Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:15])[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([NH:23][C:24]1([C:39](O)=[O:40])[CH2:29][CH2:28][N:27]([C:30]2[C:31]3[CH:38]=[CH:37][NH:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH2:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:15][C:39]([C:24]2([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:25][CH2:26][N:27]([C:30]3[C:31]4[CH:38]=[CH:37][NH:36][C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:28][CH2:29]2)=[O:40])[CH2:9][CH2:10][CH2:11][N:12]([CH3:13])[CH3:14])=[CH:6][CH:7]=1
Reactant: CN(C)CCCC(N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)CCCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
1-(4-Chlorophenyl)-N4,N4-dimethylbutane-1,4-diamine (Intermediate 57) (330 mg, 1.46 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (526 mg, 1.46 mmol) and DIPEA (0.763 mL, 4.37 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (609 mg, 1.60 mmol) was added and the resulting solution was stirred at 50° C. for 2 hours. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 10% MeOH with ammonia in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(1-(4-chlorophenyl)-4-(dimethylamino)butylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (423 mg, 51.0%) as a colourless gum. tert-Butyl 4-(1-(4-chlorophenyl)-4-(dimethylamino)butylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (423 mg, 0.74 mmol) was dissolved in DCM (5.00 mL) and TFA (1 mL) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness to afford crude product which was triturated with diethyl ether to afford 4-amino-N-(1-(4-chlorophenyl)-4-(dimethylamino)butyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (245 mg, 35.8%) as a white solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[CH:6]=[C:7]([CH:10]=[C:11](Br)[C:12]=1[NH:13][CH3:14])[C:8]#[N:9].CN(C)[CH:18]=[O:19].C>CO.[Cu]Cl.O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:19][CH3:18])[C:12]=1[NH:13][CH3:14])[C:8]#[N:9]
Reactant: C[O-]
Reactant: CNc1c(Br)cc(C#N)cc1Br
Reactant: CN(C)C=O
Agent: Cl[Cu]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CNc1c(OC)cc(C#N)cc1OC

Procedure:
167 g of sodium methoxide are dissolved in 460 ml of methanol while stirring and cooling. Thereafter, 25 g of copper(I) chloride and 153 g of 3,5-dibromo-4-methylaminobenzonitrile as well as 76 ml of dimethylformamide are added. The mixture is heated to reflux for 4.5 hours, cooled to 25°-30° C. and treated with 450 ml of toluene, 450 ml of water and 7.5 g of active charcoal. The mixture is filtered and the organic phase is washed with a solution of 160 ml of water and 16 ml of acetic acid (pH about 6). The organic phase is separated and concentrated under reduced pressure, whereby there are obtained about 91 g of 3,5-dimethoxy-4-methylaminobenzonitrile in the form of an oily residue which crystallizes upon standing and which is used in this form in the next reaction step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][C:14]([C:26](=[O:28])[CH3:27])=[N:15][C:16]=2[C:17]2[CH:22]=[C:21]([S:23][CH3:24])[N:20]=[C:19]([CH3:25])[N:18]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].ClC1C=C(C=CC=1)C(OO)=[O:34]>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][C:14]([C:26](=[O:28])[CH3:27])=[N:15][C:16]=2[C:17]2[CH:22]=[C:21]([S:23]([CH3:24])=[O:34])[N:20]=[C:19]([CH3:25])[N:18]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ncc(Nc2ncc(C(C)=O)nc2-c2cc(SC)nc(C)n2)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Product: COc1ncc(Nc2ncc(C(C)=O)nc2-c2cc(S(C)=O)nc(C)n2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(5-(5-fluoro-6-methoxypyridin-3-ylamino)-6-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-yl)ethanone (52 mg, 0.130 mmol) and 3-chloroperoxybenzoic acid (44.8 mg, 0.260 mmol, Aldrich, St. Louis, Mo.) in dioxane (1 mL) was stirred at room temperature for 2 h. The mixture was taken on directly to the next step without work-up.
Reaction SMILES: C([O:4][C:5]1[C:22]2[C@@H:21]3[C@@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24]C(=O)C)[CH:6]=1)(=O)C.C(Cl)Cl.CO.Cl(O)(=O)(=O)=O>C(OCC)(=O)C>[OH:4][C:5]1[C:22]2[C@@H:21]3[C@@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([OH:24])[CH:6]=1
Reactant: CC(=O)Oc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@H]1CC2
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: C[C@]12CC[C@@H]3c4c(O)cc(O)cc4CC[C@@H]3[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3 g. of 1,3-diacetoxy-8α-estra-1,3,5(10)-trien-17-one in 9 ml. of methylene chloride and 18 ml. of methanol is combined at 0° C. and under nitrogen with 0.23 ml. of perchloric acid (70%) in 1 ml. of methanol; the mixture is then agitated for 3 days at room temperature. Then, the mixture is diluted with ethyl acetate and washed neutral with saturated sodium chloride solution. After drying and evaporation, 2.9 g. of 1,3-dihydroxy-8α-estra-1,3,5(10)-trien-17-one is obtained as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.O.[NH2:9][NH2:10]>C(O)CC>[ClH:1].[NH:9]([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[NH2:10]
Reactant: Clc1ccncc1
Reactant: NN
Solvent: CCCO
Solvent: O
Product: Cl
Product: NNc1ccncc1
Temperature: 0 °C
Yield: 72 %

Procedure:
The title compound was prepared according to the method described in J. Chem. Soc., p. 3830 (1959). A solution of 4-chloropyridine (16.5 g, 145 mmol) and hydrazine monohydrate (7.76 mL, 160 mmol) in 1-propanol (50 mL) was heated under reflux for 18 hours. The solution was cooled to 0° C., and the resulting crystals were collected by filtration. The crystals were washed with cold 1-propanol and air dried to give the title compound (15.2 g, 72% yield). The compound was used in the following process without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:36][CH2:37][CH:38]([OH:41])[CH2:39][CH3:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:25](=[O:27])[O:41][CH:38]([CH2:39][CH3:40])[CH2:37][CH3:36]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCC(O)CC
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCC(CC)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Yield: 72.9 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-pentanol (20 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (49 mg, yield 63%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([OH:9])[N:3]=1.C(O[Na])(C)=O.Br[CH:16]([CH:20]([CH3:22])[CH3:21])[CH2:17]C=O>CC#N.O>[NH2:1][C:2]1[NH:3][C:4](=[O:9])[C:5]2[C:16]([CH:20]([CH3:22])[CH3:21])=[CH:17][NH:8][C:6]=2[N:7]=1
Reactant: CC(C)C(Br)CC=O
Reactant: Nc1cc(O)nc(N)n1
Agent: CC(=O)O[Na]
Solvent: O
Solvent: CC#N
Product: CC(C)c1c[nH]c2nc(N)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
A suspension of 2,4-diamino-6-hydroxypyrimidine (6.68 g, 50 mmol), AcONa (8.3 g 100 mmol) and 3-bromo-4-methyl-pentanal (8.76 g, 50 mmol) in CH3CN (100 mL) and H2O (100 mL) was stirred at 25° C. overnight whereupon the starting materials gradually dissolved and the desired pyrrolo[2,3-d]pyrimidine precipitated. The precipitate was collected by filtration and washed with MeOH to give 2-amino-5-isopropyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (3.80 g, 40%). HPLC Rt: 4.408 min. 1H-NMR (DMSO-d6): δ 10.58 (s, 1H), 10.10 (s, 1H), 6.30 (s, 1H), 5.97 (s, 2H), 3.03 (7, 1H), 1.20 (s, 3H), 1.19 (s, 3H).
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:13](O)[CH2:14][OH:15].C[Si](Cl)(C)C>C(Cl)Cl>[O:1]1[CH2:13][CH2:14][O:15][C:2]1([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH3:8][C:2]([CH2:3][C:4]([OH:6])=[O:5])=[O:1]
Reactant: OCCO
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: CC(=O)CC(=O)O
Product: COC(=O)CC1(CC(=O)OC)OCCO1
Temperature: 50 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
To a solution of 4.2 g (24 mmol) of dimethyl 3-oxopentanedioate and 2.7 ml (48 mmol) of ethylene glycol in 50 mL of methylene chloride was added 12 mL (96 mmol) of TMSCl at room temperature. The reaction mixture was stirred at 50° C. for 3 days. The reaction was quenched with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried over Na2SO4, evaporated under reduced pressure. Chromatography on silica gel gave the desired product, dimethyl dioxolane-2,2-diyl)diacetate (2.6 g, 12 mmol, yield: 50%): MS (m/e): 219 (M+1)+.
Reaction SMILES: [N:1]([CH:4]([CH3:21])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([C:16]([CH3:19])([CH3:18])[CH:15]=[CH:14][C:13]=3[F:20])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[F:20][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])([CH3:19])[C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][CH:4]([NH2:1])[CH3:21]
Reactant: CC(Cn1ncc2c1=CC1=C(F)C=CC(C)(C)C=21)N=[N+]=[N-]
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Solvent: CCOCC
Product: CC(N)Cn1ncc2c1=CC1=C(F)C=CC(C)(C)C=21
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.8 %

Procedure:
1.66 g (5.82 mmol) of (RS)-1-(2-azido-propyl)-7-fluoro-4,4-dimethyl-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 80 ml of anhydrous ethanol were hydrogenated over 160 mg of platinum oxide for 1.5 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The yellow oil obtained was dissolved in 80 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 676 mg (5.82 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 1.81 g (83%) of (RS)-2-(7-fluoro-4,4-dimethyl-1,4-dihydroindeno[2,1-c]pyrazol-1-yl)- 1-methyl-ethylamine fumarate (1:1) with m.p. 144°-146° were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C=CC=CC=1>CN(C=O)C>[CH3:25]/[C:19](=[CH:5]\[C:4]1[CH:3]=[C:2]([F:1])[C:9]([F:10])=[C:8]([F:11])[CH:7]=1)/[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C)=C/c1cc(F)c(F)c(F)c1
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of dry DMF (50 mL) under N2 was added 3,4,5-trifluorobenzaldehyde (4.26 g, 26.6 mmol) followed by ethyl 2-(triphenylphosphoranylidene)propionate (10.6 g, 29.3 mmol) in portions, keeping the solution at room temperature. After 1 hour, TLC (10% EtOAC in Hexanes) showed complete conversion, and the solvent was removed by rotary evaporation. The resulting material was brought up in 50 mL methyl t-butyl ether (MBTE) and the precipitate removed by filtration and washed with additional MBTE (3×50 mL). After concentration, the resulting filtrate was applied onto a silica gel column (25% EtOAc in hexanes) resulting in 6.0 g of the title compound (93%) as a white powder.
Reaction SMILES: [NH2:1][C@H:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5].O.C(=O)(O)[O-].[C:15](O)(=[O:26])[C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.Cl>COCCOC>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[C:15]([NH:1][C@H:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:26]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: NC(=O)[C@@H](N)CC(=O)O
Agent: Cl
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: O
Product: NC(=O)[C@H](CC(=O)O)NC(=O)c1ccc2ccccc2n1
Yield: 69.1 %

Procedure:
To a solution of 0.50 g (3.78 mmol) of L-isoasparagine in 5.0 mL H2O containing ~45 mg (1.5 eq) of solid bicarbonate. To this was added a suspension of 1.02 g (3.78 mmol) quinaldic acid, N-hydroxysuccinamide ester in ethylene glycol dimethylether, and the suspension was solubilized by the addition of 10 mL of dimethyfformamide. After 3 hours the solution was acidified by the addition of 5% HCl (aqueous) and the product was filtered and washed with water, dried under vacuum to yield 750 mg (70% yield) of N-(2-quinolinylcarbonyl)-L-isoasparagine.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][CH:12]=1)C(OC)=O)=[O:4].[I-].[Na+]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:20]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:10][CH2:5][C:3]([O:2][CH3:1])=[O:4])#[N:21]
Reactant: COC(=O)C(Cc1c[nH]c2ccc(C#N)cc12)C(=O)OC
Agent: [I-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)CCc1c[nH]c2ccc(C#N)cc12
Yield: 80799.5 %

Procedure:
To a solution of 1.14 g (3.98 mmol, 1.0 equiv.) of methyl 2-methoxycarbonyl-3-(5-cyano-1 H-indol-3-yl)propanoate in 20 mL of pyridine was added 1.19 g (7.96 mmol, 2.0 equiv.) of sodium iodide. The mixture was heated to reflux for sixteen hours. The solution was cooled and diluted with 150 mL of chloroform. The organic layer was washed once with 25 mL of saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was filtered through a plug of silica gel with 1:1 ethyl acetate:hexane to remove colored impurities to provide 0,734 g (81%) of methyl 3-(5-cyano-1H-indol-3-yl)propanoate.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>CCCCO.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccccn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ccccn4)c23)C1

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide (194 mg, 0.579 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.348 g, 1.74 mmol) in n-BuOH (2 mL) was stirred at 149° C. for 24 hours in a sealed tube and concentrated in vacuo. The residue obtained was dissolved in ethyl acetate (20 mL) and successively washed with water (10 mL) and brine (10 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was purified by C-18 reverse phase column chromatography (Biotage Flash 25M+) on Biotage SP4 unit eluting with gradient of 10-90% CH3CN/water to provide (R)-tert-butyl 1-(5-bromo-3-(picolinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate. This material was dissolved in DCM (3 mL), treated with TFA (0.5 mL) and stirred at room temperature for 1 hour. The mixture was then concentrated in vacuo. The resulting residue was dissolved in DCM (1 mL) and treated with 2N HCl in ether (3 mL). The solid formed was collected by filtration and dried to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide hydrochloride (0.022 g, 0.0419 mmol, 7% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.90 (br s, 1H), 11.35 (br s, 1H), 8.87 (d, 1H), 8.36 (br s, 3H), 8.31 (s, 1H), 8.21-8.11 (m, 3H), 7.74 (t, 1H), 4.04-3.94 (m, 1H), 3.76-3.67 (m, 1H), 3.58-3.48 (m, 1H), 3.43-3.34 (m, 1H), 3.08-3.00 (m, 1H), 2.44-2.37 (m, 1H), 2.27-2.14 (m, 1H), 1.90-1.81 (m, 1H), 1.63-1.51 (m, 1H); LCMS (APCI+) m/z 415.1, 417 (M+H)+.
Reaction SMILES: C([C:4]([Cl:11])=[CH:5][CH2:6][C:7]([O:9]C)=[S:8])(O)=O.C([N-:15][CH:16](C)C)(C)C.[Li+].C(=O)=[O:21].O>C1COCC1>[C:16]([CH:6]([CH:5]=[CH:4][Cl:11])[C:7]([OH:9])=[S:8])(=[O:21])[NH2:15]
Reactant: COC(=S)CC=C(Cl)C(=O)O
Reactant: O=C=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)C(C=CCl)C(O)=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl (2-chlorovinyl)thioacetate (1) (2 g) and lithium diisopropylamide (1.08 g) are stirred in THF (2 ml) at -60° C. for 15 minutes. After addition of dry ice (5 g), the mixture is stirred for 30 minutes and allowed to warm to room temperature. The reaction mixture is poured into water and washed with ethyl acetate to remove neutral material. The remaining aqueous solution is acidified with HCl and extracted with ethyl acetate. The extract is washed with water and vacuum evaporated to give the desired malonic acid ester (2). Yield: 747 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11]O)[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].CS([Cl:17])(=O)=O.Cl>ClCCl>[Cl:17][CH2:11][C:4]1[CH:5]=[C:6]([F:10])[C:7]([S:8][CH3:9])=[C:2]([F:1])[CH:3]=1
Reactant: CSc1c(F)cc(CO)cc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CSc1c(F)cc(CCl)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
To a solution of [3,5-difluoro-4-(methylthio)-phenyl]-methanol (24.0 g, 0.126 mol) in dichloromethane (300 mL) cooled in an ice bath was added methanesulfonylchloride (16.9 g, 0.147 mol) in portions followed by disopropyl-ethylamine in portions. The mixture was allowed to warm to room temperature, and stirred for 18 hours. 4-dimethyl-aminopyridine was added and the mixture was heated to reflux for 2 hours, cooled, and stirred at room temperature for 18 hours. The mixture was poured into dilute HCl and extracted with dichloromethane once (75 mL) after separating. The combined extracts were washed with dilute sodium chloride, dried using magnesium sulfate, and concentrated. Purification by silica gel chromatography using 5% ethyl acetate in hexanes gave 5-(chloromethyl)-1,3-difluoro-2-(methylthio)benzene as a clear colorless liquid (24.9 g, 95%). 1H NMR (CDCl3/400 MHz) 6.92-6.96 (m, 2H), 4.49 (s, 2H), 2.44 (s, 3H). HRMS m/z 207.9893 (M+, calcd 207.9925).
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([NH2:26])=[N:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][CH:3]=[C:2]1[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1.[Si:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47](Cl)=[O:48])=[CH:42][CH:41]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[S:1]1[C:5]([C:6]2[C:7]([NH:26][C:47](=[O:48])[CH2:46][C:43]3[CH:42]=[CH:41][C:40]([O:39][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])=[CH:45][CH:44]=3)=[N:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][CH:3]=[C:2]1[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccc(-c4cccs4)s3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccc(-c3cccs3)s2)cc1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Under an argon atmosphere, to a mixture of 3-(2,2′-bithiophen-5-yl)-5-[4-(tert-butyldimethylsilyloxy)phenyl]pyrazin-2-amine (7m) (350 mg, 752 μmol) and 4-(dimethylamino)pyridine (15.0 mg, 123 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyl dimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11m (298 mg, crude) as a brown oily substance. Rf=0.26 (n-hexane/ethyl acetate=3/1); 1H NMR (400 MHz, DMSO-d6) δ 0.16 (s, 6H), 0.22 (s, 6H), 0.92 (s, 9H), 0.94 (s, 9H), 3.64 (s, 2H), 6.76-6.85 (AA′BB′, 2H), 6.98-7.05 (AA′BB′, 2H), 7.06-7.13 (m, 2H), 7.19-7.27 (AA′BB′, 2H), 7.33 (d, 1H, J=3.6 Hz), 7.36 (d, 1H, J=3.6 Hz), 7.54-7.59 (m, 1H), 8.05-8.11 (AA′BB′, 2H), 8.91 (s, 1H), 10.65 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][N:24]2[C:25](=[O:34])[C:26]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]3[C:28]2=[O:29])=[CH:4][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.8 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (5.00 g), N-hydroxyphthalimide (2.59 g), potassium carbonate (4.40 g) and N,N-dimethylformamide (50 ml) was stirred at room temperature for 20 hours, and water (500 ml) was added. The resultant crystals were filtered, and washed with water to obtain N-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]phthalimide (6.49 g, yield 93%) as colorless crystals. m.p. 155-156° C.