Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:6]=1[CH2:7][N:8]=[N+]=[N-])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:6]=1[CH2:7][NH2:8])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(OC)cc1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=CCOc1ccc(OC)cc1CN
Temperature: 25 °C
Reaction time: 7 h
Yield: 54.2 %

Procedure:
Step AS (4). To a solution of 2-allyloxy-5-methoxybenzyl azide (4.5 g, 21 mmol) in 150 mL of anhydrous THF was added triphenylphosphine (10.8 g, 41 mmol) and 0.5 mL of water. The mixture was stirred at rt for 7 h. The reaction was concentrated under vacuum and the residue was partitioned between Et2O and 2 N HCl. The aqueous layer was basified with 2 N NaOH to pH 10 and extracted with EtOAc (3×40 mL). The organic layers were combined and washed with brine then dried over magnesium sulfate. After concentration, the residue was purified by silica gel chromatography, eluting with a mixture of 30% 2N ammonia in methanol and 70% EtOAc to yield 2-allyloxy-5-methoxybenzylamine as colorless oil (2.2 g, 55%). LC-MS (M+H)+=194; 1H NMR (400 MHz, CD3OD) δ ppm 3.75 (s, 3H) 4.08 (s, 2H) 4.60 (d, J=5.29 Hz, 2H) 5.22-5.30 (m, J=10.58 Hz, 1H) 5.35-5.44 (m, J=17.37 Hz, 1H) 6.01-6.15 (m, 1H) 6.89-6.96 (m, 2H) 6.96-7.02 (m, 1H).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[C:5](Br)=[N:6][CH:7]=[CH:8][CH:9]=1.[CH:12]1(B(O)O)[CH2:14][CH2:13]1>>[F:1][CH:2]([F:11])[O:3][C:4]1[C:5]([CH:12]2[CH2:14][CH2:13]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: OB(O)C1CC1
Reactant: FC(F)Oc1cccnc1Br
Product: FC(F)Oc1cccnc1C1CC1
Temperature: 95 °C
Yield: 58 %

Procedure:
Prepared according to Preparation 48 using 3-difluoromethoxy-2-bromopyridine (Preparation 217) and cyclopropylboronic acid. The reaction was heated to 95° C. for 18 hours before cooling to room temperature and filtering through arbocel. The filtrate was concentrated in vacuo and purified using silica gel column chromatography eluting with ethylacetate:heptane 1:5 to furnish the title compound as a colourless oil (273 mg, 58%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][O:25][C:26]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[CH3:24][O:25][C:26]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:27]=1[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: COc1ccc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)c(OC)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,4-Dimethoxy-benzoic acid.
Reaction SMILES: FC1CCCC1.Cl.[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][CH:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[CH:16]3[CH2:32][CH:33]([OH:35])[CH2:34][CH:15]3[C:14]=2[CH:13]=1>C1COCC1.O>[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][CH:17]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:26][CH:27]=3)[CH:16]3[CH2:32][C:33](=[O:35])[CH2:34][CH:15]3[C:14]=2[CH:13]=1
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(O)CC32)cc1
Agent: Cl
Agent: FC1CCCC1
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(=O)CC32)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of Preparation 45 (0.012 g) in THF (20 mL) and H2O (1 mL) add HCl solution (2 mL, 3 N in H2O), and stir the mixture overnight. Pour the mixture into satd. NaHCO3 and extract with Et2O (2×50 mL) and EtOAc (2×50 mL). Wash the combined organic extracts with brine, dry over Na2SO4, and concentrate to afford crude Preparation 27 as a light yellow solid. Purify the crude material by MPLC (0% to 25% to 50% EtOAc/hexanes) to afford Example 23 (0.010g, 90%) as a white solid. 1H NMR (CD3OD) δ 7.22 (d, J=8.0 Hz, 2 H), 6.85 (m, 1 H), 6,79 (m, 3 H), 6.64 (m, 1 H), 5.22 (s, 1 H), 3.54 (m, 1 H), 2.67 (m, 1 H), 2.56 (m, 1 H), 2.26 (m, 2 H), 2.13 (m, 2 H), 1.84 (dd, J=3.9, 14.5 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[C:12](/[CH3:25])=[CH:13]/[C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1.[OH-].[K+].S(=O)(=O)(O)O>C(O)C.O>[CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[C:9](/[C:12](/[CH3:25])=[CH:13]/[C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)[CH:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCO3)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCO2
Temperature: 50 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
4.0 g of ethyl p-[(E)-2-(4,4-dimethyl-6-chromanyl)-propenyl]benzoate were dissolved in 80 ml of ethanol and the solution obtained was treated with a solution of 5.6 g of potassium hydroxide in 20 ml of water and 20 ml of ethanol. After stirring at 50° C. for 3 hours, the mixture was cooled, poured into ice/water, acidified with 2N sulphuric acid and extracted repeatedly with ethyl acetate. The organic phase was washed with water, dried over sodium sulphate and evaporated. After recrystallization of the residue from methylene chloride/hexane, there was obtained 3.4 g of p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl)propenyl]benzoic acid in the form of colorless crystals of melting point 196°-197° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].CCN(C(C)C)C(C)C.C(OC([O-])=O)(ON1C(=O)CC([C:24]([O:26][CH2:27][CH:28]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]3[C:29]2=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])C1=O)=O.O>CN(C=O)C>[C:24]([NH:5][CH2:4][C:3]#[N:2])([O:26][CH2:27][CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:25]
Reactant: N#CCN
Reactant: O=C([O-])OC(=O)ON1C(=O)CC(C(=O)OCC2c3ccccc3-c3ccccc32)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: N#CCNC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h

Procedure:
Aminoacetonitrile HCL salt (1 mmol (92.53 mg)) is dissolved in DMF 2 ml and DIEA 2 mmol 0.35 ml. Then Fmoc-Succinimidyl dicarbonate 1.1 mmol, (350 mg) is added and the reaction allowed to proceed overnight. Water and diluted HCL is added to bring the pH to 2. The product is extracted 3 times with ethylacetate and dried over Na2SO4 to yield Fmoc-NH—CH2—CN. 1 mmol of the Fmoc-NH—CH2—CN (278 mg) is dissolved in 2 ml of anhydrous methanol bubbled with HCl gas. The reaction is kept at 0° C. for 40 hrs (Voss and Gerlach Helv. Chim. Acta (1983) 66: 2294) to yield the desired Fmoc-glycine orthotrimethylester (Fmoc-NH—CH2—C(OCH3)3).
Reaction SMILES: C(O[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]2[C:17]3[C:18]([O:22][CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][N:14]=2)[CH2:7][CH2:6]1)C.[C:29]1(=[C:35]([O:41][CH3:42])[O:36][Si](C)(C)C)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.COC(=C1CCOCC1)O[Si](C)(C)C>>[O:26]1[CH2:25][CH2:24][CH:23]([O:22][C:18]2[C:17]3[C:13]([O:12][CH2:11][CH:8]4[CH2:9][CH2:10][N:5]([CH2:4][C:29]5([C:35]([O:41][CH3:42])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)[CH2:6][CH2:7]4)=[N:14][O:15][C:16]=3[CH:21]=[CH:20][CH:19]=2)[CH2:28][CH2:27]1
Reactant: CCOCN1CCC(COc2noc3cccc(OC4CCOCC4)c23)CC1
Reactant: COC(O[Si](C)(C)C)=C1CCCCC1
Agent: COC(O[Si](C)(C)C)=C1CCOCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OC5CCOCC5)c34)CC2)CCCCC1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 7 using 3-{[1-(ethoxymethyl)piperidin-4-yl]methoxy}-4-(tetrahydro-2H-pyran-4-yloxy)-1,2-benzisoxazole (EXAMPLE 30, Step 1) and [cyclohexylidene(methoxy)methoxy](trimethyl)silane (Tetrahedron 2004, 60, 8957-8966) instead of 4-(benzyloxy)-3-{2-[1-(ethoxymethyl)piperidin-4-yl]ethoxy}-1,2-benzisoxazole and [methoxy(tetrahydro-4H-pyran-4-ylidene)methoxy](trimethyl)silane.
Reaction SMILES: [C:1]([C:3](=[C:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:9]1[CH3:15])C(OC)=O)#[N:2].[Cl-].[Li+].CN1CCCC1=O.Cl>O>[CH3:14][C:11]1([CH3:13])[CH2:10][CH:9]([CH3:15])[C:8]([CH2:3][C:1]#[N:2])=[CH:12]1
Reactant: COC(=O)C(C#N)=C1CC(C)(C)CC1C
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC1CC(C)(C)C=C1CC#N
Temperature: 150 °C
Reaction time: 3 h

Procedure:
The methyl 2-cyano-2-(2,4,4-trimethylcyclopentylidene)acetate B is placed in a round-bottomed flask with 2 eq. of lithium chloride in a 98:2 mixture of NMP (N-methylpyrrolidone) and water. The mixture is stirred at 150° C. After 3 hours, the reaction medium is cooled to ambient temperature before being poured onto a 1% HCl solution. Stirring is carried out for a few minutes and then extraction is carried out twice with MTBE (methyl tert-butyl ether). The combined organic phases are washed with a sodium bicarbonate solution and then with an aqueous sodium chloride solution. After drying over magnesium sulfate, filtering through paper and evaporating the solvent, the crude product is distilled under reduced pressure. A 70:30 mixture of 2-(2,4,4-trimethylcyclopent-1-enyl)acetonitrile and 2-(3,3,5-trimethylcyclopent-1-enyl)-acetonitrile is obtained.
Reaction SMILES: C[O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]3[CH2:10][C@H:11]2[CH2:21][C@:12]21[O:22][CH3:23].S(=O)(=O)(O)O.O>CC(C)=O>[CH3:23][O:22][C@@:12]12[CH2:21][C@@H:11]1[CH2:10][C@H:9]1[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]21[CH3:14])[C:18]1[CH2:19][CH2:20][C:3](=[O:2])[CH2:4][C:5]=1[CH2:6][CH2:7]3
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3C[C@H]3C[C@]32OC)C1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CO[C@@]12C[C@@H]1C[C@H]1[C@@H]3CCC4=C(CCC(=O)C4)[C@H]3CC[C@@]12C
Temperature: 25 °C

Procedure:
10 g of 3,17-dimethoxy-16alpha,17alpha-methylene-estra-2,5(10)-diene is suspended in 165 ml of 80% aqueous acetone and is mixed with vigorous stirring with 0.2 ml of 25% sulfuric acid. Then, with stirring, it is heated on the water bath (60° C.) until all the steroid has gone into solution (about 30 minutes). Then, it is allowed to cool to room temperature and stirred one more hour. After the reaction has been completed, the steroid is precipitated by the addition of water, separated and dried. 9.5 g of crystalline 16alpha,17alpha-methylene compound, which was used in the next step without recrystallization, is obtained.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:10]3[CH2:12][CH2:13][N:14](C(=O)C(F)(F)F)[CH2:15][CH2:16][C:9]=3[CH:8]=[CH:7][C:6]=2[O:5][CH2:4]1)[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO.O>[CH2:1]([CH:3]1[C:11]2[C:10]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:9]=3[CH:8]=[CH:7][C:6]=2[O:5][CH2:4]1)[CH3:2]
Reactant: CCC1COc2ccc3c(c21)CCN(C(=O)C(F)(F)F)CC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCC1COc2ccc3c(c21)CCNCC3
Temperature: 25 °C
Yield: 50.8 %

Procedure:
The product of step (i) (45 mg, 0.143 mmol) was dissolved in an appropriately sized flask in MeOH (3 ml). To this mixture water (1 ml) and K2CO3 (500 mg, 3.62 mmol) were added. The reaction mixture was stirred at room temperature until the product formation was complete by LCMS. The reaction mixture was diluted with water (>10× total volume) and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried (Na2SO4), and solvent evaporated in vacuo to provide the title compound (15.8 mg). 1H NMR (300 MHz, CDCl3) δ 6.86 (d, J=7.8 Hz, 1H); 6.52 (d, J=8.1 Hz, 1H); 4.49-4.44 (m, 1H); 4.39-4.35 (m, 1H); 3.31-3.21 (m, 1H); 2.99-2.85 (m, 8H); 2.07 (bs, 1H); 1.58-1.52 (m, 2H); 0.92 (t, J=7.5 Hz, 3H). MS: ESI (positive): 218 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH2:29][C@@H:30]5[CH2:34][CH2:33][CH2:32][O:31]5)[CH:24]=4)[C:19]3=[O:35])=[CH:14][CH:13]=2)[CH2:7]1)C(=O)C.[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:1][NH:2][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH2:29][C@@H:30]5[CH2:34][CH2:33][CH2:32][O:31]5)[CH:24]=4)[C:19]3=[O:35])=[CH:14][CH:13]=2)[CH2:7]1
Reactant: CC(=O)N(C)C1CCCN(c2ccc(-n3ccc4cc(OC[C@@H]5CCCO5)ccc4c3=O)cc2)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CNC1CCCN(c2ccc(-n3ccc4cc(OC[C@@H]5CCCO5)ccc4c3=O)cc2)C1

Procedure:
A solution of N-methyl-N-[1-(4-{1-oxo-6-[(S)-1-(tetrahydrofuran-2-yl)methoxy]-1H-isoquinolin-2-yl}-phenyl)-piperidin-3-yl]-acetamide (552 mg) was stirred in 20% sulfuric acid (with methanol as solubilizing agent) for 16 h at 90° C. The mixture was neutralized with 2N NaOH, extracted with dichloromethane, dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. In this way the product was obtained with molecular weight 433.56 (C26H31N3O3); MS (ESI): 434 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=O)[NH:14][C:13](=[S:17])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:24]([O-:27])([O-])=O.[Cs+].[Cs+].FC(F)(F)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:24](=[O:27])[N:14]([CH2:15][C:37]([F:40])([F:39])[F:38])[C:13]([S:17][CH2:36][C:37]([F:40])([F:39])[F:38])=[N:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C1NC(=S)NC12CC(c1ccccc1)Oc1ccc(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1N(CC(F)(F)F)C(SCC(F)(F)F)=NC12CC(c1ccccc1)Oc1ccc(Br)cc12
Reaction time: 48 h
Yield: 37.4 %

Procedure:
To a solution of 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (113 mg, 0.29 mmol) in DMF (7 mL) was added Cs2CO3 (190 mg, 0.58 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (204 mg, 0.87 mmol). After stirring for 2 days, the mixture was extracted from water with EtOAc. The combined organic layers were washed with water and brine, dried and then concentrated to give the residue, which was purified by preparative TLC to give 6-bromo-2-phenyl-1′-(2,2,2-trifluoroethyl)-2′-(2,2,2-trifluoroethylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (60 mg, 36%).
Reaction SMILES: C(O)(=O)/C=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.CC([O-])=[O:17].[Na+]>CO>[O:17]=[CH:3][C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: CC(=O)[O-]
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: [Na+]
Solvent: CO
Product: COc1cc(C=O)ccc1O
Reaction time: 0.25 h

Procedure:
Metabolites of trans-ferulic acid, including the CoASH thioesters, were analysed and quantitated by HPLC using a Lichrosorb RP-18 column (20 cm×4.6 mm; Capital HPLC, Broxburn, West Lothian, UK) with a multiphasic gradient; solvent “A” was 20 mM NaOAc, adjusted to pH 6.0 and solvent “B” was MeOH; the flow rate was 1.2 ml/min; the proportion of solvent “B” rose linearly from 0% at 0 min to 10% at 15 min and thence to 50% at 40 min and 70% at 45 min, finally decreasing to 0% at 50 min. Detection was with a Spectra Focus detector (Thermo Separation Products, Stone, Staffs. UK), which permitted u/v spectral analysis of each eluting component. Typical approximate retention times were: CoASH, 3 min; vanillic acid, 7 min; trans-ferulic acid, 19 min; acetyl SCoA, 22 min; HMPHP SCoA, 29 min; vanilloyl SCoA, 31 min; vanillin, 31.5 min; trans-feruloyl SCoA, 34 min.
Reaction SMILES: [C:1]1([CH2:13][CH2:14][NH2:15])[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]3[O:10][CH2:11][CH2:12][C:6]=3[C:5]=12.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]1([CH2:13][CH2:14][NH:15][C:23](=[O:25])[CH3:24])[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]3[O:10][CH2:11][CH2:12][C:6]=3[C:5]=12
Reactant: NCCc1cnn2ccc3c(c12)CCO3
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1cnn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a solution of 2-(8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)ethanamine (75.0 mg, 0.369 mmol) and triethylamine (105 μL, 0.753 mmol) in tetrahydrofuran (4 mL) was added acetic anhydride (70.0 μL, 0.741 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. A saturated aqueous sodium hydrogen carbonate solution (50 μL) was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) and recrystallization (ethyl acetate/diisopropyl ether) to give the title compound (42.1 mg, yield 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[S:12][C:8]=2[C:7]=1[C:21]#[N:22].[F:26][C:27]([F:39])([F:38])[C:28]1[CH:29]=[C:30]([CH2:34][C:35](O)=[O:36])[CH:31]=[CH:32][CH:33]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC=CC=1>C(OCC)(=O)C>[C:21]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])=[N:10][C:9]=2[CH:19]=[CH:20][C:6]=1[O:5][C:4]1[CH:23]=[CH:24][CH:25]=[C:2]([NH:1][C:35](=[O:36])[CH2:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([F:38])([F:26])[F:39])[CH:29]=2)[CH:3]=1)#[N:22]
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#Cc1c(Oc2cccc(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 85 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (100 mg, 0.285 mmol) produced in Example 3(vi), [3-(trifluoromethyl)phenyl]acetic acid (138 mg, 0.684 mmol), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (260 mg, 0.684 mmol) and pyridine (2 mL) was stirred at 85° C. for 4 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), washed successively with saturated aqueous ammonium chloride solution (5 mL), saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-heptane (1/2) to give the title compound (87 mg, 57%) as a white powder.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH:7]1[CH2:13][OH:14].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:14][CH2:13][CH:7]1[CH2:8][CH2:9][CH:10]([CH2:11][O:12][S:2]([CH3:1])(=[O:4])=[O:3])[O:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCC(CO)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCC(COS(C)(=O)=O)O1
Temperature: 0 °C
Yield: 91.2 %

Procedure:
Methanesulphonyl chloride (307.8 g, 2.7 mol) is added dropwise to a solution of tetrahydrofuran-2,5-dimethanol (118.8 g, 900 mmol) and of triethylamine (454.5 g, 4500 mmol) in 1.54 L of dichloromethane at 0° C. The reaction medium is maintained at 0° C. for 1 hour, ice-cold water is then added and the organic phase is separated out and washed with 500 mL of dilute (1 M) hydrochloric acid solution. The organic phase is separated out and then washed with 500 mL of saturated aqueous NaHCO3 solution. The organic phase is finally separated out and concentrated to give 236.7 g of (tetrahydrofuran-2,5-diyl)bis(methylene) dimethanesulphonate in the form of a brown oil in a purity equal to 96% (determined by LCMS). Reaction yield: 91.0%. A solution of (tetrahydrofuran-2,5-diyl)bis(methylene) dimethanesulphonate (236.7 g, 821.7 mmol) and NaN3 (270.0 g, 4.1094 mol) in DMSO (1.350 L) is heated at 95° C. and stirred overnight. The reaction medium is added to ice-cold water and extracted with 3 times 700 mL of ethyl acetate. The extracts (phase containing ethyl acetate) are successively washed with water, saturated aqueous NaHCO3 solution and dried overnight on MgSO4 and then filtered to remove the MgSO4. The phase containing the ethyl acetate is concentrated to give 166.5 g of 2,5-bis(azidomethyl)tetrahydrofuran in the form of a brown oil. A mixture of 2,5-bis(azidomethyl)tetrahydrofuran (166.5 g) and of Pd-C (10%, 10.8 g) in methanol (2.7 L) is stirred overnight at room temperature under 1 atm of H2. The reaction medium is filtered and the filtrate is concentrated under vacuum to give 90.0 g of 2,5-bis(aminomethyl)tetrahydrofuran in the form of a yellow oil. The total yield for the 3 successive reactions is 75%. The process for synthesizing 2,5-bis(aminomethyl)tetrahydrofuran gives a 90/10 mixture of the cis/trans isomers according to 13C NMR analysis in deuterated methanol.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]([CH2:20][C:21]#[N:22])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C>C1COCC1>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]([CH2:20][CH2:21][NH2:22])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NCCC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Yield: 30.2 %

Procedure:
(7-Benzenesulfonyl-chroman-4-yl)-acetonitrile (397 mg, 1.26 mmol) was dissolved in 5 mL THF, and 190 ul (1.9 mmol) of BH3.DMF was added. The reaction mixture was heated to reflux for one hour and then cooled to room temperature, quenched by addition of methanol, and diluted with water. The aqueous mixture was extrated with EtOAc. The organic phase was dried over MgSO4, and solvent was removed under reduced pressure. The residue was chromatographed through silica gel (MeOH:CH2Cl2:NH4OH 8%:90%:2%), and solvent was removed under reduced pressure to yield 120 mg (0.38 mmol, 30%) of 2-(7-benzenesulfonyl-chroman-4-yl)-ethylamine. This product was dissolved in 2N HCl/EtOH and recrystallized by addition of Et2O to afford 95 mg of the corresponding hydrochloride salt. Mp: 244.6-245.8° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:6]=[N:7][C:8]2[C:9](=O)[CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+].O>C(O)C.O>[F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:6]=[N:7][C:8]2[C:9](=[N:19][OH:20])[CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1
Reactant: NO
Reactant: O=C1CCCc2cc(OCC(F)(F)F)cnc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCCc2cc(OCC(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.9 %

Procedure:
A mixture of 3-(2,2,2-trifluoroethoxy)-6,7-dihydroquinolin-8(5H)-one (155 mg, 0.63 mmol), hydroxylamine hydrochloride (88 mg, 1.3 mmol), and sodium acetate (104 mg, 1.3 mmol) in ethanol-water (3:1, 4 mL) was refluxed with stirring for 2 hours. After cooling to room temperature, the mixture was poured into water, and the aqueous layer was extracted with dichloromethane (twice). The combined organic layers were dried over Magnesium sulfate and concentrated in vacuo to give 167 mg of the crude title compound as a brown solid. This was used for the next step without purification: