Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=1.[C:7]1([CH2:13]C(O)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>OS(O)(=O)=O.O.[N+]([O-])([O-])=O.[Ag+]>[CH2:13]([C:5]1[CH:4]=[CH:3][N:2]=[N:1][CH:6]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccnnc1
Reactant: O=C(O)Cc1ccccc1
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: c1ccc(Cc2ccnnc2)cc1
Temperature: 80 °C
Yield: 21.4 %

Procedure:
A solution of pyridazine (2.2 g, 27.5 mmol) and 2-phenylacetic acid (18.7 g, 137.5 mmol), AgNO3 (1.4 g, 8.25 mmol) in 2N H2SO4 (27.7 ml) was heated to 60-70° C. under stirring, then, a solution of (NH4)2S2O8 (18.6 g, 82.5 mmol) in 80 ml of water was added within 20 minutes, After heating to 70-90° C. for 1.5 hour, the reaction solution was cooled to room temperature and extracted with DCM (2×100 ml), the combined organic layers were washed with 2NH. SO4 (3×70 ml), then, the combined aqueous layer was made alkaline with 50% NaOH and extracted with DCM (3×80 ml), dried over Na2SO4 and concentrated to get the crude product, which was purified by column chromatography on silica gel (petroleum Ether: EtOAc=2:1) to afford 4-benzylpyridazine (1.0 g, yield: 22%). 1H NMR (CDCl3 400 MHz): δ9.09 (s, 1H), 9.06 (d, J=5.2 Hz, 1H), 7.40-7.28 (m, 3H), 7.25-7.20 (m, 1H), 7.18 (d, J=7.2 Hz, 2H), 4.0 (s, 2H).
Reaction SMILES: [Li][CH2:2]CCC.[Si:6]([O:13][CH:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].CI>C1COCC1>[Si:6]([O:13][CH:14]1[CH2:15][CH2:16][C:17]([CH3:2])([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:19]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:7])[CH3:8]
Reactant: [Li]CCCC
Reactant: COC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of anhydrous DIPA (26.7 g, 263.86 mmol, 3.00 equiv) in freshly distilled THF (500 mL) was added n-BuLi (2.5 M in hexane, 110 mL) dropwise with stirring at −78° C. under nitrogen. After the addition, the resulting solution was stirred for 0.5 h at −78° C. To this was added dropwise a solution of methyl 4-[(tert-butyldimethylsilyl)oxy]cyclohexane-1-carboxylate (24 g, 88.09 mmol, 1.00 equiv) in 50 mL of THF and the resulting solution was allowed to react for an additional 1 h at −78° C. To the mixture was added CH3I (62.64 g, 441.31 mmol, 5.01 equiv) dropwise with stirring at this low temperature. Stirring was continued for 1 h. The reaction was quenched with water and extracted with 3×150 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10) to provide the desired methyl 4-[(tert-butyldimethylsilyl)oxy]-1-methylcyclohexane-1-carboxylate (22.0 g, 87%) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl.[N:30]1([CH2:37][CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:43]([C:44](O)=O)=[CH:42][N:41]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[N:30]1([CH2:37][CH2:38][O:39][C:40]2[N:41]=[CH:42][C:43]([CH2:44][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:47][CH:48]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)nc1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)nc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 41.4 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and 6-(2-azepan-1-ylethoxy)nicotinic acid hydrochloride (120 mg) according to an analogous synthetic method to Example 337 described below, the title compound (23 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])=[CH:22][CH:21]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccc(F)cc1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3ccc(F)cc3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(4-fluoro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH2:17]([NH:19][C:20]([O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])=[O:21])[CH3:18]>>[CH2:17]([NH:19][C:20]([O:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)[CH:27]=[CH:28][CH:29]=1)=[O:21])[CH3:18]
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: CCNC(=O)Oc1cccc(N)c1
Product: CCNC(=O)Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3-[(N-ethylamino)carbonyloxy]aniline were reacted to provide N2-[3-[(N-ethylamino)carbonyloxy]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.92 (d, 1H, J=3.0 Hz), 7.67-7.55 (m, 2H), 7.24 (t, 1H, J=7.5 Hz), 7.16 (t, 1H, J=7.5 Hz), 7.07-6.98 (m, 2H), 6.84-6.79 (m, 2H), 6.67 (m, 2H), 6.60 (d, 1H, J=7.5 Hz), 5.22-5.14 (m, 1H), 3.36-3.27 (m, 2H), 2.95 (s, 1H), 2.88 (s, 1H), 1.20 (t, 3H, J=7.5 Hz); 19F NMR (282 MHz, CDCl3): −47012; LCMS: purity: 99%; MS (m/e): 384 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N+:5]([O-:35])[CH:6]=[C:7]([Cl:34])[C:8]=1[CH2:9][C@@H:10]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH:20]=1)[O:11][C:12]([C@H:14]1[NH:18][CH2:17][CH2:16][S:15]1)=[O:13].[OH:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[N+:5]([O-:35])[CH:6]=[C:7]([Cl:34])[C:8]=1[CH2:9][C@@H:10]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH:20]=1)[O:11][C:12]([C@H:14]1[N:18]([CH2:40][C:39]2[CH:42]=[CH:43][CH:44]=[C:37]([OH:36])[CH:38]=2)[CH2:17][CH2:16][S:15]1)=[O:13]
Reactant: O=Cc1cccc(O)c1
Reactant: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@H]1NCCS1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@@H]1SCCN1Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide hydrochloride (I5, 300 mg, 0.52 mmol) in DCM (2 mL) was added 3-hydroxybenzaldehyde (172 mg, 1.2 mmol) followed by glacial AcOH (0.11 mL, 2.08 mmol). The reaction was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (500 mg, 2.26 mmol) was added and the reaction was stirred at room temperature for 4 h. DCM (50 mL) and 1 N HCl (20 mL) were added to quench the reaction. The layers were separated and the organic layer washed with 1 N HCl (2×20 mL), passed through a hydrophobic fit and the solvent was removed in vacuo to give the title compound.
Reaction SMILES: C([O-])(=[O:8])C1C=CC=NC=1.[Na+].[N:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[C:17]([OH:19])=[O:18].[Na:20]>>[OH:8][C:15]1[N:14]=[CH:13][C:12]([C:17]([OH:19])=[O:18])=[N:11][CH:16]=1.[Na:20]
Reactant: O=C([O-])c1cccnc1
Reactant: O=C(O)c1cnccn1
Agent: [Na+]
Agent: [Na]
Product: O=C(O)c1cnc(O)cn1
Temperature: 0 °C
Yield: 67 %

Procedure:
Pseudomonas acidovorans DSM 4746 was cultivated in a mineral salt medium (Table 1 below) under a continuous addition of sodium nicotinate (0.6 g/l/h) in a fermenter at a pH of 7.0 and at a temperature of 30° C. to an optical density, at 650 nm, of 10. Then the cells were centrifuged off and resuspended in a 2 liter solution, containing 1 mol (146 g) of pyrazinecarboxylic acid-sodium salt, at pH 7.0. The optical density at 650 nm was then 20. After an incubation time of 16 hours under aerobic conditions at pH 7.0 and a temperature of 30° C., no feedstock was able to be detected by UV-spectroscopy. A part of the formed 5-hydroxypyrazinecarboxylic acid-sodium salt crystallized already under these test conditions. The precipitated product was centrifuged off together with the biomass. The formed sediment was then resuspended in 500 ml of water and again centrifuged off. The cell-free supernatants were combined and concentrated by evaporation with a rotary evaporator to 300 ml and cooled to 0° C. The formed crystals were filtered off and dried. Altogether 0.67 mol (108 g) of 5-hydroxypyrazinecarboxylic acid-sodium salt was isolated, corresponding to a yield of 67 percent, relative to the amount of pyrazinecarboxylic acid-sodium salt used.
Reaction SMILES: NO.[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][O:17]S(C)(=O)=O)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[NH2:22][C@@H:23]([CH2:28]O)[CH2:24][CH2:25][CH2:26][CH3:27]>>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][O:17][CH2:28][C@H:23]([NH2:22])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: CCCC[C@@H](N)CO
Agent: NO
Product: CCCC[C@@H](N)COCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using amino alcohol alkylation method A, but adding 1.1 equivalents of 4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester instead of 1 equivalent, (R)-norleucinol (400 mg, 3.4 mmol) afforded, after purification (SiO2: 7:3:1 hexane:EtOAc:isopropyl amine), 195 mg (18%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C1(=O)O[CH2:16][CH2:15][O:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][CH:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:16][CH2:15][OH:14])=[CH:10][CH:11]=1)[CH2:3][CH3:4]
Reactant: CCC(C)Oc1ccc(O)cc1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCCO)cc1
Temperature: 0 °C

Procedure:
4-(1-Methylpropoxy)phenol (6.92 g, 41.6 mmol), ethylene carbonate (7.34 g, 83.2 mmol) and dimethylformamide (DMF; 45 ml) are mixed under N2. With stirring, the mixture is degassed (3X) by alternate application of vacuum and N2. Potassium carbonate (11.51 g, 83.2 mmol) is then added, under N2, and the mixture is heated at 90° for 27 hours. The reaction mixture is then poured into ice water and 10 ml of 40% potassium carbonate solution is added to increase the pH to 13. The aqueous phase is extracted with ether (3X) and the organic layers are washed with 40% KOH, with water until neutral and with brine, dried, filtered and the solvent evaporated to give 2-[4-(1-methylpropoxy)phenoxy]ethanol.
Reaction SMILES: CC(C1C=C(S[C:17]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH3:19])[CH3:18])C=C(C(C)(C)C)C=1O)(C)C.C(OC1[O:43][C@@H:42]([CH2:44][OH:45])[C@@H:41]([CH2:46]O)[O:40]1)C>>[C:32]([C:23]1[CH:22]=[C:21]([SH:20]([CH:17]([CH3:18])[CH3:19])[S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:33])([CH3:34])[CH3:35])[C:24]([OH:31])=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)[CH:26]=[C:25]([C:27]([CH3:30])([CH3:28])[CH3:29])[C:24]=1[O:31][CH2:46][C@H:41]([OH:40])[C@H:42]([OH:43])[CH2:44][OH:45])([CH3:33])([CH3:35])[CH3:34]
Reactant: CCOC1O[C@@H](CO)[C@@H](CO)O1
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CC(C)[SH](Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)c1cc(C(C)(C)C)c(OC[C@H](O)[C@H](O)CO)c(C(C)(C)C)c1

Procedure:
The title compounds can be prepared using the same procedure as described in Ex-1 starting from probucol and 2-ethoxy-1,3-dioxolane-4(S),5(R)-dimethanol and performing a chiral separation.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10]C(=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:13]([O:18][CH3:19])([O:16][CH3:17])OC>CO.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>[CH3:19][O:18][C:13]1([O:16][CH3:17])[CH2:10][CH2:11][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]1
Reactant: COC(OC)OC
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1CCC(OC)(OC)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.7 %

Procedure:
To a solution of ethyl-4-oxocyclohexane carboxylate (23.4 mL, 147 mmol) and p-TsOH (0.25 g, 1.31 mmol) in 25 mL MeOH was added HC(OMe)3 (24.10 mL, 220 mmol) dropwise. The reaction was stirred at rt for 15 h and 1.5 g of anhydrous Na2CO3 was added. The reaction was stirred at rt for another 30 min and filtered. TEA (0.18 mL, 1.31 mmol) was added to the filtrate and the resulting mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL), washed with water (4×30 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 20% EtOAc:hexanes) to afford the title compound (32 g, 100% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 4.15 (q, J=7.1 Hz, 2H), 3.21 (s, 3H), 3.18 (s, 3H), 2.41-2.28 (m, 1H), 2.08-1.96 (m, 2H), 1.91-1.79 (m, 2H), 1.77-1.61 (m, 2H), 1.43 (td, J=12.9, 4.1 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[N:18]([CH3:19])[N:17]=[CH:16][C:15]=1[C:20]([OH:22])=O.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>O1CCCC1>[Cl:13][C:14]1[N:18]([CH3:19])[N:17]=[CH:16][C:15]=1[C:20]([NH:26][CH:23]1[CH2:25][CH2:24]1)=[O:22]
Reactant: NC1CC1
Reactant: Cn1ncc(C(=O)O)c1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)NC2CC2)c1Cl
Temperature: 25 °C
Yield: 116.9 %

Procedure:
Carbonyldiimidazole (3.6 grams, 0.022 mole) was added to a solution of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (2.4 grams, 0.015 mole) in 40 ml. of tetrahydrofuran, and the solution was stirred at room temperature for twenty minutes. Cyclopropylamine (1.3 grams, 0.022 mole) was then added and the reaction mixture was stirred at room temperature for sixteen hours. Solvent was removed in vacuo and the residue was taken up in 250 ml. of chloroform, washed with water, washed with saturated brine, and dried using sodium sulfate and filter paper. The product was recrystallized from toluene, yielding 3.5 grams of 5-chloro-1-methyl-N-cyclopropyl-1H-pyrazole-4-carboxamide, mp=105°-107° C.
Reaction SMILES: [CH3:1][O:2]/[C:3](=[CH:7]\[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=1[CH3:23])[CH:12]=[CH:11]2)/[C:4]([OH:6])=[O:5].[H][H]>CO.ClCCl.[Pd]>[CH3:1][O:2][CH:3]([CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=1[CH3:23])[CH:12]=[CH:11]2)[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: CO/C(=C\c1ccc2c(ccn2Cc2nc(-c3ccccc3)oc2C)c1)C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3)oc2C)c1)C(=O)O
Yield: 60.9 %

Procedure:
A suspension of 80 mg of (Z)-2-methoxy-3-[1-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-1H-indol-5-yl]-acrylic acid in 5 ml of methanol and 2 ml of dichloromethane and 30 mg of Pd/C 10%) was hydrogenated at 22° C. and 1 bar until hydrogen uptake ceased (3 h). The mixture was filtered, the filtrate evaporated and the residue was purified by preparative HPLC (RP-18, CH3CN/H2O, gradient) to give 49 mg of the title compound as a yellow oil. MS: (M−H)− 389.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[CH:7][C:5]=2[N:6]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>O1CCOCC1>[CH2:13]([NH:15][C:16]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[CH:7][C:5]=2[N:6]=1)=[O:17])[CH3:14]
Reactant: Cc1cc2sc(N)nc2cc1O
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(O)c(C)cc2s1
Temperature: 62.5 °C
Yield: 60.9 %

Procedure:
To the solution of 2-amino-6-methyl-benzothiazol-5-ol (0.20 g, 1.11 mmol) in 1,4-dioxane (5 mL) was added ethylisocyanate (0.13 mL, 1.68 mmol) at room temperature. The resulting mixture was heated to 60-65° C. for 16 h. After completion of reaction (TLC monitoring), 1,4-dioxane was distilled off and co-evaporated with hexane (twice). The solid residue was treated with water to 60-70° C. for 2-4 h. The resulting solid was filtered off and dried under vacuum to obtain the white solid compound (0.17 g, 61%). 1H NMR (DMSO-d6, 400 MHz): δ 1.07 (t, J=7.20 Hz, 3H), 2.17 (s, 3H), 3.16 (m, 2H), 6.68 (br s, 1H), 7.00 (s, 1H), 7.47 (s, 1H), 9.33 (s, 1H), and 10.43 (br s, 1H), MS: 252.18 (M+H+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=O)=[CH:7][C:6]=1[F:20].[C:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=O)[CH2:22][CH3:23]>>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][CH3:23])=[CH:7][C:6]=1[F:20]
Reactant: CCC(=O)c1ccccc1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCBr)c(F)c1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCBr)c(F)c1)c1ccccc1
Yield: 99.6 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, (4-(2-bromoethoxy)-3-fluorophenyl)(4-hydroxyphenyl)methanone (311 mg, 0.917 mmol) was reacted with propiophenone (246 mg, 1.83 mmol) to give 403 mg desired product (99.6% yield, Z/E=1/1) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[C:19]([C:21]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=3[CH:28]=[CH:29][CH:30]=2)=[O:20])[CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:38][S:39]([O:12][CH2:11][CH2:10][C@@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]([C:21]1[C:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=2[CH:28]=[CH:29][CH:30]=1)=[O:20])(=[O:41])=[O:40]
Reactant: O=C(c1cccc2c1CCCC2)c1nccn1C[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC[C@H](Cn1ccnc1C(=O)c1cccc2c1CCCC2)c1ccc(Cl)c(Cl)c1
Reaction time: 4 h
Yield: 102.5 %

Procedure:
3(S)-(3,4-Dichlorophenyl)-4-[2-(1,2,3,4-tetrahydro-5-naphthoyl)imidazol-1-yl]butan-1-ol (0.68 g) (see Preparation 103) and triethylamine (0.22 g) were dissolved in dichloromethane (15 ml), the solution cooled in an ice-bath and methanesulphonyl chloride (0.22 g) added. The mixture was stirred for 4 hours before removal of the solvent under reduced pressure to give a residue which was partitioned between ethyl acetate and water. The organic phase was separated and washed with saturated aqueous sodium hydrogen carbonate solution before being dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure to give 1-methanesulphonyloxy-3(S)-(3,4-dichlorophenyl)-4-[2-(1,2,3,4-tetrahydro-5-naphthoyl)imidazol-1-yl]butane (0.82 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[I:8].[C:11](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH3:9])[C:7]([I:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(O)cc(C)c1I
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C)c(I)c(C)c1
Temperature: 25 °C

Procedure:
O-Methyl-3,5-dimethyl-4-iodophenol was prepared by etherifying 3,5-dimethyl-4-iodophenol as follows: In a 1 l three-necked flask equipped with an overhead stirrer were placed 63.7 g (257 mmol) of 3,5-dimethyl-4-iodophenol, 70.9 g (513 mmol) potassium carbonate, 400 ml acetone and 47.5 ml (108 g, 760 mmol) methyl iodide. The reaction mixture was refluxed for 15 hours, cooled, the precipitate filtered and washed with acetone. The combined acetone washes were concentrated under reduced pressure, dissolved in methylene chloride, washed successively with 5% sodium hydroxide, saturated sodium bisulfite and water. After drying over magnesium sulfate and filtering, the solvent was removed under reduced pressure to afford a tan oil. Recrystallization from hot methanol with cooling to room temperature and then -78° C. afforded 58.2 g (86% yield) of white needles, mp 33°-34° C., which were identified as O-methyl-3,5-dimethy-4-iodophenol. 1H NMR analysis indicated: (δ, CDCl3) 6.56 (s, 2H), 3.67 (s, 3H) and 2.37 (s, 6H). Mass spectrum analysis indicated: (m/e) 262 (m+, 100%), 247, 219, 135 and 91.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][CH:19]=3)[CH:10]=2)[NH:5][C:4](=[O:30])[CH:3]=1.[OH:31]O>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][CH:23]=3)=[O:31])[CH:10]=2)[NH:5][C:4](=[O:30])[CH:3]=1
Reactant: Cc1cc(=O)[nH]c2ccc(OCCCCSc3ccc(-c4ccccc4)cc3)cc12
Reactant: OO
Product: Cc1cc(=O)[nH]c2ccc(OCCCCS(=O)c3ccc(-c4ccccc4)cc3)cc12

Procedure:
Prepared analogous to Example 123 from 4-methyl-6-[4-(4-biphenylyl-mercapto)-butoxy]-carbostyril (m.p. 174°-176° C.) and hydrogen peroxide.
Reaction SMILES: BrB(Br)Br.[F:5][C:6]1[CH:7]=[C:8]([C:15]2([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16]2)[CH:9]=[C:10]([F:14])[C:11]=1[O:12]C.CO>ClCCl>[F:5][C:6]1[CH:7]=[C:8]([C:15]2([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17]2)[CH:9]=[C:10]([F:14])[C:11]=1[OH:12]
Reactant: COC(=O)C1(c2cc(F)c(OC)c(F)c2)CC1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1(c2cc(F)c(O)c(F)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
Tribromoborane (0.666 ml, 7.04 mmol) was added dropwise to methyl 1-(3,5-difluoro-4-methoxyphenyl)cyclopropanecarboxylate (Intermediate 28-4; 1.4216 g, 5.87 mmol) in dichloromethane (46.2 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 1 hour. The reaction mixture was added dropwise to methanol (11.87 mL, 293.45 mmol) (care reaction is vigorous and exothermic—MeOH kept in ice bath) and the mixture was stirred for a further 20 minutes. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL), and washed sequentially with saturated NaHCO3 (50 mL) and water (50 mL). The organic layer was dried with MgSO4 and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluted at 25% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 1-(3,5-difluoro-4-hydroxyphenyl)cyclopropanecarboxylate (0.657 g, 49.1%) as a white solid.