Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Br)(C)C.[F:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][C:15]=1[CH:16]=[O:17].Cl>O1CCCC1.O>[F:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:18][C:15]=1[CH:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:17]
Reactant: O=Cc1cc(OC(F)(F)F)ccc1F
Reactant: Brc1ccccn1
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccccn1)c1cc(OC(F)(F)F)ccc1F
Reaction time: 2 h

Procedure:
To a solution of 2-bromopyridine (380 mg) in anhydrous tetrahydrofuran (3 mL) is slowly added a 1M solution of isopropylmagnesium bromide in tetrahydrofuran (2.64 mL) at room temperature. After stirring for 2 hours, 2-fluoro-5-(trifluoromethoxy)benzaldehyde (0.50 mL) is added and the reaction mixture stirred for 2 hours. After hydrolysis with water and 3N hydrochloric acid, the mixture is washed with diethyl ether, basified with concentrated sodium hydroxide and extracted with ethyl acetate twice. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (heptane/ethyl acetate 2/1) to afford (2-fluoro-5-trifluoromethoxyphenyl)pyridin-2-ylmethanol as an orange oil.
Reaction SMILES: C(O[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)C#C.C([Li])CCC.C(Cl)(=[O:18])C.[O:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>[Cl-].[Zn+2].[Cl-]>[O:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[O:20][C:24]#[C:23][C:22](=[O:18])[CH3:21]
Reactant: C1CCOC1
Reactant: CC(=O)Cl
Reactant: C#CCOC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Product: CC(=O)C#COC1CCCCO1
Temperature: 0 °C

Procedure:
Under a nitrogen atmosphere tetrahydro-2-(2-propynyloxy)-2H-pyran (636 mL, 4.52 mmol) was dissolved in dry tetrahydrofuran (20 mL) and cooled to −78° C. n-Butyllithium (2.5 M in hexanes, 2.03 mL, 5.06 mmol) was added drop-wise. Zinc chloride (629 mg, 4.51 mmol) dissolved in tetrahydrofuran (5 mL) was added drop-wise and the reaction mixture was allowed to warm to 0° C. Acetyl chloride (0.35 mL, 4.93 mmol) was added followed by heating to 40 CC for 45 min. The reaction was quenched with saturated aqueous ammonium chloride. Ethyl acetate was added and the phases were separated. The organic phase was washed with saturated aqueous ammonium chloride (2×) and brine, dried over magnesium sulphate, filtered and concentrated in vacuo to give 4-(tetrahydro-pyran-2-yloxy)-but-3-yn-2-on as the crude product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)(Cl)Cl.O>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:13])[F:14])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)=[O:29]
Reactant: Nc1ccnc2cc(C(F)(F)F)ccc12
Reactant: O=C(Cl)CCCCBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(CCCCBr)Nc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 20 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
4-Amino-7-trifluoromethylquinoline (120 mg, 0.56 mmol), triethylamine (170 mg, 1.7 mmol) and CHCl3 (4 mL) were charged in a 10 ml round-bottomed flask equipped with a magnetic stirrer. 5-Bromovaleryl chloride (140 mg, 0.7 mmol in CHCl3 (2 mL) were added and the reaction mixture was stirred for 15 h at 20° C. The reaction mixture was poured in 10 mL of H2O and extracted with CH2Cl2 (100 mL). The organic layer was washed with brine (2×10 mL), dried over MgSO4, filtered and evaporated at 30° C. to dryness. The crude compound was purified by column chromatography (SiO2; CH2Cl2:MeOH=99.5:0.5 to 98:2) to give after evaporation 5-bromo-N-(7-(trifluoromethyl)quinolin-4-yl)pentanamide 32 (190 mg, 90% yield) as a beige solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1.C([Li])CCC.[CH3:25][O:26][C:27]([C:29]1[CH:34]=[C:33]([C:35](OC)=[O:36])[CH:32]=[C:31]([C:39]([O:41][CH3:42])=[O:40])[CH:30]=1)=[O:28]>O1CCCC1>[CH3:42][O:41][C:39]([C:31]1[CH:32]=[C:33]([CH:34]=[C:29]([C:27]([O:26][CH3:25])=[O:28])[CH:30]=1)[C:35]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1)=[O:36])=[O:40]
Reactant: CCCCCCCCC(O)/C=C/c1cccc(Br)n1
Reactant: COC(=O)c1cc(C(=O)OC)cc(C(=O)OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC(O)/C=C/c1cccc(C(=O)c2cc(C(=O)OC)cc(C(=O)OC)c2)n1
Yield: 14.2 %

Procedure:
Under the conditions of example 1B, 1 g of 2-bromo-6-[(1E)(3RS)-3-hydroxy-1-undecenyl)-pyridine in 10 ml of tetrahydrofuran is mixed with 4.26 ml of n-butyllithium (1.6 molar in hexane) and 807 mg of 1,3,5-benzenetricarboxylic acid trimethylester in 6 ml of tetrahydrofuran, worked up and chromatographed on silica gel with hexane/ethyl acetate=95/5 to 75/25. 203 mg of oily crude product is obtained, which is subjected to complete purification of the high-pressure liquid chromatography on silanized silica gel (RP 18 material) with methanol/H2O=9:1. 74 mg of the title compound is thus obtained as colorless oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.C(O[C:19](=[O:33])[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH:28]([OH:32])[CH2:29][O:30][CH3:31])[CH2:23][CH2:22]1)(C)(C)C.[O:34]=[C:35]1[NH:40][C:39]2[CH:41]=[C:42](C(O)=O)[CH:43]=[CH:44][C:38]=2[S:37][CH2:36]1>>[CH3:31][O:30][CH2:29][CH:28]([O:32][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1)[CH2:27][N:24]1[CH2:23][CH2:22][CH:21]([NH:20][C:19]([C:42]2[CH:43]=[CH:44][C:38]3[S:37][CH2:36][C:35](=[O:34])[NH:40][C:39]=3[CH:41]=2)=[O:33])[CH2:26][CH2:25]1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COCC(O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Reactant: COc1ccc2ncc(Cl)nc2c1
Product: COCC(CN1CCC(NC(=O)c2ccc3c(c2)NC(=O)CS3)CC1)Oc1cnc2ccc(OC)cc2n1

Procedure:
The title compound is prepared as an off-white lyophilizated powder following Scheme 1 and in analogy to Example 1 using 2-chloro-7-methoxy-quinoxaline, [1-(2-hydroxy-3-methoxy-propyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][CH:3]=1.Cl[C:15]1[CH:20]=CC(C#C)=CN=1>>[C:15]([C:2]1[N:6]([CH3:7])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][CH:3]=1)#[CH:20]
Reactant: C#Cc1ccc(Cl)nc1
Reactant: Cn1c(Br)cnc1N1CCOCC1
Product: C#Cc1cnc(N2CCOCC2)n1C

Procedure:
4-(5-Ethynyl-1-methyl-1H-imidazol-2-yl)-morpholine was prepared from 4-(5-bromo-1-methyl-1H-imidazol-2-yl)-morpholine in the same manner as 2-chloro-5-ethynyl-pyridine (Example 1).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([Br:6])[CH3:5].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.[K]>CN(C)C=O>[Br:6][CH:4]([CH3:5])[CH2:3][CH2:2][N:11]1[C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]2[C:7]1=[O:17]
Reactant: CC(Br)CCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC(Br)CCN1C(=O)c2ccccc2C1=O
Temperature: 20 °C
Reaction time: 8 h

Procedure:
1,3 dibromobutane (10.8 g, 0.05 mol) and potassium phthalimide (9.25 g, 0.05 mol) were added to dry N,N dimethylformamide (100 ml) and the resulting mixture stirred at ambient temperature (20° C.) overnight. The resulting mixture was filtered to remove any solid and the solvent removed from the filtrate to give a colourless oil. The product, N-(3-bromobutyl)phthalimide, was isolated from the oil by flash chromatography on a silica gel column using silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm) eluted with 2% methanol in dichloromethane as a brown solid in a yield of 7.9 g (55.7%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1>CO.C(Cl)Cl.O=[Mn]=O>[CH:2]([C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)=[O:1]
Reactant: O=S(=O)(NCc1ccccn1)c1cccc(CO)c1
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClCCl
Product: O=Cc1cccc(S(=O)(=O)NCc2ccccn2)c1
Yield: 75.7 %

Procedure:
3-Hydroxymethyl-N-pyridin-2-ylmethyl-benzenesulfonamide (crude from previous step, 2.87 mmol) and MnO2 (2.9 g, 28.7 mmol) in methanol (0.5 mL) and CH2Cl2 (15 mL) were reacted at 50° C. under N2 overnight. The mixture was concentrated and purified by chromatography on silica gel (50% ethyl acetate and CH2Cl2) to afford the title compound (600 mg, 79% over two steps) as a white foam.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[I:10].C([Mg]Cl)(C)C.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.[NH4+].[Cl-]>C1COCC1.CCOCC>[I:10][C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[B:16]([OH:21])[OH:17]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(C)c(I)c(I)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(I)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 1,2-diiodo-3,5-dimethylbenzene (0.5 g, 1.40 mmol) in 60 mL in a mixture of THF and Et2O (1:1), was added dropwise at −78° C. isopropylmagnesium chloride (2 M in THF, 0.70 mL, 1.40 mmol). After the mixture was stirred for 2 h at −78° C., B(OiPr)3 (0.96 ml, 4.19 mmol) was added. The solution was warmed to room temperature overnight, then a saturated solution of NH4Cl was added, and the resulting mixture was stirred for 30 min at room temperature. The aqueous layer was extracted with Et2O (50 mL, 3 times), dried over Na2SO4 and concentrated. To the concentrated sample, hexane was added and the resulting precipitate was isolated to provide the products as shown above as non separable mixture.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)[OH:6].C1(C)C=CC(S(O[CH2:23][CH2:24][Cl:25])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]([O:6][CH2:23][CH2:24][Cl:25])=[C:4]([CH:10]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1OCCCl
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of methyl-5-chlorosalicylate (19.5 g, 105 mmol), 2-chloroethyl p-toluenesulfonate (19.3 mL, 107 mmol) and K2CO3 (28.9 g, 210 mmol) in 105 mL of N,N-dimethylformamide was warmed to 50° C. and allowed to stir for 18 hours. The mixture was cooled to ambient temperature, diluted with 25 mL of ethyl acetate and 25 mL of H2O. The layers were separated and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 75% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 249 (M+H)+, 266 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][NH:8][CH:7]2[CH2:10][CH2:11][N:12]([C:13](=[O:35])[CH:14]([NH:21][C:22](=[O:34])[CH:23]([N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:26])[CH3:24])[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:6]12)=[O:4].CCN(C(C)C)C(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([S:46]([CH3:45])(=[O:48])=[O:47])[CH:7]2[CH2:10][CH2:11][N:12]([C:13](=[O:35])[CH:14]([NH:21][C:22](=[O:34])[CH:23]([N:25]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH3:26])[CH3:24])[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:6]12)=[O:4]
Reactant: COC(=O)C1CNC2CCN(C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C3CCCCC3)C21
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CN(S(C)(=O)=O)C2CCN(C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C3CCCCC3)C12
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A solution of 19 (0.31 g, 0.63 mmol) in DCM (10 mL) was cooled to 0° C. and treated with DIPEA (0.2 mL, 1.2 mmol) and DMAP (5 mg, 0.04 mmol). Methanesulfonyl chloride (0.08 mL, 1 mmol) was added. After 2 h, the solution was diluted with DCM, washed successively with 1M HCl, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 20 as an orange-colored oil (362 mg) which was used without further purification.
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH2:2][CH3:3].Br[CH2:14][C:15]1[CH:36]=[CH:35][C:18]2/[C:19](=[C:29](/[CH:32]3[CH2:34][CH2:33]3)\[C:30]#[N:31])/[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[CH:32]1(/[C:29](=[C:19]2\[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]3[CH:16]=[C:15]([CH2:14][N:8]4[C:7]5[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=5[N:5]=[C:4]4[CH2:1][CH2:2][CH3:3])[CH:36]=[CH:35][C:18]\2=3)/[C:30]#[N:31])[CH2:34][CH2:33]1
Reactant: CCCc1nc2ccccc2[nH]1
Reactant: N#C/C(=C1\c2ccc(CBr)cc2COc2cc(F)ccc21)C1CC1
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(/C#N)C1CC1
Yield: 91.9 %

Procedure:
Using 2-propyl-1H-benzo[d]imidazole (Synthetic Communication, 2002, vol. 32, p 3703, 55 mg, 0.33 mmol) and (E)-2-(8-bromomethyl-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)-2-cyclopropylacetonitrile (120 mg, 0.31 mmol) obtained in Reference Example 6, and in the same manner as in Reference Example 1A, the title compound (132 mg, 92%) was obtained.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:18])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[C:19](=[O:22])([O-])[O-].[K+].[K+].[OH2:25]>ClCCl>[CH2:2]([O:4][C:5](=[O:18])[C@@H:6]([NH:7][C:8]1[C:9]2([CH2:14][CH2:13][O:25][CH2:11][CH2:10]2)[C:19](=[O:22])[CH:6]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: O
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC1=CC(=O)C12CCOCC2
Yield: 99.2 %

Procedure:
4-Nitro-(L)-phenylalanine ethyl ester hydrochloride (28.6 g) was suspended in dichloromethane (290 mL) to which a solution of potassium carbonate (8.0 g) in water (100 mL) was added slowly with stirring. After removal of the aqueous phase, the organic layer was washed with water (2×50 mL) and then dried (Na2SO4). Following removal of the drying agent, solid Intermediate 7 (16.1 g) was added portion-wise to the stirred dichloromethane solution. The resulting mixture was left to stir-out overnight at 20-25° C. under nitrogen. The solution was sequentially washed with 5% aqueous sodium bicarbonate (100 mL), and water (2×50 mL), then dried (Na2SO4) prior to solvent removal in vacuo which afforded the title compound as an off-white foam (38.6 g, 99.2% yield).
Reaction SMILES: C[O:2][C:3](=[O:28])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[N:19]2)=[C:14]([C:24]([F:27])([F:26])[F:25])[CH:13]=1)=[CH:5]/[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+]>C(O)C>[CH:7]1([CH2:6]/[CH:5]=[C:4](\[C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:22]([CH3:23])=[N:21][N:20]=[N:19]3)=[C:14]([C:24]([F:25])([F:27])[F:26])[CH:13]=2)/[C:3]([OH:28])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)/C(=C/CC1CCCC1)c1ccc(-n2nnnc2C)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnnn1-c1ccc(/C(=C\CC2CCCC2)C(=O)O)cc1C(F)(F)F
Temperature: 47.5 °C
Yield: 99.3 %

Procedure:
A solution of (E)-4-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-but-2-enoic acid methyl ester (359 mg, 0.9 mmol) in ethanol (5 mL) was treated E with a 1N aqueous sodium hydroxide solution (3 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (20 mL) and extracted with diethyl ether (1×30 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×30 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-4-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-but-2-enoic acid (340 mg, 98%) as a yellow solid: EI-HRMS m/e calcd for C18H19F3N4O2 (M+) 380.1460, found 380.1460.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[C@H:6]([CH3:17])[CH2:5]1)(=[O:3])[CH3:2].[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:18]([OH:24])=[O:19].[CH3:17][C@H:6]1[NH:7][CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5]1
Reactant: CC(=O)N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCN[C@H](C)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 137.6 %

Procedure:
A mixture of (R)-tert-butyl 4-acetyl-2-methylpiperazine-1-carboxylate (1.34 g, 5.53 mmol) and TFA (10 mL, 130 mmol) in DCM (30 mL) was stirred at rt for 45 min, then concentrated, diluted with DCM, and then concentrated again which was repeated 3 times. Dried under high vacuum at 80° C. to give (R)-1-(3-methylpiperazin-1-yl)ethanone 2,2,2-trifluoroacetate (1.95 g). MS (ESI+) m/z 143.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.N1C=CC=CC=1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:31](=[O:32])[O:33][CH2:34][CH3:35])=[C:3]([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:4]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1COC1CCCCO1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Nc1ccc(C(=O)c2ccccc2)cc1COC1CCCCO1
Yield: 83.5 %

Procedure:
To a stirred and cooled (10° C.) solution of 13.7 parts of intermediate 57, namely [4-amino-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenyl] phenylmethanone, in 147 parts of pyridine were added dropwise 7.14 parts of ethyl chloroformate. After stirring for 1 hour at 10° C., the reaction mixture was poured into 700 parts of water. The product was extracted with dichloromethane and the extract was washed with water (3×), dried, filtered and evaporated. The residue was co-evaporated with ethanol (3×) and was then crystallized from ethanol. The product was filtered off, washed with ethanol and 2,2'-oxybispropane and dried in vacuo at 60° C., yielding 14.05 parts (83.5%) of ethyl [4-benzoyl-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenyl]carbamate; mp. 115.9° C. (interm. 58).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=O)[NH2:2].P(Cl)(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[ClH:21].[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1)#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: NC(=O)c1ccc(C2CCCc3cncn32)cc1
Solvent: ClC(Cl)Cl
Product: Cl
Product: N#Cc1ccc(C2CCCc3cncn32)cc1

Procedure:
A solution of 1.13 g of 5-(p-carbamoylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and 1.0 ml of phosphorus oxychloride in 30 ml of chloroform is refluxed for 15 h, cooled and evaporated with toluene. The resulting oil is redissolved in 30 ml of methylene chloride, cooled to 0° and 30 ml of an ice-cold solution of 50% ammonium hydroxide solution is added. The organic phase is separated, dried and evaporated to an oil. Filtration through 20 g of silica with ethyl acetate yields the free title compound which is dissolved in 20 ml of acetone and treated with 1.2 ml of 3N ethereal hydrogen chloride to yield its hydrochloride, m.p. 209°-210°.
Reaction SMILES: Cl[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=O.[NH2:12][C:13]1[C:14]([CH2:22][CH2:23][CH3:24])=[N:15][N:16]([CH3:21])[C:17]=1[C:18]([NH2:20])=[O:19].[C:25]([OH:28])(=[O:27])[CH3:26]>>[C:25]([O:28][CH:2]([C:3]1[NH:20][C:18](=[O:19])[C:17]2[N:16]([CH3:21])[N:15]=[C:14]([CH2:22][CH2:23][CH3:24])[C:13]=2[N:12]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:27])[CH3:26]
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Reactant: CC(=O)O
Reactant: O=C(Cl)C(Cl)c1ccccc1
Product: CCCc1nn(C)c2c(=O)[nH]c(C(OC(C)=O)c3ccccc3)nc12

Procedure:
2-chloro-2-phenylacetyl chloride (3.47 ml, 0.022 mol) was added dropwise to a solution of 4-amino-3-propyl-1-methyl-5-pyrazolecarboxamide (4 g, 0.022 mol) in acetic acid (30 ml) and the reaction stirred at reflux under a nitrogen atmosphere for 20 hours.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.[C:10](=O)(O)[O-].[Na+].COS(OC)(=O)=O>CC(=O)CC>[OH:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: O=C(O)c1cc(O)cs1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CCC(C)=O
Product: COC(=O)c1cc(O)cs1

Procedure:
50.0 g (0.347 mol) of 4-hydroxy-2-thiophenecarboxylic acid and 58.3 g (0.694 mol) of sodium bicarbonate are heated at the boiling point in 900 ml of absolute 2-butanone under nitrogen, and 43.7 g (0.347 mol) of dimethylsulfate are added dropwise in the course of 20 minutes. The mixture is heated under reflux for a further 2.5 hours. It is then evaporated in vacuo and the residue is partitioned between saturated sodium bicarbonate solution and ether. The aqueous phase is extracted five more times with 80 ml of ether each time. The combined organic phases are dried over sodium sulfate/active charcoal, filtered and evaporated.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O1CCOCC1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>[OH-].[Na+]>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([N:2]([CH3:1])[C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N(C)[C@@H](Cc2ccccc2)C(=O)O)cc1
Reaction time: 1 h
Yield: 45.6 %

Procedure:
N-Methyl-L-phenylalanine (500 mg, 2.79 mmol) was dissolved in 1N NaOH (6 mL). Dioxane (9 mL)) was added, followed by p-toluenesulfonyl chloride (532 mg, 2.79 mmol) and the mixture was vigorously stirred for 1 hr. The volatiles were removed in vacuo and the residue was dissolved in water (30 mL) and washed with Et2O (2×30 mL) before making acidic with 1N HCl. The mixture was extracted with CHCl3 (3×30 mL) and the extracts were evaporated in vacuo to give N-(toluene-4-sulfonyl)-N-methylphenylalanine as a solid (424 mg, 45%). N-(Toluene-4-sulfonyl)-N-methylphenylalanine was coupled to L-phenylalanine ethyl ester using the procedure described in Method 3 (400 mg, 62%). The title compound was prepared via hydrolysis of the ethyl ester using NaOH in ethanol. Proton and carbon NMR analyis indicated a mixture of diastereomers.