Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](O)=[O:8])(=[O:3])[CH3:2].S(Cl)([Cl:16])=O>>[C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([Cl:16])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(=O)Oc1ccccc1C(=O)Cl
Temperature: 80 °C

Procedure:
Acetyl salicylic acid (1.0 g) was mixed with thionyl chloride (1.0 mL) and mixture was heated in a 50 mL round bottom flask under nitrogen at 80° C. for 1 hour. The excess thionyl chloride was removed by distillation, dried in high vacuum to get acetyl salicyloyl chloride as a viscous liquid, ˜1.1 g. Used for next step with out further purification. Curcumin (0.50 g) was taken in 10 mL of DMF in a 50 mL round bottom flask under nitrogen and pyridine was added. Acetyl salicyloyl chloride (˜1.1 g) was taken in 5 mL of DMF and was added drop wise from a pressure equalizing separating funnel. The solution turned darker in color. The mixture was heated at 90° C. for 1 hour and then at room temperature overnight. To the reaction mixture 100 mL of water was added. A solid formed which was filtered, the solid was stirred with 30 mL of NaHCO3 solution. The solid was filtered, washed with water, dried under high vacuum to yield 1.10 g of the product, curcumin acetyl salicylate or curcumin-aspirin, NMR was consistent with the structure.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)=O.CC(C)=O.C([Li])CCC.[B:27](OC)([O:30]C)[O:28]C>C1COCC1>[C:1]([C:5]1[S:9][C:8]([C:10]2[S:11][C:12]([B:27]([OH:30])[OH:28])=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cccs2)s1
Reactant: COB(OC)OC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(-c2ccc(B(O)O)s2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
In a flame-dried, 500 mL round bottom flask, 5-(t-butyl)-2,2′-bithiophene (from U152-001, 13 g, 58.5 mmol) was dissolved in anhydrous THF (200 mL) and the solution was cooled to −78° C. (dry ice/acetone). n-butyl lithium (2.5 M in hexanes, 25.7 mL, 64.3 mmol) was added dropwise over a period of 10 minutes, and the resulting green solution was allowed to stir for 15 minutes. Trimethyl borate (19.6 mL, 175 mmol) was added dropwise over a period of 10 minutes, and the resulting light yellow solution was stirred for 2 hours at −78° C., then allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by pouring it into 10% HCl (500 mL). The organic phase was separated and the aqueous phase extracted with ether (250 mL). The combined organics were washed with water (500 mL), dried over MgSO4, filtered and solvent removed by rotary evaporation. The resulting green solid was dried under vacuum to afford 15 g (96% yield), which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[NH:13][C:12]2=[O:22])=[C:4]([F:23])[CH:3]=1.CI.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:26])[C:12]2=[O:22])=[C:4]([F:23])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Br
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
3-(4-Bromo-5-ethoxy-2-fluorophenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (2.38 g), methyl iodide (1.06 g) and potassium carbonate (1.04 g) were suspended in DMF (12 ml), and the mixture was stirred at room temperature for about 8 hours. After the reaction, DMF was distilled off under reduced pressure, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off, and the resulting residue was crystallized from a mixed solvent of ethyl acetate and n-hexane (1:5 v/v) to obtain the objective 3-(4-bromo-5-ethoxy-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4( 1H,3H)-pyrimidinedione (2.08 g).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]2[CH:9]3[CH2:13][CH:5]([CH2:6][N:7](C(=O)C(F)(F)F)[CH2:8]3)[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.O>[ClH:1].[Cl:1][C:2]1[CH:12]=[CH:11][C:10]2[CH:9]3[CH2:13][CH:5]([CH2:6][NH:7][CH2:8]3)[C:4]=2[CH:3]=1
Reactant: O=C(N1CC2CC(C1)c1cc(Cl)ccc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cl
Product: Clc1ccc2c(c1)C1CNCC2C1
Reaction time: 2 h

Procedure:
1-(4-Chloro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (470 mg, 1.62 mmol) and Na2CO3 (344 mg, 3.24 mmol) in methanol (30 mL) and H2O (10 mL) were heated to reflux. After 2 hours, the reaction was cooled and diluted with water then extracted with ethyl acetate (4×40 mL), dried (Na2SO4), filtered and concentrated to a yellow oil. The crude material was treated with excess 3N HCl ethyl acetate and concentrated, then dissolved in a minimum of CH2Cl2 and the solution was saturated with hexanes and stirred. After stirring 4 hours the product was collected by filtration (155 mg, 42%). 1H NMR (free base) (400 MHz, CDCl3) δ 7.15 (m, 2H), 7.09 (d, J=8.0 Hz, 1H), 3.00-2.94 (m, 4H), 2.68, (m, 2H), 2.38 (m, 1H), 1.92 (d, J=10.5 Hz, 1H). 1H NMR (HCl salt) (400 MHz, DMSO-d6) δ 7.30-7.20 (m, 3H), 3.30-3.15 (m, 6H), 2.37 (m, 1H), 1.89 (d, J=11.0 Hz, 1H). APCI MS m/e 194.1 [(M+1)+].
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:23]([NH:26][C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=1)[O:30][CH2:31][CH2:32][CH2:33]Br)(=[O:25])[CH3:24].[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42]>C(#N)C.C(O)C>[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:33][CH2:32][CH2:31][O:30][C:29]4[CH:28]=[C:27]([NH:26][C:23](=[O:25])[CH3:24])[CH:37]=[CH:36][CH:35]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:33][CH2:32][CH2:31][O:30][C:29]4[CH:28]=[C:27]([NH:26][C:23](=[O:25])[CH3:24])[CH:37]=[CH:36][CH:35]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)Nc1cccc(OCCCBr)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CC(=O)Nc1cccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (9.25 g, 42 mmol), K2CO3 (8 g, 58 mmol) and 3-(3-acetamidophenoxy)propyl bromide (11.4 g, 42 mmol) in acetonitrile (350 ml) was heated at reflux for 3 hours. At the end of the reaction, the reaction was cooled, filtered and the solids washed with dichloromethane (100 ml). The organic solvent was removed on a rotary evaporator to leave a crude oil (18 g). Purification was by flash chromatography on a silica gel column. The product thus purified was an oil, 12.2 g, 70%. Analytically pure sample was prepared by dissolving 3 g of free base in ethanol and treating with fumaric acid solution in ethanol (850 mg:5ml). The N-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamide hemifumarate crystals obtained weighed 2.73 g, m.p.=184°-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([OH:22])=[O:21])[C:9]=2CC#N)=[CH:4][CH:3]=1.[OH-:26].[Na+].[CH2:28]([OH:30])[CH3:29]>O>[C:28]([CH2:29][C:9]1[C:10]([C:20]([OH:22])=[O:21])=[N:11][N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([OH:26])=[O:30]
Reactant: CCO
Reactant: N#CCc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Yield: 86 %

Procedure:
To 1-(2-Chloro-phenyl)-5-(4-chloro-phenyl)-4-cyanomethyl-1H-pyrazole-3-carboxylic acid [B1] (30 g, 0.8 mol) were added sodium hydroxide (19 g, 4.8 mol), ethanol (250 ml) and water (150 ml). The reaction mixture was heated to reflux over night. The heating was removed and the reaction mixture was allowed to reach room temperature. The formed precipitate was collected and washed with ethanol and dried in an exicator over night. The sodium salt was dissolved in water (400 ml) and HCl (4N) was added during extensively stirring, to avoid forming a gum, and the precipitate is collected and dried in a vacuum oven, yielding 27 g (0.7 mol, 86%) of 4-Carboxymethyl-1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-1H-pyrazole-3-carboxylic acid [G1]. LCMS (method A): RT=2.1 min; ES+=390.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][I:17]>CC(C)=O>[I-:17].[CH3:16][N+:8]1([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: CI
Solvent: CC(C)=O
Product: CC1C[N+](C)(Cc2ccccc2)CCC1=O
Product: [I-]
Reaction time: 144 h

Procedure:
A mixture of 10 g of 1-benzyl-3-methyl-4-oxopiperidine and 8 mL of methyl iodide in 100 mL of acetone was stirred at 25° to 30° C. for 6 days then concentrated under reduced pressure to dryness. Drying under vacuum overnight gave 17 g of 1-methyl-1-benzyl-3-methyl-4-oxopiperidinium iodide as a beige foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]3[N:20]=[C:19]([CH2:21][O:22][C:23]4[CH:36]=[CH:35][C:26]([CH2:27][CH:28]5[S:32][C:31](=[O:33])[NH:30][C:29]5=[O:34])=[CH:25][CH:24]=4)[N:18]([CH3:37])[C:17]=3[CH:38]=1)[CH:8]=[CH:7]2.[C:39]12([N:49]=[C:50]=[O:51])[CH2:48][CH:43]3[CH2:44][CH:45]([CH2:47][CH:41]([CH2:42]3)[CH2:40]1)[CH2:46]2>CN(C)C=O>[C:39]12([NH:49][C:50]([NH:1][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]5[CH:14]=[CH:15][C:16]6[N:20]=[C:19]([CH2:21][O:22][C:23]7[CH:24]=[CH:25][C:26]([CH2:27][CH:28]8[S:32][C:31](=[O:33])[NH:30][C:29]8=[O:34])=[CH:35][CH:36]=7)[N:18]([CH3:37])[C:17]=6[CH:38]=5)[CH:10]=4)[CH:5]=[CH:4][CH:3]=3)=[O:51])[CH2:48][CH:43]3[CH2:44][CH:45]([CH2:47][CH:41]([CH2:42]3)[CH2:40]1)[CH2:46]2
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc4cccc(N)c4c3)cc21
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc4cccc(NC(=O)NC56CC7CC(CC(C7)C5)C6)c4c3)cc21
Temperature: 25 °C
Reaction time: 120 h
Yield: 67.3 %

Procedure:
To a solution of 5-[4-[6-(8-aminonaphthalen-2-yloxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.5 g) in anhydrous N,N-dimethylformamide (10 ml) was added 1-adamantyl isocyanate (0.18 g) and the mixture was stirred at room temperature for 5 days. The reaction mixture was concentrated. The residue was purified by preparative reverse phase high performance liquid chromatography using acetonitrile:water=50:50→60:40→70:30 as the eluant to afford the title compound (0.45 g, mp 250° C. (dec)).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=[S:2].N[C:14]1C=NC=C[C:19]=1[C:20]1[CH:21]=[C:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:23]=[C:24]([CH3:26])[CH:25]=1>C1COCC1.CCOC(C)=O>[N:8]([C:12]1[CH:11]=[N:10][CH:9]=[CH:14][C:19]=1[C:20]1[CH:21]=[C:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH:23]=[C:24]([CH3:26])[CH:25]=1)=[C:1]=[S:2]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cc(-c2ccncc2N)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)OC(C)(C)C)cc(-c2ccncc2N=C=S)c1
Temperature: 60 °C
Yield: 48.7 %

Procedure:
tert-butyl (3-(3-isothiocyanatopyridin-4-yl)-5-methylphenyl) carbamate. 1,1′-thiocarbonyldiimidazole (155 mg, 0.78 mmol, Sigma-Aldrich) was added to a solution of tert-butyl (3-(3-aminopyridin-4-yl)-5-methylphenyl)carbamate (117 mg, 0.39 mmol) in THF (4 mL) at RT. The reaction mixture was heated at 60° C. for 2 h. The mixture was cooled to RT, diluted with EtOAc, washed with water and the organic layer was dried over anh. Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to provide tert-butyl (3-(3-isothiocyanatopyridin-4-yl)-5-methylphenyl)carbamate (63 mg, 0.19 mmol, 47% yield) as a white solid. MS (ESI, pos. ion) m/z: 342.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.58 (s, 1 H), 8.49 (d, J=5.09 Hz, 1 H), 7.32-7.37 (m, 2 H), 7.29 (s, 1 H), 6.98 (s, 1 H), 6.56 (s, 1 H), 2.41 (s, 3 H), 1.53 (s, 9 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([C:26]2[CH:35]=[CH:34][C:29]3[O:30][CH2:31][CH2:32][O:33][C:28]=3[CH:27]=2)=[O:25])[CH2:19][C@@H:18]1[C:36](O)=[O:37])=[O:16])([CH3:13])([CH3:12])[CH3:11].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:9][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:36]([C@H:18]1[CH2:19][C@H:20]([NH:23][C:24]([C:26]2[CH:35]=[CH:34][C:29]3[O:30][CH2:31][CH2:32][O:33][C:28]=3[CH:27]=2)=[O:25])[CH2:21][CH2:22][N:17]1[C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)OCCO3)C[C@@H]1C(=O)O
Reactant: Cc1ccc(N)c(N)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)[C@H]2C[C@H](NC(=O)c3ccc4c(c3)OCCO4)CCN2C(=O)OC(C)(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
4-Methylbenzene-1,2-diamine (1.65 g, 13.5 mmol) was added to a mixture of (2R,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)piperidine-2-carboxylic acid (5.0 g, 12 mmol), BOP (5.71 g, 12.9 mmol) and DIEA (4.3 mL, 24.6 mmol) in DMF (30 mL), and the resulting solution was stirred at room temperature for 8 hours. Water (100 mL) was added to the reaction mixture and then extracted with ethyl acetate (2×100 mL). The organic layers were dried over MgSO4 and concentrated to give a red solid. Purification was done by Companion (ReadySep, 120 g, silica gel packed) with methanol/methylenechloride from 1-5% to give the title compound as a brown solid 4.85 g (80%). LC-MS: 511.2 (t=2.4 min).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C=O.[BH3-][C:13]#N.[Na+]>CO.CC(O)=O.C(Cl)Cl>[CH3:13][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: c1ccc2c(c1)CCN2
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCc2ccccc21
Reaction time: 1 h
Yield: 214.5 %

Procedure:
The indoline product from Example 47, Step B (16 mg, 0.049 mmol) was dissolved in MeOH (2 mL) in a 25-mL flask under N2. A catalytic amount of HOAc (1 drop) and aqueous formaldehyde (15 μL, 0.15 mmol) were added, and the mixture stirred for 1 h. NaBH3CN (16 mg, 0.25 mmol) was added, and the mixture stirred for an additional 1 h. The mixture was diluted with CH2Cl2 (50 mL), then washed sequentially with 0.5 N NaOH (25 mL) and sat. aq. NaCl (25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide the N-methyl indoline product (14 mg, 87%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ6.93-7.09 (m, 3H), 6.59 (d, J=8.1 Hz, 1H), 6.29 (d, J=8.1 Hz, 1H), 4.12 (t, J=5.8 Hz, 1H), 3.52 (s, 2H), 3.30-3.37 (m, 2H), 2.91 (dd, J=11.3, 5.1 Hz, 1H), 2.82 (t, J=8.0 Hz, 2H), 2.73 (s, 3H), 2.56 (dd, J=11.3, 7.3 Hz, 1H), 2.42 (s, 3H); CI MS m/z=315 [C19H20F2N2+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[NH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][C:44]1=[O:48].OS([O-])(=O)=O.[Na+]>CCO>[O:1]=[C:2]1[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:39][CH2:40][CH2:41][CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][C:44]2=[O:48])=[O:34])[C:15]1=[O:38]
Reactant: NCCCN1CCCC1=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(NCCCN1CCCC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (1 mL) under nitrogen was treated with 1-(3-aminopropyl)-2-pyrrolidinone (0.0085 mL, 0.061 mmol) for 30 min.@150° C. The reaction was further microwaved for 30 min.@150° C. after the addition of an additional equivalent (0.0085 mL) of the amine, cooled to ambient temperature, and treated with 1N NaHSO4. The resulting suspension was filtered, washed with EtOH and the filtrate was concentrated in vacuo. The filtrate residue was purified by reversed phase HPLC. Pure fractions were combined and concentrated to afford the title compound as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.59 (m, 2 H), 1.89-1.96 (m, 2 H), 2.21 (t, J=8.24 Hz, 2 H), 3.08 (t, J=6.59 Hz, 2 H), 3.15-3.21 (m, 2 H), 3.27-3.31 (m, 2 H), 3.87-3.93 (m, 2 H), 4.11 (s, 2 H), 4.55 (s, 2 H), 7.11-7.16 (m, 2 H), 7.35 (td, J=6.46, 2.29 Hz, 2 H), 7.78-7.85 (m, 4 H), 8.15 (s, 1 H), 8.51 (s, 1 H), 9.95 (s, 1 H); ES+ MS: 612 (M+H+).
Reaction SMILES: Cl.Cl.[CH:3]1([C@@H:6]([C:8]2[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[NH2:7])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Br[C:28]1[C:29]2[CH2:37][N:36]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=3)[CH2:35][CH2:34][C:30]=2[N:31]=[CH:32][N:33]=1>C(#N)C>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([N:36]2[CH2:35][CH2:34][C:30]3[N:31]=[CH:32][N:33]=[C:28]([NH:7][C@@H:6]([CH:3]4[CH2:5][CH2:4]4)[C:8]4[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=4)[C:29]=3[CH2:37]2)=[N:39][CH:40]=1
Reactant: N[C@H](c1ccc(C(F)(F)F)nc1)C1CC1
Reactant: Clc1ccc(N2CCc3ncnc(Br)c3C2)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: FC(F)(F)c1ccc([C@@H](Nc2ncnc3c2CN(c2ccc(Cl)cn2)CC3)C2CC2)cn1
Temperature: 180 °C
Yield: 12.1 %

Procedure:
To a stirred solution of (S)-cyclopropyl(6-(trifluoromethyl)pyridin-3-yl)methanamine dihydrochloride (0.048 g, 0.17 mmol) and N,N-diisopropylethylamine (96 uL, 0.55 mmol) in acetonitrile (1.8 mL) was added 4-bromo-6-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.045 g, 0.14 mmol). The reaction was heated in microwave for 7 hours at 180° C. The mixture was concentrated and the residue was purified by silica gel column followed by semi-prep HPLC to obtain 7.8 mg of white solid.
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:26]([NH:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:34])=[O:5])[S:12][CH:13]=2)=[CH:24][CH:23]=1)(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(NC(=O)c3ccccc3)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCOc2ccc(NC(=O)c3ccccc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.7 %

Procedure:
2-[(4-{2-[4-(Benzoylamino)phenoxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (550 mg) obtained in Example 54-1 was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (350 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:28](I)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Reactant: CCCCCCCI
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(CC)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (8.90 g) synthesized in Example 265-1 and heptyl iodide (5.92 g) were dissolved in N,N-dimethylformamide (100 mL), potassium tert-butoxide (2.94 g) was added thereto, and the mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=7:1) to give the title compound (6.20 g) as a colorless oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[B:22].[B].[OH:24][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].C([O-])(=O)C.[K+].ClCCl>CN(C)C=O>[CH3:26][C:25]1([CH3:27])[C:28]([CH3:30])([CH3:29])[O:31][B:22]([C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)[O:24]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: [B]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Temperature: 85 °C
Yield: 116.3 %

Procedure:
A mixture of tert-butyl 4{[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydro-1-pyridinecarboxylate (1.8 g, 2.42 mmol), pinacol diboron (1.4 g, 5.44 mmol), potassium acetate (1.6 g, 16.32 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.27 g, 0.33 mmol) in N,N-dimethylformamide (30 mL) was heated in an 85° C. oil bath for 17 hours. The solvent was evaporated under reduced pressure then the residue was triturated with dichloromethane (30 mL). The mixture was filtered through a bed of diatomaceous earth then the solvents were evaporated under reduced pressure and the residue purified by flash chromatography on silica gel with heptane/ethyl acetate (8:2) as an eluent. The appropriate fractions were concentrated under reduced pressure to provide the title compound as a crystalline solid (0.87 g, 52%); TLC RF 0.44, heptane/ethyl acetate (8:2), visualized by PMA/heat, Silica Gel 60 F254 plates; 1H NMR (CDCl3, 400 MHz) δ 6.46 (m, 1H), 3.94 (m, 2H), 3.43 (m, 2H), 2.21 (m, 2H), 1.45 (s, 9H), 1.26 (s, 12H)