Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].Cl.[Cl:7][C:8]1[CH:17]=[C:12]([C:13]([NH:15][OH:16])=[O:14])[C:11](O)=[CH:10][CH:9]=1.[OH-].[NH4+]>O.O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:5][CH:1]3[CH2:2][CH:3]([CH3:4])[O:16][N:15]3[C:13](=[O:14])[C:12]=2[CH:17]=1
Reactant: C/C=C/C=O
Reactant: O=C(NO)c1cc(Cl)ccc1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1CC2Oc3ccc(Cl)cc3C(=O)N2O1
Temperature: 90 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
360 ml. of tetrahydrofuran is combined with 90 gm. of crotonaldehyde and placed in an ice bath. 100 gm. of hydrogen chloride are passed into the mixture at 20°-30° C. 158 gm. of 5-chlorosalicylhydroxamic acid is added in one portion and the mixture stirred at 25°-30° C. for about two hours until the solid dissolves. The mixture is cooled in a water bath and 400 ml. of concentrated ammonium hydroxide diluted with 400 ml. of water is added with stirring. The temperature of the mixture is allowed to rise to about 50° C. during the alkali addition and the mixture is then heated on a steam bath to about 90° C. and a vacuum applied to remove as much tetrahydrofuarn as possible. A solid precipitates while heating. 400 ml. of water are added and the entire mixture is cooled to about 10° C. in an ice bath. The solid is filtered and washed with water and pulled dry. The cake is recrystallized from 800 ml. boiling isopropanol refrigerated overnight. The crystals are filtered, washed with cold isopropanol and dried at about 100° C. 136 gm. 7-chloro-2-methyl-3,3a-dihydro-2H, 9H-isoxazolo (3,2-b) (1,3) benzoxazin-9-one (m.p. 144°-148° C.) for a yield of 67% is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:14][N:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](Cl)=[O:17]>>[C:7]([NH:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:16](=[O:17])[N:15]([CH3:14])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)(=[O:11])[CH2:8][CH2:9][CH3:10]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CCCC(=O)Nc1ccc(O)cc1
Product: CCCC(=O)Nc1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from 4′-hydroxybutyranilide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (60%, white solid). HPLC-MS: m/z=313.2 (M+1); Rt: 3.58 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40]([O:42]C)=[O:41])=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:35][CH:36]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CCCC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.9 %

Procedure:
A solution of chiral methyl 4-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)butanoate (70.5 mg, 0.110 mmol) in THF (5 ml) was treated with LITHIUM HYDROXIDE MONOHYDRATE (18.5 mg, 0.441 mmol) in water (2.5 ml) and stirred at rt for 16 hrs. The reaction was treated with 1 N HCl (pH 5) and extracted with ethyl acetate, washed with water then sat'd sodium chloride, dried with sodium sulfate, filtered and lyophilized to give chiral-4-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)butanoic acid (67 mg, 97.2%) as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 628.19. found: 628.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([O:20][CH3:21])[CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:23]=1.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:26]([N:25]([CH3:29])[CH3:24])=[O:27])=[C:15]([O:20][CH3:21])[CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:23]=1
Reactant: CN(C)C(=O)Cl
Reactant: COc1cc(C(=O)N2CCCCc3cc(Cl)ccc32)ccc1N
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(C(=O)N2CCCCc3cc(Cl)ccc32)ccc1NC(=O)N(C)C
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-1-(3-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.7 g) in pyridine (5 ml) is added N,N-dimethyl-carbamic chloride (0.42 ml), and the mixture is stirred at 60-70° C. for two hours. The mixture is made acidic with hydrochloric acid, and then extracted with ethyl acetate. The mixture is washed with a saturated aqueous sodium hydrogen carbonate solution, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; ethyl acetate:n-hexane=1:10→1:1→3:1), and recrystallized from ethanol/diethyl ether to give 7-chloro-1-(3-methoxy-4-dimethylaminocarbonylaminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.33 g) as white plates.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]O)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Br:31])[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCO)c1CCC(=O)OCC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Temperature: 7.5 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a solution of 4-[2-(2-ethoxycarbonyl-ethyl)-3-(6-hydroxy-hexyl)-phenoxy]-butyric acid ethyl ester (0.85 mmol, 349 mg) and carbon tetrabromide (1.26 mmol, 423 mg) in dichloromethane (10 mL) was added triphenylphosphine (1.07 mmol, 281 mg) at ˜0° C. The resulting colorless solution was stirred for 3 h at 5-10° C. Then, the solvent was removed under vacuum and the crude was tried to dissolve in a mixture of ethyl acetate and hexanes (1:3, 50 mL). As a result, a cloudy solution containing some precipitate was formed and the cloudy solution was transferred into a reparatory funnel and was washed with a mixture of methanol and water (2:1, 150 mL). The aqueous layer was extracted one more time with ethyl acetate and hexanes (1:3, 50 mL). The combined organic extracts were washed with brine solution (100 mL) and the organic solution was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave a colorless oil which was purified by using a Biotage™ (40M) column chromatography eluting with 10% ethyl acetate in hexanes to obtain the desired 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (350 mg, 87.5%) as a colorless oil: ES(+)-HRMS m/e calculated for C23H35BrO5 (M+Na)+ 493.1560. found 493.1560.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3S[CH2:22][CH2:21][C:16]=3[N:17]=[C:18]([Cl:20])[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>C1COCC1.C(N(CC)CC)C.[Pd].[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH2:21][CH3:22])[N:17]=[C:18]([Cl:20])[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3c2SCC3)CC1
Agent: [Ni]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)nc(Cl)n1
Temperature: 50 °C
Reaction time: 24 h
Yield: 10.9 %

Procedure:
200 mg palladium charcoal was added to 200 mg 4-(2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 mL THF and 0.08 mL triethylamine. Raney-nickel and 5 mL ethanol was added and the reaction was stirred 24 h at 50° C. and 3 bar hydrogen. The mixture was filtered. The filtrate was evaporated and the residue was purified by HPLC to give 20 mg desired product.
Reaction SMILES: C(OC(=O)[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:8])(C)(C)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:33]2[C:34]([CH:39]=O)=[N:35][CH:36]=[CH:37][CH:38]=2)([CH3:32])[CH3:31])=[CH:26][CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(C(F)(F)F)=O.NCCCCN(CC1N=CC=CC=1C(O)=O)CC1C(C)=CC(C)=CN=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([C:33]2[C:34]([CH2:39][N:13]([CH2:14][C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:12][CH2:11][CH2:10][CH2:9][NH:7][CH3:8])=[N:35][CH:36]=[CH:37][CH:38]=2)([CH3:32])[CH3:31])=[CH:28][CH:29]=1
Reactant: CC(C)(c1ccc(Cl)cc1)c1cccnc1C=O
Reactant: CN(CCCCNCc1ncccc1F)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1cnc(CN(CCCCN)Cc2ncccc2C(=O)O)c(C)c1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CNCCCCN(Cc1ncccc1F)Cc1ncccc1C(C)(C)c1ccc(Cl)cc1

Procedure:
Using General Procedure B, {4-[(3-fluoro-pyridin-2-ylmethyl)-amino]-butyl}-methyl-carbamic acid tert-butyl ester, 3-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyridine-2-carbaldehyde and NaBH(OAc)3 were reacted to give a pale yellow oil. Deprotection with TFA using General Procedure F and conversion to the HBr salt using General Procedure D gave a white solid. 1H NMR (D2O) δ 1.21-1.25 (m, 2H), 1.36-1.42 (m, 2H), 1.67 (s, 6H), 2.30-2.36 (m, 2H), 2.65 (s, 3H), 2.89-2.91 (m, 2H), 3.75 (s, 2H), 4.10 (s, 2H), 7.18 (d, 2H, J=8.4 Hz), 7.32 (d, 2H, J=8.4 Hz), 7.87-7.94 (m, 1H), 8.19 (t, 1H, J=8.7 Hz), 8.58 (d, 1H, J=5.1 Hz), 8.66 (dd, 1H, J=5.7, 8.7 Hz); 13C NMR (D2O) δ 21.64, 23.34, 29.58, 33.16, 42.64, 48.88, 50.52, 53.30, 54.88, 126.15, 128.30 (d, J=7 Hz), 128.50, 129.41, 131.78 (d, J=19 Hz), 132.40, 140.91, 141.13, 141.21, 141.33, 143.16, 146.54 (d, J=4 Hz), 150.78, 158.93 (d, J=256 Hz). ES-MS m/z 455 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:48][C:49]([CH3:69])=[CH:50][CH2:51][CH2:52]/[C:53](/[CH3:68])=[CH:54]/[CH2:55][CH2:56]/[C:57](/[CH3:67])=[CH:58]/[CH2:59][S:60][CH2:61][C@H:62]([NH2:66])[C:63]([OH:65])=[O:64]>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([NH:66][C@@H:62]([CH2:61][S:60][CH2:59]/[CH:58]=[C:57](\[CH3:67])/[CH2:56][CH2:55]/[CH:54]=[C:53](\[CH3:68])/[CH2:52][CH2:51][CH:50]=[C:49]([CH3:69])[CH3:48])[C:63]([OH:65])=[O:64])=[O:14]
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)Cc1c[nH]c2ccc(O)cc12)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 24 mL vial, 5-hydroxyl indole-3-acetic acid (191 mg, 1.0 mmol), HATU (380 mg, 1 mmol) and N,N-diisopropyl-ethyl-amine (650 mg, 5 mmol) were mixed in THF (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. S-trans, trans-Farnesyl-L-cysteine (325 mg, 1 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. THF was removed by rotary evaporation. The resulting residue was dissolved in ethyl acetate (50 mL). The organic solution was washed with water (50 mL) and brain (50 mL), dried over Na2SO4, and concentrated to afford a crude mixture. The crude mixture was purified by preparative HPLC (210 mg, 42%) to yield Compound N-39. 1H-NMR (500 MHz, CD3OD): δ 1.49 (s, 9H), 1.56 (S, 3H), 1.85-1.98 (m, 6H), 2.62 (dd, J=8.0, 14.0 Hz, 1H), 2.80 (dd, J=4.5, 14.0 Hz, 1H), 2.88 (dd, J=7.0, 13.0 Hz, 1H), 2.98 (dd, J=8.5, 13.0 Hz, 1H), 3.55 (dd, J=6.5, 22.5 Hz, 2H), 4.49 (dd, J=5.0, 8.0 Hz, 1H), 4.98 (bs, 2H), 6.57 (d, J=8.5 Hz, 1H), 6.84 (s, 1H), 7.07 (d, J=6.5 Hz, 2H). 13C-NMR (125 MHz, CD3OD): δ 16.2, 17.8, 26.0, 27.3, 27.4, 27.8, 28.8, 30.2, 33.3, 33.8, 40.7, 40.9, 53.4, 103.7, 108.2, 112.7, 112.8, 121.5, 125.2, 125.5, 125.8, 129.3, 132.1, 133.0, 136.2, 140.5, 151.5, 173.9, 174.9; ES-MS: mass calcd for Chemical Formula: C28H38N2O4S 498.3 (M+). Found (M+1) m/z 499.2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N:23]=[C:24]=S>CO.O=[Hg]>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[NH:23][C:24]1[O:7][C:6]([C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[N:8][N:9]=1
Reactant: FC(F)(F)c1ccc(Cl)c(N=C=S)c1
Reactant: NNC(=O)c1ccc(O)cc1
Agent: O=[Hg]
Solvent: CO
Product: Oc1ccc(-c2nnc(Nc3cc(C(F)(F)F)ccc3Cl)o2)cc1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
Mercury (II) oxide yellow (1.82 g, 8.41 mmol) was suspended in ca. 50 mL of anhydrous methanol. 4-Hydroxybenzoic acid hydrazide (1.28 g, 8.41 mmol) was added to this bright-orange suspension, followed by 2-chloro-5-trifluoromethyl-phenylisothiocyanate (2.0 g, 8.41 mmol). The reaction mixture was brought to reflux and refluxed for 2 hours. The reaction mixture turned pitch-black in color and formed black precipitate. Then it was cooled down to ambient temperature and filtered through a short pad of Celite, then through a short pad of silica gel. Then methanol was removed in vacuo and the resulting grey solid was re-crystallized from ca. 20 mL of EtOAc. The formed white precipitate was filtered, washed with anhydrous Et2O and dried in vacuo to give the title product as a white solid (2.638 g). Yield 88.1%
Reaction SMILES: [NH2:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[CH:3][C:4]([O:6]CC)=O.[H-].[Na+].[F:17][C:18]([F:33])([F:32])[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=O)[O:28]CC)=[CH:22][CH:21]=1>CN(C)C=O>[F:17][C:18]([F:32])([F:33])[O:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[NH:1][C:27]2=[O:28])=[CH:24][CH:25]=1
Reactant: CCOC(=O)Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C=C(N)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccccn2)[nH]c(=O)n1-c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Yield: 55 %

Procedure:
1.0 g of ethyl 3-amino-3-(2-pyridyl)-2-propenoate was added dropwise to a 20 ml dimethylformamide solution of 0.26 g of sodium hydride (purity: 55%) under stirring at 0° C. This solution was stirred at room temperature for 15 minutes and then added with 1.3 g of ethyl 4-trifluoromethoxyphenylcarbamate. The mixed solution was stirred at 100° C. for 3 hours and then the solvent was distilled away under reduced pressure. The residue was dissolved by adding 100 ml of water and washed with diethyl ether. The obtained aqueous layer was added into a mixed solution of 20 ml of concentrated hydrochloric acid and 50 g of ice. Then precipitated crystals were filtered out and dried under reduced pressure to obtain 1.0 g of 3-(4-trifluoromethoxyphenyl)-6-(2-pyridyl)-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([F:20])[CH:22]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: NCc1cccc(F)c1
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1cccc(F)c1
Yield: 90 %

Procedure:
The compound prepared in Example 3 was reacted with 3-fluoro-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 90%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]2)[NH:11][C:10]3=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][NH:29][CH3:30]>>[CH3:28][N:29]([CH3:30])[C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:8]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:11]=1
Reactant: CNC
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N4CCCCC4)cc3c(=O)[nH]2)c1
Product: CN(C)c1nc(-n2cc(C(=O)O)cn2)nc2ccc(N3CCCCC3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI/CI): predicted mass C19H22N6O2, 366.2.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:14]2[CH3:30])=[CH:9][CH:8]=1.[Li+].[OH-].CO.O>C1COCC1>[CH3:30][C:14]1[N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][C:3]([OH:31])=[O:2])=[CH:12][CH:11]=2)[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][C:15]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)CCOc1ccc(-n2c(-c3ccccc3)cc(-c3ccccc3)c2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2ccccc2)cc(-c2ccccc2)n1-c1ccc(OCCC(=O)O)cc1
Temperature: 40 °C
Yield: 18.9 %

Procedure:
A mixture of 3-[4-(2-methyl-3,5-diphenyl-pyrrol-1-yl)-phenoxy]-propionic acid methyl ester (51 mg; 0.12 mmol) and LiOH (5.4 mg; 0.23 mmol) in THF (1.0 mL)/MeOH (0.5 mL)/H2O (0.4 mL) was heated at 40° C. for 4 h then quenched with aq. citric acid. Product was extracted into EtOAc then washed with water and satd NaCl; then dried over MgSO4, filtered through silica with an EtOAc wash, concd then purified by MPLC (silica; 0-->100% EtOAc in hexanes gradient) yielding product as a grey solid (9 mg). 1H NMR (CDCl3) δ 7.53-7.48 (m, 2H), 7.41 (m, 2H), 7.24 (m, 1H), 7.20-7.08 (m, 7H), 6.91 (m, 2H), 6.55 (s, 1H), 4.27 (t, J=6.4 Hz, 2H), 2.89 (t, J=6.2 Hz, 2H), 2.23 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH:3]([O:5][CH2:6][CH3:7])=[O:4].C(O[CH:11](OCC)[CH2:12][C:13](OCC)=O)C.Cl.[C:22]([NH2:25])(=[NH:24])[CH3:23]>O.C(O)(=O)C.CCOCC>[CH3:23][C:22]1[N:25]=[CH:11][C:12]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:13][N:24]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(OCC)OCC
Reactant: CCOC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(C)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.1 %

Procedure:
Into 25 ml of ether was suspended 762 mg of 60% NaH, and then 20 g of ethyl formate was added dropwise under ice-cooling. Then, 12 ml of an ether solution of 5.0 g of ethyl 3.3-diethoxypropanoate was added dropwise thereto. After 2 days of stirring at the same temperature, 2.50 g of acetamidine hydrochloride was added thereto, followed by 1 day of stirring at room temperature. Then, 5 ml of acetic acid and water were added to the reaction solution, followed by extraction with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by evaporation and the resulting residue was subjected to silica gel column chromatography to obtain 2.93 g of the title compound from an eluate eluted with ethyl acetate-hexane (3:7, v/v).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[N:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[S:12][C:10]3=2)[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[N:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[S:12][C:10]3=2)[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1cnc2ccc3nc(S(C)(=O)=O)sc3c2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccc3nc(S(C)(=O)=O)sc3c2c1Cl

Procedure:
A mixture of 3.52 g of ethyl 9-hydroxy-2-methylsulfonylthiazolo[5,4-f]quinoline-8-carboxylate and 30 ml of phosphorus oxychloride was refluxed for 6 hours.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:18](O)=[O:19])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[O:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH:58]1[O:63][NH2:64]>C(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:25])([S:21]([CH3:24])(=[O:22])=[O:23])[C:18]([NH:64][O:63][CH:58]2[CH2:59][CH2:60][CH2:61][CH2:62][O:57]2)=[O:19])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CCn1ccc(OCc2ccccc2)cc1=O)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(CCn1ccc(OCc2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (670 mg, 1.77 mmol) in methylene chloride (18 mL) at ambient temperature was added 1, (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (474 mg, 2.47 mmol), 1-hydroxy benzotriazole monohydrate (487 mg, 3.18 mmol), triethylamine (443 uL, 3.18 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (310 mg, 2.65 mmol). The resulting mixture was stirred at ambient temperature overnight. The mixture was diluted with methylene chloride and water. The phases were separated and the aqueous layer was extracted with methylene chloride two times. The organic extracts were combined and dried over magnesium sulfate, filtered and concentrated to a crude residue. The crude residue was purified via silica gel chromatography eluting with methylene chloride and methanol. The fractions containing desired product were combined and concentrated to afford 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as an oil. 536.3 mg
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:29][NH2:30])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH2:29][C:19]3[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[C:17]([Cl:16])[CH:18]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: NCc1ccc(OCC(F)(F)F)c(Cl)c1
Agent: Cl
Product: O=C1c2ccnc(Cl)c2CN1Cc1ccc(OCC(F)(F)F)c(Cl)c1
Yield: 84 %

Procedure:
The title compound is prepared in 84% yield (300 mg, pale brown oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (250 mg, 0.90 mmol, Step-1 of Intermediate-1) and (3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride (250 mg, 0.90 mmol, Amine-54) in a similar manner to Intermediate-2.