Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]([Si](C(C)C)(C(C)C)C(C)C)[CH:20]=2)O)=[C:11]([F:38])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH2:17][C:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[C:11]([F:38])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)c(F)cc1OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cc2c[nH]c3ncccc23)c(F)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
(4-Benzyloxy-2-fluoro-5-methoxy-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (84, 1.49 g, 2.79 mmol) was dissolved in acetonitrile (50 mL) and trifluoroacetic Acid (1.1 mL) was added. The reaction was stirred for 5 minutes. Triethylsilane (2.2 mL) was added to the reaction. The reaction was heated at 80° C. for 6 hours. The reaction was concentrated and the crude material was dissolved into ethyl acetate and washed with 1 N HCl, saturated sodium bicarbonate, and brine. The organic portion was dried over anhydrous sodium sulfate and concentrated. The solid obtained was used in the next reaction without further purification (85, 833 mg, 83%). MS (ESI) [M+H+]+=363.4.
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.CN(C=O)C.[F:17][C:18]1[C:23]([OH:24])=[C:22]([CH:25]=[O:26])[CH:21]=[CH:20][C:19]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>O>[Br:1][C:20]1[C:19]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[C:18]([F:17])[C:23]([OH:24])=[C:22]([CH:25]=[O:26])[CH:21]=1
Reactant: O=Cc1ccc(-c2ccc(F)cc2)c(F)c1O
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)c(-c2ccc(F)cc2)c(F)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 181.8 %

Procedure:
Dibromoisocyanuric acid (8.87 g) was added at room temperature to a DMF (75 mL) solution of 2,4′-difluoro-3-hydroxybiphenyl-4-carbaldehyde (12.7 g), and the mixture was stirred at room temperature for 30 minutes. Water (50 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The resulting solid was collected by filtration, then washed with DMF-water, and dried to obtain the title compound (17.6 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:29][CH3:30])[CH:27]=[CH2:28]>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:29]([CH2:26][CH:27]=[CH2:28])[CH3:30])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(OCCCCCCBr)ccc21
Reactant: C=CCNC
Product: C=CCN(C)CCCCCCOc1ccc2c(c1)CCCN2C(=O)OC(C)(C)C

Procedure:
In analogy to example 2.6, 6-(6-Bromo-hexyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester and N-allyl-methylamine were converted to yield 6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as colorless gum, MS: 403 (MH+).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5]CCC1.C1(C)C=C[C:10]([S:13](O)(=O)=O)=CC=1.[CH2:18]([OH:22])[CH:19]([OH:21])[CH3:20].CCCC=S>O>[CH3:20][CH:19]1[CH2:18][O:22][CH:1]([CH2:6][CH2:5][S:13][CH3:10])[O:21]1
Reactant: C1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(O)CO
Agent: CCCC=S
Solvent: O
Product: CSCCC1OCC(C)O1
Reaction time: 8 h

Procedure:
Into a 100 ml reaction flask equipped with spin bar, reflux condenser, heating mantle and hot plate with magnetic stirring apparatus is placed 5 ml cyclohexane, 0.2 grams para-toluenesulfonic acid and 3.8 grams (0.05 moles) of 1,2-propanediol. Over a period of 8 hours, 3-methylthiopropionaldehyde is added to the reaction mass. The reaction mass is then heated to reflux and during refluxing water of formation is removed. The refluxing continues for a period of 7 hours. At the end of the 7 hour period, the reaction mass is transferred to a separatory funnel and washed with one 50 ml portion of saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, filtered and distilled on a Microvigreux column yielding the following fractions:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=1)[C:11]([NH:13][C@H:14]([C:22]([N:24]1[CH2:30][CH2:29][CH2:28][C@H:25]1[CH2:26][OH:27])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.CS(C)=O>O>[O:1]([C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=1)[C:11]([NH:13][C@H:14]([C:22]([N:24]1[CH2:30][CH2:29][CH2:28][C@H:25]1[CH:26]=[O:27])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1CO)c1cccc(Oc2ccccc2)c1
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: O=C[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 39.7 %

Procedure:
To 216.4 mg of N-(N-(3-phenoxybenzoyl)-L-phenylalanyl)-L-prolinol were added 0.92 ml of acetic anhydride-and 2.6 ml of DMSO. The mixture was stirred at room temperature for 22 hours. Then 40 ml of water was added to the reaction mixture. After stirring for an hour, the mixture was extracted 3 times with 20 ml each of dichloromethane. The oily layer was dried over anhydrous sodium sulfate and the solvent was distilled off to give 248.7 mg of an oily substance. The oily substance was purified by column chromatography (silica gel, developed with hexane-ethyl acetate) to give 85.5 mg of an amorphous solid. The solid was further purified by column chromatography (silica gel, developed with dichloromethane-ethyl acetate) to give 46.4 mg of the title compound as a colorless transparent amorphous solid. Yield, 21.5%.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:10][C:9](=[O:11])[NH:8][C:7]=2[CH:12]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]C.CN(C)C=O>C(O)C.CS(C)=O>[CH2:2]([C:3]1[CH:4]=[CH:5][C:6]2=[N:10][C:9](=[O:11])[N:8]=[C:7]2[CH:12]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCBr
Reactant: Cc1ccc2[nH]c(=O)[nH]c2c1
Agent: [Na]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCCCCCCCCCCc1ccc2c(c1)=NC(=O)N=2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium (0.05 g, 2.17 mg atom) was dissolved in ethanol (5 ml) and to this was added 6-methyl-1,3-dihydro-benzoimidazol-2-one (0.20 g, 1.35 mmol) and the solution was stirred at room temperature for 1 h. The solvent was removed in vacuo and the white solid was taken up in tetrahydrofuran (5 ml) and dimethyl sulfoxide (5 ml), and to this was added 1-bromododecane (0.34 g, 1.36 mmol) and the whole was stirred at room temperature for 2 h. N,N-Dimethylformamide (5 ml) was added to the mixture and the whole was stirred for a further 2 h. The mixture was filtered and the filtrate was evaporated in vacuo to give a yellow residue. The residue was placed on a silica column and chromatographed with 12.5% hexane-ethyl acetate to give (19) as a yellow oil.
Reaction SMILES: [CH2:1]([S:3][CH:4]1[N:7]([CH:8](O)[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:23])[CH2:5]1)[CH3:2].CC1C=CC=C(C)N=1.S(Cl)([Cl:34])=O>O1CCCC1>[CH2:1]([S:3][CH:4]1[N:7]([CH:8]([Cl:34])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:23])[CH2:5]1)[CH3:2]
Reactant: CCSC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CCSC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 6.8 g. of p-nitrobenzyl 2-(4-ethylthio-2-oxo-1-azetidinyl)-2-hydroxyacetate in 200 ml. of tetrahydrofuran, at 0°-5° C., was added 2.98 ml. of 2,6-dimethylpyridine, followed by dropwise addition of a solution of 1.73 ml. of thionyl chloride in 20 ml. of tetrahydrofuran, over a 5-minute period. Stirring was continued at 0°-5° C. for 15 minutes, and then the reaction mixture was filtered. The filtrate was evaporated to dryness in vacuo, and the residue was dissolved in 200 ml. of dichloromethane. The resulting solution was washed successively with dilute hydrochloric acid and water, and then dried over anhydrous sodium sulfate. Evaporation in vacuo gave 7.12 g of the title compound as a yellow, viscous liquid. The IR spectrum chloroform of the product showed an absorption at 5.63 microns. The NMR spectrum deuterochloroform of the product showed peaks at 1.3 (t, 3H); 2.47-3.7 (m, 4H); 4.9-5.3 (m, 1H); 5.4 (s, 4H); 6.06 and 6.18 (ss, 1H); 7.58 (d, 2H); and 8.22 (d, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.[CH2:10]([OH:15])[CH2:11][CH2:12][C:13]#[CH:14]>C(NCC)C.ClCCl.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:14]#[C:13][CH2:12][CH2:11][CH2:10][OH:15]
Reactant: C#CCCCO
Reactant: Clc1ccc(Cl)c(I)c1
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCl
Product: OCCCC#Cc1cc(Cl)ccc1Cl

Procedure:
A solution of 1,4-dichloro-2-iodobenzene (20.0 g, 73.3 mmol), 4-pentyn-1-ol (6.17 g, 73.3 mmol), bistriphenylphosphine(Pd II) chloride (1.03 g, 1.47 mmol), and copper(I) iodide (0.14 g, 0.733 mmol) in 400 ml of diethylamine was stirred under nitrogen for three days. This was diluted with dichloromethane and the oily layer was adsorbed onto silica gel and eluted with hexanes-ethyl acetate (5:1)to give 5-(2,5-dichlorophenyl)-pent-4-yn-1-ol, 13.7 g (82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[Cl:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C>ClCCl>[Cl:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][N:27]([C:6]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=2)=[O:7])[CH2:26][CH2:25]1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: Cc1cccc(N2CCNCC2)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCN(c3cccc(C)c3Cl)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
3,4,5-Trimethoxybenzoyl chloride (2.03 g, 8.8 mmol) in dichloromethane (10 mL) is added dropwise to a solution of 2-chloro-3-methylphenyl piperazine (1.98 g, 8.0 mmol) and triethylamine (4.5 mL, 32.0 mmol) in dichloromethane (90 mL) and stirred for 2 hours at room temperature. The reaction mixture is washed with water, dried (magnesium sulfate), and concentrated in vacuo. The resulting solid is purified by medium pressure liquid chromatography (MPLC) on silica gel eluting with 40% ethyl acetate/hexane to give 2.52 g of the title compound as a white solid; mp 156-159° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16](OS(C)(=O)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OS(C)(=O)=O
Reactant: Nc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Nc1ccccc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl 3-(4-benzyloxyphenyl)-2-methanesulfonyloxypropionate (4.00 g) and aniline (5 ml) was stirred at 110° C. for 24 hours. The reaction mixture was purified via chromatography on silica gel column using ethyl acetate/hexane=1/4 as the eluant to afford the desired compound (3.94 g) as a syrup.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[C:6]([S-:10])(=[S:9])[NH:7][NH2:8].[K+].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>CN1CCCC1=O>[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:8][NH:7][C:6]([S:10][CH2:1][CH2:2][CH2:3][CH3:4])=[S:9])=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: NNC(=S)[S-]
Reactant: CCCCBr
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCCCSC(=S)NNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
85.9 parts n-butyl bromide are added to a suspension of 91 parts of potassium dithiocarbazate in 900 parts of N-methylpyrrolidone, while cooling with ice, and the mixture is then stirred for 2 hours at room temperature. Thereafter, 116.7 parts of p-nitrobenzoyl chloride are added while cooling with ice, stirring is continued for a further 2 hours at room temperature, and the reaction mixture is poured into 3,000 parts of ice water. The butyl 3-(p-nitrobenzoyl)-dithiocarbazate initially obtained as an oil crystallizes on standing overnight, and is then filtered off under suction and washed with water. The residue is sucked thoroughly dry and then introduced into 1,000 parts of concentrated sulfuric acid, the mixture is stirred for 1 hour at 50° C. and then poured into 3,000 parts of ice water, and the precipitate is filtered off under suction, dried, and recrystallized from glacial acetic acid. 130 parts (70% of theory) of pure 2-butylthio-5-(p-nitrophenyl)-1,3,4-thiadiazole of melting point 140° C. are obtained.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[C:18](Cl)(=[O:20])[CH3:19]>C1(C)C=CC=CC=1>[C:18]([N:7]1[C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc2c(c1)Nc1ccccc1S2
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc2c(c1)N(C(C)=O)c1ccccc1S2
Temperature: 0 °C

Procedure:
30 g (0.118 mol) of 2-acetylphenothiazine and 9.28 g (1 eq.) of acetyl chloride are introduced into a 500 ml flask containing 150 ml of toluene. The reaction mixture is heated to reflux for 45 minutes before the introduction of a new portion of 4.6 g (0.5 eq.) of acetyl chloride. Stirring is maintained under heating at reflux for another 2 hours. The reaction medium is then poured onto approximately 200 g of ice. After stirring, the organic phase is decanted and washed successively with 100 ml of water and 100 ml of salt water. The organic solution is dried over sodium sulphate, filtered and concentrated to dryness using a rotary evaporator. A yellow solid (33 g; 100%) is obtained which is used in the following stage without additional purification.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1.[ClH:11].[S:12](=[O:14])=[O:13].CCOCC>O.C(O)(=O)C>[Cl-:11].[S:12](=[C:2]1[NH:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[S:3]1)(=[O:14])=[O:13]
Reactant: Cl
Reactant: Nc1nnc(C(F)(F)F)s1
Reactant: O=S=O
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: O=S(=O)=c1[nH]nc(C(F)(F)F)s1
Product: [Cl-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
50.74 (300 mmoles) of 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (commercially available from Aldrich) were added under stirring to a mixture of 100 ml of concentrated hydrochloric acid and 30 ml of glacial acetic acid. The reaction mixture was brought to −10° C. and there is slowly added 22.42 g (325 mmoles) of sodium nitrite NaNO2 in 35 ml of water. The diazotation reaction is continued for 1 hour. At the same time, a flow of sulfur dioxide SO2 (commercially available from Fluka) in 300 ml of glacial acetic acid was passed through a fritted member until saturation. Then, there is added 7.5 g of copper(I) chloride CuCl and the addition of sulfur dioxide was continued until the color of the reaction mixture changed from yellow-green to blue-green. After having brought the reaction mixture to a temperature <10° C., during a period of 30 min, the previously prepared diazonium was added. A small amount of ether was added to decrease the quantity of foam which is formed after each addition. After the end of the addition of diazonium, the reaction mixture was poured into 1 liter of a mixture of water-ice (1:1). After melting of the ice, a yellow oil was separated in a decanting ampulla, and the aqueous phase was extracted with two fractions of 100 ml ether. After addition of the ether phase to the collected oil, the solution was washed with a concentrated solution of sodium bicarbonate until neutrality, then with water, and finally it was dried with magnesium sulfate. After evaporation of the solvent, there is recovered after distillation under vacuum 46.99 g of 2-sulfonyl-5-trifluoromethyl-1,3,4-thiadiazole chloride (62% yield) with a purity characterized by a proton and fluorine RMN higher than 98%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[OH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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:1][C:2]1[N:3]=[C:4]([NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:30]3[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(NC3CCCC3)nc(Cl)nc21
Reactant: OB(O)c1ccc(O)cc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2ccc(O)cc2)c2c(NC3CCCC3)nc(Cl)nc21
Temperature: 100 °C
Reaction time: 16 h
Yield: 32.2 %

Procedure:
2-Chloro-N-cyclopentyl-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1 equiv), 4-hydroxyphenylboronic acid (1 equiv), potassium carbonate (2.5 equiv) and tetrakis(triphenylphosphine)palladium(0) (0.2 equiv), suspended in 1,4-dioxane/water, and flushed with nitrogen, were stirred at 100° C. for 16 h. The reaction mixture was loaded directly onto a silica gel column and purified using 5-100% ethyl acetate in hexanes. Fractions containing desired product were combined and volatile organics were removed under reduced pressure to give 4-(2-chloro-4-(cyclopentylamino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol (32.2% yield) as a yellow solid. MS (ESI) m/z 459.3 [M+1]+.
Reaction SMILES: O[C:2]1[N:3]=[N:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.CC1C(=[S:19])CN=NN=1.CC1C(=O)CN=NN=1>>[SH:19][C:2]1[N:3]=[N:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Oc1nnc2ccccc2n1
Reactant: CC1=NN=NCC1=S
Agent: CC1=NN=NCC1=O
Product: Sc1nnc2ccccc2n1

Procedure:
3-Mercapto-1,2,4-benzotriazine was prepared from 3-hydroxy-1,2,4-benzotriazine and 6-methyl-1,2,3-triazine-5-(4H)-thione from 6-methyl-1,2,3-triazine-5-(4H)-one following essentially the above procedure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([C:16](O)=[O:17])=[CH:14][N:13]=[C:12]2[N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[N:20]=[CH:21][C:11]=12.[CH:31]([O:33][CH2:34][CH2:35][O:36][NH2:37])=[CH2:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:31]([O:33][CH2:34][CH2:35][O:36][NH:37][C:16]([C:15]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[C:11]2[CH:21]=[N:20][N:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[C:12]2=[N:13][CH:14]=1)=[O:17])=[CH2:32]
Reactant: COc1ccc(Cn2ncc3c(Nc4ccc(I)cc4F)c(C(=O)O)cnc32)cc1
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
4-(2-Fluoro-4-iodophenylamino)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (360 mg, 0.71 mmol), O-(2-vinyloxyethyl)-hydroxylamine (79 mg, 0.77 mmol), HOBt (103 mg, 0.77 mmol), EDCI (147 mg, 0.77 mmol) and DIPEA (130 μL, 0.77 mmol) were dissolved in DMF (10 mL). The reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (346 mg, 81%). LCMS (Method B): RT=4.08 min, [M+H]+=604.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4]([CH2:6][N:7]([CH3:9])[CH3:8])=[CH2:5].CO[CH2:13][N:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][Si](C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3]([C:4]1([CH2:6][N:7]([CH3:9])[CH3:8])[CH2:5][CH2:13][N:14]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15]1)=[O:10]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(CN(C)C)C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(CN(C)C)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.8 %

Procedure:
To a cold solution of 2-dimethylaminomethyl-acrylic acid methyl ester (0.266 g, 1.86 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzyl-amine (1.43 ml, 5.59 mmol) in dichloromethane (25 ml) was added at 0° C. trifluoroacetic acid (83 μl, 1.12 mmol). The resulting solution was warmed to room temperature and stirred for 72 hours. Saturated aq. NaHCO3 (60 ml) was added to the reaction mixture and stirred for 10 minutes. Diluted with dichloromethane (50 ml) and the organic layer was separated. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica get eluting with a solution of ethyl acetate in hexanes (1:2) followed by CH2Cl2/MeOH/NH4OH (9/1/0.01) to give the title compound (400 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:34]C(=O)OC(C)(C)C)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)=[CH:22][N:21]=[C:20]4[NH:31][CH:32]=[CH:33][C:19]=34)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[NH2:34][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:22][N:21]=[C:20]3[NH:31][CH:32]=[CH:33][C:19]=23)[CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(-c3cccc(F)c3)cnc3[nH]ccc23)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(-c3cccc(F)c3)cnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
(R)-tert-Butyl 3-(4-chlorophenyl)-1-(4-(5-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (0.045 g, 0.078 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give (R)-2-amino-3-(4-chlorophenyl)-1-(4-(5-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)propan-1-one (0.018 g, 48% yield) as the dihydrochloride salt. MS ESI (+) m/z 478 detected.