Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][C:10](O)([CH3:12])[CH3:11]>CCCCCC.P(=O)(O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][C:7]=1[C:10]([CH3:12])([CH3:11])[CH3:9]
Reactant: CC(C)(C)O
Reactant: Oc1cccc(Cl)c1
Agent: O=P(O)(O)O
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(O)cc1Cl
Yield: 0.6 %

Procedure:
A mixture of 50 g (0.39 mol) of 3-chlorophenol in 250 ml of hexane and 125 ml of 85% phosphoric acid was heated to reflux. A solution of 43.2 g (0.584 mol) of 2-methyl-2-propanol in 25 ml of hexane was added over 1.5 hours. After addition, the reaction mixture was refluxed for 4 hours. The organic phase was separated and extracted four times with 30 ml of lN sodium hydroxide solution. The combined aqueous fractions were made acidic and extracted with methylene chloride. The organic phase was dried and evaporated at 90° C. (25 mm). The residue was crystallized from hexane. There was obtained 0.46 g (2.49 mmol, 0.6%) of 3-chloro-4-(1,1-dimethylethyl)phenol as a white solid after crystallization from hexane; mp 65°-67° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:13]2[C:9](=[CH:10][N:11]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:12]=2)[CH:8]=1)[C:3]([OH:5])=O.C(N(C(C)C)CC)(C)C.[N:34]1([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.ClCCl>[OH:1][C@H:2]([CH2:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:13]2[C:9](=[CH:10][N:11]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[N:12]=2)[CH:8]=1)[C:3]([N:43]1[CH2:44][CH2:45][CH:40]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:41][CH2:42]1)=[O:5]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](O)C(=O)O)cc2cn(COCC[Si](C)(C)C)nc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C[C@@H](O)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the (R)-2-hydroxy-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)propanoic acid (610 mg, 1.74 mmol), diisopropylethylamine (0.61 mL, 3.48 mmol), and 4-piperidinopiperidine (585.76 mg, 2.0 equiv) in dimethylformamide (20 mL) and dichloromethane (20 mL) at 0° C. was added PyBOP® (951 mg, 1.83 mmol). The reaction was stirred at 0° C. for 2 h. The reaction was concentrated, diluted with ethyl acetate, washed with water, then brine, dried over magnesium sulfate, and concentrated. The product was purified by column chromatography (4:96:1 methanol/dichloromethane/triethylamine) to give 795 mg (91%). Mass spec.: 501.40 (MH)+.
Reaction SMILES: C(CCC1C=CC([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=CC=1)(O)=O.[CH3:44][S:45]([NH:48][C:49]1[CH:50]=[C:51](B(O)O)[CH:52]=[CH:53][CH:54]=1)(=[O:47])=[O:46].B(O)O>>[CH3:40][C@:18]12[C@@:17]3([CH3:41])[C@@H:26]([C@:27]4([CH3:30])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:42])([CH3:43])[C:12]([C:51]3[CH:52]=[CH:53][CH:54]=[C:49]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])[CH:50]=3)=[CH:29][CH2:28]4)[CH2:25][CH2:24][C@@H:23]1[C@H:22]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]1([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]2
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6cccc(NS(C)(=O)=O)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (example 4a) using 3-(methylsulfonamido)phenylboronic acid as the reactant boronic acid. The product was isolated as a white solid (46.41 mg, 90%). LCMS: m/e 606.58 (M−H)−, 4.37 min (method 2). 1H NMR (599 MHz, DMSO-D6_CDCl3) δ ppm 0.93 (s, 6H), 0.99 (s, 3H), 1.00 (s, 3H), 1.02 (s, 3H), 1.03-1.74 (m, 17H), 1.71 (s, 3H), 1.84-1.96 (m, 2H), 2.11 (dd, J=16.99, 5.86 Hz, 1H), 2.20 (d, J=12.30 Hz, 1H), 2.30-2.39 (m, 1H), 2.96 (s, 3H), 2.99-3.07 (m, 1H), 4.61 (s., 1H), 4.74 (s, 1H), 5.28 (d, J=4.69 Hz, 1H), 6.87 (d, J=7.62 Hz, 1H), 7.03 (s, 1H), 7.14 (d, J=8.20 Hz, 1H), 7.25 (t, J=7.62 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:15])=[C:9]([CH3:14])[C:10]=1[C:11](=[O:13])[CH3:12])=[O:5])C.[OH-].[K+]>C(O)C>[C:11]([C:10]1[C:9]([CH3:14])=[C:8]([CH3:15])[NH:7][C:6]=1[C:4]([OH:5])=[O:3])(=[O:13])[CH3:12]
Reactant: CCOC(=O)c1[nH]c(C)c(C)c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)c1c(C(=O)O)[nH]c(C)c1C
Yield: 81.7 %

Procedure:
A mixture of pyrrole ester 34 (8.2 g, 0.0392 mol), in ethanol and 100 mL of 10% potassium hydroxide were refluxed for 1 h. The mixture was cooled and concentrated in vacuo to an oil. Water was added to the oil, the mixture acidified with dilute HCl and extracted with ether. The organic phase was dried with anhy. sodium sulfate and concentrated in vacuo to a solid residue. The compound was recrystallized in 80 mL of ethanol to give 5.8 g of pure 3-acetyl-4,5-dimethyl-2-pyrrole carboxylic acid 35 as a solid. 1H NMR (DMSO-d6) δ 2.5 (s, 3H), 2.2 (s, 3H), 2.0 (s, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:28]([NH2:30])[CH3:29]>>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[NH:30][CH2:28][CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Reactant: CCN
Agent: Cl
Product: CCNc1ccc([N+](=O)[O-])cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 52 %

Procedure:
Using the compound obtained in Example 263 as a starting material and also using ethylamine hydrochloride as a reagent, the same procedure of Example 264 gave the titled compound (yield, 52%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]23[CH2:15][CH:14]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)=[CH:2]1.[ClH:23]>O1CCOCC1>[ClH:23].[C:10]12([C:3]3[C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:1][CH:2]=3)[CH2:15][CH:14]1[CH2:13][NH:12][CH2:11]2
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2c[nH]c3ncccc23)C1
Agent: Cl
Solvent: C1COCCO1
Product: c1cnc2[nH]cc(C34CNCC3C4)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To tert-butyl 1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 0.3 mmol) in dioxan (3 ml) was added 1 mL of a 4M solution of HCl in dioxan. The reaction mixture was stirred at RT for 12 h and concentrated to dryness to afford the title compound as a buff colored solid (60 mg), which was used immediately in the following step.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:37]=[CH:36][C:22]([CH2:23][O:24][C:25](SC2N=C(C)C=C(C)N=2)=[O:26])=[CH:21][CH:20]=1>O.CN(C)C=O>[CH3:17][O:18][C:19]1[CH:37]=[CH:36][C:22]([CH2:23][O:24][C:25]([N:5]2[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]2[C:7]([OH:9])=[O:8])=[O:26])=[CH:21][CH:20]=1
Reactant: COc1ccc(COC(=O)Sc2nc(C)cc(C)n2)cc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
trans-4-Hydroxy-L-proline (13.1 g) and triethylamine (21 ml) were dissolved in 55 ml of water, and a solution of 33.44 g of S-p-methoxybenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine in 55 ml of dimethylformamide was added thereto. The resulting mixture was stirred at room temperature for 12 hours, diluted with water and washed with ethyl acetate. The aqueous layer was acidified with 5N hydrochloric acid (pH 2) under ice-cooling and extracted with ethyl acetate. The extract was washed successively with dilute hydrochloric acid and brine, dried over anhydrous sodium sulfate and distilled to obtain trans-1-(p-methoxybenzyloxycarbonyl)-4-hydroxy-L-proline. IR maxneat cm-1 : 1670, 1435, 1350, 1240, 1168.
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:36]=[N:35][C:33]([NH2:34])=[N:32][C:30]3=[O:31])[CH2:26][CH2:25]2)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1>C(Cl)(Cl)Cl>[C@@H:27]1([N:29]2[CH:36]=[N:35][C:33]([NH2:34])=[N:32][C:30]2=[O:31])[O:28][C@H:24]([CH2:23][OH:22])[CH2:25][CH2:26]1
Reactant: COc1ccc(C(OC[C@@H]2CC[C@H](n3cnc(N)nc3=O)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClC(Cl)Cl
Product: Nc1ncn([C@H]2CC[C@@H](CO)O2)c(=O)n1
Reaction time: 24 h
Yield: 58.9 %

Procedure:
Compound 9 (0.08 g, 0.16 mmol) was dissolved in chloroform (2 mL) and poured onto a silica gel column (3 g, Whatman Partisil 40). The column was washed with benzene (40 mL) and left at ambient temperature for 24 h. The column was eluted with ethyl acetate followed by 10% methanol/ethyl acetate to give 0.02 g of crude product along with 0.04 g of unchanged starting material. The crude product was dissolved in water, filtered through a Millex-GS Filter, and the filtrate was chromatographed through a C18 reverse-phase column (10% methanol/water) to give 0.005 g (30%) of white, lyophilized product. NMR (D2O); δ 2.06 (m, 4H), 3.72 (m, 2H), 4.18 (m, 1H), 5.89 (d, 2H, J=5 Hz), 8.51 (s, 1H). FAB mass spectrum, m/z (relative intensity) 113 (b+2H, 100), 213 (MH+, 88). MH+ calc. 213.0988; found 213.0991±0.0020 (n=8).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:15]=[O:16])C.O=P(Cl)(Cl)Cl>>[C:1]1([N:7]2[CH:11]=[C:10]([CH:15]=[O:16])[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: c1ccc(-n2cccn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn(-c2ccccc2)c1
Temperature: 106 °C
Reaction time: 0.17 h
Yield: 112.7 %

Procedure:
1-Phenyl-1H-pyrazole (250 mg, 1.7 mmol) was added to a cold (0-4° C.) solution of DMF (1.5 g, 1.6 mL, 9.7 mmol) and POCl3 (1.86 g, 1.1 mL, 19.2 mmol) and stirring continued for 10 minutes. The resulting mixture was heated at 106° C. for 2.5 hrs. The reaction mixture was cooled and quenched with ice cold water, basified with 20% aqueous NaOH solution, the solid was collected to afford 330 mg (crude) of 1-phenyl-1H-pyrazole-4-carbaldehyde. 1H NMR (300 MHz, CDCl3): δ 10.0 (s, 1H), 8.45 (s, 1H), 8.2 (s, 1H), 7.75 (d, 2H), 7.55 (t, 2H), 7.45 (t, 1H). Sulphamic acid (253 mg, 2.6 mmol) in water (0.5 mL) was added at 0° C. to a mixture of phenyl-1H-pyrazole-4-carbaldehyde (0.5 g, 2.34 mmol) in acetone (3 mL). After 2 minutes sodium chlorite (315 mg, 3.5 mmol) was added and the resulting mixture was stirred at 0° C. for 30 minutes. Water was added and the solid obtained was isolated by filtration to afford 140 mg (85% yield) of 1-phenyl-1H-pyrazole-4-carboxylic acid.
Reaction SMILES: C(N(CC)CC)C.C(Cl)(=O)C(Cl)=O.C(OC[C:19]1[CH2:20][S:21][C@@H:22]2[C@H:29](N)[C:28](=[O:31])[N:23]2[C:24]=1[C:25]([OH:27])=[O:26])(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.CN(C)C=O.O.CC(C)=O>[S:21]1[C@@H:22]2[CH2:29][C:28](=[O:31])[N:23]2[C:24]([C:25]([OH:27])=[O:26])=[CH:19][CH2:20]1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)C1=CCS[C@@H]2CC(=O)N12
Reaction time: 1.5 h

Procedure:
Following the procedure described in Example 1, a solution of the appropriate 2-aryl-2-t-butoxycarbonyl-Rq -oxyiminoacetic acid (syn-isomer) (1 equiv) in methylene chloride optionally containing a few drops of N,N-dimethylformamide and triethylamine (1 equiv) was treated with oxalyl chloride (1 equiv) at 0°-5° for ca. 1 hour. The mixture was then evaporated to dryness. The residue was suspended or dissolved in acetone and added to a stirred, ice-cold solution of (6R,7R)-3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid (1-1.2 equiv) in water or a mixture of acetone and water containing sodium hydrogen carbonate (2-2.5 equiv). The reaction mixture was stirred for 0.5-2.5 hours, allowing the temperature to rise to room temperature, whereafter the acetone was removed under reduced pressure. The pH was adjusted to 1.5- 2.0 and the product extracted into ethyl acetate (alternatively ether or methylene chloride may be used). The organic layer was washed with water and/or saturated brine, dried and evaporated to give the corresponding (6R,7R)-3-acetoxymethyl-7-(2-aryl-2-t-butoxycarbonyl-R q -oxyiminoacetamido)ceph-3-em-4-carboxylic acid (syn-isomer) which was characterised by optical rotation and/or by spectroscopy.
Reaction SMILES: [OH:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:17])[C:3]=1[C:18](OCC)=[O:19].C(N(C(C)C)C(C)C)C.Cl.[NH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>O1CCOCC1.CCOC(C)=O>[OH:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:17])[C:3]=1[C:18]([NH:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:19]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2ccccc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccccc2C2(CCOCC2)C1=O
Temperature: 80 °C
Yield: 46.8 %

Procedure:
Ethyl 4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (450 mg, 1488 μmol) was dissolved in 1,4-dioxane (1488 μL) and N-ethyl-N-isopropylpropan-2-amine (778 mL, 4465 μmol). tert-Butyl 2-aminoacetate hydrochloride (374 mg, 2233 μmol) was added, and the mixture was heated at 80° C. for 3 hours. The resulting mixture was then cooled to ambient temperature, diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed with NaHCO3 (saturated, aqueous) (2×75 mL), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (270 mg) as a white solid. MS m/e=388 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=1>CCO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1cccnc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(F)cc1Nc1cccnc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of (5-fluoro-2-nitrophenyl)pyridin-3-yl-amine (25 mmol) in EtOH (300 mL) was added 10% Pd/C (1.0 g) and the reaction mixture stirred at RT under a hydrogen atmosphere for 18 h. Additional Pd/C (1.0 g) was added and stirring at RT under a hydrogen atmosphere continued for 2 h. The suspension was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to afford the title compound as a brown solid (quantitative). 1H NMR (CDCl3, 300 MHz): δ 8.27 (1H, dd, J=2.64, 0.91 Hz), 8.15 (1H, dd, J=4.41, 1.71 Hz), 7.20-7.09 (2H, m), 6.87 (1H, dd, J=9.61, 2.59 Hz), 6.80-6.68 (2H, m), 5.50 (1H, br s), 2.96 (2H, br s)
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(OCC)(=O)C.[OH-].[K+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1
Reactant: O=C(NCCc1ccccc1F)c1ccc(C(F)(F)F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Fc1cccc2c1CCN=C2c1ccc(C(F)(F)F)cc1
Temperature: 125 °C

Procedure:
A suspension of N-(2-fluorophenethyl)-4-(trifluoromethyl)benzamide (2.0 g, 6.5 mmol) and phosphoric pentoxide (2.7 g, 19.1 mmol) in anhydrous toluene (40 mL) was heated at 125° C. for 4 h. At this stage more phosphoric pentoxide (2.7 g, 19.1 mmol) was added and continued stirring the reaction at 125° C. for additional 16 h. The reaction was cooled to RT, added ethyl acetate (100 mL), and the resulting slurry was slowly poured into ice-water (100 mL). Then more ethyl acetate (75 mL) was added and the resulting suspension was treated with KOH (3.0 N) until pH˜11.0 was achieved. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum to provide 5-fluoro-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline as a yellow oil. MS (ESI pos. ion) m/z: 294 (M+H).
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[NH2:9][CH2:10][CH2:11][C:12]#[N:13].C[O-].[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[C:20]([CH2:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:19]=1>CO.C(#N)C>[Cl:17][C:18]1[N:23]=[C:22]([NH:13][CH2:12][CH2:11][C:10]#[N:9])[CH:21]=[C:20]([CH2:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:19]=1
Reactant: N#CCCN
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Agent: C[O-]
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: N#CCCNc1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C

Procedure:
A solution of 3-aminopropanenitrile fumarate (147 mg, 0.74 mmol) and sodium methoxide (1.1 mL, 0.54 mmol) in MeOH (2 mL) was added dropwise to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (64 mg, 0.25 mmol) in acetonitrile (2 mL). The mixture stirred at rt over night. The mixture was heated to 50° C. for 20 h. The reaction mixture was concentrated in vacuo and the crude was partitioned between EtOAc and 1M NaOH. The organic layer was concentrated in vacuo and the residue was purified by preparative HPLC to give the title compound, 29 mg (40%).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][CH:19]=4)=[C:11]3[C:10]([CH3:40])=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>C([O-])([O-])=O.[Na+].[Na+]>[F:39][C:36]1[CH:37]=[CH:38][C:33]([N:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:8][N:9]=[C:10]([CH3:40])[C:11]=34)=[CH:19][CH:20]=2)[C:25]([C:27]2([C:30]([NH2:32])=[O:31])[CH2:28][CH2:29]2)=[O:26])=[CH:34][CH:35]=1
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4)ccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2nccc(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3)c12
Temperature: 65 °C

Procedure:
A 40 mL vial was charged with N-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (90 mg, 0.11 mmol) and TFA (2.0 mL). The reaction mixture was heated to 65° C. under nitrogen for 2 hours, the diluted with saturated Na2CO3 (15 mL) and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was purified by preparative TLC (0.5 mm) eluting with EtOAc/MeOH (9:1) to provide the product as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.22 (d, J=5.5 Hz, 1H), 7.71 (d, J=9.0 Hz, 2H), 7.56 (m, 2H), 7.22 (d, J=9.0 Hz, 2H), 7.06 (t, J=9.0 Hz, 2H), 6.27 (d, J=5.5 Hz, 1H), 2.68 (s, 3H), 1.64 (s, 4H). LRMS (esi pos) m/e 446 (M+1).
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[C:9]([C:14](OC)=[O:15])[N:8]=2)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[CH:1]([NH:4][C:5]1[S:6][C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[C:9]([CH2:14][OH:15])[N:8]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(NC(C)C)sc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Nc1nc2ccc(CO)nc2s1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 84.3 %

Procedure:
To a solution of methyl 2-(isopropylamino)thiazolo[5,4-b]pyridine-5-carboxylate (1.67 g, 6.64 mmol, 1.0 eq.) in THF (17 mL) under nitrogen at 0° C. was added LAH (1M, THF; 10 mL, 10 mmol, 1.5 eq.). After 2.25 hr, ice and EtOAc were added, the cold bath was removed, and the solution was stirred to room temperature. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography using CH2Cl2:MeOH (10:0.4) as eluent afforded (2-(isopropylamino)thiazolo[5,4-b]pyridin-5-yl)methanol as a white solid (1.25 g, 84% yield).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>CN1CCCC1=O.CCOCC>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10]([N:26]3[CH2:25][CH2:24][NH:23][CH:22]([CH3:21])[CH2:27]3)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: CC1CNCCN1
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(N3CCNC(C)C3)c(F)c21
Reaction time: 18 h

Procedure:
A 289 mg portion of 1-ethyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was dissolved in 3 ml of 1-methyl-2-pyrrolidone. A 390 mg portion of 2-methyl piperazine was added, the mixture was stirred for 18 hours and then diluted with ether. The solid was collected, washed with hexane, dried and recrystallized from dichloromethane-acetone, giving 240 mg of solid. This solid was purified by chromatography, eluting with a gradient of chloroform-methanol-water and then a gradient of chloroform-methanol-water-acetic acid. The active fractions were combined and partitioned between dilute sodium bicarbonate and dichloromethane. The organic layer was dried and evaporated. The solid was recrystallized from dichloromethane-hexane, giving 100 mg of the desired product as off-white crystals, mp 220°-222° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][C@@H:14]([NH:19][C:20](=[O:33])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:15][CH2:16][C:17]#[N:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].N(CC)CC.Cl>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][C@@H:14]([NH:19][C:20](=[O:33])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:15][CH2:16][C:17]2[NH:38][N:37]=[N:36][N:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCC[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCNCC
Solvent: Cc1ccccc1
Product: O=C(CCCCCCc1ccccc1)N[C@@H](CCc1nnn[nH]1)Cc1ccc(OCc2ccccc2)cc1
Yield: 219.9 %

Procedure:
A mixture of (65) (74 mg, 0.16 mmol), NaN3 (103 mg, 1.58 mmol) and Et2NH.HCl (173 mg, 1.58 mmol) in toluene (1.5 mL) was heated at reflux for 48 h. The organic phase was decanted, and the remaining gum washed several times with CH2Cl2. The washings were filtered (Celite™), and the organic phases combined. Evaporation of the solvent under reduced pressure afforded a brown gum (180 mg) which was chromatographed on a C-18 reverse phase column to provide (66) (29 mg, 36%). 1H NMR (500 MHz, d4-MeOH) δ 7.43-7.07 (m, 12H), 6.9 (d, 2H, J=8.6 Hz), 4.99 (s, 2H), 4.15-4.04 (m, 1H), 3.03-2.86 (m, 2H), 2.79 (dd, 1H, J=5.7, 13 Hz), 2.65 (dd, 1H, J=8.7, 13 Hz), 2.54 (t, 2H, J=7.6 Hz), 2.12-2.00 (m, 3H), 1.90-1.78 (m, 1H), 1.50-1.36 (m, 2H), 1.33-1.10 (m, 4H). 13C NMR (125 MHz, d4-MeOH) δ 176.2, 158.9, 156.2, 143.9, 138.8, 131.9, 131.3, 129.5, 129.4, 129.3, 128.8, 128.5, 126.6, 115.8, 71.0, 51.5, 41.1, 37.2, 36.8, 33.5, 32.5, 30.0 (two superimposed), 27.0, 21.3. ESMS 512 (M+H)+.