Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]2[C:22](=[O:31])[NH:23][C:24]4[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15]3)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[B-](F)(F)(F)[F:33].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:33][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([CH2:11][N:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH2:7]3)[CH:13]=2)[NH:17][C:16]=1[C:21]1[C:22](=[O:31])[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: CS(=O)(=O)N1CCN(Cc2ccc3[nH]c(-c4cc5ccccc5[nH]c4=O)cc3c2)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(Cc2ccc3[nH]c(-c4cc5ccccc5[nH]c4=O)c(F)c3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-(5-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-indol-2-yl)quinolin-2(1H)-one (3-1, 60 mg, 1.37 mmol) was dissolved in 5 mL of anhydrous dimethylsolfoxide and diluted with 5 mL of anhydrous acetonitrile. The solution was cooled to 0° C., and the fluorinating reagent, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate, 3-2 (0.25 equiv., 12 mg, 0.03 mmol) was added. After addition, the ice bath was removed, and the reaction stirred at room temperature for 30 minutes. 3-2 was continually added in this fashion until half of the starting material was consumed. At which point, the reaction was diluted with ethyl acetate (150 mL) and partitioned with water (25 mL). The two layers were separated, and the organic layer was washed several times with water. The organic layer was condensed under vacuum. The crude residue was purified by reverse phase HPLC (5-95% ACN/H2O-40 minutes). The pure fractions were combined and volatiles were removed under reduced pressure. The resulting solution was partitioned with ethyl acetate (200 mL) and washed with 1 N NaOH (15 mL) and brine. The organic layer was dried with Na2SO4, filtered and condensed under vacuum. The resulting pure product was isolated as yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 12.3 (s, 1H), 11.3 (s, 1H), 8.47 (s, 1H), 7.83 (d, 1H, J=7.8 Hz), 7.58-7.52 (m, 2H), 7.46 (s, 1H), 7.39 (d, 1H, J=8.3 Hz), 7.26 (t, 1H, J=7.8 Hz), 7.13 (d, 1H, J=8.5 Hz), 3.60 (s, H), 3.11 (m, 4H), 2.87 (s, 3H), 2.48 (m, 4H).
Reaction SMILES: [O:1]=O.[CH2:3]([N:5]1[C:11]2[N:12]=[CH:13][C:14]([CH2:16][CH:17]=C)=[CH:15][C:10]=2[C:9](=[O:19])[N:8]([CH3:20])[C:7]2[CH:21]=[CH:22][C:23]([F:25])=[N:24][C:6]1=2)[CH3:4].[BH4-].[Na+].[NH4+].[Cl-]>C(Cl)Cl.CO>[CH2:3]([N:5]1[C:11]2[N:12]=[CH:13][C:14]([CH2:16][CH2:17][OH:1])=[CH:15][C:10]=2[C:9](=[O:19])[N:8]([CH3:20])[C:7]2[CH:21]=[CH:22][C:23]([F:25])=[N:24][C:6]1=2)[CH3:4]
Reactant: O=O
Reactant: C=CCc1cnc2c(c1)C(=O)N(C)c1ccc(F)nc1N2CC
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: CCN1c2ncc(CCO)cc2C(=O)N(C)c2ccc(F)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A stream of ozonised oxygen was bubbled through a cold (−78° C.) solution of 5,11-dihydro-11-ethyl-2-fluoro-5-methyl-8-(2-propenyl)-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (22.38 g, 71.6 mmol) in CH2Cl2 (100 mL) and MeOH (100 mL) for 3 h. A stream of N2 was next bubbled through the solution for 15 min and then solid NaBH4 (5.05 g, 133 mmol) was added to the solution. The reaction mixture was allowed to warm to room temperature. After 1 h, an additional portion of NaBH4 (1.62 g, 43.0 mmol) was added to the reaction mixture. After an additional hour, aqueous saturated NH4Cl (150 mL) was added and the mixture was stirred at room temperature for 30 min. The organic solvents were removed under reduced pressure. Water (200 mL) was added and the mixture was extracted with CHCl3 (3×300 mL). The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc:CHCl3, 4:1) to give the title compound (19.7 g, 72% yield) as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].C1COCC1.[CH2:12]([N:19]([CH2:28][C:29]([O:31]C)=O)[CH:20]([CH3:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:12]([N:19]1[CH2:28][C:29](=[O:31])[CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:20]1[CH3:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(C)N(CC(=O)OC)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1C(=O)CN(Cc2ccccc2)C1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
Potassium t-butoxide 1N in THF (17.5 ml, 17.5 mmol) was added to an ice cooled solution of ethyl 3-[benzyl(2-methoxy-2-oxoethyl)amino]butanoate (4.6 g, 15.6 mmol) in toluene (30 ml). The reaction was allowed to warm to room temperature and stir overnight. To this 1 N HCl (30 ml) was added, the reaction was stirred for 8 h, was neutralized with sodium carbonate and extracted with methylene chloride (3×75 ml). The combined organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give ethyl 1-benzyl-2-methyl-4-oxo-3-pyrrolidinecarboxylate (3.4 g, 83%) as an oil, MS (M+H)+=262.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1N.N([O-])=O.[Na+].S(=O)(=O)(O)N.[BrH:19]>O>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[Br:19]
Reactant: Cc1cccc(C)c1N
Reactant: Br
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C)c1Br
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To an initial charge of 65 ml of 48% aqueous HBr are added, in portions, 12.12 g [0.1 mol] of 2,6-dimethylaniline. The resulting thick suspension is stirred at 80° C. for 15 minutes. It is then cooled to −10° C., and a solution of 8 g [0.116 mol] of NaNO2 in 35 ml of water is added dropwise within approx. 1 h at such a rate that the temperature does not exceed −5° C. 80 mg of sulphamic acid are added. Then the suspension of the diazonium salt, cooled to −10° C., is metered within about 30 minutes into a solution, heated to 80° C., of 13.9 g [0.05 mol] of FeSO4×7H2O in 65 ml of 62% aqueous HBr. The reaction mixture is then stirred at 80° C. for another 1 hour, allowed to cool to room temperature and admixed with 125 ml of water, the phases are separated and the aqueous phase is extracted three times with 50 ml each time of methylene chloride. The combined organic phases are washed twice with 25 ml each time of water, dried and concentrated under reduced pressure. This gives 17.4 g of an oil which, according to GC, contains 83% 2,6-dimethylbromobenzene (78% of theory).
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[O:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[S:13]([Cl:12])(=[O:15])=[O:14])=[CH:8][N:9]=[CH:10]1
Reactant: c1ccc(-c2cnco2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccccc1-c1cnco1
Temperature: 70 °C

Procedure:
5-Phenyloxazole (2.0 g, mmol) in chloroform (50 ml) was cooled to 0° C. using an ice bath. Chlorosulfonic acid 4.8 g (2.7 ml, 3 eq) of was added slowly with stirring. The reaction mixture was heated to 70° C. for 16 h. The reaction mixture was then cooled to RT, quenched with ice and extracted with chloroform. The organic layer was washed with cold water, brine and concentrated. The brown solid obtained was purified by column chromatography using 5% ethyl acetate in pet ether as eluent, to yield a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH2:24][CH2:25][CH2:26][CH2:27][C:28](OCC)=[O:29].[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:27]([CH2:26][CH2:25][CH2:24][C:20]3[S:19][CH:23]=[CH:22][N:21]=3)[C:28]2=[O:29])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCCCc1nccs1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCc2nccs2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(2-thiazolyl)pentanoate (1.5 eq., prepared in Synthetic Example 24) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(thiazol-2-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 198 to 199° C./DMF, wherein the product was purified through flash column chromatography and recrystallization.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17]C(Cl)Cl>ClCCl>[C:1]([C:5]1[CH:14]=[C:13]([CH:16]=[O:17])[C:12]2[C:7]([C:6]=1[OH:15])=[CH:8][CH:9]=[CH:10][CH:11]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(Cl)Cl
Reactant: CC(C)(C)c1ccc2ccccc2c1O
Solvent: ClCCl
Product: CC(C)(C)c1cc(C=O)c2ccccc2c1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 43.8 %

Procedure:
To a 0° solution of 2-t-butyl-1-naphthol (7.6 g, 0.038 mole) in 50 ml of dry dichloromethane was added anhydrous stannic chloride (19.77 g, 0.076 mole). The resulting reaction mixture was stirred at 0° during the dropwise addition of 1,1-dichloromethyl methyl ether (7.75 g, 0.068 mole). The mixture was stirred for 10 minutes at 0° then poured into ice/water. The resulting mixture was extracted with diethyl ether (3×200 ml). The ethereal extracts were washed with water until the aqueous washes had a neutral pH and then dried over magnesium sulphate. The solvent was removed in vacuo to give a solid residue which was triturated with a mixture of diethyl ether: n-pentane (1:4) to give 3.8 g (44% yield) of a crystalline solid, m.p. 195°-196°.
Reaction SMILES: C(N[C:6](=[O:13])[C:7]([C:9]1([CH3:12])[CH2:11][CH2:10]1)=O)(C)(C)C.[NH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17].Cl.C(O)C>O>[NH2:14][N:15]1[C:6](=[O:13])[C:7]([C:9]2([CH3:12])[CH2:11][CH2:10]2)=[N:19][N:18]=[C:16]1[SH:17]
Reactant: NNC(=S)NN
Reactant: CC(C)(C)NC(=O)C(=O)C1(C)CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1(c2nnc(S)n(N)c2=O)CC1

Procedure:
183 g of (1-methylcyclopropyl)-glyoxylic acid tert-butylamide and 112 g of thiocarbohydrazide are added to a mixture of 1 liter of 1 N HCl and 1 liter of ethanol. The mixture is refluxed for 8 hours; it is subsequently cooled and diluted with 2 liters of H2O and the crystals are filtered off with suction. White crystals having a yellow lustre are obtained and these are dried.
Reaction SMILES: Cl[N:2]1[CH2:7][N:6]([NH:8][CH2:9][C:10]([CH3:28])([CH3:27])[CH2:11][C:12]2[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([OH:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=2)[CH2:5][N:4]([NH:29][CH2:30][C:31]([CH3:49])([CH3:48])[CH2:32][C:33]2[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([OH:43])=[C:35]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH:34]=2)[CH2:3]1.[CH2:50]([SH:62])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61].CC(C)=O.[OH-].[Na+]>O>[CH2:50]([S:62][N:2]1[CH2:7][N:6]([NH:8][CH2:9][C:10]([CH3:28])([CH3:27])[CH2:11][C:12]2[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([OH:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=2)[CH2:5][N:4]([NH:29][CH2:30][C:31]([CH3:49])([CH3:48])[CH2:32][C:33]2[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([OH:43])=[C:35]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH:34]=2)[CH2:3]1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]
Reactant: CC(C)(CNN1CN(Cl)CN(NCC(C)(C)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCCCCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCCSN1CN(NCC(C)(C)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CN(NCC(C)(C)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1
Reaction time: 5 h

Procedure:
10.0 g (0.014 mol) of 1-chloro-3,5-di-[3-(3,5-di-tert.butyl- 4-hydroxyphenyl)-2,2-dimethylpropylamino]-s-triazine (the product of Example 64) and 2.91 g (0.044 mol) of dodecylmercaptan are initially introduced into 50 ml of acetone and 0.58 g (0.0144 mol) of sodium hydroxide, dissolved in 1 ml of water, is added at room temperature. The mixture is then heated to the point of reflux and is stirred at this temperature for 5 hours It is then cooled, insoluble matter is filtered off and the filtrate is concentrated completely. The residue is purified through a silica gel column using toluene:methanol (98:2) as the migrating agent. The 1-dodecylmercapto-3,5-di-[3-(3,5-di-tert.butyl-4-hydroxyphenyl)-2,2-dimethylpropylamino]-s-triazine obtained in this way is produced as a yellowish resin. (Stabiliser No. 68).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]([NH:23][OH:24])=[NH:22])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][CH:13]1[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]1)[CH2:7]2.[Cl:25][CH2:26][C:27](Cl)=O.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[N:22]=[C:27]([CH2:26][Cl:25])[O:24][N:23]=2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][CH:13]1[CH2:14][CH2:15][C:16]([F:19])([F:20])[CH2:17][CH2:18]1)[CH2:7]2
Reactant: O=C(Cl)CCl
Reactant: N=C(NO)c1cc(Cl)c2c(c1)CN(CC1CCC(F)(F)CC1)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: O=C1c2c(Cl)cc(-c3noc(CCl)n3)cc2CN1CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-Chloro-N-hydroxy-1-oxo-2-[(4,4-difluorocyclohexyl)methyl]-2,3-dihydro-1H-isoindole-5-carboxamidine (450 mg, 1.26 mmol) in acetonitrile (10 ml), chloroacetyl chloride (170 mg, 1.51 mmol) was added, followed by K2CO3 (260 mg, 1.89 mmol). The mixture was stirred overnight. After diluter with EtOAc (20 ml), it was washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated to provide a yellow foam. This foam was stirred in DMF (2 ml) at 140° C. for 3 hours. After cooled to room temperature, it was diluted with water (5 ml). The product was extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated. The product was purified by column chromatography (40 to 60% EtOAc in hexanes) to yield the title compound as a white solid
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][CH3:35])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:34][CH3:35])[CH2:30][CH2:31]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COCCN1CCN(c2ccc(N)cc2C#N)CC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: COCCN1CCN(c2ccc(NC(=O)c3cnn(-c4ccc(Cl)cc4)c3C)cc2C#N)CC1
Yield: 47.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.8 g) and 5-amino-2-[4-(2-methoxyethyl)piperazin-1-yl]benzonitrile (0.8 g), the title compound (0.7 g) was obtained, melting point: 207° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:45])[C:20]4[C:21]([O:37][C:38]=3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:22]3[C:26](=[CH:27][CH:28]=4)[N:25](COCC[Si](C)(C)C)[N:24]=[CH:23]3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[NH2:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:45])[C:20]4[C:21]([O:37][C:38]=3[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[C:22]3[C:26](=[CH:27][CH:28]=4)[NH:25][N:24]=[CH:23]3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5c4cnn5COCC[Si](C)(C)C)c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]ncc54)c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a solution of (1-{-4-[4-oxo-2-phenyl-7-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-pyrano[2,3-e]indazol-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (67 mg, 0.13 mmol) in DCM (2.0 mL), was added TFA (500 μL, 6.7 mmol). The reaction mixture was stirred at RT for 1 hour. The solution was diluted with methanol (10 mL) and loaded onto an SCX-2 cartridge. The cartridge was washed repeatedly with methanol before elution with 2 M ammonia in methanol. The eluent was collected and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, gradient 7-10% methanol in DCM) to give the title compound as a light pink solid (25 mg, 47%). 1H NMR (400 MHz, DMSO-d6): δ 8.54 (d, J=1 Hz, 1H), 8.00 (d, J=9 Hz, 1H), 7.63 (dd, J=1 and 9 Hz, 1H), 7.52-7.49 (m, 2H), 7.44-7.34 (m, 5H), 7.17-7.14 (m, 2H), 2.41-2.33 (m, 2H), 2.11-2.03 (m, 2H), 2.03-1.92 (m, 1H), 1.70-1.60 (m, 1H). LCMS (Method E): RT=3.09 min, [M+H]+=407.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[CH2:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B1C2CCCC1CCC2.Br[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C=O)C.O.O.C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ccc(Br)cc1Cl
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
1-Boc-4-methylene piperidine (1.32 g, 6.70 mmol) was degassed (neat) for 15 minutes, and then treated with a THF solution of 9-BBN (0.5 M in THF, 13.5 mL, 6.75 mmol). The reaction mixture was refluxed for 2 h, then cooled to r.t. The reaction mixture was then added, via cannula, to a preformed solution consisting of 4-bromo-1,2-dichlorobenzene (1.49 mg, 6.64 mmol), Pd(dppf)Cl2 dichloromethane complex (148 mg, 0.181 mmol), and potassium carbonate (1.20 g, 8.68 mmol) in DMF/H2O (15 mL/1.5 mL). The resultant mixture was heated at 60° C. for 48 h, cooled to r.t., poured into water, basified to pH 11 with 1N NaOH, and extracted with EtOAc (3×). The organic layers were combined, dried (Na2SO4), and concentrated. The crude residue was purified (FCC) to give 4-(3,4-dichloro-benzyl)-piperidine-1-carboxylic acid tert-butyl ester (1.57 g, 69%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[C:47]([CH3:49])[N:46]=[C:45]([CH3:50])[CH:44]=2)=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:51])=[CH:38][C:39]([C:43]6[CH:44]=[C:45]([CH3:50])[N:46]=[C:47]([CH3:49])[CH:48]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2cc(C)c(Cl)c(C)c2)cc(C)n1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cc(C)nc(C)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(4-chloro-3,5-dimethyl-phenyl)-2,6-dimethyl-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.10 min; Mass spectrum (ESI+): m/z=552 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][C:35]=1[F:36])[NH:32][N:31]=[CH:30]2.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:32]3[C:33]4[C:29](=[CH:28][C:27]([F:26])=[C:35]([F:36])[CH:34]=4)[CH:30]=[N:31]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Fc1cc2cn[nH]c2cc1F
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(F)c(F)cc43)nc12
Temperature: 125 °C
Yield: 68.3 %

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 μmol) and 5,6-difluoro-1H-indazole (54.1 mg, 351 μmol) in dioxane (5.25 mL) was added sodium tert-butoxide (74.2 mg, 772 μmol) and bis(tri-tert-butylphosphine)palladium(0) (17.9 mg, 35.1 μmol). The mixture was degassed then heated in sealed tube at 125° C. for 15 h. The mixture was cooled, filtered through celite, the cake washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-tert-butyl-2-(5,6-difluoro-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 68%). 1H NMR (CDCl3) δ: 9.17 (s, 1H), 8.50 (d, J=2.5 Hz, 1H), 8.44 (dd, J=10.0, 6.8 Hz, 1H), 8.37 (s, 1H), 8.30 (s, 1H), 8.24 (d, J=0.8 Hz, 1H), 5.72 (s, 2H), 3.55-3.61 (m, 2H), 1.61 (s, 9H), 0.93-0.96 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([CH3:14])[C:7]=1[O:15][CH3:16])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]C(C)(C)C.[CH2:31]1[O:34][CH:32]1[CH3:33]>C1COCC1.CCCCCC.O>[OH:34][CH:32]([CH3:33])[CH2:31][C:11]1[C:6]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:17])=[C:7]([O:15][CH3:16])[C:8]([CH3:14])=[C:9]([O:12][CH3:13])[CH:10]=1
Reactant: COc1ccc(C(=O)NC(C)C)c(OC)c1C
Reactant: CC1CO1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(CC(C)O)c(C(=O)NC(C)C)c(OC)c1C
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
4.74 g (20 mmol, 1 eq.) of amide (IX) and 6.1 mL (40 mmol, 2 eq.) of TMEDA are dissolved in 200 mL of THF in a dried round-bottomed flask under argon. The medium is then placed at −78° C. 33.9 mL (44 mmol, 2.2 eq.) of t-BuLi (1.3M as a solution in hexane) are then added and the solution is immediately warmed to −15° C. Once the red/orange coloration has appeared, the medium is cooled to −78° C. 1.43 mL (20 mmol, 1 eq.) of propylene oxide are then added dropwise. Once the addition is complete, the medium is warmed rapidly to −10° C. The solution is then slowly warmed to room temperature over 1 hour 30 minutes. A second addition of propylene oxide (1 eq.) is made if necessary (monitoring of the conversion by TLC). After 30 minutes, the reaction is hydrolyzed by addition of 100 mL of water.
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([O:16][C:17]([F:20])([F:19])[F:18])[CH:10]=1.[ClH:21]>C(#N)C.[Cu](Cl)Cl>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([Cl:21])=[C:11]([O:16][C:17]([F:20])([F:19])[F:18])[CH:10]=1
Reactant: Cl
Reactant: Nc1ccc(Br)cc1OC(F)(F)F
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: FC(F)(F)Oc1cc(Br)ccc1Cl
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of tert-butyl nitrite (1.78 mL, 15.0 mmol), copper (II) chloride (1.61 g, 12.0 mmol) and 4-bromo-2-(trifluoromethoxy)aniline (2.56 g, 10.0 mmol) in acetonitrile (40 mL) was heated to 70° C., stirred for 3 hours, cooled to room temperature, poured into 0.5M HCl, and extracted with diethyl ether. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 275 (M+H)+.