Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N+:5]1[CH2:9][CH2:8][CH2:7][C:6]=1OC)([CH3:4])([CH3:3])[CH3:2].COS([O-])(=O)=O.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][C:24]#[N:25])=[CH:21][CH:20]=1.[Na]>C(O)C>[C:1]([N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[C:23]([C:24]#[N:25])[C:22]1[CH:26]=[CH:27][C:19]([Cl:18])=[CH:20][CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: COC1=[N+](C(C)(C)C)CCC1
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: CCO
Product: CC(C)(C)N1CCCC1=C(C#N)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 20 %

Procedure:
Heat 56.8 g of 1-tert.-butyl-2-methoxy-1-pyrrolinium-methylsulfate and 30.3 g of 4-chlorobenzylcyanide to 80°. Add thereto (dropwise, within 2 hours, with stirring) a solution of 8.1 g of sodium in 160 ml of ethanol. After completion of the addition, boil the prepared admixture for a further 2 hours. Concentrate the boiled admixture and distil off (at 10-3 mm of Hg) the excess 4-chlorobenzylcyanide. Recrystallize the resulting residue from 170 ml of ethanol to obtain 11 g of the title compound. Concentrate the mother liquor to obtain a further 2.5 g (24% of theory) of the title compound in the form of light-brown crystals of m.p. 150° to 153°.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[CH2:26][CH2:27][O:28][CH2:29][CH:30]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].C([O-])=O.[NH4+].C1COCC1.CO>[Pd].O.C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([CH:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)[OH:11]
Reactant: O=C(c1ccc(Oc2nccnc2C2=CCOCC2)cc1)c1nc2ccccc2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccc(Oc2nccnc2C2CCOCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 75 °C
Reaction time: 5 h

Procedure:
A 1 L heavy wall vessel equipped with a magnetic stir bar flask was charged with (1H-benzo[d]imidazol-2-yl)(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone (1.00 g, 2.26 mmol), ammonium formate (3.16 g, 50 mmol), THF (125 mL) and MeOH (125 mL). Nitrogen was bubbled into the mixture for 15 mins. The mixture was kept under nitrogen and treated with Pd/C (0.267 g, 0.251 mmol). The vessel was capped and the reaction was stirred at 75° C. After 5 hours, the reaction was cooled down to RT. An aliquot was analyzed via LC-MS showed the reaction was incomplete. The reaction was filtered through celite and the filtrate was transferred back to the reaction vessel. An additional 4.15 g of ammonium formate and 0.350 of 10% Pd/C was added to the reaction under nitrogen. The vessel capped again and heated to 75° C. overnight. The reaction was cooled down and filtered through a pad of celite. The filtrate was reduced under vacuum. The residue obtained was portioned with DCM and water. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate reduced. The volatiles were removed under vacuum. The residue obtained was triturated with hot MeOH, filtered and dried in a vacuum oven to give (1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanol as a white solid. [M+1] 402.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.O1CCOCC1.[CH3:18][NH2:19].CO>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:19][CH3:18]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CN
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
To a round bottom flask was added 4-bromo-2-fluoro-1-nitrobenzene (11.8 g, 53.7 mmol), anhydrous 1,4 Dioxane (100 mL), and a 2.0 M solution of methyl amine in methanol (56.4 mL, 113 mmol). The reaction mixture was then heated to 90° C. while stirring in a hot oil bath with a water cooled reflux condenser attached under an atmosphere of nitrogen for 3.5 hours. The crude reaction mixture was then allowed to cool to room temperature, and concentrated to give 5-bromo-N-methyl-2-nitroaniline (1-1). MS (M)+: observed=230.9, calculated=231.05.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.C(NCC)C>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Solvent: CCNCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 193.5 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (8 ml) is added to the bottle, and diethylamine (9.6 ml) is added thereto at the temperature within 20 min, the above mixture is reacted at the temperature for 0.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50 for 5 h to obtain solid purin (12.3 g). The yield is about 75.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([OH:26])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:27][CH2:28][C:29]#[N:30])[C:10]=2[CH:9]=1.[N:31]([Sn](C)(C)C)=[N+:32]=[N-:33]>C1(C)C=CC=CC=1.CN(C)C=O.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([OH:26])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:27][CH2:28][C:29]3[NH:33][N:32]=[N:31][N:30]=3)[C:10]=2[CH:9]=1
Reactant: N#CCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1c2c2cc(O)ccc2n1CCc1nnn[nH]1
Yield: 72.2 %

Procedure:
To a solution of nitrile (238) (0.68 g, 1.63 mmol) prepared as described in example 98 in toluene/dimethylformamide (5:1, 120 mL) was added azidotrimethyl tin (0.67 g, 3.26 mmol). The resulting solution was heated at reflux for 24 hours before a further portion of azidotrimethyl tin (0.34 g, 1.63 mmol) was added. After a further 24 hours at reflux the reaction was diluted with water and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetatelhexane (3:1) to ethyl acetate/methanol (9:1), followed by crystallization from ethyl acetate/hexane, gave tetrazole (272) (0.54 g, 72%) as an orange powder, mp 230–234° C. (dec). 1H NMR δ [(CD3)2SO] 11.06 (br s, 1H), 9.37 (br s, 1H), 8.36 (d, J=2.4 Hz, 1H), 7.61 (s, 1H), 7.56 (m, 1H), 7.48 (m, 4H), 7.10 (dd, J=8.8, 2.4 Hz, 1H), 4.82 (t, J=6.9 Hz, 2H), 3.32 (obscured t, J=6.9 Hz, 2H). Found: C, 52.69; H, 4.05; N, 15.91. C23H15ClN6O3.31/2H2O requires: C, 52.93; H, 4.25; N, 16.09.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>CC(C)=O>[C:34]([O:33][C:31](=[O:32])[CH2:30][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:7]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)CCCC1CNc2cccc([N+](=O)[O-])c21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCC1CN(CC(=O)OC(C)(C)C)c2cccc([N+](=O)[O-])c21
Temperature: 25 °C

Procedure:
To a solution of ethyl 4-(4-nitro-2,3-dihydro-1H-indol-3-yl)butanoate from Step B (1.10 g, 3.95 mmol), sodium carbonate (628 mg, 5.93 mmol), and potassium iodide (131 mg, 0.79 mmol) in acetone (10 mL) was added tert-butyl bromoacetate (17.5 mL, 119 mmol). The mixture was heated at reflux for 18 h, then cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between H2O (30 mL) and EtOAc (2×60 mL) and the organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 65:35, to give the title compound. MS: m/z=393 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:22]=[CH:21][C:13]2[O:14][C:15]([CH3:20])([CH3:19])[C:16]([CH3:18])=[CH:17][C:12]=2[CH:11]=1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C.ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:22]=[CH:21][C:13]2[O:14][C:15]([CH3:19])([CH3:20])[C:16]([CH3:18])=[CH:17][C:12]=2[CH:11]=1
Reactant: COc1ccccc1Sc1ccc2c(c1)C=C(C)C(C)(C)O2
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CC1=Cc2cc(Sc3ccccc3O)ccc2OC1(C)C
Temperature: 150 °C
Yield: 35.9 %

Procedure:
6-(2-Methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (3.5 g) (see Preparation 7) was dissolved in dry 2,4,6-collidine (15 ml), anhydrous lithium iodide (9.0 g) was added and the mixture was heated at 150° C. for 40 hours. After cooling, the mixture was taken up in dichloromethane and washed with 2N aqueous hydrochloric acid solution (×3). The organic layer was dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the residue was chromatographed on silica using 1:1 hexane: dichloromethane as the eluent to yield 6-(2-hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (1.2 g) as an oil.
Reaction SMILES: Cl[C:2]1[NH:11][C:5]2=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=[C:4]2[N:3]=1.[NH:12]1[CH2:17][CH2:16][C:15]2([C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[O:18]2)[CH2:14][CH2:13]1.O>CN1C(=O)CCC1>[Cl:10][C:7]1[N:6]=[C:5]2[NH:11][C:2]([N:12]3[CH2:17][CH2:16][C:15]4([C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19](=[O:26])[O:18]4)[CH2:14][CH2:13]3)=[N:3][C:4]2=[CH:9][CH:8]=1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Reactant: Clc1ccc2nc(Cl)[nH]c2n1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1OC2(CCN(c3nc4ccc(Cl)nc4[nH]3)CC2)c2ccccc21

Procedure:
Heat a solution of 2,5-dichloro-3H-imidazo[4,5-b]pyridine (0.07 g, 0.37 mmol) and spiro[isobenzofuran-1,4′-piperidin]-3-one (0.15 g, 0.74 mmol) in dry NMP (3 mL) at 100° C. for 14 hours. Pour the cooled mixture into water (10 mL) and extract twice with EtOAc (10 mL). Wash the combined extracts with brine (10 mL), dry, and evaporate in vacuo. Purify by preparative TLC (5% MeOH—CH2Cl2) to obtain 1′-(5-chloro-3H-imidazo[4,5-b]pyridine-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]=O)[CH3:2].Cl.[NH2:11]O>O>[CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]#[N:11])[CH3:2]
Reactant: NO
Reactant: CCn1cccc1C=O
Agent: Cl
Solvent: O
Product: CCn1cccc1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.8 %

Procedure:
1-Ethylpyrrole-2-carbaldehyde (cf. J. Chem. Soc. (C), 2563, 1970) (7.4 g, 60 mmole), hydroxylamine hydrochloride (4.8 g, 69 mmole) sodium acetate trihydrate (9.4 g, 69 mmole) and water (30 ml) are mixed, and the mixture is stirred at room temperature for 20 minutes and then allowed to stand in a cooled place overnight. The precipitated oxime compound is taken by filtration and dried. The oxime compound is refluxed in acetic anhydride (25 ml) for 20 minutes and then allowed to cool until room temperature. The reaction mixture is added to ice water, and the mixture is stirred for 2 hours and neutralized with sodium carbonate and extracted with ether twice. The ether layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is distilled under reduced pressure to give 1-ethylpyrrole-2-carbonitrile (5.25 g, yield: 73%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6](F)=[C:7]([C:9](=O)[CH3:10])[CH:8]=1)#[N:2].Cl.[OH:14][NH2:15].[OH-].[Na+]>CO.CN(C=O)C.[Cl-].[Na+].O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:14][N:15]=[C:9]([CH3:10])[C:7]=2[CH:8]=1)#[N:2]
Reactant: CC(=O)c1cc(C#N)ccc1F
Reactant: NO
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: Cc1noc2ccc(C#N)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5′-cyano-2′-fluoroacetophenone (500 mg, 3.06 mmol) in MeOH (5 mL) was added hydroxyamine HCl salt (223 mg, 3.22 mmol) and sodium hydroxide (129 mg, 3.22 mmol). The reaction mixture was stirred at room temperature for 0.5 h and concentrated in vacuo to afford a solid product. This solid was added to a suspension of sodium hydroxide (147 mg, 3.68 mmol) in DMF (5 mL) at 0° C. After 0.5 h the reaction mixture was warmed to room temperature for 4 h and poured into cold brine. The mixture was extracted with ethyl acetate, the organic layer was dried over MgSO4, and concentrated in vacuo to provide a residue. Purification via flash column chromatography (15×150 mm column; gradient elution with MeOH:CH2Cl2:CH2Cl2 saturated with NH3, 5:65:30 to 10:60:30 300 mL each) afforded of a solid:
Reaction SMILES: [CH:1]([C:3](=[C:8]([CH3:10])[CH3:9])[CH2:4][C:5]([OH:7])=[O:6])=[O:2].CCOCC.[Cl-:16].[Li+].Cl>O>[Cl:16][C:8]([C@H:3]1[C@H:1]([OH:2])[O:6][C:5](=[O:7])[CH2:4]1)([CH3:10])[CH3:9]
Reactant: CC(C)=C(C=O)CC(=O)O
Reactant: [Cl-]
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(Cl)[C@@H]1CC(=O)O[C@H]1O
Temperature: 25 °C
Reaction time: 54 h

Procedure:
A mixture of 1 g of 3-formyl-4-methyl-pent-3-ene-1-oic acid, 25 ml of anhydrous ether and 1 g of lithium chloride was stirred under a current of gaseous hydrogen chloride at -30° C. for 2 hours and then for 2 hours at 0° C. after which the gaseous hydrogen chloride was shut off. The mixture was stirred at room temperature for 48 hours and after 54 hours of contact, the mixture was poured into iced water. The decanted aqueous phase was extracted with benzene and the organic phase was dried and evaporated to dryness under reduced pressure. The 1.1 g of residue was chromatographed over silica gel and was eluted with a 1-1 benzene-ethyl acetate mixture to obtain 545 mg of crystalline (dl trans 4-(2-chloro-prop-2-yl)-5-hydroxy-tetrahydrofuran-2-one melting at 80° C.
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:5]([CH:6]=O)=[C:4]([O:15][CH3:16])[CH:3]=1.[C:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)(=[O:19])[CH3:18].C[O-].[Li+].Cl>CN(C)C=O.CO.O.C(O)C>[OH:1][C:2]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:5](/[CH:6]=[CH:18]/[C:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[O:19])=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(O)c(-c2cccs2)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(O)c(-c2cccs2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.1 %

Procedure:
4-Hydroxy-2-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-47B, 0.30 g, 0.86 mmol) and 4-acetylbenzoic acid (0.13 g, 0.86 mmol) were dissolved in a dimethylformamide-methanol solution (6 mL, 7:3). After complete dissolution, lithium methoxide (0.12 g, 3.3 mmol) was added and the resulting red slurry was stirred in the dark at room temperature for 18 h. The mixture was diluted with water (15 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (4×25 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was subjected to silica gel chromatography (CH2Cl2:MeOH, 20:1) to yield an orange solid containing residual amounts of starting acid. The solid was taken up in ethyl alcohol (5 mL) to remove acid impurity and the resulting precipitate was collected on filter paper and dried in vacuo to yield 0.010 g (5%) of the title compound as an orange solid, mp 243° C. (dec). 1H-NMR (300 MHz, DMSO-d6) δ 8.18–8.23 (m, 3H), 8.06–8.09 (m, 2H), 8.02 (s, 1H), 7.85 (d, 1H, J=15.6 Hz), 7.68 (d, 1H, J=3.6 Hz), 7.47 (d, 1H, J=5.1 Hz), 7.11 (dd, 1H, J=5.1, 3.6 Hz), 6.67 (s, 1H), 4.13 (s, 1H), 3.89 (s, 3H). MS (ESI) m/z=381 ([M+H]30 , 100%). HRMS (ESI) Calcd. for C21H16O5S: 381.0796. Found: 381.0800.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:34][C:35]1[CH:43]=[C:42]2[C:38]([C:39]([C:45]3[N:46]=[C:47]4[C:53]([C:54](O)=[O:55])=[CH:52][N:51]([CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:64])([CH3:63])[CH3:62])[C:48]4=[N:49][CH:50]=3)=[N:40][N:41]2[CH3:44])=[CH:37][CH:36]=1.[NH2:65][CH:66]([CH3:75])[CH:67]([CH:69]1[CH2:74][CH2:73][O:72][CH2:71][CH2:70]1)[OH:68].C([O-])(O)=O.[Na+]>CCOC(C)=O.CN(C=O)C>[OH:68][CH:67]([CH:69]1[CH2:70][CH2:71][O:72][CH2:73][CH2:74]1)[CH:66]([NH:65][C:54]([C:53]1[C:47]2[C:48](=[N:49][CH:50]=[C:45]([C:39]3[C:38]4[C:42](=[CH:43][C:35]([F:34])=[CH:36][CH:37]=4)[N:41]([CH3:44])[N:40]=3)[N:46]=2)[N:51]([CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:63])([CH3:62])[CH3:64])[CH:52]=1)=[O:55])[CH3:75]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CC(N)C(O)C1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(O)C1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a 100 mL round-bottomed flask, HBTU (112 mg, 0.29 mmol), Hunig's base (0.20 ml, 1.13 mmol) and 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.23 mmol) were combined with DMF (3.0 ml) to give a light yellow solution. 2-Amino-1-(tetrahydro-2H-pyran-4-yl)propan-1-ol (72 mg, 0.45 mmol) was added and the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with EtOAc. The reaction mixture was poured into 50 mL sat NaHCO3 and extracted with EtOAc (2×50 mL). The organic layers were combined and washed with H2O (2×50 mL) then dried over MgSO4 and concentrated in vacuo to provide the crude material. The product was purified by flash chromatography (silica gel, 80 g, 20% to 50% EtOAc in hexanes) to provide 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [2-hydroxy-1-methyl-2-(tetrahydro-pyran-4-yl)-ethyl]-amide as two discreet diastereomers (arbitrarily assigned). Diastereomer A (30 mg, 22%) as a white powder: 1H NMR (300 MHz, CDCl3) δ ppm 9.20 (m, 1H), 8.68 (dd, J=8.69, 5.29 Hz, 1H), 8.41 (d, J=9.44 Hz, 1H), 8.27 (s, 1H) 6.96-7.13 (m, 2H) 5.70 (s, 2H) 4.54-4.67 (m, 1H) 4.06-4.20 (m, 4H) 3.87-4.04 (m, 2H) 3.56-3.65 (m, 2H) 3.42 (d, J=6.80 Hz, 1H) 3.21-3.39 (m, 2H), 2.53 (d, J=4.15 Hz, 1H) 1.85 (d, J=12.84 Hz, 2H) 1.76 (ddd, J=11.52, 7.93, 3.97 Hz, 1H), 1.33-1.56 (m, 5H), 0.75-1.04 (m, 2H), −0.05 (s, 9H). Diastereomer B (70 mg, 53%) as a white powder: 1H NMR (300 MHz, CDCl3) δ ppm 9.21 (s, 1H) 8.42-8.61 (m, 2H) 8.27 (s, 1H) 6.96-7.15 (m, 2H) 5.51-5.76 (m, 2H) 4.40-4.64 (m, 1H) 3.93-4.24 (m, 3H) 3.62-3.83 (m, 2H) 3.50-3.62 (m, 2H) 3.26-3.50 (m, 2H) 2.70 (d, J=5.29 Hz, 1H) 1.92-2.10 (m, 2H) 1.14-1.84 (m, 5H) 0.67-1.07 (m, 2H) −0.33-0.16 (m, 9H).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(C)c1F
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 2-fluoro-3-methylbenzoic acid (12.4 g, 80.2 mmol) in methanol (100 mL) at 0° C. was added thionyl chloride (14 g, 120.3 mmol) dropwise. The reaction mixture was stirred at reflux until complete by TLC (1-2 h). After cooling to room temperature, the mixture was partitioned between sat. NaHCO3 and ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and concentrated to give methyl 2-fluoro-3-methylbenzoate as a yellow oil (13.8 g, 100%): 1H NMR (300 MHz, CDCl3) δ 7.74 (t, J=8.1 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 3.90 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.CCOCC>C1(C)C=CC=CC=1.C(O)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.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([F:27])[CH:33]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1cccc(F)c1
Yield: 70.7 %

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.335 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.03 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 3-fluorophenylboronic acid (0.210 g) in ethanol (1 ml). The mixture was heated under reflux for 6 hours, cooled and then poured into ether (25 ml) and water (25 ml). The organic layer was separated, washed with water (25 ml), brine (25 ml) and then dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (50 g) eluted with dichloromethane:ethanol (99:1). Combination and evaporation of suitable fractions gave a pale yellow solid (0.22 g) which was further purified by HPLC. Combination and processing of suitable fractions gave the title compound as an white crystalline solid, m.p. 164° C.