Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[C:7]([NH2:17])[N:8]=[C:9](N3C=NC=N3)[C:10]=2[N:11]=1.[CH2:18]([Mg]Br)[CH2:19][CH3:20]>O1CCCC1.CN1CCCC1=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[C:7]([NH2:17])[N:8]=[C:9]([CH2:18][CH2:19][CH3:20])[C:10]=2[N:11]=1
Reactant: CCC[Mg]Br
Reactant: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCCc1nc(N)nc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of the intermediate of example 1 (0.47 g, 1.9 mmol) and iron tris(acetylacetonate) (34 mg, 0.095 mmol) in tetrahydrofuran (50 ml, hereinafter THF) and N-methylpyrrolidone (20 ml, hereinafter NMP) was added n-propylmagnesium bromide (1.9 ml, 3.8 mmol as a 2.0 M solution in THF). After stirring at room temperature for 40 minutes, the solution was diluted with THF and then quenched by adding a solution of 1N HCl. The mixture was extracted with ethyl acetate (150 ml), then dried over Na2SO4 and concentrated to afford 6-chloro-4-n-propyl-pyrido[3,2-d]pyrimidin-2-ylamine as a brown solid (0.32 g), which was used in the next step without purification. Its mass spectrum data was as follows: MS (m/z) 223.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][C:8]=2[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][C:8]=2[F:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(F)c(C2=CCCCC2)n1
Agent: [Pd]
Solvent: CO
Product: O=C(O)c1ccc(F)c(C2CCCCC2)n1
Reaction time: 8 h
Yield: 65 %

Procedure:
To a degassed solution of 6-cyclohexenyl-5-fluoropicolinic acid (1.0 equiv.) in MeOH (0.07M) was added 10% Pd/C (0.1 equiv.) and the reaction was stirred under a hydrogen balloon overnight. The solution was then filtered, rinsed with MeOH, and the filtrate was concentrated to afford 6-cyclohexyl-5-fluoropicolinic acid in 65% yield. LC/MS=224.2 (M+H), Rt=0.95 min.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([OH:16])[CH:9]=[CH:10][C:11]=1[C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=1[C:12]([CH3:15])([CH3:14])[CH3:13])[O:16][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CBr
Reactant: CCCCOc1cc(O)ccc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOc1cc(OCC(=O)OCC)ccc1C(C)(C)C
Yield: 95.7 %

Procedure:
3-Butoxy-4-tert-butylphenol (640 mg, 2.9 mmol), potassium carbonate (1.2 g, 8.6 mmol) and ethyl bromoacetate (480 ul, 4.3 mmol) were treated in the same procedure described in Example 33(d). The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethyl acetate (19/1 to 4/1) to furnish 856 mg (96% yield) of the title compound as a colorless oil.
Reaction SMILES: Cl/[C:2](/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]/[O-].[K+].Cl.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=1.[OH-].[Na+]>C(#N)C.O>[Cl:12][C:13]1[CH:18]=[CH:17][N:16]2[C:2]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][N:19]=[C:15]2[CH:14]=1
Reactant: CCOC(=O)/C(Cl)=C\[O-]
Reactant: Nc1cc(Cl)ccn1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cnc2cc(Cl)ccn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
Potassium (E)-2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (300.8 g, 1594 mmol) was suspended in acetonitrile (800 mL) and 12.1 M aqueous HCl (32.1 mL, 388.9 mmol) was added slowly. The mixture was stirred at ambient temperature for 15 minutes. 4-Chloropyridin-2-amine (100 g, 777.8 mmol) was added to the mixture and heated to 35° C. for 20 hours. The mixture was cooled to ambient temperature and water (2500 mL) was added. The pH of the mixture was adjusted to 8.0-8.5 with 2.5 N aqueous NaOH (100 mL, 250 mmol) to precipitate the product. The solids were collected by filtration and washed with water (4000 mL). The material was dried under vacuum at 40° C. to the crude product (174.1 g, 100% yield). The crude material was further purified by dissolving the material in IPA (220 mL) at 65° C. At 65° C., water (130 mL) was added to the solution (maintaining a temperature>60° C.). The solution was slowly cooled over four hours to 20° C., during which time solid product crystallized out of the solution. The mixture was cooled to 10° C. and stirred for 16 hours. The solids were collected by filtration and washed with 10% IPA/water (v:v) (1000 mL). The material was dried under vacuum at 40° C. to give the purified product (134 g, 76.6% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=2)[N:10]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[CH:9]=1.[OH-].[Na+].O.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[N:10]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[CH:9]=1
Reactant: COC(=O)c1ccc2c(-c3ccccc3Cl)cn(-c3ccc(C)cc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-n2cc(-c3ccccc3Cl)c3ccc(C(=O)O)cc32)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
To a solution of methyl 3-(2-chlorophenyl)-1-(4-methylphenyl)-1H-indole-6-carboxylate (0.11 g, 0.28 mmol) in tetrahydrofuran (2.8 mL) was added sodium hydroxide (2.0 M; 1.40 mL, 2.80 mmol). Water (1.5 mL) was added and the mixture was stirred at 50° C. After 18 h, the mixture was cooled to ambient temperature and 1.0 M hydrochloric acid was added until pH<3. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with saturated aqueous sodium chloride (1×10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (98 mg): LC-MS [M+1]=362.1.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[C:7](CC#N)=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].Cl.[C:25]([OH:28])(=[O:27])[CH3:26]>>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[C:7]([CH2:26][C:25]([OH:28])=[O:27])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCc1nc(Cl)c(CC#N)n1Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCCCc1nc(Cl)c(CC(=O)O)n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
2-Butyl-4-chloro-5-(cyanomethyl)-1-(4-nitrobenzyl)imidazole (7.08 g) and a 1:1 mixture of 12N HCl and glacial acetic acid (175 mL) were mixed and refluxed for 6 hours. The solvents were removed by rotary evaporation and water (300 mL) was then added to the residue. After a few minutes, the product precipitated and was collected and dried to give 7.35 g of a solid; m.p. 207.0°-210.0°. NMR (200 MHz, DMSO-d6 /CDCl3) δ 8.20 (d, 2H, J=10 Hz); 7.22 (d, 2H, J=10 Hz); 5.28 (s, 2H); 3.42 (s, 2H); 2.52 (t, 2H, J=7 Hz); 1.64 (m, 2H); 1.34 (m, 2H); 0.86 (t, 3H, J=7 Hz). Anal. Calcd. for C16H18ClN3O4 ; C, 54.63; H, 5.16; N, 11.94. Found: C, 54.52; H, 5.05; N, 12.21.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:12][C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:23][C:21]1([CH3:24])[CH2:22][C@H:18]([O:17][C:13]2[C:14]([F:16])=[CH:15][C:10]([S:7]([NH:6][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)(=[O:8])=[O:9])=[C:11]([F:31])[CH:12]=2)[C@@H:19]([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)[CH2:20]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CC(C)(C)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CC(C)(C)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 90.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-4,4-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (309 mg, 0.504 mmol) prepared in Example 93f, triethylsilane (0.30 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (212 mg, 91%) as a colorless solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:14]=[CH:15][C:16]([N+:25]([O-:27])=[O:26])=[C:17]([CH:24]=1)[O:18][C@H:19]1[CH2:22][C@H:21]([NH2:23])[CH2:20]1.C(N(CC)CC)C>C(Cl)Cl>[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:14]=[CH:15][C:16]([N+:25]([O-:27])=[O:26])=[C:17]([CH:24]=1)[O:18][C@H:19]1[CH2:20][C@H:21]([NH:23][C:1](=[O:3])[CH3:2])[CH2:22]1
Reactant: N[C@H]1C[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1
Reactant: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1C[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
450 μl Acetylchloride were added to a mixture of 1.8 g trans-3-(5-fluoro-2-nitrophenoxy)-cyclobutylamine trifluoroacetate and 3.7 ml triethylamine in 30 ml methylene chloride and stirred for 2 hours at rt. The mixture was extracted two times with water. The organic phase was dried and concentrated. The residue was stirred with diethylether and filtrated. The residue was dried in a drying cabinet.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:18])[CH2:14][CH2:15][CH:16]=[CH2:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH2:33][C:34](O)=[O:35])[CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH2:33][C:34]([NH:18][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][CH2:15][CH:16]=[CH2:17])=[O:35])[CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:20]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: C=CCCC(N)c1ccccc1N1CCCCC1
Product: C=CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared analogously to Example 19 from 1-(2-piperidino-phenyl)-4-penten-1-yl-amine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][CH:28]([CH3:34])[CH2:29][CH2:30][C:31](O)=[O:32]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][CH2:29][CH:28]([CH3:34])[CH3:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CC(C)CCC(=O)O
Agent: Cl
Product: CC(C)CCC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (72 mg, 68%), MS (ISP) m/z=425.3 [(M+H)+], mp 179° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-methyl-pentanoic acid.
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][NH:38][C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl[CH2:43][C:44]([C:46]1[S:54][CH:53]2[CH:48]([CH2:49][N:50]([CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=3[Cl:62])[CH2:51][CH2:52]2)[CH:47]=1)=[O:45]>>[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][N:38]([CH2:43][C:44]([C:46]2[S:54][C:53]3[CH2:52][CH2:51][N:50]([CH2:55][C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=4[Cl:62])[CH2:49][C:48]=3[CH:47]=2)=[O:45])[C:37](=[O:41])[CH:36]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(CCl)C1=CC2CN(Cc3ccccc3Cl)CCC2S1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1cc2c(s1)CCN(Cc1ccccc1Cl)C2

Procedure:
4-Benzyloxy-1-{2-[5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-2-yl]-2-oxo-ethyl}-1H-pyridin-2-one is prepared following preparation 15b (in DMSO as solvent) from 500 mg (2.49 mmol) 4-benzyloxy-1H-pyridin-2-one and 936 mg (2.49 mmol) 2-chloro-1-[5-(2-chloro-benzyl)-3a,4,5,6,7,7a-hexahydro-thieno[3,2-c]pyridin-2-yl]-ethanone (preparation 24).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([CH2:17][C:18]([O:20][CH2:21][CH2:22][C:23]#[N:24])=[O:19])(=[O:16])[CH2:13][CH2:14][CH3:15]>CC(O)C.N1CCCCC1.C(O)(=O)C>[C:23]([CH2:22][CH2:21][O:20][C:18](=[O:19])[C:17](=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:12](=[O:16])[CH2:13][CH2:14][CH3:15])#[N:24]
Reactant: CCCC(=O)CC(=O)OCCC#N
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCCC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)OCCC#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
A suspension of 4-nitrobenzaldehyde (16.61 g, 110 mmol), 2-cyanoethyl butyrylacetate (19.34 g, 100 mmol), piperidine (430 mg, 5.00 mmol) and acetic acid (300 mg, 5.00 mmol) in 350 ml of 2-propanol was stirred at room temperature for 48 hrs. The reaction mixture was filtered and resulting solid was air dried to give 2-[(4-nitrophenyl)methylene]-3-oxohexanoic acid 2-cyanoethyl ester as a white powder (31.0 g, 95%).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][S:11](O)(=[O:13])=[O:12].ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][C:6]([S:11]([Cl:10])(=[O:13])=[O:12])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CN(C)c1ccc(S(=O)(=O)Cl)cc1

Procedure:
N,N-Dimethylaniline (8 ml) was dissolved in 20 ml of chloroform, and chlorosulfonic acid (20 ml) was slowly added with cooling. The reaction mixture was refluxed for 6 hr. The reaction mixture was cooled and poured on ice (100 g). Dichloromethane (120 ml) was added and aqueous layer was neutralized by concentrated sodium carbonate solution with keeping temperature below 4 ° C. Organic layer was again washed with ice-cold 0.1N sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. Organic layer was concentrated under reduced pressure. Residual material was crystallized from ethyl ether-heptane to give yellowish green solid. p-(Dimethylamino)benzenesulfonyl chloride (4.2 g) was obtained. M. P. 108-13 111° C.
Reaction SMILES: [CH:1]([N:14]1[C:17](=[O:18])[CH2:16][CH:15]1[C:19](OCC)=[O:20])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O>C(OCC)(=O)C>[CH:1]([N:14]1[CH:15]([CH2:19][OH:20])[CH2:16][C:17]1=[O:18])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CC(=O)N1C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C1CC(CO)N1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 73 %

Procedure:
To a solution of 1.3 g. (4.2 mmoles) of ethyl 1-benzhydryl-4-oxo-2-azetidine-carboxylate in 5 ml. of methanol 0.32 g. (8.4 mmoles) of sodium tetrahydrido-borate(III) are added with outer cooling with ice water and stirring. The mixture is stirred for 10 minutes, whereupon it is poured onto 20 ml. of water and shaken with three 10-ml. portions of ethyl acetate. The ethyl acetate solution is dried with magnesium sulfate, filtered and the filtrate is evaporated. The oily residue is crystallized by trituration with 10 ml. of ether. 0.82 g. (73%) of the named compound are obtained, melting at 101° to 102° C. (ethyl acetate/petroleum ether).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[CH2:16][S:17][CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:12])=[C:6]([C:30]2[CH:35]=[C:34]([C:36](=[O:49])[NH:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=3)[CH:33]=[CH:32][N:31]=2)[CH:5]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[CH2:16][S:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:12])=[C:6]([C:30]2[CH:35]=[C:34]([C:36](=[O:49])[NH:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:47])([F:48])[F:46])[CH:40]=3)[CH:33]=[CH:32][N:31]=2)[CH:5]=1)[CH3:2]
Reactant: CCSc1ccc(NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCSc1ccc(NC(=O)c2cccc(CSCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 3-(3-(4-(ethylthio)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)benzylthio)propanoate (200 mg, 0.28 mmol, 1.00 equiv) in dichloromethane (5 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product (0.2 g) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained 40.4 mg (21%) of a light yellow solid. 1H-NMR (400 MHz, DMSO-d6, ppm): δ 12.85 (s, 1H), 12.28 (s, 1H), 9.60-9.57 (m, 1H), 9.01-8.99 (m, 1H), 8.55-8.53 (m, 1H), 8.39 (s, 1H), 7.96-7.51 (m, 11H), 4.65-4.64 (d, J=5.2 Hz, 2H), 3.90 (s, 2H), 3.08-3.03 (m, 2H), 2.63-2.59 (t, J=5.1 Hz, 2H), 1.28-1.24 (t, J=5.7 Hz, 3H). MS (ES, m/z): 654 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[OH:17].[CH3:18][O:19][CH2:20]Cl>CC(C)=O>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:10]([O:17][CH2:18][O:19][CH3:20])=[C:9]([O:8][CH3:7])[CH:14]=1
Reactant: COc1ccc(O)c(OC)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To anhydrous K2CO3 (3.55 g) in acetone (10 mL) under N2 was added 2,4-dimethoxyphenol (3.3 g, J.O.C. 1984, 49, 4740) in acetone (20 mL). Chloromethyl methyl ether (1.79 mL) was added dropwise and the mixture was stirred at room temperature for 18 h then heated to 50° C. for 24 h. Additional quantity of chloromethyl methyl ether (1.79 mL) was added and the mixture was stirred for another day at 50° C. and evaporated. The residue was taken up with water and extracted with AcOEt. The extract was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane/AcOEt 20:1 to 10:1) to give 1,3-dimethoxy-4-methoxymethoxybenzene (1.18 g).
Reaction SMILES: FCC1CN([C@@H](CC)C(N)=O)C(=O)C1.[O:15]=[C:16]1[CH2:20][CH:19]([CH2:21][N:22]2C=N[N:24]=[N:23]2)[CH2:18][N:17]1[C@@H:27]([CH2:31][CH3:32])[C:28]([NH2:30])=[O:29].O=C1CC(CN2C=NC=N2)CN1[C@@H](CC)C(N)=O.O=C1CC(CN2C=CN=N2)CN1C(CC)C(N)=O.C(SCC1CN([C@@H](CC)C(N)=O)C(=O)C1)(C)C.O=C1CC(CN2CCCC2)CN1[C@@H](CC)C(N)=O.O=C1CC(CN2CCSCC2)CN1[C@@H](CC)C(N)=O>>[N:22]([CH2:21][CH:19]1[CH2:18][N:17]([C@@H:27]([CH2:31][CH3:32])[C:28]([NH2:30])=[O:29])[C:16](=[O:15])[CH2:20]1)=[N+:23]=[N-:24]
Reactant: CC[C@@H](C(N)=O)N1CC(Cn2cnnn2)CC1=O
Agent: CCC(C(N)=O)N1CC(Cn2ccnn2)CC1=O
Agent: CC[C@@H](C(N)=O)N1CC(CF)CC1=O
Agent: CC[C@@H](C(N)=O)N1CC(CN2CCCC2)CC1=O
Product: CC[C@@H](C(N)=O)N1CC(CN=[N+]=[N-])CC1=O

Procedure:
Alternatively, (2S)-2-[4-(fluoromethyl)-2-oxo-1-pyrrolidinyl]butanamide 44, (2S)-2-[2-oxo-4-(1H-tetrazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 39, (2S)-2-[2-oxo-4-(1H-tetrazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 40, (2S)-2-[2-oxo-4-(1H-1,2,4-triazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 55, 2-[2-oxo-4-(1H-1,2,3-triazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 56, (2S)-2-{4-[(isopropylsulfanyl)methyl]-2-oxo-1-pyrrolidinyl}butanamide 24, (2S)-2-[2-oxo-4-(1-pyrrolidinylmethyl)-1-pyrrolidinyl]butanamide 15, (2S)-2-[2-oxo-4-(4-thiomorpholinylmethyl)-1-pyrrolidinyl]butanamide 17, are prepared in similar ways, from activated alcohol derivatives, such as mesylates, tosylates or halides.
Reaction SMILES: [N:1]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:6][CH2:5][CH:4]([N:7]2[C@@H:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[C:23](O)(=[O:27])[CH2:24][CH2:25][CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:24]([C:23]([N:20]1[CH2:21][CH2:22][CH:17]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C@@H:11]4[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]4[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH2:18][CH2:19]1)=[O:27])[CH2:25][CH3:26]
Reactant: O=C1N[C@@H]2CCCC[C@H]2N1C1CCN(C2CCNCC2)CC1
Reactant: CCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC(=O)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To the solution of (3aR,7aR)-1-(1,4′-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one, 0.25 mmol) in dry DMF (3 mL) was added butyric acid (26 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (5 mL) and the solvent was removed in vacuo. Dichloromethane (15 mL) was added and washed with saturated NaHCO3 (10 mL) and brine (10 mL), and dried over Na2SO4. The crude product was purified with high pH prep-LCMS to to provide the title compound (53 mg, 56%) as white powder. 1H NMR (400 MHz, METHANOL-D4): δ ppm 0.94 (t, J=7.42 Hz, 3H), 1.25-1.48 (m, 6H), 1.51-1.65 (m, 3H), 1.68 (d, J=11.72 Hz, 1H), 1.74-2.01 (m, 7H), 2.19-2.32 (m, 3H), 2.35 (t, J=7.62 Hz, 2H), 2.55 (t, J=12.11 Hz, 2H), 2.89-3.11 (m, 5H), 3.56-3.69 (m, 1H), 4.01 (d, J=13.28 Hz, 1H), 4.57 (d, J=13.28 Hz, 1H). MS (M+1): 377.2
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:18]O.C1(C)C=CC=CC=1>C(O)(=O)C.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+].O.C(OCC)(=O)C>[C:1]1([S:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][CH:13]=2)=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)c1ccc(Sc2ccccc2)cc1
Reactant: OO
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)c2ccccc2)cc1
Reaction time: 18 h
Yield: 98 %

Procedure:
In 160 g of acetic acid was dissolved 27.4 g of 4-tert-butylphenyl phenyl sulfide which had been synthesized according to the well-known formulation. While the solution was maintained at an internal temperature of 30° C., 9 g of 35 wt % aqueous hydrogen peroxide was added dropwise. The reaction solution was aged at room temperature for 18 hours, after which under ice cooling, a mixture of 1 g sodium thiosulfate pentahydrate and 50 g water was added dropwise to quench the reaction. The solution was combined with 200 g of toluene, 100 g of ethyl acetate, and 100 g of water. The organic layer was separated, washed with water, and concentrated in vacuum. This was followed by crystallization from hexane, filtration, and drying. There was obtained 25.4 g of the target compound, 4-tert-butylphenyl phenyl sulfoxide as white crystals. Yield 98%.