Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:59][C:60]1[CH:61]=[C:62]([CH:65]=[CH:66][CH:67]=1)[CH2:63][NH2:64].Cl>CN(C=O)C.O>[F:59][C:60]1[CH:61]=[C:62]([CH:65]=[CH:66][CH:67]=1)[CH2:63][NH:64][C:8](=[O:10])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: NCc1cccc(F)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(-c2ccccc2)cc1)NCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.2 %

Procedure:
To a solution of 4-biphenyl acetic acid (2.00 g, 9.42 mmol) in DMF (20 ml) was added DIEA (3.29 ml, 18.84 mmol) and stirred at room temperature for 15 min, then PyBOP (4.90 g, 9.42 mmol) added and the stirring continued for further 30 min, then 3-fluorobenzylamine (1.18 g, 9.42 mmol) added and the stirring continued for 24 hrs, then the reaction mixture poured on to ice cooled water acidified with (10 ml) 1 N HCl and extracted with ethyl acetate (100 ml) and the organic layer washed with saturated solution of NaHCO3, water and brine, dried over Na2SO4 and the solvent removed under vacuum to give a white powder of the desired compound (1.00 g) 33% yield. Another method involves the acid chloride coupling method described below.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)O)=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+].[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:8][CH:7]=1
Reactant: C1CNCCN1
Reactant: OC(c1ccccc1)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
Thionyl chloride was added to (±)-(4-fluorophenyl)phenylmethanol, and the mixture was stirred at a room temperature overnight. After the completion of the reaction was confirmed by HPLC, ethyl acetate was added thereto, and water was added to the mixture. The resulting mixture was neutralized with sodium hydrogen carbonate, and then washed water twice and dried over magnesium sulfate. After the solvent was distilled off, the residue was dissolved in acetonitrile, and piperazine (1.7 g, 20 mmol), potassium iodide (3.3 g, 20 mmol), and potassium carbonate (3.3 g, 24 mmol) were added thereto. The mixture was refluxed overnight. After the completion of the reaction was confirmed by HPLC, the insoluble matter was removed, and the solvent was distilled off. The resulting residue was dissolved in ethyl acetate and washed with water 3 times. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off. Thus the title compound (3.9 g, 72.7%) was obtained as a yellowish white solid.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:22](I)[CH3:23].CN(C)C=O>CN(P(N(C)C)(N(C)C)=O)C>[CH2:22]([N:5]1[CH:4]=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2](=[O:1])[N:7]2[N:8]=[CH:9][N:10]=[C:6]12)[CH3:23]
Reactant: CCOC(=O)c1cnc2ncnn2c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1cn(CC)c2ncnn2c1=O
Yield: 37.9 %

Procedure:
Ethyl 7-hydroxy-1,2,4-triazolo [1,5-a]pyrimidine-6-carboxylate (10.4g, 50mM), potassium carbonate (7.0g, 50mM), ethyl iodide (8.0ml, 15mM), dry dimethylformamide (80ml) and hexamethylphosphorotriamide (80ml) was heated at 80° C for 4 hours. The resulting mixture was evaporated in vacuo and water added (100ml). The solution was washed with ether (5 × 100ml) then extracted with ethyl acetate (10 × 100ml). The ethyl acetate extracts were dried over magnesium sulphate, filtered and evaporated in vacuo. The crystals were filtered off and recrystallised from ethyl acetate. 37.9% yield (4.47g); mpt 129° - 131° C. δ (CDCl3) 8.62 (1H,s) and 8.12 (1H,s), ##STR55## 4.47 (2H,q) and 4.38 (2H,q), (OCH2CH3 and NCH2CH3), 1.62 (3H,t) and 1.50 (3H,t), (OCH2CH3 and NCH2CH3); ν max (KBr) 3400 (broad) 1715, 1690, 1610, 1570, 1480, 1370, 1325, 1210, 1175, 790cm-1 ; λmax (EtOH) 209 (εm 12,400), 252 (εm 8,260) and 290 (εm 11,800)nm.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:20]=[O:21])=[CH:19][C:14]=2[CH:13]=[CH:12]1>C1COCC1>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:20]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[OH:21])=[CH:19][C:14]=2[CH:13]=[CH:12]1
Reactant: O=Cc1ccc2occc2c1
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccc2occc2c1)c1nccs1
Reaction time: 0.75 h

Procedure:
Under argon at −78° C., a mixture of thiazole (1.13 g, 13.2 mmol) in THF (50 mL) was dropwise treated with 2.5M n-BuLi (1.05 equiv., 5.04 mL, in hexanes) over a period of 10 min and stirred for 45 min. The resulting yellow mixture was treated dropwise with a solution of benzofuran-5-carbaldehyde (1.76 g, 12.0 mmol) in THF (10 mL). Cooling was removed after addition. When the mixture reached room temperature, it was treated with EtOAc, washed with 1M aqueous HCl and brine, dried over MgSO4, and evaporated, to give benzofuran-5-yl(thiazol-2-yl)methanol as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.71-7.75 (m, 2H), 7.64 (d, J=2.2 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.39 (dd, J=8.6, 1.7 Hz, 1H), 7.29 (d, J=3.1 Hz, 1H), 6.76-6.75 (m, 1H), 6.17 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].C([Li])CCC.CN(C)[CH:18]=[O:19].[Cl-].[Na+]>O1CCCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH:18]=[O:19])=[C:3]([CH3:10])[CH:4]=1)#[N:7]
Reactant: CN(C)C=O
Reactant: Cc1cc(C#N)ccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C#N)ccc1C=O
Temperature: -100 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 4-bromo-3-methylbenzonitrile (4 g, 20 mmol) in tetrahydrofuran (100 ml), cooled to -100° C. under a nitrogen atmosphere, was added dropwise a solution of n-butyllithium in hexanes (1.6M, 12.8 ml). After addition, the pale red solution was stirred for 5 minutes at -100° C. and dry dimethylformamide (2.2 ml) then added dropwise. After 20 minutes, during which the temperature reached -60° C., the reaction mixture was poured onto a saturated solution of sodium chloride (100 ml). The organic phase was separated and combined with a diethyl ether (100 ml) wash of the aqueous phase, dried, filtered and evaporated. Crystallised from diethyl ether-hexane to give 4-cyano-2-methylbenzaldehyde as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C@@:7]2([OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]2O)=[CH:5][CH:4]=[N:3]1.C(OC)(OC)(OC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br-].[Li+].C(Br)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(#N)C.ClCCl>[CH3:1][N:2]1[C:6]([C@:7]23[O:14][C@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12]3)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1[C@@]1(O)CCCC[C@@H]1O
Agent: CC(=O)Br
Agent: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: Cn1nccc1[C@@]12CCCC[C@@H]1O2
Yield: 47 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 102b by using the (1S,2S)-1-(1-methyl-1H-pyrazol-5-yl)cyclohexane-1,2-diol (423 mg, 2.15 mmol) prepared in Example 123c, trimethyl orthoacetate (0.688 mL, 5.38 mmol), p-toluenesulfonic acid (20.5 mg, 0.11 mmol), dichloromethane (6.0 mL), acetonitrile (6.0 mL), lithium bromide (466 mg, 5.38 mmol), acetyl bromide (0.398 mL, 5.38 mmol), methanol (6.0 mL) and potassium carbonate (743 mg, 5.38 mmol), to yield the title compound (180 mg, 47%).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Li+].O>C1COCC1>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]#[C:8][C:5]2([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]2)=[CH:15][CH:14]=1
Reactant: COC(=O)C1(C#Cc2ccc(OC)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C#CC2(C(=O)O)CC2)cc1
Reaction time: 6 h
Yield: 0.1 %

Procedure:
A mixture of 1-(4-methoxy-phenylethynyl)-cyclopropanecarboxylic acid methyl ester (2.2 g, 9.4 mmol), lithium hydroxide (0.6 g, 14 mmol) in THF (30 mL), and water (30 mL) was stirred for 6 hours. The solution was washed with ether and the aqueous layer was acidified to pH=4 and then extracted with ether. The organic layer was dried over sodium sulfate, and evaporated to dryness to yield 1-(4-methoxy-phenylethynyl)-cyclopropanecarboxylic acid as a white solid (2.0 g, 0.0092 mmol, 98%). ESI-MS m/z calc. 216.1. found; 217.16 (M+1)+ 1H NMR (CDCl3): δ 7.35 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.8 Hz. 2H), 3.79 (s, 3H), 1.69 (m, 2H), 1.47 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[C:5]([C:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([CH3:21])([CH3:20])[CH:13]=2)[CH:4]=1.CO>[Pd].O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([CH:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)[CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(C2=CC(C)(C)CC(C)(C)C2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(N)c(C2CC(C)(C)CC(C)(C)C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-methoxy-1-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene (1.0 g, 3.46 mmol) produced in Example (85a), 10% palladium on carbon (500 mg, wet), methanol (8 mL) and tetrahydrofuran (2 mL) was stirred overnight at room temperature and atmospheric pressure under a hydrogen atmosphere. The mixture was filtered through Celite to remove the catalyst, and the filtrate was concentrated. A crude product of the title compound was obtained as a brown oil. The crude product was used without purification for the following reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:8]([OH:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23][N:24]([S:28][C:29]([Cl:32])([Cl:31])[Cl:30])[C:25](F)=[O:26].[Na]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:8]([O:13][C:25](=[O:26])[N:24]([CH3:23])[S:28][C:29]([Cl:32])([Cl:31])[Cl:30])[C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:19][CH:20]=1
Reactant: CC(C)(C)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Reactant: CN(SC(Cl)(Cl)Cl)C(=O)F
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CN(SC(Cl)(Cl)Cl)C(=O)OC(C(Oc1ccc(Cl)cc1)n1cncn1)C(C)(C)C
Yield: 38.5 %

Procedure:
22.3 g (0.075 mol) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol, in the form of the pure diastereomer, were dissolved in 200 ml of tetrahydrofuran and the solution was added dropwise to 2.3 g of 80% pure sodium hydride in 150 ml of tetrahydrofuran at room temperature, while stirring. Thereafter, the mixture was stirred at 50° C. for 12 hours. After cooling, 17 g (0.075 mol) of N-methyl-N-trichloromethylmercaptocarbamoyl fluoride were added dropwise, at room temperature, to the sodium salt thus obtained, whereupon the temperature rose to about 35° C. The mixture was then heated under reflux for 16 hours, left to cool and concentrated by distilling off the solvent. The oily residue was taken up in 500 ml of methylene chloride, washed twice with 1,000 ml of water each time, dried over sodium sulphate and concentrated. The oil which remained was taken up in 300 ml of isopropyl ether, whereupon it crystallized out. 14.5 g (37% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-2-(N-methyl-N-trichloromethylmercapto-carbamoyloxy)-1-(1,2,4-triazol-1-yl)-butane were obtained in the form of the pure diastereomer of melting point 110°-112° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl>N1CCCCC1>[O:14]1[CH2:13][CH:12]1[CH2:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: ClCC1CO1
Reactant: N#Cc1ccccc1O
Solvent: C1CCNCC1
Product: N#Cc1ccccc1OCC1CO1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A solution of 2-cyanophenol (25.0 g., 0.21 mole), epichlorohydrin (117 g., 1.26 mole), and piperidine (10 drops) was stirred and heated at 115°-120° in an oil bath for 2 hours. The reaction mixture was then concentrated (90°/30 mm) to remove unreacted epichlorohydrin. The residue was diluted with toluene and taken to dryness twice to help remove the last traces of volatile material. The residual oil was dissolved in 263 ml. of THF, and the solution stirred at 40°-50° for 1 hour with 263 ml. of 1 N NaOH. The organic layer was separated and concentrated to give an oil which was combined with the aqueous phase. The mixture was extracted with CH2Cl2, and the extract dried (MgSO4) and concentrated to give 36.6 g (100%) of oil which slowly crystallized to a waxy solid. This product was used without further purification in Procedure 26A.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20].[CH:22]1([O:27][C:28]2[CH:29]=[C:30]([C:33]([F:38])=[CH:34][C:35]=2[O:36][CH3:37])[CH:31]=[O:32])[CH2:26][CH2:25][CH2:24][CH2:23]1.[Cl-].[NH4+]>O1CCCC1>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH2:20][CH:31]([C:30]1[C:33]([F:38])=[CH:34][C:35]([O:36][CH3:37])=[C:28]([O:27][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:29]=1)[OH:32]
Reactant: COc1cc(F)c(C=O)cc1OC1CCCC1
Reactant: Cc1c(Cl)cncc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cc(F)c(C(O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
To a solution of diisopropylamine (0.16 g) in tetrahydrofuran (2 mL) at −78° C. is added a 2.5 N solution of n-butyl lithium in hexanes (0.62 mL). The solution is allowed to warm to −10° C. and cooled back to −78° C. A solution of 3,5-dichloro-4-methylpyridine (0.25 g) in dry tetrahydrofuran (4 mL) is added, stirred for 0.5 hours at −60° C. and treated with 3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (0.25 g) in dry tetrahydrofuran (4 mL). The reaction mixture is allowed to warm to room temperature over 1 hour and stirred overnight. The mixture is treated with 2N ammonium chloride (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts are washed with brine (50 mL), dried (magnesium sulfate) and evaporated to give 2-(3,5-dichloropyrid-4-yl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)ethanol (0.22 g). [NMR (CDCl3):— 8.44 (s, 2H), 6.97 (d, 1H, J=7 Hz), 6.56 (d, 1H, J=12 Hz), 5.34 (m, 1H), 4.74 (m, 1H), 3.83 (s, 3H), 3.5 (dd, 1H, J=8 Hz, 8 Hz), 3.32 (dd, 1H, J=5 Hz, 6 Hz), 2.07 (d, 1H, J=6 Hz), 1.93-1.55 (m, 8H)].
Reaction SMILES: [C:1]1([C:7]2[CH:30]=[CH:29][C:10]([CH2:11][O:12][C:13]3[CH:28]=[CH:27][C:16]4[CH2:17][CH2:18][CH2:19][CH:20]([C:23]([O:25][CH3:26])=[O:24])[C:21](=O)[C:15]=4[CH:14]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].C(N(CC)CC)C.CS(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1>ClCCl.CO.O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][O:12][C:13]3[CH:28]=[CH:27][C:16]4[CH2:17][CH2:18][CH2:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:15]=4[CH:14]=3)=[CH:29][CH:30]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1CCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2C1=O
Agent: CS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1=Cc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2CCC1
Temperature: -40 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To methyl 3-(4-phenylbenzyloxy)-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylate (2.31 g, 5.77 mmol) dissolved in a mixed solvent of dichloromethane (50 ml) and methanol (15 ml) was added at −40° C. (inner temperature) sodium borohydride (327 mg, 8.64 mmol), and the resulting mixture was stirred at −20° C. to −10° C. for 2 hours. The reaction mixture was cooled to −40° C., was mixed with water (20 ml) and extracted with dichloromethane (50 ml, 10 ml×2). The combined organic layers were dried with anhydrous magnesium sulfate and were then concentrated under reduced pressure. To the residue dissolved in dichloromethane (40 ml) were added at 0° C. triethylamine (4.02 ml, 28.8 mmol) and methanesulfonyl chloride (0.67 ml, 8.7 mmol), and the resulting mixture was stirred at room temperature for 16 hours. In order to complete the reaction, DBU (2.59 ml, 17.3 mmol) was added, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, was mixed with water (30 ml) and was extracted with ethyl acetate (40 ml, 15 ml×2). The combined organic layers were washed with 1 N hydrochloric acid (5 ml×3), were dried with anhydrous magnesium sulfate and were then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 60 g, toluene). The objective fractions were concentrated under reduced pressure and the residue was mixed with ethyl acetate and diisopropyl ether, and an insoluble material was collected by filtration. The insoluble material was washed with diisopropyl ether and was then dried under reduced pressure to obtain methyl 2-(4-phenylbenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (1.31 g, 3.41 mmol, 59%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.[CH2:12]([O:14][C:15](=[O:20])[C:16](=O)[CH2:17]Br)[CH3:13].O>CN(C=O)C>[CH2:12]([O:14][C:15]([C:16]1[N:11]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[S:10][CH:17]=1)=[O:20])[CH3:13]
Reactant: NC(=S)Nc1ccc(Br)cn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1csc(Nc2ccc(Br)cn2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
(5-Bromo-pyridine-2-yl)-thiourea (1 mmol) is dissolved in DMF (2 ml) and 3-Bromo-2-oxo-propionic acid ethyl ester (1 eq.) is added and stirred 2 h at 70° C. The suspension is diluted with DMF (2 ml). After cooling to RT the reaction solution is poured into water and the resulting precipitate is filtered, washed with water and dried 16 h in vacuo at 40° C. “A4” is obtained as colourless powder in a yield of 78%; mp. 299.8-300.8° C.; HPLC (method C): 2.01 min; LC-MS (method A): 2.002 min, 327.95 (M+H+);
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:9]=1)([CH3:6])[C:3](O)=[O:4].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.[NH2:44][C:45]1[S:46][C:47]([Cl:50])=[CH:48][N:49]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:50][C:47]1[S:46][C:45]([NH:44][C:3](=[O:4])[C:2]([CH3:6])([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=3)[CH:9]=2)[CH3:1])=[N:49][CH:48]=1
Reactant: Nc1ncc(Cl)s1
Reactant: CC(C)(Oc1cccc(NCCc2ccc(C(F)(F)F)cc2)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(Oc1cccc(NCCc2ccc(C(F)(F)F)cc2)c1)C(=O)Nc1ncc(Cl)s1
Reaction time: 0.08 h
Yield: 30.4 %

Procedure:
To a solution of 2-Methyl-2-{3-[2-(4-trifluoromethyl-phenyl)-ethylamino]-phenoxy}-propionic acid (0.075 g, 0.204 mmol) in DCM (5 ml) added triethyl amine (0.034 ml, 0.24 mmol) and HOBt (0.0.037 g, 0.24 mmol) at 0° C. After stirring at this temperature for 5 min. added 2-amino-5-chlorothiazole (0.041 g, 0.285 mmol) and followed by EDCI (0.047 g, 0.244 mmol). The resulting solution was stirred for 12 h. then quenched with sat NH4Cl solution (15 ml). The aqueous phase was extracted with CH2Cl2 (3×50 ml). The organic phase were successively washed with 2% HCl (50 ml), brine (50 ml) and dried over Na2SO4. After evaporation, the residue was purified by flash chromatography (1:5 ethyl acetate:hexanes) to give N-(5-Chloro-thiazol-2-yl)-2-methyl-2-{3-[2-(4-trifluoromethyl-phenyl)-ethylamino]-phenoxy}-propionamide (0.03 g, 30%). 1H NMR (400 MHz, CDCl3): δ 1.59 (s, 6H), 2.96 (t, J=6.8 Hz, 2H), 3.39 (bs, 2H), 3.7 (bs, 1H), 6.18 (s, 1H), 6.26-6.38 (m, 2H), 7.07 (m, 1H), 7.31 (m, 2H), 7.58 (d, J=8 Hz, 2H), 10.0 (s, 1H), MS (EI) m/z: 484.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([O:16]C)[C:13]([Cl:18])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].B(Br)(Br)Br.Cl.CCCCCC.CCOC(C)=O>C(Cl)Cl.CCO>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([OH:16])[C:13]([Cl:18])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cc(OC)c(Cl)cc2c1C
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1oc2cc(O)c(Cl)cc2c1C
Temperature: 0 °C
Reaction time: 5 h
Yield: 73.1 %

Procedure:
The above prepared 5-chloro-6-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (2.32 g, 8.63 mmol) was dissolved in 50 mL of CH2Cl2, cooled to 0° C., and treated with BBr3 (17.3 mL of 1M solution in CH2Cl2, 2 eq.). After 5 h at 0° C., the reaction mixture was carefully poured onto crashed ice, twofold extracted with AcOEt, washed with water, dried over magnesium sulfate, and evaporated to dryness. Since substantial amount of free acid had been formed, the crude product was again esterified by treatment with anhydrous HCl in EtOH for 48 h at 48° C. Standard work-up and ensuing flash chromatography (SiO2, hexane/AcOEt=8/2) yielded finally 1.607 g of the title compound as light yellow crystals.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([Br:12])[C:5]=2[N:6]=1.[SH2:13].[Na]>CO>[Br:12][C:7]1[C:5]2[N:6]=[C:2]([SH:13])[S:3][C:4]=2[CH:10]=[C:9]([CH3:11])[CH:8]=1
Reactant: S
Reactant: Cc1cc(Br)c2nc(Br)sc2c1
Agent: [Na]
Solvent: CO
Product: Cc1cc(Br)c2nc(S)sc2c1
Temperature: 25 °C
Yield: 84 %

Procedure:
3.1 g of 2,4-dibromo-6-methylbenzothiazole, 1.0 g of sodium hydrogensulfide and 30 ml of methanol were mixed and the obtained mixture was refluxed for one hour, cooled to room temperature and then distilled under reduced pressure to remove methanol. The residue was extracted with dichloromethane by adding water and dichloromethane. The dichloromethane layer was dried with anhydrous sodium sulfate and evaporated to obtain the title compound in a solid state (Yield: 84%).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH2:24]([NH:27][C:28](=[O:34])[CH2:29][CH2:30][C:31](O)=[O:32])[CH2:25][CH3:26]>>[O:34]=[C:28]([NH:27][CH2:24][CH2:25][CH3:26])[CH2:29][CH2:30][C:31]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:32]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCCNC(=O)CCC(=O)O
Product: CCCNC(=O)CCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and N-propyl-succinamic acid to yield (3aR,4S,7aR)-methyl 4-(4-oxo-4-(propylamino)butanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=455; RT=1.18 min; UPLC Method I