Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([NH2:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:21][CH2:22][S:23](Cl)(=[O:25])=[O:24].O>C1COCC1.CCCCCC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3=[N:17][S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][N:13]3[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)c1ccc(-c2cccnc2N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
A mixture of 3-(4-tert-butylphenyl)pyridin-2-amine (350 mg) in dehydrated THF (5 mL) was added to a mixture of sodium hydride (60%, 309 mg) and 2-chloroethanesulfonyl chloride (756 mg) in dehydrated THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, and water and hexane were added. The resulting precipitate was collected by filtration, and washed with water and diisopropyl ether to give the title compound (376 mg) as a white solid. The obtained solid was crystallized from THF, acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:16]=1)[C:14]#[N:15].[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)#[CH:18]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:26][C:25]([F:27])([F:28])[C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])[CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1cncc(Br)c1
Reactant: C#Cc1cccc(C(F)(F)F)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1cncc(C#Cc2cccc(C(F)(F)F)c2)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
Add triethylamine (1.93 mL, 13.64 mmol), copper (I) iodide (37.3 mg, 0.190 mmol) and bis(triphenylphosphine)palladium (II) dichloride (120 mg, 0.170 mmol) to a solution of 5-bromonicotinonitrile (624 mg, 3.41 mmol) and 1-ethynyl-3-trifluoromethylbenzene, (prepared essentially as described in PREPARATION 13), (580 mg, 3.41 mmol) in ethyl acetate (3 mL). Stir in a sealed tube at 50° C. for 18 h, concentrate and purify by silica gel chromatography, eluting with 100:0 to 0:100 hexanes:ethyl acetate to give the title compound (400 mg, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=4[Cl:28])[C:22](O)=[O:23])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:60][NH:61][CH2:62][CH2:63][OH:64]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([C:22](=[O:23])[N:61]([CH2:62][CH2:63][OH:64])[CH3:60])[CH:25]=[CH:26][C:27]=4[Cl:28])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)O)ccc1Cl
Reactant: CNCCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(CCO)C(=O)c1ccc(Cl)c(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c1
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a mixture of 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoic acid (3 g, 6.09 mmol) in THF (50 mL) was added EDCI (2.34 g, 12.18 mmol), HOBt (1.23 g, 9.13 mmol), DIPEA (5 mL) and 2-(methylamino)ethanol (0.69 g, 9.13 mmol) by sequence under nitrogen atmosphere at room temperature. The reaction mixture was stirred overnight, diluted with water. The resulting precipitate was washed with water and EtOAc to give 8-bromo-N-(2-chloro-5-((2-hydroxyethyl)(methyl)carbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (2.8 g, yield: 87%). LC-MS: (ESI, m/z)=549 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CS(C)=O>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:12]#[N:13]
Reactant: BrCCCCCBr
Reactant: COc1ccc(C(C#N)Sc2ccccn2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(C(C#N)(CCCCCBr)Sc2ccccn2)cc1OC
Yield: 81.5 %

Procedure:
The title compound is prepared by the procedure of Example 113 using 1.3 g of product from Example 117, 0,218 g of 50% sodium hydride, 2.15 g of 1,5-dibromopentane and 16 ml of dimethyl sulfoxide to give after chromatography 1.61 g of the desired product as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([OH:13])=O)[CH:8]=2)[NH:3]1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[CH3:35][O:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH2:40]>CN(C)C=O.C(#N)C>[CH3:35][O:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH:40][C:11]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH2:10]2)=[O:13]
Reactant: COc1ccccc1CN
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccccc1CNC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
To a solution of 2-oxoindoline-5-carboxylic acid (0.200 g, 1.12 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.477 g, 2.47 mmol), diisopropylethylamine (0.586 mL, 3.37 mmol) and catalytic amount of N,N-dimethylaminopyridine in N,N-dimethylformamide/acteonitrile (1:1, 4 mL) was added 2-methoxybenzylamine (0.295 mL, 2.26 mmol) and the reaction mixture stirred at room temperature for 1 h. The solvent was evaporated and the crude material was purified on a short silica gel column using dichloromethane containing 5% methanol as the eluent. This was followed by triturating from ethyl acetate to give 0.10 g (33% yield) of the yellow title compound: 1H NMR (DMSO-d6, 400 MHz) δ 10.60 (br s, 1H), 8.65 (t, J=6 Hz, 1H), 7.79-7.77 (m, 2H), 7.21 (t, J=8 Hz, 1H), 7.15 (d, J=8 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 6.90-6.84 (m, 2H), 4.42 (d, J=6 Hz, 2H), 3.81 (s, 3H), 3.53 (s, 2H); MS (ES) m/z 297 (M++1), m/z 295 (M−−1).
Reaction SMILES: O1CCC[CH2:2]1.[OH:6][C:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][C:9](=[O:17])[C:8]=1[C:18](=[O:33])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28](=[O:32])[CH2:29][O:30][CH3:31])[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.CO.ClCCl>[CH3:2][O:6][C:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][C:9](=[O:17])[C:8]=1[C:18](=[O:33])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28](=[O:32])[CH2:29][O:30][CH3:31])[CH:22]=1
Reactant: C1CCOC1
Reactant: COCC(=O)Nc1cccc(C=CC(=O)c2c(O)c3ccccc3oc2=O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: COCC(=O)Nc1cccc(C=CC(=O)c2c(OC)c3ccccc3oc2=O)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a mixture of 5 ml of tetrahydrofuran and 6 ml of dichloromethane were added 0.59 g of 4-hydroxy-3-[3-[3-(methoxyacetylamino)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one, 0.45 g of triphenylphosphine and 55 mg of methanol, and to the mixture was added dropwise 0.74 g of a 40% toluene solution of diethyl azodicarboxylate. The mixture was stirred at room temperature for 40 minutes, and the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.18 g of 4-methoxy-3-[3-[3-(methoxyacetylamino)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one [Compound No. (22d)].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[C:30](Cl)(=[O:39])/[CH:31]=[CH:32]/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>CN(C)C=O.ClCCl.O1CCOCC1.O>[C:30]([N:11]1[CH2:12][CH2:13][NH:8][C@H:9]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:10]1)(=[O:39])/[CH:31]=[CH:32]/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(/C=C/c1ccccc1)N1CCN[C@H](Cc2c[nH]c3ccccc23)C1
Reaction time: 3 h
Yield: 60.6 %

Procedure:
To a stirred mixture of (2R)-1-(tert-butoxycarbonyl)-2-(1H-indol-3-yl-methyl)piperazine (250 mg) and potassium carbonate (165 mg) in dimethylformamide (1 ml) was added trans-cinnamoyl chloride (150 mg) at room temperature. The resulting mixture was stirred for 3 hours and then poured into water. Extraction with ethyl acetate followed by drying over magnesium sulfate and evaporation in vacuo gave a syrup, which was dissolved in dichloromethane (2 ml). A solution of 4N hydrogen chloride in dioxane solution (1 ml) was added to the solution at ice-bath temperature and the resulting mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate solution. The organic layer was separated, washed with brine and dried over magnesium sulfate. Evaporation of the solvent in vacuo gave (3R)-1-(transcinnamoyl)-3-(1H-indol-3-yl-methyl)piperazine (166 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][S:10]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][N:18]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:20])[CH2:9][S:10]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][N:18]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(CS(=O)(=O)c1ccc(=O)[nH]n1)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=c1ccc(S(=O)(=O)CC(O)c2ccc(Cl)cc2)n[nH]1
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A suspension was prepared of 6-[2-(4-chloro-phenyl)-2-oxo-ethanesulfonyl]-2H-pyridazin-3-one (1.0 mmol, 312 mg) prepared according to Example 18 in methanol (10 mL). Sodium borohydride (1.5 mmol, 55 mg) was added to the suspension at room temperature and stirred for 1 hour. The reaction mixture was evaporated and the residue was triturated with 10% hydrochloric acid (5 mL). The resulting white precipitate was filtered and air-dried to afford the title compound (69%, 218 mg); mp, 178-179° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@@:9]12[C:15]([CH3:17])([CH3:16])[C@@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(O[C:27]([N:29](C)[NH:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[Cl:38])=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[Cl:38][C:32]1[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:31]=1[N:30]1[C:18](=[O:19])[C:11]2[C@H:12]3[C:15]([CH3:17])([CH3:16])[C@:9]([CH3:8])([CH2:14][CH2:13]3)[C:10]=2[N:29]1[CH3:27]
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Reactant: CN(Nc1cc(Cl)ccc1Cl)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: C1COCCO1
Product: Cn1c2c(c(=O)n1-c1cc(Cl)ccc1Cl)[C@@H]1CC[C@@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 6.6 %

Procedure:
Triethylamine (440 μL, 3.2 mmol) was added to solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 329 mg, 1.5 mmol) in 1,2-dichloroethane (4 mL) over 1 min. Then a solution of N′-(2,5-dichloro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (300 mg, 1.03 mmol) in 1,2-dichloroethane (8 mL) was added over 2 min. The reaction mixture was stirred at room temperature for 15 min and then heated in an oil bath at 50° C. for 30 min. An additional portion of N′-(2,5-dichloro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (290 mg, 1.0 mmol) in 1,2-dichloroethane (4 mL) was added and the mixture was heated in an oil bath at 50° C. for 1.5 h. A solution of HCl in dioxane (4 M; 8 mL, 32 mmol) was added and the mixture was heated in an oil-bath at 100° C. for 1 h. The reaction mixture was allowed to cool, silica gel was added, the solvent was evaporated and the mixture was purified using an ISCO 40 g column, eluting with 60-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated successively with methanol and diethyl ether, and then dried under high vacuum at 95° C. to give (4R,7S)-2-(2,5-dichloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (24 mg, 37%) as a pale yellow solid. ES(+)-MS (M+H) 351.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[S:8])[NH2:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Cl[CH2:15][CH:16]=O>C(O)C>[N+:11]([C:3]1[CH:4]=[C:5]([C:6]2[S:8][CH:15]=[CH:16][N:7]=2)[CH:9]=[CH:10][C:2]=1[NH2:1])([O-:13])=[O:12]
Reactant: NC(=S)c1ccc(N)c([N+](=O)[O-])c1
Reactant: O=CCCl
Solvent: CCO
Product: Nc1ccc(-c2nccs2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 18.6 %

Procedure:
To a stirred suspension of 220 (500 mg, 2.53 mmol) in ethanol (15 mL) was added chloroacetaldehyde (50% solution in water, 0.796 ml, 5.0 mmol). The mixture was heated at 80° C. for 18 hours, evaporated under reduced pressure and the residue was dissolved in DCM, washed with brine, dried with sodium sulfate and concentrated. The crude material was purified by flash chromatography on silica gel, eluents hexane-EtOAc (4:1), then EtOAC (100%), to afford the title compound 221a (104 mg, 19% yield). 1H NMR: (CD3OD) δ (ppm): 8.62 (d, J=2.0 Hz, 1H), 7.91 (dd, J=2.4, 8.8 Hz, 1H), 7.78 (d, J=3.2 Hz, 1H), 7.51 (d, J=3.2 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H). MS: (calc.) 221.2; (obt.) 222.1 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:22]3[CH2:25][CH2:24][CH2:23]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=3)=[CH:4][CH:3]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N+]([O-])=O)=C[CH:31]=1)=[O:28].N1C=CC=CC=1.C1(C(C)O)CC1>C(Cl)Cl.ClCCCl>[CH:35]1([CH:30]([O:29][C:27](=[O:28])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]([CH:22]4[CH2:23][CH2:24][CH2:25]4)[C:10]4[C:15]([C:16]=3[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=4)=[CH:6][CH:7]=2)[CH3:31])[CH2:34][CH2:33]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CCC3)c2c1
Agent: CC(O)C1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCOc1ccc2c(C#N)c(-c3ccc(NC(=O)OC(C)C4CC4)cc3)n(C3CCC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
2-(4-Aminophenyl)-1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (50 mg, 0.15 mmol), prepared as in example 1CM, step B, ias combined with 4-nitrophenyl chloroformate (76 mg, 0.38 mmol), DCE (0.5 mL), and pyridine (30 μL, 0.37 mmol). This suspension is stirred at room temperature for 1 h. Rac-cyclopropyl methyl carbinol (100 μL, 0.98 mmol) is added. This mixture is heated at 75° C. overnight. The reaction mixture is then diluted in CH2Cl2 and is washed with dilute aqueous NaOH to remove the yellow nitrophenol byproduct. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2) yields rac-[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (40 mg, 60%) as a white solid.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH:11]1[O:15][CH2:14][CH2:13][O:12]1)CCC.[N+:24]([C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br)([O-:26])=[O:25].CCCCCC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:24]([C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH:11]1[O:12][CH2:13][CH2:14][O:15]1)([O-:26])=[O:25]
Reactant: CCCC[Sn](CCCC)(CCCC)c1sccc1C1OCCO1
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccccc1Cc1sccc1C1OCCO1
Temperature: 25 °C

Procedure:
A mixture of 2-[2-(tributylstannyl)-3-thienyl]-1,3-dioxolane (8.8 gms, 20 mmols), 2-nitrobenzyl bromide (4.5 gms, 22 mmol) and tetrakis (triphenylphosphine)-palladium (0) (200 mg) is refluxed in degassed toluene for 16 hours under nitrogen atmosphere. At the end, the reaction mixture is cooled to room temperature and filtered through diatomaceous earth. The toluene is removed by concentrating at reduced pressure and the product isolated by silica gel column chromatography by elution with 30% ethyl acetate:hexane to give 4.5 gms. of the desired product as a viscous liquid. Mass Spectrum; M+ 292.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[OH:20][C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CCO.CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:24]2[CH2:25][CH2:26][C:21]([OH:20])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:22][CH2:23]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCC(O)(c3ccccc3)CC2)nc1
Temperature: 140 °C

Procedure:
To a solution of 2-chloro-5-nitropyridine (0.9 g) in EtOH (5 mL) was added N,N-diisopropylethylamine (2.9 mL) and 4-hydroxy-4-phenylpiperidine (1.5 g). The reaction mixture was heated at 140° C. for 20 min by microwave. Then the reaction mixture was cooled to RT, diluted with EtOAc (150 mL), washed with H2O (2×100 mL), saturated NH4Cl (3×100 mL), brine (1×100 mL), dried over Na2SO4, filtered, and concentrated to give B-1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[C:19]1([CH3:33])[CH:24]=[CH:23][C:22]([C:25]2[S:26][CH:27]=[C:28]([CH2:30][CH2:31]O)[N:29]=2)=[CH:21][CH:20]=1.C(OC(=O)CC1N=C(C2C=CC(C)=CC=2)SC=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:31][CH2:30][C:28]2[N:29]=[C:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:33])=[CH:20][CH:21]=3)[S:26][CH:27]=2)=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: Cc1ccc(-c2nc(CCO)cs2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Agent: CCOC(=O)Cc1csc(-c2ccc(C)cc2)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Al+3]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2csc(-c3ccc(C)cc3)n2)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-(2-p-tolyl-thiazol-4-yl)-ethanol (prepared from (2-p-tolyl-thiazol-4-yl)-acetic acid ethyl ester [Collection of Czechoslovak Chemical Communications (2001), 66(12), 1809-1830] with lithium aluminium hydride in analogy to the procedure described in example 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-{3-fluoro-4-[2-(2-p-tolyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-{3-fluoro-4-[2-(2-p-tolyl-thiazol-4-yl)-ethoxy)-phenyl}-propionic acid as light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:22])[C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2ccc(F)cc2NC1=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
To a solution of 1.62 g (5.46 mmol) ((S)-2-Fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester in 20 ml tetrahydrofurane were added at −75° C. 4.57 g (5.46 mmol) lithium bis(trimethylsilyl)amide (20% in tetrahydrofurane) followed after 10 minutes by 0.34 ml (6.55 mmol) methyliodide. Stirring was continued overnight while the mixture was allowed to warm to room temperature. The solvent was removed by distillation and 300 ml saturated aqueous sodium hydrogensulfate solution was added. Extraction with ethylacetate and chromatography on silicagel with ethylacetate/heptane 2:8 yielded 0.87 g (51%) ((S)-2-fluoro-9-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester as white solid, MS m/e (%): 333 (M+Na+, 15), 311 (M+H+, 70), 255 (100).
Reaction SMILES: O[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Cl-].[Al+3].[Cl-].[Cl-].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:8]1([C:2]2([C:15]3[O:14][CH:18]=[CH:17][CH:16]=3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: c1ccoc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: c1ccc(C2(c3ccco3)CCNCC2)cc1
Reaction time: 3 h
Yield: 75.4 %

Procedure:
To a solution of 4-hydroxy-4-phenyl-piperidine(0.50 g, 2.8 mmol) in 10 ml of CH2Cl2 at 25° C. was added furan (0.40 ml, 5.6 mmol) and aluminum chloride (0.75 g, 5.6 mmol) in a portion and the resulting heterogeneous solution was stirred for 3 h. Reaction mixture was poured into cold aqueous NaHCO3 and extracted with EtOAc. Organic layer was dried over Na2SO4 and concentrated in vacuo to provide oily residue, which was purified by column chromatography (30% NH3 sat'd MeOH/EtOAc) to yield 0.48 g (76%) of the desired product as an oil.