Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([N:24]5[CH2:28][CH2:27][CH2:26][C:25]5=[O:29])[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.Cl>CC#N.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([N:24]5[CH2:28][CH2:27][CH2:26][C:25]5=[O:29])[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](N5CCCC5=O)C4)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: O=C1CCCN1[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C

Procedure:
A mixture of partially purified 1-((1R,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexyl)pyrrolidin-2-one, 45d, (0.105 g, 0.180 mmol) in CH3CN (5 mL) was treated with HCl (2 mL of 4 M, 8.00 mmol) in dioxane at 70° C. After 2H, the mixture was cooled to room temperature. Then CH3CN was added and the solid that precipitated was triturated with more CH3CN (3×). Preparative HPLC provided the desired product as the HCl salt (35 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18](O)=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([C:29]([NH2:32])([CH3:31])[CH3:30])[CH:25]=[C:26]([Cl:28])[CH:27]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:32][C:29]([C:24]3[CH:25]=[C:26]([Cl:28])[CH:27]=[C:22]([Cl:21])[CH:23]=3)([CH3:30])[CH3:31])=[O:19])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: CC(C)(N)c1cc(Cl)cc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)c1cc(Cl)cc(Cl)c1
Reaction time: 0.17 h

Procedure:
70.0 mg (0.238 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 88A and 48.6 mg (0.238 mmol) of 2-(3,5-dichlorophenyl)propan-2-amine are placed in 2 ml of dimethylformamide and treated with 38.6 mg (0.286 mmol) of HOBt. After 10 mins' stirring, 59.4 mg (0.310 mmol) of EDC hydrochloride are added and the mixture is stirred overnight at room temperature. Without further workup, the mixture is purified directly by preparative HPLC [Method 10]. 70 mg (61% of theory) of the target compound are thus obtained.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C([C:10]1[C:15]([OH:16])=[C:14](C(C)(C)C)[CH:13]=[C:12](C)[CH:11]=1)(C)(C)C>>[C:1]([O:5][CH2:14][CH:15]([OH:16])[CH2:10][O:16][C:15]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: C=CC(=O)OCC(O)COc1ccccc1

Procedure:
3-Phenoxy-2-hydroxypropyl acrylate was prepared as described in Example 17 except that the acrylic acid was added over 1 hour at 100°, 2,6-di-tert. butyl-p-cresol was used in place of hydroquinone, and the mixture was heated for 4 hours at 100° after the acrylic acid had been added.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[C:16]2[N:15]=[CH:14][N:13]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]=2[C:11](=[O:36])[NH:10][C:9]1=[O:37].[CH2:38]([O:45][CH2:46]Cl)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>CN(C)C=O>[CH2:38]([O:45][CH2:46][N:10]1[C:11](=[O:36])[C:12]2[N:13]([C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:14]=[N:15][C:16]=2[N:8]([CH3:7])[C:9]1=[O:37])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(COCc2ccccc2)c(=O)c2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
1.3 g (9.44 mmol) of potassium carbonate were added at 60° C. to a solution of 2.4 g (5.9 mmol) of 3-methyl-7-tritylxanthine from stage a) in 50 ml of dimethylformamide and the mixture was stirred at this temperature for one hour. 1.06 ml (7.67 mmol) of benzyloxymethyl chloride were then added dropwise and the mixture was stirred at 80° C. for 7 hours. 50 ml of water were then added and the mixture was extracted three times using 60 ml of methyl tert-butyl ether each time. The combined organic phases were washed twice with 30 ml of water each time, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, heptane/ethyl acetate (3/2).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20](OC)[O:21]C)[N:16]([C:25]([NH:27][C:28]1[CH:33]=[C:32]([NH:34][C@H:35]3[C@@H:40]([CH2:41][O:42][Si](CC)(CC)CC)[C@H:39]4[CH2:50][C@@H:36]3[CH2:37][CH2:38]4)[C:31]([C:51]#[N:52])=[CH:30][N:29]=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)(C(C)(C)C)(C)C.O.Cl>C1COCC1>[C:51]([C:31]1[C:32]([NH:34][C@H:35]2[C@@H:40]([CH2:41][OH:42])[C@H:39]3[CH2:50][C@@H:36]2[CH2:37][CH2:38]3)=[CH:33][C:28]([NH:27][C:25]([N:16]2[C:17]3[C:12](=[CH:11][C:10]([CH2:9][OH:8])=[C:19]([CH:20]=[O:21])[N:18]=3)[CH2:13][CH2:14][CH2:15]2)=[O:26])=[N:29][CH:30]=1)#[N:52]
Reactant: CC[Si](CC)(CC)OC[C@H]1[C@@H]2CC[C@@H](C2)[C@H]1Nc1cc(NC(=O)N2CCCc3cc(CO[Si](C)(C)C(C)(C)C)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cnc(NC(=O)N2CCCc3cc(CO)c(C=O)nc32)cc1N[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1CO
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Racemic 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-(((1S*,2R*,3S*,4R*)-3-(((triethylsilyl)oxy)methyl)bicyclo[2.2.1]heptan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 37N, 64 mg, 0.085 mmol) was dissolved in THF (2 ml) and water (1 ml) and treated with conc. HCl (0.28 ml). The reaction mixture was stirred 30 h at room temperature. The reaction mixture was then quenched with sat. aq. NaHCO3 and extracted 3× with DCM. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The residue was triturated in a small quantity of DCM and then, the product was precipitated by addition of heptanes. The solid was collected by centrifugation and dried to give the title compound as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16](=[O:25])[C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)Nc2nc3cccc(-c4ccoc4)n3n2)c1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and m-anisoyl chloride (85 mg; 0.50 mmol; 2.0 eq.). Crude was purified on SPE NH2 column and the title compound was isolated as a white powder (26.9 mg, 32%). HPLC, Rt: 3.32 min. (purity 89.0%). LC/MS, M+(ESI): 306.4.
Reaction SMILES: [O:1]=[S:2]1(=[O:8])[CH2:5][CH:4]([C:6]#[N:7])[CH2:3]1.[ClH:9]>CO.[Ni]>[ClH:9].[O:1]=[S:2]1(=[O:8])[CH2:5][CH:4]([CH2:6][NH2:7])[CH2:3]1
Reactant: N#CC1CS(=O)(=O)C1
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: NCC1CS(=O)(=O)C1

Procedure:
1,1-dioxothietane-3-carbonitrile (0.1 g) dissolved in methanol (45 ml) was passed through H-Cube equipped with a Ra—Ni cartridge at 50 bars, 1 ml/min and room temperature. The reaction mixture was poured into HCl (4M in dioxane) and after evaporation of the solvent, 60 mg of (1,1-dioxothietan-3-yl)methanamine hydrochloride as a yellow solid was obtained. 1H NMR (D2O): 4.49-4.49 (m, 2H); 4.2-4.07 (m, 2H); 3.46 (d, 1H, J=7.3 Hz); 3.34 (d, 1H, J=7.3 Hz); 3.12-2.93 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][C:5]2[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21]C)=[O:20])[CH:14]=3)=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:4]=2[O:3]1.[OH-].[Na+]>C(O)C>[C:19]([C:15]1[CH:14]=[C:13]([C:7]2[C:5]3[CH2:6][C:2]([CH3:1])([CH3:23])[O:3][C:4]=3[C:10]([O:11][CH3:12])=[CH:9][CH:8]=2)[CH:18]=[CH:17][CH:16]=1)([OH:21])=[O:20]
Reactant: COC(=O)c1cccc(-c2ccc(OC)c3c2CC(C)(C)O3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2cccc(C(=O)O)c2)c2c1OC(C)(C)C2
Yield: 92.6 %

Procedure:
A mixture of Compound 146 (1.3 g) obtained in Example 146, a 4N aqueous solution (10.4 ml) of sodium hydroxide, and ethanol (50 ml) was stirred at room temperature for 3 hours. The solvent was removed and the residue was dissolved in water. Concentrated hydrochloric acid was dropwise added to the solution, and the generated precipitate was collected by filtration, washed with water, and dried to give Compound 147 (1.15 g, 92.7%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:15][C:14]=2[Cl:26])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([O:20][CH2:21][CH:22]=[C:23]([Cl:24])[Cl:25])=[CH:15][C:14]=2[Cl:26])=[O:35])=[CH:4][CH:3]=1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCSc2ccc(Cl)cc2)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 73.5 %

Procedure:
A mixture of 0.50 g of 1-(3-(4-chlorophenylthio)propyloxy)-2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)benzene and 20 ml of methylene chloride was stirred under cooling with ice-water, to which 0.26 g of m-chloroperbenzoic acid was added. After stirring at room temperature for 24 hours, the methylene chloride layer was separated, washed successively with saturated aqueous sodium sulfite solution, saturated aqueous sodium hydrogencarbonate solution and saturated saline solution, dried with magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.38 g of 1-(3-(4-chlorophenylsulfinyl)propyloxy)-2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)benzene (73% yield), nD24.5 1.5962.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH2:12][CH2:13][CH3:14])[CH:3]=1.[C:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([O:11][C:4]1[CH:3]=[C:2]([N:21]2[CH2:22][CH2:23][N:18]([C:15](=[O:17])[CH3:16])[CH2:19][CH2:20]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[CH2:13][CH3:14]
Reactant: CCCOc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cc(N2CCN(C(C)=O)CC2)ccc1[N+](=O)[O-]

Procedure:
The compound obtained in Step 1 above (300 mg), N-acetylpiperazine (300 mg), and potassium carbonate (500 mg) were dissolved in dimethylformamide (3 mL) and reacted at 80° C. overnight. The dimethylformamide of the reaction mixture was removed under reduced pressure, and added with water to form a solid. The solid was filtered to obtain a target compound as a yellow solid.
Reaction SMILES: [CH3:1]C1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[CH2:24]([C@@H:31]1[CH2:35][N:34]([C:36]2[S:37][C:38]([C:42]([O:44]CC)=[O:43])=[C:39](C)[N:40]=2)[C:33](=[O:47])[NH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([C@@H:31]1[CH2:35][N:34]([C:36]2[SH:37]([CH3:1])[C:38]([C:42]([OH:44])=[O:43])=[CH:39][N:40]=2)[C:33](=[O:47])[NH:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Reactant: CCOC(=O)c1sc(N2C[C@@H](Cc3ccccc3)NC2=O)nc1C
Product: C[SH]1C(C(=O)O)=CN=C1N1C[C@@H](Cc2ccccc2)NC1=O
Yield: 83 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with (R)-ethyl 2-(4-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 83% yield: MS (ES+) m/z 318.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[C:11]1[CH2:16][CH2:15][N:14](C)[CH2:13][CH2:12]1.ClC(OCC)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[C:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CN1CCC(=C2c3ccccc3CC2(C)C)CC1
Agent: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CC1(C)Cc2ccccc2C1=C1CCNCC1

Procedure:
43 g 4-(2,2-dimethylindane-1-ylidene)-1-methyl-piperidine and 65 g ethyl chloroformate in 800 ml toluene are refluxed for 3 hours. After cooling, the solution is washed with 1 N hydrochloric acid and water, dried over magnesium sulfate and the toluene distilled off. The oily residue is then refluxed for 6 hours in 90 ml n-butanol and 9 g potassium hydroxide. The reaction mixture is cooled, filtered, diluted with ether and shaken out with water until neutral. The organic phase is then dried over magnesium sulfate and evaporated, to give the title compound as the hydrogenofumarate: m.p. 200°-202°.
Reaction SMILES: [NH:1]([C:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:2]([C:24](ON1C(=O)CCC1=O)=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:53][C@H:54]([C:62]([O:64][CH3:65])=[O:63])[CH2:55][S:56][CH2:57][NH:58][C:59]([CH3:61])=[O:60]>C(Cl)(Cl)Cl>[NH:1]([C:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C@H:2]([C:24]([NH:53][C@H:54]([C:62]([O:64][CH3:65])=[O:63])[CH2:55][S:56][CH2:57][NH:58][C:59]([CH3:61])=[O:60])=[O:25])[CH2:3][S:4][C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)[C@@H](N)CSCNC(C)=O
Reactant: O=C(ON1C(=O)CCC1=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CSCNC(C)=O)NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 20 h

Procedure:
7.0 g of Trt-Cys(Trt)-OSu and 2.0 g of H-Cys(Acm)-OMe in 50 ml of chloroform are left to stand for 20 hours at room temperature. The solution is then diluted with 100 ml of chloroform and washed with 1 N citric acid, 1 N sodium bicarbonate and water, dried over sodium sulphate and evaporated. The residue is recrystallised from ethyl acetate-ether. Melting point 197°-198°C.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:32])=[C:6]([C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:16][C@H:15]2[O:28]C(=O)C)[C:7]([O:12][CH3:13])=[CH:8][C:9]=1[O:10][CH3:11])(=[O:3])[CH3:2].[OH-].[Na+]>CO>[OH:32][C:5]1[C:6]([C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:16][C@H:15]2[OH:28])=[C:7]([O:12][CH3:13])[CH:8]=[C:9]([O:10][CH3:11])[C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: COc1ccc(N2CC[C@@H](c3c(OC)cc(OC)c(C(C)=O)c3O)[C@H](OC(C)=O)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(N2CC[C@@H](c3c(OC)cc(OC)c(C(C)=O)c3O)[C@H](O)C2)cc1

Procedure:
Compound of example 120 (0.25 g, 0.5 mmol) in MeOH (2 mL) was subjected to hydrolysis using 10% aqueous NaOH (2.0 mL) as given in example 6 to obtain the title compound.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:5]1[N:6]([CH3:31])[C:7](=[O:30])[C:8]2[C:13]([C:14]=1[C:15]1[C:16]([CH3:25])=[C:17]3[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=[C:10]([O:26][CH2:27][CH2:28][OH:29])[CH:9]=2.[Li+].[OH-]>C1COCC1>[C:33]([O:32][CH:4]([C:5]1[N:6]([CH3:31])[C:7](=[O:30])[C:8]2[C:13]([C:14]=1[C:15]1[C:16]([CH3:25])=[C:17]3[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=[C:10]([O:26][CH2:27][CH2:28][OH:29])[CH:9]=2)[C:3]([OH:37])=[O:2])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2ccc(OCCO)cc2c(=O)n1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3cc(OCCO)ccc23)ccc2c1CCCO2
Yield: 30.8 %

Procedure:
To a solution of tert-Butoxy-[7-(2-hydroxy-ethoxy)-2-methyl-4-(5-methyl-chroman-6-yl)-1-oxo-1,2-dihydro-isoquinolin-3-yl]-acetic acid methyl ester (30 mg, 0.059 mmol) in THF (3 ml), was added 1N LiOH (3 mL). The resultant mixture was stirred at 70° C. overnight. The solvent was removed in vacuo; the reaction mixture was acidified by 1N HCl solution to pH 5-6. The white solid was filtered to afford the title product (9 mg, 30.8%). LCMS (10-80 AB—2MIN.M): Rt=1.190, purity=97.3%, M+1=496.
Reaction SMILES: C([Li])CCC.[C:6]([Si:10]([CH3:29])([CH3:28])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[N:26][OH:27])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)([CH3:9])([CH3:8])[CH3:7].[C:30]1([C:38](OCC)=[O:39])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:32][CH2:31]1>C1COCC1>[CH2:36]([O:35][C:33]([C:30]1([C:38]2([OH:39])[O:27][N:26]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([O:11][Si:10]([C:6]([CH3:7])([CH3:9])[CH3:8])([CH3:29])[CH3:28])=[CH:13][CH:14]=3)[CH:19]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:32][CH2:31]1)=[O:34])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(Cc2ccccc2)=NO)cc1
Reactant: CCOC(=O)C1(C(=O)OCC)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(C2(O)ON=C(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2c2ccccc2)CC1
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5 M in hexane, 983.8 mL) is added to a solution of 1-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-phenyl-ethanone oxime, which may be produced as in Example 136 (400 g) in THF (4 L) at 0° C. and the reaction solution is stirred for one hour at this temperature. Diethyl 1,1-cyclopropanedicarboxylate (227 mL) is added to the reaction solution, stirred for one hour at 0° C. and then the reaction is quenched with saturated ammonium chloride, diluted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated under reduced pressure. The crude product is purified by column chromatography with 5-10% ethyl acetate in hexane to give a light yellow solid, which is triturated with pentane and filtered to give 1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-5-hydroxy-4-phenyl-4,5-dihydro-isoxazol-5-yl}-cyclopropanecarboxylic acid ethyl ester (230.8 g.)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH3:15][CH:16]1[CH2:20][CH2:19][CH2:18][NH:17]1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:17]1[CH2:18][CH2:19][CH2:20][CH:16]1[CH3:15])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CC1CCCN1
Product: CC1CCCN1C(=O)c1ccc2cc(O)ccc2c1

Procedure:
The title compound was synthesised from 6-Hydroxy-2-naphtoic acid (commercially available) and 2-methyl-pyrrolidine (commercially available) according to the procedure described for Example A. MS (m/e): 254.1 (MH−, 100%)
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[N:15]=[C:16]2[S:29][CH:28]=[C:27]([CH3:30])[N:17]2[C:18](=[O:26])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[CH3:30][C:27]1[N:17]2[C:18](=[O:26])[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[C:14]([CH:12]([NH:11][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:13])[N:15]=[C:16]2[S:29][CH:28]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1csc2nc(C(C)N)c(-c3ccccn3)c(=O)n12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc2nc(C(C)Nc3ncnc4[nH]cnc34)c(-c3ccccn3)c(=O)n12

Procedure:
A mixture of 6-bromo-9H-purine (9.300 mg, 0.004673 mmol), 7-(1-aminoethyl)-3-methyl-6-pyridin-2-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (11 mg, 0.039 mmol), and N,N-diisopropylethylamine (8.152 μL, 0.004680 mmol) in ethanol (0.3 mL) was refluxed under nitrogen overnight. The mixture was concentrated under reduced pressure and the residue was purified on RP-HPLC (eluting with a gradient of methanol/water containing 1% TFA) to provide the product as a TFA salt. LCMS calculated for C19H17N8OS (M+H)+: m/z=405.1. Found: 405.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]Cl)[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]([F:33])([F:32])[CH2:29][CH2:30][CH3:31])[CH:26]=3)[C:21]([CH3:35])([CH3:34])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][C@@H:38]1[CH2:43][O:42][CH2:41][CH2:40][NH:39]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:39]2[CH2:40][CH2:41][O:42][CH2:43][C@H:38]2[CH3:37])[N:11]([CH2:16][C:17]([N:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]([F:33])([F:32])[CH2:29][CH2:30][CH3:31])[CH:26]=3)[C:21]([CH3:35])([CH3:34])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:36])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1COCCN1
Reactant: CCCC(F)(F)c1cnc2c(c1)N(C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1CCl)CC2(C)C
Product: CCCC(F)(F)c1cnc2c(c1)N(C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1CN1CCOC[C@H]1C)CC2(C)C

Procedure:
Prepared from (2R,5R)-5-chloromethyl-4-{2-[6-(1,1-difluoro-butyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-piperazine-1-carboxylic acid tert-butyl ester and (R)-3-methyl-morpholine in a similar manner to General Procedure 6. MS: [M+H]+=594.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17]CC)=O)[CH2:10][CH2:9]1.[NH2:26][NH2:27]>C(O)C>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:26][NH2:27])=[O:17])[CH2:10][CH2:9]1
Reactant: CCOC(=O)CN1CCN(Cc2ccccc2-c2ccccc2)CC1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccccc2-c2ccccc2)CC1

Procedure:
Synthesized according to General Procedure C: 6{12} (4.34 g, 13.4 mmol, 1 equiv.), anhydrous hydrazine (1.3 mL, 40.1 mmol, 3 equiv.), ethanol (27.0 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{12} (4.02 g, 93%) as a beige solid. 1H-NMR (500 MHz, CDCl3): δ 8.12 (br s, 1H), 7.50 (dd, 1H, J=2.0, 7.0 Hz), 7.41-7.34 (m, 5H) 7.33-7.29 (m, 2H), 7.26-7.24 (m, 1H), 3.83 (br s, 2H), 3.40 (s, 2H), 3.04 (s, 2H), 2.47 (br s, 4H), 2.36 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.4, 142.6, 141.3, 135.3, 130.0, 129.8, 129.4, 127.8, 127.0, 126.8, 60.5, 59.5, 53.7, 52.7.
Reaction SMILES: [O:1]([C:8]1[CH:39]=[CH:38][C:11]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15]([O:23]CC3C=CC(OC4C=CC=CC=4)=CC=3)=[N:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[C].[Pd].O1CCCC1>[OH:23][C:15]1[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:17][N:13]([CH2:12][C:11]2[CH:38]=[CH:39][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[N:14]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1ccc(Oc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1O
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A mixture of ethyl 1-(4-phenoxybenzyl)-3-(4-phenoxybenzyloxy)-1H-pyrazole-4-carboxylate (21.50 g), 5% palladium-carbon (10.43 g) and tetrahydrofuran (300 ml) was stirred overnight under a hydrogen atmosphere. After the palladium-carbon was removed by filtration, the filtrate was concentrated to obtain ethyl 3-hydroxy-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (13.35 g, yield 96%) as colorless crystals. This was recrystallized from acetone-hexane. Melting point: 117–118° C.