Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.[N+:13]([O-])([OH:15])=[O:14]>>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc(-n2nnnc2Cl)cc1
Temperature: 65 °C
Yield: 87 %

Procedure:
5-Chloro-1-phenyl-1H-tetrazole (500 g, 2.78 mol) was carefully added in one portion to stirred white fuming nitric acid (91.5% HNO3, 2.5 L). The internal temperature of the mixture increased steadily to 65° C. then fell. An aliquot was removed and partitioned between water and dichloromethane. TLC analysis (80:20 hexanes/ethyl acetate) indicated consumption of starting material. The mixture was carefully poured into stirred ice (3 L), water (2 L) and dichloromethane (2 L). The layers were separated and the aqueous was extracted with dichloromethane (2 L). The combined organic phase was washed with 5% aqueous sodium bicarbonate solution (1 L), dried (MgSO4), filtered, and concentrated to a solid. The solid was mixed with 90:10 hexanes/ethyl acetate (3 L) and heated to 65° C. The mixture was cooled overnight (2-5° C.). Filtration afforded a white crystalline solid (544 g, 87%). 1H NMR (CDCl3, 300 MHz) δ 8.51 (d, 9.5 Hz, 2H), 7.91 (d, 8.8 Hz, 2H); mp 96.5° C.; Rf=0.2 (K).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH2:11][OH:12])[CH:5]=1>Cl>[OH:12][CH2:11][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([CH3:10])[N:7]=1)[C:3]([OH:13])=[O:2]
Reactant: COC(=O)c1cc(C)nc(CO)c1
Agent: Cl
Product: Cc1cc(C(=O)O)cc(CO)n1
Yield: 104 %

Procedure:
A solution of 2-hydroxymethyl-6-methyl-isonicotinic acid methyl ester (500 mg, 2.76 mmol) in 32% aq. HCl (10 mL) is stirred at 60° C. for 5 h before it is evaporated and dried under HV to give the title compound as a yellow solid (480 mg); LC-MS: tR=0.16 min, [M+1]+=168.04.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([CH2:31][CH3:32])([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]([OH:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:18]([CH3:30])[CH:17]=3)[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:33]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[CH2:14]([C:13]([C:11]1[O:12][C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:33][C:9]=2[CH:10]=1)([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]([OH:29])[C:25]([CH3:27])([CH3:28])[CH3:26])=[C:18]([CH3:30])[CH:17]=1)[CH2:31][CH3:32])[CH3:15]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)OC)ccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)O)ccc2o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.6 %

Procedure:
A solution of 2-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-benzofuran-5-carboxylic acid methyl ester (555 mg, 1.226 mmol) in methanol (3.0 mL) and THF (3.0 mL) and is treated with NaOH (2.0 M, 6.0 mL). The resulting mixture is stirred at RT for 18 h. The mixture is concentrated and neutralized with HCl (1 N) till pH˜2, and extracted with EtOAc (3×10 mL). The organic layer is dried over Na2SO4, concentrated to afford the title compound (530 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[CH:12][C:11]1=[O:21].[CH:28](C1C(=O)NC2C(C=1O)=CC=CC=2)=[O:29]>>[Cl:1][C:2]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[C:12]([CH:28]=[O:29])[C:11]1=[O:21]
Reactant: COc1ccc(OCCCOCn2c(=O)cc(O)c3ccccc32)c(Cl)c1
Reactant: O=Cc1c(O)c2ccccc2[nH]c1=O
Product: COc1ccc(OCCCOCn2c(=O)c(C=O)c(O)c3ccccc32)c(Cl)c1

Procedure:
Following the procedure set forth in Preparation B, 1-[3-(2-chloro-4-methoxyphenoxy)propyloxymethyl]-4-hydroxy-2(1H)-quinolinone was converted to 1[3-(2-chloro-4-methoxy)phenoxy)propyloxymethyl]-3-formyl-4-hydroxy-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS: m/e 417 (M·+); NMR (CDCl3): δ2.01 (q, 2H, CH2), 3.75 (s, 3H, OCH3), 3.85 (q, 4H, CH2 --O), 10.21 (s, 1H, CHO).
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:5][CH:4]([CH2:6][CH2:7][OH:8])[CH2:3]1.CC(C)=[O:12].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[F:1][C:2]1([F:9])[CH2:5][CH:4]([CH2:6][C:7]([OH:12])=[O:8])[CH2:3]1
Reactant: CC(C)=O
Reactant: OCCC1CC(F)(F)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CC1CC(F)(F)C1
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of 2-(3,3-difluorocyclobutyl)ethanol (270 mg, 2.0 mmol, prepared as described in Bogen, S. et al., Bioorg. Med. Chem. Lett., 18:4219 (2008)) in acetone (5 mL) was treated with Jones reagent (2.7 mmol, 1 mL of 2.7 M solution) over a period of 30 minutes at room temperature. After 2 hours, additional Jones reagent (0.25 mL) was added. After 1 hour, the reaction mixture was filtered through CELITE®, and concentrated under reduced pressure. The reaction mixture was re-dissolved in ethyl acetate (10 mL), washed with water (2×20 mL), brine (20 mL), and then dried over MgSO4, The mixture was then filtered and concentrated to isolate Intermediate S-9A (275 mg, 92% yield) as a tan solid. 1H NMR (500 MHz, chloroform-d) δ 2.74-2.87 (2H, m), 2.57-2.62 (2H, m), 2.48-2.56 (1H, m, J=8.60, 4.30, 4.30, 1.94 Hz), 2.23-2.35 (2H, m).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH3:13].[CH:14]1([O:19][C:20]2[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:21]=2[CH:22]=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.[O-]CC.[Na+]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1/[CH:13]=[CH:22]/[C:21]1[CH:24]=[CH:25][CH:26]=[C:27]([O:28][CH3:29])[C:20]=1[O:19][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cccc(C=O)c1OC1CCCC1
Reactant: Cc1nc2ccccn2c(=O)c1Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3ccccn3c(=O)c2Br)c1OC1CCCC1

Procedure:
The title compound was prepared from 3-bromo-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (700 mg, 2.921 mmol) and 2-(cyclopentyloxy)-3-methoxybenzaldehyde (998 mg, 4.391 mmol) in the presence of sodium ethoxide (398 mg, 5.842 mmol) in absolute ethanol (30 ml) as described in Intermediate 1 to give 358 mg of the product as a light yellow solid; IR (KBr) 2958, 1679, 1620, 1528, 1436, 1264, 1065, 971 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.60-1.75 (m, 4H), 1.95-2.10 (m, 4H), 3.87 (s, 3H), 4.94 (br s, 1H), 6.90 (d, J=7.8 Hz, 1H), 7.02-7.10 (m, 1H), 7.35 (d, J=7.5 Hz, 2H), 7.56-7.72 (m, 3H), 8.44 (d, J=16.2 Hz, 1H), 8.94 (d, J=7.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.Br[CH2:15][C:16]([C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)=O>>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]2[S:8][CH:15]=[C:16]([C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=3)[N:9]=2)=[CH:5][CH:4]=1
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Product: CCOC(=O)c1ccc(-c2csc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Yield: 56 %

Procedure:
In the same manner as in Example 74, 4-trifluoromethylthiobenzamide was reacted with ethyl 4-bromoacetylbenzoate to obtain ethyl 4-[2-(4-trifluoromethylphenyl)-4-thiazolyl)benzoate. The product was recrystallized from ethanol. Yield: 56%. Pale yellow prisms. Melting point: 163 to 164° C.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][CH:7]([NH:12]C(OCC2C=CC=CC=2)=O)[C:8]([O:10][CH3:11])=[O:9])=[N:4][N:3]=[N:2]1.[ClH:23]>CO>[ClH:23].[NH:4]1[C:5]([CH2:6][CH:7]([NH2:12])[C:8]([O:10][CH3:11])=[O:9])=[N:1][N:2]=[N:3]1
Reactant: COC(=O)C(Cc1nnn[nH]1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Product: COC(=O)C(N)Cc1nnn[nH]1
Reaction time: 2 h

Procedure:
0.53 g (1.74 mmol, 1 equiv.) of the compound of Example 52 (3-tetrazolyl-2-benzyloxymethanamidopropionic acid, methyl ester) was dissolved in 30 mL of methanol and 1 mL of conc. HCl was added. The reaction was flushed with nitrogen and 80 mg of 10% palladium on carbon was added. The solution was hydrogenated for 2 hours at 40 psi. Filtration of the catalyst followed by counteraction in vacuo yielded 354 mg of the title compound. 1H-NMR (CD3OD): 4.7 p.p.m. (m, 1H); 3.8 p.p.m. (s, 3H); 3.6 p.p.m. (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[CH:10][O:9][C:8]=12.[Li][CH2:13]CCC.CI>C1COCC1>[CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[C:10]([CH3:13])[O:9][C:8]=12
Reactant: [Li]CCCC
Reactant: COc1nccc2ccoc12
Solvent: C1CCOC1
Solvent: CI
Product: COc1nccc2cc(C)oc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of 7-methoxyfuro[2,3-c]pyridine (2.9 g, 19.6 mmol) in THF (20 mL) stirred under an atmosphere of argon was added n-BuLi (7.8 mL, 19.6 mmol) at −78° C.; the mixture was transferred to a −30° C. ice bath and was stirred for 2 h. The mixture was cooled to −78° C. and MeI (4.2 g, 29.4 mmol) was added. After the mixture was stirred at rt for 18 h, the reaction mixture was quenched with water (30 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over Na2SO4 and concentrated in vacuo to afford the title compound (3.2 g, 100%) as a yellow solid. The material was carried forward without any further purification. LCMS (M+H)+=164.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15]>O1CCCC1>[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:13]([C:14]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)=[O:15])=[C:12]([OH:11])[CH:20]=1
Reactant: COc1ccc(C(=O)O)c(O)c1
Reactant: Nc1cccc2[nH]ccc12
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2cccc3[nH]ccc23)c(O)c1
Yield: 84.6 %

Procedure:
A mixture of 3.96 g of 4-amino-1H-indole, 70 ml of tetrahydrofuran, 5 g of 2-hydroxy-4-methoxy-benzoic acid and 6.2 g of dicyclohexycarbodiimide was refluxed for 24 hours and was evaporated to dryness under reduced pressure at 50° C. The residue was taken up in ethyl acetate and excess 4-amino-1H-indole was removed by washing with 2N hydrochloric acid. The mixture was evaporated to dryness under reduced pressure and the residue was taken up in ether and dried at 50° C. to obtain 7.1 g of 4-methoxy-2-hydroxy-N-(1H-indol-4-yl)-benzamide melting at 190° C.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[C:8]([C:14]#[N:15])[C:7]=1[Cl:16].[OH-:18].[Na+]>O>[C:14]([C:8]1[C:7]([Cl:16])=[C:6]([C:11]([Cl:12])=[CH:10][C:9]=1[Cl:13])[O:5][CH2:4][C:3]([OH:2])=[O:17])(=[O:18])[NH2:15]
Reactant: [OH-]
Reactant: COC(=O)COc1c(Cl)cc(Cl)c(C#N)c1Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(Cl)cc(Cl)c(OCC(=O)O)c1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
29.4 g (0.1 mol) of 3-cyano-2,4,6-trichlorophenoxyacetic acid methyl ester are suspended in 300 ml of water. After addition of 35 ml of concentrated sodium hydroxide, the reaction mixture is heated at 60° C. until a clear solution is obtained. After filtration over active carbon, the solution is cooled and brought to pH 2 by dropwise addition of 50% concentrated hydrochloric acid. The mixture is stirred for 2 hours in an ice bath, after which the resultant precipitate is vacuum-filtered, washed with water and dried at 50° C., thus producing 25.4 g (85% of theory) of 3-carbamoyl-2,4,6-trichlorophenoxyacetic acid as a white powder, mp 261°-262° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Br:11]Br>C(O)(=O)C>[Br:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: O=C(O)c1cccc(O)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1ccc(Br)c(O)c1
Temperature: 25 °C
Reaction time: 33 h

Procedure:
In acetic acid (24.5 ml), 3-hydroxybenzoic acid (5.00 g) was suspended. To the resulting suspension, a solution of bromine (1.9 ml) in acetic acid (acetic acid: 5 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 33 hours. The reaction mixture was ice cooled. The crystals so precipitated were collected by filtration and then washed with acetic acid, whereby the title compound (1.68 g, 21%) was obtained.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.[CH2:33]([NH2:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH2:33]([NH:35][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:24])([F:25])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH3:34]
Reactant: CCN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCNC(=O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 30 mg, 0.070 mmol), ethanamine-HCl (8.51 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). This was stirred for 1 h and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention 12.1=min) to provide (R/S)-N-ethyl-2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (25 mg, 0.049 mmol, 69.8% yield): LCMS=459.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14 (2 H, d, J=8.36 Hz), 7.48-7.85 (7 H, m), 5.10 (1 H, s), 3.28 (2 H, dd, J=7.15, 0.99 Hz), 1.14 (3 H, t, J=7.26 Hz); HPLC peak RT=9.2 min (Method A).
Reaction SMILES: [N:1]([C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].[CH2:12]([O:14][C:15](=[O:22])[C:16]#[C:17][C:18]([F:21])([F:20])[F:19])[CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15]([C:16]1[N:1]([C:4]2[C:5]([Cl:11])=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:10])[N:2]=[N:3][C:17]=1[C:18]([F:19])([F:20])[F:21])=[O:22])[CH3:13]
Reactant: [N-]=[N+]=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)C#CC(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(F)(F)F)nnn1-c1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 59.5 %

Procedure:
A mixture of 2-Azido-1,3-dichloro-benzene (25.0 g, 132.9 mmol) and 4,4,4-trifluoro-but-2-ynoic acid ethyl ester (26.5 g, 159.6 mmol) in toluene (30 mL) are heated at 80° C. for 18 h. A large exotherm is observed at 25 minutes. The reaction is removed from heat until exotherm subsides. Two regioisomers are observed in a range of 1:1 to 3:1 in favor of the desired product. The reaction mixture is concentrated under reduced pressure to 51 g of crude material and purified via column chromatography using a gradient of 35-60% DCM in Hexanes to yield the title compound (28 g, 59%). ES/MS m/e 353.0 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:22]([O:29][C:30](=[O:39])[CH2:31][NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C=O)C.ClCCl>[CH2:22]([O:29][C:30](=[O:39])[CH2:31][N:32]([C:8](=[O:10])[C@H:2]([CH2:3][CH2:4][C:5](=[O:6])[OH:7])[NH2:1])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: O=C(CNc1ccccc1)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N[C@@H](CCC(=O)O)C(=O)N(CC(=O)OCc1ccccc1)c1ccccc1

Procedure:
A solution of 20 mmoles of pyro-L-glutamic acid and 20 mmoles phenylglycine benzyl ester toluene sulfonic acid, neutrallized with N-ethyl morpholine, in dichloromethane:DMF (4:1) is cooled in an ice bath with stirring. A solution of 20 mmoles of dicyclohexylcarbodiimide in dichloromethane is added to the above reaction mixture. The reaction mixture is stirred in an ice water bath for 1 hour and then at room temperature overnight. Dicyclohexylurea is removed by filtration and the product is washed in ethyl acetate. Solvents of the combined filtrates are removed under reduced pressure with a rotary evaporator at 40° C. Ethyl acetate is added to the residue and the organic solution is washed until neutral. The organic phase is dried over anhydrous MgSO4, filtered and then the solvent is removed with a rotary evaporator. The material is crystallized from isopropanol and ether yielding the named product.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.[H-].[Na+].O>O1CCOCC1>[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:13][CH2:12]1
Reactant: CN1CCC(O)CC1
Reactant: N#Cc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCC(Oc2ccccc2C#N)CC1
Temperature: 50 °C
Yield: 30.5 %

Procedure:
To a mixture of 2-fluoro-benzonitrile (1.6 g, 13.2 mmol) and 1-methyl-piperidin-4-ol (1.52 g, 13.2 mmol) in dioxane (50 mL) was added NaH (60%)(634 mg, 15.8 mmol) in portion. The reaction was heated at 50° C. overnight. The mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographered using ethyl acetate/methanol (20:1-10:1) to give the title compound (870 mg, 31%). MS (DCI/NH3) m/z 217 (M+1)+. 1HNMR (400 MHz, DMSO-d6) δ ppm 1.63 (m, 2 H) 1.86 (m, 2 H) 2.11 (s, 3 H) 2.18 (m, 2 H) 2.48 (m, 2 H) 4.55 (m, 1 H) 7.00 (td, J=7.67, 0.61 Hz, 1 H) 7.23 (d, J=8.59 Hz, 1 H) 7.56 (td, J=10.13, 7.36, 1.84 Hz, 1 H) 7.63 (dd, J=7.67, 1.84 Hz, 1 H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([CH:20]4[CH2:22][CH2:21]4)[CH:13]=[C:14]([C:15]([O:17]CC)=[O:16])[C:9]=3[C:8]([CH3:23])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([CH:20]4[CH2:21][CH2:22]4)[CH:13]=[C:14]([C:15]([OH:17])=[O:16])[C:9]=3[C:8]([CH3:23])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C2CCCC2)c2nc(C3CC3)cc(C(=O)O)c12
Reaction time: 1 h

Procedure:
The title compound was prepared in the same manner as described for intermediate 46 using ethyl 1-cyclopentyl-6-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (740 mg, 2.361 mmol), sodium hydroxide (4 ml, 4.00 mmol), and ethanol (30 mL), wherein the stir time was 1 h. The final product was collected as 0.530 g (79%). LCMS E-S (M+H)=286.3 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.12 (m, 4H) 1.52-1.74 (m, 2H) 1.82-2.13 (m, 6H) 2.26-2.37 (m, 1H) 2.55 (s, 3H) 5.17-5.30 (m, 1H) 7.43 (s, 1H) 13.70 (br. s., 1H).
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][CH:26]=1>CN(C=O)C>[C:1]1([NH:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[O:15][CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:24]([O:23][CH3:22])=[O:33])=[CH:26][CH:27]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc(CNc2ccccc2)c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2cccc(CNc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 19.1 %

Procedure:
To a suspension of 3-((phenylamino)methyl)phenol (398 mg, 2 mmol) and cesium carbonate (651 mg, 2 mmol) in anhydrous DMF (8 mL) was added methyl-4-(bromomethyl)benzoate (481 mg, 2.1 mmol). The resulting mixture was stirred for 22 hours at room temperature, after which time the solvent was removed in vacuo. The residue was partitioned between dichloromethane (30 mL) and water (10 mL). The mixture was passed through a phase separator, washed with dichloromethane and solvent was removed in vacuo to afford a brown oil. The crude material was purified by silica gel chromatography eluting with 25% ethyl acetate in iso-hexane to afford the title compound as a yellow oil (133 mg, 19%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][C:7](O)=[O:8].O=S(Cl)[Cl:16]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][C:7]([Cl:16])=[O:8]
Reactant: Cc1cc(C)cc(OCC(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cc(C)cc(OCC(=O)Cl)c1

Procedure:
A mixture of the 3,5-dimethylphenoxyacetic acid (prepared as described above, 9.3 g, 51.6 mmol) and SOCl2 (11.3 mL, 18.5 g, 156 mmol, 3.0 eq) in 10 mL of benzene was refluxed for 2 h. Then volatile materials were removed by vacuum distillation to give 3,5-dimethylphenoxyacetic acid chloride as a light brown oil. To an ice-bath cooled solution of 6-amino-n-caproic acid (13.5 g, 103 mmol, 2.0 eq) and NaOH (4.2 g, 105 mmol) in 100 mL of H2O and 130 mL of CH3CN were added drop-wise a solution of the acid chloride (prepared in previous step) in 100 mL of CH3CN and a solution of NaHCO3 (6.5 g, 77.0 mmol, 1.5 eq) in 80 mL of H2O. The mixture was stirred vigorously overnight. Then most of the CH3CN was removed under reduced pressure and the mixture was acidified to pH 2 at room temperature with conc-HCl. The resulting white precipitates were collected by filtration, washed with H2O, followed by hexane, and thereafter dried under high vacuum to yield Intermediate 15 (14.5 g, 95%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7].Cl[C:14]1[N:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1>CO>[CH3:8][C:4]1[S:5][C:6]([CH3:7])=[C:2]2[C:3]=1[C:9](=[O:11])[N:19]1[CH:18]=[C:17]([C:20]([OH:22])=[O:21])[CH:16]=[CH:15][C:14]1=[N:1]2
Reactant: COC(=O)c1c(C)sc(C)c1N
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: CO
Product: Cc1sc(C)c2c(=O)n3cc(C(=O)O)ccc3nc12
Yield: 6.4 %

Procedure:
A mixture of 18.5 g (0.1 mol) of 4-amino-2,5-dimethyl-3-thiophenecarboxylic acid, methyl ester and 15.76 g (0.1 mol) of 6-chloro-3-pyridinecarboxylic acid (Aldrich Chemical Company) is heated in a wax bath at 168°-186° C. for one hundred ten minutes and then at 185°-186° C. for ninety minutes under nitrogen. The mixture is cooled, suspended in hot methanol, cooled and 4.2 g of crude product is collected. This material is dissolved in hot pyridine, activated charcoal (Darco-G60, Matheson, Coleman and Bell) is added and the hot suspension is filtered through Supercell Hyflo® (Johns-Manville). The filtrate is cooled to give 1.75 g of 1,3-dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid; mp 336° C. (dec) after recrystallization from pyridine.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:19]([CH3:32])[C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[Cl:31])=[O:21])[CH2:11][C@@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][NH:22][C:20](=[O:21])[N:19]([C@H:10]([CH2:9][OH:8])[CH2:11][C@@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]1)[CH3:32]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](CO[Si](C)(C)C(C)(C)C)C[C@@H]1COC(C)(C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](CO)C[C@@H]1COC(C)(C)O1
Reaction time: 0.5 h

Procedure:
To a solution of 1-((S)-1-(tert-butyldimethylsilyloxy)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-yl)-3-(2-chloro-3-fluorobenzyl)-1-methylurea (11.4 g, 23 mmol) in THF at 0° C., was added TBAF (23 mmol, 1 equiv.) dropwise. The reaction was completed in 30 min. The solvents were removed. The residue was dissolved in EtOAc (150 mL) and washed with 3% citric acid (150 mL) twice, followed by saturated NaHCO3 (100 mL) and brine (100 mL). The organic layer was concentrated to give 3-(2-chloro-3-fluorobenzyl)-1-((S)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-hydroxypropan-2-yl)-1-methylurea, which was used without further purification. LRMS (M+H+) m/z 375.4.