Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:37])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:36])[CH2:33][S:34][CH3:35])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:45]OS([O-])=O.[K+]>CN(C=O)C.O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:37])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:36])[CH2:33][S:34]([CH3:35])=[O:45])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CSCC(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CS(C)=O)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58.7 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(methylthio)acetamide (Example 19) (20 mg, 0.03 mmol) in a mixture of DMF/H2O (1:1 v/v, 1.0 mL) was added Oxone (10 mg, 0.03 mmol) and the reaction was stirred at RT for 3 days. A second portion of Oxone® (10 mg, 0.03 mmol) was added, the mixture was stirred for a further 24 hr and was then partitioned between brine (20 mL) and DCM (20 mL). The organic extract was washed with brine (20 mL), dried (MgSO4) and evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 4 g, 30-100% EtOAc in isohexane, gradient elution) and subjected to SCX capture and release to afford the title compound (Example 20) as a tan coloured solid (11 mg, 52%): m/z 625 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 2.69 (3H, s), 3.88 (2H, d), 4.04 (2H, d) 5.39 (2H, s), 6.35 (1H, s), 7.02 (1H, d), 7.31 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.64 (3H, overlapping m), 7.93 (1H, m), 8.30-8.33 (2H, overlapping m), 8.37 (1H, d), 8.59 (1H, br s), 8.79 (1H, br s), 10.85 (1H, br s).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C@@H:11]([CH3:16])[CH2:10][C@H:9]2[NH:17][CH:18]=[O:19].Cl>C(Cl)Cl.N1C=CC=CC=1>[C:1]([N:12]1[C:13]2[C:8](=[CH:7][C:6]([Br:5])=[CH:15][CH:14]=2)[C@H:9]([NH:17][CH:18]=[O:19])[CH2:10][C@@H:11]1[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: C[C@H]1C[C@@H](NC=O)c2cc(Br)ccc2N1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(Br)cc2[C@H](NC=O)C[C@@H]1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Acetyl chloride (21 mL, 0.29 mol) was added dropwise at 0° C. to a solution of ((cis)-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)formamide (for a preparation see Intermediate 41) (71 g, 0.26 mol) in a mixture of DCM (1 L) and pyridine (350 mL). After stirring 2 hours at 0° C. the mixture was poured into a mixture of crushed ice (2 kg) and concentrated HCl (450 mL). The product was extracted with DCM (1 L) washed with brine and dried over Na2SO4. Concentration under vacuo afforded the expected product as an off white solid (82 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+]>CO>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=Cc1ccccc1
Reactant: Nc1cc(N)cc(C(=O)O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Nc1cc(NCc2ccccc2)cc(C(=O)O)c1

Procedure:
15.2 g. (0.1 mol) of 3,5-diaminobenzoic acid was placed in a 500 ml. round bottom flask to which 200 ml of methanol was added. To the round bottom flask 10.3 g. (0.1 mol) of benzaldehyde was added. The solution was stirred for several minutes. While the solution stirred 3.77 g. (0.06 mol) sodium cyanoborohydride was added slowly. After 5 hours the solution was filtered and then concentrated to dryness. The reaction mixture was dissolved in 200 ml. of 2M hydrochloric acid. The acid solution was extracted twice with 200 ml. ethyl acetate. The ethyl acetate solutions were combined and back washed with 200 ml. distilled water, and then dried over sodium sulfate. The solution was concentrated to dryness and 4.58 gm. of product was collected. The product was then purified by column chromatography using a solution of tetrahydrofuran/ethanol/water/ammonium hydroxide in the following ratio--10:3:1:0.04 as the eluent. Structural verification was obtained by carbon magnetic resonance, proton magnetic resonance and infra-red analysis.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:13])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH:14](OCC)(OCC)OCC>C1COCC1>[N+:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]2[N:13]=[CH:14][O:1][N:2]=2)=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: N=C(NO)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(OCC)OCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2ncon2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.5 %

Procedure:
To a stirred solution of 4-nitrobenzonitrile (1 g, 0.0068 mol) in ethanol (20 mL) and water (8 mL) was added hydroxylamine hydrochloride (1.9 g, 0.0272 mol) followed by sodium carbonate (2.2 g, 0.0204 mol). The resulting mixture was heated to reflux at 85° C. under an atmosphere of nitrogen for 2 hours The reaction was monitored by TLC (50% Ethyl acetate in Hexane). The volatiles were evaporated and the residue was extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to get afford 1.2 g (98%) of N-hydroxy-4-nitro-benzamidine. 1H NMR (DMSO-d6): δ 10.2 (s, 1H), 8.24 (d, 2H), 7.97 (d, 2H), 6.03 (s, 2H). To a stirred solution of N-hydroxy-4-nitro-benzamidine (1.2 g, 0.0066 mol) in THF (15 mL) was added triethyl orthoformate (2.93 g, 0.0198 mol). The resulting mixture was cooled to between 0 and 5° C. Boron trifluoride dimethyl ether (0.9 g, 0.0079 mol) was then added dropwise and the resulting mixture was stirred at ambient temperature for 3 hours. Volatiles were evaporated under reduced pressure and the resulting residue was washed with ether and dried to afford 0.65 g (55%) of 3-(4-nitro-phenyl)-[1, 2, 4]oxadiazole. To a stirred solution of 3-(4-nitro-phenyl)-[1, 2, 4]oxadiazole (0.2 g, 0.001 mol) in THF (15 mL) was added ammonium chloride (0.214 g, 0.004 mol) in water (5 mL) followed by zinc powder (0.262 g, 0.004 mol) portionwise. The resulting mixture was stirred at ambient temperature for 1 hr and then heated to 65° C. for 5 hours. The mixture was then filtered through celite and the organic layers were concentrated under reduced pressure. The residue was extracted with ethyl acetate. The organic layers were washed with brine solution, dried over Na2SO4 and evaporated under reduced pressure to afford 0.155 g (92%) of 4-[1, 2, 4]oxadiazol-3-yl-phenylamine. 1H NMR (DMSO-d6): δ 9.5 (s, 1H), 7.7 (d, 2H), 6.7 (d, 2H), 5.8 (s, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]2[CH:12]=[N:13]C(C#N)=[C:10]2[N:9]=[CH:8][CH:7]=1.Cl.[C:18]([OH:21])(=[O:20])[CH3:19]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]2[CH:12]=[N:13][C:19]([C:18]([OH:21])=[O:20])=[C:10]2[N:9]=[CH:8][CH:7]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncn2c(-c3cccs3)ccnc12
Agent: Cl
Product: O=C(O)c1ncn2c(-c3cccs3)ccnc12

Procedure:
A mixture of 0.01 mol of 4-(2-thienyl)imidazo[1,5-a]pyrimidine-8-carbonitrile (Example 1), 15 ml. of glacial acetic acid and 15 ml. of concentrated hydrochloric acid can be refluxed for 16 hours. The reaction mixture can be cooled and evaporated to dryness in vacuo, water added, and the precipitated solid recovered by filtration to produce 4-(2-thienyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2O)[CH:3]=[CH:2]1.P(Br)(Br)([Br:13])=O.[OH-].[Na+]>>[Br:13][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[CH:2][S:1][C:9]=12
Reactant: Oc1ccnc2ccsc12
Reactant: O=P(Br)(Br)Br
Agent: [Na+]
Agent: [OH-]
Product: Brc1ccnc2ccsc12
Yield: 59.3 %

Procedure:
Heat thieno[3,2-b]pyridin-7-ol (5.00 g, 33 mmol) and phosphorus oxybromide (50 g, 174 mmol) together at 110° C. for 3 h. Pour the hot reaction mixture into a mixture of ice and 5 N NaOH and extract with CH2Cl2. Dry the organic portion over Na2SO4 and evaporate. Purify the resulting crude material using a silica gel chromatography column (hexane:EtOAC=3:1) to give the title compound (4.19 g, 59%). ES/MS m/z (81Br) 215 (M+).
Reaction SMILES: [Br:1][C:2]1[C:12]([OH:13])=[C:11]([Br:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].IC.[CH2:23](N(CC)C=O)[CH3:24]>CN(C=O)C>[Br:1][C:2]1[C:12]([O:13][CH2:23][CH3:24])=[C:11]([Br:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCN(C=O)CC
Reactant: CCOC(=O)c1ccc(Br)c(O)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1ccc(Br)c(OCC)c1Br
Temperature: 85 °C

Procedure:
Ethyl 2,4-dibromo-3-hydroxybenzoate (5.0 g) was added to a stirred suspension of potassium carbonate (106.4 g) in dry N,N-diethylformamide (DMF). A solution of iodomethane (25.7 g) in DMF was added over 18 minutes, and the resulting mixture was heated at 85° C. for 1.3 hours. The cooled mixture was poured onto water and extracted with ether. The extract was washed (brine solution), dried (anhydrous magnesium sulphate) and the solvent evaporated in vacuo to give ethyl 2,4-dibromo-3-ethoxybenzoate (52.08 g), NMR 1.4(t,3H), 1.5(t,3H), 4.1(q,2H), 4.4(q,2H), 7.35(d,1H), 7.55(d,1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]=[CH:16][NH:17][C:18](=O)[C:19]=3[N:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)([Cl:24])=O.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1>[Cl:24][C:18]1[C:19]2[N:20]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:12]=[CH:13][C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: COc1ccc(-c2ccc3nc[nH]c(=O)c3n2)cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: COc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1OC
Yield: 76.9 %

Procedure:
To a suspension of 6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidin-4(3H)-one (150 mg, 0.53 mmol) in toluene (30 ml) was added phosphorus oxychloride (148 μl, 1.59 mmol) and 2,6-lutidine (185 μl, 1.59 mmol). The reaction mixture was refluxed overnight until a black solution was obtained. After evaporation to dryness, the residue was redissolved in ethyl acetate and extracted with a saturated sodium bicarbonate solution. The combined organic layers were evaporated in vacuo. The residue was purified by silica gel column chromatography, the mobile phase being an ethyl acetate/hexane mixture, in a ratio gradually ranging from 2:8 to 3:7, resulting in the pure title compound (123 mg, yield 77%) which was characterised by its mass spectrum as follows: MS (m/z): 302, 304 ([M+H]+, 100).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][C:3]=1[C:30]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33].[CH:40]1([NH2:45])[CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH:40]1([NH:45][C:2]2[N:7]3[N:8]=[C:9]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:12]=4)=[C:6]3[CH:5]=[CH:4][C:3]=2[C:30]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: NC1CCCC1
Reactant: CCOC(OCC)(OCC)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1Cl
Product: CCOC(OCC)(OCC)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1NC1CCCC1
Temperature: 80 °C
Yield: 96.1 %

Procedure:
A mixture of 4-[7-chloro-2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (2.37 g, 4.28 mmol) and cyclopentylamine (10 mL, 100 mmol) was heated in a sealed tube at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and excess cyclopentylamine was removed in vacuo. The crude solid was triturated in water. The solids were collected on a filter to provide N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-7-amine (2.48 g, 96%). Rf 0.42 (4:1 hexanes:ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.04 (d, 1H), 7.75 (d, 1H), 7.68–7.60 (m, 3H), 7.12 (t, 2H), 6.36–6.31 (m, 2H), 5.30 (m, 1H), 5.07 (d, 1H), 4.53 (m, 1H), 3.45 (q, 6H), 2.12–1.95 (m, 4H), 1.80–1.45 (m, 12H), 1.25 (t, 9H); MS m/z 603 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:30]=O)=[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[O:9].Cl.[NH2:33]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([C:30]#[N:33])=[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[O:9]
Reactant: NO
Reactant: CCOCCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOCCOC(=O)C1=C(C)NC(C#N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
A mixture of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (3.00 g), hydroxylamine hydrochloride (0.5547 g), sodium acetate (1.1382 g) in acetic acid (10 ml) was stirred for 30 minutes at room temperature. To this mixture was added acetic anhydride (1.4 ml) and the resultant mixture was stirred for an hour at room temperature and refluxed for an hour. The acetic acid was distilled off under reduced pressure, and to the residue was added water. The resultant mixture was neutrallized with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate twice. The extract was washed with water and an aqueous solution saturated with sodium chloride and dried. The solvent was distilled off and thus obtained viscous oily substance (3.19 g) was subjected to column chromatography on silica gel with an eluent [a mixture of 5 parts of benzene and one part of ethyl acetate by volume] and a yellow oil (1.74 g) was obtained from the fraction which contained the designated product. The oil turned into crystals (1.56 g). These crystals were recrystallized from benzene to give yellow powder (1.5 g) of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate.1/3benzene, m.p. 89° to 91° C. Thus obtained yellow powder was further recrystallized from a mixture of diethyl ether and n-hexane to give crystals of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate, m.p. 115° to 116° C.
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].N1C=CC=CC=1.C(=O)=O.[CH2:18]([O:20][C:21](Cl)=[O:22])[CH3:19]>COC(C)(C)C>[C:21](=[O:22])([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])[O:20][CH2:18][CH3:19]
Reactant: CCOC(=O)Cl
Reactant: OCC(F)(F)C(F)F
Agent: O=C=O
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Product: CCOC(=O)OCC(F)(F)C(F)F
Temperature: 25 °C

Procedure:
2,2,3,3-tetrafluoropropan-1-ol (121 g 0.92 mol), pyridine (76 g 0.96 mol) and 350 mL of methyl-t-butyl ether were combined in a 1 L 3-neck round bottom flask. The flask was equipped with an overhead stirring mechanism, thermocouple, addition funnel, cold water condenser, and a dry nitrogen bubbler. The reaction flask was kept cool using solid CO2 in a water bath. Ethylchloroformate (100 g, 0.92 mol) was added via an addition funnel dropwise at a rate such that the temperature of the reaction mix did not exceed 0° C. Once the addition was complete the mix was allowed to warm to room temperature on its own. The reaction mix was then quenched with 100 mL of water. The water portion was extracted with 2×100 mL portions of methyl t-butyl ether. The combined organic extracts were washed with 100 mL of 1N HCl and 100 mL of water. The solvent was removed by rotary evaporation and the carbonate was purified by fractional distillation using a concentric tube column. The structure of the product was confirmed by GC/MS and the purity by GC-FID was 99.05% of the desired compound.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:11]([NH:13][C@H:14]([C:19]([NH2:21])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].[ClH:29]>C(O)(=O)C>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:11]([NH:13][C@H:14]([C:19]([NH2:21])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].[ClH:29]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CN)C(N)=O
Yield: 56 %

Procedure:
Condensation of BocGlyOH (4.4 g.) and HLeu-MetNH2 hydrochloride salt (Example 1, 7.5 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocGly-Leu-MetNH2 in 51% yield. De-t-butoxycarbonylation of BocGly-Leu-MetNH2 using hydrogen chloride in acetic acid gave HGly-Leu-MetNH2 hydrochloride salt in 56% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:9][C:10]1[CH:28]=[CH:27][C:13]([CH2:14][N:15]2[CH2:19][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:16]2=[O:26])=[CH:12][CH:11]=1.[H-].[Na+]>CN(C=O)C.ClCCl>[C:20]1([C@H:18]2[O:17][C:16](=[O:26])[N:15]([CH2:14][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][O:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[CH:28][CH:27]=3)[CH2:19]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1O[C@H](c2ccccc2)CN1Cc1ccc(CBr)cc1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1O[C@H](c2ccccc2)CN1Cc1ccc(COc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
A solution of 3-hydroxypyridine (23 mg, 0.24 mmol) in DMF (1 mL) was added to a suspension of 3-(4-bromomethyl-benzyl)-5-(R)-phenyl-oxazolidin-2-one (70 mg, 0.20 mmol) (synthesized according to procedure 4) and sodium hydride (60%) (9 mg, 0.22 mmol) in DMF (1.5 mL) and the reaction mixture was stirred overnight at RT. It was diluted with dichloromethane (6 mL), washed with water (2×5 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by chromatography on silica gel, eluting with dichloromethane containing 0.25-1% of methyl alcohol, to yield the title compound as a white solid (33 mg, 45%). 1H NMR (300 MHz, CDCl3): δ 8.40 (s, 1H), 8.25 (s, 1H), 7.38 (m, 1H), 5.50 (dd, 1H), 5.11 (s, 2H), 4.59 (d, 1H), 4.43 (d, 1H), 3.80 (t, 1H), 3.34 (dd, 1H).
Reaction SMILES: Cl.N1(S([N:10]=[N+:11]=[N-])(=O)=O)C=CN=C1.[NH2:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.C([O-])([O-])=O.[K+].[K+]>CO>[N:13]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)=[N+:10]=[N-:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: [N-]=[N+]=NS(=O)(=O)n1ccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.5 %

Procedure:
Imidazole-1-sulfonyl azide hydrochloride (1.03 g, 6.0 mmol) was added to (R)-tert-butyl 3-aminopiperidine-1-carboxylate (1.0 g, 5.0 mmol), K2CO3 (1.33 g, 10.0 mmol) and CuSO4.5H2O (0.012 g, 0.05 mmol) in MeOH (30 mL) and the mixture was stirred at room temperature for 12 h. The mixture was concentrated, diluted with H2O (50 mL), extracted with EtOAc (3×60 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give (R)-tert-butyl 3-azidopiperidine-1-carboxylate (0.65 g).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)(O)[CH:15]([OH:27])[CH2:14]3)=[N:9][C:8]2=[O:28])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[C:15](=[O:27])[CH2:14]3)=[N:9][C:8]2=[O:28])=[CH:4][CH:3]=1
Reactant: O=c1nc(N2CCC(O)(c3ccc(F)cc3)C(O)C2)ncn1Cc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CN(c2ncn(Cc3ccc(Cl)cc3)c(=O)n2)CCC1c1ccc(F)cc1
Yield: 7.8 %

Procedure:
A toluene solution (10 mL) of 1-(4-chlorobenzyl)-4-[4-(4-fluorophenyl)-3,4-dihydroxypiperidin-1-yl]-1,3,5-triazin-2(1H)-one (202 mg, 0.468 mmol) synthesized in Synthesis Example 91 and p-toluenesulfonic acid monohydrate (341 mg, 1.99 mmol) was stirred under reflux by heating for 4 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure and to the resultant residue, saturated sodium bicarbonate aqueous solution was added, and extraction with ethyl acetate was performed. The organic layer was concentrated under reduced pressure and the resultant residue was purified by reverse-phase column chromatography (water/acetonitrile) to obtain the title compound (15.0 mg, yield: 8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)([CH3:19])[CH3:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C[Si](C)(C)[O:23][CH:24]=[CH2:25]>ClCCl.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([CH3:19])([CH3:18])[CH2:23][CH:24]=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C=CO[Si](C)(C)C
Reactant: CC(C)(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(C)(CC=O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-(1-(4-fluorophenyl)-1H-indazol-5-yl)propan-2-ol (Example 113(d), 200 mg, 0.74 mmol) and trimethyl(vinyloxy)silane (0.5 mL) in anhydrous dichloromethane (1 mL) was added zinc chloride (1M solution in diethyl ether, 2.2 mL, 2.2 mmol) dropwise at 0° C. under argon. The reaction mixture was stirred at rt for 1.5 hr before being quenched by the addition of saturated aqueous ammonium chloride solution (2 mL). The aqueous layer was separated and extracted with ethyl acetate (2×2 mL). The combined organic layers were dried (Na2SO4), concentrated and purified by silica gel flash chromatography to give 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutanal as a liquid.
Reaction SMILES: [F:1][C:2](=[C:13]([F:15])[F:14])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>C1COCC1>[F:1][C:2](=[C:13]([F:15])[F:14])[CH2:3][C:4](=[S:17])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(CC(F)=C(F)F)Nc1ccccc1
Solvent: C1CCOC1
Product: FC(F)=C(F)CC(=S)Nc1ccccc1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A mixture of 3,4,4-trifluoro-N-phenyl-3-butenamide (1.0 g, 4.65 mmol) and phosphorus pentasulfide (2.07 g, 4.65 mmol) in anhyd. THF (100 mL) was heated at reflux under nitrogen for 1 hour. The reaction mixture was cooled to r.t. and filtered. The filtrate was concentrated and the residue was chromatographed over silica gel (dichloromethane/hexanes, 80/20) to give 0.65 g (60%) of the desired compound as a pale yellow solid. m.p. 65-67° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.Cl>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1conc1-c1ccc(F)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1conc1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A mixture of 0.79 g of Compound 8C, 3.5 mL of acetic acid and 3.05 mL of 37% HCl was refluxed for 4 h. After cooling to r.t., the solvent was evaporated to dryness at reduced pressure and the crude was taken up with 15 mL of water The precipitate was filtered off and dried to give 0.632 g (85.9%) of the title compound. M.p. 170-174° C.