Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([C:7]1[N:8]=[C:9]([CH2:17][CH2:18][CH3:19])[NH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:6])[CH3:5].[C:20]([N:39]1[C:43]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[C:50]2[CH:57]=[CH:56][C:53]([CH2:54]Br)=[CH:52][CH:51]=2)=[N:42][N:41]=[N:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.C(OCC)(=O)C>[OH:3][C:4]([C:7]1[N:8]=[C:9]([CH2:17][CH2:18][CH3:19])[N:10]([CH2:54][C:53]2[CH:52]=[CH:51][C:50]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[C:43]3[N:39]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:40]=[N:41][N:42]=3)=[CH:57][CH:56]=2)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:6])[CH3:5]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
48 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to a solution of 0.26 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9) in 5 ml of N,N-dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 0.72 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 5 ml of N,N-dimethylformamide was then added, and the reaction mixture was stirred at room temperature for 2 hours and then at 60° C. for 4 hours. At the end of this time, it was dissolved in ethyl acetate and the solution was washed three times with water. The solution was then dried over anhydrous sodium sulfate, after which it was freed from the solvent by distillation. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.62 g of the title compound as an amorphous solid. This was crystallized from diisopropyl ether, to give the title compound as crystals, melting at 167°-168° C. (with decomposition).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([NH2:14])[C:6]([NH2:13])=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].C([O:21][C:22](=O)[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:39][C:34]1[CH:33]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:21])[NH:13][C:6]4[CH:7]=[C:8]([C:9]([F:12])([F:11])[F:10])[C:3]([C:2]([F:15])([F:16])[F:1])=[CH:4][C:5]=4[N:14]=3)[CH:31]=[CH:30][CH:29]=2)[CH:37]=[C:36]([CH3:38])[N:35]=1
Reactant: Nc1cc(C(F)(F)F)c(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(C(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from 4,5-bis-trifluoromethyl-benzene-1,2-diamine [CAS-No. 30454-92-3] (244 mg, 1.0 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (325 mg, 1.0 mmol) in toluene (10 ml) under reflux conditions for 2 h according to the general procedure M and subsequent treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (132 mg, 28%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:23]([Cl:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:9]=1[C:10]([N:12]=[S:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[O:11].[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38](Cl)=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:43])[F:42])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1.O>C1(C)C=CC=CC=1>[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38]([NH:7][C:8]3[C:9]([C:10](=[O:11])[N:12]=[S:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])=[CH:20][C:21]([Cl:25])=[CH:22][C:23]=3[Cl:24])=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:42])[F:43])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)S(=NC(=O)c1cc(Cl)cc(Cl)c1N)C(C)C
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)S(=NC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl)C(C)C
Reaction time: 0.75 h

Procedure:
To a suspension of potassium carbonate (0.892 g, 6.46 mmol, 1.10 equiv.) and 2-amino-3,5-dichloro-N-(bis-2-propyl-λ4-sulfanylidene)benzamide (2.05 g, 5.87 mmol) in toluene (30 mL) was added a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)-pyrazole-3-carbonyl chloride (2.02 g, 5.87 mmol, 1.00 equiv.) in toluene (20 mL) at 60° C. After 45 min at this temperature, the mixture was cooled and water was added.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][C:34]([OH:38])([C:36]#[CH:37])[CH3:35]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:25][O:24][C:19]1[C:18]([NH:17][C:13]2[N:14]=[CH:15][N:16]=[C:11]([N:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([C:37]#[C:36][C:34]([CH3:35])([OH:38])[CH3:33])[CH:10]=4)[CH:6]=[N:7]3)[CH:12]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: COc1ncccc1Nc1cc(-n2ncc3ccc(I)cc32)ncn1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ncccc1Nc1cc(-n2ncc3ccc(C#CC(C)(C)O)cc32)ncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a pressure tube was added 6-(6-iodoindazol-1-yl)-N-(2-methoxypyridin-3-yl)pyrimidin-4-amine (120 mg, 0.27 mmol) followed by triethylamine (2 mL) and THF (2 mL). Next, copper(I) iodide (5.15 mg, 0.027 mmol), bis(triphenylphosphine)palladium(II) chloride (18.96 mg, 0.027 mmol) and 2-methylbut-3-yn-2-ol (0.05 ml, 0.54 mmol) were added and the reaction vessel was sealed and stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and DCM (5 ml) was added. The organics were washed with 0.5M HCl (2×3 ml), water (3 ml) and brine (3 ml), and dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Isolute column, 4:6 to 1:1 EtOAc:heptanes) to surrender the title compound as a white solid: 1H NMR (500 MHz, CDCl3) delta 1.69 (6H, s), 2.08 (1H, br. s.), 4.07 (3H, s), 6.99 (1H, dd, J=7.80, 4.97 Hz), 7.32-7.41 (2H, m), 7.69 (1H, d, J=8.20 Hz), 7.88 (1H, dd, J=4.97, 1.66 Hz), 8.19 (1H, s), 8.54-8.61 (1H, m), 8.77 (1H, s), 8.99 (1H, s); LC-MS: m/z=+401.10 (M+H)+.
Reaction SMILES: [Br:1][C:2]([F:10])([C:6]([Br:9])([F:8])[F:7])[C:3](F)=[O:4].[Cl-:11].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]([F:10])([C:6]([Br:9])([F:8])[F:7])[C:3]([Cl:11])=[O:4]
Reactant: O=C(F)C(F)(Br)C(F)(F)Br
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClCCl
Product: O=C(Cl)C(F)(Br)C(F)(F)Br
Yield: 57 %

Procedure:
A 163-g (0.56 mole) sample of 2,3-dibromo-2,3,3-trifluoropropionyl fluoride was added dropwise to a mechanically stirred suspension of 76 g (0.56 mole) of aluminum chloride in 282 ml of methylene chloride. The reaction mixture warmed spontaneously to 40°. After cooling, the volatile portion of the reaction mixture was distilled under reduced pressure into a Dry Ice-cooled trap. Redistillation gave 97.5 g (57%) of 2,3-dibromo-2,3,3-trifluoropropionyl chloride as a colorless liquid: bp 128°-129°; nD25 1.4436; ir (liquid) 5.57 μ (COCl); 19F nmr (CCl3F) μ 55.7 ppm (d, J = 175 Hz to d, J = 14.5 Hz, 1F), 57.9 ppm (d, J = 175 Hz to d, J = 16 Hz, 1F) and 116.5 ppm (d, J = 16 Hz to d, J = 14.5 Hz, 1F).
Reaction SMILES: [CH2:1]([OH:12])[C:2]([C@@H:4]([OH:11])[C@H:5]([OH:10])[C:6]([CH2:8][OH:9])=[O:7])=O.C([BH3-])#N.[Na+].[CH:17]([NH2:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C>CO>[CH:17]([N:30]1[C@:2]2([CH2:1][OH:12])[O:7][C@:6]1([C@H:5]([C@@H:4]2[OH:11])[OH:10])[CH2:8][OH:9])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CO)[C@@H](O)[C@H](O)C(=O)CO
Reactant: NC(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC[C@]12O[C@](CO)([C@@H](O)[C@@H]1O)N2C(c1ccccc1)c1ccccc1
Yield: 62.2 %

Procedure:
A suspension of 5-keto-D-fructose (Formula X, 50 g, 0.28 mol; obtained from Chemical Dynamics) in 400 mL of MeOH was treated with sodium cyanoborohydride (40 g, 0.476 mol). A slurry of benzhydrylamine (42.0 mL, 0.234 mol) in 120-mL of MEOH was treated with sufficient acetic acid to bring the pH to 6-7 and then added over a 0.5 h period to the 5-keto-D-fructose (Formula X) and sodium cyanoborohydride suspension. An additional portion of sodium cyanoborohydride (20 g. 0.235 mol) was added and the mixture was stirred at reflux for 6 h. The solvent was then removed, and the residue treated with 10% sodium carbonate (ca. 100 mi), and the product was extracted into chloroform. The chloroform layers were dried (MgSO4), filtered and concentrated to give a tacky yellow solid. This was purified on two Waters Prep 500 columns (CHCl3 /MeOH/NH4OH, 88:11:1) to give ca. 50 g of the target compound. Recrystallization from ethyl acetate gave 21.3 g (28%) of white needles, 152.5°-154.5° C. (corrected). Both 1H and 13C NMR in CDCl3 supported the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CS[C:34]([NH:46][C:47](=[O:56])[O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[N:35][C:36](=[O:45])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C>CN(C)C=O.FC(F)(F)S([O-])(=O)=O.[Ag+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[CH:20]=4)[CH2:15][CH2:14][N:13]3/[C:34](/[NH:46][C:47](=[O:56])[O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[N:35]/[C:36](=[O:45])[O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:9][CH2:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)NCC2
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)CC2
Reaction time: 3 h

Procedure:
N-[2-({1-[1-(4-Fluorophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}oxy)ethyl]propane-1-sulfonamide (100 mg, 0.224 mmol, cf. example 65) and dibenzyl [(methylsulfanyl)methylylidene]biscarbamate (104 mg, 0.291 mmol) were dissolved in dry dimethylformamide (1 mL). Triethylamine (0.094 mL, 0.672 mmol) was added followed by silver trifluoromethanesulfonate (81 mg, 0.313 mmol). A yellow precipitate was formed and the reaction mixture turned dark brown. Stirring was continued at room temperature for 3 h. The solvent was evaporated in vacuo. Dichloromethane (15 mL) was added, the solid was removed by filtration and washed with dichloromethane. The combined dichloromethane phases were concentrated in vacuo and the crude product was purified by flash chromatography (silica, dichloromethane then dichlorometane:methanol=100:1). Yield: 100 mg (0.132 mmol, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].C(Cl)(=O)C(Cl)=O.[CH:25]1[CH:26]=[CH:27][N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[NH:31][CH2:30][C:29]=12.C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([N:31]2[C:32]3[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=3[CH2:34][N:28]3[CH:27]=[CH:26][CH:25]=[C:29]3[CH2:30]2)=[O:11])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: COc1cc(C(=O)O)ccc1-c1ccccc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 93.3 %

Procedure:
To a solution of 2-methoxy-2′-methyl-biphenyl-4-carboxylic acid of step D (23 mmol) in dichloromethane (50 mL) was added a drop of N,N-dimethylformamide. Oxalyl chloride (36 mmol) then was added dropwise to the solution, which then was stirred at reflux temperature for 2 hours. The solvents were evaporated and the resulting acid chloride was dissolved in 20 mL dichloromethane. This was added dropwise to a stirred mixture of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (25 mmol) and triethylamine (34 mmol) in dichloromethane (30 mL) at 0° C. under nitrogen atmosphere. After 20 hours the mixture was quenched with water and washed with 0.5 N hydrochloric acid, 1.0 N sodium hydroxide, and brine. The solution was dried over anhydrous sodium sulfate, and evaporated to a solid. The product was purified by flash chromatography using ethyl acetate/hexane (1:3) to yield 8.77 g (95%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](=O)([O-])[O-].[K+].[K+].C=O.O>CN1CCCC1=O>[C:8]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:13]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C=C(C(=O)OCC)c1ccccc1
Yield: 53.5 %

Procedure:
94 g of ethyl phenylacetate (methyl ester content 0.01%) were stirred in 300 ml of N-methylpyrrolidone with 120 g of potassium carbonate and 25 g of paraformaldehyde at 75 to 80° C. for 1.5 h. After cooling, 150 ml of water were added, and the aqueous phase was separated off. The N-methylpyrrolidone phase was extracted twice with 75 ml of diisopropyl ether each time. The combined diisopropyl ether phases were washed with 50 ml of water and concentrated in vacuo. 58 g of product were obtained, corresponding to 54 g of ethyl atropate (53% of theory) with a methyl atropate content of 0.03%.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](I)=[CH:24][N:23]=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:34][C:35]1[C:40]([CH:41]([CH3:43])[CH3:42])=[CH:39][C:38](B(O)O)=[C:37]([O:47][CH3:48])[CH:36]=1.O>C(=O)([O-])[O-].[K+].[K+].C1COCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:38]4[CH:39]=[C:40]([CH:41]([CH3:43])[CH3:42])[C:35]([F:34])=[CH:36][C:37]=4[O:47][CH3:48])=[CH:24][N:23]=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ncc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)C)cc1-c1cnc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 85 °C

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-iodo-2-(trifluoromethyl)pyridin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (9.7 mg, 0.0162 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (5.2 mg, 0.0243 mmol), and 1,1′-bis(di-t-butylphosphinoferrocene)palladium dichloride (1.0 mg, 0.00162 mmol) in 1N aqueous potassium carbonate (0.7 mL) and THF (0.7 mL) was heated at 85° C. in a sealed tube for 2 h. The reaction mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with EtOAc (3×20 mL) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-40% EtOAc in hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-(4-fluoro-5-isopropyl-2-methoxyphenyl)-2-(trifluoromethyl)pyridin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.40 (20% EtOAc/hexanes). LCMS calc. 639.2; found 639.2 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers): δ 8.55 (s, 1H); 7.87 (s, 1H); 7.74-7.68 (m, 3H); 7.02 (dd, J=4.5, 8.1 Hz, 1H); 6.72 (d, J=11.7 Hz, 1H); 5.64 (d, J=8.0 Hz, 0.5H); 5.48 (d, J=7.9 Hz, 0.5H); 4.84 (d, J=16.4 Hz, 0.5H); 4.77 (d, J=16.5 Hz, 0.5H); 4.21 (d, J=16.5 Hz, 0.5H); 3.96 (d, J=16.3 Hz, 0.5H); 3.92-3.85 (m, 0.5H); 3.8-3.73 (m, 3.5H); 3.25-3.17 (m, 1H); 1.30-1.18 (m, 6H); 0.56 (d, J=6.4 Hz, 1.5H); 0.42 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: Br[C:2]1(OC)[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.C([Li])CCC.CN(C)[CH:21]=[O:22].C[CH2:25][O:26]CC>C(OC(C)C)(C)C>[CH3:25][O:26][C:5]1[CH:6]=[C:7]([CH:21]=[O:22])[CH:8]=[C:9]2[C:4]=1[O:3][CH2:2][CH2:11][CH2:10]2
Reactant: COC1(Br)CCc2ccccc2O1
Reactant: CCOCC
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)OC(C)C
Product: COc1cc(C=O)cc2c1OCCC2
Temperature: -50 °C
Yield: 51 %

Procedure:
The procedure is as according to the method described for preparation III, but maintaining the temperature at -50° C. From 186 g (7.7×10-1M) of bromo-methoxy-chroman Ib2 in 500 cm3 of anhydrous ether and 7.7×10-1M of n-butyllithium in 650 cm3 of anhydrous ether, and after addition of 78 g (1.1M) of N,N-dimethylformamide in 200 cm3 of anhydrous ether and recrystallisation in isopropyl ether, 75 g (yield=51%) of expected compound are isolated.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C[N:9]1[CH:13]2[CH2:14][C:15]([CH2:17][CH:10]1[CH2:11][CH2:12]2)=[O:16]>ClC(Cl)C.CO>[ClH:1].[CH:10]12[NH:9][CH:13]([CH2:12][CH2:11]1)[CH2:14][C:15](=[O:16])[CH2:17]2
Reactant: CN1C2CCC1CC(=O)C2
Reactant: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: CC(Cl)Cl
Product: Cl
Product: O=C1CC2CCC(C1)N2
Yield: 60.3 %

Procedure:
Add α-chloroethyl chloroformate (15.4 g, 108 mmol) to a solution of tropinone (10 g, 71.84 mmol) in dichloroethane (200 ml) dropwise at 0° C. Heat the reaction to reflux for 2 h. Evaporate the solvent to produce a brown residue. Dissolve the residue in MeOH (200 ml) and heat it to reflux for 2 h. Evaporate the MeOH and stir the solid in EtOAc, filter, collect the solid and wash with ether to give the product (7 g). Crude product was used without further purification. 1H NMR (CDCl3) δ4.45 (s, br, 2H), 3.35 (dd, 2H), 2.58 (d, 2H), 2.49 (dd, 2H), 2.0 (m, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][SH:17].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[CH3:18][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][S:17][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CS
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1CSc1ccc(C=O)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
4-fluoro-benzaldehyde (1.16 g, 9.32 mmol) was added dropwise over 2 minutes to a solution of o-tolyl-methanethiol (1.35 g, 9.79 mmol) and Cesium carbonate (3.19 g, 9.79 mmol) in DMF (20 mL). The solution was stirred at 40° C. overnight and then poured into copious water. The pH of the solution was adjusted to 4 with 1N HCl(aq), and the aqueous solution was extracted with ethyl acetate (2×35 mL). The combined organic layers were washed with water, followed by brine. The combined organic layers were then dried (Na2SO4) and the solvent removed under reduced pressure. The resulting residue was purified via radial chromatography (15% ethyl acetate in hexanes) to yield 1.29 g (54%) of 4-(2-Methyl-benzylsulfanyl)-benzaldehyde (28.1). LC/MSD mle: 243.0 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:38]=[CH:37][C:17]([C:18]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:30][CH2:29][C:27]4=[O:28])[CH2:22][CH2:21]3)=[O:19])=[CH:16][CH:15]=2)[CH2:4][CH2:3]1.[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)CC)C.CNN1C=CC(NC)=CC1>ClCCl.O>[C:39]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:38]=[CH:37][C:17]([C:18]([N:20]3[CH2:21][CH2:22][CH:23]([N:26]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:30][CH2:29][C:27]4=[O:28])[CH2:24][CH2:25]3)=[O:19])=[CH:16][CH:15]=2)[CH2:6][CH2:7]1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCN(CCCCCOc2ccc(C(=O)N3CCC(N4C(=O)CCc5ccccc54)CC3)cc2)CC1
Agent: CNC1=CCN(NC)C=C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1CCN(CCCCCOc2ccc(C(=O)N3CCC(N4C(=O)CCc5ccccc54)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[1-{4-[5-(4-Amino-1-piperidinyl)pentyloxy]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (0.6 g) and acetic anhydride (0.2 ml) are dissolved in dichloromethane (20 ml), and thereto are added triethylamine (0.56 ml) and 1,4-dimethylaminopyridine (20 mg), and the mixture is stirred at room temperature overnight. Water is added to the reaction mixture and the mixture is extracted with chloroform, dried over sodium carbonate, and purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to give 1-[1-{4-[5-(4-acetylamino-1-piperidinyl)pentyloxy]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (310 mg) as colorless oil.
Reaction SMILES: [CH:1]([C:3]1[N:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1)=O.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1.Cl>O.N1C=CC=CC=1>[C:20](/[CH:19]=[CH:1]/[C:3]1[N:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1)([OH:22])=[O:21]
Reactant: COC(=O)c1cccc(-n2cccc2C=O)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: O
Product: COC(=O)c1cccc(-n2cccc2/C=C/C(=O)O)c1
Reaction time: 3 h

Procedure:
The mixture of methyl 3-(2-formylpyrrol-1-yl)benzoate (3.0 g), malonic acid (2.7 g), pyridine (30 ml) and piperidine (0.3 ml) was stirred for 3 hours at 90°-100° C. The reaction mixture was poured into water, and the mixture was adjusted to pH 1 with 6N-hydrochloric acid. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to give methyl 3-[2-((E)-2-carboxyethenyl)pyrrol-1-yl)benzoate.
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([CH:7]([CH3:9])[CH3:8])=[N:4][C:3]=1[CH3:10].C(C1C[CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]C1)=O>>[I:1][C:2]1[NH:6][C:5]([CH:7]2[CH2:9][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:8]2)=[N:4][C:3]=1[CH3:10]
Reactant: Cc1nc(C(C)C)[nH]c1I
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Product: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1I

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 159.2, except tert-butyl 4-formylpiperidine-1-carboxylate was used in place of isobutyraldehyde. m/z (ES+) 392 (M+H)+.
Reaction SMILES: [Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[C:3]1=[O:13].[CH3:14][NH:15][C:16]([NH2:18])=[S:17]>CC(C)=O>[BrH:1].[OH:13][C:3]12[C:4]3[CH:5]=[CH:6][C:7]([C:11]#[N:12])=[CH:8][C:9]=3[CH2:10][CH:2]1[S:17][C:16]([NH:15][CH3:14])=[N:18]2.[OH:13][C:3]12[C:4]3[CH:5]=[CH:6][C:7]([C:11]#[N:12])=[CH:8][C:9]=3[CH2:10][CH:2]1[S:17][C:16]([NH:15][CH3:14])=[N:18]2
Reactant: CNC(N)=S
Reactant: N#Cc1ccc2c(c1)CC(Br)C2=O
Solvent: CC(C)=O
Product: Br
Product: CNC1=NC2(O)c3ccc(C#N)cc3CC2S1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
236 mg of 2-bromo-1-oxoindane-5-carbonitrile are dissolved in 10 ml of acetone and, at 0° C., 135 mg of N-methylthiourea are added. The mixture is stirred at room temperature for 3 h and at ice-bath temperature for 90 minutes. The precipitate is filtered off with suction, washed with acetone and dried in vacuo. The hydrobromide of 3a-hydroxy-2-methylamino-8,8a-dihydro-3aH-indeno[1,2-d]thiazole-6-carbonitrile is obtained with a melting point of 287-288° C.