Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@H:23]2[C:32]3[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=3)[CH2:26][CH2:25][N:24]2[C:35]([C@H:37]2[CH2:40][C@H:39]([CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[CH2:38]2)=[O:36])=[O:22])[CH:12]=[C:13]([F:19])[C:14]=1[Si:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])O.[Na+]>>[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@H:23]2[C:32]3[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=3)[CH2:26][CH2:25][N:24]2[C:35]([C@H:37]2[CH2:40][C@H:39]([CH2:41][C:42]([OH:44])=[O:43])[CH2:38]2)=[O:36])=[O:22])[CH:12]=[C:13]([F:19])[C:14]=1[Si:15]([CH3:17])([CH3:18])[CH3:16]
Reactant: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@H](CC(=O)O)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Cooled TFA (2 mL) was added to tert-butyl 2-(trans-3-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (64 mg, 0.11 mmol) at 0° C., and the mixture was stirred at 0° C. for 30 min. The pH of the reaction mixture was adjusted to 6 with cooled aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 50→100% ethyl acetate/hexane) to give the title compound (41.5 mg, 0.078 mmol, 71.7%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16](O)=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:19]#[N:20])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[C:27]#[N:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][CH2:54][CH2:55][NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60].C(N(CC)C(C)C)(C)C>CN(C=O)C.O1CCCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([NH:53][CH2:54][CH2:55][NH:56][C:57](=[O:63])[O:58][C:59]([CH3:60])([CH3:62])[CH3:61])=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:19]#[N:20])=[C:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:3]=1[C:27]#[N:28]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: N#Cc1c(N)nc(SCc2cccc(C(=O)O)c2)c(C#N)c1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNC(=O)c1cccc(CSc2nc(N)c(C#N)c(-c3ccccc3)c2C#N)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
200 mg (0.52 mmol) of 3-{[(6-amino-3,5-dicyano-4-phenylpyridin-2-yl)sulfanyl]methyl}-benzenecarboxylic acid (Example 11) were charged in 5 ml of DMF. The reaction solution was cooled to 0° C. 393.58 mg (1.04 mmol) of HATU were added, and the mixture was then stirred at 0° C. for 20 min. 165.84 mg (1.04 mmol) of tert-butyl (2-aminoethyl)carbamate and 133.78 mg (1.04 mmol) of N,N-diisopropylethylamine were added, and the reaction solution was stirred at RT overnight. Water and tetrahydrofuran were added to the reaction mixture until a clear solution had formed. The solution was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:37]1([CH2:42][CH2:43]O)[CH2:41][CH2:40][CH2:39][CH2:38]1>O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:43][CH2:42][CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Reactant: OCCC1CCCC1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCCC2CCCC2)cc1

Procedure:
The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 2-cyclopentyl-1-ethanol in place of 2-ethyl-1-hexanol (yield: 115 mg, 60%). mp 100-101° C. 1H NMR (300 MHz, DMSO-d6) δ 1.00 (m, 2H), 1.38 (m, 2H), 1.57 (m, 7H), 3.30 (s, 3H), 4.42 (t, J=7 Hz, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 475 (M+H)+; (APCI−) m/z 509 (M+Cl)−. Anal. calc. for C24H24F2N2O4S.0.25 H2O: C, 60.17; H, 5.15; N, 5.84. Found: C, 60.12; H, 5.14; N, 5.76.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:10]([NH:12][C@H:13]2[CH2:21][CH2:20][CH2:19][C@H:18]([O:22][CH2:23][CH2:24][CH3:25])[C@@H:17]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C@H:16]([CH3:31])[O:15][C:14]2=[O:32])=[O:11])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([O-])([O-])=O.[K+].[K+].[C:39]([O:42][CH2:43]Br)(=[O:41])[CH3:40]>CC(C)=O.C(Cl)Cl>[C:39]([O:42][CH2:43][O:1][C:2]1[C:3]([C:10](=[O:11])[NH:12][C@H:13]2[CH2:21][CH2:20][CH2:19][C@H:18]([O:22][CH2:23][CH2:24][CH3:25])[C@@H:17]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C@H:16]([CH3:31])[O:15][C:14]2=[O:32])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9])(=[O:41])[CH3:40]
Reactant: CCCO[C@H]1CCC[C@H](NC(=O)c2nccc(OC)c2O)C(=O)O[C@@H](C)[C@@H]1CCC(C)C
Reactant: CC(=O)OCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCO[C@H]1CCC[C@H](NC(=O)c2nccc(OC)c2OCOC(C)=O)C(=O)O[C@@H](C)[C@@H]1CCC(C)C
Temperature: 50 °C
Reaction time: 6 h
Yield: 77.3 %

Procedure:
To a solution of 3-hydroxy-N-((3S,7S,8S,9S)-8-isopentyl-9-methyl-2-oxo-7-propoxyoxonan-3-yl)-4-methoxypicolinamide (125 mg, 0.277 mmol) and K2CO3 (77 mg, 0.555 mmol) in acetone (2.77 mL) was added bromomethyl acetate (54.4 μL, 0.555 mmol). The reaction was sealed, heated to 50° C., stirred at this temperature for 6 h, and then cooled to room temperature. The mixture was diluted with DCM (4 mL) and treated with Celite® (3 scoopula tip-fulls). The solvent was removed under reduced pressure and the resulting adsorbed material was directly loaded onto a column and purified using flash column chromatography (24 g SiO2, 0→100% EtOAc/hexanes) to afford the title compound (112 mg, 0.214 mmol, 77%) as a sticky, slightly yellow oil: IR (thin film): 3378, 2954, 2872, 1740, 1677, 1504, 1202 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J=8.1 Hz, 1H), 8.28 (d, J=5.4 Hz, 1H), 6.95 (d, J=5.4 Hz, 1H), 5.74 (s, 2H), 4.74 (dq, J=10.1, 6.3 Hz, 1H), 4.61 (app dt, J=10.7, 7.6 Hz, 1H), 3.91 (s, 3H), 3.52 (app dt, J=8.9, 6.4 Hz, 1H), 3.31-3.22 (m, 1H), 3.15 (app dt, J=8.9, 6.6 Hz, 1H), 2.45-2.33 (m, 1H), 2.21-2.09 (m, 1H), 2.07 (s, 3H), 1.98-1.86 (m, 1H), 1.85-1.70 (m, 1H), 1.67-1.28 (m, 10H), 1.24-1.03 (m, 2H), 0.97-0.84 (m, 10H); HRMS-ESI m/z [M+Na]1 calcd for: C27H42N2NaO8, 545.2833; found, 545.2853.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[CH3:6][N:7]1[C:11]([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:18]=2)=[N:10][N:9]=[C:8]1[CH:30]=O>C(O)C>[CH3:6][N:7]1[C:11]([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:18]=2)=[N:10][N:9]=[C:8]1[CH:30]=[N:2][OH:3]
Reactant: NO
Reactant: Cn1c(C=O)nnc1NCCCOc1cccc(CN2CCCCC2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(C=NO)nnc1NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.3 %

Procedure:
A solution of hydroxylamine hydrochloride (0.13 g) in ethanol (10 ml) was treated with potassium hydroxide (0.11 g). A solution of 4-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-triazole-3-carboxaldehyde (0.54 g) in ethanol (10 ml) was added. The mixture was stirred at room temperature for 15 min and then filtered. The filtrate was evaporated and the residue was crystallised from a mixture of ethanol (5 ml) and ethyl acetate (5 ml) to give the title compound as a white crystalline solid (0.21 g) m.p. 187°-188°.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[NH:6][CH:5]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[N:15]1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[N:14]1([CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=3)[NH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=[N:15]1
Reactant: c1c[nH]nn1
Reactant: Fc1ccc2[nH]cc(CCBr)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Fc1ccc2[nH]cc(CCn3ccnn3)c2c1

Procedure:
A solution of 3-(2-bromo-ethyl)-5-fluoro-1H-indole (7.26 g, 30 mmol), 1,2,3-triazole (2.07 g, 30 mmol) and ethyl-diisopropylamine (5.1 ml, 30 mmol) in abs. chloroform (70 ml) was boiled under reflux for 24 h. The reaction solution was then washed twice with water, dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with EA/cyclohexane (1:1→4:1).).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][NH:7][C:8](=[O:22])[NH:9][C:10]1[CH:15]=[C:14](Cl)[CH:13]=[C:12]([S:17]([OH:20])(=[O:19])=[O:18])[C:11]=1O)[C:3]([OH:5])=[O:4].N[C@@H](CNC(=O)NC1C=C(S(O)(=O)=O)C(C)=C(Cl)C=1)C(O)=O.N[C@@H](CNC(=O)NC1C=C(S(O)(=O)=O)C=C(Cl)C=1C)C(O)=O>>[NH2:1][C@@H:2]([CH2:6][NH:7][C:8](=[O:22])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:17]([OH:20])(=[O:19])=[O:18])[CH:11]=1)[C:3]([OH:5])=[O:4]
Reactant: N[C@@H](CNC(=O)Nc1cc(Cl)cc(S(=O)(=O)O)c1O)C(=O)O
Agent: Cc1c(Cl)cc(NC(=O)NC[C@H](N)C(=O)O)cc1S(=O)(=O)O
Agent: Cc1c(Cl)cc(S(=O)(=O)O)cc1NC(=O)NC[C@H](N)C(=O)O
Product: N[C@@H](CNC(=O)Nc1cccc(S(=O)(=O)O)c1)C(=O)O

Procedure:
Above all, (2S)-2-amino-3-{[(5-chloro-2-hydroxy-3-sulfophenyl)carbamoyl]amino}propanoic acid, (2S)-2-amino-3-{[(3-chloro-4-methyl-5-sulfophenyl)carbamoyl]amino}propanoic acid and (2S)-2-amino-3-{[(3-chloro-2-methyl-5-sulfophenyl)carbamoyl]amino}propanoic acid, or salts thereof, are particularly preferable as a compound that is used as a prophylactic or therapeutic agent for diabetes or obesity of the present invention.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[C:13]([O-])(O)=O.[Na+].IC>CN(C=O)C>[CH3:13][O:11][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1
Reactant: CSc1ccc(CC(=O)O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)Cc1ccc(SC)cc1
Yield: 97 %

Procedure:
1.82 g (10 mmol) of the 4-methylthiophenylacetic acid were dissolved in 30 mL of DMF and 1.34 g (16 mmol) of NaHCO3 are then added; the agitation mixture is stirred for 15 min approx. Next, 1.9 mL of ICH3 are added while keeping agitation at room temperature for 24 h. Once this time elapsed the mixture is poured on water/ice. As no precipitation occurs ether is added and extracted. The organic phase is washed with water and after drying on sodium sulfate anhydride, the organic phase is concentrated in a rotary evaporator getting 1.92 g (9.7 mmol, 97% yield) of colorless oil which spectroscopic data confirm the expected structure. This product will be used in the next step of the synthesis process without purification as it provides a single stain in TLC (eluting dichloromethane/methanol 9/1).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:18][O:19][CH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][C@H:23]([CH2:27][O:28][C:29]([CH3:38])([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])[CH2:22]1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:18][O:19][CH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][C@H:23]([CH2:27][O:28][C:29]([CH3:37])([CH3:38])[C:30]([OH:32])=[O:31])[CH2:22]1)[CH3:2]
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)nc1COC[C@@H]1CCC[C@H](COC(C)(C)C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)nc1COC[C@@H]1CCC[C@H](COC(C)(C)C(=O)O)C1

Procedure:
270 mg of tert-butyl 2-{(1S,3R)-3-[5-ethyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxymethyl]cyclohexylmethoxy}-2-methylpropionate are dissolved in 5 ml of dichloromethane and 2.5 ml of trifluoroacetic acid and stirred overnight. The solution is then completely evaporated, and the residue is purified by preparative HPLC, resulting in 127 mg of 2-{(1S,3R)-3-[5-ethyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxymethyl]cyclohexylmethoxy}-2-methylpropionic acid as yellow oil.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:11][CH2:10][CH:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:4]1.[CH3:12]O.S(Cl)(Cl)=O>>[CH3:2][N:3]1[CH2:11][CH2:10][CH:6]([C:7]([O:9][CH3:12])=[O:8])[CH2:5][CH2:4]1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCN(C)CC1
Reaction time: 2 h
Yield: 87 %

Procedure:
To a stirred solution of 1-methylisonipecotic acid hydrochloride (178.64 g, 1 mol) in 350 mL of methanol (8 equivalents) was added, dropwise with stirring and cooling (ice-salt bath) to -10° C., 112.8 mL (1.55 equivalents) of thionyl chloride. After completion of the addition (1 hour), the ice-salt bath was removed and the temperature allowed to rise to 40° C. and held at this point for 2 hours. The solution was brought to about pH 8 with sodium carbonate and extracted with methylene chloride. The methylene chloride solution was dried and evaporated to give 136.88 g (87%) of methyl 1-methylpiperidine-4-carboxylate as a clear liquid. The IR spectrum confirmed that the product was the methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:7]1[CH:12]=[CH:11][N:10]2[CH:13]=[CH:14][N:15]=[C:9]2[N:8]=1)([O:5][CH3:6])[CH3:4].[Br-:16].[K+].C([O-])(=O)C.[Na+].BrBr.S([O-])([O-])=O.[Na+].[Na+]>CO>[Br:16][C:13]1[N:10]2[CH:11]=[CH:12][C:7]([C:3]([O:5][CH3:6])([O:2][CH3:1])[CH3:4])=[N:8][C:9]2=[N:15][CH:14]=1
Reactant: [Br-]
Reactant: COC(C)(OC)c1ccn2ccnc2n1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Solvent: CO
Product: COC(C)(OC)c1ccn2c(Br)cnc2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
A mixture of 7-(1,1-dimethoxyethyl)imidazo[1,2-α]pyrimidine (5.3 g, 26 mmol), potassium bromide (3.1 g, 26 mmol) and sodium acetate (3.2 g, 39 mmol) in methanol (50 ml) was cooled to 0° C. before dropwise addition of bromine (4.5 g, 28 mmol) over 10 min. After stirring at 0° C. for a further 15 min the reaction was treated with 1M sodium sulphite solution (5 ml) and the solvent removed in vacuo. The residue was treated with dichloromethane (100 ml) then saturated sodium hydrogencarbonate solution (100 ml) was added. After stirring vigorously for 10 min the organic layer was collected, washed with 1M sodium sulphite solution (100 ml), water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Trituration of the residue with diethyl ether furnished 3-bromo-7-(1,1-dimethoxyethyl)imidazo[1,2-α]pyrimidine (5.05 g, 69%) as a cream-coloured solid: δH (360 MHz, CDCl3) 1.70 (3H, s), 3.28 (6H, s), 7.43 (1H, d, J 7), 7.82 (1H, s), 8.39 (1H, d, J 7).
Reaction SMILES: [C:1]([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].Cl.[NH2:17][CH2:18][C:19]([NH2:21])=[O:20].C([BH3-])#N.[Na+].Cl.C(O)(=O)/C=C\C(O)=O>CO.CCOCC.CC(C)=O.O>[ClH:14].[Cl:15][C:10]1[CH:9]=[C:8]([C:4]2([CH:1]([NH:17][CH2:18][C:19]([NH2:21])=[O:20])[CH3:2])[CH2:7][CH2:6][CH2:5]2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: NCC(N)=O
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Agent: [BH3-]C#N
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: CC(NCC(N)=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reaction time: 2 h

Procedure:
A mixture of 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane (2.43 g), glycinamide hydrochloride (2.21 g) powdered potassium hydroxide (1.2 g) and sodium cyanoborohydride (1.5 g) in methanol (20 ml) was stirred at 0°-5° C. for 2 hours then for a total of 10 days at ambient temperature. The mixture was cooled and 5N hydrochloric acid added. The mixture was then basified, extracted into ether, washed with water, dried and evaporated to give an oil. This oil was dissolved in ether and a solution of maleic acid (1.0 g) in dry ether (100 ml) was added to give an oil which was dissolved in acetone. Ether was then added to give a white solid which was dissolved in water, basified and extracted into ether. Passing hydrogen chloride gas through the dried ethereal extract gave 2-{1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamino}acetamide hydrochloride (m.p. 240°-245° C.).
Reaction SMILES: [CH2:1]([C:3](=[CH:17][CH2:18][CH:19]1[CH2:23][CH:22]=[C:21]([CH3:24])[C:20]1([CH3:26])[CH3:25])[CH2:4][O:5][C:6](=[O:16])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[CH3:2].C(OC(=O)C=CC1C=CC=CC=1O)C>>[CH2:1]([C:3](=[CH:17][CH2:18][CH:19]1[CH2:23][CH:22]=[C:21]([CH3:24])[C:20]1([CH3:25])[CH3:26])[CH2:4][O:5][C:6](=[O:16])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[CH3:2]
Reactant: CCC(=CCC1CC=C(C)C1(C)C)COC(=O)C=Cc1ccccc1O
Agent: CCOC(=O)C=Cc1ccccc1O
Product: CCC(=CCC1CC=C(C)C1(C)C)COC(=O)/C=C/c1ccccc1O

Procedure:
According to the same procedure, 3-(2-hydroxy-phenyl)-acrylic acid 2-ethyl-4-(2,2,3-trimethyl-cyclopent-3-enyl)-but-2-enyl ester was prepared from 3-(2-hydroxy-phenyl)-acrylic acid ethyl ester, 2-ethyl-4(2,2,3-trimethyl cyclopentyl-3-en-1-yl)-but-2-en-1-ol and tetraisopropyl-o-titanate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][CH:11]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][CH2:11][CH:10]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2c(CN3CCN(C(=O)OC(C)(C)C)CC3)coc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c1OCC2CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 4-{[7-(methoxycarbonyl)-1-benzofuran-3-yl]methyl}piperazine-1-carboxylate (600 mg, 1.6 mmol) in 100 mL of HOAc was added 300 mg of Pd/C and the mixture was stirred at 65° C. under H2 atmosphere (50 psi) overnight. The reaction mixture was added Na2CO3 (aq.) to pH=8 in ice bath. The mixture was filtrated and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified with silica gel chromatography to give tert-butyl 4-{[7-(methoxycarbonyl)-2,3-dihydro-1-benzofuran-3-yl]methyl}piperazine-1-carboxylate. 1H-NMR (400 MHz, CDCL3) δ ppm 7.75 (d, J=8.0, 1 H), 7.38 (d, J=7.6, 1 H), 6.88 (t, J=8.0 Hz, 1H), 4.74 (t, J=9.0 Hz, 1H), 4.57 (dd, J=9.2, 6.2 Hz, 1H), 3.90 (s, 3H), 3.58-3.67 (m, 1H), 3.38-3.50 (m, 4H), 2.36-2.61 (m, 6H), 1.46 (s, 9H); MS m/z 377 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([S:23]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)(=[O:25])=[O:24])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([O:20]CC)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[CH3:1][N:2]([S:23]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)(=[O:25])=[O:24])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
Ethyl (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (0.52 g) was dissolved in a mixed solvent of tetrahydrofuran (6 mL)-methanol (6 mL), and the mixture was ice-cooled. Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (0.25 g) in water (5 mL))) was added to this solution, and the mixture was stirred from under ice-cooling to room temperature for 7 hr. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained amorphous solid was crystallized from ethyl acetate-hexane to give the title compound (407 mg, yield: 83%) as pale-yellow prism crystals. MS: 436 (MH+). melting point 232-234° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11](/[CH:23]=[CH:24]/[CH2:25][CH2:26][N:27]2[C:35](=[O:36])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:37])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])C1C=CC=CC=1.CC[OH:40].CC(O)=O>[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([OH:37])=[O:40])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21]
Reactant: O=C1CN(c2ccc(/C=C/CCN3C(=O)c4ccccc4C3=O)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: CCO
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1CN(c2ccc(CCCCNC(=O)c3ccccc3C(=O)O)cc2O)S(=O)(=O)N1

Procedure:
A solution of 2-{(E)-4-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-but-3-enyl}-isoindole-1,3-dione (70 mg, 0.135 mmol) in 6 mL of EtOH/HOAc (4:2) is hydrogenated at 50 psi over 10% Pd/C (70 mg) for 18 h. The catalyst is filtered, the solvent is removed under reduced pressure and the residual yellow foam triturated with EtOAc to give the title compound as a solid: (M−1)−=446.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:4][N:3]=1.Cl>C(O)C.O1CCCC1.O.NN>[NH2:17][CH2:16][CH2:15][CH2:14][C:13]#[C:12][C:5]1[C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: CCCNc1nc(Cl)ncc1C#CCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCCNc1nc(Cl)ncc1C#CCCCN
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
To a solution of 2-(5-(2-chloro-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (K1, 2.0 g) in ethanol (15 mL) and tetrahydrofuran (15 mL), hydrazine monohydrate (2.6 mL) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours and 30 minutes. The reaction mixture was cooled on ice, and then neutralized by adding 1.0 mol/L aqueous hydrochloric acid. The insoluble matter was removed by filtration, and then water and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with saturated aqueous sodium hydrogencarbonate, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 95 to 93% ethyl acetate in methanol) to obtain oily 5-(5-amino-1-pentyn-1-yl)-2-chloro-N-propylpyrimidin-4-amine (K2, 510 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.O[Li].O>C1COCC1.O>[CH3:1][N:2]([CH3:16])[C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: COC(=O)c1ccc2nc(N(C)C)oc2c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1nc2ccc(C(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of methyl 2-(dimethylamino)benzo[d]oxazole-6-carboxylate (2.2 g, ca. 10.0 mmol) in THF (10 mL) and H2O (10 mL) was added LiOH—H2O (1.26 g, 30.0 mmol, 3.0 eq) at room temperature. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure then the reaction was quenched with 1N aqueous HCl (20 mL). The resulting mixture was extracted by CH2Cl2 (3×30 mL). The solvent was removed to give 2-(dimethylamino)benzo[d]oxazole-6-carboxylic acid (1.32 g, 6.4 mmol, 65%) over two steps. The crude product was used in the next step without further purification.