Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1N(CC2C=CC=CC=2)N=NC=1C(N)=O.N1C=CC=CC=1.C(Cl)(=O)C(C)(C)C.[CH2:30]([N:37]1[C:41]([NH:42][C:43](=O)[C:44]([CH3:47])([CH3:46])[CH3:45])=[C:40]([C:49]([NH2:51])=[O:50])[N:39]=[N:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C(=O)C.O>[CH2:30]([N:37]1[C:41]2[NH:42][C:43]([C:44]([CH3:47])([CH3:46])[CH3:45])=[N:51][C:49](=[O:50])[C:40]=2[N:39]=[N:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)C(=O)Nc1c(C(N)=O)nnn1Cc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: NC(=O)c1nnn(Cc2ccccc2)c1N
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)c1nc(=O)c2nnn(Cc3ccccc3)c2[nH]1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5-amino-1-benzyl-1H-1,2,3-triazole-4-carboxamide (150 g, 691 mmol, Eq: 1.00) was suspended in N,N-dimethylacetamide (512 g, 550 ml). Pyridine (82.1 g, 83.5 ml, 1.04 mol, Eq: 1.5) was added followed by pivaloyl chloride (126 g, 129 ml, 1.04 mol, Eq: 1.5) and the reaction mixture was heated to Tj=80° C. After complete acylation (ca 1 h30), KHCO3 (347 g, 3.45 mol, Eq: 5.00) was added and the suspension was heated to Tj=155° C. to convert the 1-benzyl-5-(2,2-dimethylpropanoylamino)triazole-4-carboxamide intermediate to the product. After 18 h30 at 155° C., the reaction mixture was cooled to RT and water (3.48 kg, 3.48 l) was added dropwise within 30 Min. The light yellow suspension was stirred for 30 min at RT, 2 h at 0° C. and filtered. The filter cake was washed with cold (0-5° C.) water (600 g, 600 ml) and dried at 50° C./5 mbar to give 161.3 g of the title compound as an off-white powder. MS(m/e): 284.0 (MH+).
Reaction SMILES: C([Mg]Cl)CCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[N:14]=1.C1(C)C=CC(S([C:29]#[N:30])(=O)=O)=CC=1>O1CCCC1.CCCCCC.C1(C)C=CC=CC=1.C(O)(=O)C>[Br:19][C:15]1[N:14]=[C:13]([C:29]#[N:30])[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: Brc1cccc(Br)n1
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.5 %

Procedure:
n-Butylmagnesium chloride (3.49 mmol) in 2.05M tetrahydrofuran solution (1.70 mL) was added to ice-cooled n-butyllithium (7.03 mmol) in 1.45M hexane (4.85 mL). The mixture was stirred at 0° C. for 15 minutes, and cooled to −10° C. to give a suspension. 2,6-Dibromopyridine (2.37 g, 10 mmol) in toluene (25 mL) was added to the suspension below −5° C. over a period of 10 minutes or more. The mixture was stirred at −10° C. for 3 hours, and p-toluenesulfonyl cyanide (2.48 g, 13.3 mmol) was added. After the mixture was stirred at 0° C. for 30 minutes, an aqueous solution (15 mL) of 1M acetic acid was added thereto. The reaction mixture was extracted twice with ethyl acetate (50 mL). The organic extracts combined were washed with an aqueous saturated solution (15 mL) of sodium chloride, dried over magnesium sulfate, and purified by flash column chromatography on silica gel in a developing solvent system of hexane-ethyl acetate (10:1, v/v) to give the title compound (942 mg, about 51% yield) as orange powder.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Cl-].[F:8][C:9]([F:27])([F:26])[O:10][C:11]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:12]=1[CH2:13][CH2:14][C:15]1([O:21]2)[CH2:20][CH2:19][NH2+:18][CH2:17][CH2:16]1.C([O:32][C:33](=[O:46])[CH2:34][N:35]1[N:39]=[N:38][C:37]([CH:40]2[O:44][N:43]=[C:42](Br)[CH2:41]2)=[N:36]1)(C)(C)C.[NH4+].[Cl-]>CC(O)(C)C.CC(OC)(C)C>[F:27][C:9]([F:8])([F:26])[O:10][C:11]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:12]=1[CH2:13][CH2:14][C:15]1([O:21]2)[CH2:16][CH2:17][N:18]([C:42]2[CH:41]=[C:40]([C:37]3[N:38]=[N:39][N:35]([CH2:34][C:33]([OH:46])=[O:32])[N:36]=3)[O:44][N:43]=2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)Cn1nnc(C2CC(Br)=NO2)n1
Reactant: FC(F)(F)Oc1cccc2c1CCC1(CC[NH2+]CC1)O2
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: CC(C)(C)O
Product: O=C(O)Cn1nnc(-c2cc(N3CCC4(CCc5c(OC(F)(F)F)cccc5O4)CC3)no2)n1
Temperature: 115 °C

Procedure:
tert-Butyl (5-{3-[5-(trifluoromethoxy)-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidin]-1′-yl]-4,5-dihydroisoxazol-5-yl}-2H-tetrazol-2-yl)acetate A suspension of dried Na2CO3 (694 mg, 6.55 mmol) in anhydrous t-BuOH was added 5-(trifluoromethoxy)-3,4-dihydrospiro[chromene-2,4′-piperidinium]chloride (848 mg, 2.62 mmol) (Intermediate 8) and tert-butyl[5-(3-bromo-4,5-dihydroisoxazol-5-yl)-2H-tetrazol-2-yl]acetate (725 mg, 2.183 mmol) (Intermediate 7). The mixture was directly heated to 115° C. for 24 h. The reaction mixture was diluted with MTBE, poured into aq. NH4Cl and extracted with EtOAc. The organic layer was washed with water and brine. The aqueous phases were back extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on SiO2 (50 g, gradient from 0 to 70% EtOAc/hexanes) to afford the title compound as a white solid. LC-MS: m/z=539.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].B(Br)(Br)Br.C([O-])([O-])=O.[Cs+].[Cs+].ClC1[S:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.Cl>C(Cl)Cl.CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([O:14][C:15]3[S:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[N:31]=3)[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: Clc1nc2ccccc2s1
Reactant: COC(=O)c1cc2ccc(OC)cc2s1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc2ccc(Oc3nc4ccccc4s3)cc2s1
Temperature: 25 °C
Yield: 5.3 %

Procedure:
To a cooled (−78° C.) solution of 6-methoxy-benzo[b]thiophene-2-carboxylic acid methyl ester (4.7 g, 21 mmol) in DCM (210 mL) was added BBr3 (6.0 mL, 15.9 g, 63 mmol) dropwise and the reaction mixture was allowed to warm (rt, 4 h). The reaction mixture was cooled (0° C.), diluted with EtOAc (200 mL) and treated with H2O (25 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×100 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was dissolved in MeCN (150 mL) and treated with Cs2CO3 (9.8 g, 30 mmol) and 2-chlorobenzothiazole (1.9 mL, 2.5 g, 15 mmol) and the reaction mixture was heated (60° C., 4 h). The reaction mixture was cooled (rt) and treated with 1 M HCl (50 mL) and partitioned between EtOAc (100 mL) and H2O (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×100 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using EtOAc:hexane (0-60%) to provide the title compound as a colorless foam (0.27 g, 5%). MS (ESI): mass calcd. for O11H10O3S2, 341.0; m/z found, 342.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.07 (s, J=0.6, 1H), 7.93 (dd, J=5.4, 3.2, 2H), 7.75 (dd, J=8.1, 0.6, 1H), 7.70 (dd, J=8.0, 0.7, 1H), 7.50-7.37 (m, 2H), 7.35-7.27 (m, 1H), 3.96 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[C:4]([Cl:19])[N:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:19])=[CH:5][C:6]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Tert-butyl 2,6-dichloro-3-nitropyridin-4-ylcarbamate 2.42 (2.0 g, 6.49 mmol) was dissolved in THF (10 mL) and cooled to 0° C. in ice-bath. To this solution sodium dithionite (3.39 g, 19.47 mmol), and NaHCO3 (1.6 g) dissolved in 10 mL of water, were added and the mixture was stirred at 0° C. After 1 hr, LC/MS indicated full conversion to desired product, solvent was removed under reduced pressure. Solids re-dissolved and extracted with ethyl acetate and water. Organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Residue obtained was recrystallized from acetonitrile to obtain tert-butyl 3-amino-2,6-dichloropyridin-4-ylcarbamate 2.43 that was used for next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1)=O.Cl.[NH2:12]O.C(OC(=O)C)(=O)C.Cl>O.N1C=CC=CC=1>[C:1]([C:3]1[O:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1)#[N:12]
Reactant: O=Cc1ccc(C(=O)O)o1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccc(C(=O)O)o1
Temperature: 85 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
To a flask with a stir bar and Vigreaux column under Ar was added 2-formyl-5-furancarboxylic acid (2.8 g, 20 mmol), hydroxylamine hydrochloride (2.7 g, 40 mmol), and dry pyridine (50 mL). The mixture was heated to 85° C., acetic anhydride (40 mL) was added and the mixture was stirred for 3 h. After cooling to 60° C., water (250 mL) was added and the mixture was stirred at RT for 70 h. The mixture was acidified to pH 2 with concentrated hydrochloric acid and extracted with 3:1 dichloromethane-isopropanol (8×100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anh sodium sulfate and concentrated in vacuo to afford the title compound as a tan solid (1.26 g, 46%). 1H-NMR NMR (CD3OD; 400 MHz): δ 14.05 (br s, 1H), 7.74 (d, 1H, J=3.8 Hz), 7.42 (d, 1H, J=3.8 Hz).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH:32]1([NH2:35])[CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH:32]1([NH:35][CH2:27][C:23]2[CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:11][CH2:10]3)[CH:26]=[CH:25][CH:24]=2)[CH2:34][CH2:33]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC5CC5)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.113 mmol) in DCM (2 mL) was added cyclopropanamine (19.3 mg, 0.339 mmol). The reaction solution was stirred at ambient temperature for 30 min prior to addition of HOAc (1 drop) and NaBH(OAc)3 (75 mg, 0.545 mmol). The resulting mixture was stirred overnight at ambient temperature after which time the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (18.2 mg, 34%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:8]([CH2:19][NH2:20])=[CH:7]2.[NH2:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24](Cl)[N:23]=1.C(N(CC)CC)C>CC(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:8]([CH2:19][NH:20][C:24]1[N:23]=[C:22]([NH2:21])[N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)=[CH:7]2
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1CN
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1CNc1nc(N)nc2[nH]cnc12
Temperature: 150 °C

Procedure:
A mixture of (8-methyl-2-o-tolylquinolin-3-yl)methanamine (40 mg, 0.15 mmol), 2-amino-6-chloropurine (52 mg, 0.30 mmol), and triethylamine (42 μL, 0.30 mmol) in i-PrOH (0.8 mL) was heated in a microwave reactor at 150° C. four times for 20 min. The mixture was partitioned between saturated aqueous NaHCO3 (15 mL) and EtOAc (15 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (2×15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow oil was dissolved in CH2Cl2, evaporated onto silica gel, and purified by flash chroma-tography (Biotage® Si 25+M) eluting with MeOH/CH2Cl2 (5% to 10%) to provide a white solid. The compound was further purified by reversed-phase HPLC (Gilson) eluting with H2O/MeCN/TFA to provide a white solid [PI3Kδ IC50=82 nM]. MS (ESI+) m/z=396.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH2:10][C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5][C:4](=O)[CH:3]=1.C([O-])(=O)C.[NH4+:16].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[NH2:16][C:4]1[CH2:5][C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:10][C:2](=[O:1])[CH:3]=1
Reactant: [NH4+]
Reactant: O=C1C=C(O)CC2(CCC2)C1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: NC1=CC(=O)CC2(CCC2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
10 g 8-hydroxyspiro[3.5]non-7-en-6-one and 10.1 g ammonium acetate are dissolved in 100 ml toluene and 3.2 ml acetic acid. The mixture is refluxed for 2 hours using a Dean-Stark trap. After cooling to room temperature the mixture is cautiously added to 200 ml of a saturated solution of sodium bicarbonate and 100 g ice. Then the mixture is stirred for 15 minutes, the solid product is collected by filtration and dried at 50° C. in vacuo.
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])=[O:4].[Cl:12][C:13]1[N:14]=[C:15]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:16]2[CH:21]=[C:20]([CH:22]=O)[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:16]2[CH:21]=[C:20]([CH2:22][N:9]3[CH2:10][CH2:11][N:6]([S:3]([CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]3)[S:19][C:17]=2[N:18]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: Cl
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Reaction between 1-methanesulfonyl-piperazine HCL salt and 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde 33 using General Procedure C Yielded 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[S:6][CH:7]=[CH:8][C:2]1=2.[Li]CCCC.CCCCCC.[CH3:20][Sn:21](Cl)([CH3:23])[CH3:22]>C1COCC1.C(Cl)(Cl)Cl.O>[CH3:20][Sn:21]([CH3:23])([CH3:22])[C:5]1[S:1][C:2]2[CH:8]=[C:7]([Sn:21]([CH3:23])([CH3:22])[CH3:20])[S:6][C:3]=2[CH:4]=1
Reactant: c1cc2sccc2s1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: C[Sn](C)(C)c1cc2sc([Sn](C)(C)C)cc2s1
Temperature: -50 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
To a solution of thieno[3,2-b]thiophene (1.2 g, 8.56 mmol) in 60 mL THF, 2.5 M solution of n-BuLi in hexane (7.25 mL, 18.0 mmol) was added dropwise at −50° C. under N2. The solution was stirred at −50° C. for 2 h and 1.0 M solution of trimethyltin chloride (18.9 mL, 18.8 mmol) in THF was added in one portion. After stirring at −50° C. for 2 h, the solution was warmed to room temperature and stirred for 24 h. The resulting mixture was poured into deionized water and 100 mL of CHCl3. The organic layer was washed twice with 50 mL of water and dried over anhydrous Na2SO4. The organic layer was evaporated and dried over vacuum to afford brown solid. The solid was then purified by recrystallization from Et2O to give colourless crystals (0.6 g, 82% yield). 1H NMR (CDCl3, 300 MHz, ppm): δ 7.26 (s, 2H), 0.48 (s, 18H).
Reaction SMILES: O=P(Cl)(Cl)Cl.O.[C:7](=[O:10])(O)[O-].[Na+].[CH:12]([N:15]([CH2:23][C:24]#[CH:25])[C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)([CH3:14])[CH3:13]>CN(C=O)C>[OH:22][C:18]1[CH:17]=[C:16]([N:15]([CH:12]([CH3:14])[CH3:13])[CH2:23][C:24]#[CH:25])[CH:21]=[CH:20][C:19]=1[CH:7]=[O:10]
Reactant: C#CCN(c1cccc(O)c1)C(C)C
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: C#CCN(c1ccc(C=O)c(O)c1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
After DMF (13.30 mL, 172.6 mmol) was cooled to 0° C. and POCl3 (2.68 mL, 28.79 mmol) was added dropwise thereto, the mixture was stirred for 20 minutes, warmed to room temperature, and then stirred for 1 hour. To this reactant, a solution in which the 3-(isopropyl(prop-2-ynyl)amino)phenol compound of Chemical Formula 3 (2.18 g, 11.51 mmol) was dissolved in DMF (10 mL) was added, and then the mixture was stirred for 12 hours. Distilled water (30 mL) was added to the post-reaction mixture, and the result was neutralized to between pH 7 and 8 by adding sodium bicarbonate solid. After this mixture was partitioned to acetic acid (100 mL) and distilled water (30 mL), the organic layer was separated, washed with saturated salted water (10 mL), dried with anhydrous sodium sulfate, filtered and vacuum distilled, and the residue obtained was column chromatographed on silica gel (hexane/ethyl acetate (7:1)) to give 2-hydroxy-4-(isopropyl(prop-2-ynyl)amino)benzaldehyde (2.05 g, 82%). 1H NMR (500 MHz, CDCl3) d 11.52 (s, 1H), 9.55 (s, 1H), 7.33 (d, 1H, J=8.7 Hz), 6.46 (dd, 1H, J=2.3, 8.7 Hz), 6.29 (d, 1H, J=2.3 Hz), 4.19-4.22 (m, 1H), 3.98 (d, 2H, J=2.7 Hz), 2.23 (t, 1H, J=2.7 Hz), 1.29 (d, 6H, J=6.9 Hz); 13C NMR (125 MHz, CDCl3) d 192.7, 164.2, 154.7, 135.3, 112.4, 105.4, 98.5, 80.4, 72.0, 49.1, 33.3, 20.2 (2).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:16]1[C:17](=[O:27])[N:18]([CH3:26])[C:19](=[O:25])[N:20]([CH3:24])[C:21]=1[CH2:22]Br)(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:28]([S:47][CH2:48][CH2:49][NH2:50])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCO.C(Cl)Cl>[CH3:24][N:20]1[C:21]2=[CH:22][N:50]([CH2:49][CH2:48][S:47][C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]1=[O:25]
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Temperature: 100 °C

Procedure:
Triethylamine (0.211 ml, 1.513 mmol) was added to a solution of 5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C) (510 mg, 1.513 mmol) and 2-tritylsulfanyl-ethylamine (Intermediate D) (483 mg, 1.513 mmol) in EtOH (5 ml) and the mixture heated at 100° C. under microwave irradiation for 2 hours. The reaction mixture was diluted with DCM (10 mL) and was washed with water (3×10 mL). The organic phase was passed through a hydrophobic frit and the solvent was evaporated under reduced pressure. The title product was obtained as a pale yellow solid and used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]>C(O)C>[CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)C1(Cc2ccccc2)CCCC1
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccccc2)CCCC1
Yield: 99.3 %

Procedure:
A solution of 4-nitro-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (185 mg, 0.45 mmol) in 10 mL of ethanol was hydrogenated at atmospheric pressure over 47 mg of 10% Pd(C.) for 3 hours. The reaction mixture was filtered through a pad of celite and evaporated to dryness to give 4-amino-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (170 mg, 99%) of as a white solid suitable for use in the next step.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=2)[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc2nc(O)ccc2c1
Product: Oc1ccc2nc(Cl)ccc2c1

Procedure:
As set forth in reaction Scheme C, quinoline2,6-diol is chlorinated with POCl3 to obtain 2-chloroquinolin-6-ol, which is reacted with a desired amine substituent, in this case 4-bromo-3-methylaniline, and to obtain the amine substituted quinolinol. A mixture of the alcohol and potassium bis(trimethylsilyl)amide in dimethylformamide is reacted with a desired substituent at the alcohol group, in this case dimethylformamide, to obtain the desire product, in this case (4-{2-[(4-bromo-3-methylphenyl)amino](6-quinolyloxy)}(2-pyridyl))-N-methylcarboxamide.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)C=C.[CH3:12][CH2:13][CH2:14]CCC>>[CH2:14]([C:10]1[CH:9]=[C:8]([F:11])[CH:7]=[CH:6][C:5]=1[OH:4])[CH:13]=[CH2:12]
Reactant: C=CCOc1ccc(F)cc1
Reactant: CCCCCC
Product: C=CCc1cc(F)ccc1O

Procedure:
381.8 parts of oily 4-allyloxy-fluorobenzene are heated in a oil-bath for 8 hours at a temperature of about 245°-250° C. After cooling, the reaction mixture is poured onto 1200 parts of hexane. The mixture is extracted three times with sodium hydroxide solution 20% (total volume of sodium hydroxide: 2000 parts). The aqueous layer is washed with petroleum ether, acidified with 1300 parts of concentrated hydrochloric acid solution and extracted with ether. The extract is dried over calcium chloride, filtered and evaporated. The oily residue is distilled in vacuo, yielding 313.6 parts of 2-allyl-4-fluorophenol; bp.143° C at 48 mm. pressure; nD20 : 1.5225; d2020 : 1.1130.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[C:18]2[C:19]3[CH:28]=[CH:27][NH:26][C:20]=3[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=2)[CH2:4][CH2:3]1.CN1C=C(C2C=C([N+]([O-])=O)C=CC=2OC2C=CC=CC=2)C2C=CNC=2C1=O>>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH:5]2[CH2:4][CH2:3][C:2]([F:1])([F:29])[CH2:7][CH2:6]2)=[C:10]([C:18]2[C:19]3[CH:28]=[CH:27][NH:26][C:20]=3[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=2)[CH:11]=1
Reactant: Cn1cc(-c2cc([N+](=O)[O-])ccc2OC2CCC(F)(F)CC2)c2cc[nH]c2c1=O
Agent: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Product: Cn1cc(-c2cc(N)ccc2OC2CCC(F)(F)CC2)c2cc[nH]c2c1=O

Procedure:
Example 59b was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 59a for the product of Example 2b, to provide the title compound.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.[H-].[Na+].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>CN(C=O)C>[CH3:21][N:22]([CH3:26])[C:23]([O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1)=[O:24]
Reactant: CN(C)C(=O)Cl
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OC(=O)N(C)C)cc(C)c21
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (500 mg, 2 mmol) in DMF (5 mL) was slowly added NaH (360 mg, 6 mmol) at 0° C. The mixture was stirred for 20 min and N,N-dimethylcarbamic chloride (430 mg, 4 mmol) was added at 0° C. The mixture was stirred overnight at room temperature and quenched with ice water. The resulting mixture was extracted with EtOAc (2×25 mL) and the combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was used directly in the next step reaction without further purification, MS (ESI) m/z=322 [M+H]+.