Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH3:9][NH2:10].O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][CH3:9])=[N:6][CH:7]=1
Reactant: CN
Reactant: Fc1ccc(Br)cn1
Solvent: C1CCOC1
Solvent: O
Product: CNc1ccc(Br)cn1
Yield: 24 %

Procedure:
A solution of 5-bromo-2-fluoropyridine (2.5 g, 14 mmol) in THF (50 mL) was stirred with a solution of methylamine in THF (c=2 mol/L) (35 mL, 70 mmol) at 23° C. for 16 h. Water was added and the mixture was extracted with ether, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a residue which was purified by silica gel column chromatography with heptane/ether, followed by trituration with heptane to give the title compound as a white solid (630 mg, 24%). MS (ISP) 187.1 [(M+H)+], 189.2 [(M+2+H)+].
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1.C(N(CC)CC)C.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>C(Cl)Cl>[CH3:32][S:29]([O:1][CH2:2][C@@H:3]([NH:11][C:12]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:21])[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N[C@H](CO)C[C@H]1CCCOC1)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H](C[C@H]1CCCOC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 138.5 %

Procedure:
To a solution of benzyl (5)-1-hydroxy-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate (26 g, 69.99 mmol) and triethylamine (21.21 g, 210 mmol) in CH2Cl2 at 0° C. was added mesyl chloride (16.1 g, 140 mmol) dropwise. The reaction mixture was stirred at room temperature until the staring material disappeared. The reaction was quenched with ice-cold water, extracted with CH2Cl2 (3×100 ml), washed with water (3×50 ml), dried over Na2SO4, and concentrated in vacuo to give the product (36 g), which was used for the next step without purification.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([CH:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:30][CH:31]=1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Yield: 39.7 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (600 mg, 1.9 mmol) was reacted with tert-butyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate (1.34 g, 3.87 mmol) to afford the desired product (340 mg, 39%) as a brown solid: ESI MS m/z 451 [C25H26N2O4S+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:13][CH:14]([CH:22]([CH3:24])[CH3:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.N1C=CC=CC=1.[S:31](Cl)(Cl)=[O:32]>C(Cl)Cl>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH:3]2[CH2:2][O:1][S:31](=[O:32])[N:13]2[CH:14]([CH:22]([CH3:24])[CH3:23])[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CC(CO)NC(C(=O)OC(C)(C)C)C(C)C)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CC2COS(=O)N2C(C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 8.2 %

Procedure:
t-Butyl 2-(1-hydroxymethyl-2-(4-methoxyphenyl)ethylamino)-3-methylbutyrate (2.49 g; 7.4 mmol) was dissolved in CH2Cl2 (180 ml). The reaction solution was cooled to −78° C. Then pyridine (3 ml; 37 mmol) was added and subsequently thionyl chloride (0.64 ml; 8.88 mmol) was added dropwise. The reaction mixture was stirred for 1 h, during which the temperature was allowed to reach 0° C. It was taken up in CH2Cl2 and washed with aqueous HCl (1%; 2×) and NaHCO3 solution. The organic phase was dried over Na2SO4 and concentrated in a rotary evaporator. The crude product was purified by filtration through silica gel (100 g). t-Butyl 2-(4-(4-methoxybenzyl)-2-oxo-(1,2,3)oxathiazolidin-3-yl)-3-methylbutyrate (2.35 g; 0.61 mmol) was obtained as a dark yellow oil. MS: 384.20 (M+H); Rt: 1.76 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH:14]([OH:16])[CH2:15][CH:9]1[CH2:10][C:11](=[O:17])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(Cl)Cl>[CH2:1]([N:8]1[CH:13]2[CH:14]([O:16][Si:27]([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28])[CH2:15][CH:9]1[CH2:10][C:11](=[O:17])[CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CC2CC(O)C(C1)N2Cc1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CC2CC(=O)CC1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a mixture of 8-benzyl-6-hydroxy-8-azabicyclo[3.2.1]octan-3-one (prepared according to the procedure reported in Journal of Heterocyclic Chemistry 1992, 29(6), 1541-4; 46.2 g, 0.2 mol, 1.0 eq) and imidazole (16.3 g, 0.24 mol, 1.2 eq) in DCM (500 mL) was added TBSCl (33.1 g, 0.22 mol, 1.1 eq) in DCM (100 mL) slowly at room temperature in 10 min, then the mixture was stirred at room temperature for 2 h, washed with water (300 mL) and brine (300 mL), the organic layer was dried over Na2SO4 and concentrated to give 8-benzyl-6-[tert-butyl(dimethyl)silyl]oxy-8-azabicyclo[3.2.1]octan-3-one 86a as a colorless oil, 62 g, yield: 90%. MS: calc'd (MH+) 232, measured (MH+) 232.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])C1C=CC=CC=1.S(Cl)(Cl)=O.[CH3:19][CH:20]([OH:22])[CH3:21]>>[OH:13][CH2:12][CH2:11][CH2:10][C:9]([O:22][CH:20]([CH3:21])[CH3:19])=[O:8]
Reactant: CC(C)O
Reactant: O=C(O)CCCOCc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)CCCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-benzyloxybutyric acid (20.59 mmol) in propan-2-ol (30 mL) under nitrogen at 0° C. was added dropwise thionyl chloride (22.65 mmol). The reaction mixture was allowed to reach room temperature over 30 minutes and stirred at room temperature during 20 hours. The mixture was concentrated under reduced pressure and co-evaporated with CH2Cl2. The crude was dried under vacuum pump to give the expected compound as yellow oil in quantitative yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.22 (d, J=6.26 Hz, 6H), 1.94 (quintuplet, J=6.70 Hz, 2H), 2.40 (t, J=7.47 Hz, 2H), 3.50-3.53 (m, 2H), 4.51 (s, 2H), 5 (heptuplet, J=6.22 Hz, 1H), 7.28-7.38 (m, 5H); MS (ESI) m/z=259.6 (MNa+).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH2:9][CH2:8][C:7]3[S:10][C:11]([NH:13][C:14]([CH:16]4[C:18]([CH3:20])([CH3:19])[C:17]4([CH3:22])[CH3:21])=[O:15])=[N:12][C:6]=3[C:5]=12.CC(C)([O-])C.[K+].[CH3:29][O:30][CH2:31][CH2:32]Br>CN(C=O)C.CCOC(C)=O>[CH3:29][O:30][CH2:31][CH2:32][N:12]1[C:6]2[C:5]3=[N:1][O:2][N:3]=[C:4]3[CH2:9][CH2:8][C:7]=2[S:10]/[C:11]/1=[N:13]\[C:14]([CH:16]1[C:18]([CH3:20])([CH3:19])[C:17]1([CH3:22])[CH3:21])=[O:15]
Reactant: CC1(C)C(C(=O)Nc2nc3c(s2)CCc2nonc2-3)C1(C)C
Reactant: COCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCn1c2c(s/c1=N\C(=O)C1C(C)(C)C1(C)C)CCc1nonc1-2
Temperature: 250 °C

Procedure:
The product of Example 123B (1 equiv), potassium tert-butoxide (1.1 equiv) and 2-bromoethyl methyl ether (1 equiv) were combined in DMF (0.1 M) and heated in a SmithSynthesizer™ microwave at 250° C. for 15 minutes. The mixture was diluted with EtOAc and washed with 1 M aqueous NaHCO3. The phases were separated and the aqueous phase was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography afforded the title compound and the product of Example 124. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (s, 6H), 1.26 (s, 6H), 1.57 (s, 1H), 3.10 (t, J=7.5 Hz, 2H), 3.23 (s, 3H), 3.26 (t, J=7.4 Hz, 2H), 3.71 (t, J=5.8 Hz, 2H), 4.67 (t, J=5.8 Hz, 2H); MS (ESI+) m/z 377 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH:13]([CH2:20][CH3:21])[CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[CH2:7][C:8]([O:10]CC)=[O:9])=[O:5])[CH3:2]>CCO.[OH-].[Na+].O>[CH2:1]([O:3][C:4]([N:6]([CH2:7][C:8]([OH:10])=[O:9])[CH:13]([CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[CH2:20][CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)CN(C(=O)OCC)C(CC)Cc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)N(CC(=O)O)C(CC)Cc1cccs1
Yield: 80.8 %

Procedure:
A solution of Compound 1035 (3.03 g, 9.668 mmol) in EtOH (50 mL) was treated with 1 M NaOH (48 mL) at RT overnight. The reaction mixture was diluted with 50 mL 1 M NaOH and 100 mL water, washed with EtOAc, and the aqueous layer was acidified with 6M HCl (30 mL) and extracted with EtOAc (2×). The organics were dried over Na2SO4, and the volatiles were evaporated under vacuum to give 2.23 g of (ethoxycarbonyl-(1-thiophen-2-ylmethyl-propyl)-amino)-acetic acid (Compound 1036).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][N:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[Br:13]N1C(=O)CCC1=O>ClCCCl.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>[NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][N:8]=[C:7]([CH3:10])[C:6]=2[C:11]=1[Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nsc2cc(F)c(N)cc12
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClCCCl
Product: Cc1nsc2cc(F)c(N)c(Br)c12
Temperature: 70 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
To a solution of 5-amino-6-fluoro-3-methyl-1,2-benzisothiazole (0.600 g, 0.00329 mol) in 1,2-dichloroethane is added N-bromosuccinimide (0.586 g, 0.00329 mol) followed by 1,1′-azobis(cyclohexanecarbonitrile) (0.0200 g). The mixture is stirred two hours at 70° C., additional N-bromosuccinimide (0.240 g, 0.00135 mol) is added, and the mixture is stirred 40 minutes at 70° C. The mixture is then cooled to room temperature, filtered and concentrated in vacuo to obtain a residue. The residue is chromatographed on silica gel to give the title compound (0.870 g, 100%) which is identified by NMR spectral analysis.
Reaction SMILES: Cl[C:2](=[C:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C:27](=[CH:28][CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:32])[CH2:23][CH2:24]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)[CH:3]([Cl:12])[S:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].CN([CH:36]=[O:37])C.C[O-].[Na+]>CO.O>[Cl:12][CH:3]([S:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[C:2]([O:37][CH3:36])=[C:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C:27](=[CH:28][CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:32])[CH2:23][CH2:24]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=C(Cl)C(Cl)S(=O)c3ccccc3)CC[C@@H]12
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]12C)C(Cl)S(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
20,21-Dichloro-21-(phenylsulfinyl)pregna-4,9(11),17(20)-trien-3-one (VII, Example 2, 1.0 g), dry DMF (20 ml) and methanol (4 ml) are stirred under nitrogen and cooled to -25°. Sodium methoxide in methanol (25%, 1 ml) is added dropwise. After 30 minutes, the mixture is quenched with water (0.33 ml) and allowed to warm to 20°-25°. The product is isolated by diluting the mixture with water and extracting with ethyl acetate. The organic layer is separated and dried over sodium sulfate and then concentrated under reduced pressure to give the title compound: NMR (CDCl3) 0.85, 0.87, 0.98, 1.36, 1.34, 3.89, 3.84, 5.03, 5.10, 5.23, 5.43, 5.53, 5.72, 5.75 and 7.4-8.0δ.
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:14]([NH:16][C:17]([NH:19][C:20]1[S:21][C:22]2[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:27][C:26](B(O)O)=[CH:25][C:23]=2[N:24]=1)=[O:18])[CH3:15]>C1COCC1.O>[Cl:1][C:2]1[N:6]=[C:5]([C:26]2[CH:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:22]3[S:21][C:20]([NH:19][C:17]([NH:16][CH2:14][CH3:15])=[O:18])=[N:24][C:23]=3[CH:25]=2)[S:4][N:3]=1
Reactant: CCNC(=O)Nc1nc2cc(B(O)O)cc(-c3ccccn3)c2s1
Reactant: Clc1nsc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3nc(Cl)ns3)cc(-c3ccccn3)c2s1
Temperature: 110 °C

Procedure:
3,5-dichloro-1,2,4-thiadiazole (50 mg, 0.32 mmol), Cesium carbonate (285.6 mg, 0.88 mmol), Pd(dppf)2C12 (20 mg, 0.03 mmol) and {2-[(ethylcarbamoyl)amino]-7-(pyridin-2-yl)-1,3-benzothiazol-5-yl}boronic acid (100 mg, 0.29 mmol) was suspended in a mixture of THF (9 mL) and water (1 mL) and heated in the microwave at 110° C. for 50 min. The reaction mixture was concentrated in vacuo and the residue partitioned between 10% IPA/DCM (10 mL) and water (10 mL). The organic layer was separated and the aqueous extracted with further 10% IPA/DCM (3×10 mL), the organic layers were combined, dried (MgSO4), filtered and concentrated, then pre-absorbed onto silica and purified by flash column chromatography (Biotage SP4 12 g, 2% MeoH/DCM-5% MeoH/DCM-8% MeOH/DCM) to give 1-[5-(3-chloro-1,2,4-thiadiazol-5-yl)-7-(pyridin-2-yl)-1,3-benzothiazol-2-yl]-3-ethylurea as a brown solid. (100 mg, 81%) MS: 416.92 [M+H]+.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][NH:20][CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:22]O>C(O)(=O)C>[C:1]1([S:7]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:21]=[N:20][NH:19][CH:18]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[O:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(Sc2cnc3[nH]cc(-c4cn[nH]c4)c3c2)cc1
Reactant: OO
Solvent: CC(=O)O
Product: O=S(c1ccccc1)c1cnc2[nH]cc(-c3cn[nH]c3)c2c1
Reaction time: 72 h
Yield: 64.9 %

Procedure:
A mixture of sulfide 8 (20 mg, 0.068 mmol) and 30% aqueous H2O2 (10.5 μL, 0.103 mmol) in glacial acetic acid (224 μL) was stirred for 72 h then purified by preparative LCMS (column LUNA 10 μl C18(2) 00G-4253-V0 250×50 mm) using water—acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to give sulfoxide 9 as a white solid (13.6 mg, 64%); 1H NMR (400 MHz, CDCl3+6 drops CD3OD) δ 7.35-7.50 (m, 4H), 7.60 (m, 2H), 7.78 (s, 2H), 8.35 (d, J=2.0 Hz, 1H), 8.40 (d, J=2.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:27][C:28]1[CH:37]=[CH:36][C:31]2[NH:32][C:33](=[O:35])[NH:34][C:30]=2[CH:29]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:27][C:28]3[CH:37]=[CH:36][C:31]4[NH:32][C:33](=[O:35])[NH:34][C:30]=4[CH:29]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2[nH]c(=O)[nH]c2c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.6 %

Procedure:
A mixture of 2.5 g (9.6 mmol) of [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b), 1.1 ml (8 mmol) of triethylamine, 1.2 g (8 mmol) of 5-amino-1,3-dihydro-benzimidazol-2-one [J. Amer. Chem. Soc., 80, 1657. (1958)] 3.03 g (8 mmol) of HBTU and 80 ml of dimethylformamide is stirred at room temperature for 24 hours. The reaction mixture is concentrated, then 100 ml of 8% sodium hydrogencarbonate solution is added. The precipitated product is filtered off and recrystallized from methanol to yield 1.51 g (48%) of the title compound. Melting Point: >260° C. (methanol)
Reaction SMILES: CS[C:3](=[N:13][CH3:14])[NH:4][CH2:5][C:6]1[CH:7]=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1.[N+:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])([O-:17])=[O:16]>>[Cl:12][C:9]1[N:8]=[CH:7][C:6]([CH2:5][NH:4][C:3]([NH:13][CH3:14])=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CN=C(NCc1ccc(Cl)nc1)SC
Reactant: CCOC(=O)C[N+](=O)[O-]
Product: CCOC(=O)C(=C(NC)NCc1ccc(Cl)nc1)[N+](=O)[O-]
Temperature: 77.5 °C
Yield: 57.3 %

Procedure:
A mixture of 1.4 g (0.0061 mole) of S-methyl-N-(6-chloro-3-pyridylmethyl)-N'-methylisothiourea obtained in Example 64 (2) and 2.7 g of ethyl nitroacetate was stirred with heating at 75-80° C. for 3 hours. After cooling, the crystals were collected by filtration, washed with CH3CN and dried. The procedure gave 1.1 g of the title compound as white crystals.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])[N:5]=[C:4]1[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:2].[C:26]1(=O)[CH2:29][CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[CH:26]1([N:13]2[CH2:12][CH2:11][CH:10]([CH:8]([C:6]3[N:5]=[C:4]([C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:18][CH:17]=4)[N:3]([CH2:1][CH3:2])[CH:7]=3)[OH:9])[CH2:15][CH2:14]2)[CH2:29][CH2:28][CH2:27]1
Reactant: O=C1CCC1
Reactant: CCn1cc(C(O)C2CCNCC2)nc1-c1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCn1cc(C(O)C2CCN(C3CCC3)CC2)nc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1-ethyl-2-naphthalen-1-yl-1H-imidazol-4-yl)-piperidin-4-yl-methanol (0.53 g) in CH2ClCH2Cl (12 ml) is added cyclobutanone (0.95 ml), followed by NaBH(OAc)3 and acetic acid (0.1 ml). The resulting mixture is stirred at rt overnight, diluted with CH2Cl2, washed with Na2CO3 (1M), H2O and brine, dried and solvent removed. The crude is purified by column (2% Et3N, 3% MeOH in EtOAc) to afford the title compound as a white solid, LCMS 390.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[C:10]1([CH2:16][CH2:17][CH2:18]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: BrCCCc1ccccc1
Product: CCOC(CNCCCc1ccccc1)OCC
Yield: 27.3 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-1, 2,2-diethoxyethanamine (5.82 ml, 40 mmol) was reacted with 3-phenylpropyl bromide (3.02 ml, 20 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: chloroform only) to obtain the title compound (1.37 g, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][CH2:11][CH2:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[CH:24]=1.CC1ON=C(CCC(OC)=O)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][CH2:11][CH2:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[CH:24]=1
Reactant: Cc1cc(CCCCCCCCBr)on1
Reactant: Oc1ccc(C2=NCCO2)cc1Cl
Agent: COC(=O)CCc1cc(C)on1
Product: Cc1cc(CCCCCCCCOc2ccc(C3=NCCO3)cc2Cl)on1

Procedure:
5-{8-[2-Chloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]octyl}-3-methylisoxazole [IX; R=CH3, R2, R3, R4, R5 and R6 =H, R1 =2-Cl, Y=(CH2)8, oxazole at 4-position] was prepared from 4,5-dihydro-2-(3-chloro-4-hydroxyphenyl)oxazole (Example 13b) and 5-(8-bromooctyl)-3-methylisoxazole (Example 18a) according to the procedure of Example 9, part (d), and was obtained in the form of a colorless solid, m.p. 63°-65° C. when recrystallized from ether.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:3]=1.[NH3:13]>CCO>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[N:3]=[C:2]([NH2:13])[S:6][N:5]=1
Reactant: Clc1nc(-c2ccccn2)ns1
Reactant: N
Solvent: CCO
Product: Nc1nc(-c2ccccn2)ns1

Procedure:
A solution of 2-(5-chloro-1,2,4-thiadiazol-3-yl)pyridine in 2 M ammonia in EtOH (10 ml) was heated overnight at 70° C. Volatiles were removed by concentration under reduced pressure. Purification by chromatography on silica (eluted with 0->10% MeOH/CH2Cl2+0->1% NH4OH) gave 3-(pyridin-2-yl)-1,2,4-thiadiazol-5-amine.
Reaction SMILES: C(=O)(OC)O[C@@H:3]1[C@H:10]2[C@H:6]([O:7][C:8]([CH3:12])([CH3:11])[O:9]2)[C:5]([CH2:13][O:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4]1.[Cu]C#N.[CH:40]([Mg]Br)=[CH2:41]>C1COCC1>[CH3:11][C:8]1([CH3:12])[O:7][C@@H:6]2[C:5]([CH2:13][O:14][C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:4][C@@H:3]([CH:40]=[CH2:41])[C@@H:10]2[O:9]1
Reactant: COC(=O)O[C@H]1C=C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]2OC(C)(C)O[C@@H]12
Reactant: C=C[Mg]Br
Agent: N#C[Cu]
Solvent: C1CCOC1
Product: C=C[C@@H]1C=C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]2OC(C)(C)O[C@@H]12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(3aS,4S,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methyl carbonate (1-2) (1.2 g, 2.19 mmol, 1 equiv) was dissolved in anhydrous THF (22 mL) and cooled to 0° C. To the resulting mixture was added copper(I) cyanide (65 mg, 0.72 mmol, 0.33 equiv) followed by 0.7 M vinylmagnesium bromide solution in THF (7.84 mL, 5.49 mmol, 2.5 equiv). After 1 h at 0° C., the reaction was quenched with NH4Cl (10 mL) and extracted with Et2O (3×25 mL). The combined organic extracts were washed with water, dried (MgSO4), and concentrated. Purification via flash chromatography on silica gel column (ethyl acetate/hexanes) gave (3aS,4R,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4-vinyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole (1-3). 1H NMR (500 MHz, CDCl3) δ 7.25-7.55 (m, 15H), 5.94 (brd, 1H, J=0.5 Hz), 5.85 (ddd, 1H, J=7.5, 3, 17.5 Hz), 5.18 (dt, 1H, J=1.5, 17.5 Hz), 5.12 (dd, 1H, J=1, 10 Hz), 5.07 (d, 1H, J=5.5 Hz), 4.52 (d, 1H, J=6 Hz), 3.93 (d, 1H, J=14 Hz), 3.76 (d, 1H, J=14 Hz), 3.53 (d, 1H, J=7.5 Hz), 1.43 (s, 3H), 1.37 (s, 3H).