Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]12[CH2:11][CH2:10][C@:9]1([CH2:12][O:13]CC1C=CC=CC=1)[CH2:8][N:7]([C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:6]2=[O:29])=[O:4].O1CCCC1.[H][H]>[C].[Pd].C(O)C>[CH3:1][O:2][C:3]([C@@:5]12[CH2:11][CH2:10][C@:9]1([CH2:12][OH:13])[CH2:8][N:7]([C@@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22])[C:6]2=[O:29])=[O:4]
Reactant: [H][H]
Reactant: COC(=O)[C@@]12CC[C@]1(COCc1ccccc1)CN([C@H](C)c1ccccc1)C2=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)[C@@]12CC[C@]1(CO)CN([C@H](C)c1ccccc1)C2=O

Procedure:
A 10% palladium-carbon catalyst (50% wet, 200 mg) was added to a solution of (1S,5R)-5-benzyloxymethyl-2-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane-1-carboxylic acid methyl ester (1.82 g, 4.62 mmol) in ethanol (20 mL)-tetrahydrofuran (20 mL), and the mixture was stirred in a hydrogen atmosphere at 40° C. for 2.5 hours. After removing the catalyst by filtration, the filtrate was concentrated to give the title compound as colorless crystals.
Reaction SMILES: [N:1]([C@H:4]1[C@H:9]([OH:10])[CH2:8][CH:7]=[CH:6][CH2:5]1)=[N+:2]=[N-:3].C(=O)(O)[O-:12].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[N:1]([C@@H:4]1[CH2:5][CH:6]2[C@@H:7]([O:12]2)[CH2:8][C@H:9]1[OH:10])=[N+:2]=[N-:3]
Reactant: O=C([O-])O
Reactant: [N-]=[N+]=N[C@@H]1CC=CC[C@H]1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: [N-]=[N+]=N[C@@H]1CC2O[C@H]2C[C@H]1O
Reaction time: 12 h
Yield: 64.5 %

Procedure:
(1R,6R)-6-Azidocyclohex-3-en-1-ol 3c (500 mg, 3.60 mmol) was dissolved in 150 mL of dichloromethane followed by the addition of sodium bicarbonate (600 mg, 7.20 mmol) and m-Chloroperbenzoic acid (2.40 g, 9.60 mmol), the reaction solution was stirred for 12 hours. The resulting solution was washed with saturated sodium bicarbonate solution (50 mL), saturated sodium thiosulfate solution (50 mL) and saturated sodium chloride solution (50 mL×3) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure, the residue was purified by HPLC to obtain the title compound (1S,3R,4R)-4-azido-7-oxabicyclo[4.1.0]heptan-3-ol 3d (360 mg, yield: 64.6%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([S:29]([O-:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.[Na+]>>[Cl:22][C:23]1[CH:24]=[C:25]([S:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Reactant: O=S([O-])c1cccc(Cl)c1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4cccc(Cl)c4)cc3c2C1
Yield: 26.8 %

Procedure:
The product of Example 29, step B (230 mg, 0.65 mmol) and sodium 3-chlorobenzenesulfinate (155 mg, 0.78 mmol) were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 3:2 hexanes/ethyl acetate) provided tert-butyl 8-(3-chlorophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (78 mg, 26%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.08 (s, 1H), 7.93 (t, J=1.8 Hz, 1H), 7.86-7.83 (m, 1H), 7.83-7.81 (m, 1H), 7.56-7.48 (m, 2H), 7.43 (t, J=7.8 Hz, 1H), 4.58 (s, 2H), 3.84 (t, J=5.4 Hz, 2H), 2.91-2.84 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][C:11]([C:19]4[CH:20]=[N:21][CH:22]=[N:23][CH:24]=4)=[CH:12][CH:13]=3)[C:8]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:7]=2[CH:6]=1.C(=O)=O>CO>[CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][C:11]([C:19]4[CH:20]=[N:21][CH:22]=[N:23][CH:24]=4)=[CH:12][CH:13]=3)[C@:8]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:7]=2[CH:6]=1
Reactant: CC(C)(C)COc1ccc2c(c1)C1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Agent: O=C=O
Solvent: CO
Product: CC(C)(C)COc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Yield: 36.6 %

Procedure:
2′-(2,2-Dimethylpropoxy)-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (139 mg) was subjected to chromatography using 40:60:0.2 MeOH:CO2:DEA at 70 ml/min on a 20×250 mm, 5 μm ChiralPak AD-H column and 100-bar system pressure. The first peak (RT=2.0 min) provided (R)-2′-(2,2-dimethylpropoxy)-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (50.9 mg, >99% ee), and the second peak (RT=3.9 min) provided (S)-2′-(2,2-dimethylpropoxy)-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (52.7 mg, >99% ee).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH:7]1[CH2:20][C:11]2=[N:12][C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:19]=[C:10]2[CH2:9][CH2:8]1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH:7]1[CH2:20][C:11]2=[N:12][C:13]3[NH:14][CH2:15][CH2:16][CH2:17][C:18]=3[CH:19]=[C:10]2[CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)CCC1CCc2cc3cccnc3nc2C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1CCc2cc3c(nc2C1)NCCC3
Reaction time: 12 h

Procedure:
A mixture of 14-2 (0.298 g, 1.05 mmol) and Pd on carbon (0.060 g) in ethanol (10 mL) was placed under 1 atm of H2 and stirred for 12 h. The solution was concentrated. The residue was purified by flash chromatography (5% MeOH in CH2Cl2) to give 14-3.
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:5]=[C:6]([N:11]2[CH2:16][CH2:15][O:14][NH:13][C:12]2=[O:17])[CH:7]=[CH:8][C:9]=1[Cl:10].[C:18]([O-])(=[O:20])C.[Na+]>O1CCOCC1>[OH:20][CH2:18][N:13]1[C:12](=[O:17])[N:11]([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH2:16][CH2:15][O:14]1
Reactant: O=C1NOCCN1c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1N(CO)OCCN1c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 89.2 %

Procedure:
300 ml of an aqueous solution of 30% formic aldehyde were added to a mixture of 30 g of 4-(3',4'-dichlorophenyl)-3-oxo-5,6-dihydro-1,2,4-oxadiazine, 30 g of anhydrous sodium acetate and 300 ml of dioxane and then the mixture was stirred for 2 hours at 20°-25° C and was acidified. The mixture was extracted with ethyl acetate and the extracts were dried and evaporated to dryness under reduced pressure. The residue was taken up in isopropyl ether and the mixture was vacuum filtered. The recovered solids were dried to obtain 30 g of 2-hydroxymethyl-4-(3',4'-dichlorophenyl)-3-oxo-5,6-dihydro-1,2,4-oxadiazine melting at 134° C.
Reaction SMILES: OO.[CH3:3][O:4][C:5]1[C:10]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]#[N:15])=[CH:9][CH:8]=[CH:7][N:6]=1.C(=O)([O-])[O-:27].[K+].[K+]>CS(C)=O>[CH3:3][O:4][C:5]1[C:10]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]([NH2:15])=[O:27])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ncccc1-c1cc(C#N)ccc1Oc1ccccc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ncccc1-c1cc(C(N)=O)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A solution of 30% aqueous hydrogen peroxide (1 mL, 7.6 mmol) was added dropwise to a suspension of 3-(2-methoxypyridin-3-yl)-4-phenoxybenzonitrile (Preparation 20, 0.23 g, 0.76 mmol) and potassium carbonate (0.64 g, 4.6 mmol) in DMSO (3 mL). The reaction mixture was stirred for 2 hours at room temperature, then quenched with aqueous sodium thiosulfate solution (10% w/v, 10 mL) and extracted with EtOAc (50 mL). The organic layer was dried over sodium sulfate and the solvent removed in vacuo to afford the title compound as a pale yellow solid (0.2 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[N:11]1[CH2:10][CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cnccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cnccn2)CC1
Temperature: 100 °C
Yield: 44.5 %

Procedure:
A mixture of 2-chloropyrazine (2.13 g, 18.7 mmol), tert-butyl piperazine-1-carboxylate (3.16 g, 17 mmol) and caesium carbonate (7.7 g, 23.7 mmol) in DMF (35 ml) was heated at 100° C. for 16 hours. Cooled to RT and diluted with ether. Ether layer was washed with water and brine, dried over sodium sulphate and distilled off the solvent to afford 2 g (40.7% yield) of the titled product after purification with (60/120 silica gel) column chromatography using 40% ethyl acetate in hexane as eluent.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][N:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Cl:18][C:19]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:23][N:22]=[C:21]2[N:31]([CH2:40][C:41](O)=[O:42])[N:32]=[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:20]=12.Cl.CN(C)CCCN=C=NCC.OC1C=CC=C[N+]=1[O-]>C(Cl)Cl>[Cl:18][C:19]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:23][N:22]=[C:21]2[N:31]([CH2:40][C:41]([N:14]3[CH2:15][CH2:16][CH2:17][N:11]([CH3:10])[CH2:12][CH2:13]3)=[O:42])[N:32]=[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:20]=12
Reactant: CN1CCCNCC1
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCCN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.1 %

Procedure:
A solution of diisopropylethylamine (DIPEA) (120 μL, 0.67 mmol) and 1-methyl 1,4-diazepane (34 mg, 0.3 mmol) in CH2Cl2 (1 mL) was added to a mixture of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (60 mg, 0.3 mmol) and 2-hydroxypyridine-N-oxide (HOPO) (30 mg, 0.27 mmol). The solution obtained was stirred at room temperature for 18 h. The reaction was purified using chromatography (silica gel, gradient 0 to 5% triethylamine/acetone) followed by preparative HPLC yielding Compound 65 as a white solid (25 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:5]=1[CH2:6][NH:7][CH2:8][CH2:9][OH:10])([O-:3])=[O:2].[N:19]#[C:20]Br>O1CCCC1>[N+:1]([C:4]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:5]=1[CH2:6][N:7]1[CH2:8][CH2:9][O:10][C:20]1=[NH:19])([O-:3])=[O:2]
Reactant: N#CBr
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1CNCCO
Solvent: C1CCOC1
Product: N=C1OCCN1Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 56 h

Procedure:
In a sealed tube, added 2-(2-nitro-4-(trifluoromethyl)benzylamino)ethanol (Step 1, 1.10 g, 4.16 mmol), cyanogen bromide (1.32 g, 12.4 mmol), and tetrahydrofuran (4.2 mL). Stirred at room temperature for 56 hours. Concentrated down to yield 3-(2-nitro-4-(trifluoromethyl)benzyl)oxazolidin-2-imine. MS (M+H)+=290; Calc'd 289.22 for C11H10F3N3O3.
Reaction SMILES: [CH:1]([NH:4][C:5]([CH:7]1[CH2:12][N:11]([C:13](OC(C)(C)C)=O)[CH2:10][CH2:9][N:8]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:6])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.ClC1[N:43]=[CH:42][N:41]=[C:40]([NH:44][C:45]2[S:46][C:47]([C:50]#[N:51])=[CH:48][N:49]=2)[CH:39]=1.C(N(CC)CC)C>>[C:50]([C:47]1[S:46][C:45]([NH:44][C:40]2[N:41]=[CH:42][N:43]=[C:13]([N:11]3[CH2:10][CH2:9][N:8]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])[CH:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:12]3)[CH:39]=2)=[N:49][CH:48]=1)#[N:51]
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)s1
Reactant: CC(C)NC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)C1CN(c2cc(Nc3ncc(C#N)s3)ncn2)CCN1C(=O)OCc1ccccc1
Temperature: 150 °C

Procedure:
47-2 (0.24 g, 0.78 mmol) was first treated with 3 mL of trifluoroacetic acid for 30 minutes at 25° C. and then the reaction was evaporated to dryness. The residue was dissolved in n-butanol and 35-1 (0.18 g, 0.78 mmol) and triethylamine (0.39 g, 3.88 mmol) were added. After heating at 150° C. for 18 hours, the reaction was cooled and the product was filtered off, washed with n-butanol, ethyl ether and then dried to afford the product 47-3. Hi-Res MS: calc: 507.1921 found: 507.1914. 1H-NMR (DMSO-d6): 12.15(s, 1H); 8.39(s, 1H); 8.25(s, 1H); 7.33(m, 5H); 6.11(s, 1H); 5.14(m, 2H); 4.47(m, 2H); 3.85(m, 2H); 3.69(m, 2H); 3.25(m, 1H); 3.17(m, 1H); 0.93(m, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1)=[N:7][CH:6]=[C:5]2[CH:24]=[O:25].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][O:35][CH2:36][CH3:37]>CN(C)C=O>[CH2:22]([O:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][C:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH2:33][CH2:34][O:35][CH2:36][CH3:37])=[C:11]([O:12][CH3:13])[CH:10]=2)[C:5]([CH:24]=[O:25])=[CH:6][N:7]=1)[CH3:23]
Reactant: CCOCCBr
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(O)c(OC)cc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCOc1cc2c(C=O)cnc(Cc3cccc(OCC)c3)c2cc1OC
Temperature: 85 °C
Yield: 87.6 %

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (60 g, 0.17 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (234 mg, 1.70 mmol) and 1-bromo-2-ethoxy-ethane (0.095 mL, 0.85 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the residue was purified on a flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) to afford product 1-(3-ethoxy-benzyl)-6-(2-ethoxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde as a colorless oil (61 mg, 88% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Li+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methyl 2-methoxy-4-(1-Boc-4-piperidyloxy)benzoate (4.5 g, 12.3 mmol) was dissolved in THF (200 ml) and treated with a solution of lithium hydroxide (17 ml of a 1.1M aqueous solution, 18.7 mmol) added over 5 min. The mixture was stirred at ambient temperature for 72 hours. An additional 4 ml of 1.1M lithium hydroxide was added and the mixture was heated at reflux for 13 hours, then stirred at ambient temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to give 2-methoxy-4-(1-Boc-4-piperidyloxy)benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:20][CH3:21])[N:6]2[CH2:16][CH2:17][CH2:18][OH:19].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>CN1C(=O)CCC1>[CH3:29][S:30]([O:19][CH2:18][CH2:17][CH2:16][N:6]1[C:5]([O:20][CH3:21])=[N:4][C:3]2[C:7]1=[N:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:10][C:2]=2[NH2:1])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCO)c2n1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCOS(C)(=O)=O)c2n1
Temperature: 5 °C

Procedure:
To a solution of 3-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)propan-1-ol (18.0 g, 61.0 mmol) in NMP (146 g) was added triethylamine (9.3 g, 91.4 mmol) and the mixture stirred at 5° C. Methanesulfonylchloride (9.1 g, 79.2 mmol) was added dropwise to the solution and stirred at 5° C. for 30 min. Water (144 g) was added, the mixture stirred for 1 hr and the suspension filtered to give the subtitle compound as water wet cake, which was directly used in the next reaction. Yield 42.4 g as a crude product.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1.[CH2:11](OCC)C>>[CH3:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: c1cc2c(cn1)CCCC2
Reactant: CCOCC
Product: Cc1nccc2c1CCCC2

Procedure:
2.155 g (16.20 mmol) of 5,6,7,8-tetrahydroisoquinoline, 20 ml of diethylether, and 13 ml (19.50 mmol) of a 1.5 molar solution of methyllithium-lithium bromide complex in diethylether are reacted for approximately 16 hours at 45° C. The excess methyllithium is destroyed by cautious addition of water, and the crude product is obtained by chloroform extraction. Removal of the chloroform in vacuo gives the crude product which is purified by LPLC (methylene chloride-acetone, 4:1) to give 1.00 g of product. The product exhibits NMR peaks (CDCl3, δ) at 8.25, 6.85, 2.65, 2.5, and 1.80.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([I:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4].[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.C1(C=CC(O)=CC=1)O>>[CH3:10][C:6]1[CH:5]=[C:3]([NH:4][CH2:13][CH2:12][C:11]([O:15][CH3:16])=[O:14])[C:2]([CH3:1])=[CH:8][C:7]=1[I:9]
Reactant: C=CC(=O)OC
Reactant: Cc1cc(I)c(C)cc1N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Oc1ccc(O)cc1
Agent: [OH-]
Product: COC(=O)CCNc1cc(C)c(I)cc1C

Procedure:
15.0 g (0.061 mol) of 2,5-dimethyl-4-iodo-aniline, 55 ml of (0.611 mol) of methyl acrylate, 6 ml of benzyltrimethyl ammonium hydroxide and 0.3 g (3 mmol) of hydroquinone are refluxed for 11 days. Then the excess acrylate is distilled off and the residue is chromatographed on silica gel, eluting with methylene chloride.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[NH2:40][CH:41]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[CH3:53])[CH2:42][C:43]([O:45][CH3:46])=[O:44]>CN(C=O)C>[CH3:46][O:45][C:43](=[O:44])[CH2:42][CH:41]([NH:40][C:7]([C:5]1[N:6]=[C:2]([Br:1])[S:3][CH:4]=1)=[O:9])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[CH3:53]
Reactant: O=C(O)c1csc(Br)n1
Reactant: COC(=O)CC(N)c1ccccc1C
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)CC(NC(=O)c1csc(Br)n1)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
100 mg (0.48 mmol) of 2-bromo-1,3-thiazole-4-carboxylic acid are dissolved in 10 ml of DMF, N-ethylmorpholine (122 mg, 2.2 Eq) and TOTU (174 mg, 1.1 Eq) are added and the mixture is stirred at RT for 5 minutes. Then 93 mg (1 Eq) of methyl 3-amino-3-(2-methylphenyl)propanoate are added and the mixture is stirred overnight. The solvent is removed in vacuo and the residue subjected to preparative HPLC delivering 3-[(2-bromo-thiazole-4-carbonyl)-amino]-3-o-tolyl-propionic acid methyl ester yields in yields below 80%
Reaction SMILES: NC1C=CC(C2C3C(=NC=NC=3N)N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=2)=CC=1.[NH2:31][C:32]1[C:37]([OH:38])=[CH:36][CH:35]=[C:34]([CH3:39])[CH:33]=1.[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C@H:67]3[CH2:72][CH2:71][C@@H:70]([N:73]4[CH2:78][CH2:77][N:76]([CH3:79])[CH2:75][CH2:74]4)[CH2:69][CH2:68]3)[N:48]=[C:49]([C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4OC5C=CC=C(C)C=5N=4)=[CH:52][CH:51]=3)[C:42]=12>>[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C@H:67]3[CH2:72][CH2:71][C@@H:70]([N:73]4[CH2:74][CH2:75][N:76]([CH3:79])[CH2:77][CH2:78]4)[CH2:69][CH2:68]3)[N:48]=[C:49]([C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4[O:38][C:37]5[CH:36]=[CH:35][C:34]([CH3:39])=[CH:33][C:32]=5[N:31]=4)=[CH:52][CH:51]=3)[C:42]=12
Reactant: Cc1ccc(O)c(N)c1
Reactant: Cc1cccc2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc12
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Product: Cc1ccc2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc2c1

Procedure:
Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-methyl-1,3-benzoxazol-2-amine was prepared from cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.057 g, 0.140 mmol) and 2-amino-p-cresol (0.017 g, 0.140 mmol) in a manner similar to that used for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-methyl-1,3-benzoxazol-2-amine. The compound was formed as an off-white solid (0.010 g, 13%): 1H NMR (DMSO-d6, 400 MHz) δ 10.81 (s, 1H), 8.23 (s, 1H), 7.93 (d, 2H), 7.66 (d, 2H), 7.38 (d, 1H), 7.30 (s, 1H), 6.96 (d, 1H), 4.80 (m, 1H), 2.60-2.07 (m, 12H), 2.39 (s, 3H), 2.15 (s, 3H), 1.71-1.59 (m, 5H); RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=7.48 min., 90%; m/z 538 (MH+).
Reaction SMILES: [C:1]1([CH:7]([C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:28]=[S:29])C.S>O1CCCC1>[S:29]=[CH:28][NH:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: NC(C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CCOC=S
Agent: S
Solvent: C1CCOC1
Product: O=C(OC(c1ccccc1)c1ccccc1)C(NC=S)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of 15.9 g. (0.05 mol.) of α-phenylglycine, diphenylmethyl ester, and 9 g. (0.1 mol.) of ethylthioformate in 50 ml. of tetrahydrofuran is stirred overnight at room temperature. Then a stream of hydrogen sulfide is passed into the solution for 10 minutes, the reaction mixture is permitted to stand overnight, then concentrated and petroleum ether is added to the residue. 16.9 g. of α-[(thioxomethyl)amino]benzeneacetic acid, diphenylmethyl ester, crystallizes. The crude product is recrystallized from methanol, m.p. 129°-130°.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](Cl)=[O:32].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)=[O:32])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: O=C(Cl)c1ccccn1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(CNC(=O)c3ccccn3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.3 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.55 g, 1.6 mmol) in acetonitrile (10 mL), was added picolinoyl chloride hydrogen chloride (0.32 g, 1.8 mmol) and N,N-diisopropyl ethylamine (0.62 mL, 3.8 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give pyridine-2-carboxylicacid[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-amide as an off-white solid (67 mg, 10% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.85 min (99.4%); mp, 261-263° C.; 1HNMR (DMSO-d6) 2.08-2.27 (m, 1H, CHH), 2.64-2.93 (m, 6H, CHCH2, CH3), 4.91-5.05 (m, 2H, CH2NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 7.33-8.69 (m, 7H, Ar), 9.32 (t, J=6 Hz, 1H, CH2NH), 11.06 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.73, 23.31, 30.62, 42.12, 56.57, 117.72, 121.86, 125.18, 125.76, 126.60, 134.05, 137.82, 140.30, 148.55, 149.77, 154.87, 161.17, 163.79, 169.47, 172.65. LCMS MH=406; Anal Calcd For C21H19N5O4+0.5H2O: C, 60.86; H, 4.86; N, 16.90. Found: C, 60.72; H, 4.62; N, 16.69.