Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]12[CH2:16][CH:15]1[CH:14]([OH:17])[CH2:13][CH2:12]2.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]12[CH2:16][CH:15]1[C:14](=[O:17])[CH2:13][CH2:12]2
Reactant: OC1CCC2(c3ccc4ccccc4c3)CC12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C1CCC2(c3ccc4ccccc4c3)CC12
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A solution of 5-(naphthalen-2-yl)bicyclo[3.1.0]hexan-2-ol (2.35 g, 10.5 mmol) in dichloromethane (110 mL) was treated with pyridine (1.18 mL, 14.6 mmol, 1.4 eq.) followed by Dess-Martin periodinane (5.34 g, 12.6 mmol, 1.2 eq.) and warmed to ambient temperature. After 2 h, 3 drops of water were added. After 0.5 h, the reaction was quenched with saturated sodium hydrogen carbonate (50 mL), saturated sodium sulphite (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic extracts was dried over magnesium sulphate and concentrated in vacuo. Purification by silica gel chromatography using 1:6 ethyl acetate/petrol as the eluting solvent afforded the desired compound (1.44 g, 62%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.56-1.58 (1H, m, CH), 1.71-1.75 (1H, m, CH), 2.22-2.25 (1H, m, CH), 2.30-2.34 (2H, m, CH2), 2.44-2.57 (2H, m CH2), 7.34 (1H, dd, J 1.9, 8.5, ArH), 7.44-7.51 (2H, m, ArH), 7.72-7.73 (1H, m, ArH), 7.80-7.83 (3H, m, ArH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12](I)[N:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:10]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)CCC.CC(O)=O>CN(C=O)C.[Cu]I.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>[CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[N:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:10]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(I)n1-c1ccc(OC)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(-c2ccccn2)n1-c1ccc(OC)cc1
Temperature: 140 °C
Yield: 84.7 %

Procedure:
To a solution of ethyl 3,4-bis(benzyloxy)-5-iodo-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (28) (300 mg, 0.51 mmol) in DMF (5 mL) was added 2-(tributylstannyl)pyridine (280 μL, 0.87 mmol), copper(I) iodide (19.6 mg, 0.10 mmol) and dichlorobis(triphenylphosphine)palladium(II) (36.1 mg, 0.05 mmol). The mixture was heated in a microwave at 140° C. for 30 min, AcOH (2 mL) was added and the crude product was loaded onto a column of SCX (5 g). The column was washed with MeOH and then the product was eluted with 1% NH3 in MeOH. The resultant mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (12 g, 20-100% EtOAc in isohexane) to afford ethyl 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-5-(pyridin-2-yl)-1H-pyrrole-2-carboxylate (UL1-082) (231 mg, 83%) as a pale yellow oil: m/z 535 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1H NMR (400 MHz, DMSO-d6) δ: 8.47-8.40 (m, 1H), 7.71-7.63 (m, 1H), 7.54-7.47 (m, 2H), 7.45-7.16 (m, 10H), 7.12-7.03 (m, 2H), 6.83-6.76 (m, 2H), 5.18 (s, 2H), 4.96 (s, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.72 (s, 3H), 1.03 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][C:5](O)=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:36][NH:37][S:38]([CH3:41])(=[O:40])=[O:39]>O.C(OCCCC)(=O)C>[Br:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][C:5]([N:37]([CH3:36])[S:38]([CH3:41])(=[O:40])=[O:39])=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: CNS(C)(=O)=O
Reactant: CC(C)c1nc(O)nc(-c2ccc(F)cc2)c1Br
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOC(C)=O
Solvent: O
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1Br
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 38.1 %

Procedure:
5-Bromo-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-ol (62.2 g, 199 mmol), potassium carbonate (35.83 g, 259 mmol) and butyl acetate (435.4 mL) were charged to a 2 L multi-neck flask and stirred/heated to 42° C. p-Toluenesulfonyl chloride (41.83 g, 219 mmol) was then added in portions over 50 minutes, maintaining the temperature at ≦45° C. The reaction was stirred at this temp for 2.5 hours, at which point LCMS showed only the desired intermediate (MH+=467) present. Potassium carbonate (41.25 g, 299 mmol) and butyl acetate (186.6 mL) were then added and reaction heated to 120° C. Once at this temperature N-methylmethanesulfonamide (28.21 g, 259 mmol) was added over 30 mins. The reaction was held at this temperature for 18 hours, then butyl acetate (330 mL) and water (412 mL) were added, reducing the reaction temperature to 75° C. Stirring was continued at this temperature for 20 minutes, then the reaction mixture was transferred to a separating funnel, and allowed to stand for 10 mins to separate. The aqueous layer was separated off and re-extracted with butyl acetate (250 mL) by stirring at 60° C. for 15 mins. The organic layers were combined and 1 M aqueous NaOH (330 mL) added. This mixture was stirred at 60° C. for 20 minutes, then the lower aqueous phase separated off. The organic layer was concentrated in vacuo to 20% original volume, then allowed to cool and crystallize. The crude solid was isolated by filtration (50.5 g slightly damp), and this material recrystallized from methanol (500 mL), filtered and dried at 50° C. to constant weight to give the title compound (30.54 g, 38% yield) as a white crystalline solid.
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].Cl.O>[Cl-].C[N+](C)(C)CCCCCCCCCCCCCCCC.C(OC(C)C)(C)C>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CC(C)OC(C)C
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 2-keto-L-gulonic acid (125 g, 0.584 mol, content: 90.7%, water: 8.5%) and trimethylcetylammonium chloride (0.084 g) was stirred in diisopropyl ether (500 ml), and 36% conc. hydrochloric acid (18.0 g) was added. At this time, the amount of water in the reaction system was calculated as 2.1 mol per mol of 2-keto-L-gulonic acid. This mixture was stirred at 60° C. for 1 hour, a solution of hydrogen chloride gas (17.2 g) in diisopropyl ether (88 g) was added, and the mixture was stirred at the same temperature for 5 hours. Then, about 900 g of the solvent was distilled away under reduced pressure while continuously introducing diisopropyl ether (1000 ml). The residue was filtered to give crude crystals of L-ascorbic acid. The crude crystals were dissolved in water. Quantitative analysis of the solution by HPLC showed that the solution contained L-ascorbic acid (95.8 g, yield: 93.1%) and 2-keto-L-gulonic acid (0.9 g, residual ratio: 0.8%). Quantitative analysis of diisopropyl ether in the distillate and filtrate showed that the recovery ratio was not less than 99%.
Reaction SMILES: C=C[C@@H]1[C@@H]2C[C@H]([C@@H]([OH:22])C3C4C(=CC=CC=4)N=CC=3)N(CC2)C1.N1C=CC=CC=1.[CH3:29][NH:30][C:31]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43]([C:45]3[N:46]=[CH:47][N:48]([C:50]([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH:49]=3)=[O:44])[CH:39]=2)[CH:34]=1)=[O:32].Cl.[O:70]1[CH2:74]C[CH2:72][CH2:71]1>C(OCC)(=O)C>[OH:44][C@@:43]([C:38]1[CH:37]=[CH:36][C:35]2[C:40](=[CH:41][CH:42]=[C:33]([C:31]([NH:30][CH3:29])=[O:32])[CH:34]=2)[CH:39]=1)([C:45]1[N:46]=[CH:47][N:48]([C:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:49]=1)[CH2:72][C:71]([O:70][CH3:74])=[O:22]
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccccc12
Reactant: C1CCOC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2cc([C@@](O)(CC(=O)OC)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reaction time: 0.33 h
Yield: 92 %

Procedure:
Under argon atmosphere, 0.49 g (1.66 mmol, 1.25 equivalents) of (+)-cinchonine was added to 10 mL (5.4 mmol) of the solution of methyl bromozincacetate in tetrahydrofuran obtained in Example 55 at 5˜8° C. 0.43 mL (5.32 mmol, 4 equivalents) of pyridine was added dropwise at 6˜8° C. The mixture was stirred at 4˜6° C. for 20 minutes. A solution of 0.69 g (1.32 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 6.9 mL of THF was added dropwise at −35˜−40° C. The mixture was stirred at −40˜−35° C. for 1 hour. 2.5 mL (1.32 mmol) of the solution of methyl bromozincacetate in tetrahydrofuran obtained in Example 55 was added dropwise at −40° C., and the mixture was stirred at −40˜−35° C. for 1 hour. 20 mL of 1N hydrochloric acid was added dropwise at 0° C. or lower, followed by dilution with 30 mL of ethyl acetate. The layers were separated. The organic layer was washed successively with 5 mL of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, 5 mL of water, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing and concentration under reduced pressure, 4 mL of IPE was added, crystals were loosened, filtered, and washed with 1 mL (×2) of IPE. After washing, vacuum drying (40° C.) to a constant weight afforded 0.72 g of methyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 92%, enantiomer excess 93.6% ee).
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][NH2:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:23](OCC)(=[O:28])[CH2:24][C:25]([CH3:27])=O>>[CH2:1]([O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][N:19]1[C:23](=[O:28])[CH2:24][C:25]([CH3:27])=[N:22][CH2:21][CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCCCCCCCCCCOCCNCCNCCN
Product: CCCCCCCCCCCCOCCNCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 315.1 g (1 mole) of N-dodecoxyethyldiethylenetriamine and 130.1 g (1 mole) of ethyl acetoacetate at 150° to 160° C., 18 g of water and 46 g of ethanol were distilled off to obtain 4-dodecoxyethylaminoethyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: [C@@H:1]12[O:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:10]=[C:11]([NH:15][C:16]3[C:17]4[N:25]=[CH:24][S:23][C:18]=4[N:19]=[C:20](Cl)[N:21]=3)[CH:12]=[CH:13][CH:14]=1)[CH2:2]2.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=2)[C:37]([O:39][CH3:40])=[O:38])O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C@@H:1]12[O:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:10]=[C:11]([NH:15][C:16]3[C:17]4[N:25]=[CH:24][S:23][C:18]=4[N:19]=[C:20]([C:34]4[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=4)[C:37]([O:39][CH3:40])=[O:38])[N:21]=3)[CH:12]=[CH:13][CH:14]=1)[CH2:2]2
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Clc1nc(Nc2cccc(N3C[C@H]4CC[C@@H](C3)O4)c2)c2ncsc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2nc(Nc3cccc(N4C[C@H]5CC[C@@H](C4)O5)c3)c3ncsc3n2)c1
Temperature: 100 °C
Yield: 78.2 %

Procedure:
The mixture of N-(3-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)-5-chlorothiazolo[5,4-d]pyrimidin-7-amine (0.095 g, 0.254 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.073 g, 0.28 mmol), Pd (PPh3)4 (0.015 g, 0.013 mmol) and Na2CO3 (0.081 g, 0.762 mmol) in dioxane (20 mL) and H2O (5 mL) was heated to 100° C. for 16 h under N2 atmosphere. Then it was concentrated to dryness. The residue was purified by column chromatography (silica gel, 200˜300 mesh, eluting with ethyl acetate:petroleum ether=1:2) to afford methyl 3-(7-(3-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (0.094 g, 78%) as a yellow solid. LC-MS: 474 [M+H]+, tR=1.84 min.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]([CH3:38])[CH:32]=[C:31]2[NH:39][NH2:40]>>[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]([CH3:38])[CH:32]=[C:31]2[N:39]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:40]1
Reactant: Cc1cc(NN)c2cc(F)ccc2n1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N(C)C)c2)ccc1=O
Product: Cc1cc(-n2nccc2-c2nn(-c3cccc(S(=O)(=O)N(C)C)c3)ccc2=O)c2cc(F)ccc2n1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-dimethyl-benzenesulfonamide (A-12) and (6-fluoro-2-methyl-quinolin-4-yl)-hydrazine according to the method described for example 91.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].O.[NH2:12][NH2:13]>CN(C)C1C=CN=CC=1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:12][NH2:13])=[O:6]
Reactant: NN
Reactant: O=C(O)c1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.3 %

Procedure:
A mixture of 3-chlorobenzoic acid (0.5 g, 3.19 mmol), 1,3-diccyclohexylcarbodiimide (0.72 g, 3.51 mmol), 4-dimethylaminopyridine (0.04 g, 0.32 mmol) in ethanol was stirred at ambient temperature for 1.5 hour. The white solid was filtered off and the filtrate diluted with dichloromethane (100 mL). The organic solution was washed with 1N sodium hydrogen sulfate (100 mL), saturated sodium bicarbonate (100 mL), water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude residue was dissolved in ethanol (15 mL) and treated with hydrazine monohydrate (0.46 mL, 9.58 mmol). The resulting clear solution was stirred overnight at ambient temperature. The reaction mixture was then concentrated to dryness in vacuo. Silica gel chromatography of the residue, using 3% methanol in dichloromethane, afforded 0.29 g (53%) of 3-chlorobenzhydrazide as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][C:4]12[CH2:11][O:10][C:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[C:19][Si](C)(C)C)=[CH:14][CH:13]=3)([O:8][CH2:9]1)[O:6][CH2:5]2.CC(C)(C)CC12CO[C:32](C3C=CC(I)=CC=3)(OC1)[O:31][CH2:30]2.C[Si](C#C)(C)C>>[CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][C:4]12[CH2:11][O:10][C:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:30][O:31][CH3:32])=[CH:14][CH:13]=3)([O:8][CH2:9]1)[O:6][CH2:5]2
Reactant: CC(C)(C)CC12COC(c3ccc(I)cc3)(OC1)OC2
Reactant: CC(C)(C)CC12COC(c3ccc(C#C[Si](C)(C)C)cc3)(OC1)OC2
Agent: C#C[Si](C)(C)C
Product: COCCCc1ccc(C23OCC(CC(C)(C)C)(CO2)CO3)cc1

Procedure:
Using methodology described in Example 1, 4-(2,2-dimethylpropyl)-1-[4-(2-trimethylsilylethynyl)phenyl]-2,6,7-trioxabicyclo[2,2,2]octane was prepared from 4-(2,2-dimethyl-propyl)-1-(4-iodophenyl)-2,6,7-trioxabicyclo[2,2,2]octane and trimethylsilylacetylene.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][CH2:10][N:11]([C:13]([O:15][C@@H:16]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[O:14])[CH3:12])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[S:1]1[CH2:2][CH2:3][N:4]([C:7]([CH2:9][CH2:10][N:11]([C:13]([O:15][C@@H:16]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]([OH:19])=[O:18])=[O:14])[CH3:12])=[O:8])[CH2:5][CH2:6]1
Reactant: CN(CCC(=O)N1CCSCC1)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CCC(=O)N1CCSCC1)C(=O)O[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93209.8 %

Procedure:
To a solution of benzyl 2(S)-[N-(2-thiomorpholinocarbonylethyl)-N-methylaminocarbonyloxy]-3-phenylpropionate (418 mg) in methanol (5 ml), which was cooled to 0° C., was added 1N sodium hydroxide aqueous solution (1.33 ml). The mixture was stirred at ambient temperature for one hour. After evaporation of methanol, the residual basic aqueous solution was washed with chloroform (5 ml×2). Then the aqueous solution was acidified to pH 2 with 5% hydrochloric acid, and extracted with ethyl acetate (10 ml×2). The extract was washed with water (10 ml) and saturated sodium chloride solution (10 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give 2(S)-[N-(2-thiomorpholinocarbonylethyl)-N-methylaminocarbonyloxy]-3-phenylpropionic acid (315 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[O:5][CH:6]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[CH:3]=[C:4]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])[O:5][CH:6]=2)[CH:21]=1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(Br)co1
Reactant: OB(O)c1cccnc1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(-c2cccnc2)co1

Procedure:
The title compound was prepared by a method analogous to that described in Example 12 from (R)-3′-(4-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and pyridine-3-boronic acid. The title compound (105 mg) was obtained as a pale solid, m/z 326 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]([OH:10])([CH3:9])[C:5]([F:8])([F:7])[F:6].[Br:12][C:13]1[CH:14]=[C:15]([C:19](=[O:23])[CH:20]=[N+]=[N-])[CH:16]=[CH:17][CH:18]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(O)(C(F)(F)F)=O.C(O)(C(F)(F)F)=O.C(O)(C(F)(F)F)=O.[Rh].[Rh]>[CH3:1][O:2][C:3](=[O:11])[C:4]([O:10][CH2:20][C:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Br:12])[CH:14]=1)=[O:23])([CH3:9])[C:5]([F:7])([F:6])[F:8]
Reactant: [N-]=[N+]=CC(=O)c1cccc(Br)c1
Reactant: COC(=O)C(C)(O)C(F)(F)F
Agent: [Rh]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(C)(OCC(=O)c1cccc(Br)c1)C(F)(F)F

Procedure:
To a solution of 3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid methyl ester (22.94 g, 133 mmol) in CH2Cl2 (400 ml) was added rhodium(II) trifluoroacetate dimer (0.439 g, 0.667 mmol). After cooling to 0° C. a solution of 1-(3-bromo-phenyl)-2-diazo-ethanone (15.0 g, 66.7 mmol) dissolved in CH2Cl2 (100 ml) was added over a period of 2 h. The reaction mixture was concentrated and the title compound was obtained after flash-chromatography on silica gel (toluene) as a yellow oil: TLC (toluene/EtOAc 10:1): Rf=0.45; HPLC RtH5=1.352 min; 1H NMR (360 MHz, CDCl3): δ 8.15 (s, 1H), 7.94 (d, 1H), 7.76 (d, 1H), 7.40 (t, 1H), 4.87 (s, 2H), 3.89 (s, 3H), 1.72 (s, 3H); ESIMS: 386, 388 [(M+NH4)+].
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]([CH:9]([NH:11]C(=O)OC(C)(C)C)[CH3:10])=[CH:7][N:8]=1.[ClH:19]>CO.O1CCOCC1.C(OCC)(=O)C>[ClH:19].[CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]([CH:9]([NH2:11])[CH3:10])=[CH:7][N:8]=1
Reactant: CSc1ncc(C(C)NC(=O)OC(C)(C)C)nn1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CSc1ncc(C(C)N)nn1
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl 1-[3-(methylthio)-1,2,4-triazin-6-yl]ethylcarbamate (Intermediate 3) (13.3 g, 49 mmol) in methanol (100 mL) was added 4N HCl in dioxane (50 mL). After stirring for 30 minutes the volatiles were removed under reduced pressure to provide a colorless oil. The oil was taken up in ethyl acetate, and the volatiles again removed under reduced pressure to give 1-[3-(methylthio)-1,2,4-triazin-6-yl]ethanamine hydrochloride (10.1 g) as a white solid. MS m/z 171 (M+1). A portion of the white solid (90 mg) was slurried in ethyl acetate and washed with saturated sodium bicarbonate solution causing the solid to dissolve. The volatiles were removed under reduced pressure to give 1-[3-(methylthio)-1,2,4-triazin-6-yl]ethanamine (68 mg) as a foam. MS m/z 171 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:3]1.C(N(CC)C(C)C)(C)C.Cl[C:40]([O:42][CH2:43][CH3:44])=[O:41]>ClCCl.CN(C)C1C=CN=CC=1>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([CH:4]2[N:3]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:2](=[O:1])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=3)[C:6]3[CH2:18][CH2:19][C:20](=[O:21])[C:5]2=3)=[CH:29][CH:28]=1)#[N:27]
Reactant: CCOC(=O)Cl
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 40 mg, 0.10 mmol) in dichloromethane (1.0 mL) is treated with N,N-diisopropylethylamine (70 μL, 0.4 mmol) and 4-dimethylaminopyridine (13 mg, 0.11 mmol). Ethyl chloroformate (11 μL, 0.11 mmol) is added and the mixture is stirred at room temperature for 2 h. All volatiles are evaporated pi and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 46 mg; ESI mass spectrum [M+H]+=470; Retention time HPLC: 0.90 min (Z011_S03).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:25]([C:26]2[NH:27][CH:28]=[C:29]([CH3:31])[N:30]=2)=[CH:24][N:23]=[C:22]([NH:32][CH2:33][CH2:34][NH:35]C2N=CC(C#N)=CC=2)[N:21]=1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:35][CH2:34][CH2:33][NH:32][C:22]2[N:21]=[C:20]([C:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=3[Cl:12])[C:25]([C:26]3[NH:27][CH:28]=[C:29]([CH3:31])[N:30]=3)=[CH:24][N:23]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C#N)cn3)nc2-c2ccc(Cl)cc2Cl)n1
Product: Cc1c[nH]c(-c2cnc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc2-c2ccc(Cl)cc2Cl)n1

Procedure:
{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[4-(2,4-dichlorophenyl)-5-(4-methyl imidazol-2-yl)pyrimidin-2-yl]amine was prepared from 2-amino-6-chloro-3-nitropyridine using the general method for 6-[(2-{[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)-pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile.