Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(CSC2NC(C)=C(C(OCC)=O)C([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)N=2)=CC=1.N1C=CC=CC=1.ClC(OC(C)C)=O.[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][S:54][C:55]2[N:56]([C:76]([O:78][CH:79]([CH3:81])[CH3:80])=[O:77])[CH:57](C3C=CC=C([N+]([O-])=O)C=3)[C:58]([C:62]([O:64][CH2:65][CH3:66])=[O:63])=[C:59]([CH3:61])[N:60]=2)=[CH:49][CH:48]=1>ClCCl>[CH3:81][CH:79]([O:78][C:76]([N:56]1[CH2:57][C:58]([C:62]([O:64][CH2:65][CH3:66])=[O:63])=[C:59]([CH3:61])[N:60]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[CH:55]1[S:54][CH2:53][C:50]1[CH:49]=[CH:48][C:47]([O:46][CH3:45])=[CH:52][CH:51]=1)=[O:77])[CH3:80]
Reactant: CCOC(=O)C1=C(C)N=C(SCc2ccc(OC)cc2)N(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc([N+](=O)[O-])c1
Agent: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)N(c2cccc([N+](=O)[O-])c2)C(SCc2ccc(OC)cc2)N(C(=O)OC(C)C)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1,4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester (2.0 g., 4.5 mmole) in dichloromethane (20 ml.) containing pyridine (0.71 g., 9.1 mmole) is cooled to -10° and treated dropwise with a solution of isopropyl chloroformate (0.66 g., 5.4 mmole) in dichloromethane (3 ml.). After stirring at room temperature for 16 hours, dichloromethane is added and the solution is washed with water, 1N hydrochloric acid, sodium bicarbonate, and brine. The dried solution is evaporated to give 2.6 g. of an oil. Flash chromatography using dichloromethane gives 2.3 g. of 2-[[(4-methoxyphenyl)methyl]thio]-4-methyl-6-(3-nitrophenyl)-1,5(6H)-pyrimidinedicarboxylic acid, 5-ethyl 1-(1-methylethyl) ester as an oil.
Reaction SMILES: CN(P(N(C)C)N(C)C)C.Br[C:12](Br)([F:14])[F:13].[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=O.O>COCCOCCOCCOC>[F:13][C:12]([F:14])=[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH3:16]
Reactant: COc1ccc(C(C)=O)cc1
Reactant: FC(F)(Br)Br
Agent: CN(C)P(N(C)C)N(C)C
Solvent: COCCOCCOCCOC
Solvent: O
Product: COc1ccc(C(C)=C(F)F)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
At between 0° C. and −10° C., 181 g of tris(dimethylamino)phosphine in 75 ml of triglyme were added dropwise to 84 g of dibromodifluoromethane in 50 ml of triglyme. At 0° C., 30 g of 4-methoxyacetophenone dissolved in 125 ml of triglyme were subsequently added dropwise and the mixture was stirred for ½ h at room temperature and for 24 h at 80° C. The mixture was cooled to room temperature, mixed with 200 ml of water and extracted with petroleum ether. The combined organic phases were dried and concentrated. For purification, the crude product was chromatographed over silica gel (petroleum ether/ethyl acetate 5:1), to give the title product as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O[C@@H:19]1[CH:24]2C[CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1>C1(C)C=CC=CC=1>[N:21]12[CH2:22][CH2:23][CH:24]([CH2:19][CH2:20]1)[C@@H:1]([O:2][C:3](=[O:17])[C:4]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:26]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COC(=O)C(O)(c1ccccc1)c1ccco1
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1ccccc1)c1ccco1
Temperature: 25 °C

Procedure:
3.24 g (0.014 mols) of (Furan-2-yl)-hydroxy-phenylacetic acid methyl ester were dissolved in 85 ml of toluene. To this solution were added 2.08 g (0.016 mols) of 3-(R)-hydroxy-1-azabicyclo[2.2.2]octane and 0.224 g (5.6 mmols) of HNa (60% dispersion in mineral oil). The mixture was refluxed with continuous removal of distillate and when necessary replacement with fresh toluene for 1.5 hours. The cooled mixture was extracted with 2N HCl acid, the aqueous layer washed with ethyl acetate, basified with K2CO3 and extracted with CHCl3. The organic layer was dried over Na2SO4 and evaporated. The oil obtained (3.47 g) crystallised after cooling at room temperature. This solid was suspended in hexane and filtered. The yield was 2.5 g (54%) of a mixture of diastereoisomers, mp: 140-142° C.; GC/MS [M]+: 327;
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH2:7]([CH:10]([CH2:22][CH:23]=[CH2:24])[CH2:11][O:12][SiH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH:8]=[CH2:9]>C1(C)C=CC=CC=1>[CH2:7]([CH:10]([CH2:22][CH:23]=[CH2:24])[CH2:11][O:12][SiH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH2:1])=[CH:16][CH:15]=1)[CH:8]=[CH2:9]
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(C=O)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=CCC(CC=C)CO[SiH2]c1ccc(C=C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
Firstly, PPh3MeI (317 mg, 0.78 mmol: Me=methyl) was added with dist. toluene (4 mL). The resultant mixture was then added with KOt-Bu (88 mg, 0.78 mmol) at 0° C., and then was stirred under a nitrogen atmosphere at 0° C. for 30 minutes to obtain a mixture. Subsequently, the obtained mixture was added dropwise with a mixed solution (2 mL) of 4-(diallylethoxysilyl)benzaldehyde (204.2 mg, 0.78 mmol) obtained in Example 12 and dist. toluene under a nitrogen atmosphere at 0° C. The resultant mixture was stirred under a nitrogen atmosphere at 0° C. for 1.5 hours, and then was stirred at room temperature for 17 hours to obtain a reaction mixture. After that, a salt contained in the reaction mixture was removed through a celite filtration process. The organic layer thus obtained was then concentrated under reduced pressure to obtain a crude product. The obtained crude product was separated and purified by silica gel column chromatography (hexane/EtOAc=20/1) to obtain 4-(diallylethoxysilyl)styrene (134.3 mg, 66% yield).
Reaction SMILES: O[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[N:4][CH:3]=1.Cl[Si](C)(C)[CH3:13].C1COCC1.[CH3:21][OH:22]>>[CH3:21][O:22][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:13])=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(O)n1
Reactant: C[Si](C)(C)Cl
Reactant: CO
Solvent: C1CCOC1
Product: COC(=O)c1cncc(OC)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22 %

Procedure:
To 0.42 g (0.003 mol) of 6-hydroxy-pyrazinoic acid suspended in 10 mL of anhydrous methanol was added 4 mL of (0.030 mol) of chlorotrimethylsilane. The resultant mixture was allowed to stir for 48 hours at room temperature during which time the suspension became a solution. It is expected that this procedure may be used to convert 6-hydroxypyrazinoic acid to any 6-alkoxypyrazinoic ester by the use of the appropriate alcohol and, when the alcohol is not a liquid, the use of an inert solvent such as THF. The solvent and excess chlorotrimethylsilane were removed in vacuo by rotary evaporation. The crude product was purified by column chromatography on silica gel with a hexane-ethyl acetate gradient to yield 0.11 g (22%) of methyl 6-methoxypyrazinecarboxylate.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:13]1[C:18](=[O:19])[NH:17][C:16](=[O:20])[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:14]1)(=O)C.N1C=CC=CC=1.Cl.O>O1CCOCC1>[C:21]1([C:15]2[C:16](=[O:20])[N:17]([C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:18](=[O:19])[NH:13][N:14]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)n1nc(-c2ccccc2)c(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccccc1)n1c(=O)[nH]nc(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
Benzoyl chloride (0.253 ml, 2.180 mmol) was added to a solution of 2-acetyl-6-phenyl-1,2,4-triazine-3,5(2H,4H)-dione (420 mg, 1.817 mmol) and pyridine (0.441 ml, 5.45 mmol) in 1,4-Dioxane (5 ml) at 5° C. Mixture was stirred at r.t. overnight. Solids were filtered off and rinsed with DCM, solvent was concentrated under reduced pressure. Residue was diluted in ethanol (20 ml), hydrochloric acid 37% in water (0.250 ml, 3.04 mmol) was added and mixture heated at 90° C. for 3 h. Solvent was concentrated and residue purified on biotage 25M silica cartridge, eluting with Cy/AcOEt 8:2 to AcOEt 100%, to give 87 mg of title compound (16% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[O:14]([CH2:21][CH2:22][NH2:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:14]([CH2:21][CH2:22][NH:23][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCOc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Product: O=C(NCCOc1ccccc1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-phenoxyethylamine. The product was purified by chromatography on silica gel eluting with methanol/dichloromethane (1:19) to give the title compound as a yellow solid. δH (CD3OD): 3.79 (2H, t), 4.17 (2H, t), 6.88–6.97 (3H, m), 7.08 (1H, s), 7.16 (2H, t), 7.67 (1H, s), 8.58 (1H, s); m/z (ES+)=316 [M+H]+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([O:16]C(OC(C)(C)C)=O)=O)([CH3:12])([CH3:11])[CH3:10].C([N:27](C(C)C)CC)(C)C>C1COCC1>[C:14]([C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([NH2:27])[CH:3]=1)([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Nc1ccc(O)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(O)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a solution of 4-aminophenol (10.9 g, 100 mmol) in THF (150 mL) cooled in an ice bath was added di-tert-butyl-dicarbonate (21.8 g, 100 mmol) followed by diisopropylethylamine (17.4 mL, 100 mmol). The mixture was stirred at room temperature overnight and concentrated. The residue was taken up in ethyl acetate and the solution was washed with brine, dried (MgSO4), and concentrated. Purification on a silica gel column eluting with 5% methanol/40% ethyl acetate hexane gave 4Boc-aminophenol (20.1 g, 96%). MS(NH3—CI): (M+NH3+H)=227.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:20][C:21]1[CH:22]=[CH:23][C:24]2[O:34][CH2:33][C:27]3([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:25]=2[CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([N:30]3[CH2:31][CH2:32][C:27]4([C:25]5[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=5[O:34][CH2:33]4)[CH2:28][CH2:29]3)=[O:18])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Reactant: Fc1ccc2c(c1)C1(CCNCC1)CO2
Agent: Cl
Product: CCOC(=O)c1cnn2c(O)c(C(=O)N3CCC4(CC3)COc3ccc(F)cc34)cnc12
Yield: 64.3 %

Procedure:
In the same manner as in Example 1, step 2 and using 3-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.416 g, 1.66 mmol) obtained in Example 19, step 2 and 5-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.500 g, 1.99 mmol) obtained in Reference Example 3, the title compound (0.470 g, 54%) was obtained.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].[C:13](Cl)(=[O:15])[CH3:14].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:13](=[O:15])[CH3:14])=[C:7]([O:11][CH3:12])[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)Cl
Reactant: COc1cccc(CC(C)C)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc(CC(C)C)ccc1C(C)=O

Procedure:
46 g of 3 -isobutyl anisole are added to 500 cc of absolute benzene, and 22 g of acetyl chloride are added. 73 g of tin(IV) chloride are subsequently added dropwise while stirring and cooling at 5°-10°. After stirring at 23° for 16 hours, the reaction mixture is poured on ice, washed once with 2 N hydrochloric acid, twice with a 2 N caustic soda solution and once with water, and the water phases are again extracted twice with benzene. The organic phases are dried over anhydrous sodium sulphate and concentrated. The desired product is obtained in amorphous, pure form from methanol with the careful addition of water. NMR spectrum (CDCl3) inter alia δ=0.9 d (J=6 Hz), 1.3-2.3 m, 2.45 s, 2.55 s, 3.9 s, 6.6-6.9 m, 7.65 d (J=8.6).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([O:8][C:9](=[O:32])[CH2:10][CH2:11][NH:12][C:13](=[O:31])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[NH2:30])[CH3:7]>C(Cl)Cl.O>[CH2:6]([O:8][C:9](=[O:32])[CH2:10][CH2:11][NH:12][C:13](=[O:31])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=2)[CH:17]=[CH:16][C:15]=1[NH:30][C:3](=[O:4])[CH2:2][Br:1])[CH3:7]
Reactant: O=C(Br)CBr
Reactant: CCOC(=O)CCNC(=O)c1cc(OCc2ccc(C#N)cc2)ccc1N
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1cc(OCc2ccc(C#N)cc2)ccc1NC(=O)CBr
Reaction time: 0.5 h

Procedure:
A solution of 1.44 g (7.15 mmol, 1.1 eq.) bromoacetyl bromide in 10 mL of methylene chloride was added over 10 mins. to a stirred biphasic solution of 2.38 g (6.5 mmol, 1.0 eq.) of N-(5-(4-cyanobenzyloxy)-2-aminobenzoyl)-β-alanine ethyl ester in 100 ml of methylene chloride and 30 mL of water cooled to 0° C. The reaction was complete in 1/2 hr. (TLC, 96 CH2Cl2 :4 MeOH, product Rf =0.71) and was partitioned between dilute aqueous sodium bicarbonate and methylene chloride. The organic phase was dried over sodium sulfate, filtered and concentrated to give 3.11 g (98%) of off white crystals of N-(5-(4-cyanobenzyloxy)-2-(bromoacetyl)aminobenzoyl)-β-alanine ethyl ester which was used unpurified but may be recrystallized from ethyl acetate/hexane. 1H NMR (CDCl3, δTMS) 8.41(1H,d,ArH), 7.60 (4H,abq,ArH), 7.02(2H,d,ArH), 6.98(1H,t,NH), 5.12 (2H,s,ArCH2O),4.16 (2H,q,COOCH2),3.97 (2H,s,CH2Br), 3.68 (2H, q, NCH2), 2.61 (2H,t,CH2COO), 1.25 (3H,t, CH3). IR (KBr): 3389(NH), 3355(NH), 2226(CN), 1735(ester), 1675,1642(amides),1609,1523,1423,1244,1184,819. MS (FAB,M+H+) cald for C22H22N3O5Br 488.3, found (M+H+) 489.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[CH2:13][CH2:12][N:11](C(OCC)=O)[CH2:10][CH2:9]1)=[O:7].[BrH:19]>O>[BrH:19].[NH:11]1[CH2:12][CH2:13][CH:8]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:9][CH2:10]1
Reactant: CCOC(=O)N1CCC(C(=O)c2cccs2)CC1
Agent: Br
Solvent: O
Product: O=C(c1cccs1)C1CCNCC1
Yield: 85 %

Procedure:
A mixture of 20 parts of ethyl 4-(2-thienylcarbonyl)-1-piperidinecarboxylate and 120 parts of hydrobromic acid solution 48% in water is stirred and refluxed for 2 hours. The reaction mixture is cooled and the precipitated product is filtered off. It is washed with 2-propanol and dried, yielding 17 parts (85%) of (4-piperidinyl) (2-thienyl)methanone hydrobromide.
Reaction SMILES: [C:1]1(=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:16]O.C([O-])(=O)C.[Na+]>C(O)C.O>[CH:1]1([NH2:16])[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCCc2c1[nH]c1ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC1CCCc2c1[nH]c1ccccc21
Reaction time: 0.25 h

Procedure:
To a solution of 2,3,4,9-tetrahydro-1H-carbazol-1-one (1.5 g, 8.10 mmol) in ethanol (20 mL) was added a solution of hydroxylamine hydrochloride (1.13 g, 16.2 mmol) in water (10 mL) and a solution of sodium acetate (2.19 g, 26.7 mmol) in water (10 mL). The reaction mixture was heated at reflux for 2 h, cooled, and concentrated. The residue was diluted with water and extracted with ethyl acetate (2×100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to a brown solid. The oxime was dissolved in THF (80 mL) and lithium aluminium hydride (1.0 M in THF, 24.3 mL) was added dropwise. The reaction was heated at reflux for 7 h and cooled in an ice bath. Methanol was added dropwise until bubbling ceased. The mixture was diluted with aqueous Na/K tartrate, stirred vigorously for 15 min and extracted with ethyl acetate (2×100 mL). The extracts were combined, dried over sodium sulfate, filtered, and concentrated. The crude amine was purified by flash chromatography on silica (2% to 5% methanol/methylene chloride gradient) to provide 2,3,4,9-tetrahydro-1H-carbazol-1-amine as a brown oil. The oil was diluted in diethyl ether and HCl (1.0 M in diethyl ether) was added. The resulting precipitate was collected by filtration to provide 2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride (760 mg, 42%). as a light brown solid. 1H-NMR (CD3OD): δ 7.54 (d, 1H), 7.42 (d, 1H), 7.22 (t, 1H), 7.09 (t, 1H), 4.66 (t, 1H), 2.95-2.73 (m, 2H), 2.39-2.28 (m, 1H), 2.18-2.03 (m, 3H); MS m/z (M+1) 187.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[F:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl>[F:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:1](=[O:3])[CH3:2])[CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)Cl
Reactant: Fc1cccc(CC[C@@H]2CCCN2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC[C@H]1CCc1cccc(F)c1
Reaction time: 1.5 h

Procedure:
Acetyl chloride (0.29 ml) was added to a solution of N,N-diisopropyl-N-ethylamine (0.71 ml) and (R)-2-[2-(3-fluorophenyl)ethyl]-pyrrolidine (Intermediate 233, 0.39 g) in DCM (30 ml) and the mixture was stirred for 1.5 hours. The mixture was washed with 1M HCl, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 1-{(R)-2-[2-(3-fluorophenyl)ethyl]-pyrrolidin-1-yl}ethanone (0.48 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:21][CH3:22])=[C:17]([CH:20]=1)[CH:18]=O.[CH2:23]=[C:24]([CH3:26])[CH3:25].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:18]([C:17]1[CH:20]=[C:13]([Br:12])[CH:14]=[CH:15][C:16]=1[CH2:21][CH3:22])[CH2:23][C:24]2([CH3:26])[CH3:25])=[O:11]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: C=C(C)C
Reactant: CCc1ccc(Br)cc1C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCc1ccc(Br)cc1C1CC(C)(C)c2cc(C(=O)OC)ccc2N1
Temperature: 85 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
To a stirred solution of 4-amino-benzoic acid methyl ester (1 g, 6 mmol) and 5-bromo-2-ethyl-benzaldehyde (1.2 g, 5.6 mmol) in acetonitrile (40 mL) were added isobutene (1.7 mL, 24 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (0.55 g, 0.9 mmol). The resulting mixture was stirred at 85° C. for 16 h in sealed tube. The mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL×2) and brine (50 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(5-bromo-2-ethyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.5 g, 64%) as a light yellow solid: MS (ESI) M+1=416.0.
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([P:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.O.[Ru:24](Cl)([Cl:26])[Cl:25]>CO>[Ru:24]([Cl:26])[Cl:25].[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([P:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[C:4]2[CH:5]=[CH:6][C:1]([CH3:22])=[CH:2][CH:3]=2)=[CH:16][CH:17]=1.[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([P:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[C:4]2[CH:5]=[CH:6][C:1]([CH3:22])=[CH:2][CH:3]=2)=[CH:16][CH:17]=1.[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([P:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[C:4]2[CH:5]=[CH:6][C:1]([CH3:22])=[CH:2][CH:3]=2)=[CH:16][CH:17]=1
Reactant: Cl[Ru](Cl)Cl
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Solvent: CO
Solvent: O
Product: Cl[Ru]Cl

Procedure:
Using the procedure of Example 1, 50 mls. of methanol, 6.0 grams of tri-paratolylphosphine and 1.0 gram of ruthenium trichloride hydrate are stirred and heated at reflux under nitrogen for 24 hours to form tris(tri-paratolylphosphine) ruthenium dichloride as an insoluble powder which is recovered by filtration (4.2 grams). A portion of this powder (0.5 gram) is dissolved in a mixture containing 50 mls. of methanol and 0.5 gram of anhydrous sodium acetate. The resulting mixture is heated with stirring at reflux temperature under nitrogen for 5 hours to form yellow solids (0.21 gram) which are identified as the desired hydridoacetato ruthenium tris(tri-paratolylphosphine).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.[CH2:13]([C@H:15]1[CH2:20][C@H:19]2[C@H:21]3[C@H:30]([CH2:31][CH2:32][C@:17]2([CH3:18])[C@H:16]1[O:34][C:35](=[O:38])[CH2:36]Br)[C@@H:29]1[C:24](=[CH:25][C:26](=[O:33])[CH2:27][CH2:28]1)[CH2:23][CH2:22]3)[CH3:14]>CC(C)=O>[CH2:13]([C@H:15]1[CH2:20][C@H:19]2[C@H:21]3[C@H:30]([CH2:31][CH2:32][C@:17]2([CH3:18])[C@H:16]1[O:34][C:35](=[O:38])[CH2:36][O:8][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:29]1[C:24](=[CH:25][C:26](=[O:33])[CH2:27][CH2:28]1)[CH2:23][CH2:22]3)[CH3:14]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: O=C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)c1ccccc1
Yield: 89.1 %

Procedure:
In 30 ml of acetone is dissolved 0.49 g of benzoic acid, and 2 ml of 2 N-NaOH and 5 ml of water are added, followed by addition of 0.88 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one. The mixture is refluxed for 3 hours. After cooling, the solvent is distilled off under reduced pressure and the residue is extracted with 100 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is chromatographed on a silica gel column. After passage of 350 ml of diisopropyl ether, the solvent is distilled off under reduced pressure. To the residue is added a small amount of diisopropyl ether, followed by filtration to give 0.86 g of the above-identified compound as a white powder.
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]=1[C:14]([OH:16])=O)[CH3:2].Cl.[Cl:18][CH2:19][CH2:20][CH2:21][NH2:22].C(N(CC)CC)C.O>CN(C)C=O>[Cl:18][CH2:19][CH2:20][CH2:21][NH:22][C:14]([C:4]1[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][O:7][C:3]=1[CH2:1][CH3:2])=[O:16]
Reactant: CCc1onc(-c2ccccc2)c1C(=O)O
Reactant: NCCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCc1onc(-c2ccccc2)c1C(=O)NCCCCl
Yield: 80.2 %

Procedure:
A solution of 3.1 g of 5-ethyl-3-phenylisoxazole-4-carboxylic acid (prepared as described in J. Org. Chem. 1985, 50, 5660-5666), 2.94 g of 3-chloropropylamine hydrochloride, 2.62 mL of 92% diethyl cianoposphonate and 4.38 mL of triethylamine in 50 mL of anhydrous dimethylformamide was stirred at room temperature for 3 hours, poured into 500 mL of water and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water, dried (sodium sulphate) and the solvent was evaporated under vacuum. The crude was purified by flash chromatography (ethyl acetate-petroleum ether 3:7) to give 3.35 g (73%) of the title compound. M.p. 75-76° C.