Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:13][CH:14]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:25][CH2:24]2)=[O:22])[C:15]2[NH:19][N:18]=[N:17][N:16]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[CH3:12])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:46](Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CS(C)=O.O>[CH2:46]([N:19]1[C:15]([CH:14]([NH:20][C:21]([N:23]2[CH2:24][CH2:25][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:27][CH2:28]2)=[O:22])[CH2:13][C:5]2[CH:6]=[C:7]3[C:11](=[C:3]([CH2:1][CH3:2])[CH:4]=2)[NH:10][N:9]=[C:8]3[CH3:12])=[N:16][N:17]=[N:18]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CCc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nnn[nH]2)cc2c(C)n[nH]c12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nnnn2Cc2ccccc2)cc2c(C)n[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(7-ethyl-3-methyl-1H-indazol-5-yl)-1-(1H-tetrazol-5-yl)-ethyl]-amide (30 mg, 0.05 mmol, 1.0 equiv), sodium carbonate (18.0 mg, 3.0 equiv), and benzyl bromide (8 μL, 1.1 equiv) were combined in dimethylsulfoxide and the mixture stirred at room temperature overnight. The mixture was then diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine (3×), dried over sodium sulfate, and concentrated. Purification by preparative HPLC afforded a mixture of the two alkylated regioisomers which were not separated. LC/MS: tR=1.68 min, 619.44 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9](OCC)=[O:10])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:15])([CH3:14])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of the material from Step 1 (2.4 g, 8.9 mmol) in 30 mL of THF at −78° C. was added LiAlH4 (337 mg, 8.9 mmol). The mixture was stirred at or below −60° C. for 2 hr, and then stirred at room temperature for 1 hr. The reaction was quenched with 10% NaOH (aq) solution, and the mixture was extracted with EtOAc. The organic layer was separated, dried over MgSO4, and concentrated to get 2-(4-bromophenyl)-2-methylpropan-1-ol (2.03 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[O:5][CH2:6][C:7](=[N:9]O)[CH3:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[O:5][CH2:6][CH:7]([NH2:9])[CH3:8]
Reactant: CC(COc1cccc(C)c1)=NO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: Cc1cccc(OCC(C)N)c1
Reaction time: 4 h

Procedure:
A solution of 1-(3-methylphenoxy)propan-2-one oxime (13.7 g.) in dry ether (100 ml.) was added dropwise, over 45 minutes, to a stirred, refluxing mixture of lithium aluminium hydride (5.85 g.) in dry ether (200 ml.). Stirring and heating were continued for 4 hours and the mixture was cooled and treated cautiously with water (5.8 ml.) followed by 15% aqueous sodium hydroxide (5.8 ml.), and finally, water (17.5 ml.). The mixture was stirred for 30 minutes and then filtered. The filtrate was dried over anhydrous potassium carbonate and evaporated. The residue was distilled to give 1-(3-methylphenoxy)prop-2-ylamine, b.p. 124°-128°/13 mm.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH3:20])[CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15]([O:17]CC)=[O:16])[CH:11]=1.O.[OH-].[Li+]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH3:20])[CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1
Reactant: CCOC(=O)c1cc(CC(C)OC2CCCCO2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(Cc1cc(C(=O)O)no1)OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 5-(2-(tetrahydro-2H-pyran-2-yloxy)propyl)isoxazole-3-carboxylate (1.87 g, 6.60 mmol) was dissolved in THF (20 ml). Lithium hydroxide monohydrate 1 M (6.60 ml) was added and the resulting mixture was stirred for overnight at RT. Next day more lithium hydroxide monohydrate 1 M (3.3 ml+13.20 ml) was added and the mixture was again stirred overnight. THF was evaporated, water was added and pH was adjusted to 4 with citric acid solution. The mixture was extracted four times with ethyl acetate and the combined organic phases dried and evaporated. LC-MS: [M+1]=256.27.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:20]([C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]2[C:31]([CH2:32]Cl)=[CH:30][N:29]=[CH:28]2)=[CH:24][CH:23]=1)#[N:21].C(N(C(C)C)CC)(C)C>C(O)C>[O:18]=[C:11]1[C:12]2([CH2:17][CH2:16][N:15]([CH2:32][C:31]3[N:27]([CH2:26][C:25]4[CH:34]=[CH:35][C:22]([C:20]#[N:21])=[CH:23][CH:24]=4)[CH:28]=[N:29][CH:30]=3)[CH2:14][CH2:13]2)[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH2:9][NH:10]1
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Reactant: Cc1cccc(N2CNC(=O)C23CCNCC3)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CNC(=O)C23CCN(Cc2cncn2Cc2ccc(C#N)cc2)CC3)c1

Procedure:
A solution of 1-(3-methylphenyl)-1,3,8-triazaspiro[4.5]decan-4-one (0.25 g, 0.94 mmol), 1-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt (0.23 g, 0.94 mmol), and diisopropylethylamine (0.5 mL, 2.8 mmol) in absolute ethanol (5 mL) was heated under reflux overnight. The resulting mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluting with 5% methanol in ethyl acetate. The appropriate fractions were collected and concentrated. The residue was triturated with diethyl ether, and the white solid precipitated was collected by filtration to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][N:12]([CH:14]([CH3:18])[C:15](=[O:17])[CH3:16])[CH:13]=2)[O:3]1.[CH3:20][Mg+].[Br-]>C1COCC1.[Cl-].[Na+].O>[CH3:16][C:15]([OH:17])([CH:14]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:19])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:18])[CH3:20]
Reactant: C[Mg+]
Reactant: CC(=O)C(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Br-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(n1cc(B2OC(C)(C)C(C)(C)O2)cn1)C(C)(C)O
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butan-2-one (Preparation 133, in THF (6 mL) at 0° C. was added MeMgBr (3M, 0.24 mL, 0.71 mmol). After stirring for 3 hours, another portion of MeMgBr was added. The solution was stirred at room temperature for 16 hours. The reaction was diluted with brine and extracted with EtOAc. The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford the title compound as a yellow oil (99 mg, 70%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[CH:13][C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[CH:13][C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc2c(c1)C(=Cc1ccc[nH]1)C(=O)N2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1Nc2ccc(O)cc2C1=Cc1ccc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-methoxy-3-[(pyrrol-2-yl)methylene]indolin-2-one; (0.10 g, 0.4 mmol) in dichloromethane (5 mL) was treated with BBr3 solution (2.0 mL of a 1M solution in dichloromethane, 20 mmol, 5.0 eq.). After stirring overnight at ambient temperature, the reaction mixture was concentrated. The resulting oil was chromatographed on SiO2 (5 g) using 1:3 hexane/ethyl acetate to afford 5-hydroxy-3-[(pyrrol-2-yl)methylene]indolin-2-one; (0.04 g); 1H NMR (400 MHz, DMSO-d6) δ 6.30 (m, 1H), 6.60 (m, 2H), 6.78 (m, 1H), 6.98 (m, 1H), 7.32 (m, 1H), 7.58 (m, 1H), 9.00 (s, 1H), 10.60 (s, 1H) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([CH3:20])[CH:12]=2)[CH2:4][CH2:3]1>C(O)C.[Pd]>[CH3:20][C:13]1[CH:12]=[C:11]([O:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:16]=[CH:15][C:14]=1[NH2:17]
Reactant: Cc1cc(OCCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(OCCN2CCN(C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-Methyl-4-[2-(3-methyl-4-nitrophenoxy)ethyl]piperazine (0.69 g, 2.5 mmol) was dissolved in ethanol (10 mL) and 10% wt palladium on carbon (0.055 g) was added at ambient temperature. The reaction mixture was agitated under a hydrogen atmosphere at ambient temperature for 4 h. Palladium on carbon was removed by filtration with Celite and the solvent was removed under reduced pressure to afford 2-methyl-4-[2-(4-methylpiperazinyl)ethoxy]aniline as oil (0.60 g, y. 97%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[C:17](Cl)(Cl)=[O:18].ClC(OC(Cl)(Cl)Cl)=O>O1CCCC1>[O:18]=[C:17]1[O:1][CH2:2][C:3]2[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=2[NH:5]1
Reactant: Nc1ccccc1CO
Reactant: O=C(Cl)Cl
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2CO1

Procedure:
To a mixture of 2-hydroxymethylaniline (25 g), triethylamine (32 ml) and tetrahydrofuran (250 ml) was introduced phosgene generated from trichloromethyl chloroformate (12.2 ml) and active carbon at room temperature with stirring. After stirring for 1 hour at room temperature, the reaction mixture was filtered off and the filtrate was concentrated. The resulting residue was recrystallized from diethyl ether-n-hexane to give 4H-1,2-dihydro-2-oxo-[3,1]benzoxazine (22.3 g).
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:8]([C:10]1([C:16]2[N:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[CH:26]=[N:27][N:28]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=4)[C:29]=3[CH3:30])=[O:24])=[CH:18][CH:17]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)#[N:9].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:8]([C:10]1([C:16]2[N:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[CH:26]=[N:27][N:28]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=4)[C:29]=3[CH3:30])=[O:24])=[CH:18][CH:17]=2)[CH2:11][CH2:12][N:13]([S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:6])=[O:5])[CH2:14][CH2:15]1)#[N:9]
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: O=S(=O)(Cl)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(C3(C#N)CCN(S(=O)(=O)C4CC4)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
Cyclopropanesulfonyl chloride (66 μl) was added to a suspension of N-[6-(4-cyanopiperidine-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (227 mg) described in Reference Example 169 and potassium carbonate (207 mg) in N,N-dimethylformamide (1.7 ml), and stirred at room temperature for 5.5 hours. Water was added to the reaction solution and the precipitated solid was purified with silica gel chromatography (chloroform/methanol) to give the titled compound (242 mg) as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])(C(C)(C)C)(C)C>C(O)(=O)C.O>[OH:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19]
Reactant: CCOP(=O)(/C=C\CCO[Si](C)(C)C(C)(C)C)OCC
Solvent: CC(=O)O
Solvent: O
Product: CCOP(=O)(/C=C\CCO)OCC
Yield: 58.7 %

Procedure:
A solution of diethyl (Z)-4-(t-butyldimethylsilyloxy)but-1-enylphosphonate (1.32 g, 4.09 mmol) in acetic acid-water (2:1) (35 ml) was stirred at room temperature for 2 hr. The solvent was removed and the residue was purified by column chromatography on silica gel eluting with dichloromethane-methanol (19:1) to give diethyl (Z)-4-hydroxybut-1-enylphosphonate as a colourless liquid (0.5 g, 59%); νmax (film) 3380, 2980, 1720, 1620, 1390, 1230 and 1020 cm-1 ; δH (CDCl3) 1.33 (6H, t, J 7 Hz, CH3), 2.70 (2H, m, CH2), 3.15 (1H, s, OH), 3.73 (2H, t, J 7 Hz, CH2O ), 4.00 (4H, qu, J 7 Hz, CH3CH2), 5.70 (1H, dd, J 14 Hz and 20 Hz, PCH=CH), 6.60 (1H, ddt, J 7 Hz, 14 Hz and 54 Hz, PCH=CH) (Found: MH+ 209.0942. C8H17O4P requires MH+ 209.0943).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:22]([O-])([O-])=O.[K+].[K+].COC(=O)C1C=CC(O)=CC=1.BrCCCCCCCCCC=C>>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:22]
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: C=CCCCCCCCCCBr
Agent: COC(=O)c1ccc(O)cc1
Agent: [K+]
Product: C=CCCCCCCCCCOc1ccc(C(=O)OC)cc1

Procedure:
Synthesized as described above for compound 1. Quantities: K2CO3 (9.08 g, 66 mmol), methyl-4-hydroxy-benzoate (5.00 g, 33 mmol), 11-bromo-1-undecene (7.6 mL, 34 mmol). Yield 10.1 g (quant). 1NMR: δH (CDCl3; 300 MHz): 1.24-1.52 (12 H, m, CH2), 1.80 (2 H, m, O—CH2—CH2), 2.04 (2 H, m, CH2═CH—CH2), 3.87 (3 H, s, OCH3), 4.00 (2 H, t, 3J=6.5 Hz, O—CH2), 4.95 (2 H, m, CH2═CH), 5.82 (1 H, m, CH2═CH), 6.90 (2 H, d, 3J=9.0 Hz, Ar—H), 7.97 (2 H, d, 3J=9.0 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 26.4, 29.3, 29.5, 29.7, 29.8, 29.9, 34.2, 52.2, 68.6, 114.45, 114.5, 122.7, 131.9, 139.6, 163.4, 167.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]([OH:21])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2/[CH:11]=[CH:12]/[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C(N(CC)C(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.[CH2:42]([NH2:48])[C:43]1[O:47][CH:46]=[CH:45][CH:44]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(OCC)(=O)C>[O:47]1[CH:46]=[CH:45][CH:44]=[C:43]1[CH2:42][NH:48][C:19]([C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[NH:9][N:8]=[C:7]2/[CH:11]=[CH:12]/[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:21]
Reactant: O=C(O)c1cc(F)c2[nH]nc(/C=C/c3cccnc3)c2c1
Reactant: NCc1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(NCc1ccco1)c1cc(F)c2[nH]nc(/C=C/c3cccnc3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
376 mg of 7-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic acid was dissolved in 10 mL of N,N-dimethylformamide, and added with 903 μl of N,N-diisopropylethylamine, 244 mg of 1-hydroxybenzotriazole monohydrate and 147 μl of furfurylamine, and stirred at room temperature for 10 minutes. The solution was cooled to 0° C., added with 509 mg of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, and stirred at room temperature overnight. After diluting with water and ethyl acetate, the organic phase was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the resultant crude product was purified by silica gel column chromatography, to afford 159 mg of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][CH:2]1[CH2:5][C:4]([CH2:28][C:29]#[N:30])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][N:17](COCC[Si](C)(C)C)[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:3]1.C(#N)C.F[B-](F)(F)F.[Li+].[OH-].[NH4+]>O>[CH3:1][CH:2]1[CH2:3][C:4]([CH2:28][C:29]#[N:30])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:5]1
Reactant: CC1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: F[B-](F)(F)F
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CC1CC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-methyl-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (0.5 g, 0.001 mol) in acetonitrile (8.07 mL, 0.154 mol) and water (0.70 mL, 0.039 mol) was added lithium tetrafluoroborate (1.10 g, 0.0114 mol). The solution was warmed to reflux at 100° C. over 5 days. Charged 7.2 M of ammonium hydroxide in water (0.59 mL) in portions over a period of 5 minutes at rt adjusting pH to 9-10. The reaction mixture was stirred for 2 h at rt. The reaction was filtered and the filtrate was diluted with acetonitrile, water and MeOH and purified with prep. HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the first isomer with retention time 1.057 min, LCMS calculated for C1-6H17N6(M+H)+: 293.2; Found: 293.3. 1H NMR (500 MHz, CDCl3): δ 10.07(1H, br s), 8.88 (1H, s), 8.45 (1H, s), 8.34 (1H, s), 7.43 (1H, d, J=3.5 Hz), 6.85 (1H, d, J=3.5 Hz), 3.16 (2H, s), 2.77 (2H, m), 2.55 (1H, m), 2.43 (2H, m), 1.24 (3H, d, J=6.5 Hz) ppm; then the second isomer with retention time 1.107 min; LCMS calculated for C16H17N6(M+H)+: 293.2; Found: 293.3. 1H NMR (500 MHz, CDCl3): δ 10.21(1H, br s), 8.89 (1H, s), 8.61 (1H, s), 8.37 (1H, s), 7.44 (1H, d, J=3.5 Hz),6.86 (1 H, d, J =3.5 Hz), 3.07 (2H, s), 3.05 (2H, m), 2.61 (1H, m), 2.26 (2H, m), 1.25 (3H, d, J=7.0 Hz) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH2:10]O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>CN(C=O)C>[Br:35][CH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([OH:1])[CH:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1ccc(CO)cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc(CBr)cc1O
Reaction time: 2 h

Procedure:
2-hydroxy-4-hydroxymethylbenzonitrile (0.20 g, 1.34 mmol) was dissolved in DMF (5 mL) and CH2Cl2(5 mL) and then treated with triphenylphosphine (0.53 g, 2.01 mmol) and carbon tetrabromide (0.67 g, 2.01 mmol) at ambient temperature with stirring. After 2 h, the reaction mixture was partitioned between EtOAc (100 mL) and H2O (100 mL), the organic layer were separated, dried (MgSO4), and filtered to give the title compound after silica gel chromatography (15% EtOAc/hexane to 25% EtOAc/hexane).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[O:11]1CC[CH2:13][CH2:12]1.C(Cl)Cl.C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:12]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:11])[CH3:13]
Reactant: C1CCOC1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C(=O)O)cc1

Procedure:
To 20 g. of 4-hydroxybenzoic acid in suspension in 150 ml. of tetrahydrofuran (THF) and 150 ml. methylene chloride, 35 g. of triethylamine, 35 g. of acetic anhydride and 3 g. of 4-dimethylaminopyridine are added and the mixture refluxed for 30 minutes. The solvents are thereafter evaporated under reduced pressure and 6N hydrochloric acid is added to the residue. The resulting slurry is filtered, washed with water and dried, affording 20 g. of the captioned compound.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.B(F)(F)F.CCOCC.[CH:21](=[O:30])/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C1COCC1>[OH:30][CH:21]([CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCCC/C=C\C=O
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCC/C=C\CC(O)C#C[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Trimethylsilylacetylene (6.9 g, 48.6 mmole) is dissolved in 125 ml dry THF in a flamed dried 500 ml 3-neck round bottom flask under nitrogen at -78° C. The solution is treated with n-butyllithium (29.9 ml, 46.3 mmole) slowly dropwise over 10 minutes and stirred 30 minutes at -78° C. The reaction mixture is subsequently treated slowly dropwise with boron trifluoride etherate (6.0 ml, 48.8 mmole) and the resultant mixture is stirred 20 minutes at -78° C. 3-Z-Nonenal (6.2 g, 44 mmole), in 3×12 ml dry THF, is added rapidly dropwise to the reaction mixture at -78° C. The reaction is warmed to 0° C. and stirred an additional 20 minutes. The mixture is quenched with 100 ml saturated sodium chloride, the layers separated, and the aqueous phase extracted with 3×60 ml diethyl ether. The organics are combined, dried over magnesium sulfate, and concentrated in vacuo to a dark yellow oil (10.5 g). The crude oil is chromatographed over 200 g silica gel (230-400 mesh), eluting with 6% ethyl acetate/hexane and collecting 60 ml fractions. Fractions 8-16 are combined and concentrated to afford 6.3 g of the title compound as a pale yellow oil. Following the above procedure gives the title compound having the physical characteristic described below:
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[N:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[Br:12]N1C(=O)CCC1=O.O>C(#N)C>[Br:12][C:8]1[C:7]([NH2:10])=[CH:6][CH:5]=[C:4]([O:3][CH:2]([F:1])[F:11])[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(OC(F)F)nc1
Solvent: O
Solvent: CC#N
Product: Nc1ccc(OC(F)F)nc1Br

Procedure:
6-Difluoromethoxy-pyridin-3-yl-amine obtained in Step B (1.36 g) was treated with N-bromosuccinimide (1.51 g) in acetonitrile for 10 minutes. The solution was poured into water, extracted with ethyl acetate, the organic layer dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (eluent: cyclohexane/ethyl acetate 7:3) afforded 2-bromo-6-difluoromethoxy-pyridin-3-yl-amine as a red oil. 1H NMR (400 MHz, CDCl3) 3.95 (br s, 2H), 6.72 (d, 1H), 7.07 (d, 1H), 7.24 (dd, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[N:7]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([CH2:34][OH:35])=[C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=2)[C:22]=1[CH3:23])[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6](=[O:36])[N:7]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([CH:34]=[O:35])=[C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=2)[C:22]=1[CH3:23])[C:8]1[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)cnc(CO)c1OCc1cccc(C#N)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Product: Cc1c(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)cnc(C=O)c1OCc1cccc(C#N)c1
Yield: 65.9 %

Procedure:
A solution of [5-(3-cyano-benzyloxy)-6-hydroxymethyl-4-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (137) (235 mg, 0.484 mmol) and manganese (IV) dioxide (198 mg, 1.93 mmol) in methyl alcohol (5 mL) at room temperature for 2 hours. Excess manganese (IV) dioxide was filtered through a celite pad and washed with ethyl acetate. The filtrate was evaporated to give a crude residue, which was purified by column chromatography on silica gel using a gradient mixture of ethyl acetate:hexane (0:1 to 1:0) as eluant to give [5-(3-cyano-benzyloxy)-6-formyl-4-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (141) (154 mg, 66% yield) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]([C:13](N)=[O:14])[CH2:11][O:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH2:16]>Cl>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]([C:13]([OH:14])=[O:16])[CH2:11][O:12][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O
Reactant: COc1cccc2c1OC(C(N)=O)CO2
Agent: Cl
Product: COc1cccc2c1OC(C(=O)O)CO2

Procedure:
8-Methoxy-1,4-benzodioxan-2-carboxamide (2.41 g.) in 50% hydrochloric acid (35 ml.) was stirred at 100° C. for 1 hour. The resulting solution was cooled, diluted with water (200 ml.), extracted with chloroform (3×100 ml.) then the extracts dried (MgSO4) and evaporated in vacuo. The solid residue (1.8 g.) was recrystallized from water (m.p. 75°-78° C.) then from ethyl acetate/hexane to give 8-methoxy-1,4-benzodioxan-2-carboxylic acid, m.p. 131°-132° C.