Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=2N)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(=O)C>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:30]2[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][C:35]=2[NH:2][C:1]2[C:3]3[CH:8]=[CH:7][C:6]([CH3:9])=[N:5][C:4]=3[N:10]=[CH:11][N:12]=2)=[CH:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Product: Cc1ccc2c(Nc3cc([N+](=O)[O-])ccc3Sc3ccc(OCc4ccccc4)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.4 %

Procedure:
A solution of the product from Example 10B (62 mg, 0.331 mmol), and the product of Example 85B (120 mg, 0.331 mmol) in acetic acid (1 mL) was stirred in an oil bath preheated to 130° C. for 20 minutes. The mixture was then cooled to room temperature, the acetic acid removed under vacuum leaving a brown oil as the title compound (0.15 g, 92%). The compound was used without purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[NH:7][C:6](C(O)=O)=[CH:5]2.[H-].[Na+].[CH3:20][C@@H:21]1[CH2:23][O:22]1>C1(OC2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:12])([F:13])[F:14])[N:7]([CH2:20][C@H:21]([OH:22])[CH3:23])[CH:6]=[CH:5]2
Reactant: O=C(O)c1cc2cc(F)c(C(F)(F)F)cc2[nH]1
Reactant: C[C@@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: C[C@@H](O)Cn1ccc2cc(F)c(C(F)(F)F)cc21
Reaction time: 4 h
Yield: 18.9 %

Procedure:
A suspension of 0.75 g of 5-fluoro-6-trifluoromethylindole-2-carboxylic acid in 16 ml of diphenyl ether was stirred at 260° for 4 hours and, after cooling to 0°, diluted with 16 ml of tetrahydrofuran. 113 mg of sodium hydride dispersion were added and the mixture was stirred for 1 hour. Subsequently, 0.43 ml of (R)-methyloxirane was added and the reaction mixture was stirred at room temperature for 60 hours. The mixture was extracted with diethyl ether, water and saturated sodium chloride solution and the organic phase was dried over sodium sulfate. The solvent was removed and the residue was chromatographed over 40 g of silica gel with hexane-toluene (1:1) and subsequently with toluene-ethyl acetate (15:1). There was obtained 0.15 g (18.9%) of (R)-1-(5-fluoro-6-trifluoromethyl-indol-1-yl)-propan-2-ol as light brown crystals.
Reaction SMILES: [OH-].[K+].[CH:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](C(=O)C(F)(F)F)[CH:10]=[CH:9]2)([CH3:5])[CH3:4]>CO>[CH:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)([CH3:5])[CH3:4]
Reactant: CC(C)c1ccc2c(ccn2C(=O)C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A solution of potassium hydroxide in methanol (5% w/v, 17 mL) containing 5-isopropyl-1-trifluoroacetylindole (Example 2a, 1.163 g, 4.55 mmol) was stirred at room temperature overnight. After removal of the methanol, the product was partitioned between ethyl acetate and water, washed sequentially with water and brine, and dried over sodium sulfate. Flash chromatography (silica, 10% ethyl acetate in hexanes) yielded 5-isopropyl-1H-indole (715 mg, 98%).
Reaction SMILES: C[O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:6]([O:7]C)=[C:5]([CH3:13])[C:4]=1[CH2:14][Cl:15].[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C.O>[Cl:15][CH2:14][C:4]1[C:3](=[O:2])[C:10]([CH3:11])=[C:9]([CH3:12])[C:6](=[O:7])[C:5]=1[CH3:13]
Reactant: COc1c(C)c(C)c(OC)c(CCl)c1C
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CC1=C(C)C(=O)C(CCl)=C(C)C1=O

Procedure:
0.8 g (3.5 mmol) of 2-chloromethyl-3,5,6-trimethylhydroquinone dimethylether was dissolved in 20 mL of acetonitrile. After addition of 9.6 g of ammonium cerium (IV) nitrate in 200 mL of water to the solution, the mixture was extracted with ethyl acetate (100 mL and 50 mL). The combined extract dried over magnesium sulfate and the solvent was removed under reduced pressure. 50 mL of water was added to the residue and then the mixture was extracted with ethyl acetate (50 mL). The extract was washed with saturated NaCl solution (100 mL). The extract dried over magnesium sulfate and the solvent was removed under reduced pressure to give 2-chloromethyl-3,5,6-trimethylbenzoquinone as a yellow crystal. 1H NMR (300 MHz, CDCl3): 4.47 (s, 2H), 2.16 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H). ESMS: Calc. for C10H11ClO2 : 198.65; Found: 199.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:16]=[O:17].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[Cl:21][C:20]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][C:13]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(Cl)c(Br)c1
Reactant: COc1ccc(B(O)O)cc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cc(C=O)ccc2Cl)cc1
Yield: 62.6 %

Procedure:
To a degassed solution of 4-methoxybenzeneboronic acid (1.51 g, 10 mmol), 3-bromo-4-chlorobenzaldehyde (2 g, 9.13 mmol), and potassium carbonate (3.13 g, 22.8 mmol) in toluene/ethanol 2/1, (60 mL), Pd(PPh3)4 (130 mg, 1 mol %) is added and the mixture is degassed for further 5 minutes. The mixture is then refluxed for 2 days. The mixture was partitioned between ethyl acetate and water and extracted. The organic solvent was dried over sodium sulphate, removed under reduced pressure, and the residue purified by column chromatography (heptane/ethyl acetate 19/1 to afford 1.41 g of product.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[NH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=2)=[CH:20][CH:19]=1>>[C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=2)=[CH:22][CH:23]=1)#[N:2]
Reactant: CC1CC(=O)NN=C1c1ccc(OCCN)cc1
Reactant: N#Cc1ccccc1OCC1CO1
Product: CC1CC(=O)NN=C1c1ccc(OCCNCC(O)COc2ccccc2C#N)cc1

Procedure:
Prepared analogously to Example 1 from 1-(2-cyano- phenoxy)-2,3-epoxypropane and 6-[4-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH2:10][CH:11]2[CH2:16][CH:15]3[N:17](C(OC(C)(C)C)=O)[CH:12]2[CH2:13][CH2:14]3)[N:4]=1.[ClH:27]>CO>[ClH:27].[F:25][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH2:10][CH:11]2[CH2:16][CH:15]3[NH:17][CH:12]2[CH2:13][CH2:14]3)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(COc1nccc(C(F)(F)F)n1)C2
Agent: Cl
Solvent: CO
Product: FC(F)(F)c1ccnc(OCC2CC3CCC2N3)n1

Procedure:
To the title compound of step A (752 mg, 2 mmol) in MeOH (6 mL) was added HCl.
Reaction SMILES: [C:1]([CH:4]1[NH:9][CH2:8][C:7]2[CH:10]=[CH:11][S:12][C:6]=2[CH2:5]1)(O)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:2][CH2:1][CH:4]1[NH:9][CH2:8][C:7]2[CH:10]=[CH:11][S:12][C:6]=2[CH2:5]1
Reactant: O=C(O)C1Cc2sccc2CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1Cc2sccc2CN1
Reaction time: 20 h
Yield: 35.1 %

Procedure:
(RS)-6-Carboxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (3.7 g) is added, under a nitrogen atmosphere and in small portions, to a solution of lithium aluminum hydride (1.1 g) in tetrahydrofuran (45 cc); the resulting suspension is heated under reflux for 4 hours. After cooling, water (1.35 cc), 5N aqueous sodium hydroxide solution (0.95 cc) and water (4.35 cc) are successively added dropwise. The inorganic salts formed are filtered off and washed with methylene chloride (5×20 cc). The filtrates are combined and evaporated to dryness under reduced pressure (25 mm Hg; 3.3 kPa) at 60° C. The residue is dissolved in boiling acetonitrile (15 cc) and the solution is cooled and then kept at 5° C. for 20 hours. The resulting crystals are filtered off, washed with cyclohexane and dried at 20° C. under reduced pressure (0.1 mm Hg; 0.013 kPa). (RS)-6-Hydroxymethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1.2 g), melting at 110° C., is thus obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7](/[C:9](=[CH:16]\[CH2:17][CH3:18])/[CH:10]=[CH:11]/[C:12](OC)=[O:13])[CH3:8].C(OCC)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(OCC)C>[CH2:7](/[C:9](=[CH:16]\[CH2:17][CH3:18])/[CH:10]=[CH:11]/[CH2:12][OH:13])[CH3:8]
Reactant: CC/C=C(/C=C/C(=O)OC)CC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC/C=C(/C=C/CO)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a suspension of lithium aluminum hydride (2.38 g) in ethyl ether (160 ml) was added a solution of methyl (E,E)-4-ethyl-2,4-heptadienoate (13.2 g) in ethyl ether (100 ml) while keeping the temperature below 30° C. When addition was completed, the mixture was allowed to stir at room temperature for one hour. To this resultant mixture at 10° C. were added dropwise ethyl acetate (50 ml) and a saturated aqueous solution of potassium sodium tartrate (50 ml). The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give (E,E)-4-ethyl-2,4-heptadien-1-ol (10.1 g) as an oil. This oil was used in the next reaction without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:27])[C:18]([NH:20][CH:21]2[CH2:26][CH2:25]S[CH2:23][CH2:22]2)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.[OH:39][S:40]([O-:42])=O.[Na+].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:27])[C:18]([NH:20][CH:21]2[CH2:22][CH2:23][S:40](=[O:42])(=[O:39])[CH2:25][CH2:26]2)=[O:19])[CH2:15][CH2:16]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: O=S([O-])O
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCSCC2)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCS(=O)(=O)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxo-N-(tetrahydro-2H-thiopyran-4-yl)acetamide (Example 193, 0.21 g, 0.54 mmol) and m-chloroperbenzoic acid (0.29 g, 1.13 mmol) in ethyl acetate (10 mL) was stirred at 0° C. for 2 h. Then the mixture was added saturated NaHSO3 solution and stirred for 1 h. The mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 60:40 to 0:100 then ethyl acetate/methanol 100/0 to 70/30) to give the title compound (0.20 g, 88%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[CH2:41][C:42]1[C:43]([C:50]2[C:55]([Cl:56])=[CH:54][CH:53]=[CH:52][C:51]=2[Cl:57])=[N:44][O:45][C:46]=1[CH:47]1[CH2:49][CH2:48]1>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15][CH2:41][C:42]2[C:43]([C:50]3[C:51]([Cl:57])=[CH:52][CH:53]=[CH:54][C:55]=3[Cl:56])=[N:44][O:45][C:46]=2[CH:47]2[CH2:49][CH2:48]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Reactant: CC(C)(C)OC(=O)N1CCCC(O)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.2 %

Procedure:
To a solution of 36.11 g (167.7 mmol) of 4-hydroxy-azepane-1-carboxylic acid tert-butyl ester in 300 mL of tetrahydrofuran at 0° C. (ice bath), 18-crown-6 (63.43 g, 237.58 mmol) and potassium tert-butoxide (28.06 g, 250.04 mmol) are added. The resulting mixture is stirred for 20 min at room temperature under nitrogen, followed by addition of a solution of 48.5 g (139.75 mmol) of 4-Bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole in 100 mL tetrahydrofuran over a 1 hour period. The resulting mixture is stirred at room temperature under nitrogen atmosphere for 12 hours. Water (200 mL) is added to the reaction mixture and the solvent is removed under reduced pressure. The resulting brown oil is diluted with EtOAc (2×250 mL), and washed with brine (2×150 mL). The organic layer is dried (Na2SO4), filtered and concentrated to afford a crude which is purified on silica gel column chromatography (Eluting with Hexanes/EtOAc 8:2) to obtain 56 g of the title compound as a white/yellow oil. (83%). MS (m/e): 481 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[NH:12][C:11](=O)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:11]1[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:14]=[C:13]([CH3:15])[N:12]=1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(3,4-dichloro-phenyl)-6-methyl-1H-pyrimidin-2-one (2.51 g, 9.84 mmol) and phosphoroxychloride (35 mL) according to the general procedure I. Obtained as a brown solid (1.55 g, 58%). MS (EI) 272.1 [(M)+]; mp 123° C. (dec.).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[N:4]1)[CH3:2].[NH2:15][C@H:16]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:19]([CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH2:18][CH2:17]1>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([NH:15][C@H:16]2[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C@@H:19]([CH2:29][C:30]3([OH:36])[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[CH2:18][CH2:17]2)=[O:14])=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)CC[C@@H]1CC1(O)CCOCC1
Reactant: CCn1nc(C(=O)O)c2ccccc21
Product: CCn1nc(C(=O)N[C@@H]2CC[C@H](CC3(O)CCOCC3)N(C(=O)OC(C)(C)C)C2)c2ccccc21

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 2 from 1-ethyl-1H-indazole-3-carboxylic acid (Chemical & Pharmaceutical Bulletin, 1995, 43, 1912-1930) and (+)-tert-butyl cis-5-amino-2-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidine-1-carboxylate (step 1 of Example 27).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[Cl-].[Cl-].[Cl-].[Al+3].[C:15]1(=[O:25])[O:20][C:18](=[O:19])[C@H:17]2[CH2:21][CH:22]=[CH:23][CH2:24][C@@H:16]12>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:9][CH3:10])[C:15]([C@H:16]1[CH2:24][CH:23]=[CH:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:25]
Reactant: COc1ccccc1OC
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)[C@H]2CC=CC[C@H]2C(=O)O)cc1OC

Procedure:
0.5 mole of 1,2-dimethoxybenzene was added slowly to a suspension of 0.5 mole aluminiumtrichloride in 1 l of dichloromethane at 0° C. After complete addition, cis-1,2,3,6-tetrahydrophthalic acid anhydride was added to the solution. After 8 hours of reflux the solution was poured onto ice. The organic layer was dried over magnesium sulfate and evaporated. The residue was washed with diethyl ether and dried. M.p. 110-112° C.
Reaction SMILES: S(C)C.[CH:4]([Li])([CH3:6])[CH3:5].[C:8]([NH:27][C@@H:28]([CH2:31][CH3:32])[CH:29]=[O:30])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH4+].[Cl-]>CCOCC>[CH3:5][CH:4]([CH:29]([OH:30])[C@@H:28]([NH:27][C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:31][CH3:32])[CH3:6]
Reactant: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CSC
Product: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)C
Temperature: 25 °C

Procedure:
To a stirred suspension of CuBr.SMe2 (1.37 g, 2.2 eq, 6.66 mmol) in Et2O (100 mL) under an argon atmosphere at −78° C., was added isopropyllithium (0.7 M in pentane, 17.29 mL, 4 eq, 12.1 mmol) dropwise and the solution allowed to warm to room temperature. The mixture was recooled to −70° C., to which was added a solution of (S)-2-(trityl-amino)-butyraldehyde (1 g, 1 eq, 3.03 mmol) in Et2O (25 mL) dropwise with stirring. The reaction mixture was stirred at this temperature for 1 h, then allowed to warm to −55° C. and stirred at this temperature for 3 h. To the reaction mixture was added a saturated aqueous solution of NH4Cl (100 mL) and allowed to warm to room temperature over 16 h. The reaction mixture was extracted with Et2O (2×200 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane:ether (100:0→90:10) to afford the title compound as a colourless oil; Yield: 0.36 g (32%). (50% de 3R,4S: 50% de 3S,4S). 1H-NMR (d6-DMSO, 250 MHz): δ0.44 (t, 3H, J=6.79 Hz, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 0.52 & 0.76 (2×d, 6H, J=6.63 Hz, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 0.80-1.15 (m, 2H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 1.70 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 2.10 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 2.76 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 2.99 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 4.55 (d, 1H, J=5.84 Hz, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 7.17-7.46 (m, 15H, 3×Ph).
Reaction SMILES: C([O:8][C:9](=[O:26])[C:10]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=1[O:20][C:21](=[O:25])[N:22]([CH3:24])[CH3:23])C1C=CC=CC=1>CO.[Pd]>[CH3:23][N:22]([CH3:24])[C:21]([O:20][C:11]1[CH:12]=[CH:13][C:14]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:15][C:10]=1[C:9]([OH:26])=[O:8])=[O:25]
Reactant: CN(C)C(=O)Oc1ccc(S(C)(=O)=O)cc1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)Oc1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
1 mmol of 2-dimethylcarbamoyloxy-5-methanesulfonyl-benzoic acid benzyl ester was dissolved in 5 ml of methanol. 25 mg of palladium 10% on charcoal was added and the reaction mixture hydrogenated at room temperature to yield the title compound as a slightly yellowish solid. MS (m/e): 288.0 (MH+, 66%)
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3)[NH:8][C:4]=2[C:3]=1[CH2:23][C:24]([O:26]CC)=[O:25].[OH-].[K+]>C(O)C>[F:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=3)[NH:8][C:4]=2[C:3]=1[CH2:23][C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)Cc1c(F)ccc2nc(-c3cc(OC)c(OC)c(OC)c3)[nH]c12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(-c2nc3ccc(F)c(CC(=O)O)c3[nH]2)cc(OC)c1OC

Procedure:
A mixture of ethyl 2-[5-Fluoro-2-(3,4,5-trimethoxyphenyl)benzimidazolyl]acetate (11.99 mmole, 4.65 g) and potassium hydroxide (40 mmole, 2.24 g) in ethanol (80 ml) is stirred at reflux for 2 hours. The solvent is evaporated and the residue is charged with water (100 ml) and ether (100 ml). The aqueous layer is washed with ether (2×50 ml) and charged with concentrated HCl (pH 1). After 24 hours the colorless precipitate is filtered off and dried in vacuo (R1=(CH2)x—C(O)—OR4, x=1, R2=3,4,5-trimethoxyphenyl, R3=F, R4=hydrogen, n=1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[Br-].[S:11]1[CH:15]=[CH:14][N:13]=[C:12]1[Zn+].C1COCC1.C(Cl)Cl>O.[Na+].[Cl-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CO>[Cl:8][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([C:12]2[S:11][CH:15]=[CH:14][N:13]=2)[CH:7]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: [Zn+]c1nccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Clc1cc(Cl)nc(-c2nccs2)c1
Reaction time: 3 h
Yield: 46 %

Procedure:
To a 15 mL vial equipped with a stir bar was added 2,4,6-trichloropyridine (182 mg, 1.00 mmol) and Pd(dppf)Cl2 (73.2 mg, 0.100 mmol). The vial was sealed with a septum screwcap and was then placed under N2 atmosphere. To the vial was added thiazol-2-ylzinc(II) bromide in THF (8.00 mL, 4.00 mmol). The vial was placed in a 60° C. heating block with stirring for 3 h. The reaction mixture was transfered to a separatory funnel and diluted with water (25 mL) and sat. aq. NaCl (“brine”, 25 mL). The mixture was extracted with EtOAc:Et2O (40 mL:20 mL). The organic phase was washed with brine (25 mL); dried over MgSO4; filtered; then concentrated in vacuo to afford an orange solid. This material was subjected to silica gel chromatography (CH2Cl2:MeOH, 100:0 to 99:1) to afford 2-(4,6-dichloropyridin-2-yl)thiazole as a white solid (231 mg, 46%). 1H-NMR (400 MHz, CDCl3) δ 8.16 (d, J=1.8 Hz, 1H), 7.95 (d, J=3.3 Hz, 1H), 7.52 (d, J=3.0 Hz, 1H), 7.37 (d, J=1.8 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:15])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2.C([O-])(O)=[O:17].[Na+]>CC(C)=O.O>[F:15][C:4]1[C:3]([CH2:2][OH:17])=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc2ccc(F)c(CBr)c2n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2ccc(F)c(CO)c2n1
Yield: 73.2 %

Procedure:
A suspension of 8-bromomethyl-7-fluoro-2-methoxy-quinoline (25 g, 92.56 mmol) in acetone (360 mL) and water (460 mL) was treated with NaHCO3 (12.74 g, 151.64 mmol, 1.6 eq.). The mixture was heated to reflux overnight. After cooling, the volatiles were removed in vacuo and the residue was partitioned between EA (300 mL) and water (100 mL). The aq. layer was extracted once with EA (250 mL) and the combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA 3:1) to afford the title alcohol as a yellowish solid (14.04 g).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].O[CH:18]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:25][C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2>C(O)C.C(O)(=O)C>[Br:16][C:14]1[CH:13]=[CH:12][C:3]([C:4]([CH:6]([CH:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[O:25][C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])=[C:2]([CH3:1])[CH:15]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1C
Reactant: OC1c2ccccc2Oc2ccccc21
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)c1ccc(Br)cc1C)C1c2ccccc2Oc2ccccc21

Procedure:
A solution of ethyl 2-methyl-4-bromobenzoylacetate (18.5 g, 65.0 mmol) was heated at 60° C. with 9-hydroxyxanthene (14.2 g, 71.5 mmol) in ethanol-acetic acid (1:1, 200 ml) for 40 h. The product was isolated as in Example 1 (iii), except the aqueous phase was extracted with diethyl ether. The crude product was purified on flash silica eluting with hexane-dichloromethane (3:2 then 1:1) to give ethyl 2-(4-bromo-2-methylbenzoyl)-2-(9H-xanthen-9-yl)acetate as an oil.