Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([C:18]([O:20]C)=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][C:30]1[C:31]([C:38]2[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=2[Cl:45])=[N:32][O:33][C:34]=1[CH:35]([CH3:37])[CH3:36].[OH-].[Na+]>CN(C=O)C.CCOC(C)=O.O.C1COCC1.CCO>[Cl:44][C:43]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:45])[C:38]=1[C:31]1[C:30]([CH2:29][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:17]=[C:16]4[C:15](=[CH:10][CH:9]=3)[CH:14]=[C:13]([C:18]([OH:20])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)=[C:34]([CH:35]([CH3:37])[CH3:36])[O:33][N:32]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3cc(C(=O)O)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.4 %

Procedure:
To solution of methyl 6-(4-hydroxyphenyl)-2-naphthoate (55 mg, 0.20 mmol) in DMF (1.0 mL) was added K2CO3 (68 mg, 0.49 mmol) and 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-isopropylisoxazole (91 mg, 0.30 mmol) and the mixture was stirred at ambient temperature for 12 hr. Additional 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-isopropylisoxazole (50 mg, 0.16 mmol) and K2CO3 (68 mg, 0.49 mmol) in DMF (0.5 mL) was added and the mixture stirred at 70° C. for 3 hr. The solution was diluted with 50 mL EtOAc then washed with three 25 mL portions of H2O followed by 25 mL of brine then dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (12 g of silica gel eluting with 0-40% EtOAc in hexanes over 45 minutes.) Product fractions were pooled and concentrated. To this residue was added EtOH (2.5 mL), THF (1.0 mL), H2O (0.5 mL) and NaOH (35 mg, 0.84 mmol) and the solution was stirred at 60° C. for 12 hr. The solution was concentrated to ˜⅓ volume then added dropwise to 1.0 N HCl (6 mL, aq.) The resulting solids were collected by suction filtration, washed with H2O and dried to give the title compound as an off-white solid (42 mg, 94%.) 1H NMR (DMSO-d6): δ 13.0 (broad s, 1H), 8.57 (s, 1H), 8.18 (s, 1H), 8.12 (d, J=9 Hz, 1H), 8.01 (d, J=9 Hz, 1H), 7.95 (d, J=9 Hz, 1H), 7.85 (d, J=9 Hz, 1H), 7.69 (d, J=8 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 7.59-7.51 (m, 1H), 6.91 (d, J=8 Hz, 2H), 4.87 (s, 2 H), 3.45 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). ESI-LCMS m/z 532 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[O:16][C:17]([CH3:20])=[CH:18][N:19]=2)[CH:12]=[C:11]([O:21]C)[C:10]=1[C:23]1[N:28]=[N:27][C:26]([N:29]([CH3:40])[CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)=[CH:25][CH:24]=1)C1C=CC=CC=1.[H][H].Cl.CO>[Pd].C(Cl)Cl.C(OCC)C.C(OCC)(=O)C.CO>[CH3:1][O:8][C:9]1[C:10]([C:23]2[N:28]=[N:27][C:26]([N:29]([CH3:40])[CH:30]3[CH2:35][C:34]([CH3:36])([CH3:37])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]3)=[CH:25][CH:24]=2)=[C:11]([OH:21])[CH:12]=[C:13]([C:15]2[O:16][C:17]([CH3:20])=[CH:18][N:19]=2)[CH:14]=1
Reactant: [H][H]
Reactant: COc1cc(-c2ncc(C)o2)cc(OCc2ccccc2)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(-c2ncc(C)o2)cc(O)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a solution of 6-(2-(benzyloxy)-6-methoxy-4-(5-methyloxazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (36 mg, 0.066 mmol) in 1:1 ethyl acetate/MeOH (1.3 mL) under an atmosphere of nitrogen was added palladium on carbon (10% Pd content, 7 mg, 6.6 umol). The atmosphere was replaced by hydrogen (balloon) and the mixture stirred rapidly at RT overnight. The solution was diluted with DCM and filtered through celite. The filtrate was concentrated to a yellow residue and acidified with HCl in MeOH (produced by slow addition of acetyl chloride (14 uL, 0.199 mmol) to 1 mL MeOH). The solution was concentrated under vacuum, the residue redissolved into MeOH, and loaded onto an SCX column preconditioned with MeOH. The column was washed with MeOH (20 mL) and eluted with 3.5 N ammonia in MeOH (20 mL). Evaporation of the eluent afforded the product as a light yellow residue. Sonication with diethyl ether resulted in formation of a light yellow solid. Solvent was removed under reduced pressure to provide 3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol (22 mg). LCMS Rt=0.54 min (LCMS method Q); MS=352.3 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.22 (d, J=10.11 Hz, 1H), 7.18-7.29 (m, 3H), 6.96 (d, J=1.01 Hz, 1H), 5.07-5.20 (m, 1H), 3.98 (s, 3H), 3.03 (s, 3H), 2.46 (d, J=1.52 Hz, 3H), 1.73 (dd, J=12.5, 3.4 Hz, 2H), 1.62 (t, J=12.5 Hz, 2H), 1.42 (s, 6H), 1.26 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C@@H:5]([O:24][CH2:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([O:19]C(C)(C)C)=[O:18])([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH3:2].C(OC(=O)[C@@H](OC)CC1C=CC(OCC(O)=O)=CC=1)C>>[CH2:1]([O:3][C:4](=[O:27])[C@@H:5]([O:24][CH2:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=[O:18])([CH3:15])[CH3:16])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1)OCC
Agent: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Product: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC

Procedure:
The title compound was prepared from (2S)-3-[4-(1-tert-butoxycarbonyl-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 1) via the same procedure used to prepare (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) to produce a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]([O:24]CC)=[O:23])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1)=[O:10].[OH-].[Na+].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1)=[O:10]
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2nccc3ccccc23)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)c2nccc3ccccc23)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
Ethyl (3-bromo-4-((1-isoquinolinylcarbonyl)amino)phenyl)acetate (1.64 g, 3.97 mmol) was dissolved in THF (40 ml). To the resulting solution was added 0.25N NaOH (24.0 ml, 5.95 mmol), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into 1N HCl (50 ml) to acidify the mixture. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water, and dried under reduced pressure to give (3-bromo-4-((1-isoquinolinylcarbonyl)amino)phenyl)acetic acid (1.50 g, 98%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:37][C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40](Cl)=[O:41]>ClCCl>[F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][N:34]([C:40]([C:39]3[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=3[CH3:37])=[O:41])[CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[C:7]([CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Product: Cc1ccccc1C(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
80 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.026 ml 2-Methyl-benzoyl chloride (0.2 mmol). After 5 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 74 mg light yellow solid (73%). MS (ISP) 619.4 (M+H)+.
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)C=CC=CC=1.[F:17][C:18]1([F:34])[O:22][C:21]2[CH:23]=[CH:24][C:25]([CH2:27][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][C:20]=2[O:19]1.O>CS(C)=O>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][C:8]([N:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:25]3[CH:24]=[CH:23][C:21]4[O:22][C:18]([F:34])([F:17])[O:19][C:20]=4[CH:26]=3)[CH2:29][CH2:30]2)=[O:16])[CH:11]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: FC1(F)Oc2ccc(CN3CCNCC3)cc2O1
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cccnc1)N1CCN(Cc2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of pyridine-3-yl-carbamic acid phenyl ester (9.08 g, 42.4 mmol) in DMSO (84 mL) was added 1-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine (11.4 g, 44.5 mmol). The reaction mixture was stirred at room temperature for 16 h, then treated with water (130 mL). The resulting solid was isolated by filtration, rinsed with water (4×50 mL) and dried under vacuum. The solid was recrystallized (EtOH—H2O) to give 4-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine-1-carboxylic acid pyridin-3-ylamide (13.4 g, 84%). MS (ESI+): calcd for C18H18F2N4O3 m/z 376.13. found 377.1 (M+H)+. 1H NMR (CDCl3): 8.46 (d, J=2.5 Hz, 1H), 8.23-8.21 (m, 1H), 7.99-7.96 (m, 1H), 7.22-7.19 (m, 2H), 7.11 (s, 1H), 6.99-6.98 (m, 2H), 3.54-3.52 (m, 4H), 3.49 (s, 2H, 2.46-2.44 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.[NH4+].O[N:34]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH2:34])=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 0 °C
Yield: 90.2 %

Procedure:
To an ice-cooled and stirred mixture of (2-{7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (80 mg) in N,N-dimethylformamide (10 mL) were added 1-hydroxybenzotriazole ammonium salt (53 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (67 mg). After stirring at 4° C. to room temperature for 15 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated to give a pale yellow oil, which was crystallized from ethyl acetate-hexane to give the title compound (72 mg, 91%) as colorless crystals. MS 460 (MH+). mp 169-170° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([NH:16][NH:17][C:18]([C@H:20]3[C@H:25]([CH3:26])[CH2:24][CH2:23][N:22]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:21]3)=O)[N:15]=[C:10]2[CH:9]=[CH:8]1.C(N(CC)C(C)C)(C)C.C(P(CC)CC)C>>[CH2:30]([S:27]([N:22]1[CH2:23][CH2:24][C@@H:25]([CH3:26])[C@H:20]([C:18]2[N:15]3[C:14]([CH:13]=[N:12][C:11]4[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:33])([CH3:32])[CH3:1])[CH:8]=[CH:9][C:10]=43)=[N:16][N:17]=2)[CH2:21]1)(=[O:29])=[O:28])[CH3:31]
Reactant: CCS(=O)(=O)N1CC[C@@H](C)[C@H](C(=O)NNc2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Agent: CCP(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CC[C@@H](C)[C@H](c2nnc3cnc4c(ccn4COCC[Si](C)(C)C)n23)C1
Reaction time: 6 h
Yield: 38.9 %

Procedure:
(+/−)-Ethanesulfonyl-trans-4-methyl-piperidine-3-carboxylic acid N′-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-hydrazide (107 mg, 0.22 mmol) was cyclized to triazolo-tricyclic product using similar conditions to those described in example 17 above [however, after over-night stirring an extra 4 equivalents of N,N-diisopropylethylamine and an extra 3 equivalents of triethylphosphine were added and the mixture was stirred an extra 6 hours before work up]. The crude product was purified by preparative TLC, eluting with 90% ethyl acetate in hexanes. The impure product was collected and purified again by preparative TLC eluting first with 3.75% methanol in methylene chloride and then a second time with 5% methanol in methylene chloride. The product band was collected to afford 41 mg of (+/−)-1-(1-ethanesulfonyl-trans-4-methyl-piperidin-3-yl)-6-(2-trimethylsilanyl-ethoxymethyl)-6H-2,3,5,6,8b-pentaaza-as-indacene as a light yellow-white powder. MS (M+H)+=479.
Reaction SMILES: O.[CH2:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][C:11](=[CH:14][CH3:15])[C:12]#[N:13].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:10][C:11]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([CH:14]=[CH2:15])[C:12]#[N:13]
Reactant: CC=C(C)C#N
Reactant: ClCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC(C)(C#N)Cc1ccccc1

Procedure:
Into a 500 ml 4-neck flask, equipped with a stirrer, reflux cooler, dropping funnel and water separator, 126.5 g (1 mole) of benzylchloride, 81 g (1 mole) of 2-methyl-2-butene-nitrile, 100 ml of toluene, and 10 g of tetrabutylammonium bromide were first introduced and heated to reflux. To this mixture, 40 g (1 mole) of solid sodium hyroxide were added in portions. The reaction mixture was then maintained one more hour at reflux. Thereupon, it was washed to neutrality with water, the phases were separated and the organic phase distilled as described in Example 1. The yield in desired product was 103.5 g, corresponding to 61% of the theoretical.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([O:8][C:9]2[CH:10]=[N:11][C:12]([O:15]CC3C=CC=CC=3)=[CH:13][CH:14]=2)[CH2:7][CH2:6]1)=[O:4]>C(O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1([O:8][C:9]2[CH:10]=[N:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(Oc2ccc(OCc3ccccc3)nc2)CC1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1(Oc2ccc(O)nc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 0.39 g (1.3 mmol) 1-(6-benzyloxy-pyridin-3-yloxy)-cyclopropanecarboxylic acid methyl ester in 4 mL ethanol, 39 mg 10% palladium on charcoal was added. The suspension was hydrogenated at 1.5 bar for 1 h. The catalyst was filtered off over Dicalite Speed Plus, washed with ethanol and the filtrate evaporated to dryness to the desired compound as a light brown solid (97%). MS (Turbo Spray): m/z=210.1 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]([CH2:8][Cl:9])=[O:7])[CH3:2]>C(O)C>[Cl:9][CH2:8][C@@H:6]([OH:7])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:10]
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)C[C@H](O)CCl
Reaction time: 0.08 h
Yield: 98 %

Procedure:
A 600 ml stainless steel Parr reactor was charged with ethanol (340 ml) and ethyl-4-chloroacetoacetate (53 g). The reactor agitator was started and the speed set to 600 rpm. The reactor was pressurised using nitrogen to 7 bar and stirring continued for 5 minutes. After 5 minutes the reactor was slowly vented to ambient pressure, the pressurisation/depressurisation cycle was repeated for a total of five times to ensure complete removal of dissolved oxygen. At the end of the last cycle the reactor set-point temperature was adjusted to 95° C. (R)-[RuCl2(BINAP)]n catalyst was accurately weighed (23 mg) into a catalyst transfer vessel and the vessel then purged using nitrogen for 5 minutes. The catalyst was flushed from the transfer vessel using deoxygenated solvent into a 100 ml stainless steel injection bomb which was attached to the Parr reactor. When the Parr reactor temperature was between 95° C. and 100° C. the injection bomb was pressurised to 100 bar using hydrogen. Appropriate valves were then opened to transfer the catalyst mixture and hydrogen into the reactor. The contents of the reactor were stirred at 600 rpm for 30 minutes before being cooled to less than 30° C. The reactor was then slowly vented to ambient pressure. The reactor contents were transferred into a 1 L rotary film evaporator flask and the mixture evaporated to constant weight by application of vacuum and by using a heated water bath. The residue was subjected to pot to pot distillation under vacuum to afford a clear colourless oily liquid product of ethyl (S)-(−)-4-chloro-3-hydroxybutyrate in >98% yield, >98% purity and 94% enantiomeric excess.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[H][H]>[C].[Pd].C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C/c1ccc2c(c1)CCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc2c(c1)CCO2
Yield: 99.4 %

Procedure:
5% Palladium-carbon (1 g, containing 50% water) was added to an ethanol (150 ml) solution of ethyl (E)-3-(2.3-dihydrobenzofuran-5-yl)-2-propenoate (14.7 g, 66.7 mmols), and the mixture was stirred in a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 14.6 g (yield: 99%) of the target compound. This was oily.
Reaction SMILES: [N:1]1[C:2](=[O:10])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[OH:11][C:12]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O>N1CCCCC1.C(O)C>[OH:11][C:12]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=1[CH:14]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1C=c2ccccc2=N1
Reactant: O=Cc1ccc(O)cc1O
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2C1=Cc1ccc(O)cc1O
Temperature: 25 °C

Procedure:
A mixture of 1.33 g of indole-2-one (10 mmol), 1.38 g of 2,4-dihydroxybenzaldehyde (10 mmol) and 3 drops of piperidine are refluxed in 40 ml of ethanol for 5 hours. The desired product precipitates as a yellow solid during the reaction. After cooling to room temperature, the product is filtered off, washed with ethanol and dried in vacuo. Yield 1.28 g (51%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]([Cl:23])([Cl:22])[CH:8](Cl)[CH:9]([N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>O1CCCC1>[Cl:6][C:7]([Cl:23])([Cl:22])[CH:8]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:9]([N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CCNCC
Reactant: CC(C)(C)C(=O)C(C(Cl)C(Cl)(Cl)Cl)n1cncn1
Solvent: C1CCOC1
Product: CCN(CC)C(C(C(=O)C(C)(C)C)n1cncn1)C(Cl)(Cl)Cl
Reaction time: 3 h

Procedure:
14.6 g (0.2 mol) of diethylamine were slowly added dropwise to 33.4 g (0.1 mol) of 1,1,1,2-tetrachloro-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one (Example 3) in 150 ml of tetrahydrofuran at room temperature. The mixture was then subsequently stirred at 50°-60° C. for 3 hours. The diethylamine hydrochloride which had precipitated was filtered off and the filtrate was concentrated in vacuo. According to thin layer chromatography of the residue over silica gel 60 (Merck, particle size 0.063-0.200 mm) and with ether/hexane in the ratio 1:1 as the running agent, 1,1,1-trichloro-2-diethylamino-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one was obtained as the pure diastereomer of the A* form, as a yellow oil, in a yield of 8.9 g (24.1% of theory), and as the pure diastereomer of the B* form, of melting point 103°-110° C., in a yield of 6.4 g (19.4% of theory).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[O-:12][CH2:13][CH3:14].[Na+]>C(O)C>[CH2:13]([O:12][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1)[CH3:14]
Reactant: CC[O-]
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc([N+](=O)[O-])c(C)n1
Temperature: 25 °C

Procedure:
To a stirred solution of 6-chloro-2-methyl-3-nitropyridine (2.15 g) in ethanol (25 mL) was added sodium ethoxide (4.88 mL) solution at room temperature. The reaction mixture immediately turned dark purple and was refluxed for 2 hours. The reaction mixture was allowed to cool down to room temperature, concentrated in vacuo, and poured into ice. The precipitated solids were collected by filtration to provide the title compound (1.88 g) having the following physical data.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][C:18]3[O:19][C:20]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:21]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[N:22]=3)=[CH:15][CH:14]=2)[N:10]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][C:18]3[O:19][C:20]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[N:22]=3)=[CH:35][CH:36]=2)[N:10]=1
Reactant: COC(=O)CCc1nc(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)oc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(Cc2nc(CCC(=O)O)c(-c3ccccc3)o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A mixture of methyl 3-[2-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-5-phenyl-4-oxazolyl]propionate (489 mg), lithium hydroxide hydrate (127 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3.1 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-[2-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-5-phenyl-4-oxazolyl]propionic acid (448 mg, yield 94%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 154–155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH:5]=[N:6][OH:7].[ClH:12].OOS([O-])=O.[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([Cl:12])=[N:6][OH:7])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: ON=Cc1cc(Cl)cc(Cl)c1
Reactant: Cl
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: ON=C(Cl)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
30.00 g (157.9 mmol) of 3,5-dichlorobenzaldehyde oxime were initially charged in ml of 0.5M HCl in DMF, and 116.7 g (189.5 mmol) of Oxone (potassium peroxomonosulfate) were added a little at a time at room temperature (RT). So that the internal temperature of the reaction mixture did not exceed 50° C., the mixture was cooled with an ice bath. After 2 h, the reaction solution was poured into 1 l of ice water and extracted twice with 500 ml of ether each time. The combined organic phases were then washed with 400 ml of 0.5M aqueous HCl and with 200 ml of saturated NaCl solution, dried over Na2SO4, filtered off and concentrated. The residue was used without further purification. Yield: 28.40 g (80%)