Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[C:5]([O:9][C:10](=[O:26])[NH:11][C@H:12]([C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=1)[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C>[C:5]([O:9][C:10](=[O:26])[NH:11][C@H:12]([C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21]([NH2:1])=[CH:20][CH:19]=1)[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)c1ccc(F)cc1)C(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)c1ccc(N)cc1)C(C)(C)C
Temperature: 120 °C
Yield: 31.2 %

Procedure:
Sodium azide (1.26 g, 19.4 mmol) was added to a solution of [1(S)-(4-fluorobenzoyl)-2,2-dimethylpropyl]-carbamic acid tert-butyl ester (0.20 g, 0.7 mmol) in DMF (15 mL), and the mixture heated at 120° C. for 40 hours. The solvent was removed in vacuo before addition of 10% NaHCO3 (aq.) (30 mL) to the residual solid. The aqueous phase was extracted with ethyl acetate (2×30 mL) and the organic phases washed with brine (1×30 mL), dried over MgSO4, filtered and the solvent removed in vacuo to give a yellow solid. Purification by column chromatography (SiO2, 4:1 iso-hexane:ethyl acetate) afforded the title compound as a yellow solid (67 mg, 36%).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]3[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]3)=[CH:9][CH:8]=2)=[N:3]1.[C-:21]#[N:22].[Na+].Cl.C(OCC)(=O)C>CCOCC.O>[OH:20][C:17]1([C:21]#[N:22])[CH2:18][CH2:19][N:14]([CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:4]3[N:5]=[N:6][N:2]([CH3:1])[N:3]=3)=[CH:12][CH:11]=2)[CH2:15][CH2:16]1
Reactant: [C-]#N
Reactant: Cn1nnc(-c2ccc(CN3CCC(=O)CC3)cc2)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cn1nnc(-c2ccc(CN3CCC(O)(C#N)CC3)cc2)n1
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 100.6 %

Procedure:
A stirred solution of 8.62 grams (0.032 mole) of 1-{[4-(2-methyl-1,2,3,4-tetrazol-5-yl)phenyl]methyl}piperidin-4-one in 100 mL of ether and 150 mL of water was cooled to about 10° C. and 3.9 grams (2.5 equivalents) of sodium cyanide was added in one portion. To this was added 6.6 mL (2.5 equivalents) of hydrochloric acid (12 M) dropwise while maintaining the reaction mixture temperature at about 10° C. Upon completion of the addition, the reaction mixture was stirred for 1.5 hours while warming to ambient temperature. The reaction mixture was then poured into 200 mL of water, to which was then added 200 mL of ethyl acetate. The organic layer was separated and concentrated under reduced pressure to yield 9.6 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:23]O>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH3:23])=[O:14])=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: Cc1cc(OCc2ccccc2)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(OCc2ccccc2)cc1C

Procedure:
Using 1.40 g (5.78 mmol) of 4-benzyloxy-2-methylbenzoic acid, 1.37 g (11.6 mmol) of thionyl chloride and 50 ml of methanol, the reaction was carried out in a manner similar to Reference Example 6 to obtain 0.77 g of methyl 4-benzyloxy-2-methylbenzoate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10](=[O:12])[CH3:11])=O)[CH3:2].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:13]([C:9]1[N:8]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:20])[O:12][C:10]=1[CH3:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CC(=O)NC(Cc1ccccc1)C(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1nc(Cc2ccccc2)c(C)o1
Reaction time: 1 h
Yield: 72.7 %

Procedure:
A mixture of N-(1-benzyl-2-oxopropyl)malonamidic acid ethyl ester (7.0 g), phosphorus oxychloride (POCl3) (5.8 g) and toluene (40 ml) was stirred under refluxing conditions for 1 hour. The reaction mixture was concentrated under reduced pressure; the residue was then neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure and the residue was subjected to silica gel chromatography. From the fraction eluted with hexane-ethyl acetate (1:3, v/v), ethyl 2-(4-benzyl-5-methyl-2-oxazolyl)acetate (4.76 g, 63%) was obtained as an oily substance.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4].[CH3:23]I.O>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)c1cc2ccccc2n1CCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n1CCOCCOC
Temperature: 25 °C

Procedure:
To a suspension of sodium hydride (0.11 g, 4 mmol) and anhydrous DMF (2 mL) was added a solution of 1-[2-(2-Hydroxy-ethoxy)-ethyl]-1H-indole-2-carboxylic acid ethyl ester (0.64 g, 2.3 mmol) in anhydrous DMF (5 mL). The reaction was allowed to stir at room temperature then was added methyl iodide (0.15 mL, 2.4 mmol). The reaction was allowed to stir for an additional 5.5 hours and then was poured onto 50 mL water and extracted with three 50 mL portions of ethyl acetate. The combined organics were washed with three 50 mL portions of water, dried on sodium sulfate, and concentrated. Purification by column chromatography (25:75 ethyl acetate:hexane) gave 1-[2-(2-Methoxy-ethoxy)ethyl]-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]([O:29]C)=O)=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:31][NH2:32]>CO>[CH2:1]([C:5]1[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]([NH:31][NH2:32])=[O:29])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NN
Reactant: CCCCc1nc(CCCC)n(Cc2ccc(-c3ccccc3C(=O)OC)cc2)n1
Solvent: CO
Product: CCCCc1nc(CCCC)n(Cc2ccc(-c3ccccc3C(=O)NN)cc2)n1
Yield: 99 %

Procedure:
A 7.10 g (17.5 mmol) sample of the methyl ester product compound of Example 1 was dissolved in 150 ml of methanol and treated with 22 ml (22.2 g 695 mmol) of anhydrous hydrazine under a static nitrogen atmosphere. The reaction was stirred at reflux for 2 days and concentrated in vacuo to give 7.03 g (99%) of compound which was a colorless glass: NMR (CDCl3) δ 0.88 (t, J=7 Hz, 3H), 0.94 (t, J=7 Hz, 3H), 1.28–1.47 (m, 4H), 1.62–1.78 (m, 4H), 2.62–2.73 (m, 4H), 3.5–4.1 (br s, 2H), 5.26 (s, 2H), 6.53 (s, 1H), 7.13–7.63 (m, 8H).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[C:23]([CH3:29])[NH:24]2.C(N(C(C)C)C(C)C)C>C(O)CCC>[CH3:29][C:23]1[NH:24][C:25]2[C:21]([N:22]=1)=[C:20]([NH:18][C@H:16]([C:8]1[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=1)[CH3:17])[N:28]=[CH:27][N:26]=2
Reactant: Cc1nc2c(Cl)ncnc2[nH]1
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(N[C@@H](C)c3nc4ccccc4n3-c3ccccc3)ncnc2[nH]1
Yield: 32.7 %

Procedure:
A solution of (1S)-1-(1-phenyl-1H-1,3-benzodiazol-2-yl)ethan-1-amine from Example 4 (150 mg, 0.62 mmol, 1.00 equiv, 98%), 6-chloro-8-methyl-9H-purine (150 mg, 0.87 mmol, 1.41 equiv) and ethylbis(propan-2-yl)amine (0.3 mL, 98%) in butan-1-ol (6 mL) was stirred overnight at 130° C. The resulting mixture was concentrated under vacuum. The residue was purified on a C18 column eluted with water/acetonitrile to give 75 mg (30%) of 158 as a white solid. LC-MS (ES, m/z) 370 [M+H]+. H-NMR (300 MHz CD3OD, ppm) δ 8.04 (s, 1H), 7.69 (d, 1H), 7.55 (m, 5H), 7.30 (m, 2H), 7.11 (d, 1H), 5.63 (s, 1H), 2.55 (s, 3H), 1.71 (d, 3H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]([C:36](O)=[O:37])([CH3:35])[CH3:34])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[F:70][C:71]([F:75])([F:74])[CH2:72][NH2:73]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]([CH3:35])([C:36](=[O:37])[NH:73][CH2:72][C:71]([F:75])([F:74])[F:70])[CH3:34])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: CC(C)(Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a mixture of racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.065 mmol), EDCI (18.7 mg, 0.098 mmol), HOBt (15 mg, 0.098 mmol) and DIPEA (75 mg, 0.6 mmol) in THF (2 mL) was added 2,2,2-trifluoroethylamine hydrochloride (25 mg, 0.185 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (19 mg).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]([C:13]#[N:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[CH3:23].CCN(CC)CC.O>C(#N)C.CCOC(C)=O>[Cl:12][C:10]1[CH:9]=[C:8]([C:13]#[N:14])[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([F:15])=[C:17]([CH3:23])[CH:18]=2)[N:11]=1
Reactant: Cc1cc(N)ccc1F
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C#N)cc(Cl)nc1Nc1ccc(F)c(C)c1

Procedure:
A solution of methyl 2,6-dichloro-4-cyanonicotinate (500 mg, 2.164 mmol), 4-fluoro-3-methylaniline (325 mg, 2.60 mmol) and Et3N (0.452 mL, 3.25 mmol) in ACN (5 mL) was stirred at 50° C. for 24 h. Water and EtOAc were added to the mixture and the aqueous phase was extracted with EtOAc. The organic phases were combined, washed with H2O and brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2 to give the title compound, which contains some starting material and was used without further purification (390 mg). [M+H] calc'd for C15H11ClFN3O2, 320. found, 320.
Reaction SMILES: S(Cl)(Cl)=O.N1C=CC=C([C:11]2[N:19]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)=[C:13]([C:20]([OH:22])=[O:21])[CH:12]=2)C=1>C(Cl)(Cl)Cl.CN(C)C=O>[N:19]1[CH:14]=[CH:15][CH:16]=[C:17]([C:12]2[C:13]([C:20]([OH:22])=[O:21])=[C:14]3[N:19]([CH:11]=2)[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:18]=1
Reactant: O=C(O)c1cc(-c2cccnc2)n2c1CCCC2
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(O)c1c(-c2cccnc2)cn2c1CCCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.3 cm3 of thionyl chloride are added dropwise to a suspension 4.8 g of 3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylic acid in 120 cm3 of chloroform, followed by a few drops of dimethylformamide. The resulting suspension is then stirred at ambient temperature for 16 hours (slow gas release) and is then heated to reflux (75° C.) for 1 hour, at the end of which there is no further gas release. It is then cooled to ambient temperature and then concentrated at reduced pressure (2.7 kPa) and taken up twice in ethanol-free dichloromethane and then concentrated again in the same way. 5.4 g of 3-(3-pyridyl-5,6,7,8-tetrahydroindolizine-1-carboxylic acid are thus obtained in the form of a greenish solid. (Rf=0.44; thin layer chromatography on silica gel; eluent: 10/90 by volume mixture of methanol and of dichloromethane).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].Br[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.O>[C:28]([C:27]1[CH:26]=[C:25]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9][CH2:10]3)[CH:16]=2)[CH:32]=[CH:31][CH:30]=1)#[N:29]
Reactant: N#Cc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cccc(C#N)c3)c2)CC1
Temperature: 150 °C
Yield: 77.5 %

Procedure:
A mixture of {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (1 g), 3-bromobenzonitrile (0.56 g), potassium carbonate (1.725 g) and tetrakis triphenylphosphine palladium (180 mg) in dioxan/water (3:1, 4 mL) was sealed in a tube and heated at 150° C. for 15 minutes in a microwave vessel. After cooling to room temperature, the reaction mixture was then diluted with water (25 mL) and extracted with ethyl acetate (2×25 mL). The combined organic phases were dried (MgSO4) and concentrated under vacuum. The resulting crude residue was further purified by flash column chromatography on silica (100 g) to give the title compound (0.9 g) (purity ca 75%). LC/MS: m/z, 378 (M+H), 2.57 min.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:13])[CH2:8]2
Reactant: C1CCNC1
Reactant: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Product: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCCC1

Procedure:
Heating a mixture of 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (100 mg; 0.30 mmol) and pyrrolidine (0.25 mL; 3.0 mmol) under microwave irradiation according to the procedure described in Example 37, Step 5 provided after purification by reverse phase HPLC, 1-tert-butyl-5-piperidin-1-yl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (14 mg, 16%) as an white solid. ES-HRMS m/e calcd for C22H34N4O (M+H+) 371.2806, found 371.2801.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])=[C:8]([Cl:19])[C:7]=1[Cl:20])=[O:5].[OH-].[K+]>C(O)C>[OH:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[C:8]([Cl:19])[C:7]=1[Cl:20])=[O:5]
Reactant: CCOC(=O)COc1ccc(C(=O)c2ccccc2O)c(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(C(=O)c2ccccc2O)c(Cl)c1Cl

Procedure:
4-(2-Hydroxybenzoyl)-2,3-dichlorophenoxyacetic acid was prepared by hydrolysis of ethyl 4-(2-hydroxybenzoyl)-2,3-dichlorophenoxyacetate with potassium hydroxide in ethanol at room temperature; m.p. 201°-203° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)=[O:18])[CH:13]=[CH:14][CH:15]=2)=[CH:6][C:5]([C:31]2[N:32]=[N:33][N:34]([CH2:36][CH2:37][CH2:38][O:39][Si](C(C)(C)C)(C)C)[N:35]=2)=[CH:4][N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:30])([F:28])[F:29])[CH:21]=3)=[O:18])[CH:13]=[CH:14][CH:15]=2)=[CH:6][C:5]([C:31]2[N:32]=[N:33][N:34]([CH2:36][CH2:37][CH2:38][OH:39])[N:35]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCn1nnc(-c2cnc(N)c(C#Cc3cccc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)c2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1ncc(-c2nnn(CCCO)n2)cc1C#Cc1cccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 1-(3-((2-amino-5-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)pyridin-3-yl)ethynyl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (188 mg, 0.28 mmol, 1 eq) in anhydrous tetrahydrofuran (5 mL) under nitrogen atmosphere at 0° C. was added dropwise tetrabutylammonium fluoride (1.0 M in THF, 0.84 mL, 3 eq). The reaction was stirred at room temperature for 3 hours and then concentrated and loaded onto silica. The mixture was subject to a column chromatography (EtOAc-Hex 4:1 to MeOH-EtOAc 1:25) to yield 1-[3-({2-amino-5-[2-(3-hydroxypropyl)-2H-tetrazol-5-yl]pyridin-3-yl}ethynyl)phenyl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea as a white solid in the amount of 127 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][C:13]([O:16][C:17]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:18])([CH3:15])[CH3:14]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:17](=[O:18])[O:16][C:13]([CH3:14])([CH3:12])[CH3:15])[CH2:25][CH2:24]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)cc2[N+](=O)[O-])CC1
Yield: 95 %

Procedure:
Method 1 was followed using 1 eq each of 4-chloro-1-fluoro-2-nitrobenzene, 4-N-Boc-aminopiperidine, and TEA yielding tert-butyl 1-(4-chloro-2-nitrophenyl)piperidin-4-ylcarbamate (95%). LCMS (m/z): 356.1 (MH+); LC Rt=3.43 min.
Reaction SMILES: CC([CH:5]1[CH:9]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[N:23][C:22]([NH2:25])=[C:21]([C:26]([NH:28][CH3:29])=[O:27])[N:20]=3)[CH:14]=2)=[O:12])[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:25][C:22]1[C:21]([C:26]([NH:28][CH3:29])=[O:27])=[N:20][C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([NH:10][C@@H:9]3[CH2:8][CH2:7][NH:6][CH2:5]3)=[O:12])[CH:14]=2)=[CH:24][N:23]=1
Reactant: CNC(=O)c1nc(-c2cccc(C(=O)NC3CCN(C(=O)[O-])C3C(C)(C)C)c2)cnc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1nc(-c2cccc(C(=O)N[C@@H]3CCNC3)c2)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
1,1-dimethylethyl-3-{[(3-{5-amino-6[(methylamino)carbonyl )pyrazin-2-yl}phenyl}carbonyl}amino}pyrrolidine-1-carboxylate (0.7 g, mmol) was suspended in dichloromethane (4 mL) and TFA (3 mL) was added. The mixture was stirred at ambient temperature for 2 hr. After removal of volatiles under reduced pressure, the residue was partitioned between saturated solution K2CO3 (300 mg) and dichloromethane (10 mL). The organic layer was separated, dried (Na2SO4) and evaporated to dryness to afford 0.4 g (74% yield) of 3-amino-N-methyl-6-(3-{[(3R)-pyrrolidin-3-ylamino]carbonyl}phenyl) pyrazine-2-carboxamide. 1H NMR (400 MHz; DMSO-D6): 8.9 (s, 1H); 8.85 (m, 1H); 8.71 (d, 1H); 8.48 (m, 1H); 7.4 (d, 1H); 7.84 (d, 1H); 7.6 (t, 1H); 4.54 (m, 2H); 3.6-3.18 (m, 4H); 2.85 (d, 3H); 2.25 (m, 1H); 2.1 (m, 1H); MS (EI) for C17H20N6O2: 341 (MH+)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH3:17])=[O:15])=[C:8]2[S:18][CH3:19].I[CH3:21].O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:21])[C:9]([C:14]([O:16][CH3:17])=[O:15])=[C:8]2[S:18][CH3:19]
Reactant: COC(=O)c1[nH]c2ccc(OC)cc2c1SC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(SC)c2cc(OC)ccc2n1C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 87 %

Procedure:
A suspension of 60% sodium hydride in mineral oil (0.30 g, 7.5 mmol) in 3.0 mL of N,N-dimethylformamide is cooled in ice while a solution of methyl 5-methoxy-3-(methylthio)-1H-indole-2-carboxylate (1.3 g, 5.2 mmol) in 10 mL of N,N-dimethylformamide is added dropwise. The mixture is stirred for 45 minutes, then iodomethane (0.50 mL, 1.1 g, 8.0 mmol) is added in one portion. After stirring at room temperature for 8 hours, the mixture is added to 100 g of ice and water. The solid is filtered and washed with 10% methanol-water to yield 1.2 g (88%) of product. A sample purified by flash chromatography (silica gel, 25% hexane in dichloromethane elution) and recrystallized from hexane has mp 89°-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 5-chloro-2-methoxybenzoate (23.1 g, 0.115 mol) in dioxane (300 mL) was added 2.5N NaOH (230 mL). The resulting mixture was stirred at room temperature for 4 hours, concentrated, diluted with H2O, and acidified with 2N HCl. 19.70 g (91%) of the desired product was collected by filtration as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.ClCCl.S([O-])([O-])(=O)=O.[Na+].[Na+]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C(=O)CCN(Cc2ccccc2)C1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)CN(Cc2ccccc2)CCC1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
A solution of 0.30 gm (1.3 mMol) 1-benzyl-2,4-dioxo-3,3-dimethylpiperidine in 5 mL tetrahydrofuran was stirred at room temperature as 2 mL (2 mMol) lithium aluminum hydride (2M in tetrahydrofuran) was added dropwise. The reaction mixture was then heated to reflux for 3 hours. The reaction mixture was then allowed to cool to room temperature. After stirring at room temperature for about 16 hours, the reaction mixture was cooled in an ice bath and treated sequentially with 0.5 mL water, 0.5 mL 5N sodium hydroxide, and 0.5 mL water with vigorous stirring. The resulting slurry was diluted with dichloromethane and anhydrous sodium sulfate was added. The slurry was filtered and the filter cake washed with dichloromethane. The combined filtrates were concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with dichloromethane containing from 0-10% methanol containing 0.1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide 0.25 gm (88%) of the desired compound.