Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([NH:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])=[O:13].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O>C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC.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>[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([NH:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])=[O:13]
Reactant: OB(O)c1cccs1
Reactant: Cc1ccc(C(=O)O)c(NC(=O)Cc2c[nH]c3ccc(Br)cc23)c1
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: COCCOC
Product: Cc1ccc(C(=O)O)c(NC(=O)Cc2c[nH]c3ccc(-c4cccs4)cc23)c1
Yield: 4.1 %

Procedure:
2-{[(5-bromo-1H-indol-3-yl)acetyl]amino}-4-methylbenzoic acid (product of example 6, 48 mg), thiophene-2-boronic acid (17 mg), tetrakis(triphenylphosphine)palladium(0) (12 mg) was heated in a mixture of 2M sodium carbonate solution (0.5 ml) and dimethoxyethane (0.5 ml) for 18 h at 80° C. The mixture was concentrated and diluted with DCM, then washed with 2N HCl for 1 hr. The solvent was reduced and the residue purified by mass-directed automated HPLC to give the title compound (2 mg). MH+391.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].[OH-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[CH2:13]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH2:7][OH:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
A solution of 5-bromo-2-hydroxybenzylalcohol (3.677 g, 18.11 mmol) in abs. EtOH (80 ml) and NaOH (0.797 g, 19.921 mmol) was stirred under a N2 atmosphere for 20 min at RT then a solution of benzylbromide (2.15 ml, 18.11 mmol) in abs. EtOH (10 ml) was added and the mixture was stirred at RT overnight. The volatiles was removed under vacuum. The reminder was partitioned between HCl (2M aq.) and EtOAc. The organic layer was washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by MPLC (50 g SiO2 cartridge, eluent 90% iso-hexane-10% EtOAc) yielding 4.36 g of (2-benzyloxy-5-bromo-phenyl)-methanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:8]=2[N:9]=1.C([O-])(=O)C.[Na+].[I:22]Cl.O>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:16])[NH:4][C:5]1[S:6][C:7]2[C:13]([I:22])=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:8]=2[N:9]=1
Reactant: ClI
Reactant: COC(=O)Nc1nc2c(OC)cccc2s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2c(OC)ccc(I)c2s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(4-Methoxy-benzothiazol-2-yl)-carbamic acid methyl ester (31.0 g, 130 mmol) and sodium acetate (32.3 g, 394 mmol) are dissolved in 400 ml of glacial acetic acid and slowly treated with iodine monochloride (13.5 ml, 264 mmol) at 0° C. The reaction mixture is then slowly warmed to room temperature and stirred for 15 hours. After addition of water (1.31), the formed precipitate is filtered off and washed with water. The filter cake is then dissolved in a minimal amount of tetrahydrofurane (about 150 ml) and decolorized with 1M aqueous sodium thiosulfate. The product is precipitated by the addition of water (about 2.0 l), filtered off and dried at 60° C. for 12 hours. 42.3 g (89%) white solid. MS: m/e=364 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1.C([N-]C(C)C)(C)C.[Li+:20].[S:21](=[O:23])=[O:22]>C(OCC)C>[Cl:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([S:21]([O-:23])=[O:22])[N:4]([CH3:12])[N:3]=1.[Li+:20]
Reactant: O=S=O
Reactant: CCOC(=O)c1cn(C)nc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CCOC(=O)c1c(Cl)nn(C)c1S(=O)[O-]
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
5.0 g of ethyl 3-chloro-1-methylpyrazole-4-carboxylate was dispersed in dry diethyl ether under cooling at -60° C. or lower. Into this solution there was added lithium diisopropylamide (1.2 molar equivalent) and after stirring for an hour sulfur dioxide gas was passed into this solution for 30 minutes. After stirring at -60° C. for 2 hours the reaction mixture was stirred at room temperature for 2 hours. Filtration and drying of the precipitate gave 6.0 g of lithium 3-chloro-4-ethoxycarbonyl-1-methlpyrazole-5-sulfinate. This product was added into a solution of 100 ml of ice-water and 100 ml of dichloromethane and 6.0 g of N-chloro succinimide was added thereinto at 0°-5° C. After stirring for 45 minutes at room temperature the dichloromethane layer was separated and water layer was extracted with 100 ml of dichloromethane. The combined dichloromethane solution of 3-chloro-4-ethoxycarbonyl-1-methylpyrazole-5-sulfonyl chloride (b.p.: 133° C./0.25 mmHg.) was added dropwise into 80 ml of aqueous ammonia (28%) under cooling at 10° C. After stirring for an hour, evaporation of the solvent gave 3.6 g of 3-chloro-4-ethoxycarbonyl-1-methylpyrazole-5-sulfonamide.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]2[S:49][C:50](Br)=[CH:51][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:54]([C:56]1[CH:57]=[C:58](B(O)O)[CH:59]=[CH:60][CH:61]=1)#[N:55].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]2[S:49][C:50]([C:60]3[CH:59]=[CH:58][CH:57]=[C:56]([C:54]#[N:55])[CH:61]=3)=[CH:51][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(Br)s1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-c2ccc(Cc3cc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)ccc3Cl)s2)c1

Procedure:
A mixed solution of 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 53 (1.24 g) obtained in Example 119-(6), 3-cyanophenylboronic acid (270 ml), bis(triphenylphosphine)palladium(II)dichloride (54 mg) and 2M aqueous sodium carbonate solution (2.3 ml) in 1,2-dimethoxyethane (12 ml) was heated under reflux for 4 hours. The mixture was diluted with ethyl acetate and washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The mixture was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1-5:1) to give 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene (1.12 g) as colorless oil. APCI-Mass m/Z 849/851 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene was used and treated in a manner similar to Example 3-(3) to give the target compound as colorless powder. APCI-Mass m/Z 489/491 (M+NH4).
Reaction SMILES: [C:1]([CH2:6][S:7][CH2:8][C:9]1[CH:14]=[N:13][C:12]([CH3:15])=[C:11]2[O:16]C(C)(C)[O:18][CH2:19][C:10]=12)([O:3][CH2:4][CH3:5])=[O:2].[ClH:22].C(=O)(O)[O-].[Na+]>O>[ClH:22].[CH3:15][C:12]1[C:11]([OH:16])=[C:10]([CH2:19][OH:18])[C:9]([CH2:8][S:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:14][N:13]=1
Reactant: CCOC(=O)CSCc1cnc(C)c2c1COC(C)(C)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CSCc1cnc(C)c(O)c1CO
Temperature: 0 °C

Procedure:
A mixture of 1.0 g. of the compound from Step A, 6.0 ml. of 2.5 N hydrochloric acid and 10 ml. of water is heated at 50° C. for 45 minutes. The mixture is made alkaline with solid sodium bicarbonate and concentrated to dryness. The residue is extracted with 50 ml. of hot isopropanol. The extract is cooled to 0° C., saturated with dry hydrogen chloride and concentrated to dryness. The solid residue is isolated by tritaration with ether and filtration and dried to give 2-methyl-3-hydroxy-4-hydroxymethyl-5-ethoxycarbonylmethylthiomethylpyridine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[CH:9][N:8]([CH2:19][O:20]CC[Si](C)(C)C)[C:4]=2[N:5]=[CH:6][N:7]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[CH:9][N:8]([CH2:19][OH:20])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cccc(C#N)c2)c2c(Cl)ncnc21
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(-c2cn(CO)c3ncnc(Cl)c23)c1

Procedure:
A solution of 3-(4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (C12) (3.8 g, 9.9 mmol) in trifluoroacetic acid (25 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to afford the product (4 g, >100% mass recovery) as a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[CH:11][CH:12]=2)[NH:7][C:6](=[O:30])[CH:5]=1.[H][H]>C(O)C.[Pd]>[ClH:1].[ClH:1].[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][N:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:22][CH2:23]3)=[CH:11][CH:12]=2)[NH:7][C:6](=[O:30])[CH2:5]1
Reactant: [H][H]
Reactant: Cc1cc(=O)[nH]c2cc(OCCCN3CCN(c4ccccc4)CC3)ccc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1CC(=O)Nc2cc(OCCCN3CCN(c4ccccc4)CC3)ccc21
Reaction time: 8 h
Yield: 60 %

Procedure:
1.0 Gram of 4-methyl-7-[3-(4-phenylpiperazinyl)propoxy]carbostyril dihydrochloride and 0.3 g of palladium black are dispersed in 200 ml of ethanol under 2 atmospheres of hydrogen pressure at room temperature and catalytic reduction is carried out at 70°-80° C. for 8 hours. After cooling the reaction mixture, the palladium black is removed by filtration and the mother liquor is concentrated to dryness. The residue is recrystallized from a mixture of methanol-ether to obtain 0.6 g (yield: 60%) of 4-methyl-7-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril.dihydrochloride.dihydrate in the form of colorless crystals with a melting point of 260°-265° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:30]1[CH2:31][CH2:32][C@H:27]([NH:26][C:24]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:8]4[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:15]=3[NH:22][C:21]=2[CH3:23])=[O:25])[C@@H:28]([OH:33])[CH2:29]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CCNC[C@H]1O
Agent: Cl
Product: CC(=O)N1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)[C@@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-N-[(3R*,4S*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f11) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([NH:9]O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([OH:15])=[O:14].[OH-].[Na+]>CO>[CH2:1]([NH:9][CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCl
Reactant: O=C(NO)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CNCc1ccccc1

Procedure:
13.7 Grams (0.1 mole) of benzhydroxamic acid and 8.8 g (0.1 mole) of chloroacetic acid were dissolved in 60 ml of methyl alcohol. To the resulting solution, 20 g (0.2 moles) of 40% aqueous solution of sodium hydroxide was slowly added dropwise. After completion of the addition, the reaction solution was heated under reflux for 8 hours and subsequently cooled. After distilling of methyl alcohol under vacuum, concentrated hydrochloric acid was added to the remaining aqueous solution so as to adjust pH to 1. Ethyl acetate (50 ml) was added to the solution. The separated organic layer was washed twice with 50 ml of a saturated sodium chloride solution. By distilling off ethyl acetate, benzamidooxyacetic acid (m.p. 144°145° C.) was obtained in an amount of 18.2 g (yield, 93 mol %).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH2:19]([O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[Br:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCc2ccccc2)c(Br)c1
Yield: 74.7 %

Procedure:
Methyl 3-bromo-4-hydroxybenzoate [prepared as per Tetrahedron, 2003, 59, 9173] (3.47 g, 15.0 mmol) was dissolved in acetonitrile (50 ml), anhydrous potassium carbonate (3.11 g, 22.5 mmol) was added and the stirred mixture was treated with benzyl bromide (3.08 g, 18.0 mmol) and held at reflux for 5 hours. Upon cooling the solvent was removed in vacuo and the mixture partitioned between water and dichloromethane. The organic layer was separated, the solvent removed in vacuo and the residue subjected to column chromatography on silica. Elution with 10% ethyl acetate in petroleum ether afforded methyl 4-benzyloxy-3-bromobenzoate (3.6 g, 75%) as a colourless solid. 1H NMR (DMSO-d6) 8.12 (1H, d), 7.96 (1H, dd), 7.51 (2H, m), 7.43 (2H, t), 7.35 (2H, m), 5.32 (2H, s), 3.84 (3H, s).
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:13]=[C:14]([C:18]3([CH2:22][NH:23]C(=O)OC(C)(C)C)[CH2:21][O:20][CH2:19]3)[CH:15]=[CH:16][CH:17]=2)[N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:4]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:50][C:2]([F:1])([F:51])[C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:13]=[C:14]([C:18]3([CH2:22][NH2:23])[CH2:19][O:20][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[NH:5][N:4]=1
Reactant: CC(C)(C)OC(=O)NCC1(c2cccc(-c3ccnc4c3c(C(F)(F)F)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)COC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1(c2cccc(-c3ccnc4[nH]nc(C(F)(F)F)c34)c2)COC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
tert-Butyl N-[[3-[3-[3-(trifluoromethyl)-1-trityl-pyrazolo[3,4-b]pyridin-4-yl]phenyl]oxetan-3-yl]methyl]carbamate (58 mg, 0.08397 mmol) was dissolved in DCM (2 mL) and cooled to 0° C. Triethylsilane (39.06 mg, 53.65 μL, 0.3359 mmol) was added followed by TFA (0.5 mL). The reaction was stirred at 0° C. for 1 hour then the solvent removed under reduced pressure. The crude product was dissolved in DMSO and purified by FractionLynx. The fractions were passed through bicarbonate cartridges to obtain free base and lyophilised to give (3-(3-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)oxetan-3-yl)methanamine (7.8 mg, 25%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH:11]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Si](OCC(C)(C)CO)(C(C)(C)C)(C)C.[NH2:51][C:52]1[N:57]=[CH:56][N:55]=[C:54]2[N:58]([C@@H:75]3[CH2:80][CH2:79][CH2:78][N:77]([C:81](=[O:85])[CH2:82][C:83]#[N:84])[CH2:76]3)[N:59]=[C:60]([C:61]3[CH:66]=[CH:65][C:64]([O:67][C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[CH:63][C:62]=3[F:74])[C:53]=12.[Si](Cl)(C)(C)C.N1CCCC1>C(Cl)Cl>[NH2:51][C:52]1[N:57]=[CH:56][N:55]=[C:54]2[N:58]([C@@H:75]3[CH2:80][CH2:79][CH2:78][N:77]([C:81]([C:82](=[CH:11][C:10]([CH3:14])([CH3:13])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:83]#[N:84])=[O:85])[CH2:76]3)[N:59]=[C:60]([C:61]3[CH:66]=[CH:65][C:64]([O:67][C:68]4[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=4)=[CH:63][C:62]=3[F:74])[C:53]=12
Reactant: CC(C)(C=O)CO[Si](C)(C)C(C)(C)C
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)(CO)CO[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
A crude mixture of 3-[tert-butyl(dimethyl)silyl]oxy-2,2-dimethyl-propanal (1.15 g, 5.31 mmol) was prepared by addition of 1.1 equivalents of Dess-Martin periodinane to a solution of 3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropan-1-ol in 25 mL of DCM at 0° C. After 1 h, the slurry was diluted with hexanes and filtered over a plug of silica. The residue was concentrated to a thick oil and then dissolved in DCM (10 mL). 3-[(3R)-3-[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]-3-oxo-propanenitrile (236.79 mg, 0.5000 mmol) was added, then TMS-Cl (0.2 mL, 1.59 mmol), followed by pyrrolidine (0.13 mL, 1.59 mmol). The solution was stirred at rt, monitoring the reaction by LCMS. After 16 h, the mixture was partitioned between water and DCM and then the organic phase was washed with brine and dried over sodium sulfate. Filtration and removal of solvents afforded a colorless oil that was purified by silica gel choromatography (9:1 to 90:10 methylene chloride:MeOH gradient) to afford 350 mg of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-5-((tert-butyldimethylsilyl)oxy)-4,4-dimethylpent-2-enenitrile.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:18]=[N:19][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:21][CH:22]=3)[N:11]=2)=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH:31]1[CH2:35][CH2:34][CH2:33][CH:32]1[CH2:36][C:37]([NH2:39])=[O:38].CCN(C(C)C)C(C)C.CO.C(Cl)(Cl)Cl>CCO>[C:4]([C:3]1[C:2]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[CH2:36][C:37]([NH2:39])=[O:38])=[N:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:18]=[N:19][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:21][CH:22]=3)[N:11]=2)[CH:6]=1)#[N:5]
Reactant: N#Cc1cc(-c2ccnc(Nc3ccc(CN4CCOCC4)nc3)n2)cnc1Cl
Reactant: NC(=O)CC1CCCN1
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(-c2ccnc(Nc3ccc(CN4CCOCC4)nc3)n2)cnc1N1CCCC1CC(N)=O
Temperature: 25 °C

Procedure:
To a solution of compound 18 (100 mg, 0.24 mmol) in EtOH (5 mL) was added 2-(pyrrolidin-2-yl)acetamide-HCl (160 mg, 1.22 mmol) and DIPEA (0.22 mL, 1.22 mmol) at rt and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to rt, concentrated to half of its volume and triturated with n-pentane, the precipitated solid was collected by filtration to obtain DMX-130 (80 mg, 65%) as a white solid. Rf: 0.4 (10% MeOH/CHCl3); (m/z): 499.8 [M+1]+; 1H NMR (300 MHz, DMSO-d6): δ 9.77 (1H, s), 9.13 (1H, d, J=2.4 Hz), 8.87 (1H, d, J=2.4 Hz), 8.66 (1H, d, J=1.8 Hz), 8.50 (1H, d, J=5.1 Hz), 8.16 (1H, dd, J=2.7, 9.0 Hz), 7.46 (1H, d, J=5.7 Hz), 7.38 (1H, d, J=9.0 Hz), 7.30 (1H, br), 6.84 (1H, br), 4.74 (1H, br), 3.97 (1H, br), 3.80-3.76 (1H, br), 3.59-3.53 (6H, m), 2.76-2.70 (1H, m), 2.40 (4H, br), 2.23-2.15 (1H, m), 2.10-2.98 (3H, m), 1.86-1.84 (1H, m).
Reaction SMILES: Br.[Br:2][C:3]1[C:4]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:5][S:6][CH:7]=1.[OH-].[Na+].C(Cl)(Cl)Cl.[CH3:19][N:20]=[C:21]=[S:22]>C(O)C>[CH3:19][NH:20][C:21]([NH:12][CH2:11][CH2:10][S:9][CH2:8][C:4]1[C:3]([Br:2])=[CH:7][S:6][N:5]=1)=[S:22]
Reactant: CN=C=S
Reactant: NCCSCc1nscc1Br
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CNC(=S)NCCSCc1nscc1Br
Yield: 108.8 %

Procedure:
The reaction of 4-bromo-3-(bromomethyl)isothiazole (8.5 g.) with cysteamine (from cysteamine hydrochloride (3.76 g.)) was performed under conditions similar to those described in Example 122. From the reaction there was obtained 4-bromo-3-[(2-aminoethyl)thiomethyl]isothiazole hydrobromide, which, following recrystallisation from ethanol-ether and acetonitrile, gave needles (4.05 g.), m.p. 111°-112°. The amine base (2.73 g.) was isolated by basification with sodium hydroxide and extraction with chloroform and then dissolved in ethanol and treated with methyl isothiocyanate (0.78 g.). The solution was heated under reflux for 30 minutes, concentrated and the residue triturated with ether to yield the crystalline thiourea (2.9 g.) m.p. 60°-61°. Recrystallisation from isopropyl acetate gave N-methyl-N'-[2-((4-bromo-3-isothiazolyl)-methylthio)ethyl]thiourea (2.3 g.) as needles, m.p. 62°-63°.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[CH3:12][C:13]([O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][C:29]#[CH:30])=[CH:21][C:20]=1[CH3:31])([CH3:17])[C:14]([OH:16])=[O:15]>>[CH3:17][C:13]([O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][C:29]#[C:30][C:2]2[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=2)=[CH:21][C:20]=1[CH3:31])([CH3:12])[C:14]([OH:16])=[O:15]
Reactant: C#CCCCOc1ccc(OC(C)(C)C(=O)O)c(C)c1
Reactant: FC(F)(F)c1ncc(Cl)cn1
Product: Cc1cc(OCCCC#Cc2cnc(C(F)(F)F)nc2)ccc1OC(C)(C)C(=O)O

Procedure:
In analogy to the procedure described in example 24E], 5-chloro-2-trifluoromethyl-pyrimidine (example 28B]) and 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid (example 26B]), followed by flash chromatography (SiO2, CH2Cl2/MeOH 2.5 to 10%) and precipitation ether/n-pentane yielded the title compound as white powder, mp. 95-97° C., dec.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][CH2:20][N:19]([S:23]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=4[O:33][CH3:34])(=[O:25])=[O:24])[C:18]=3[CH:35]=2)=[O:13])=[CH:7][CH:6]=1)=[NH:4].N1C=CC=CC=1.C(C(CCCC)[CH2:45][O:46]C(Cl)=O)C>CN(C)C=O.O>[O:46]=[C:45]1[O:1][N:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]3[CH:15]=[CH:16][C:17]4[O:22][CH2:21][CH2:20][N:19]([S:23]([C:26]5[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=5[O:33][CH3:34])(=[O:24])=[O:25])[C:18]=4[CH:35]=3)=[O:13])=[CH:7][CH:6]=2)[NH:4]1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C(=N)NO)cc3)cc21
Reactant: CCCCC(CC)COC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(-c4noc(=O)[nH]4)cc3)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [4-(N-hydroxycarbamimidoyl)-phenyl]-amide (97 mg, 0.19 mmol) in dimethylformamide (2.0 mL) was treated with pyridine (0.020 mL, 0.20 mmol) and the mixture was cooled at 0° C. Chloroformic acid 2-ethylhexyl ester (36 mg, 0.19 mmol) was added dropwise and the mixture was stirred at 0° C. for 30 min. The mixture was diluted with water and extracted three times with ethyl acetate. The combined organic extracts were dried over sodium sulfate and evaporated. The residue was suspended in xylene (8.0 mL) and refluxed for 2 hours. Upon cooling to room temperature a solid precipitated, which was filtered and dried under high vacuum. 4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide was obtained as a white solid, 74 mg (73%), MS (ISP): m/e=541.1, 542.7 (M−H).