Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:18]=[C:17]([OH:19])[C:16]([Cl:20])=[CH:15][C:14]=2[F:21])[C:3]1=[O:22].[N+:23]([O-])([OH:25])=[O:24]>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]([N+:23]([O-:25])=[O:24])=[C:17]([OH:19])[C:16]([Cl:20])=[CH:15][C:14]=2[F:21])[C:3]1=[O:22]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2[N+](=O)[O-])c1=O
Yield: 35.5 %

Procedure:
This compound was prepared in the manner of Step A of Example 1, using 3.8 grams (0.011 mole) of 1-methyl-6-trifluoromethyl-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione, 1.0 gram (0.011 mole) of 70% nitric acid, and 50 mL of sulfuric acid, yielding 1.5 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:45])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22]2([CH2:28][OH:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=[C:16]([C:30]([O:32]CC)=[O:31])[C:15]3=[O:35])=[C:8]([C:36]2[S:37][CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[N:40]=2)[CH:7]=1)[CH3:2].C1COCC1.[Li+].[OH-].Cl>CO>[CH2:1]([NH:3][C:4](=[O:45])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22]2([CH2:28][OH:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=[C:16]([C:30]([OH:32])=[O:31])[C:15]3=[O:35])=[C:8]([C:36]2[S:37][CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[N:40]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C2(CO)CCOCC2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3C2(CO)CCOCC2)cn1
Temperature: 100 °C

Procedure:
Ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 132, 0.225 g, 0.35 mmol) was diluted with 2:1 MeOH:THF (3 mL). A 2 M aq solution of LiOH (0.35 mL, 0.7 mmol) was added and the reaction mixture was heated in the microwave to 100° C. for 15 min. The mixture was conc in vacuo and acidified to approx. pH 3 with 1 N aq HCl. The resultant solid was collected and purified by column chromatography (silica 95:5 methylene chloride/methanol) followed by purification by reverse phase HPLC (C18, 0-95% acetonitrile/water gradient).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:4]2[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([N:11](CC3C=CC=CC=3)CC3C=CC=CC=3)[C:5]=2[N:26]=1.C(=O)(O)[O-].[Na+].O>C(O)=O.CO.[OH-].[OH-].[Pd+2]>[CH3:1][C:2]1[N:3]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:4]2[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH2:11])[C:5]=2[N:26]=1
Reactant: Cc1cc2c(nc(C)n2CCc2ccccc2)c(N(Cc2ccccc2)Cc2ccccc2)n1
Agent: [Pd+2]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: O
Solvent: CO
Product: Cc1cc2c(nc(C)n2CCc2ccccc2)c(N)n1
Reaction time: 8 h
Yield: 87.5 %

Procedure:
Palladium hydroxide on carbon (0.5 g, Pearlman's catalyst) was added to a mixture of 2,6-dimethyl-1-(2-phenylethyl)-N4,N4 -bis(phenylmethyl)-1H-imidazo[4,5-c]pyridin-4-amine (2.3 g, 5.15 mmole) in formic acid (10 mL). The reaction mixture was heated at reflux overnight. An additional 0.5 g of catalyst was added and refluxing was continued overnight. The reaction mixture was neutralized with saturated sodium bicarbonate solution, diluted with methanol then filtered through a layer of celite to remove the catalyst. The celite layer was flushed with methylene chloride and methanol. The filtrates were combined and concentrated under vacuum to provide a mixture of water and a solid. This mixture was extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate and concentrated under vacuum to provide 1.2 g of a tan solid. This solid was recrystallized from ethanol to provide 0.24 g of the desired product as a solid, m.p. 185°-187° C. Analysis: Calculated for C16H18N4 : % C, 72.15; % H, 6.81; % N, 21.04; Found: % C, 71.51; % H, 6.88; % N, 20.61.
Reaction SMILES: [I:1]I.[CH2:3]([C:10]1[N:15]=[C:14]([Cl:16])[C:13]([OH:17])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>O>[CH2:3]([C:10]1[N:15]=[C:14]([Cl:16])[C:13]([OH:17])=[C:12]([I:1])[CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: II
Reactant: Oc1ccc(Cc2ccccc2)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: O
Product: Oc1c(I)cc(Cc2ccccc2)nc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Iodine (5.87 g, 23.1 mmol) was added to a solution of 6-benzyl-2-chloropyridin-3-ol (2.54 g, 11.6 mmol) in water (45 mL) containing potassium carbonate (3.20 g, 23.1 mmol). The mixture was allowed to stir for 3 h at room temperature, treated with sodium thiosulfate, and acidified to pH 2 using 12M aqueous HCl. The mixture was extracted with EtOAc. The organic phase was dried over MgSO4 and evaporated. Purification by flash chromatography using EtOAc/hexanes gave 6-benzyl-2-chloro-4-iodopyridin-3-ol. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.36 (br. s, 1H), 7.68 (s, 1H), 7.15-7.35 (m, 5H), 3.93 (s, 2H). MS (ESI) m/z: Calculated; 345.0; Observed: 345.9 (M++1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][OH:23]>C(O)CC>[OH:23][CH2:22][CH2:21][CH2:20][NH:19][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[NH:5][C:6](=[O:8])[CH:7]=1
Reactant: NCCCO
Reactant: CCCOc1ccccc1-c1nc(O)cc(Cl)n1
Solvent: CCCO
Product: CCCOc1ccccc1-c1nc(NCCCO)cc(=O)[nH]1

Procedure:
A stirred solution of 4-chloro-6-hydroxy-2-(2-propoxyphenyl)pyrimidine (0.66 g) and 3-amino-1-propanol (0.56 g) in n-propanol was heated under reflux for 16 hours. The cooled reaction mixture was evaporated under reduced pressure to yield an oil which was partitioned between chloroform (20 ml) and water (20 ml). The chloroform layer was separated from the aqueous layer which was extracted with chloroform (2×10 ml) and the combined chloroform layers were washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from isopropanol:diethyl ether to yield the title compound, 0.54 g, m.p. 147.5°-148.5° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]1([C:27]2[N:28]=[CH:29][NH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:30]4[CH:31]=[C:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:28]=[CH:29]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: c1ccc(-c2c[nH]cn2)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2c(F)c(-n3cnc(-c4ccccc4)c3)c(F)cc2c1=O
Yield: 56.5 %

Procedure:
A mixture of 2.8 g (10 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 4.3 g (30 mmol) of 4-phenylimidazole, 20 ml of triethylamine and 100 ml of DMSO is refluxed for 3 hours. It is allowed to cool, poured into a water/ice mixture and adjusted to pH 5 to give a precipitate, which is filtered off and washed with water. The solid is dried under vacuum to give 2.3 g of 1-cyclopropyl-6,8-difluoro-7-(4-phenylimidazol-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid melting at 286°-288° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][O:38][C:39](=[O:56])[C:40]1[CH:45]=[CH:44][C:43](B2OC(C)(C)C(C)(C)O2)=[C:42]([F:55])[CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)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>[CH3:37][O:38][C:39](=[O:56])[C:40]1[CH:45]=[CH:44][C:43]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:42]([F:55])[CH:41]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c(F)c1
Yield: 51.5 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.55 g, 1 mmol), 3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (1.0 g, 3 mmol) and dichlorobis(triphenylphosphine)palladium (II) (70 mg, 0.1 mmol) in dioxane (6 mL) was added an aqueous sodium carbonate solution (2 M, 1.5 mL). The mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-3-fluoro-benzoic acid methyl ester (260 mg, 49%) as a white solid: LC/MS m/e calcd for C28H25FN2O4S [M+H]+ 505.58, observed 505.0.
Reaction SMILES: [CH:1]1[N:9]=[C:8](N)[C:7]2[C:3](=[C:4]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[NH:5][N:6]=2)[N:2]=1.N([O:22][CH2:23][CH2:24]CC)=O>C1COCC1>[C:14]([O:19][C@@H:12]1[C@H:13]([O:18][C:12](=[O:19])[CH3:11])[C@@H:14]([CH2:16][O:17][C:23](=[O:22])[CH3:24])[O:15][C@H:11]1[C:4]1[C:3]2[N:2]=[CH:1][N:9]=[CH:8][C:7]=2[NH:6][N:5]=1)(=[O:15])[CH3:13]
Reactant: Nc1ncnc2c([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)[nH]nc12
Reactant: CCCCON=O
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](c2n[nH]c3cncnc23)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 50 °C

Procedure:
A mixture of 2′,3′,5′-tri-O-acetyl-formycin A (prepared from formycin A by modification of the method from Synthesis (1989) 401) (1.1 g, 2.8 mmol) and n-butyl nitrite (2.6 ml, 22 mmol) in THF (30 ml) was heated at 50° C. for 25 h. After cooling to room temperature, the solvent was removed under reduced pressure. The mixture was dissolved in EtOH and reconcentrated (in each case twice). Silica gel chromatography using 2% MeOH in DCM gave compound (Ia) (0.49 g, 46%), the analysis of which confirmed the chemical identity with the product from method A.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](=[O:21])[CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>[C].[Pd].CN(C)C=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](=[O:21])[CH:11]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cc(=O)cc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(=O)cc(-c2ccc(N)cc2)o1
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A mixture of ethyl 6-(4-nitrophenyl)-4H-pyran-4-one-2-carboxylate (59 g), 10% palladium-carbon (6 g), potassium carbonate (10 g) and dimethylformamide (400 ml) is shaken under hydrogen gas stream at room temperature under atmospheric pressure. After the reduction reaction is finished, the insoluble materials are removed by filtration, and thereto is added water. The precipitated crystals are collected by filtration to give ethyl 6-(4-aminophenyl)-4H-pyran-4-one-2-carboxylate (30 g). M.P. 190°-193° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH:11]([NH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][CH:28]=[C:29]([C:31]3[CH:40]=[CH:39][C:38]4[C:37]([CH3:42])([CH3:41])[CH2:36][CH2:35][C:34]([CH3:44])([CH3:43])[C:33]=4[CH:32]=3)[N:30]=2)[CH2:22][CH2:21]1)[CH2:12][CH2:13][C:14](OCC)=[O:15])C.O>C1COCC1>[CH3:41][C:37]1([CH3:42])[CH2:36][CH2:35][C:34]([CH3:43])([CH3:44])[C:33]2[CH:32]=[C:31]([C:29]3[N:30]=[C:26]([N:23]4[CH2:24][CH2:25][CH:20]([NH:19][CH:11]([CH2:12][CH2:13][CH2:14][OH:15])[CH2:10][OH:9])[CH2:21][CH2:22]4)[S:27][CH:28]=3)[CH:40]=[CH:39][C:38]1=2
Reactant: CCOC(=O)CCC(NC1CCN(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NC(CO)CCCO)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.3 mg (0.11 mmol) of lithium aluminium hydride were initially introduced in 2 ml of THF, and 21 mg (0.04 mmol) of 2-{1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamino}pentanedioic acid diethyl ester from step a, pre-dissolved in 2 ml of THF, were slowly added. The reaction mixture was stirred at room temperature overnight, 20 ml of water were added, and the mixture was extracted twice with EA. The organic phase was dried over sodium sulfate, filtered, stripped off to dryness and purified by means of preparative HPLC. The product is in the form of the TFA salt.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][CH2:15][C@@H:16]1[O:21][CH2:20][C@@:19]([NH:30][C:31]([NH:33][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[S:32])([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[C@H:18]([CH2:42]O)[CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O>ClCCl>[CH2:7]([O:14][CH2:15][C@@H:16]1[O:21][CH2:20][C@:19]2([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])[N:30]=[C:31]([NH:33][C:34](=[O:41])[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[S:32][CH2:42][C@@H:18]2[CH2:17]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1)c1ccccc1
Temperature: -55 °C

Procedure:
Pyridine (11.0 mL, 137 mmol) was added to a solution of C7 (19.00 g, 36.08 mmol) in dichloromethane (150 mL), and the resulting solution was cooled to −50 to −60° C. Trifluoromethanesulfonic anhydride (12.1 mL, 71.9 mmol) in dichloromethane (50 mL) was added drop-wise, and the reaction mixture was gradually warmed to −5° C. over 3 hours. Water was added, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 20% to 40% ethyl acetate in heptane) provided the product as a yellow foam. Yield: 15.51 g, 30.50 mmol, 85%. LCMS m/z 509.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.23 (br d, J=7 Hz, 2H), 7.37-7.57 (br m, 4H), 7.24-7.36 (m, 5H), 6.85-6.97 (m, 2H), 4.58 (AB quartet, upfield signals are slightly broadened, JAB=11.9 Hz, ΔνAB=23.5 Hz, 2H), 4.17 (br d, J=12 Hz, 1H), 3.90-3.97 (m, 1H), 3.83 (br d, J=12 Hz, 1H), 3.64 (dd, half of ABX pattern, J=10.1, 6.4 Hz, 1H), 3.50 (dd, half of ABX pattern, J=10.2, 4.4 Hz, 1H), 3.11-3.21 (br m, 1H), 3.02 (dd, J=12.9, 4.1 Hz, 1H), 2.64 (br d, J=13 Hz, 1H), 1.92-2.05 (br m, 1H), 1.71 (br d, J=13 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][Br:36])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.1 %

Procedure:
To a solution 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (8.75 g, 40.64 mmol) in diethyl ether (200 mL) at 0° C. under nitrogen. were added triphenyl phosphine (21.32 g, 81.28 mmol) and carbon tetrabromide (26.96 g, 81.28 mmol). The mixture was allowed to warm to room temperature and stirred under nitrogen for 48 h. The reaction mixture was filtered through a pad of Celite and the organic filtrate was washed with 5% NaS2O3, water, brine, and dried. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate/hexane, 1:9) to give 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (8.26 g, 73%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][OH:10])[CH2:4][CH2:3]1.[H-].[Na+].Cl[CH2:14][C:15](=[O:29])[CH2:16][C:17]([O:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:18].Cl>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][CH2:14][C:15](=[O:29])[CH2:16][C:17]([O:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:18])[CH2:4][CH2:3]1
Reactant: O=C(CCl)CC(=O)OCCCc1ccccc1
Reactant: CN1CCN(CCO)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(CCOCC(=O)CC(=O)OCCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.1 %

Procedure:
2-(4-Methyl-1-piperazinyl)ethanol (8.14 g, 56.5 mmol) in THF (50 mL) was added dropwise to a suspension of sodium hydride (3.5 g, 87.5 mmol) in THF (200 mL) at 0° C. The mixture was then stirred for 3 h at room temperature, cooled to 0° C., 3-phenylpropyl 4-chloroacetoacetate (11.10 mL, 51.5 mmol) in THF (50 mL) was added dropwise, and the reaction mixture was then stirred for 18 h whilst warming to room temperature. 1N Hydrochloric acid was added until the mixture was acidic and the aqueous layer was then separated. The organic layer was extracted twice more with 1N hydrochloric acid. The combined acid layers were washed two times with ethyl acetate and then made basic to pH 8 with sodium hydrogen carbonate and extracted with chloroform three times. The combined extracts were washed with brine, dried and evaporated to give the title compound (8.8 g) as an oil. Electrospray MS m/z 363 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:12]3=[N:19][N:20]=[CH:21][N:11]3[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:22].CC([OH:26])C>>[OH2:26].[ClH:22].[N:1]1([CH2:6][CH2:7][NH:8][C:9]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:12]3=[N:19][N:20]=[CH:21][N:11]3[N:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)O
Agent: Cl
Agent: c1nnc2c3c(c(NCCN4CCCC4)nn12)CCCC3
Product: O

Procedure:
A solution of 20.0 g of 6-[2-(1-pyrrolidinyl)ethylamino]-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine in 60 ml of 2-propanol was heated to reflux and 6 ml of concentrated hydrochloric acid was added slowly. An exothermic reaction took place and a white precipitate formed immediately. The mixture was refluxed for 30 minutes and then cooled. The solid was separated by filtration, washed thoroughly with 2-propanol and then dried at 50° C. under reduced pressure to give 6-[2-(1-pyrrolidinyl)ethylamino]-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine hydrochloride hydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14](O)=[O:15])[CH:12]=2)[C:7]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[C:6]1[CH2:22][CH2:23][CH3:24].O[N:30]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>CN(C)C=O>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH2:30])=[O:15])[CH:12]=2)[C:7]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[C:6]1[CH2:22][CH2:23][CH3:24]
Reactant: On1nnc2ccccc21
Reactant: CCCc1c(C(=O)C(C)C)c2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: CCCc1c(C(=O)C(C)C)c2ccc(C(N)=O)cc2n1Cc1ccccc1Cl
Temperature: 20 °C
Yield: 82.2 %

Procedure:
To a solution of 1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carboxylic acid (150 mg) in dimethylformamide (3 ml) were added 1-hydroxybenzotriazole (102 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (109 mg). After stirred at 20° C. over night, the resulting mixture was poured into 28% aqueous ammonia (5 ml). The mixture was partitioned between ethyl acetate and water, and the organic phase was washed with 1N hydrochloric acid and brine, dried over sodium sulfate and evaporated in vacuo. The crystalline residue was recrystallized from a mixture of ethyl acetate and hexane to give 1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carboxamide (123 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]([Cl:16])([F:15])[S:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13]O)[CH:5]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Cl:19][CH2:13][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([S:3][C:2]([Cl:16])([Cl:1])[F:15])=[CH:5]1
Reactant: O=S(Cl)Cl
Reactant: OCn1cc(SC(F)(Cl)Cl)c2ccccc21
Solvent: ClC(Cl)Cl
Product: FC(Cl)(Cl)Sc1cn(CCl)c2ccccc12

Procedure:
0.54 g of 3-{[dichlorofluoromethyl]thio}-1H-indole-1-ylmethanol was dissolved to 10 ml of chloroform. 0.3 ml of thionyl chloride was added to the solution, and refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain 0.61 g of 1-(chloromethyl)-3-{[dichlorofluoromethyl]thio}-1H-indole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[CH:57]=[N:56][C:55]([CH3:58])=[CH:54][N:53]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]2)[C:13]([NH:51][C:52]2[CH:57]=[N:56][C:55]([CH3:58])=[CH:54][N:53]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cc1cnc(N)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cc1cnc(NC(=O)[C@H](CC2CCC(=O)CC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.1 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (prepared as in Example 60, 263 mg, 0.73 mmol) and triphenylphosphine (250 mg, 0.95 mmol) in methylene chloride (5.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (167 mg, 0.95 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-methylpyrazine (160 mg, 1.46 mmol) and 2,6-lutidine (0.36 mL, 2.92 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10% aqueous hydrochloric acid solution 1×20 mL), a saturated aqueous sodium bicarbonate solution 1×20 mL) and water 1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate to 3/7 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-methyl-pyrazin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (158 mg, 48%) as a white foam: [α]23589=−41.52° (c=0.33, chloroform); EI-HRMS m/e calcd for C20H21Cl2N3O4S (M+H)+ 450.1249. found 450.1253.