Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:6]([CH2:13][CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH2:7][CH2:8][CH2:9][C:10]([NH2:12])=O)(OCC)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:12][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]([CH2:13][CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH2:1][OH:2]
Reactant: CCOC(=O)C(CCCOC1CCCCO1)CCCC(N)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCCCC(CO)CCCOC1CCCCO1
Reaction time: 0.25 h

Procedure:
A solution of 1.0 g (3.17 mmol) of 5-carbethoxy-5-[3-(tetrahydropyranyloxy)propyl]-valeramide in 5 mL tetrahydrofuran is added dropwise to a suspension of 0.481 g (12.68 mmol) lithium aluminum hydride in 20 mL dry tetrahydrofuran. The reaction is refluxed for 21/2 hours, cooled in an ice-bath and quenched by the addition of 0.5 mL water, 0.5 mL 15% sodium hydroxide followed by 1.5 mL water. The mixture is stirred for 15 minutes and filtered, washed and then subjected to evaporation to give 6-amino-2-[3-(tetrahydropyranyloxy)-propyl]hexan-1-ol.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28](I)[C:23]2=[CH:22][N:21]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[C:40]3[C:45](=[CH:46][CH:47]=2)[C:44](=[O:48])[NH:43][CH2:42][CH2:41]3)O1>>[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28]([C:38]3[CH:39]=[C:40]4[C:45](=[CH:46][CH:47]=3)[C:44](=[O:48])[NH:43][CH2:42][CH2:41]4)[C:23]2=[CH:22][N:21]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCNC3=O)OC1(C)C
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CCNC5=O)n[nH]c3n2)c1F

Procedure:
This compound was prepared as a TFA salt by using procedures analogous to those described for the synthesis of Example 7, Step 3 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one. LCMS (M+H)+=438.0.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](=[NH:14])OCC.[O-]CC.[Na+].[N:19]#[C:20][NH2:21]>C(O)C>[C:20]([N:21]=[C:10]([NH2:14])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:2])#[N:19]
Reactant: N#CN
Reactant: CCOC(=N)Cc1ccccc1C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1CC(N)=NC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
A solution of Example 1B (4 g, 18.72 mmol)) in absolute ethanol (50 ml) was treated with a 21% sodium ethoxide solution in ethanol (7 ml, 18.72 mmol) and the precipitated sodium chloride was filtered off. The filtrate was then treated with a solution of cyanamide (0.79 g, 18.72 mmol) in absolute ethanol (25 ml) and stirred at room temperature for one hour. The solvent was evaporated under reduced pressure. The residual oil was triturated with ether to afford white crystals that were filtered and dried to yield 2.5 g of product. MS (ESI+) m/z 174 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6]/[CH:7]=[C:8](/[C:16]2[N:21]=[C:20](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])[CH:19]=[CH:18][CH:17]=2)\[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Ni]>[N:1]1([CH2:6]/[CH:7]=[C:8](/[C:16]2[N:21]=[C:20]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:18][CH:17]=2)\[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(/C=C/C(=O)O)n2)cc1
Agent: [Ni]
Product: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(CCC(=O)O)n2)cc1
Temperature: 25 °C

Procedure:
A solution of compound 2, vide supra, (3 g) in alcohol (100 mL) containing Raney nickel (1 g) was stirred under hydrogen at room temperature and pressure until the calculated quantity of hydrogen had been absorbed (ca. 45 minutes). The reduced ester was recovered by filtration and evaporation and purified by column chromatography on silica gel using petroleum ether as eluent. Butyllithium (10 mL, 1.64M in hexane) was added under nitrogen to a stirred suspension of triphenyl-2-pyrrolidinoethylphosphonium bromide (7.2 g) in dry toluene (75 mL) to prepare a Wittig reagent. Treatment of this ester with Wittig reagent by the method of Example 1 followed by saponification gave a mixture of two isomeric acids which were separated by fractional crystallization from ethyl acetate/petroleum ether mixtures. The less soluble E isomer, 3-{6-[3-Pyrrolidino-1-(4-tolyl)prop-1E-enyl]-2-pyridyl}-propionic acid (Compound B), melted at 156°-157°.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[C:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>ClC1C=CC=CC=1>[C:13]1([NH:23][C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)=[NH:11])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc2ccccc12
Reactant: CCc1cccc(NC#N)c1
Agent: Cl
Solvent: Clc1ccccc1
Product: CCc1cccc(NC(=N)Nc2cccc3ccccc23)c1
Temperature: 25 °C
Yield: 6.4 %

Procedure:
A solution of m-ethylphenylcyanamide (730 mg, 2.99 mmol) and 1-naphthylamine hydrochloride (900 mg, 5.05 mmol) in chlorobenzene (20 ml) was heated at 140°-145° C. for 12 hours. It was allowed to cool to room temperature, concentrated and the residue was partitioned between dichloromethane and 10% NaOH solution. The organic layer was concentrated and the resulting residue was recrystallized from abs. EtOH-H2O to give N-(1-naphthyl)-N'-(m-ethylphenyl)guanidine (55 mg, 4%) as off-white needles, mp 96°-98° C.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[ClH:12].Cl.[CH2:14]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:12].[ClH:12].[C:3]([CH:2]([N:26]1[CH2:27][CH2:28][N:23]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[CH2:24][CH2:25]1)[CH3:11])(=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: O=C(CN1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C(=O)c1ccccc1)N1CCN(CC(=O)c2ccccc2)CC1

Procedure:
A mixture of 2-bromo-1-phenylpropan-1-one (3 mmol), N-phenacyl piperazine dihydrochloride (2.5 mmol) and K2CO3 (8.75 mmol) in 30 ml of DMF was treated according to the general preparation 2 to give compound (IV-8), 0.64 g (62%), mp 236-238° C., M+ 336.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][S:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[C:4]([Cl:28])[CH:3]=1.Cl.[CH2:30]([O:32][C:33](=[O:36])[CH2:34][NH2:35])[CH3:31]>>[CH2:30]([O:32][C:33](=[O:36])[CH2:34][NH:35][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([S:14](=[O:16])(=[O:15])[NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:26]=[CH:27][C:2]([Br:1])=[CH:3][C:4]=2[Cl:28])=[CH:18][CH:19]=1)[CH3:31]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Br)cc2Cl)cc1
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Br)cc2Cl)cc1

Procedure:
The title compound was prepared from 4-[2-(4-bromo-2-chloro-phenoxy)-phenylsulfamoyl]-benzoic acid and glycine ethyl ester hydrochloride according to the method described in Example 1.1/d.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[Cl:9].[Cl:10]C1C=CC=CC=1>>[Cl:9][C:3]1[C:4]([Cl:10])=[C:5]([Cl:8])[CH:6]=[CH:7][CH:2]=1
Reactant: Clc1ccc(Cl)c(Cl)c1
Reactant: Clc1ccccc1
Product: Clc1cccc(Cl)c1Cl
Yield: 381.3 %

Procedure:
Example 3 was repeated replacing the benzene with 139.5 g of chlorobenzene. After 20 hours reaction, 25.7 g of 1,2,4-trichlorobenzene-insoluble polymer and 98.0 g of trichlorobenzene-soluble polymer were obtained. This indicates that while less reactive than benzene, chlorobenzene is also a suitable aromatic reactant.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:20][CH2:19][C:18]3[N:17]4[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]4)=[CH:11][C:10]=3[C:9]2=[O:21])[C:3]=1[CH2:22][OH:23].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:31]([O:23][CH2:22][C:3]1[C:4]([N:8]2[CH2:20][CH2:19][C:18]3[N:17]4[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]4)=[CH:11][C:10]=3[C:9]2=[O:21])=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:33])[CH3:32]
Reactant: O=C1c2cc3n(c2CCN1c1nccc(Cl)c1CO)CCCC3
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1c(Cl)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a mixture of 244a (900 mg, 2.7 mmol) and triethylamine (810 mg, 8.1 mmol) in dichloromethane (30 mL) was added acetyl chloride (630 mg, 8.1 mmol) dropwise. The reaction mixture was stirred at 30° C. for 1 h. It was then concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with dichloromethane to afford 244b as white solid (900 mg, 90%). MS-ESI: [M+H]+ 374.2
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][O:14][CH3:15])[CH:7]=1)[CH3:2].[H-].[Na+].I[CH3:20]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][O:14][CH3:15])[CH:7]=1)[CH3:20])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)Cc1cccc(OCOC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1cccc(OCOC)c1
Reaction time: 20 h

Procedure:
To a stirred solution of (3-Methoxymethoxy-phenyl)-acetic acid ethyl ester (31.2 g) in DMF (200 mL) was slowly added sodium hydride (6.21 g) and iodomethane (22.3 g) at 0°. After stirred for 20 h at 0°, this reaction mixture was quenched with water. This mixture was extracted with EtOAc, and combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=10:1) to afford the product as colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[C:12]2[OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)CC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:20]([O-:22])=[O:21])=[C:12]2[OH:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccnc2ccc(OCc3ccccc3)cc12
Solvent: CCC(=O)O
Product: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1O
Temperature: 110 °C

Procedure:
A mixture of 6-benzyloxyquinolin-4-ol (65.7 g) and propionic acid (660 mL) was heated at 110° C. with vigorous stirring. Nitric acid (19.2 mL of 16 M) was slowly added over a period of 30 minutes while maintaining the reaction temperature below 120° C. After the addition, the reaction was allowed to cool to ambient temperature. The resulting solid was isolated by filtration, washed sequentially with propionic acid, isopropanol, and diethyl ether. The material was dried in a vacuum dessicator for 2 days to provide 46.0 g of 6-benzyloxy-3-nitroquinolin-4-ol as a tan powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])(=[O:14])[CH3:13].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([C:12](=[O:14])[CH3:13])[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)c1cccc(C(=O)NCCNC(=O)OC(C)(C)C)c1
Reaction time: 2.5 h

Procedure:
N-(t-Butoxycarbonyl)ethylenediamine 2 (5 mmol, 800 mg) was weighed directly into a clean dry flask, which was then tightly stoppered. 3-Acetylbenzoic acid 3 (5 mmol, 820 mg) was added directly to the amine in the flask. Under an inert atmosphere dry dimethylformamide (15 mL) was added to the flask. Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (5 mmol, 2.21 g) was added to the solution, and subsequently N-methylmorpholine (15 mmol, 1.51 g, 1.7 mL) was added to the solution, and the mixture was allowed to stir for 2-3 hrs. The reaction mixture was quenched by the addition of 15 mL of water to the reaction flask, and partitioned between water (300 mL) and ethyl acetate (300 mL). The organic phase was washed successively with saturated sodium bicarbonate (200 mL), water (4×300 mL), and brine (200 mL) and then dried over anhydrous sodium sulfate. Filtering off the drying agent and concentration of the organic phase to ˜10-15 mL yielded a tan solid. Hexanes (˜30 mL) were added and the mixture gently heated to reflux. Upon cooling semicrystalline product was precipitated as a white powder. The product was collected by filtration and dried. Yield 775 mg, 51%.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[OH:36])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:44](Br)[CH:45]=[CH2:46].O>CC(C)=O>[CH2:46]([O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH:28]1[O:27][N:26]=[C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:12](=[O:13])[CH2:11][N:5]4[C:6]([CH:8]([F:10])[F:9])=[CH:7][C:3]([CH:2]([F:1])[F:37])=[N:4]4)[CH2:19][CH2:18]3)[S:21][CH:22]=2)[CH2:29]1)[CH:45]=[CH2:44]
Reactant: C=CCBr
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4O)C3)cs2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Yield: 55.1 %

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (81 mg) and potassium carbonate (105 mg) in acetone (5 ml) is added, at room temperature, allyl bromide (73 mg). The reaction mixture is stirred at reflux for 5 h. Then the mixture is admixed with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 1-[4-(4-{5-[2-(allyloxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]-2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanone (48 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:37])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([CH:34]=4)=[C:32]([CH3:35])[CH:31]=[CH:30][C:29]=5[F:36])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:39].[ClH:41].CCOCC>>[ClH:39].[ClH:41].[ClH:39].[F:36][C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[C:33]2[C:28]=1[CH:27]=[N:26][C:25]([C:23]1[C:22]([NH2:37])=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:18]=3)[CH:24]=1)=[CH:34]2
Reactant: Cc1ccc(F)c2cnc(-c3cc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc3N)cc12
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Product: Cc1ccc(F)c2cnc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{4-[6-amino-5-(8-fluoro-5-methylisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (11.5 mg, 0.0229 mmol) in DCM (0.60 mL, 9.4 mmol) was added 1.0 M of HCl in Et2O (0.80 mL, 0.80 mmol), and the mixture was stirred at ambient temperature for 2 h. Almost immediately a pale yellow solid precipitated. The solvents were evaporated, and the residue was transferred into a vial and dried in vacuo overnight, yielding the title compound as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=14.6 (very brs, 1H), 9.59 (d, J=0.8 Hz, 1H), 9.19-9.09 (brm, 1H), 9.02-8.91 (brm, 1H), 8.88 (d, J=2.4 Hz, 1H), 8.56 (brs, 1H), 8.54 (s, 1H), 8.48 (s, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.15 (s, 1H), 7.73 (ddd, J=0.8, 6.4, 8.0 Hz, 1H), 7.51 (dd, J=8.0, 10.2 Hz, 1H), 4.59-4.50 (mc, 1H), 3.40 (brd, J=12.2 Hz, 2H), 3.11 (brq, J=11.4 Hz, 2H), 2.76 (s, 3H), 2.30-2.12 (m, 4H). MS(ES+): m/z=403.16 (23) [MH+], 320.12 (100) [MH+-piperidine]. HPLC: tR=1.89 min (polar—5 min, ZQ2).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]2([CH3:38])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27]C(=O)OC(C)(C)C)=[CH:26][C:20]=4[S:19](=[O:36])(=[O:35])[N:18]=3)[C:7]2=[O:37])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:17]([C:8]3[C:7](=[O:37])[C:6]([CH2:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)([CH3:38])[C:15]4[C:10]([C:9]=3[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:18][S:19](=[O:36])(=[O:35])[C:20]=2[CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CCC3CC3)C1=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(CCC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 157F (1.06 g, 2.00 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (10 mL) at room temperature for 1 hour. After concentrating in. vacuo, the resulting oil was partitioned between ethyl acetate and aqueous NaHCO3, the organic layer was removed and the aqueous layer extracted 3 times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in. vacuo to yield a solid that was used without further purification. 1H NMR (300 MHz, DMSO-d6): δ ppm−0.25 (m, 2H) 0.25 (m, 2H) 0.46 (m, 2H) 0.80 (m, 1H) 1.57 (s, 3H) 2.15 (m, 1H) 2.32 (m, 1H) 6.99 (m, 2H) 7.44 (d, J=8.82 Hz, 1H) 7.54 (m, 1H) 7.77 (d, J=4.04 Hz, 2H) 8.15 (d, J=7.72 Hz, 1H) 13.55 (s, 1H). MS (ESI+) m/z=438 (M+H)+, 455 (M+NH4)+.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH2:6]1[CH2:10][O:9][CH2:8][CH2:7]1>>[CH3:2][CH:3]([C:4]#[CH:5])[CH2:8][O:9][CH2:10][C:6]1[CH:7]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: C1CCOC1
Product: C#CC(C)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of BuLi (4.32 ml, 6.92 mmol) (1.6M in hexanes) was added dropwise to a stirred solution of the dibromo alkene (above, 1.1 g, 3.29 mmol) in dry THF (15 ml) under N2, such that the internal temperature <−70° C. The reaction was stirred at this temperature for 30 minutes and then quenched with saturated aqueous ammonium chloride (1 ml) before being allowed to warm to RT. The mixture was partitioned between diethyl ether and water. The aqueous layer was extracted with diethyl ether (×2). The combined extracts were washed with brine (×1), dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, 1-4% Et2O/isohexane) to give the alkyne (0.55 g) as a colourless liquid.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])[CH3:11].[OH-].[K+].O>CS(C)=O>[C:10]([N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccccc1
Reactant: CCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCN(C(C)=O)c1ccccc1
Temperature: 52.5 °C
Reaction time: 0.75 h
Yield: 98 %

Procedure:
1-Octylbromide (39 mL, 224 mmol, 1.12 eq) was added dropwise to a mixture of acetanilide (27 g, 200 mmol, 1 eq) in dimethylsulfoxide (130 mL), containing potassium hydroxide pellets (18.87 g, 300 mmol, 1.5 eq), at room temperature. After all the octyl bromide was added the reaction mixture was heated to 50-55° C. for 1.5 hours. The reaction mixture was cooled and poured into water (1 L), stirred for 45 minutes and extracted with hexanes (3×400 mL). The hexane extracts were combined, dried over sodium sulfate and evaporated to give 48.4 g (196 mmol, 98%) of colorless oil. The product was identified by NMR spectroscopy and mass spectrometry and was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:28])=[C:11]([C:13]3[C:14](=[O:27])/[C:15](=[CH:20]/[CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)/[CH2:16][C:17]=3[O:18]C)[N:12]=2)=[CH:4][CH:3]=1.Cl>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:28])=[C:11]([CH:13]3[C:14](=[O:27])/[C:15](=[CH:20]/[CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)/[CH2:16][C:17]3=[O:18])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC1=C(c2nc(-c3ccc(Cl)cc3)sc2C)C(=O)/C(=C/C2CCOCC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)C/C(=C\C2CCOCC2)C1=O
Temperature: 120 °C
Yield: 92.9 %

Procedure:
To a solution of 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-3-methoxy-5-[1-(tetrahydro-pyran-4-yl)-meth-(E)-ylidene]-cyclopent-2-enone (190 mg, 0.45 mmol) in acetone (2 ml) was added 2N hydrochloric acid (2 ml) and the reaction heated to 120° C. for 30 minutes by microwave irradiation. The crude reaction was diluted with ethyl acetate (25 ml) and washed with saturated aqueous ammonium chloride solution (25 ml), brine (25 ml) and the organic later separated, dried over magnesium sulphate and the solvent removed under reduced pressure to give 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-4-[1-(tetrahydro-pyran-4-yl)-meth-(E)-ylidene]-cyclopentane-1,3-dione (168 mg).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([Si](C)(C)C)([F:12])[F:11].O>CCCCCC>[C:2]1([CH:1]([OH:8])[C:10]([F:12])([F:11])[F:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C[Si](C)(C)C(F)(F)F
Solvent: CCCCCC
Solvent: O
Product: OC(c1ccccc1)C(F)(F)F
Temperature: 80 °C
Yield: 88 %

Procedure:
Benzaldehyde was reacted with trifluoromethyltrimethylsilane as in Example 10. After a reaction time of 5 hours, 20 ml of water were added, and the reaction mixture was heated briefly to 80° C. 50 ml of hexane were then added. The reaction mixture was then extracted twice with 100 ml of water, and the resultant organic phase was dried over Na2SO4. On distillation of the crude product, 15.4 g (88% yield) of 1-phenyl-2,2,2-trifluoroethanol (boiling point 68°-69° C./6 mbar) were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:11]1[CH2:17][S:14](=[O:16])(=[O:15])[O:13][CH2:12]1>O1CCCC1>[C:1]([O:5][C:6](=[O:10])[C@@H:7]([NH:8][CH2:12][CH2:11][CH2:17][S:14]([OH:16])(=[O:15])=[O:13])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCCO1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C[C@H](NCCCS(=O)(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 53.4 %

Procedure:
To a solution of L-Alanine tert-butylester (1.53 g, 10.5 mmol) in tetrahydrofuran (20 mL) was added 1,3-propanesultone (1.16 g, 9.6 mmol). The solution stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×20 mL). The solid was dissolved in water (80 mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid was suspended in acetone (80 mL), filtered and dried in the vacuum oven (50° C.), affording the title compound (1.37 g, 54%). 1H NMR (D2O, 500 MHz) δ ppm 3.88 (m, 1H), 3.09 (m, 2H), 2.86 (t, 2H, J=7.3 Hz), 2.00 (m, 2H), 1.39 (d, 3H, J=7.3 Hz), 1.35 (s, 9H). 13C (D2O, 125 MHz) δ ppm 169.13, 86.12, 56.24, 47.94, 44.71, 27.11, 21.52, 14.17. [α]D=−1.1° (c=0.0027 in water), ES-MS 266 (M−1).