Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:13]2[C:17]([C:18]([O:20]C)=[O:19])=[C:16]([C:22]([O:24]C)=[O:23])[S:15][N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+].Cl>O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:22]([OH:24])=[O:23])[S:15][N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:27])[F:26])[CH:8]=1
Reactant: COC(=O)c1snc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1snc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1C(=O)O

Procedure:
A mixture of 14.7 g (0.0356 mol) of dimethyl 3-(α,α,α,α',α',α'-hexafluoro-3,5-xylyl)-4,5-isothiazoledicarboxylate, 7.2 g (0.18 mol) of NaOH, and 45 ml of water was held at reflux for 2 hours, was cooled, extracted twice with ether, and acidified with 30 ml (0.36 mol) of concentrated HCl. The resultant mixture was extracted three times with ether; these ether extracts were combined, dried (CaSO4), and concentrated under vacuum to 12.8 g (93.4%) of white solid, m.p. 193°-193.5° with decomposition.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@:7]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:6]=2[CH:5]=[C:4]([O:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH:3]=1.[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@:7]([OH:19])([C:15]([F:17])([F:18])[F:16])[C:6]=2[CH:5]=[C:4]([O:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:3]=1
Reactant: CCOC(=O)CCCOc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCOc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
Ethyl 4-[(9R)-4-chloro-9-hydroxy-9-(trifluoromethyl)-9H-fluoren-2-yloxy]butyrate (92.2 g) was dissolved in ethanol (100 ml), 4N aqueous sodium hydroxide (100 ml) was added, and the mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, water (200 ml) was added, and the mixture was washed twice with toluene (100 ml). The obtained aqueous layer was neutralized with concentrated hydrochloric acid (40 ml), and extracted twice with ethyl acetate (300 ml). The obtained ethyl acetate extract was washed successively with water (100 ml, twice), and saturated brine (100 ml), anhydrous magnesium sulfate and activated carbon (4.2 g) were added, and the mixture was stirred at room temperature for 10 min. The insoluble material was filtered off, and the solvent in the filtrate was evaporated. To the obtained residue was added chloroform (80 ml), and the mixture was heated to 50° C. Hexane (400 ml) was added dropwise, and the mixture was stirred at the same temperature for 30 min, and at room temperature for 2 hr. The precipitated solid was collected by filtration, washed with a mixed solvent of hexane and chloroform (hexane:chloroform=9:1, 50 ml), and dried under reduced pressure at 80° C. for 2 hr to give the title compound (72.5 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C1COCC1>[CH3:21][C:19]1[CH:18]=[C:17]([CH3:22])[N:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:20]=1
Reactant: Cc1cc(C)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(C)nc(NC2CCNCC2)n1
Temperature: 25 °C
Reaction time: 22 h
Yield: 59 %

Procedure:
To a solution of 4-(4,6-dimethyl-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester in THF (50 mL) was added dropwise at 0° C. hydrochloric acid (4 M in dioxane, 44.3 mL) and the reaction mixture was stirred for 22 hours at ambient temperature. The resulting suspension was filtered and dried. The residue was diluted with water (160 mL) and washed with ethyl acetate (130 mL). To the aqueous layer were added ethyl acetate (160 mL) and sodium carbonate (28.5 g) and it was extracted with ethyl acetate (160 mL). Drying of the combined organic layers over sodium sulfate afforded the title compound (2.15 g, 59%) as a light yellow solid.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 22.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.078 mmol), β-alanine (692 mg, 7.8 mmol), and NaOMe solution (12 mL, 5.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After cooling to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-30% EtOAc/CH2Cl2+1% AcOH). The product isolated was then dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 2 with 4 M HCl, and the resulting precipitate was isolated by filtration to give 7.7 mg of the title compound. MS: (+) m/z 444.37 (M+1).
Reaction SMILES: [NH2:1][NH2:2].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=3[CH:19]=2)=O)=[CH:9][CH:8]=1)([O:5][CH3:6])=[O:4].[OH-].[Na+]>C(O)C.O>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:1]=[N:2][C:16]([C:18]3[CH:27]=[CH:26][C:25]4[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=4[CH:19]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([O:5][CH3:6])=[O:4]
Reactant: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)nn2)cc1

Procedure:
0.3 g (10 millimoles) of 100% pure hydrazine were added dropwise at room temperature to a solution of 4.0 g (10 millimoles) of 1-(4-carbomethoxyphenyl)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-butane-1,4-dione (for preparation see Example 9) in 50 ml of ethanol. The reaction mixture was then refluxed for 20 minutes, cooled and then stirred into water, and the yellow crystals were filtered off under suction and dried in a stream of nitrogen. For aromatization of unoxidized dihydropyridazine, the crude product was stirred with periodic acid in ethanol until checking by thin layer chromatography showed that mainly a pure product was obtained. The product was then diluted with water, rendered basic with 2N sodium hydroxide solution and extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulfate and evaporated down. 3.1 g of the title compound remained as an oil; H-NMR (CF3COOH):=8.82 and 8.88 ppm (in each case, d, 2 H, pyridazine-H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](=[N:9][O:10][CH2:11][CH2:12][OH:13])[CH3:8])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7](=[N:9][O:10][CH2:11][CH2:12][O:13][C:21]2[CH:53]=[CH:52][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]3=[O:51])=[CH:23][CH:22]=2)[CH3:8])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1cn(C)c(-c2ccccc2)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1cn(C)c(-c2ccccc2)n1
Yield: 82.2 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 396 mg of 2-[1-(1-methyl-2-phenylimidazol-4-yl)ethylideneaminooxy]ethanol (prepared as described in Preparation 25), 694 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 440 mg of triphenylphosphine and 292 mg of diethyl azodicarboxylate, 866 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [OH:1][C@@H:2]1[C@@:26]2([CH3:27])[C:6]([CH:7]=[CH:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:5][C:4](=[O:29])[CH2:3]1.C[Si](O[Si](C)(C)C)(C)C.C[Si](C)(C)N[Si](C)(C)C.C[Si](C)(C)Cl.[Li].N.[Cl-].[NH4+]>O1CCCC1.C(Cl)Cl.CCOCC.O.N1C=CC=CC=1>[OH:1][C@@H:2]1[C@@:26]2([CH3:27])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:29])[CH2:3]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Solvent: CCOCC
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: c1ccncc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The hydroxy dienone from (a) (0.6 gms) was converted to its trimethylsilyl ether by treatment of a solution in tetrahydrofuran (2 mls) and pyridine (2 mls) with hexamethyldisilazane (1.5 mls) and trimethylchlorosilane (0.6 mls). The crude trimethylsilyl ether was dissolved in tetrahydrofuran (10 mls) and the solution added dropwise to a stirred solution of lithium metal (approx. 200 mgs) in liquid ammonia (20 mls). After a few minutes ammonium chloride (2 gms) was added and the solution stirred. A further portion of lithium metal (approx. 100 mgs) was added. Again the solution was stirred. An additional portion of ammonium chloride was then added and the mixture poured into cold water. The produce was isolated by extraction into ether and methylene dichloride followed by column chromatography which afforded the title compound crystallized from ethanol, melting point 158°-161°. After recrystallisation the melting point was 161.5°-163°. [α]D (CHCl3)-38 °. This material was identical to the product of Example 1(c), and on hydrogenation gave a sample of 1α,3β-dihydroxy-5α-cholestane identical in every way to an authentic specimen.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].C(Cl)(=O)C([Cl:14])=O>C(#N)C.CN(C=O)C>[ClH:14].[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7]([Cl:1])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN(C)C/C=C/C(=O)Cl
Temperature: 60 °C

Procedure:
To (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (110 mg, 0.664 mmol) in acetonitrile (1.5 mL) was added oxalyl dichloride (75.9 mg, 0.598 mmol) followed by one drop of DMF. After heating to 60° C. for 30 minutes, the mixture was cooled to room temperature and concentrated to 0.5 mL total volume. The resulting solution was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)C(O)=O)([O-:3])=[O:2].S(=O)(=O)(O)O.[N-:21]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[NH2:21])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
To a solution of 3,5-dinitrobenzoic acid (4.0 g, 18.9 mmol) in a mixture of concentrated sulfuric acid (6 mL), 30% fuming sulfuric acid (18 mL) and CHCl3 (25 mL) was added sodium azide (1.4 g, 21.7 mmol), in small portions. The resulting mixture was heated to reflux (80° C.) for 3 hours and then cooled to 25° C. after which it was poured on ice. An orange solid was isolated after vacuum filtration (3.25 g, 17.7 mmol, 94%). 1H NMR (300 MHz, CDCl3) δ 8.14 (t, J=1.8 Hz, 1H), 7.64 (d, J=1.8 Hz, 2H), 4.39 (s (br), 2H); 13C NMR (75 MHz, CDCl3) δ 151.9, 150.1, 113.1, 105.2; HRMS (ESI) Calculated for C6H4N3O4 [M−H]−: 182.0195. Found: 182.0207. m.p.: 113.1° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH:17]=2)[S:30]([CH3:29])(=[O:32])=[O:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(NCc2cccc(-c3ccnc(Cl)n3)c2)C1
Product: CC(C)(C)OC(=O)N1CCCC(N(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)C1

Procedure:
Intermediate 51 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 481.
Reaction SMILES: [OH-].[Na+].BrBr.O(Br)[Na].[OH:8][C@H:9]1[CH2:14][C@H:13]([CH3:15])[CH2:12][CH2:11][C@H:10]1[C:16](=[O:18])C.[O-:19]S([O-])=O.[Na+].[Na+].Cl>O.O1CCOCC1>[OH:8][C@H:9]1[CH2:14][C@H:13]([CH3:15])[CH2:12][CH2:11][C@H:10]1[C:16]([OH:18])=[O:19]
Reactant: CC(=O)[C@@H]1CC[C@@H](C)C[C@@H]1O
Reactant: O=S([O-])[O-]
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CC[C@@H](C(=O)O)[C@@H](O)C1
Temperature: 12.5 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
To a ice-cold solution of NaOH (4.8 g, 119.2 mmol) in water (40 mL) and 1,4-dioxane (30 mL) was added bromine (1.5 mL, 29.57 mmol). To the resultant NaOBr yellow solution was added drop wise a solution (1R,2S,4R)-1-(2-Hydroxy-4-methyl-cyclohexyl)-ethanone (1.4 g, 8.962 mmol) in dioxane (130 mL) and water (35 mL). The resulting solution was stirred for 3 h at 10-15° C. The excess NaOBr solution was decomposed by adding a solution of Na2SO3 (1.1 g in 11 mL water), acidified with 10% HCl, extracted with DCM. The combined organic extract was washed with brine, dried and concentrated to give (1R,2S,4R)-2-hydroxy-4-methyl-cyclohexanecarboxylic acid (1.30 g, 92%). NMR 1H (CDCl3, 400 MHz): 4.34 ppm (s, 1H); 2.43-2.39 ppm (m, 1H); 1.96-1.76 ppm (m, 5H); 1.14-1.08 ppm (m, 1H); 1.02-0.93 ppm (m, 1H); 0.90 ppm (d, 3H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].I[CH2:6][C:7]12[CH2:14][CH2:13][C:10]([CH3:15])([CH2:11][CH2:12]1)[C:9](=[O:16])[O:8]2.[Cl-].[Na+]>CN(C=O)C>[N:1]([CH2:6][C:7]12[CH2:14][CH2:13][C:10]([CH3:15])([CH2:11][CH2:12]1)[C:9](=[O:16])[O:8]2)=[N+:2]=[N-:3]
Reactant: CC12CCC(CI)(CC1)OC2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC12CCC(CN=[N+]=[N-])(CC1)OC2=O
Temperature: 100 °C
Yield: 78.3 %

Procedure:
2.6 g of sodium azide was added to a solution of 1.1 g of 1-iodomethyl-4-methyl-2-oxabicyclo[2.2.2]-octan-3-one (Example 28) in 10 ml of DMF. The solution was reacted for 15 hours, while being heated to 100° C. After reaction, 50 ml of an aqueous sodium chloride solution was added to the reaction solution. The solution was then extracted three times with 30 ml of ethyl acetate. The organic layer obtained was washed twice with an aqueous sodium chloride solution and dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The oily substance formed was subjected to column chromatography using 5 g of silica gel. From the fraction eluted with hexane and ethyl acetate=1:1, the solvent was removed in vacuo, yielding 0.6 g of 1-azidomethyl-4-methyl-2-oxabicyclo[2.2.2]octan-3-one as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:6]=2[C:5](=[O:24])[N:4]([CH2:25][CH2:26][CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[C:3]1=[O:35].[Li+].CC([N-]C(C)C)C.[CH3:44][CH:45]([CH3:49])[CH2:46][CH:47]=[O:48]>C1COCC1>[OH:48][CH:47]([C:11]1[C:6]2[C:5](=[O:24])[N:4]([CH2:25][CH2:26][CH2:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[C:3](=[O:35])[N:2]([CH3:1])[C:7]=2[N:8]=[CH:9][C:10]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:22])[F:23])[CH:14]=1)[CH2:46][CH:45]([CH3:49])[CH3:44]
Reactant: CC(C)CC=O
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cccc(OC(F)(F)F)c3)cnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC(O)c1c(Oc2cccc(OC(F)(F)F)c2)cnc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a solution of 1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy) phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 45, step 1, 100 mg, 0.2 mmol) in THF (4 mL) at −78° C. was added LDA (2M in THF, 0.4 mL, 0.8 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 3-methylbutanal (34 mg, 0.4 mmol) in THF (1 mL) was added. The reaction was stirred at −78° C. for 1 h, quenched with aq. NH4Cl (10 mL) then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (2:1) to give 5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (60 mg, 51.7% yield) as a solid. LCMS: [MH+-THP] 498 and TR=1.733 min.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][CH2:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[Cl:42][CH2:43][S:44]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:46])=[O:45]
Reactant: O=S(=O)(Cl)CCl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)CCl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 35.4 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0853 g, 0.185 mmol) was dissolved in dichloromethane (3.0 mL), and the solution was treated with triethylamine (0.129 mL, 0.924 mmol) and chloromethanesulfonyl chloride (0.0490 mL, 0.554 mmol) to obtain 4-chloromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0376 g, yield 35%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:25]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:26])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCN2)on1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCN2C(=O)N2CCOCC2)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-pyrrolidine-2-carboxylic acid (3-tert-butyl-isoxazol-5-yl)-amide; hydrochloride (0.2 g; 0.731 mmol) in N,N-dimethylformamide (2 mL) is added morpholine carbonylchloride (0.084 mL; 0.731 mmol) and N,N-diisopropylethylamine (0.267 mL; 1.535 mmol) and the reaction mixture stirred overnight at room temperature. After this time, the mixture is diluted with water and extracted with ethyl acetate. The combined organics are washed with 1N hydrochloric acid and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude material is purified by preparative HPLC to afford title compound. ESI m/z 351 [M+H]+/349 [M−H]−
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([NH2:10])[N:3]=1.Cl.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH2:19])([O-:14])=[O:13].C(N(CC)CC)C>CCCCO>[Cl:9][C:6]1[N:5]=[C:4]([NH2:10])[N:3]=[C:2]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:7]=1[NH2:8]
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)c(N)c(NCc2cccc([N+](=O)[O-])c2)n1
Yield: 78.6 %

Procedure:
A mixture of 4,6-dichloropyrimidine-2,5-diamine (700 mg, 3.91 mmol), 3-nitrobenzylamine hydrochloride (885 mg, 4.69 mmol) and triethylamine (1.6 mL, 11.7 mmol) in n-BuOH (20 mL) was refluxed for 17 h, concentrated in vacuo and the residue partitioned between EtOAc (10 mL) and H2O (5 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound as an orange solid (906 mg, 76%) which was used in the next reaction without further purification; NMR δH (400 MHz, CDCl3) 8.16 (1H, s), 8.10 (1H, d, J 8.0 Hz), 7.80 (1H, d, J 7.5 Hz), 7.62 (1H, t, J 7.5 Hz), 7.25 (1H, t, J 6.0 Hz), 5.69 (2H, s), 4.67 (2H, d, J 6.0 Hz) and 3.93 (2H, br s);
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][SH:3].[C:6]([C:8]1[C:13]([C:14]#[N:15])=[N:12][C:11](Cl)=[CH:10][N:9]=1)#[N:7].C(N(CC)CC)C>CC(C)=O>[C:6]([C:8]1[C:13]([C:14]#[N:15])=[N:12][C:11]([S:3][CH2:2][C:1]([OH:5])=[O:4])=[CH:10][N:9]=1)#[N:7]
Reactant: O=C(O)CS
Reactant: N#Cc1ncc(Cl)nc1C#N
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: N#Cc1ncc(SCC(=O)O)nc1C#N
Reaction time: 2 h
Yield: 74.9 %

Procedure:
Thioglycolic acid (0.92 g; 0.01 mole) and 1.64 g (0.01 mole) of 2,3-dicyano-5-chloropyrazine were dissolved in 40 ml of acetone, and while the solution was cooled to 0° to 5° C., 2.12 g (0.021 mole) of triethylamine was added dropwise. After the addition, the mixture was stirred at 20° to 25° C. for 2 hours. The precipitate was separated by filtration. The filtrate was concentrated under reduced pressure, and 100 ml of a 1% aqueous solution of hydrochloric acid was added. The separated oily product was extracted with 50 ml of ethyl acetate. The ethyl acetate layer was washed twice with 50 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford a crude product. Recrystallization from toluene afforded 1.65 g (yield 75%) of 2,3-dicyano-5-(carboxymethylthio)pyrazine.