Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([Cl:20])[C:14]=2[Cl:21])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CN(C)C=O>[Cl:20][C:15]1[C:14]([Cl:21])=[C:13]([CH2:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:5][N:4]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)CBr
Reactant: Oc1ccc(Cc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1Cl
Temperature: 0 °C

Procedure:
At 23° C., 2.0 g of 3-chloro-2-(2,3-dichloro-4-hydroxybenzyl)-5-trifluoromethylpyridine, 1.5 g of anhydrous potassium carbonate and 1.0 g of methyl bromoacetate were stirred in 60 ml of anhydrous dimethylformamide for 16 hours. The reaction mixture was then poured into 400 ml of ice-water. The resulting solid product was separated off, washed with water and purified by stirring in n-hexane. Yield: 2.4 g (100%; white crystals); mp.: 110-111° C.
Reaction SMILES: [CH:1]1([C:7]2[C:8]([CH3:14])=[N+:9]([O-])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][C:16]([O:18]C(C)=O)=[O:17]>>[CH:1]1([C:7]2[C:8]([CH2:14][O:18][C:16](=[O:17])[CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C2CCCCC2)ccc[n+]1[O-]
Product: CC(=O)OCc1ncccc1C1CCCCC1
Temperature: 90 °C

Procedure:
The N-oxide from above (0.215 g) was dissolved in Ac2O (2.5 mL) and heated to 90° C. for 24 h followed by removal of the solvent under reduced pressure. The crude material was purified by column chromatography (50:1 CH2Cl2/MeOH) to give the rearranged acetic acid 3-cyclohexyl-pyridin-2-ylmethyl ester as a light brown solid (0.23 g, 99%, 2 steps). 1H NMR (CDCl3) δ 1.25-1.45 (m, 5H), 1.78-1.86 (m, 5H), 2.13 (s, 3H), 2.70 (m, 1H), 7.24 (m, 1H), 7.62 (d, 1H, J=6.0 Hz), 8.46 (d, 1H, J=2.8 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][O:6][C:7]1[CH:11]=[C:10]([N:12]2[C:20]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[N:14]=[CH:13]2)[S:9][C:8]=1[C:21]([O:23]C)=O)#[N:2].[NH3:29]>CO>[C:1]([C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][O:6][C:7]1[CH:11]=[C:10]([N:12]2[C:20]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[N:14]=[CH:13]2)[S:9][C:8]=1[C:21]([NH2:29])=[O:23])#[N:2]
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1C#N
Reactant: N
Solvent: CO
Product: N#Cc1ccccc1COc1cc(-n2cnc3cnccc32)sc1C(N)=O

Procedure:
In a similar manner as described for example 38, 55 mg of methyl 3-[(2-cyanobenzyl)oxy]-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate and 20 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [C:1]1([CH:11]([NH2:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C1C=CC=CC=1>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:13][CH:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH3:12])=[O:27])=[CH:24][CH:23]=1
Reactant: CC(N)c1cccc2ccccc12
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(NC(=O)c1ccc(Cl)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 23.6 grams (0.138 mole) of α-naphthylethylamine and 20.2 grams (0.20 mole) triethylamine in 150ml of dry benzene, there is added dropwise a solution of 24.8 grams (0.142 mole) of p-chlorobenzoyl chloride in 150 ml of benzene. After stirring overnight at room temperature the salts are filtered off and the filtrate is concentrated in vacuo. The resultant residue is crystallized from methylene chloride/hexane to give N-(p-chlorobenzoyl)-α-naphthylethylamine, m.p. 117°-118° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][CH3:19])[NH:15][CH:16]=2)[OH:11])=[CH:6][CH:5]=1)([O-])=O>CO.C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][CH3:19])[NH:15][CH:16]=2)[OH:11])=[CH:8][CH:9]=1
Reactant: CCCc1nc(C(O)c2ccc([N+](=O)[O-])cc2)c[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCCc1nc(C(O)c2ccc(N)cc2)c[nH]1
Reaction time: 4 h
Yield: 88.4 %

Procedure:
To a mixed solution of (4-nitrophenyl)[2-(1-propyl)imidazolyl]methanol (4.5 g) in methanol (150 ml) and ethanol (100 ml), 10% palladium carbon (450 mg) was added, and the mixture was stirred for 4 hours under hydrogen atmosphere. The insolubles were filtered off, and the residue was purified by basic silica gel column chromatography (methanol-ethyl acetate=1:8) and recrystallized from ethyl acetate-diisopropyl ether, to give (4-aminophenyl)[2-(1-propyl)imidazolyl]methanol (3.52 g) as brown crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[N:16][C:17]=4[NH2:19])[N:12]([CH3:20])[N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29](O)=[O:30])[CH:25]=[CH:26][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:20][N:12]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([NH2:19])=[C:18]2[C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[N:1]([C:29](=[O:30])[CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=2)[CH2:2][CH2:3]3)=[N:11]1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: Cc1cccc(CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4nn(C)c5ncnc(N)c45)ccc32)c1
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine.2HCl (70 mg, 0.206 mmol), (3-methylphenyl)acetic acid (31.0 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at room temperaturet for overnight. LCMS showed the reaction was completed. The reaction was poured into water, white solid formed. The white solid was filtered to give the product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[N:9][N:10]=2)[N:7]=1.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:23][N:24]1[CH:28]=[C:27]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]([C:13]4[CH:14]=[C:15]5[C:20](=[CH:21][CH:22]=4)[N:19]=[CH:18][CH:17]=[CH:16]5)[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:26]=[N:25]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(c1ccc2ncccc2c1)c1nnc2ccc(Cl)nn12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccc2ncccc2c1)c1nnc2ccc(-c3cnn(C)c3)nn12
Temperature: 100 °C

Procedure:
A suspension of 6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (106 mg, 342 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (142 mg, 684 μmol), dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(ii) dichloromethane adduct (25 mg, 34 μmol), and cesium carbonate (446 mg, 1369 μmol) in DMF (1 mL) and water (0.5 mL) was sparged for 5 min with argon then heated to 100° C. in an appropriately sealed vial for 30 min. Reaction then partitioned between 9:1 CHCl3/IPA (20 mL) and 1M NaOH (5 mL). Aqueous further extracted with 9:1 CHCl3/IPA (5 mL) and combined organics dried over MgSO4, concentrated to a solid from toluene, then purified on silica (12 g) eluting with 30>50% of 10% 2M NH3 in MeOH/DCM. 6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline isolated as off white crystals from ACN (1 mL). MS (ESI pos. ion) m/z: 356 (MH+). Calc'd exact mass for C20H17N7: 355.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([N:11]3[CH2:16][N:15]([CH3:17])[CH2:14][N:13]([CH2:18][CH3:19])[C:12]3=[O:20])=[N:7][C:6]=2[CH:5]=[C:4]([C:21]2[CH:22]=[N:23][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)[CH:3]=1.C([O-])(=O)C.[K+].[B:36]1(B2OCC(C)(C)CO2)[O:41]CC(C)(C)C[O:37]1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:18]([N:13]1[CH2:14][N:15]([CH3:17])[CH2:16][N:11]([C:8]2[S:9][C:10]3[C:2]([B:36]([OH:41])[OH:37])=[CH:3][C:4]([C:21]4[CH:22]=[N:23][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:25][CH:26]=4)=[CH:5][C:6]=3[N:7]=2)[C:12]1=[O:20])[CH3:19]
Reactant: CCN1CN(C)CN(c2nc3cc(-c4cnc(C(C)(C)O)nc4)cc(Br)c3s2)C1=O
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCN1CN(C)CN(c2nc3cc(-c4cnc(C(C)(C)O)nc4)cc(B(O)O)c3s2)C1=O
Temperature: 130 °C

Procedure:
A mixture of Intermediate 4 (500 mg), potassium acetate (300 mg), bis(neopentyl glycolato)diboron (460 mg) and Pd(dppf)2Cl2 (70 mg) in toluene (10 mL) was degassed (×3) under vacuum then heated at 130° C. for 90 min. The mixture was cooled and filtered through Celite. The filtrate was concentrated to give i (465 mg). MS: 457.02 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]2[C:10]=1[CH2:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:22][O:21][C:5]1[CH:4]=[CH:3][CH:2]=[C:10]2[C:6]=1[CH:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9]2
Reactant: CCOC(=O)C1=C(C(=O)OCC)c2c(OC)ccc(Br)c2C1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Product: CCOC(=O)C1Cc2cccc(OC)c2C1C(=O)OCC
Yield: 96.9 %

Procedure:
The diester from Example 2 (19.39 g) was dissolved in 250 ml ethanol. To the solution was added 5.20 g of 10% Pd/BaSO4 and 7.15 g NaOAc.3H2O. The reaction was hydrogenated at 4 atm pressure. The catalyst was filtered and the solvent evaporated. The product was dissolved in ether, washed with 5% NaHCO3, dried (MgSO4), and the solvent was evaporated to yield 14.87 g of the desired product as a colorless oil. NMR (CDCl3) δ 1.20 (t, 3H), 1.27 (t, 3H), 3.13 (dd, 1H), 3.48-3.56 (m, 2H), 3.82 (s, 3H), 3.95-4.22 (m, 4H), 4.39 (d, 1H), 6.70 (d, 1H), 6.87 (d, 1H), 7.21 (t, 1H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]#[N:23]>CN(C)C=O>[C:22]([CH2:21][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)#[N:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.6 %

Procedure:
To a stirred solution of 2.7 g (15 mmol) of tert-butyl piperazine-1-carboxylate in 30 mL of anhydrous N,N-dimethylformamide was added 2.4 g (17 mmol) of potassium carbonate followed by 2.1 g (17 mmol) of bromoacetonitrile. The resulting heterogeneous mixture was stirred at ambient temperature of 12 h, quenched with water then extracted with ethyl acetate. The combined organic layers were washed with water then brine, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography eluting with a 0-75% acetone in hexanes gradient to afford the title compound as clear gum (1.0 g, 30%). 1H-NMR (500 MHz, CDCl3) δ 3.53 (s, 2H), 3.48 (t, J=5.0 Hz, 4H), 2.53 (t, J=5.0 Hz, 4H), 1.45 (s, 9H). LC-MS: m/z (ES) 226.2 (MH)+.
Reaction SMILES: S(Cl)(Cl)=O.CC1SC(C(O)=O)=CC=1.CC1SC(C(Cl)=O)=CC=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1.[CH3:45][C:46]1[S:50][C:49]([C:51]([N:53]=[C:54]=[S:55])=[O:52])=[CH:48][CH:47]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH:42][C:54]([NH:53][C:51]([C:49]2[S:50][C:46]([CH3:45])=[CH:47][CH:48]=2)=[O:52])=[S:55])=[CH:40][CH:39]=1
Reactant: Cc1ccc(C(=O)N=C=S)s1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: Cc1ccc(C(=O)Cl)s1
Agent: Cc1ccc(C(=O)O)s1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)s4)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 5-methyl-2-thiophenecarboxylic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 5-methyl-2-thiophenecarbonyl isothiocyanate was prepared using the resultant 5-methyl-2-thiophenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 5-methyl-2-thiophenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (42 mg, yield 52%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15](O)[CH2:16][CH3:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:38]N1C(=O)CCC1=O>C(Cl)Cl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][CH2:17][Br:38])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(O)c1ccc(OC)c(OC2CCCC2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCCBr)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3.3 g (13.2 mmol) of -(3-cyclopentoxy-4-methoxyphenyl)-1-propanol in 75 mL of dry methylene chloride at 0° C. under a nitrogen atmosphere was added 4.3 g (16.4 mmol) of triphenylphosphine followed by a slow, portionwise addition of N-bromosuccinimide over a 5 minute period. The reaction mixture was stirred at 0° C. for 1.5 hours at the end of which time the mixture was quenched with excess methanol and stirred for an additional 10 minutes. Concentration of the mixture to dryness followed by liquid chromatography purification using 200 g of silica gel and elution 50% chloroform in hexane provided an analytically pure oil upon drying in vacuo.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])O)O)O.C(OS(C1C=CC=CC=1)(=O)=O)CCCCCCCCCCC.[Na].O.[ClH:37]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C(Cl)(Cl)(Cl)Cl>[Cl:37][CH2:11][C:9]1[O:10][C:3]([CH:2]=[O:1])=[CH:5][CH:7]=1
Reactant: Cl
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1ccc(CCl)o1
Reaction time: 7 h

Procedure:
To the same three-necked flask were added 5 g of a commercially available D-glucose and two kinds of surface active agent, i.e., 97.6 mg of sodium laurylbenzenesulfonate and 89.6 mg of cetyltrimethylammonium chloride. Then, 5 ml of water and 30 ml of carbon tetrachloride were added thereto and the mixture was stirred. Thereafter, a molar excess of hydrogen chloride was passed through the mixture at room temperature for 25 minutes. Stirring was continued at 50° C. for a further 7 hours. The reaction solution which seemed to gel slightly was filtered through Celite while being washed with small amounts of water and carbon tetrachloride. The lower carbon tetrachloride layer was neutralized, dried and concentrated to obtain about 1.5 g of 5-chloromethylfurfural.
Reaction SMILES: [OH-].[K+].O.[CH3:4][C:5]1[NH:10][C:9](=[S:11])[NH:8][C:7](=[O:12])[CH:6]=1.[Cl-].Cl[CH2:15][C:16]1[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][NH+:17]=1>C(O)C>[CH3:22][C:21]1[C:16]([CH2:15][S:11][C:9]2[NH:8][C:7](=[O:12])[CH:6]=[C:5]([CH3:4])[N:10]=2)=[N:17][CH:18]=[C:19]([CH3:25])[C:20]=1[O:23][CH3:24]
Reactant: COc1c(C)c[nH+]c(CCl)c1C
Reactant: Cc1cc(=O)[nH]c(=S)[nH]1
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1c(C)cnc(CSc2nc(C)cc(=O)[nH]2)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 36 %

Procedure:
After dissolving 0.22 g (4.0 mmol) of potassium hydroxide in the mixture of 15 ml of ethanol and 3 ml of water, first 0.28 g (2.0 mmol) of 6-methyl-2-thiouracil, then a solution of 0.44 g (2.0 mmol) of 2-chloromethyl-3,5-dimethyl-4-methoxypyridinium chloride (m.p.: 127°-128° C.) in 15 ml of ethanol are added. The reaction mixture is stirred at room temperature for 20 hours, then ethanol is evaporated under reduced pressure, 10 ml of water are added to the residue and the product is extracted 3 times with 5 ml of chloroform each. The combined organic phase is washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue is recrystallized from 2-propanol to obtain 0.21 g (36%) of the title compound as a white crystalline product, m.p.: 231°-233° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:20])=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][C:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[NH:7][C:8]=2[CH3:20])=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cc(CCc2ccc(Cl)cc2)c(C)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1[nH]c(C(=O)O)cc1CCc1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
To a solution of 4-[2-(4-Chlorophenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (109) in dioxane, 10 equiv of NaOH aq (1.5 M) was added then the mixture was heated at 80° C. for 3 hours. When the reaction is judged complete, the solvent is removed under vacuum, H2O was added and an equal volume of Et2O was added. The organic layer was removed then the aqueous layer was made acidic with HCl (1M). If the product precipitates out at this point, it was filtered off, washed with H2O, and dried to obtain pure desired product. If the product didn't crash out when the aqueous layer is made acidic, Et2O was added, and the organic layer was removed (2×). The organic layer was dried with Na2SO4, filtered, and concentrated to obtain desired product. Purification: precipitation. Amount: 20.6 mg. 1H (MeOD, 400 MHz): δ 7.2 (2H, dd), 7.08 (2H, dd), 6.59 (1H, s), 2.76 (2H, dd), 2.63 (2H, dd), 1.97 (3H, s) ppm. DEPT (CD3OD, 100 MHz): CH3: δ 10.8, CH2: □□ 28.9, 38.0, CH: 116.4, 129.1, 131.3 ppm. HPLC (20 min): 97.8%. LC/MS: 100%.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C@@H:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH2:30][CH2:29][CH2:28][C@@:19]3([CH2:23][C@@H:22]([O:24]C(=O)C)[CH2:21][CH2:20]3)[CH:18]=2)=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8].CO.[OH-].[Na+].Cl>O1CCCC1>[OH:24][C@H:22]1[CH2:21][CH2:20][C@:19]2([CH2:28][CH2:29][CH2:30][C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([C@@H:5]([C:6]#[C:7][CH3:8])[CH2:4][C:3]([OH:31])=[O:2])=[CH:14][CH:13]=3)=[CH:18]2)[CH2:23]1
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(OCC2=C[C@]3(CCC2)CC[C@H](OC(C)=O)C3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#C[C@@H](CC(=O)O)c1ccc(OCC2=C[C@]3(CCC2)CC[C@H](O)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a solution of (3S)-3-[4-((2S,5R)-2-acetoxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid methyl ester (107 mg) obtained in Step 1 in a mixed solvent of methanol (0.65 mL)-tetrahydrofuran (0.65 mL) was added 2N aqueous sodium hydroxide solution (0.28 mL) under ice-cooling, followed by stirring the mixture at room temperature overnight. To the reaction mixture was added 2N aqueous hydrochloric acid solution (0.28 mL), followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by thin-layer column chromatography on silica gel (acetic acid: methanol:chloroform (volume ratio)=0.1:1:20) to give (3S)-3-[4-((2S,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid (79 mg). Configuration of the structure was determined by NMR spectrum (NOESY, HSQC).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:20]2[CH:25]=[CH:24][C:23]([O:26][C@H:27]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+:39].C(O)C>C(O)C>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:20]2[CH:21]=[CH:22][C:23]([O:26][C@H:27]([CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:28]([O-:30])=[O:29])=[CH:24][CH:25]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Na+:39]
Reactant: CCCCCc1ccc(CCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCc1ccc(CCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)[O-])cc2)cc1
Yield: 62 %

Procedure:
To a solution of (2R)-2-([4-[1-(4-pentylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoic acid (615 mg, 1.24 mmol) in ethanol (10 ml) was added 1N sodium hydroxide-ethanol (1.21 ml, 1.21 mmol) and the mixture was concentrated. To the residue was added hexane to give the object compound as a solid. 500 mg, (yield 62%)
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3]1.[BH4-].[Na+]>>[CH:2]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[SH:3])([CH3:11])[CH3:1]
Reactant: CC1(C)Nc2ccccc2S1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)Nc1ccccc1S

Procedure:
Use the method of Example 17b, reaction of 2,2-dimethylbenzothiazolidine with sodium borohydride to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:12]=[N:11][CH:10]=2)=[CH:5][CH:4]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][C:28](=[O:30])[CH3:29])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:12]=[N:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2c(Oc3cncc(-c4ccc(C(F)(F)F)cc4)n3)cccc2s1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(Oc3cncc(-c4ccc(C(F)(F)F)cc4)n3)cccc2s1

Procedure:
A solution of 4-[6-(4-trifluoromethyl-phenyl)-pyrazin-2-yloxy]-benzothiazol-2-ylamine (42 mg, 0.11 mmol), acetic anhydride (50 uL, 0.53 mmol) and pyridine (2 mL) was heated at 70° C. for 18 h. The solution was concentrated under a N2 stream and the resulting solid was purified by prep LC (10-90% CH3CN/H2O modified with 0.1% TFA) to give N-{4-[6-(4-trifluoromethyl-phenyl)-pyrazin-2-yloxy]-benzothiazol-2-yl}-acetamide as a white solid [MS (ESI, pos. ion) m/z: 431 (M+1)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:4]=1[CH:5]=[O:6].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:13])([F:15])[F:14])=[CH:7][C:4]=1[CH2:5][OH:6]
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(OC(F)(F)F)cc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
Dissolve 2-methoxy-5-trifluoromethoxy-benzaldehyde (9.0 g, 40.9 mmol) in MeOH (100 mL) and treat with sodium borohydride (1.45 g, 38.3 mmol). Stir at RT for 1 h., then carefully quench with 1N HCl to pH 3. Concentrate, then extract the aqueous mixture with CH2Cl2 (3×100 mL). Combine the organic phases and wash with saturated NaHCO3 (100 mL) and brine (100 mL). Dry the organic layer, then filter, and concentrate. Purify the crude material by flash chromatography using a linear gradient of 100% hexanes to 40% EtOAc/hexanes to give (2-methoxy-5-trifluoromethoxy-phenyl)-methanol (6.86 g, 75%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.19 (m, 1H), 7.10 (dd, 1H, J=2.9, 8.8 Hz), 6.83 (d, 1H, J=8.8 Hz), 4.66 (d, 2H, J=6.4 Hz), 3.85 (s, 3H), 2.21 (t, 1H, J=6.4 Hz).