Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][CH:5]([C:7]([O:9][C@@H:10]2[CH2:15][C@H:14]([CH3:16])[CH2:13][CH2:12][C@H:11]2[CH:17]([CH3:19])[CH3:18])=[O:8])[CH2:4][O:3]1>C(O)C>[OH:6][CH:5]([CH2:4][OH:3])[C:7]([O:9][C@@H:10]1[CH2:15][C@H:14]([CH3:16])[CH2:13][CH2:12][C@H:11]1[CH:17]([CH3:18])[CH3:19])=[O:8]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)C1COC(C)(C)O1
Solvent: CCO
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)C(O)CO

Procedure:
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2,2-dimethyl-1,3-dioxolane-4-carboxylate (1.00 g, 35.2 mmol) was dissolved in 98% aqueous ethanol (10 ml). Amberlyst 15 (wet) ion exchange resin (0.30 g) and bumping granulate were added. The reaction mixture was refluxed for 4 h without stirring (under argon). After that, the reaction was brought to room temperature, the resin and bumping granulate were removed and the solvent was removed under reduced pressure. The product was obtained in quantitative yield (0.94 g)
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[CH2:10]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:11]#[CH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1.O>[O:16]1[CH2:17][CH2:18][N:13]([CH2:10][C:11]2[O:8][N:7]=[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:12]=2)[CH2:14][CH2:15]1
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1cc(CN2CCOCC2)on1

Procedure:
To the solution of ethyl chlorooximidoacetate (0.588 g, 3.88 mmol) and 4-(prop-2-ynyl)morpholine (0.971 g, 7.76 mmol) in toluene (5 mL) was added solution of triethylamine (0.54 mL, 3.88 mmol) in toluene (5 mL) dropwise. The resultant mixture was stirred at RT for 5 h. After the completion of the reaction as evidenced by LC-MS, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic solvent was then dried over anhydrous sodium sulfate and evaporated. The crude product was purified by Combiflash (Heptane:EtOAc eluent). Yield 0.2 g. 1H NMR (400 MHz; MeOD): δ 1.38 (t, 3H), 2.53 (m, 4H), 3.69 (m, 4H), 3.78 (d, 2H), 4.41 (q, 2H), 6.73 (m, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]12[CH2:15][CH:14]1[C:13](=[O:16])[N:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[O:26][CH3:27])[CH2:11]2)(C(C)(C)C)(C)C.[F-].C([NH3+])CCC>O1CCCC1>[CH3:27][O:26][C:19]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=1[CH2:17][N:12]1[CH2:11][C:10]2([CH2:9][OH:8])[CH:14]([CH2:15]2)[C:13]1=[O:16]
Reactant: COc1ccc(CN2CC3(CO[Si](C)(C)C(C)(C)C)CC3C2=O)c(OC)c1
Agent: CCCC[NH3+]
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CN2CC3(CO)CC3C2=O)c(OC)c1
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a solution of 5-(tert-butyldimethylsilanyloxymethyl)-3-(2,4-dimethoxybenzyl)-3-azabicyclo[3.1.0]hexan-2-one (14.2 mg) in tetrahydrofuran (0.3 ml) was added n-butylammonium fluoride (54 μl, 1.0M solution in tetrahydrofuran) at room temperature, and the mixture was stirred for 1 hour. This reaction mixture was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate, to chloroform/methanol=9/1) to give the titled compound (9.2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2([C:18]([O:20]C)=[O:19])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]2)=[CH:4][CH:3]=1.[OH-].[Na+:23].C1(C)C=CC=CC=1.CCCCCCC>CO.O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2([C:18]([O-:20])=[O:19])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]2)=[CH:6][CH:7]=1.[Na+:23]
Reactant: COC(=O)C1(CCCCc2ccc(Cl)cc2)CC=CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1COCCO1
Product: O=C([O-])C1(CCCCc2ccc(Cl)cc2)CC=CCC1

Procedure:
22.7 g of methyl 1-[4-(4-chlorophenyl)butyl]cyclohex-3-ene-1-carboxylate 70B are dissolved in 100ml of methanol +100 ml of dioxane. To this is added a solution of 8 g of sodium hydroxide in 50 ml of water, and the mixture is refluxed under protective gas for 16 h. The reaction solution is cooled and 200 ml of water, 100 ml of toluene and 100 ml of n-heptane are added, and the mixture is stirred thoroughly. The precipitated product is filtered off with suction, washed with a little cold water and n-heptane/toluene (1:1 vol/vol) and dried in vacuo. 70C of the formula ##STR34## is obtained as colorless shining flakes which do not melt up to 240° C. The free acid obtained from the sodium salt 70C by acidification with concentrated hydrochloric acid melts at 86°-7° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:17]1[CH2:23][C:22]3([CH3:25])[CH2:24][CH:18]1[CH2:19][C:20]([CH3:27])([CH3:26])[CH2:21]3)=[O:16])=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[CH3:25][C:22]12[CH2:24][CH:18]([N:17]([C:15]([C:11]3[CH:12]=[C:13]4[C:8](=[CH:9][CH:10]=3)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]4)=[O:16])[CH2:23]1)[CH2:19][C:20]([CH3:27])([CH3:26])[CH2:21]2
Reactant: CCOC(=O)c1cc2cc(C(=O)N3CC4(C)CC3CC(C)(C)C4)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)C1
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of 5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-1H-indole-2-carboxylic acid ethyl ester (500 mg, 1.35 mmol) in ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10 mL), and the resulting solution stirred for 16 h. The solution was acidified with 1N hydrochloric acid solution before the organic volatiles were removed in vacuo and the aqueous residues were extracted with DCM (3×5 mL). The combined organic phases were dried (MgSO4), filtered and evaporated in vacuo. The resulting solid was dried in vacuo at 50° C. affording 460 mg (100%) of the title compound as a solid. MS-ESI m/z 341; 1H NMR (300 MHz, DMSO-d6) δ 0.88-0.99 (m, 6H), 1.07 (d, 3H), 1.16-1.19 (m, 1H), 1.27-1.50 (m, 4H), 1.74-1.77 (m, 1H), 3.10-3.19 (m, 1H), 3.40-3.48 (m, 1H), 3.99-4.07 (m) and 4.38-4.40 (m, 1H), 7.16 (s, 1H), 7.32-7.37 (m, 1H), 7.42-7.48 (m, 1H), 7.77 (d, 1H), 11.93 (s, 1H), 13.04 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:13][C@@H:12]([CH2:14][OH:15])[C@H:11]([OH:16])[C@@H:10]2[OH:17])[C:5]([N:18]=[N:19]C2C=CC(Cl)=CC=2)=[C:4]([Cl:27])[N:3]=1.[Cl:28][C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1N>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:13][C@@H:12]([CH2:14][OH:15])[C@H:11]([OH:16])[C@@H:10]2[OH:17])[C:5]([N:18]=[N:19][C:30]2[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=2[Cl:28])=[C:4]([Cl:27])[N:3]=1
Reactant: Nc1ccccc1Cl
Reactant: Nc1nc(Cl)c(N=Nc2ccc(Cl)cc2)c(N[C@H]2C[C@@H](CO)[C@H](O)[C@@H]2O)n1
Product: Nc1nc(Cl)c(N=Nc2ccccc2Cl)c(N[C@H]2C[C@@H](CO)[C@H](O)[C@@H]2O)n1

Procedure:
Compound 9, (1S,2R,3S,5S)-3-[[2-amino-6-chloro-5-[(2-chlorophenyl)azo]-4-pyrimidinyl]amino]-5-(hydroxymethyl)-1,2-cyclopentanediol was prepared by the same method used for Compound 11, using a stoichiometric amount of 2-chloroaniline instead of 4-chloroaniline.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][C:7]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5]1)[CH3:3].[OH-].[K+].Cl.[OH-].[Na+]>O.C(O)CO>[CH3:3][CH:2]([N:4]1[CH2:9][CH2:8][C:7]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)[CH3:1]
Reactant: CCOC(=O)C1(Nc2ccccc2)CCN(C(C)C)CC1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: CC(C)N1CCC(Nc2ccccc2)(C(=O)O)CC1
Yield: 68.5 %

Procedure:
A mixture of 43.6 parts of ethyl 1-(1-methylethyl)-4-(phenylamino)-4-piperidinecarboxylate, 25.5 parts of potassium hydroxide and 137.5 parts of 1,2-ethanediol is stirred and refluxed for 3 hours. The reaction mixture is cooled, poured onto 250 parts of water and acidified with a concentrated hydrochloric acid solution. The whole is alkalized and saturated with sodium hydroxide solution 50%. The precipitated product is filtered off and dissolved in 300 parts of water while heating. The solution is neutralized with acetic acid. The precipitated product is filtered off, washed with distilled water and suspended in 80 parts of 2-propanol. The product is filtered off and dried, yielding 27 parts (68.5%) of 1-(1-methylethyl)-4-(phenylamino)-4-piperidinecarboxylic acid; mp. 200° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.Cl.[CH2:26]([O:28][C:29](=[O:37])[CH2:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:27].C(N(CC)CC)C>CO>[CH2:26]([O:28][C:29](=[O:37])[CH2:30][CH:31]1[CH2:36][CH2:35][N:34]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:13]([O:23][CH3:24])[CH:12]=3)[N:3]=2)[CH2:33][CH2:32]1)[CH3:27]
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: CCOC(=O)CC1CCNCC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1CCN(c2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc(OC)n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (100 mg, 0.29 mmol) and ethyl-2-(piperidin-4-yl)acetate hydrochloride (63 mg, 0.30 mmol) in 3 ml of methanol was treated with triethylamine (0.13 ml, 0.92 mmol). The mixture was stirred for 3 hours at room temperature, concentrated and the product purified by chromatography on silica gel using ethyl acetate as an eluent. The title compound was isolated as a colorless solid (137 mg, 99%).
Reaction SMILES: C(OC(=O)[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25](O)[C:26]2[C:34]3[C:29](=[N:30][CH:31]=[C:32]([O:35][Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])[CH:33]=3)[NH:28][CH:27]=2)=[CH:21][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[F:17][C:15]([F:16])([F:18])[C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]3[C:34]4[C:29](=[N:30][CH:31]=[C:32]([O:35][Si:36]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:38])[CH3:39])[CH:43]([CH3:44])[CH3:45])[CH:33]=4)[NH:28][CH:27]=3)=[CH:21][N:20]=2)=[CH:10][CH:11]=1
Reactant: CC(C)[Si](Oc1cnc2[nH]cc(C(O)c3ccc(N(Cc4ccc(C(F)(F)F)cc4)C(=O)OC(C)(C)C)nc3)c2c1)(C(C)C)C(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)[Si](Oc1cnc2[nH]cc(Cc3ccc(NCc4ccc(C(F)(F)F)cc4)nc3)c2c1)(C(C)C)C(C)C
Temperature: 0 °C
Yield: 103 %

Procedure:
A mixture of {5-[hydroxy-(5-triisopropylsilanyloxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (84, 0.05 g, 0.07 mmol), trifluoroacetic acid (0.5 mL, 0.006 mol), and triethylsilane (1 mL, 0.006 mol) in acetonitrile (10 mL) was refluxed for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with saturated sodium bicarbonate, brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a viscous liquid (85, 0.04 g, 97%). MS (ESI) [M+H+]+=555.38.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5](CCCCCCCCC2C=CC(N)=CC=2)[C:6]2[C:11]([C:12]=1OC)=[CH:10][CH:9]=[CH:8][CH:7]=2.CCN(CC)CC.Cl[C:38]1[C:39]2[C:44]([N:45]=[C:46]3[C:51]=1[CH:50]=[CH:49][CH:48]=[CH:47]3)=[CH:43][CH:42]=[CH:41][CH:40]=2>CO>[C:10]1([C:40]2[C:39]3[C:44](=[N:45][C:46]4[C:51]([CH:38]=3)=[CH:50][CH:49]=[CH:48][CH:47]=4)[CH:43]=[CH:42][CH:41]=2)[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][CH:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Clc1c2ccccc2nc2ccccc12
Reactant: COc1cc(CCCCCCCCc2ccc(N)cc2)c2ccccc2c1OC
Solvent: CO
Solvent: CCN(CC)CC
Product: c1ccc2nc3cccc(-c4cccc5ccccc45)c3cc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 153 %

Procedure:
To a solution of 99 mg (2.53×10−4 mol) of 1-(3,4-dimethoxy-1-naphthyl)-8-(4-aminophenyl)-octane 537 and 35 mL (2.51×10−4 mol) of Et3N in 4 mL of MeOH were added 54 mg (2.53×10−4 mol) of 9-chloroacridine. The reaction mixture was stirred at room temperature for 20 hr. Evaporation of solvent and column chromatography on silica gel with first 1% MeOH in CH2Cl2 and then 3% MeOH in CH2Cl2 afforded 118.2 mg (82%) of acridine 538: 1H NMR (250 MHz, CDCl3, TMS) δ 8.14 (d, J=8 Hz, 1H), 8.0-7.9 (m, 5H), 7.66 (br t, 2H), 7.46 (t, J=8 Hz, 1H), 7.37 (t, J=8 Hz, 1H), 7.3-7.2 (m, 2H), 7.12 (s, 1H), 7.06 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 3.1-3.0 (m, 2H), 2.6-2.5 (m, 2H), 1.8-1.3 (m, 12H).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[CH2:24][CH2:23]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:18][P:16]([CH3:19])([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:31][C:30]4[CH:32]=[CH:33][CH:34]=[C:28]([N:25]5[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]5)[CH:29]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)=[O:17]
Reactant: CP(C)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(P(C)(C)=O)cc5)cccn4n3)c2)CC1

Procedure:
198 a) 8-(4-Bromo-phenyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (1.0 g, 4.5 mmol) and 4-bromobenzeneboronic acid (1.0 g, 5.0 mmol) in a manner analogous to Example 2c. Product isolated as an off-white solid (1.0 g, 72%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.5 Hz, 1H), 7.88 (d, J=7.1 Hz, 2H), 7.70 (d, J=7.0 Hz, 1H), 7.65 (d, J=7.1 Hz, 2H), 7.16 (t, J=7.5 Hz, 1H). MS=310, 312 (MH)+. 198 b) To an oven dried tube was added 8-(4-bromo-phenyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.90 g, 2.9 mmol), methylphosphinoylmethane (0.24 g, 3.1 mmol)(prepared as described in WO2005/009348), palladium acetate (13.5 mg, 0.0601 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (36.0 mg, 0.0622 mmol), cesium carbonate (1422.0 mg, 4.3644 mmol) and 1,4-dioxane (9 mL). The tube was evacuated, carefully, and backflushed with nitrogen. The tube was sealed and heated at 90° C. for 24 hours then cooled to room temperature, diluted with dichloromethane (30 mL), filtered through a plug of diatomaceous earth and evaporated. The residue was purified via chromatography using an ISCO automated purification apparatus (silica gel column 40 g and 0%→7% dichloromethane:methanol). 2-Chloro-8-[4-(dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine was isolated as a white solid (0.303 g, 34%). MP=220-223° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.55 (d, J=6.9 Hz, 1H), 8.11 (d, J=7.7 Hz, 2H), 7.94-7.86 (m, 2H), 7.77 (t, J=7.4 Hz, 1H), 7.21 (t, J=6.9 Hz, 1H), 1.80 (s, 3H), 1.77 (s, 3H). MS=306, 308 (MH)+. 198 c) {8-[4-(Dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 2-chloro-8-[4-(dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3271 mmol) and 3-(4-methylpiperazin-1-yl)aniline (70.0 mg, 0.366 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (28.0 mg, 0.0512 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan solid (0.097 g, 64%). MP=243-246° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (d, J=6.2 Hz, 1H), 8.15 (d, J=8.0 Hz, 2H), 7.92-7.84 (m, 2H), 7.63-7.50 (m, 1H), 7.34 (s, 1H), 7.23 (t, J=8.2 Hz, 1H), 7.02-6.96 (m, 2H), 6.84 (s, 1H), 6.59 (d, J=7.8 Hz, 1H), 3.30-3.25 (m, 4H), 2.63-2.58 (m, 4H), 2.37 (s, 3H), 1.80 (s, 3H), 1.77 (s, 3H). MS=461 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][N:9]2[C:13]([CH:14]=[CH:15][C:16](OCC)=[O:17])=[C:12]([Cl:21])[N:11]=[C:10]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].C([Al+]C(C)C)(C)C>C1COCC1.CCOCC>[N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][N:9]2[C:13]([CH2:14][CH:15]=[CH:16][OH:17])=[C:12]([Cl:21])[N:11]=[C:10]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCc1nc(Cl)c(C=CC(=O)OCC)n1Cc1ccc([N+](=O)[O-])cc1
Agent: CC(C)[Al+]C(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCc1nc(Cl)c(CC=CO)n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.5 g of 3-[1-(4-nitrobenzyl)-2-butyl-4-chloroimidazol-5-yl]propenoic acid, ethyl ester, E isomer in 20 mL of THF was cooled with an ice bath, 1.7 mL of 1.5M diisopropylaluminum hydride (in toluene) was added slowly. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then quenched with 3 mL of conc. NH4Cl solution and the mixture was stirred for an additional 30 minutes. During this period an extensive gel-like material formed. The reaction mixture was further diluted with ether and filtered through celite. The filtrate was concentrated and the crude product was purified by flash column chromatography on silica gel (Hexane: EtOAc=1:1 elution). The desired compound was obtained as a thick liquid; NMR (200 MHz, CDCl3): δ 6.5-6.15 (m, 2H); 5.21 (s, 2H); 4.25 (d, 2H, J=4.5 Hz); 2.35 (t, 3H, J=7.4 Hz); 1.68 (m, 2H); 1.34 (m, 2H); 0.86 (t, 3H, J=7.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:10][C:9]2[N:8]=[C:7]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:6]3=[C:5]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:4]=2[C:3]=1[C:21]#[N:22].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:21]([C:3]1[C:4]2[C:5]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[C:6]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:7]3=[N:8][C:9]=2[S:10][C:2]=1[NH:1][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=1)#[N:22]
Reactant: N#Cc1c(N)sc2nc3c(c(-c4cccs4)c12)CCCCC3
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: N#Cc1c(NC(=O)c2cccc(C(F)(F)F)c2)sc2nc3c(c(-c4cccs4)c12)CCCCC3
Yield: 26 %

Procedure:
A mixture of 2-amino-4-thiophen-2-yl-6,7,8,9-tetrahydro-5H-1-thia-10-aza-cyclohepta[f]indene-3-carbonitrile, prepared using the chemistry described in Example 1G (100 mg, 0.31 mmol), 3-trifluoromethyl-benzoyl chloride (77 mg, 0.37 mmol) and a catalytic amount of DMAP in pyridine (20 mL) was heated under reflux for one day. After concentration, the residue was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give N-(3-cyano-4-thiophen-2-yl-6,7,8,9-tetrahydro-5H-1-thia-10-aza-cyclohepta[f]inden-2-yl)-3-trifluoromethyl-benzamide (40 mg, 26%).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][N:7]([CH3:25])[C:8]1[CH:13]=[N:12][N:11]([CH:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)[C:10](=[O:24])[CH:9]=1.CN([CH:29]=[O:30])C>>[CH3:25][N:7]([CH3:6])[C:8]1[CH:13]=[N:12][N:11]([CH:14]2[CH2:19][C:18]([CH3:20])([CH3:21])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)[C:10](=[O:24])[C:9]=1[CH:29]=[O:30]
Reactant: CN(C)c1cnn(C2CC(C)(C)CC(C)(C)C2)c(=O)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1cnn(C2CC(C)(C)CC(C)(C)C2)c(=O)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
POCl3 (0.9 mL, 9.75 mmol) was slowly added to precooled (0° C.), anhydrous DMF (5 mL). After stirring at room temperature for 30 min, a solution of 5-dimethylamino-2-(3,3,5,5-tetramethyl-cyclohexyl)-2H-pyridazin-3-one (749 mg, 2.70 mmol) in anhydrous DMF (6 mL) was added and the mixture was stirred at 70° C. for 1.5 h. After cooling, the mixture was poured over saturated NaHCO3/ice. The aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were dried (Na2SO4), filtered and evaporated in vacuo to provide 5-dimethylamino-3-oxo-2-(3,3,5,5-tetramethyl-cyclohexyl)-2,3-dihydro-pyridazine-4-carbaldehyde (1.19 g, 100%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 10.33 (1H, s), 7.80 (1H, s), 5.27 (1H, app tt, J=3.7, 11.7 Hz), 3.13 (6H, s), 1.63-1.44 (4H, m), 1.30 (2H, app t, J=11.0 Hz), 1.16 (6H, s), 0.98 (6H, s).
Reaction SMILES: C(OC=CC[S:8]C)(=O)C.CO.[C]=O.[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=O)(=[O:16])[CH3:15]>C1C=CC=CC=1.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.C1(C)C=CC=CC=1>[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=[S:8])(=[O:16])[CH3:15]
Reactant: CSCC=COC(C)=O
Reactant: COC(=O)C(CCSC)OC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Solvent: Cc1ccccc1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=S)C(CCSC)OC(C)=O
Temperature: 100 °C
Yield: 10 %

Procedure:
0.5 mmoles 1-acetoxy-3-methylthiopropene, (Z:E ratio 43:57) and 2.5 mmoles methanol were charged into a 71 cc stainless steel. bomb equipped with a glass liner and a Teflon coated stir bar. Ten mole percent, based on 1-acetoxy-3methythiopropene, of a catalyst comprising bis(triphenylphosphine)dichloropalladium, (φ3P)2PdCl2, was added. Toluene was included as an internal standard. Five milliliters of benzene as a solvent were also included in the reaction system. The reaction mixture was charged under argon. The bomb was sealed and carbon monoxide at a pressure of 1000 psi (at room temperature) was charged to the bomb, and the bomb was heated to 100° C. and allowed to react for 44 hours with stirring. At the termination of the reaction, the reaction products were analyzed by gas chromatography and it was found that 2-acetoxy-4-(methylthio)butanoic acid, methyl ester was produced in a yield of 22 percent, and that 2-acetoxy-4-(methylthio)thiobutanoic acid, methyl ester was produced in a yield of 10 percent, based on the 1-acetoxy-3-methylthiopropene reactant charged. Each of the products is hydrolyzable to methionine hydroxy analog.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[OH:5])[CH2:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[CH:1]1([C:4]([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: OC(c1nccs1)C1CC1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=C(c1nccs1)C1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.4 %

Procedure:
A mixture of cyclopropyl(thiazol-2-yl)methanol (327 mg, 2.1 mmol) and MnO2 (1.0 g, 11 mmol) in DCM (10 mL) was stirred at rt for 2 days. The mixture was diluted with DCM, filtered through a cake of Celite and the filtrate was concentrated to give the title compound as a colourless oil (278 mg, 86%). The product used without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 7.93 (d, J=3.0 Hz, 1H), 7.61 (d, J=3.0 Hz, 1H), 3.05-3.22 (m, 1H), 1.16-1.30 (m, 2H), 0.98-1.11 (m, 2H); MS ESI 154.0 [M+M]+, calcd for [C7H7NOS+H]+ 154.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]([CH:19]=[C:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:32]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:9]2[C:18]([CH:19]=[C:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[O:32])=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2cc3ccccc3nc2Sc2ccc(Cl)cc2)S1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: O=C1NC(=O)C(=Cc2cc3ccccc3nc2S(=O)c2ccc(Cl)cc2)S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
The compound prepared in Example 224 was dissolved in CH2Cl2/CH3OH (5:1), and to this solution was added 3-chloroperoxybenzoic acid (2 eq. of 77% max. purity). The mixture was stirring at RT for 4 hrs before TLC analysis showed the disappearance of the starting compound. The reaction mixture was stirring for an additionally 2 hrs. At the end of the reaction, white crystalline product precipitated. The product was collected by filteration, washed several times with ether, and air dried for 48 hrs to provide the final product with a yield of 30%.