
Cool a solution of (R)-3-[1-methyl-1-(2-trifluoromethyl-pyrimidin-4-yl)-ethylamino]-1-(4-trifluoromethyl-phenyl)-5-(3-trifluoromethoxy-phenyl)-1,5-dihydro-pyrrol-2-one (7.5 g, 12.7 mmol) in acetic acid (60 mL) and THF (15 mL) to 0° C. and add sodium cyanoborohydride (1.60 g, 25.4 mmol). Remove the cooling bath after 5 minutes and stir 60 minutes at ambient temperature. Dilute the reaction mixture with ethyl acetate and slowly pour into saturated aqueous sodium bicarbonate solution. Separate the organic layer and concentrate under reduced pressure. Purify the residue by silica gel chromatography (15-40% ethyl acetate-hexane) to obtain (3R,5R)-3-[1-methyl-1-(2-trifluoromethyl-pyrimidin-4-yl)-ethylamino]-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (5.20 g, 69%) as a purple foam. To remove purple color, dissolve (3R,5R)-3-[1-methyl-1-(2-trifluoromethyl-pyrimidin-4-yl)-ethylamino]-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one in methanol (150 mL) and add activated carbon. Stir at ambient temperature for 20 min, filter, and concentrate under reduced pressure to give a white foam (4.6 g, 88%). 1H NMR (400 MHz, CDCl3): δ 8.79 (d, J=5.3 Hz, 1H), 7.90 (d, J=5.3 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H), 7.27 (t, J=7.9 Hz, 1H), 7.08 (d, J=7.9 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.98 (s, 1H), 5.04 (dd, J=6.2, 9.7 Hz, 1H), 3.51-3.45 (m, 1H), 2.90-2.81 (m, 1H), 1.89-1.81 (m, 1H), 1.56 (s, 3H), 1.50 (s, 3H). LC-MS ESI m/z: 593 (M+H)+, Tr=3.07 min., method 2.
Reaction SMILES: C(O)=O.Cl[C:5]1[CH:6]=[C:7]([N:12]2[CH2:16][CH:15](C)[C:14]([NH:18][CH:19]=[O:20])=[N:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]>O>[Cl:11][C:10]1[CH:5]=[CH:6][C:7]([N:12]2[CH:16]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:15][C:14]([NH:18][CH:19]=[O:20])=[N:13]2)=[CH:8][CH:9]=1
Reactant: CC1CN(c2ccc(Cl)c(Cl)c2)N=C1NC=O
Solvent: O
Solvent: O=CO
Product: O=CNC1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Reaction time: 2 h

Procedure:
A mixture of 15.0 g. of the above crude product and 85.0 ml. of a mixture of formic acid and acetic anhydride (Example 15) is allowed to remain at room temperature for 2 hours. The reaction mixture is poured into water and filtered to collect the solid. The solid is wahsed with a solution of saturated sodium bicarbonate, then water. The material is dried, dissolved in dichloromethane, then is columnized and recrystallized as above to give 12.0 g. of the desired product as pale yellow crystals. A 5.0 g. amount of this material is recrystallized as above to give 4.70 g. of the desired product, m.p. 164°-166° C.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.CN(C)CCN(C)C.CCCCCC.CN(C)[CH:32]=[O:33].[NH4+].[Cl-]>CCOCC>[CH:32]([CH:7]1[N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][C:3]2([CH2:2][CH2:1]2)[CH2:8]1)=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC2
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CC2)CC1C=O
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
tert-butyl 6-azaspiro[2.5]octane-6-carboxylate (Intermediate 2, 1 g, 4.73 mmol) dissolved in 20 ml of Et2O was cooled to −60° C., then N,N,N′,N′-tetramethyl ethylendiamine (0.71 ml, 4.73 mmol) and secBuLi 1.4M in hexane (4.05 ml, 5.68 mmol) were added. After 10 minutes at −60° C., the temperature was raised to −20° C. for 30 minutes, then the reaction was cooled to −78° C. and dimethylformamide (0.55 ml, 7.09 mmol, dissolved in 5 ml of Et2O) was added. After 30 minutes a saturated aqueous solution of NH4Cl (8 ml) was slowly added, then reaction was allowed to reach room temperature. Reaction was extracted with Et2O (3×50 ml), the organic solvent was dried (Na2SO4) and evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether/ethylacetate from 95/5 to 85/15). (±) tert-butyl 5-formyl-6-azaspiro[2.5]octane-6-carboxylate was obtained as light yellow solid (400 mg).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[N:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[C:10]([C:18]#[N:19])[C:11](=[O:17])[NH:12]2.[OH-:20].[NH4+]>C(O)(=O)C>[CH3:6][C:7]1[N:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[C:10]([C:18]([NH2:19])=[O:20])[C:11](=[O:17])[NH:12]2
Reactant: [OH-]
Reactant: Cc1nccc2[nH]c(=O)c(C#N)cc12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1nccc2[nH]c(=O)c(C(N)=O)cc12
Reaction time: 8 h

Procedure:
To 200 ml of concentrated sulfuric acid chilled in an ice bath was added with stirring 37 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile and the reaction mixture was allowed to stand at room temperature overnight. The reaction mixture was then poured on ice (1 liter beaker, half filled), the resulting mixture cooled in an ice bath and then neutralized by adding aqueous ammonium hydroxide, followed by addition of acetic acid to make the mixture slightly acidic. The separated solid was collected, washed with water, air-dried, then recrystallized from a large volume of dimethylformamide (1.2 1.) and dried at 95° C. to yield 28.4 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxamide, m.p.>320° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:29]([O:31]CC)=[O:30])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([NH:18][CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[OH:21])[CH3:17])=[CH:14][C:8]=2[O:7]1)=O)C.[CH2:34]([NH2:38])[CH2:35][CH2:36][CH3:37]>C(O)C>[CH2:34]([N:38]([CH2:14][CH2:8][CH2:9][CH3:11])[C:4]([C:6]1([C:29]([OH:31])=[O:30])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([NH:18][CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[OH:21])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:3])[CH2:35][CH2:36][CH3:37]
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2O1
Reactant: CCCCN
Solvent: CCO
Product: CCCCN(CCCC)C(=O)C1(C(=O)O)Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2O1

Procedure:
A mixture of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo-[1,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (2.4 g, 5 mmol) and n-butylamine (10 mL, excess) was refluxed in ethanol for 48 h. The reaction mixture was concentrated and the residue obtained was extracted with chloroform:methanol (3:1). It was washed with water and dried over anhydrous MgSO4. The organic layer was filtered and concentrated. The residue obtained was chromatographed over silica gel eluted with 9:1 chloroform:methanol to yield a brown semi solid; yield 1.6 g; 61%; M+H 532.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=[O:12])[CH2:2]1.Cl.[CH3:15]O>>[CH3:15][O:12][C:11]([C:3]1[CH2:2][O:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:13]
Reactant: O=C(O)C1=Cc2ccccc2OC1
Reactant: CO
Agent: Cl
Product: COC(=O)C1=Cc2ccccc2OC1

Procedure:
Compound 16B (5 g) and concentrated HCl (2 mL) in MeOH (200 mL) were heated to reflux for 30 h. The reaction mixture was quenched with water (200 mL) and ether (200 mL). Separated the organic layer, washed with water, brine, dried (MgSO4), concentrated to give an off-white solid, compound 16C (4.2 g). mp 56-57° C.; MS: 191 (M+1)+. Preparation of 6-Chlorosulfonyl-2H-chromene-3-carboxylic acid methyl ester (Compound 16D)
Reaction SMILES: [CH:1]([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])=[O:17])([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:17])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccccc1NC(=O)CCCCCCCCCCCSC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)SCCCCCCCCCCCC(=O)Nc1ccccc1OCCCC(=O)O
Yield: 17.1 %

Procedure:
A stirred solution of ester (7) (0.124 g, 0.258 mM) in methanol (10 mL) was treated at room temperature under a nitrogen atmosphere with 2.5N sodium hydroxide solution (0.6 mL). Methanol (2×2 mL) was used to clear the mixture, and the reaction allowed to continue until TLC analysis showed no ester remained. The filtered mixture was concentrated in vacuo and the residue obtained stirred with water (30 mL). After aging, the mixture was filtered (The cake is the sodium salt of the product (100 mg), and the stirred filtrate acidified with dilute hydrochloric acid, aged, filtered, washed with water and dried to give product 8 (0.02 g) as a white solid. M.P. 82°-84° C., with softening from 66° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:18][N:19]([CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[CH3:20].CO.N>C(O)CCC>[CH3:20][N:19]([CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=3[CH3:16])[CH:5]=[CH:4][N:3]=2)=[CH:30][CH:31]=1)[CH3:18]
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Reactant: Cc1ccc(C)c(Nc2ccnc(Cl)n2)c1
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCCCO
Product: Cc1ccc(C)c(Nc2ccnc(Nc3ccc(OCC(O)CN(C)C)cc3)n2)c1
Temperature: 100 °C
Yield: 23.9 %

Procedure:
2-Chloro-4-(2,5-dimethylanilino)pyrimidine (Reference Example A-1; 250 mg, 1.07 mmol) was dissolved in n-butanol (5 ml) and 4-[3-(N,N-dimethyl)amino-2-hydroxypropoxy]aniline hydrochloride (Reference Example D-1; 295 mg, 1.07 mmol) was added. The resulting suspension was treated with methanol until all the solid dissolved. The reaction mixture was heated at 100° C. for 8 hours and allowed to cool to ambient temperature. The reaction mixture was then basified to pH 9–10 using methanolic ammonia and then evaporated onto silica (5 ml). The residue was purified by column chromatography eluting with methanol (15%):DCM:aqueous ammonia (1%). The resulting gum was recrystallized from acetonitrile to give the title product as a solid (104 mg, 24%). NMR (300 MHz): 2.13 (s, 3H), 2.25 (s, 3H), 2.79 (s, 6H), 3.19 (m, 2H), 3.88 (m, 2H), 4.21 (m, 1H), 5.88 (brs, 1H), 6.05 (d, 1H), 6.73 (d, 2H), 6.93 (d, 1H), 7.12 (d, 1H), 7.26 (s, 1H), 7.55 (d, 2H), 7.9 (d, 1H), 8.6 (s, 1H), 8.88 (s, 1H); m/z: (ES+) 408.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[OH-].[Na+]>C(O)C.C1(C)C=CC=CC=1.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>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:10]2[NH:11][C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:31]4[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)=[CH:3][CH:4]=3)[N:9]=2)=[CH:20][CH:21]=1
Reactant: Clc1ccc(-c2nc(-c3ccc(Br)cc3)c(-c3ccncc3)[nH]2)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc(-c3nc(-c4ccc(Cl)cc4)[nH]c3-c3ccncc3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of 60 mg (0.146 mmol) of 4-(4-bromophenyl)-2-(4-chlorophenyl)-5-(4-pyridyl)imidazole (from Step C) in 1 mL of ethanol and 1.5 mL of toluene was added 56 mg (0.365 mmol) of 4-methoxybenzeneboronic acid, followed by 0.73 mmol (584 μL of a 1.25 N solution) of aqueous NaOH, and 17 mg (0.146 mmol) of tetrakis(triphenylphosphine)palladium(0). The resulting reaction mixture was stirred at 90° C. overnight. After being cooled to room temperature, the reaction was quenched by addition of water and extracted with ethyl acetate twice. The organic layers were combined, washed with water and brine, and dried over sodium sulfate. After filtration and removal of volatiles, the crude product was flash chromatographed over silica gel (gradient elution using 20-50% EtOAc in hexane). This material appeared to be homogeneous by TLC but contained some uncoupled material as shown by HPLC trace. Therefore, it was further purified via a chromatotron, eluting slowly using a 5:95:0.5 mixture of methanol/DCM/HOAc to provide 16 mg of the desired product as a pale yellow solid, homogeneous by TLC, mass spectrum (CI) m/e 438 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH3:9])=[C:7]([C:10]([NH2:12])=[O:11])[O:6][N:5]=1)[CH3:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH:18]=[N:12][C:10]([C:7]1[O:6][N:5]=[C:4]([O:3][CH2:1][CH3:2])[C:8]=1[CH3:9])=[O:11])[CH3:17]
Reactant: COC(OC)N(C)C
Reactant: CCOc1noc(C(N)=O)c1C
Product: CCOc1noc(C(=O)N=CN(C)C)c1C

Procedure:
A solution of 3-ethoxy-4-methylisoxazole-5-carboxamide (3.5 g, 21 mmol) in N,N-dimethylformamide dimethyl acetal (15 mL) was stirred at 120° C. for 15 min. After being cooled, the title compound was collected as a colourless crystals (4.2 g, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][CH2:12][Mg+].[Br-].B(F)(F)F.CCOCC>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]1([NH2:5])[CH2:12][CH2:11]1
Reactant: N#Cc1cc(Cl)ccc1Br
Reactant: CC[Mg+]
Agent: FB(F)F
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC1(c2cc(Cl)ccc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.6 %

Procedure:
To a stirred solution of 2-bromo-5-chlorobenzonitrile (10 g, 46 mmol) and Ti(Oi-Pr)4 (16.64 mL, 55 mmol) in THF (200 mL) at −78° C. was added EtMgBr (138 mL, 138 mmol) dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 2 hours. BF3-Et2O (17.2 mL) was added, and the solution was stirred for another 16 hours before it was quenched with aq. HCl solution and washed with EtOAc. The aqueous phase was adjusted to pH˜10 with aq. NaOH solution, and exacted with EtOAc (3×). The combined organic layers were concentrated to give a crude product which was purified by chromatography to afford title compound (2 g, yield 17.6%). MS: 246.7 (M+H+, 1C1) as oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[F:34][C:35]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[CH:37][C:36]=1[N:50]1[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:34][C:35]1[CH:40]=[C:39]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[N:13][N:14]([CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=5)[CH:15]=4)=[CH:9][N:8]([S:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=4)(=[O:25])=[O:26])[C:5]3=[N:6][CH:7]=2)[CH:38]=[CH:37][C:36]=1[N:50]1[CH2:51][CH2:52][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:54][CH2:55]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 68.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (160 g, 0.304 mmol) was coupled with tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (intermediate 69) (216 mg, 0.530 mmol) using sodium carbonate (97 mg, 0.912 mmol) and Pd(PPh3)2Cl2 (11 mg, 0.015 mmol) in DME/water (5/2 mL). This afforded 150 mg (68.10% yield) after purification by column (Silica gel 60/120) using 25% ethyl acetate in hexane as eluent. MS: m/z=725.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH3:10])[CH:3]=1.[C:11]1(O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CO
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Br)ccc1COc1ccccc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 46.2 %

Procedure:
To a solution of (4-bromo-2-methylphenyl)methanol (1 g, 5 mmol), phenol (525 mg, 5.6 mmol) and triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0° C. The mixture was stirred at 20° C. for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give 4-bromo-2-methyl-1-(phenoxymethyl)benzene (640 mg, 46%).
Reaction SMILES: CC([N:5]([C@H:9]([CH3:29])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2[CH3:28])=[CH:15][CH:14]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[O:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:29])[NH2:5])=[CH:14][CH:15]=1
Reactant: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N)cc2)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 114.4 %

Procedure:
1,1-dimethylethyl{(1R)-1-methyl-2-[(4-{[2-methyl-5-(methyloxy)phenyl]oxy}phenyl)amino]-2-oxoethyl}carbamate (Intermediate 15, 150 mg) was dissolved in 3 mL of dry dichloromethane. To this solution at 0° C. under argon was added dropwise 30 equivalents of TFA (0.866 mL, 11.24 mmol). The reaction was stirred at 0° C. for 4 hours. The reaction mixture was evaporated. The residue obtained was purified with an SCX cartridge (the cartridge was washed with 3 CV of methanol, then the compound was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N)). Evaporation of the volatiles, afforded the title compound (129 mg).
Reaction SMILES: [O:1]=[C:2]([CH3:34])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[C:8]([NH:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([NH:21][C:22]([C:24]4[CH:29]=[N:28][CH:27]=[C:26]([CH3:30])[N:25]=4)=[O:23])([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:9].[CH3:35][Mg+].[Br-]>C1COCC1.CCOCC>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[C:8]([NH:10][C:11]12[CH2:18][CH:17]3[CH2:16][CH:15]([CH2:14][C:13]([NH:21][C:22]([C:24]4[CH:29]=[N:28][CH:27]=[C:26]([CH3:30])[N:25]=4)=[O:23])([CH2:19]3)[CH2:12]1)[CH2:20]2)=[O:9]
Reactant: CC(=O)COc1cccc(C(=O)NC23CC4CC(C2)CC(NC(=O)c2cncc(C)n2)(C4)C3)c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cncc(C(=O)NC23CC4CC(CC(NC(=O)c5cccc(OCC(C)(C)O)c5)(C4)C2)C3)n1

Procedure:
Reaction of 6-methyl-pyrazine-2-carboxylic acid {3-[3-(2-oxo-propoxy)-benzoyl-amino]-adamantan-1-yl}-amide with MeMgBr in THF or ether at 0° C. could yield the title compound, 6-methyl-pyrazine-2-carboxylic acid {3-[3-(2-hydroxy-2-methylpropoxy)-benzoylamino]-adamantan-1-yl}-amide.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH2:25])[N:19]=1>CN(C=O)C>[NH2:25][C:20]1[N:21]=[C:22]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:10]=3)[C:6]([C:11]([OH:14])([CH3:12])[CH3:13])=[N:7]2)[C:23]([Cl:24])=[CH:18][N:19]=1
Reactant: Nc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(O)c1n[nH]c2cc(I)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(O)c1nn(-c2nc(N)ncc2Cl)c2cc(I)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(6-iodo-1H-indazol-3-yl)propan-2-ol (300 mg, 0.99 mmol) in dry DMF (10 mL) at 0° C. under an atmosphere of nitrogen was introduced sodium hydride (63 mg of a 60% dispersion in mineral oil, 1.59 mmol). After 20 minutes at this temperature, 4,5-dichloropyrimidin-2-amine (326 mg, 1.99 mmol) was added and the solution warmed to RT for 10 minutes, then to 65° C. for 18 hr. Following cooling to RT, the reaction mixture was re-treated with additional sodium hydride (24 mg of a 60% dispersion in mineral oil) then warmed to 75° C. under nitrogen for 6 hr. The reaction mixture was cooled to RT, quenched carefully with water (20 mL) and extracted with EtOAc (2×20 mL extractions). The organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by silica gel flash column chromatography (4:1 to 1:1 heptane/EtOAc gradient) furnished the title compound as an off-white solid: 1H NMR (500 MHz, CDCl3) delta 1.79 (6H, s), 5.19 (2H, br. s.), 7.61 (1H, dd, J=8.35, 1.42 Hz), 7.76 (1H, d, J=8.51 Hz), 8.42 (1H, s), 8.64 (1H, d, J=0.95 Hz); LC-MS: m/z=+429.90/431.65 (M+H)+.