Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[O:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:21]3[CH:20]=[N:19][O:18][CH:22]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1nc(N2CCOCC2)c2sc(-c3cnoc3)cc2n1
Yield: 67 %

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (150 mg), 84 mg of 4-isoxazoleboronic acid pinacol ester and 14 mg of bis(triphenylphosphine)palladium(II) dichloride in 0.7 mL of 1M Na2CO3 aqueous solution and 0.7 mL of acetonitrile was heated to 100° C. in a sealed microwave reactor for 10 min. The reaction mixture was evaporated. The crude product was purified by flash chromatography eluting with 0-20% MeOH/DCM to yield 2-chloro-6-(isoxazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine (85 mg, 67%).
Reaction SMILES: [C:1]([O:25]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[NH2:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31].C[O-].[Na+]>CO>[OH:32][CH:29]([CH2:30][OH:31])[CH2:28][NH:27][C:1](=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)OC
Reactant: NCC(O)CO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)NCC(O)CO

Procedure:
methyl 10,12-tricosadiynoate (1.69 g, 4.67 mmol) was dissolved in methanol. 3-Amino-1,2-propanediol (0.509 g, 5.6 mmol) and sodium methoxide 2.5% solution in methanol (0.146 g, 3 mol %) was added. The mixture was refluxed for 3 hours and the solvent evaporated. The crude product was recrystallized from chloroform. Yield: 1.00 g (51%). 1H NMR (60 MHz, CDCl3): δ 0.7-1.0 (m, 3H, CH3CH2), 1.3 (s, br, 28H, CH2), 2.0-2.4 (m, 6H, CH2), 3.3-3.8 (m, 5H, 2×CH2 +CH (propanediol)), 6.0-6.3 (m, 1H, NH).
Reaction SMILES: [C:1]([N:4]1[CH:8]=[CH:7]N=C1)(=[O:3])[CH3:2].N[C:10]1[CH:15]=[C:14](CC)[N:13]=[C:12]([CH2:18][CH3:19])[CH:11]=1>C1(C)C=CC=CC=1>[C:1]([NH:4][C:8]1[CH:7]=[C:14]([CH2:15][CH3:10])[N:13]=[C:12]([CH2:18][CH3:19])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1ccnc1
Reactant: CCc1cc(N)cc(CC)n1
Solvent: Cc1ccccc1
Product: CCc1cc(NC(C)=O)cc(CC)n1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
N-acetylimidazole (0.61 g) was added to a solution of 4-amino-2,6-diethylpyridine (0.61 g) in toluene (10 ml) and the mixture was heated at reflux for 16 hours. The mixture was cooled to ambient temperature and solvent was removed by evaporation. The residue was purified by flash chromatography eluting with ethyl acetate to give 4-(N-acetylamino)-2,6-diethylpyridine (B) (0.66 g) as a solid, m.p. 74°-78° C.; NMR (CDCl3): 1.26(t, 6H), 2.18(s, 3H), 2.74(q, 4H), 7.18(s, 2H), 7.75(broad s, 1H); mass spectrum (chemical ionisation, ammonia): 193(M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]([C:22]([O:24]CC)=[O:23])[CH3:21].[OH-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]([C:22]([OH:24])=[O:23])[CH3:21]
Reactant: CCOC(=O)C(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br)C(=O)O
Reaction time: 1 h

Procedure:
A mixture of 4.7 g. of N-[4-bromo-3-(1-ethoxycarbonylethyloxy)phenyl]-3,4,5,6-tetrahydrophthalimide, 15 ml. of methanol and 4 ml. of 40% aqueous solution of sodium hydroxide was refluxed with stirring for 1 hour and the solvent was distilled off under a reduced pressure. The residue was mixed with 0.4 g. of cyclohexane-1,2-dicarboxylic anhydride and 20 ml. of glacial acetic acid and the mixture was refluxed with stirring for 3 hours and the reaction mixture was poured into 1 liter of water to precipitate the product. The precipitate was separated by a filtration and washed with water and dried. The residue was purified by a chromatography on a column of silica gel (developing solvent: ethyl acetate:n-hexane of 8:1) to obtain 3.8 g. of Compound No. 10 shown in Table 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][C:33](B(O)O)=[CH:34][CH:35]=2)[CH:30]=[N:29]1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:33]5[CH:32]=[C:31]6[C:36](=[CH:35][CH:34]=5)[N:28]([CH3:27])[N:29]=[CH:30]6)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Cn1ncc2cc(B(O)O)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6c(cnn6C)c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 1-methyl-indazole-5-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.65 min; Mass spectrum (ESI+): m/z=489 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=3)[CH:9]=[CH:10][C:4]=2[O:3]1.[CH3:23][NH:24][O:25][CH3:26]>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:24]([O:25][CH3:26])[CH3:23])=[O:22])=[CH:16][CH:15]=3)[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CC1Cc2cc(CCOc3ccc(N=C=O)cc3)ccc2O1
Reactant: CNOC
Solvent: Cc1ccccc1
Product: CON(C)C(=O)Nc1ccc(OCCc2ccc3c(c2)CC(C)O3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
1.8 g of 4-[2-(2,3-dihydro-2-methyl-5-benzofuranyl)ethyloxy]phenyl isocyanate was dissolved into 20 ml of toluene, and 2.0 g of N,O-dimethylhydroxylamine dissolved in 5 ml of toluene was slowly added dropwise thereto at room temperature. After the mixture was stirred at room temperature for 2 hours, toluene was distilled off and the residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (2/3) as a developer to obtain 1.8 g of Compound No. 42 shown in Table 2.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[Cl:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][NH2:39])[CH:34]=[CH:35][CH:36]=1>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:3])[N:39]([CH2:38][CH2:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([Cl:30])[CH:32]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1)(=[O:13])=[O:14]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: NCCc1cccc(Cl)c1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(CCc2cccc(Cl)c2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 2-(3-Chloro-phenyl)-ethylamine. MS (ESI): 467.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:6]=1[C:7]([O:9]CC)=O.[CH:18]([NH2:20])=O>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:5]1[C:6]2[C:7]([OH:9])=[N:20][CH:18]=[N:1][C:2]=2[S:3][CH:4]=1
Reactant: CCOC(=O)c1c(-c2ccccn2)csc1N
Reactant: NC=O
Product: Oc1ncnc2scc(-c3ccccn3)c12
Temperature: 180 °C
Reaction time: 4 h

Procedure:
A 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with ethyl 2-amino-4-(pyridin-2-yl)thiophene-3-carboxylate (10 g, 40.27 mmol, 1.00 equiv) and formamide (100 mL). The resulting solution was stirred for 4 h at 180° C. The reaction mixture was cooled to 20° C. with a water/ice bath. The reaction was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 5×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×100 mL of brine. The organic layers combined was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/methanol (30:1-10:1). Purification resulted in 4 g (43%) of 5-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-ol as a yellow solid. MS: m/z 249 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]([F:31])([F:30])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](O)=[O:28])=[CH:21][CH:20]=1>>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:27](=[O:28])[CH2:26][CH2:25][C:22]4[CH:21]=[CH:20][C:19]([C:18]([F:30])([F:31])[F:17])=[CH:24][CH:23]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Product: Cc1c(C2CC2)nc2ccc(NC(=O)CCc3ccc(C(F)(F)F)cc3)cn12

Procedure:
Conducting the operations similar to those of Example 1 using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 3-[4-(trifluoromethyl)phenyl]propionic acid, the title compound was obtained as white solid.
Reaction SMILES: [C:1](=O)([O-])[O-].[Na+].[Na+].CI.[F:9][C:10]([F:47])([F:46])[C:11]1[CH:12]=[C:13]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:14][N:15]([C:34]1[NH:38][N:37]=[N:36][N:35]=1)[CH:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[C:18]2[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:17]1=2.O>CN(C)C=O.CC(C)=O.ClCCl>[F:45][C:42]([F:43])([F:44])[C:40]1[CH:39]=[C:13]([CH:12]=[C:11]([C:10]([F:9])([F:46])[F:47])[CH:41]=1)[CH2:14][N:15]([C:34]1[N:35]=[N:36][N:37]([CH3:1])[N:38]=1)[CH:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[C:18]2[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:17]1=2
Reactant: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn[nH]2)c2ccc(Cl)cc21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
Add sodium carbonate (36 mg, 0.34 mmol) and methyl iodide (0.021 mL, 0.34 mmol) to a solution of (+/−)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (98 mg, 0.17 mmol) in dimethylformamide/acetone (1:1) (1 mL). Stir the reaction mixture at room temperature overnight. Then add water and dichloromethane. Separate the layers and wash the organic phase with brine. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (70 mg, 70%). MS (ES+): 591 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:15](=O)[CH2:16]Br>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:15]2[N:1]=[C:2]3[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]3[CH:16]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(C(=O)CBr)cc1OC
Reactant: COc1ccnc(N)c1
Product: COc1ccn2cc(-c3ccc(OC)c(OC)c3)nc2c1

Procedure:
The title compound, pale yellow solid, m.p. 142° C. and MS: m/e=284.1 (M+), was prepared in accordance with the general method of example 1 from 2-amino-4-methoxy-pyridine and 3,4-dimethoxy-phenacylbromide.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[C:14]([N:21]1[CH2:28][CH2:27][C@@H:26]([OH:29])[C@H:22]1[C:23]([OH:25])=[O:24])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Cl>O>[C:7]([O:29][C@@H:26]1[CH2:27][CH2:28][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:22]1[C:23]([OH:25])=[O:24])(=[O:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
Pyridine (5 mL) and acetic anhydride (2 mL) were added to N-boc-cis-3-hydroxy-L-proline (400 mg, 1.73 mmol) and the reaction was stirred for 4 hours at room temperature. The reaction was diluted with water, acidified with 1N HCl and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound (370 mg, 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To (2R,3S)-3-(tert-butyl-dimethylsilanyloxy)-2-hydroxymethyl pyrrolidine-1-carboxylic acid tert-butyl ester (61A) (9.85 g, 29.7 mmol) in CH2Cl2 (200 mL) at 0° C. was added Dess-Martin periodinane. The ice bath was removed and the reaction was warmed to rt. After 2 h, saturated aqueous Na2S2O3 and NaHCO3 (ca. 100 mL each) were added and the reaction mixture was stirred vigorously for 0.5 h. The layers were separated, and the organic layer was washed with a mixture of saturated aqueous Na2S2O3 and saturated aqueous NaHCO3 followed by brine, dried (MgSO4), and was then filtered and concentrated to obtain the title compound (9.23 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH3:19])[CH3:18]>CC(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)Br
Reactant: Cc1cccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(OC(C)C)c1C

Procedure:
To a stirred solution/suspension of 2,3-dimethylphenol (10 g) and potassium carbonate (6.8 g) in acetone (150 ml) at reflux was added 2-bromopropane (46 ml) drop-wise over 30 min. The solution was heated at reflux for 4 days. After cooling, the solvent was evaporated and the residue was dissolved in ether and water. The ether phase was separated and was worked up according to the general procedure. Column chromatography on silica gel (eluent: ethyl acetate/heptane 1:19) afforded pure 2,3-dimethyl-1-(2-propyl)oxybenzene (13.2 g) as a mobile, slightly brown oil which was used without further purification.
Reaction SMILES: [OH-:1].[K+].C([O:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]([CH3:30])([CH3:29])[CH2:13]1)(=O)C1C=CC=CC=1>C(O)C>[OH:1][CH:12]1[CH2:17][C:16]([CH3:18])([CH3:19])[N:15]([O:20][CH:21]([O:20][N:15]2[C:14]([CH3:29])([CH3:30])[CH2:13][CH:12]([OH:11])[CH2:17][C:16]2([CH3:18])[CH3:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]([CH3:30])([CH3:29])[CH2:13]1
Reactant: CCCCCCCCON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCC(ON1C(C)(C)CC(O)CC1(C)C)ON1C(C)(C)CC(O)CC1(C)C

Procedure:
The title compound is prepared by basic hydrolysis (potassium hydroxide in ethanol) of the compound prepared in Example 3.
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[C:10]([Br:17])[CH:11]=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Br:17][C:10]1[CH:11]=[CH:12][C:13]2[C:8]([CH:9]=1)=[N:7][N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=1)([C:3]#[N:4])[CH3:18])[C:14]=2[O:15][CH3:16]
Reactant: COc1c2ccc(Br)cc2nn1CC(C)(N)C#N
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: COc1c2ccc(Br)cc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-bromo-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (50 mg, described in Example 118) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (80 mg, 96%). MS (ES): M/Z [M+H]=513. 1H NMR: (400 MHz, DMSO-d6): 1.71 (s, 3H), 4.19 (s, 3H), 4.77 (d, 1H), 4.89 (d, 1H), 6.97 (dd, J=9.1, 1.5 Hz, 1H), 7.68 (d, J=0.9 Hz, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.86-7.91 (m, 2H), 7.94-7.99 (m, 2H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.9 (s, 3F).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.B(O)(O)[C:24]1[CH:29]=[CH:28][C:27](C(O)=O)=[CH:26][CH:25]=1>>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:16]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3ccccc3)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 4-carboxylphenylboronic acid in step 1 F.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:23]2[CH2:22][CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]2)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1NCc1cccc(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(NCc3cccc(Cl)c3)c2)CC1
Yield: 32.1 %

Procedure:
N-(3-Chlorobenzyl)-5-fluoro-2-nitrobenzenamine (624 mg, 2.2 mmol), t-butyl piperazine-1-carboxylate (414 mg, 2.2 mmol), N,N-diisopropylethylamine (287 mg, 2.2 mmol) were stirred at 80° C. in dry acetonitrile (10 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (316 mg, 32% yield). 1H NMR (400 MHz, CDCl3): δ 8.77 (s, 1H), 8.05 (d, 1H), 7.32-7.21 (m, 4H), 6.18 (d, 1H), 5.72 (s, 1H), 4.46 (d, 2H), 3.49 (m, 4H), 3.27 (m, 4H), 1.45 (s, 9H); MS (ESI) m/z: Calculated for C22H27ClN4O4: 446.17; Observed: 469.4 (M++Na).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]3[N:30]=[C:31]([CH2:33][OH:34])[CH:32]=[C:26]3[C:25]2=[O:35])=[CH:20][CH:19]=1.[CH:36]1[C:41](O)=[CH:40][CH:39]=[C:38]([CH3:43])[CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]3[N:30]=[C:31]([CH2:33][O:34][C:41]4[CH:40]=[CH:39][C:38]([CH3:43])=[CH:37][CH:36]=4)[CH:32]=[C:26]3[C:25]2=[O:35])=[CH:20][CH:19]=1
Reactant: O=C1c2cc(CO)nn2CCN1c1ccc(F)cc1
Reactant: Cc1ccc(O)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(OCc2cc3n(n2)CCN(c2ccc(F)cc2)C3=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.4 %

Procedure:
Di-tert-butyl azodicarboxylate (0.027 g, 1.2 mmol) was added portionwise to a stirred solution of 5-(4-fluoro-phenyl)-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (104 mg, 0.4 mmol), p-cresol (0.13 mL, 1.2 mmol) and triphenylphosphine (0.31 g, 1.2 mmol) in THF (2 mL) at 0° C. The mixture was stirred at room temperature for 16 hours. More di-tert-butyl azodicarboxylate (0.027 g, 1.2 mmol), p-cresol (0.13 mL, 1.2 mmol) and triphenylphosphine (0.31 g, 1.2 mmol) were added at 0° C. and the mixture was stirred at 130° C. for 20 minutes. The mixture was diluted with AcOEt and washed with a 10% solution of NaOH. The organic layer was separated, dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The crude product was purified by open column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo. The crude product was dissolved in a mixture of TFA (2.5 mL) and DCM (2.5 mL) and stirred at room temperature for 2 days. The mixture was basified with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with DIPE to yield 5-(4-fluorophenyl)-2-(p-tolyloxymethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (54 mg, 38% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 2.29 (s, 3H), 4.16 (dd, J=6.8, 5.3 Hz, 2H), 4.53 (dd, J=6.9, 5.2 Hz, 2H), 5.09 (s, 2H), 6.90 (d, J=8.7 Hz, 2H), 7.01 (s, 1H), 7.09 (d, J=8.4 Hz, 2H), 7.13 (t, J=8.7 Hz, 2H), 7.28-7.35 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[N:13]=[C:14]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[O:15][C:16]=2[S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=2)=[CH:6][CH:5]=1.[Li+].[OH-].Cl>CO.C1COCC1.O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([S:17][C:16]2[O:15][C:14]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[N:13][C:12]=2[CH2:11][O:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:32])=[O:2])=[CH:9][CH:8]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1ccc(OCc2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(OCc2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Methyl-4-({5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methoxy)benzoate (0.31 g, 0.66 mmol) in 6 ml of 1:1 MeOH/THF was added 1N LiOH (1.98 ml, 1.98 mmol). The reaction was allowed to proceed at 55° C. for 2 h, at which point it was cooled to room temperature and was acidified by 3N HCl. The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to yield 4-({5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methoxy)benzoic acid as a white solid. It was used as is for the next step. LCMS [M+H]=457.3.