Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:13]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][C@H:23]([CH2:25][C:26]([O-:28])=[O:27])[C:22](=[O:29])[N:21]([CH3:30])[CH2:20][C:19]=3[CH:31]=2)=[O:14])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C(C(O)=O)(F)(F)F.N1(C(C2C=CC3N[C@@H](CC([O-])=O)C(=O)N(C)CC=3C=2)=O)CCC(C2CCNCC2)CC1>O.C(#N)C>[N:1]1([C:13]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][C@H:23]([CH2:25][C:26]([OH:28])=[O:27])[C:22](=[O:29])[N:21]([CH3:30])[CH2:20][C:19]=3[CH:31]=2)=[O:14])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CN1Cc2cc(C(=O)N3CCC(C4CCNCC4)CC3)ccc2N[C@H](CC(=O)[O-])C1=O
Agent: CN1Cc2cc(C(=O)N3CCC(C4CCNCC4)CC3)ccc2N[C@@H](CC(=O)[O-])C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: CN1Cc2cc(C(=O)N3CCC(C4CCNCC4)CC3)ccc2N[C@H](CC(=O)O)C1=O

Procedure:
Using the procedure of Preparation 8(j), except substituting the compounds of Example 26(b) and 27(b) for the compound of Preparation 8(i) gave the following compounds: 26(c). (R)-7-[(4,4'-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate: [α]D +92.4 (c 0.5,CH3OH); MS(ES) m/e 429 [M+H]+ ; 427 [M-H]- ; HPLC tR 12.7 min (Ultrasphere C18, 4.6×250 mm, 1.5 mL/min, gradient, A:acetonitrile B: water-0.1% TFA, 5-60% acetonitrile over 20 min, UV detection at 220 nm); Anal. (C23H32N4O4.4.5 CF3CO2H.3.33 H2O) calcd: C, 37.44; H, 4.16; N, 5.29. found: C, 37.43; H, 3.81; N, 5.20. 27(c). (S)-7-[(4,4'-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate: [α]D -105.9 (c 0.6,CH3OH); MS(ES) m/e 429 [M+H]+ ; 427 [M-H]- ; HPLC tR 12.6 min (Ultrasphere C18, 4.6×250 mm, 1.5 mL/min, gradient, A:acetonitrile B: water-0.1% TFA, 5-60% acetonitrile over 20 min, UV detection at 220 nm); Anal. (C23H32N4O4.3 CF3CO2H.1.25 H2O) calcd: C, 43.92; H, 4.77; N, 7.06. found: C, 44.09; H, 5.00; N, 7.29.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[C:17]([N:28]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH:16]=2)[CH2:11][CH2:10]1>ClCCl>[CH3:8][N:9]1[CH2:10][CH2:11][CH:12]([C:15]2[CH:27]=[CH:26][C:18]([C:19]([OH:21])=[O:20])=[C:17]([N:28]([CH:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[C:29](=[O:34])[C:30]([F:31])([F:32])[F:33])[CH:16]=2)[CH2:13][CH2:14]1
Reactant: CN1CCC(c2ccc(C(=O)OC(C)(C)C)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(c2ccc(C(=O)O)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
6.33 mL of 2,2,2-trifluoroacetic acid (82 mmol) is added under stirring to a solution of 3.2 g of tert-butyl 4-(1-methylpiperidin-4-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzoate (5.47 mmol) (in the form of a salt of trifluoroacetic acid) in 30 mL of dichloromethane. The reaction medium is stirred at room temperature for 16 h, and then evaporated under reduced pressure. The residue is taken up in ethanol, and the white solid formed is filtered on a fritted disc to yield 1.61 g (53%) of white crystals.
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3][OH:4].Br[CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1.[H-].[Na+].C(OCC1C=CC(C(O)=O)=CC=1)CC=C>>[CH3:5][C:2](=[CH2:1])[CH2:3][O:4][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: C=C(C)CO
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: C=CCCOCc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Product: C=C(C)COCc1ccc(C(=O)O)cc1

Procedure:
The reaction of 2-Methyl-prop-2-en-1-ol and 4-Bromomethyl-benzoic acid in the presence of sodium hydride was performed as described for Compound 33 to give 4-(2-Methyl-allyloxymethyl)benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.85 (S, COOH); 7.91 (d, J=8.3, 2 arom. H); 7.42 (d, J=8.3, 2 arom.H); 4.96, 4.88 (2 s-like; C═CH2); 4.51 (s, —OCH2—C6H4); 3.90 (s, CH2O); 1.69 (s, CH3). 13C-NMR (100 MHz, d6-DMSO): 167.12 (—C═O); 143.60; 141.98; 129.74; 129.32 (2 arom.C); 127.09 (2 arom.C); 111.74; 73.50; 70.52; 19.29.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1.S(Cl)([Cl:16])=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:16][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-n2nccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1ccc(-n2nccn2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 50.58 g (289 mmol) of (4-[1,2,3]triazol-2-yl-phenyl)-methanol in 2000 ml of CH2Cl2, 31.59 ml (433 mmol) of thionyl chloride Is added dropwise at 0-5° C. and the reaction mixture is allowed to warm to r.t. After stirring for 16 h, the reaction mixture is basified with sat. NaHCO3 at 0-5° C. and extracted with CH2Cl2. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].[CH2:12]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH2:15][CH3:16]>[Pd]>[F:11][C:6]1[C:7]([F:10])=[CH:8][CH:9]=[C:2]([C:20]2[CH:19]=[CH:18][C:17]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:22][CH:21]=2)[C:3]=1[CH:4]=[O:5]
Reactant: CCCCCc1ccc(B(O)O)cc1
Reactant: O=Cc1c(Br)ccc(F)c1F
Agent: [Pd]
Product: CCCCCc1ccc(-c2ccc(F)c(F)c2C=O)cc1

Procedure:
2-bromo-5,6-difluorobenzaldehyde is reacted with 4-pentylphenylboronic acid in the presence of a Pd catalyst to give 3,4-difluoro-4′-pentylbiphenyl-2-carbaldehyde. This compound is reacted with trimethylsulfonium iodide, to give 3,4-difluoro-2-(oxiran-2-yl)-4′-pentyl-biphenyl. Without further purification, this compound is converted into 1,2-difluoro-7-pentylphenanthrene in the presence of BF3 etherate. The raw product is purified by the procedure typical for this type of liquid-crystal materials (cf. DE-A 195 00 768), yielding 1,2-difluoro-7-pentylphenanthrene in the form of colorless crystals. Kumar, J. Org. Chem. 1997, 62, 8535-8539 discloses the coupling of boronic acid compounds with a bromo compound having aldehyde functionality.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)Br.[Cl:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[O:24][CH2:25][C:26]([NH2:28])=[S:27]>C(#N)C.CO>[Cl:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[O:24][CH2:25][C:26]1[S:27][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:28]=1
Reactant: CSc1ccc(C(Br)C(=O)c2ccccc2F)cc1
Reactant: NC(=S)COc1cccc(Cl)c1
Solvent: CO
Solvent: CC#N
Product: CSc1ccc(-c2sc(COc3cccc(Cl)c3)nc2-c2ccccc2F)cc1
Temperature: 0 °C
Yield: 32.5 %

Procedure:
A solution of 1-(2-fluorophenyl)-2-(4-methylthiophenyl)-2-bromo ethanone, (1.64 g, 4.8 mmol) (Example 34, Step 3) and 3-chlorophenoxy thioacetamide (0.98 g, 4.8 mmol) in 25 mL of acetonitrile was heated to reflux for 14 hours. The solution was diluted with methanol, cooled to 0° C. in an ice bath and a precipitate formed that was removed by filtration to provide pure 2-((3-chlorophenoxy)methyl)-4-(2-fluorophenyl)-5-(4-methylthiophenyl)thiazole (0.69 g; 32%). The filtrate was concentrated in vacuo, and the residue dissolved in ethyl acetate, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide additional product that was crystallized from a mixture of dichloromethane and isooctane to provide 200 mg of additional material for a total yield of 890 mg (42%): mp 115°-118° C.: 1H NMR (CDCl3) 300 MHz 7.52-6.90 (m, 12H), 5.38 (s, 2H), 2.46 (s, 3H). 19F NMR (CDCl3) -113.61 (m). High resolution mass spectrum calc'd. for C23H17ClFNOS2 (M+): 441.0424. Found: 441.0467.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=O)[CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(NC(=O)CNCc2ccc(OC)c(OC)c2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cc(Br)cc(NCCNCc2ccc(OC)c(OC)c2)c1

Procedure:
In a manner similar to Preparation 2, react N-(3-bromo-5-methoxyphenyl)-2-[[(3,4-dimethoxyphenyl)methyl]amino]acetamide with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]=[O:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:30][Mg]Br.O.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]([OH:29])[CH3:30])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1

Procedure:
In 30 mL of tetrahydrofuran was dissolved 620 mg of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-formylquinazoline (IV-1), the solution was cooled to 0° C. under the nitrogen atmosphere, and 4.9 mL of methylmagnesium bromide (0.93M tetrahydrofuran solution) was added dropwise. After the reaction at 0° C. for 1 hour under the nitrogen atmosphere, water and ethyl acetate were added to separate the layers. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After concentration, the resulting crystal was washed with chloroform to obtain 330 mg of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-hydroxyethan-1-yl)quinazoline (VI-1).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[NH:16][N:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:10][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[C:7]=1[CH:8]=[N:11][C:12]1[N:16]2[N:15]=[CH:14][CH:13]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: Nc1ccn[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Clc1ncnc2c1cnc1ccnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
The product from Example 1a (1.24 g, 7.01 mmol) in 30 mL of THF was reacted with 5-aminopyrazole (0.58 g, 7.01 mmol) in 10 mL of THF under an argon atmosphere by dropwise addition. The mixture was stirred at room temperature for 1 hour and then added diisopropylethylamine (1.22 mL, 7.01 mmol) dropwise with stirring. The mixture was heated overnight at 60° C., and quenched with water and extracted with EtOAc, washed with brine, and dried over Na2SO4. The product was filtered and the solvent was removed under vacuum. The product was purified by silica gel chromatography eluting with EtOAc/hexane to give the title compound as a pale yellow solid (405 mg, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:10][C:11]=2[C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:10][C:11]=2[C:12](=[O:14])/[CH:13]=[CH:25]/[N:26]([CH3:28])[CH3:27])=[CH:21][CH:22]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Product: CN(C)/C=C/C(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Yield: 90.5 %

Procedure:
A solution of 1-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)ethanone (370 mg, 1.12 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (10.0 mL, 75.3 mmol) was heated to 80 degrees for 6 hours. The reaction was cooled and concentrated in vacuo. The residue was purified by silica gel chromatography (EA/DCM=0/100→100/0) to give 389 mg (90% yield) of the title compound as a yellow solid. LC/MS (FA) ES+ 384, 386. 1H NMR (300 MHz, CDCl3) δ: 8.70-8.68 (m, 2H), 7.81-7.75 (m, 3H), 7.36-7.33 (m, 2H), 7.26-7.24 (m, 2H), 5.41 (d, 1H, J=12.3 Hz), 4.55 (s, 2H), 3.16 (s, 3H), 2.88 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH3:15][S:16]([O-:18])=[O:17].[Na+].[OH-].[Na+]>CS(C)=O>[CH3:15][S:16]([C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1)(=[O:18])=[O:17]
Reactant: CS(=O)[O-]
Reactant: O=[N+]([O-])c1cc(Br)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Yield: 33.5 %

Procedure:
Stir the mixture of 1-bromo-3-nitro-5-(trifluoromethyl)benzene (6 g, 22.2 mmol), sodium methanesulfinate (2.8 g, 26.7 mmol), cuprous iodide (0.5 g, 2.22 mmol), L(−)-proline (0.5 g, 4.44 mmol) and sodium hydroxide (0.088 g, 4.44 mmol) in DMSO (20 mL) at 100° C. for 15 hrs under nitrogen atmosphere. Add water, extract the mixture with ethyl acetate (200 mL×3), combine the organic layers, dry over anhydrous sodium sulfate, and concentrate the mixture under reduced pressure. Purify the residue by flash chromatography to afford the desired product (2 g, 33.3%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([CH3:3])[CH3:2]>CCO.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)Oc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CC(C)Oc1ccc(N)cc1C(=O)O
Reaction time: 2 h
Yield: 79.5 %

Procedure:
Methyl 2-isopropoxy-5-nitrobenzoate (6.92 g, 28.95 mmol) was taken up in THF/H2O (35 ml of each) and LiOH (1.39 g, 57.9 mmol) was added. The mixture was stirred at RT overnight then the pH was lowered to 1 by the addition of concentrated HCl and the product extracted in ethyl acetate (50 ml). The organic layer was dried (MgSO4) and evaporated to give 2-isopropoxy-5-nitrobenzoic acid (6.02 g, 92.5%) as a yellow solid. 1H NMR (δ, 250 MHz, DMSO-d6): 1.32 (d, 6-H, CH3), 4.88 (septet, 1-H, CH), 7.37 (d, 1-H, aromatic), 8.32 (dd, 1-H, aromatic), 8.40 (d, 1-H, aromatic), 13.13 (s, 1-H, CO2H). 2-Isopropoxy-5-nitrobenzoic acid (6.02 g, 26.75 mmol) was suspended in EtOH (100 ml) and 10% Pd on C (wet basis) (600 mg) was added. The mixture was hydrogenated at 50 psi for 2 hrs. The mixture was filtered through celite and the volatiles were removed in vacuo. The residue was triturated with IPA, and the resulting solid filtered off, washed with MTBE and dried in vacuo to give 4.15 g of 5-amino-2-isopropoxybenzoic acid (79.5%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Br:1])[CH:3]=1
Reactant: N#Cc1ccc(CC(=O)O)cc1Br
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(C#N)c(Br)c1
Temperature: 85 °C

Procedure:
(3-Bromo-4-cyanophenyl)acetic acid (1.0 g, 4.2 mmol) was dissolved in methanol (20 mL), and thionyl chloride (0.5 mL) was added drop wise to the solution. The reaction was heated to 85° C. for 4 h. Then it was cooled to room temperature and evaporated to dryness in vacuo. The residue was partitioned between ethyl acetate and sat. NaHCO3. The organic layer was dried over MgSO4, filtered, and the filtrate was evaporated to dryness under reduced pressure to yield the crude title compound as an off white solid. 1H NMR (500 MHz, CDCl3): δ 7.07 (d, J=7.07 Hz, 1H), 7.00-6.97 (m, 2H), 3.74 (s, 3H), 3.73 (s, 2H). LC-MS (IE, m/z): 195.2 [(M+1)−CO2CH3]+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:20]=[C:12]2[N:13]=[C:14]([CH2:18][F:19])[CH:15]=[C:16](O)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O.O>C(Cl)Cl.CCCCCC>[CH2:1]([S:8][C:9]1[N:20]=[C:12]2[N:13]=[C:14]([CH2:18][F:19])[CH:15]=[C:16]([Cl:23])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(CF)nc2nc(SCc3ccccc3)nn12
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: FCc1cc(Cl)n2nc(SCc3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 17.0 g (58.6 mmol) of 2-benzylthio-5-fluoromethyl-7-hydroxy-1,2,4-triazolo[1,5-a]pyrimidine and 100 ml of phosphorus oxychloride was heated at reflux for three hours and was then concentrated by simple distillation using a water aspirator to reduce the pressure to obtain a dark, viscous oil. This was dissolved in 300 ml of methylene chloride and treated cautiously with stirring with 200 ml of water. The mixture was stirred vigorously for 30 min. at ambient temperature and then allowed to separate into phases. The organic phase was separated, washed with water and saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure to obtain a dark oil. This solidified on trituration in hexane containing a little methylene chloride to yield 12.2 g (67 percent of theory) of the title compound as a tan solid melting at 81°-86° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:3]=12.Cl.[NH2:23]O.Cl>C(O)(=O)C>[CH2:20]([N:17]1[C:4]2[N:5]=[CH:6][C:7]3[C:2](=[N:23][O:16][C:8]=3[C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=3)[C:3]=2[CH:19]=[N:18]1)[CH3:21]
Reactant: NO
Reactant: CCn1ncc2c(Cl)c(C(=O)c3cccc(F)c3)cnc21
Agent: Cl
Solvent: CC(=O)O
Product: CCn1ncc2c3noc(-c4cccc(F)c4)c3cnc21
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
4-Chloro-1-ethyl-5-(3-fluorobenzoyl)-1H-pyrazolo[3,4-b]pyridine (4.60 g) and hydroxylamine hydrochloride (14.0 g) were refluxed in a solution of 250 ml of acetic acid and 4 ml of concentrated hydrochloric acid. After 90 minutes, the solvent was evaporated and the residue distributed between dichloromethane and an aqueous sodium bicarbonate solution. The organic phase was evaporated and the residue was chromatographed over 230-400 mesh silica gel (10% ethyl acetate/dichloromethane). Evaporation of the appropriate fractions gave 3.2 g of product, mp 182°-184°. Recrystallization from ethyl acetate gave analytically pure product, mp 183°-184° C.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[C:5]([N:8]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH:9]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](Cl)=[O:17])[C:11]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:10]1=2)(=[O:7])[CH3:6]>ClCCl>[CH:1]([NH:4][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][CH:9]([N:8]([C:5](=[O:7])[CH3:6])[CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:26]=2)[C:10]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:11]1=2)=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)Cl)c2cc(Cl)ccc21
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)NC(C)C)c2cc(Cl)ccc21
Reaction time: 1 h
Yield: 86 %

Procedure:
Add isopropyl amine (0.3 mmol) to a dichloromethane solution of 5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-8-chloro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carbonyl chloride (0.050 g, 0.11 mmol) at room temperature under nitrogen. After stirring for 1 h remove solvent under vacuum and chromatograph the crude product over silica gel using ethyl acetate/hexane (30-40%) to elute. This provides the title compound (0.052 g, 87%) as a colorless solid: MS (ES+): 550 (M+H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[CH2:7])(=[O:3])[CH3:2]>CO>[CH2:5]([OH:4])[CH:6]=[CH2:7].[C:1]([O:4][CH3:5])(=[O:3])[CH3:2]
Reactant: C=CCOC(C)=O
Solvent: CO
Product: C=CCO
Product: COC(C)=O
Yield: 91 %
Yield: 92 %

Procedure:
The tube described above was charged with 152 g. of magnesia catalyst (Harshaw Mg 0601 T, 1/8 in. extruded pellets). After pretreatment with methanol vapor at 200°-220°C. the tube was maintained at that temperature range while a mixture of 50 g. of allyl acetate and 150 g. of methanol was passed through over 1.5 hours. Quantitative glpc analysis of the effluent showed the presence of 9.1 g. of unconverted allyl acetate (18% recovery), 21.7 g of allyl alcohol (91% yield based on 82% conversion), 27.9 g of methyl acetate (92% yield) and the excess methanol. The allyl alcohol could be readily isolated by distillation.
Reaction SMILES: [CH3:1][N:2]([CH:28]([CH3:30])[CH3:29])[C:3]1[C:4]([C:17]2[O:18][CH:19]=[CH:20][C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH:28]([CH3:30])[CH3:29])[C:3]1[C:4]([C:17]2[O:18][CH:19]=[CH:20][C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nc(-c3occc3-c3ccccc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1occc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-(3-phenylfuran-2-yl)quinoxaline-6-carboxylate (140 mg, 0.35 mmol) in methanol (35 mL) and water (2.0 mL) was added sodium hydroxide (55 mg, 1.38 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL) and adjusted to pH 4 with HCl (3N). The solids were collected by filtration to afford 3-[methyl(propan-2-yl)amino]-2-(3-phenylfuran-2-yl)quinoxaline-6-carboxylic acid as a light yellow solid (100 mg, 74%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]([NH:28][C:29](=[O:33])[CH2:30][C:31]#[N:32])[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:34][CH:35]([CH3:38])[CH:36]=O.N1CCCCC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]([NH:28][C:29](=[O:33])[C:30]([C:31]#[N:32])=[CH:34][CH:35]([CH3:38])[CH3:36])[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: C[C@@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)CC#N
Reactant: CC(C)C=O
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)C=C(C#N)C(=O)N[C@@H](C)Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
A suspension of N-[(2S)-1-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]propan-2-yl]-2-cyanoacetamide (250 mg, 0.56 mmol, 1.00 equiv), 2-methylpropanal (81 mg, 1.12 mmol, 2.00 equiv) and piperidine (47 mg, 0.55 mmol, 1.00 equiv) in methanol (15 mL) was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1). The purified product was re-purified on Prep-HPLC eluting with TFA (0.05%)/H2O and CH3CN. The organic phase was removed off under reduced pressure. The aqueous phase was adjusted to 10 with potassium carbonate, which was extracted with DCM. The organic layers were combined, washed with brine, dried over sodium sulfated, filtrated and concentrated. This resulted in 46.4 mg (17%) of the title compound as a white solid. LC-MS m/z: 500 (M+1). H-NMR (400 MHz, CDCl3, ppm): 8.49 (s, 1H), 8.12 (d, J=7.2 Hz, 1H), 7.60 (t, J=8.8 Hz, 1H), 7.44 (m, 3H), 7.25-7.21 (m, 1H), 7.13 (d, J=8.4 Hz, 2H), 6.94 (dd, J=8.4, 2.4 Hz, 1H), 6.88 (dd, J=11.2, 2.4 Hz, 1H), 5.51 (brs, 2H), 4.74-4.55 (m, 3H), 3.00-2.95 (m, 1H), 1.21 (d, J=6.8, 3H), 1.15 (d, J=6.8 Hz, 6H).