Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:5](=[CH:7][S:8][CH:9]=2)[N:6]=1.C(=O)=O.[Br:13]N1C(=O)CCC1=O.[Cl-].[Na+]>O1CCCC1>[Br:13][C:9]1[S:8][CH:7]=[C:5]2[C:4]=1[O:3][C:2]([CH3:1])=[N:6]2
Reactant: Cc1nc2cscc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2csc(Br)c2o1

Procedure:
1 mmol of 2-methylthieno[3,4-d][1,3]oxazole was dissolved in 10 ml of tetrahydrofuran and the temperature was kept at −78° C. in a methanol bath cooled by dry ice. A solution in which 1.05 mmol of N-bromosuccinimide was dissolved in 5 ml of tetrahydrofuran was gradually added dropwise to carry out the reaction for 2 hours. Then an excess amount of saturated sodium chloride aqueous solution was added to stop the reaction. The reacted liquid was washed with water. Then the organic layer was recovered and dried under sodium sulfate. The solvent was evaporated out. The product was purified using column separation with the solvent of ethylacetate and hexane, obtaining 6-bromo-2-methylthieno[3,4-d][1,3]oxazole represented by formula (21).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].C[C:10]1[CH:11]=[CH:12][C:13]2[C:14]([CH3:23])([CH3:22])[CH2:15][CH2:16][C:17]([CH3:21])([CH3:20])[C:18]=2[CH:19]=1.Cl.[CH2:25](Cl)Cl>>[CH3:10][C:11]1[C:6]([C:5]([CH3:25])=[O:7])=[CH:19][C:18]2[C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15][C:14]([CH3:23])([CH3:22])[C:13]=2[CH:12]=1
Reactant: ClCCl
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C

Procedure:
To a suspension of 6.71 g (50.3 mmol) of aluminum chloride in methylene chloride at 0° C. under argon was added a solution of 3.95 g (3.58 mL, 50.3 mmol) of acetyl chloride and 10.21 g (41.9 mmol) of 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene in methylene chloride. The resulting mixture was allowed to warm to room temperature over a period of 3 hours with stirring. The mixture was recooled to 0° C. and 1N HCl was dropwise added. The mixture was then taken-up in water and extracted three times with methylene chloride. The organic layers were washed with 1N HCl, water, brine, and dried (MgSO4). Solvent was removed in-vacuo and the resulting residue purified using flash chromatography to give the title compound as an ivory solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH3:33])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[C:21]1[N:26]=[C:25]([CH2:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH:24]=[CH:23][CH:22]=1.[CH3:34][CH2:35][O:36][CH:37]=[C:38]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>O1CCCC1>[CH2:35]([O:36][CH:37]([CH:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH:27]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([C:14]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=2[CH3:33])[N:26]=1)[C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH3:34]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCCC(=O)Cc1cccc(-c2c(C)cc(C)cc2C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC(=O)C(c1cccc(-c2c(C)cc(C)cc2C)n1)C(OCC)C(C(=O)OCC)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diisopropyl amine (0.16 mL, 1.13 mmol) was dissolved in tetrahydrofuran (2 mL). n-Butyllithium (2.5M, 0.45 mL, 1.13 mmol) was added at 0° C. and the reaction stirred for 0.5 h. The solution was cooled to −78° C. and 1-(6-mesityl-pyridin-2-yl)-pentan-2-one (0.29 g, 1.0 mmol) was added. After 0.5 h, ethyl ethoxymethylene malonate (0.21 mL, 1.0 mmol) was added and the reaction was warmed to room temperature. The solution was quenched with water, extracted with ethyl acetate, dried, and concentrated. Flash chromatography (10%-20% ethyl acetate/hexanes) gave the title compound as a mixture of two isomers.
Reaction SMILES: COC(=O)CCCCN([C:10](=[O:35])[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([O:19][C:20](=[O:34])[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15][CH2:14]1)C.[Li+].[OH-:38].Cl.[C:40]([OH:44])([CH3:43])(C)C>O>[C:23]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:20]([O:19][CH:16]1[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][C:10]([CH2:14][NH:13][CH2:12][CH2:11][CH2:10][CH2:43][C:40]([OH:44])=[O:38])=[O:35])[CH2:18][CH2:17]1)=[O:34]
Reactant: [OH-]
Reactant: COC(=O)CCCCN(C)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: CC(C)(C)O
Agent: Cl
Agent: [Li+]
Solvent: O
Product: O=C(O)CCCCNCC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 5-({3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionyl}-methylamino)pentanoic acid methyl ester (10.21 g, 20.60 mmol), tert-butyl alcohol (20 mL) and water (20 mL) was added a 1:1 mixture of LiOH:water (1.97 g, 41.2 mmol). The resulting mixture was stirred at room temperature for 4 h and then the pH of the mixture was adjusted to about pH 2 using aqueous hydrochloric acid (1 N). The aqueous layer was extracted with DCM (2×˜80 mL) and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (12.23 g, quantitative) as an off-white foamy solid (containing residual tert-butyl alcohol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[I:15]I.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[C:5]([I:15])=[N:6][CH:7]=1
Reactant: II
Reactant: Oc1cncc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cc(Cl)cnc1I
Reaction time: 0.75 h

Procedure:
A 20.3 g (0.157 mol) sample of 5-chloro-3-pyridinol (Aldrich Chemical Co.) and 35 g (0.33 mol) of Na2CO3 were dissolved in 220 mL of H2O. To this solution was added 39.9 g of I2, and the reaction mixture was stirred for 45 minutes. The mixture was then poured slowly into 2 N HCl, and the acidity was adjusted to pH 3. The product was collected by filtration and crystallized from EtOH/ether, affording 23.35 g of title compound: 1H NMR (CDCl3, 300 MHz) δ 5.45 (s, 1H), 8.0 (d, 1H); MS m/z: 256 (M+H)+, 273 (M+NH4)+.
Reaction SMILES: [N+:1]([O-:4])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH2:23]([O:25][C:26](=[O:49])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]2ON=[C:36]([CH2:39][O:40]C3C=CC(OC)=CC=3)[N:35]=2)=[CH:29][CH:28]=1)[CH3:24].[Na].C(OCC)(=O)C>C(#N)C.O>[CH2:23]([O:25][C:26](=[O:49])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]2[O:4][N:1]=[C:36]([CH2:39][OH:40])[N:35]=2)=[CH:29][CH:28]=1)[CH3:24]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1ccc(Cc2nc(COc3ccc(OC)cc3)no2)cc1
Agent: [Ce+4]
Agent: [NH4+]
Agent: [Na]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Cc2nc(CO)no2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 528 %

Procedure:
Add half of the ammonium cerium(IV) nitrate (285 mg, 0.52 mmol) to a solution of 4-[3-(4-methoxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acid ethyl ester (193 mg, 0.52 mmol) in acetonitrile (9 mL) and water (2.3 mL) at room temperature. Stir the reaction mixture at room temperature for one hour and add the second half of the ammonium cerium(IV) nitrate (285 mg, 0.52 mmol). Stir at room temperature for an additional hour, dilute the reaction is with saturated aqueous sodium hydrideCO3, stir for 5 minutes, dilute with water, and extracte with ethyl acetate (3×). Wash the combined organic layers with brine, dry over MgSO4, and concentrate. Purify the residue by flash column chromatography using 50% ethyl acetate/hexane to give the title compound (720 mg, 81%). LC-MS (m/e): 263 (M+1).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[NH:45]1[C:49]2([CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[C:48](=[O:55])[NH:47][C:46]1=[O:56].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CN(C)C=O>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31][C:33]([N:52]2[CH2:53][CH2:54][C:49]3([NH:45][C:46](=[O:56])[NH:47][C:48]3=[O:55])[CH2:50][CH2:51]2)=[O:34])[CH2:18][CH2:17]1
Reactant: O=C1NC(=O)C2(CCNCC2)N1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C2(CCN(C(=O)N[C@@H]3CC[C@@H](c4cccc(F)c4F)Cn4c(CC(F)(F)F)cnc43)CC2)N1
Temperature: 40 °C
Reaction time: 1 h
Yield: 25.5 %

Procedure:
Triethylamine (12 μL, 0.087 mmol) was added to a solution of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (30 mg, 0.087 mmol) and 4-nitrophenyl chloroformate (18 mg, 0.091 mmol) in tetrahydrofuran (1 mL) at 0° C. After 1 h, 1,3,8-triazaspiro[4.5]decane-2,4-dione (15 mg, 0.091 mmol), triethylamine (48 μL, 0.348 mmol) and N,N-dimethylformamide (1 mL) were added and the mixture heated to 40° C. After 18 h, saturated aqueous sodium carbonate was added and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→88% dichloromethane/methanol] gave the title compound (12 mg). MS 541.1955 (M+1).
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.[F:19][C:20]([F:30])([F:29])[C:21](=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[C:1]1([CH:11]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([C:20]([F:19])([F:29])[F:30])[NH:13][C:14]3=[N:15][NH:16][CH:17]=[C:18]23)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: O=Cc1cccc2ccccc12
Reactant: Nc1cc[nH]n1
Product: CCOC(=O)C1=C(C(F)(F)F)Nc2n[nH]cc2C1c1cccc2ccccc12

Procedure:
The title compound was prepared from naphthalene-1-aldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:33][CH2:34][CH2:35][C:36]#[C:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:44][C:41]1[CH:42]=[CH:43][C:38]([C:37]#[C:36][CH2:35][CH2:34][CH2:33][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[CH:39][CH:40]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCCCC#Cc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCCCC#Cc1ccc(F)cc1
Reaction time: 8 h
Yield: 82 %

Procedure:
33.4 g (0.205 mol) of N-hydroxyphthalimide and 53.8 g (0.205 mol) of triphenylphosphine were added to a solution of 33.1 g (0.186 mol) of 5-hydroxy-1-(4-fluorophenyl)-1-pentyne in 430 ml of dry tetrahydrofuran. 35.7 g (0.205 mol) of diethyl azodicarboxylate were then added dropwise in the course of 2.5 hours with temperature control (max. 40° C.). Stirring was carried out overnight at room temperature, the mixture was evaporated down under reduced pressure and the residue was taken up with 300 ml of dichloromethane. The solution was washed twice with sodium carbonate solution and once with saturated sodium chloride solution. After drying and evaporating down, the crude product was purified by chromatography over silica gel. The eluents used were initially dichloromethane/n-hexane and subsequently pure dichloromethane. Yield: 82%; mp.: 85°-88° C. 250-MHz-1H-NMR (in DMSO-d6): δ[ppm]=1.9-2.1 (m, 2H); 2.68 (t, 2H); 4.342 (t, 2H); 7.18 (t, 2H); 7.4-7.6 (m, 2H); 7.85 (s, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O1CCCC1.ClCCl.C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[O:9])([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
In tetrahydrofuran (100 ml) and dichloromethane (100 ml), 3-nitrobenzoic acid (7.58 g) was dissolved. Then 1-hydroxybenzotriazole (6.74 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.57 g), and morpholine (9.47 g) were added to the solution. The mixture was stirred at room temperature overnight. After the reaction was completed, chloroform was added to the solution. The mixture was washed with 1N-HCl aqueous solution, 1N-NaOH aqueous solution, and distilled water. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Kieselgel 60=160 g, ethyl acetate) to obtain the above-captioned compound ([13]-(132)-158) (9.62 g) as white crystals.
Reaction SMILES: Cl.[CH3:2][C@@:3]([S:29]([CH3:32])(=[O:31])=[O:30])([CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][C:17]1=[O:28])[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>O1CCOCC1.O>[OH:7][NH:6][C:4](=[O:5])[C@:3]([CH3:2])([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][C:17]1=[O:28]
Reactant: C[C@@](CCn1ccc(-c2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: C[C@@](CCn1ccc(-c2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 2 h

Procedure:
HCl (4.0 N in 1,4-dioxane, 20 mL) was added to a solution of (2R)-2-Methyl-2-(methylsulfonyl)-4-(2-oxo-4-phenylpyridin-1(2H)-yl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (5.15 g, 11.5 mmol) in 1,4-dioxane (100 mL) and water (20 mL). The reaction was continued for 2 hours. The reaction was concentrated in vacuo, upon concentration a white solid precipitated. The solid was triturated with 2-propanol (150 mL) at 50° C. for 30 minutes then collected by filtration. The title compound was obtained as a white solid (3.85 g, 92%) LC-MS m/z 365.5 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 3H) 2.10-2.23 (m, 1H) 2.37-2.48 (m, 1H) 3.11 (s, 3H) 3.69-3.82 (m, 1H) 4.04-4.19 (m, 1H) 6.63-6.68 (m, 1H) 6.70 (d, J=1.76 Hz, 1H) 7.41-7.55 (m, 3H) 7.68-7.75 (m, 2H) 7.77 (d, J=6.83 Hz, 1H) 11.17 (br. s., 1H). [α]58920=+33.21°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH2:16])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:30][C:29](=O)[O:28][C:26](=[O:27])[CH2:25]2)=[CH:20][CH:19]=1.Cl>O1CCOCC1>[ClH:17].[C:5]([C:4]1[CH:13]=[CH:14][C:15]2[N:16]=[C:29]([CH2:30][CH:24]([C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=3)[CH2:25][C:26]([OH:28])=[O:27])[NH:1][C:2]=2[CH:3]=1)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CC(Cc1nc2ccc(C(=O)c3ccccc3)cc2[nH]1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 140.3 %

Procedure:
The solution of commercial 3,4-diaminobenzophenone (0.43 g) and 3-(4-chlorophenyl)glutaric anhydride (0.45 g) in 1,4-dioxane (3 ml) was stirred under reflux for 0.5 h. 4M HCl in 1,4-dioxane (3 ml) was added and the solution is further heated to reflux for 2.5 h. After cooling to rt the precipitate is collected by suction filtration and washed with 1,4-dioxane and diethyl ether. The crude is recrystallised from acetic acid to give 4-(5-benzoyl-2-benzimidazolyl)-3-(4-chlorophenyl)butanoic acid HCl (0.64 g) as light brown solid.
Reaction SMILES: NC1N=CN=C2N(CCC[N:27]3[C:31](=[O:32])[CH2:30][S:29][C:28]3=[O:33])N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12.[CH:34]1([CH:37]=O)[CH2:36][CH2:35]1.N1CCCCC1>C(O)C>[CH:34]1([CH:37]=[C:30]2[S:29][C:28](=[O:33])[NH:27][C:31]2=[O:32])[CH2:36][CH2:35]1
Reactant: O=CC1CC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2CCCN1C(=O)CSC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=CC2CC2)S1
Yield: 68.7 %

Procedure:
A solution of 3-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)thiazolidine-2,4-dione (0.20 g, 0.43 mmol), cyclopropanecarbaldehyde (91 mg, 1.3 mmol, 3.0 eq.) and a drop of piperidine in ethanol (15 mL) was refluxed overnight. The volatile phase was removed under reduced pressure. The residue was applied on silica gel and eluted with petroleum:ethyl acetate (3:2) to give 3-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)-5-(cyclopropylmethylene thiazolidine-2,4-dione (50 mg) as a white solid. MS (ESI, pos. ion) m/z: 513 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].S([O-])([O-])(=O)=O.[Mg+2].[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][N:6]=[CH:20][C:19]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C=O
Reactant: COc1ccc(CN)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COC(=O)C=NCc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture containing 16.82 g (0.101 mole) of 2,4-dimethoxybenzylamine and anhydrous magnesium sulfate in 150 ml of methylene chloride at 25° is added a solution of 10.05 g (0.114 mole) of methyl glyoxalate in 20 ml of methylene chloride. The reaction mixture is stirred at room temperature overnight (15 hours) and then is filtered and the solvents are removed in vacuo to afford the imine as a dark orange gum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[C:13]([CH3:20])([CH3:19])[C:14](OCC)=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[CH3:19][C:13]1([CH3:20])[O:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[NH:1][C:14]1=[O:15]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Temperature: 70 °C

Procedure:
2-Amino-4-nitrophenol (5 g), ethyl 2-bromo-2-methylpropanoate (5.77 mL, 1.2 eq.), and K2CO3 (6.7 g, 1.5 eq.) were suspended in DMF (50 ml). The reaction mixture was heated at 70° C. overnight. The mixture was then diluted with water (200 mL) and EtOAc (150 mL). The EtOAc layer was washed with water (2×150 mL) and evaporated. The residue was purified by Combiflash chromatography (EtOAc in hexanes=10-100%) to give 2,2-dimethyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (3.45 g).
Reaction SMILES: [O:1]=[C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]2[C:4]([C:5]([N+:17]([O-])=O)=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[H][H]>[Pd].O1CCCC1>[O:1]=[C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]2[C:4]([C:5]([NH2:17])=[CH:6][CH:7]=[CH:8]2)=[N:3]1
Reactant: [H][H]
Reactant: O=C1N=c2c([N+](=O)[O-])cccc2=C1c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc2c1=NC(=O)C=2c1ccccc1
Reaction time: 18 h

Procedure:
Two and one half grams of 2-oxo-3-phenyl-7-nitroindole were dissolved in 200 ml. of THF (tetrahydrofuran). Two grams of 5% palladium-on-carbon were added and the mixture placed in a low pressure hydrogenation apparatus at 60 psi of hydrogen. After 18 hours, the theoretical amount of hydrogen had been absorbed. The hydrogenation mixture was filtered to remove the catalyst and the filtrate was evaporated to dryness in vacuo. The residue containing the 2-oxo-3-phenyl-7-aminoindole formed in the above hydrogenation melted at 226°-30° C. after recrystallization from methanol; yield = 1.5 g.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH2:26])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:36][CH:37]([Cl:41])[C:38](Cl)=[O:39]>C(Cl)Cl>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:38](=[O:39])[CH:37]([Cl:41])[Cl:36])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:12][CH2:13]1)=[O:7])([CH3:1])[CH3:3]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CNC(=O)C(Cl)Cl)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of (S)-(-)-4-[4-[5-(aminomethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 8, 400 mg) in dry methylene chloride (4.1 mL) at 0° C. under N2 is treated with triethylamine (0.21 mL) and dichloroacetyl chloride (0.11 mL), and the resulting mixture is stirred at 0° C. for three hours, diluted with methylene chloride (10 mL), washed with water (10 mL), saturated aqueous sodium bicarbonate (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is then chromatographed on silica gel (70-230 mesh, 50 g), eluting with methanol/chloroform (5/95). Pooling and concentration of those fractions with an Rf =0.53 by TLC (methanol/chloroform, 10/90), trituration with methylene chloride/diethyl ether and filtration gives the title compound, mp 168-170° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[O:13]1[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[O:13]1[CH2:18][CH2:17][CH:16]([NH:19][CH2:1][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])[CH2:15][CH2:14]1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: NC1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cccc(CNC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
To a solution of methyl 3-formylbenzoate (492 mg, 3.0 mmol) in MeOH (10 mL) was added tetrahydro-2H-pyran-4-amine (303 mg, 3.0 mmol) and AcOH (0.05 mL). The mixture was stirred at 25° C. for 2 h. NaBH3CN (945 mg, 15.0 mmol) was added, and the resulting mixture was stirred at 25° C. for 16 h. The reaction solution was concentrated and the residue was dissolved in water and extracted with DCM. The organic layer was concentrated, and the residue was purified by prep-TLC to give the title product (500 mg, Yield 67%). LCMS (m/z): 250.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([CH:11]([OH:16])[C:12](=[NH:15])[NH:13][OH:14])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([CH:11]([OH:16])[C:12](=[NH:15])[NH:13][O:14][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(O)C(=N)NO
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CCC(NC(=O)OC(C)(C)C)C(O)C(=N)NOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
A solution of {1-[hydroxy-(N-hydroxycarbamimidoyl)-methyl]-propyl}-carbamic acid tert-butyl ester (2) (2.5 g, 10 mmol) in dichloromethyl (125 ml) was treated with benzoic acid (1.36 g, 11 mmol), EDCI (2.14 g, 11 mmol), HOBT (1.37 g, 10 mmol) and triethylamine (1.35 mL, 11 mmol) and stirred at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate solution, then water, then dried over Na2SO4 and then evaporated under reduced pressure. The residue was subjected to mplc eluting with 1% triethylamine in 2:3 v/v ethyl acetate and heptane mixture to give {1-[hydroxy-(N-benzoyloxycarbamimidoyl)-methyl]-propyl}-carbamic acid tert-butyl ester (850 mg) as a yellow solid. MS: MH+352.