Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=1)=[O:3].[Se](=O)=[O:16]>>[CH3:14][O:13][C:6]1[CH:5]=[C:4]([C:2]([CH:1]=[O:16])=[O:3])[CH:9]=[CH:8][C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[Se]=O
Reactant: COc1cc(C(C)=O)ccc1[N+](=O)[O-]
Product: COc1cc(C(=O)C=O)ccc1[N+](=O)[O-]

Procedure:
3-Methoxy-4-nitrophenylglyoxal was prepared according to the method described in Patent Application FR 2,351,108, but starting with 3-methoxy-4-nitroacetophenone (33.6 g) and selenium dioxide (22 g). The expected product (35 g) is obtained in the form of a brown oil, which was used without further purification for the subsequent steps.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:2].[CH2:13]([O:15][C:16](=[O:21])[C:17]([NH2:20])=[N:18]O)[CH3:14].O>ClCCl.CC1C=CC=C(C)N=1>[CH2:13]([O:15][C:16]([C:17]1[N:20]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[F:12])[O:8][N:18]=1)=[O:21])[CH3:14]
Reactant: N#Cc1ccc(C(=O)Cl)c(F)c1
Reactant: CCOC(=O)C(N)=NO
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCOC(=O)c1noc(-c2ccc(C#N)cc2F)n1
Temperature: 25 °C

Procedure:
A solution of 4-cyano-2-fluorobenzoyl chloride (450 mg) in dichloromethane (5 mL) is added to a solution of amino-hydroxyimino-acetic acid ethyl ester (350 mg) in 2,6-dimethyl-pyridine (1 mL) and the reaction mixture is stirred at room temperature over night. Water is added and the organic phase is separated, washed with 1 N hydrochloric acid, water, and brine, dried over MgSO4, and concentrated in vacuo. The dark residue is heated to 170° C. for 2 h. The crude product is purified by silica gel chromatography (cyclohexane/ethyl acetate 65:35). LC (method 15): tR=1.08 min; Mass spectrum (ESI+): m/z=262 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])[N:4]=1.[CH2:21](O)[CH:22]1[O:26][CH2:25][CH2:24][CH2:23]1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S(Cl)(=O)=O)(C)C.CN1C=CN=C1.Cl>O1CCCC1.C(Cl)(Cl)Cl>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([O:16][CH2:21][CH:22]2[O:26][CH2:25][CH2:24][CH2:23]2)=[O:15])[N:6]=1
Reactant: OCC1CCCO1
Reactant: COc1cc(OC)nc(Oc2ccccc2C(=O)O)n1
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: Cl
Agent: Cn1ccnc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Oc2ccccc2C(=O)OCC2CCCO2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.55 Gram of 2-(4,6-dimethoxypyrimidin-2-yl)oxybenzoic acid, 0.21 g of tetrahydrofurfuryl alcohol and 0.85 g of 2,4,6-triisopropylbenzenesulfonyl chloride were dissolved in 5 ml of tetrahydrofuran. Subsequently, 0.45 g of 1-methylimidazole was added to the mixture. After stirring the resulting solution at room temperature for 1 hour in order to carry out the reaction, the reaction solution was poured into diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer separated from the aqueous layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (mfd. by Merck & Co., Inc., solvent: chloroform) to obtain 0.30 g of tetrahydrofurfuryl 2-(4,6-dimethoxypyrimidin-2-yl)oxybenzoate [present compound (III-9)].
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.Cl.[C:13](=[NH:18])([NH2:17])[CH2:14][CH2:15][CH3:16].C[O-].[Na+]>CO.C(OCC)(=O)C>[F:11][CH:2]([F:1])[C:3]1[N:17]=[C:13]([CH2:14][CH2:15][CH3:16])[NH:18][C:5](=[O:7])[CH:4]=1
Reactant: CCOC(=O)CC(=O)C(F)F
Reactant: CCCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1nc(C(F)F)cc(=O)[nH]1
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A mixture of ethyl 4,4-difluoro-3-oxobutanoate (5.0 g), butanimidamide hydrochloride (4.1 g) and sodium methoxide (28% methanol solution, 15 mL) in methanol (50 mL) was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil (5.6 g, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH:27]=[CH2:28].CCN(CC)CC>CCOCC.CN(C=O)C.CCOC(C)=O>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([C:8](=[C:16]2[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH2:21]2)[C:5]2[CH:4]=[CH:3][C:2](/[CH:28]=[CH:27]/[C:26]([O:30][CH2:31][CH3:32])=[O:29])=[CH:7][CH:6]=2)=[CH:14][CH:13]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Reactant: C=CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Temperature: 110 °C
Yield: 75.1 %

Procedure:
To a round-bottomed flask were added 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (10.2 g, 0.0255 mol), ethyl acrylate (28 mL, 0.255 mol.), dichlorobis(triphenylphosphine) palladium (II) (0.895 g, 1.28 mmol, 5 mol %), Et3N (17.6 mL, 0.128 mol), and DMF (50 mL). The stirred reaction mixture was heated to 110° C. for 18 h under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and then diluted with Et2O (200 mL). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude product. The crude reaction mixture in DMF was diluted with EtOAc (400 mL), washed with water (2×100 mL), brine (1×100 mL), dried (Na2SO4), filtered, and then concentrated under reduced pressure to afford the crude product as an oil. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (19:1 to 1:1) as an eluent to give 8.02 g (75%) of compound 15 as a pale yellow solid. 1H NMR (300 MHz, CDCl3): δ 0.88 (s, 6 H), 0.91 (s, 6 H), 1.31 (s, 2 H), 1.35 (t, J=7.2 Hz, 3 H), 1.99 (s, 2 H), 2.00 (s, 2 H), 4.28 (q, J=7.2 Hz, 2 H), 5.35 (broad s, 1H), 6.41 (d, J=16.2 Hz, 1 H), 6.77 (d, J=8.4 Hz, 2 H), 7.04 (d, J=8.4 Hz, 2 H), 7.20 (d, J=8.10 Hz, 1 H), 7.44 (d, J=8.40 Hz, 2 H), 7.68 (d, J=16.2 Hz, 1H). HRMS (EI) Calcd for C28H34O3: 418.57 (M+). Found: 419.17. Note: Excess ethyl acrylate can be distilled from the reaction mixture before work-up.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[C:11]1([CH2:20][C:19](=[O:21])[CH:18]([C:22](=[O:25])[CH2:23][CH3:24])[C:17](=[O:26])[CH2:16]1)[CH2:10][CH2:9]2.[C:27](Cl)(=[O:29])[CH3:28].Cl>ClCCCl.ClC(Cl)C>[C:27]([C:14]1[C:13]([CH3:15])=[C:12]2[C:8]([CH2:9][CH2:10][C:11]32[CH2:16][C:17](=[O:26])[CH:18]([C:22](=[O:25])[CH2:23][CH3:24])[C:19](=[O:21])[CH2:20]3)=[CH:7][C:6]=1[CH3:5])(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: CCC(=O)C1C(=O)CC2(CCc3cc(C)cc(C)c32)CC1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: CCC(=O)C1C(=O)CC2(CCc3cc(C)c(C(C)=O)c(C)c32)CC1=O
Temperature: 20 °C
Reaction time: 12 h

Procedure:
To a stirred suspension of aluminium trichloride (4.8 g, 33 mmol) in 1,2-dichloroethane (80 ml) at 20° C. was added a solution of 5', 7'-dimethyl-4-propionylspiro[cyclohexane-1,1'-indan]-3,5-dione (3.2 g, 11 mmol) in dichloroethane (10 ml). A solution of acetyl chloride (1.0 g, 13 mmol) in dichloroethane (10 ml) was added and the mixture was stirred at 20° C. for 12 hours. The solution was poured onto cold dilute hydrochloric acid and then extracted with diethyl ether. The ether layer was separated, dried (MgSO4) and evaporated and the crude product was purified by passage through silica gel eluting with methylene chloride. A mixture of 4'-acetyl-5',7'-dimethyl-4-propionylspiro[cyclohexane-1,1'-indan]-3,5-dione and 6'-acetyl-5',7'-dimethyl-4-propionylspiro[cyclohexane-1,1'-indan]-3,5-dione was obtained as a colourless oil (1.0 g, 29%). Pmr spectrum (CDCl3, δ in ppm): 1.16 (3H, t); 1.9-3.3 (17H, complex m); 3.09 (2H, q); 6.84 (0.6H, s); 6.93 (0.4H, s); 18.26 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.Cl.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:26]3[CH2:25][CH2:24][N:23]([C:19]4[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH3:15])[CH:18]=4)[CH2:28][CH2:27]3)[N:10]=2)[CH:7]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Agent: Cl
Solvent: OCCO
Solvent: CCN(CC)CC
Product: COc1cccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c1
Yield: 72.7 %

Procedure:
Following the general procedure of Example 11 and making noncritical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.409 g), 1-(3-methoxyphenyl)piperazine dihydrochloride (Aldrich; 0.450 g), triethylamine (Aldrich; 0.686 g), and ethylene glycol (2 mL) give 0.440 g of the title compound after chromatography (silica gel, methanol/dichloromethane, 4/96) and crystallization from dichloromethane/ethyl ether/hexane; mp 132-133.5° C.; MS m/z 356; IR (mineral oil) 805, 2817, 1198, 1171, 1580, 1502 cm-1. 1H NMR (CDCl3) δ2.74, 3.24, 3.78, 6.41, 6.46, 6.55, 7.11-7.19, 7.52, 7.56, 8.14.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:8]=2[CH:9]=[N:10]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H].[ClH:20]>CO.[Ni].C(OCC)(=O)C>[ClH:20].[CH:1]1([O:6][C:7]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: COc1cccc(C=NO)c1OC1CCCC1
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cccc(CN)c1OC1CCCC1
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-(cyclopentyloxy)-3-methoxybenzaldehyde oxime (3 g, 12.448 mmol) in methanol (10 ml) was added catalytic amount of Raney nickel (0.30 g) at room temperature. The reaction mixture was stirred for 3 h at 50 psi hydrogen pressure in Paar hydrogenation apparatus. The reaction mixture was filtered through celite bed, dried (Na2SO4), filtered and concentrated to get the crude product. The crude product was then dissolved in ethyl acetate, to which hydrochloric acid in ethyl acetate was added dropwise at 10° C. and stirred for 20 min and then filtered and dried to yield 2.86 g of the product, 1H NMR (300 MHz, DMSO-d6) δ 1.57-1.63 (m, 4H), 1.65-1.72 (m, 4H), 3.81 (s, 3H), 3.94 (s, 2H), 4.90 (br s, 1H), 7.08 (s, 3H), 8.39 (br s, 3H).
Reaction SMILES: [N:1]([CH2:4][CH3:5])=[C:2]=[O:3].[F:6][C:7]([F:26])([F:25])[C:8]1[CH:9]=[C:10]([S:14]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][NH2:24])[CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:4]([NH:1][C:2]([NH:24][O:23][CH:20]1[CH2:21][CH2:22][N:17]([S:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([F:26])([F:6])[F:25])[CH:9]=2)(=[O:15])=[O:16])[CH2:18][CH2:19]1)=[O:3])[CH3:5]
Reactant: NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: CCN=C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCNC(=O)NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 63.6 %

Procedure:
Isocyanatoethane (53.0 mg, 0.74 mmol) was added to a solution of O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)hydroxylamine (200 mg, 0.62 mmol) and pyridine (98 mg, 1.23 mmol) in CH2Cl2 (4 ml) and stirred at room temperature for 17 hours. The resulting precipitation was collected, washed with aqueous 1 N HCl solution (10 ml×3), aqueous NaHCO3 solution (10 ml×3), ether (10 ml×2) to give 1-ethyl-3-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)urea (156 mg, 64%) as a white solid: LCMS: 396 [M+1]+. 1H NMR (DMSO-d6) δ: 0.98 (m, 3H), 1.73 (m, 2H), 1.86 (m, 2H), 2.85 (m, 2H), 3.00 (m, 2H), 3.18 (n, 2H), 3.60 (m, 1H), 6.65 (m, 1H), 7.91 (m, 2H), 8.01 (m, 2H), 8.82 (s, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[OH:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[O:23][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1
Reactant: O=c1cc(I)cnn1C1CCCCO1
Reactant: Oc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(Oc2c(F)cccc2F)cnn1C1CCCCO1
Temperature: 120 °C
Yield: 48.3 %

Procedure:
A solution of 5-iodo-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (204 mg, 0.67 mmol) in anhydrous N,N-dimethylformamide (8.5 mL, 0.08M) was treated with 2,6-difluorophenol (0.09 g, 0.69 mmol) and potassium carbonate (0.20 g, 1.45 mmol). The reaction was heated at 120° C. overnight. At this time, the reaction was diluted with water (25 mL) and extracted with methylene chloride (3×25 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (25 mL), dried over magnesium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 24 g, 20% to 40% ethyl acetate/hexanes) afforded 5-(2,6-difluoro-phenoxy)-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (99.7 mg, 49%) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.56 (m, 2H), 1.57-1.76 (m, 2H), 1.88-2.01 (m, 1H), 2.01-2.16 (m, 1H), 3.53-3.63 (m, 1H), 3.90-3.98 (m, 1H), 5.82 (dd, J=10.5, 1.6 Hz, 1H), 6.04 (d, J=2.7 Hz, 1H), 7.34-7.43 (m, 2H), 7.43-7.55 (m, 1H), 8.23 (d, J=2.7 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:18]1([CH2:21][C:22](=[O:33])[CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=2)[CH2:20][CH2:19]1>C1COCC1>[CH:18]1([CH2:21][C:22](=[O:33])[CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[N:25]=2)[CH2:19][CH2:20]1
Reactant: CS(=O)c1nccc(CC(=O)CC2CC2)n1
Reactant: Nc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccnc(Nc2ccncc2)n1)CC1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
To a solution of 4-aminopyridine (328 mg, 3.49 mmol) in THF (2.344 mL) cooled to −78° C. was added LHMDS (583 mg, 3.49 mmol). The reaction was warmed to rt and stirred for 15 minutes. The reaction was again cooled to −78° C. and 1-cyclopropyl-3-[2-(methylsulfinyl)pyrimidin-4-yl]propan-2-one (7) (277 mg, 1.162 mmol) was added as a solution in THF (2 mL). The reaction was warmed to rt and stirred for 1 hour. The reaction was quenched by slow addition of saturated ammonium chloride and the volatiles evaporated. The residue was then partitioned between water and DCM. The organic layer was washed with brine, dried with sodium sulfate, and concentrated in vacuo. The crude residue was purified by Biotage™ silica gel chromatography [2-10% MeOH in DCM with 1% triethylamine] to afford the desired product as a yellow oil (269 mg, 86%). MS (ES+): m/z=269.2 (100) [MH+2]. HPLC: tR=0.69 minute over 3 minutes. Purity: >95% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[N:14][NH:13][N:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.[NH2:38][CH2:39][C:40]1([OH:47])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.C(=O)([O-])[O-]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[N:14][NH:13][N:12]=2)=[CH:7][C:3]=1[C:4]([NH:38][CH2:39][C:40]1([OH:47])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)=[O:6]
Reactant: NCC1(O)CCCCCC1
Reactant: O=C(O)c1cc(-c2cn[nH]n2)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C(NCC1(O)CCCCCC1)c1cc(-c2cn[nH]n2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.4 %

Procedure:
To a solution of 2-chloro-5-(2H-[1,2,3]triazol-4-yl)-benzoic acid (0.03 g, 0.136 mmol) in DMF (1.0 mL) was added 1-hydroxybenzotriazole (28 mg, 0.204 mmol), polystyrene supported 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.4 g, 0.4 mmol) and 1-aminomethyl-cycloheptanol hydrochloride (0.036 g, 0.204 mmol). The mixture was stirred at room temperature for 10 minutes, then polystyrene supported N,N-dimethylaminopyridine (0.2 g, 0.29 mmol) was added and the mixture was shaken at room temperature for 16 h. MP-carbonate was added (200 mg) and the mixture was shaken at room temperature for 3 h. The mixture was filtered and washed with methanol. the filtrate was concentrated in vacuo and purified by reverse phase chromatography to afford the title compound (22 mg). LCMS (m/z) 349.3 M+1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[S:12][C:13]=1[CH:14]=[O:15].[BH4-].[Na+].O>O1CCCC1.C(O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)[S:12][C:13]=1[CH2:14][OH:15]
Reactant: O=Cc1sc(-c2cccc(C(F)(F)F)c2)nc1COC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1sc(-c2cccc(C(F)(F)F)c2)nc1COC1CCCCO1
Temperature: 0 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
To a mixed solution of the compound (2.2 g, 5.9 mmol) obtained in Example 89b in tetrahydrofuran/ethanol (v/v=1/1, 10 mL) was added sodium tetrahydroborate (340 mg, 8.9 mmol), and the mixture was stirred at 0° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=50/50) to give the title compound (2.0 g, 92%) as a colorless oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[CH3:13])=[N:4][C:3]=1[C:14]([F:17])([F:16])[F:15].C([Li])(C)(C)C.[CH2:23]([CH:25]([C:28]1[N:33]2[N:34]=[C:35]([CH3:38])[C:36](I)=[C:32]2[N:31]=[C:30]([CH3:39])[CH:29]=1)[CH2:26][CH3:27])[CH3:24].C(OCC)C>C1COCC1.[Cl-].[Zn+2].[Cl-].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:13][C:8]1[N:7]([C:5]2[S:6][C:2]([C:36]3[C:35]([CH3:38])=[N:34][N:33]4[C:28]([CH:25]([CH2:23][CH3:24])[CH2:26][CH3:27])=[CH:29][C:30]([CH3:39])=[N:31][C:32]=34)=[C:3]([C:14]([F:17])([F:16])[F:15])[N:4]=2)[C:11]([CH3:12])=[CH:10][CH:9]=1
Reactant: Cc1ccc(C)n1-c1nc(C(F)(F)F)c(Br)s1
Reactant: CCC(CC)c1cc(C)nc2c(I)c(C)nn12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(CC)c1cc(C)nc2c(-c3sc(-n4c(C)ccc4C)nc3C(F)(F)F)c(C)nn12
Reaction time: 0.75 h
Yield: 72.4 %

Procedure:
Cool a solution of 5-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-4-trifluoromethyl-thiazole (2.2 g, 6.6 mmol) in THF (25 mL) in a dry ice bath. Add t-butyl lithium (1.7 M in pentane, 8.5 mL, 14.5 mmol) dropwise. Stir for 45 min and then add zinc chloride (0.5 M in THF, 14.6 mL, 7.3 mmol) dropwise. Stir 5 min and remove the cooling bath. Stir 30 min and then add 7-(1-ethyl-propyl)-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (1.5 g, 4.4 mmol) and bis(tri-t-butylphosphine)palladium (0) (450 mg, 0.9 mmol). Reflux for 24 h. Cool the reaction, pour the mixture into diethyl ether, and wash with water (2×). Extract the combined water layers with diethyl ether. Dry the combined organic portions over sodium sulfate, filter, and concentrate to dryness under vacuum. Purify the resulting residue by silica gel chromatography (75-100% CH2Cl2 in hexanes) to give the title compound (1.47 g, 72%). HR-ToF-MS m/z calcd for C23H26F3N5S+H+: 462.1939, found: 462.1915.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[C:11]1([C:17]2[O:21][N:20]=[CH:19][C:18]=2[CH2:22][CH2:23][C:24](O)=[O:25])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:24](=[O:25])[CH2:23][CH2:22][C:18]2[CH:19]=[N:20][O:21][C:17]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:3][CH:4]=1)(=[O:7])[NH2:8]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(NC(=O)CCc2cnoc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
A mixture of 4-aminobenzamide (0.55 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.87 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.68 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.88 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-carbamoylphenyl)-3-(5-phenyl-4-isoxazolyl)propionamide (0.95 g, yield 71%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 250–251° C.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([NH:26]C(=O)C)[CH2:22][CH2:21]3)=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>Cl>[NH2:26][C@H:23]1[CH2:22][CH2:21][C@H:20]([O:19][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[C:9](=[O:8])[NH:10][CH:11]=[CH:12]3)[CH2:25][CH2:24]1
Reactant: CC(=O)N[C@H]1CC[C@H](Oc2ccc3c(OCc4ccccc4)nccc3c2)CC1
Agent: Cl
Product: N[C@H]1CC[C@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1

Procedure:
680 mg (1.74 mmol) of N-[4-(1-benzyloxy-isoquinolin-6-yloxy)-cyclohexyl]-acetamide (19) were heated in 2 N HCl in an autoclave at 120° C. until complete conversion is achieved. The solvent is removed in vacuo and the residue is purified by preparative HPLC. The product fractions were evaporated and dissolved in 2 N HCl. After lyophilisation 182 mg of the title compound could be obtained as hydrochloride. Rt=0.97 min (Method B). Detected mass: 259.2 (M+H+).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[CH2:6](Br)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[K+].O>CS(C)=O.O1CCCC1>[CH2:19]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH3:6]
Reactant: CCCCCCCCCCCCCCBr
Reactant: OCCCO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCOCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
In 70 ml of a mixture of dimethylsulfoxide-tetrahydrofuran (1:1) are dissolved 12.3 g of trimethylene glycol and 15 g of tetradecyl bromide. To the solution is added 12 g of powdery potassium hydroxide. The mixture is vigorously stirred for one hour at a room temperature, which is refluxed under heating for two hours. The reaction mixture is poured into 400 ml of cold water, which is neutralized and subjected to extraction with ethyl acetate, then washed with water and dried. The resultant is concentrated to dryness, and the residue is dissolved in methanol when hot. Cooling of the solution gives precipitation of crystals, which are removed by filtration. The filtrate is refined by means of chromatography employing silica-gel (eluent: chloroform) to give 5.1 g of the end-product.