Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10](Cl)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:20]([NH:24][NH2:25])(=O)[CH2:21][CH3:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:20]([CH2:21][CH3:22])=[N:24][N:25]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(N=C(Cl)c2ccc(OC)cc2)cc1
Reactant: CCC(=O)NN
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCc1nnc(-c2ccc(OC)cc2)n1-c1ccc(OC)cc1
Yield: 72.1 %

Procedure:
Using the procedure of Step B, of Example 4, 3.46 g of the product of Step A, 2.21 g of propionic acid hydrazide, 1.74 ml of triethylamine and 50 ml of toluene were reacted to obtain 2.8 g of 3,4-bis-(4-methoxyphenyl)-5-ethyl-4H-1,2,4-triazole melting at 122° C.
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:24])=[C:10]2[C:22]([CH3:23])=[N:21][S:20][C:11]2=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:7])CCC.[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>>[OH:24][C:9]1[C:8]([C:6]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:7])=[N:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:11]2[S:20][N:21]=[C:22]([CH3:23])[C:10]=12
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(-c2ccccn2)c2snc(C)c2c1O
Product: Cc1nsc2c(-c3ccccn3)nc(C(=O)NCC(=O)O)c(O)c12

Procedure:
The title compound was synthesized in analogy Example 1 from 4-hydroxy-3-methyl-7-pyridin-2-yl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and glycine: MS (m/z) 345.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:17][C@@H:16]2[N+:18]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CC(O)C.[Zn]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[CH2:17][C@H:16]2[NH2:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])[C@H]1C[C@@H]1c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Zn]
Solvent: CC(C)O
Product: N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Yield: 69.6 %

Procedure:
Zn dust (1.97 g, 30 mol) was added in small portions, over a period of 30 min, to a vigorously stirred solution of 1-(benzyloxy)-4-[(1R,2S)-2-nitrocyclopropyl]benzene (0.81 g, 3.0 mmol) in i-PrOH (25 mL) and HCl (11 mL of aqueous solution 2.7 N, 30 mmol). After 17 h the mixture was filtered through a pad of celite, that was washed with 10 mL of methanol. The filtrate was concentrated and 10 mL of water were added, washing with CH2Cl2 (3×15 mL). The organic layers were dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the crude product was purified by column chromatography on silica gel (10% MeOH/CH2Cl2) affording 0.50 g of (trans)-2-[4-(benzyloxy)phenyl]cyclopropanamine [Rf=0.2 (10% MeOH/CH2Cl2), white solid, 70% yield]. 1H-NMR (MeOH, 250 MHz, δ): 7.45-7.27 (m, 5H, ArH); 6.96 (d, J=8.5 Hz, 2H, ArH); 6.86 (d, J=8.5 Hz, 2H, ArH); 5.03 (s, 2H, CH2); 2.41-2.34 (m, 1H, CH); 1.86-1.76 (m, 1H, CH); 0.98-0.85 (m, 2H, CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=O)[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]2[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([SH:40])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]2[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[nH]c1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(S)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 70.8 %

Procedure:
A mixture of ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2(1H)-quinolone-3-carboxylate (6.8 g), Lawesson's reagent (8.0 g) and toluene (250 ml) was stirred under reflux for 18 hours. After cooling, the precipitated crystals were collected by filtration to give ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-mercaptoquinoline-3-carboxylate (5.0 g, 70%) which was then recrystallized from acetone. mp. 265°-266° C.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].Br[CH2:26][CH2:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30].C(OCC)(=O)C>O1CCCC1>[O:12]=[C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10][N:9]1[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: O=C1NCCC1(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CCCN1CCC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3,3-diphenylpyrrolidin-2-one (2.00 g, 8.43 mmol; Example 1A) in tetrahydrofuran (10 mL) was added potassium 2-methylpropan-2-olate (9.27 mL, 9.27 mmol). After stirring for 30 minutes, the reaction was a suspension so the reaction was heated to 40° C. The reaction was cooled to ambient temperature, and then tert-butyl 4-bromobutanoate (2.068 g, 9.27 mmol) as a solution in tetrahydrofuran (3 mL) was added. The reaction was stirred for 3 hours, then poured into ethyl acetate/1 N HCl (1:1, 300 mL). The organic layer was separated, washed with brine (100 mL), dried over magnesium sulfate and concentrated. The residue was loaded onto a GraceResolv™ 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 40% ethyl acetate/hexanes (Flow=40 mL/minute) over 30 minutes. The product was dissolved in 5 mL of dichloromethane then 5 mL of trifluoroacetic acid was added. After stirring for 3 hours, the reaction was concentrated to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.36-7.22 (m, 10H), 3.45 (m, 4H), 2.79 (t, J=6.5, 2H), 2.31 (t, J=7.1, 2H), 1.89 (p, J=7.0, 2H); MS (ESI+) m/z 324.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:27])=[CH:9][CH:10]=[C:5]2[C:4]2[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][C:3]1=2.Cl>CO.C(Cl)Cl>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[N:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:27])=[CH:9][CH:10]=[C:5]2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)nc31)CNCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.6 %

Procedure:
tert-Butyl 9-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (70 mg, 0.13 mmol) was treated with 1.25 M HCl in MeOH (3.4 mL), and the resulting suspension was stirred at ambient temperature for 18 h. The resulting suspension was diluted with CH2Cl2 (1.8 mL) and stirred at ambient temperature for 4 h. To the suspension 1.25 M HCl in MeOH (2.0 mL) was added, and the resulting suspension was stirred at ambient temperature for 18 h. The resulting solids were collected by filtration, dissolved in CH2Cl2 (30 mL), and washed with saturated NaHCO3 solution (50 mL). The resulting layers were separated, and the organic extraction was dried over Na2SO4 and concentrated under reduced pressure to dryness. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 1 column volumes, increased to 0:100 over 20 column volumes and held for 83 column volumes) provided the title compound (38 mg, 67%) as a yellow powder: 1H NMR (500 MHz, DMSO-d6) δ 8.71 (d, J=8.5 Hz, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.13 (d, J=7.0 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.22 (dd, J=7.5, 2.0 Hz, 1H), 3.91 (s, 2H), 3.69 (s, 3H), 3.11 (t, J=5.5 Hz, 2H), 2.78 (t, J=5.5 Hz, 2H); ESI MS m/z 427 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[CH3:2]>CO.CCOC(C)=O.[Pd].[C]>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCOC(=O)CCCCCCN(Cc1ccc(/C=C/c2ccccc2)cc1)S(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCN(Cc1ccc(CCc2ccccc2)cc1)S(C)(=O)=O
Reaction time: 20 h
Yield: 99.5 %

Procedure:
A solution of trans-7-[methanesulfonyl-(4-styryl-benzyl)-amino]-heptanoic acid ethyl ester (0.60 g) in MeOH (5 mL) and EtOAc (50 mL) was added to 10% Pd/carbon (0.2 g). The reaction mixture was placed on a Parr hydrogenator and was hydrogenated for 20 h at 50 psi. The reaction mixture was filtered through celite and concentrated in vacuo to afford 7-[methanesulfonyl-(4-phenethyl-benzyl)-amino]-heptanoic acid ethyl ester (0.60 g). 1H NMR (400 MHz, CDCl3) δ 7.30-7.10 (m, 9H), 4.32 (s, 2H), 4.10 (q, 2H), 3.12 (t, 2H), 2.90 (s, 4H), 2.79 (s, 3H), 2.25 (t, 2H), 1.60-1.45 (m, 4H), 1.30-1.19 (m, 7H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]C1.[CH3:11][CH2:12]O.[CH3:14]COC(C)=O>[Pd]>[CH3:14][C:12]1([CH3:11])[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1]1
Reactant: CCO
Reactant: C1=Cc2ccccc2NC1
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CC1(C)CCc2ccccc2N1
Reaction time: 4 h
Yield: 99 %

Procedure:
In a 1 L r.b., a solution of the dihydroquinoline (16.2 g) in 1:1 EtOH:EtOAc (300 mL) was treated with 10% Pd/C (1.05 g) and stirred under an atmosphere of hydrogen. The reaction was monitored by 1H NMR and was complete after 4 h. The reaction mixture was purged, filtered through a pad of Celite, and the pad was rinsed with EtOAc (200 mL). Concentration of the filtrate afforded 16.2 g (99%) of the tetrahydroquinoline as a pale yellow oil. 1H NMR (400 MHz, CDCl3) 6.98 (m, 2H), 6.60 (t, J=7.3, 1H), 6.44 (d, J=8.0, 1H), 2.77 (t, J=6.7, 2H), 1.70 (t, J=6.7, 2H), 1.21 (s, 6H).
Reaction SMILES: [NH2:1]OS(C1C(C)=CC(C)=CC=1C)(=O)=O.[CH:15]1[C:20]2[CH:21]([CH2:24][C:25]#[N:26])[CH2:22][CH2:23][C:19]=2[CH:18]=[CH:17][N:16]=1.[C:27]1([C:33]#[C:34][C:35]([O:37][CH3:38])=[O:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.CN(C)C=O>[C:25]([CH2:24][CH:21]1[C:20]2[C:15]3[N:16]([N:1]=[C:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:34]=3[C:35]([O:37][CH3:38])=[O:36])[CH:17]=[CH:18][C:19]=2[CH2:23][CH2:22]1)#[N:26]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: COC(=O)C#Cc1ccccc1
Reactant: N#CCC1CCc2ccncc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccccc2)nn2ccc3c(c12)C(CC#N)CC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
To a solution of 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (about 16.4 mmol) in acetonitrile (80 mL) was added a solution of 6,7-dihydro-5H-cyclopenta[c]pyridin-7-ylacetonitrile (1.30 g, 8.22 mmol) in acetonitrile (40 mL), and the mixture was stirred at room temperature for 30 min. N,N-Dimethylformamide (40 mL) was added, and the mixture was concentrated under reduced pressure. To 46% of the residual solution were added methyl 3-phenylpropiolate (671 μL, 4.55 mmol) and potassium carbonate (1.31 g, 9.48 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=25/75) to give the title compound (523 mg).
Reaction SMILES: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC=C6C[C@@H](O)CC[C@]6(C)[C@H]5CC[C@]4(C)[C@H]3[C@@H]2C)CC1.C(=O)(O)[O-].[Na+].[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[OH:43].[F:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=1.CC1CCCO1>O>[F:44][C:45]1[CH:53]=[CH:52][C:48]([C:49]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[OH:43])=[O:50])=[CH:47][CH:46]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccccc1O
Agent: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: O=C(Nc1ccccc1O)c1ccc(F)cc1
Temperature: 60 °C

Procedure:
To a 500 ml 4 necked round bottom flask equipped with a thermometer, a mechanic stirrer, a drop funnel, a nitrogen in-let, was added sodium bicarbonate (29.6 g, 0.354 mol, 1.1 eq), 2-aminophenol (34.88 g, 0.32 mol, 1 eq) and 2-Methyl THF (250 ml). The temperature of the mixture was controlled under 20° C. by ice-bath. Under vigorously stirring, 4-fluorobenzoyl chloride (50.72 g, 0.32 mol, 1 eq) was added drop wise within 10 min. Then the reaction was allowed to be stirred for another 1.5 hrs. When HPLC data showed that less than 0.3% of 2-aminophenol remained, 100 ml of water and 50 ml of 2-methyl tetrahydrofuran was added to quench the reaction and then the mixture was heated to 60° C. with stirring. The mixture was partitioned into two phases and the organic phase was washed with 100 ml of 1N H2SO4 and subsequently with 100 ml of water. Then the solvent was evaporated to almost dryness with stirring.
Reaction SMILES: F[C:2]1C=[CH:6][C:5]([CH:8]([O:15][C:16]2C=CC(CCC3C=CC(F)=CC=3)=C([CH:38]=2)C(N[C@@H](CCS(C)(=O)=O)C(OC(C)(C)C)=O)=O)CN2C=CN=C2)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[CH2:8]([O:15][CH2:16][CH3:38])[CH3:5].[CH3:2][CH2:3][CH2:4][CH:5]([CH3:8])[CH3:6]
Reactant: CC(C)(C)OC(=O)[C@H](CCS(C)(=O)=O)NC(=O)c1cc(OC(Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)C
Product: CCOCC

Procedure:
A solution of tert-butyl (2S)-2-{-5-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy]-2-(4-fluorophenethyl)benzoylamino}-4-methylsulfonylbutyrate, (88 mg, 0.13 mmol) in TFA (2 ml), was stirred and cooled in an ice-bath for 3 hours. The TFA was removed by evaporation, the residue was dissolved in ethyl acetate and 1M HCl/diethylether (5 ml). Removal of the solvent gave a brown oil which on trituration with diethylether/iso-hexane (3×) gave the HCl salt of the title compound as a sticky white solid (40 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].[C:14](=O)([O-])[O-].[K+].[K+].CBr>C(C(C)=O)C(C)C>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14])([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Agent: CBr
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 5 h

Procedure:
A 1 liter reactor is charged with 300 ml of methyl isobutyl ketone, 79.17 g of 2,4-dinitrophenol (100%) and 175.9 g of ground potassium carbonate and 63.6 g of methyl bromide. The autoclave is closed and heated for 3 hours to 115°-120° C. (pressure: 3.5 bar). The temperature is then kept for a further 5 hours at 140°-142° C. (pressure: 5-3 bar, falling). After cooling to c. 25° C., the solvent is distilled off at 50° C. under a partial vacuum and the salt-containing residue is taken up in warm water. 2,4-Dinitroanisole is isolated by filtration and washed with 1% ammonia solution and with warm water of c. 50° C. and dried at 50° C. under vacuum, to give 84.6 g (91.2% yield) of 2,4-dinitroanisole with a titre of 91.8%.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:18][Mg]Br.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)([OH:9])[CH3:18])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CSc1ccc(C(=O)c2ccc(F)nc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1ccc(C(C)(O)c2ccc(F)nc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 102.8 %

Procedure:
(6-Fluoropyridin-3-yl)(4-(methylthio)phenyl)methanone (1.256 g, 5.079 mmol) was dissolved in THF (19 mL) and the flask was cooled in an ice water bath. Then, methylmagnesium bromide (3.0 M in diethyl ether, 3.40 mL, 10.2 mmol) was added via syringe over 5 min. The reaction was stirred at 0° C. under nitrogen for 20 min, and then was treated with saturated ammonium chloride (2.5 mL, added dropwise at first as gas evolution is observed). The reaction was quenched at 0° C. Then, the reaction was diluted with water (15 mL) and the layers were separated. The aqueous phase was extracted with DCM, and the organic phases were combined, dried over sodium sulfate, filtered, concentrated, and dried under high vacuum at room temperature overnight to give 1-(6-fluoropyridin-3-yl)-1-(4-(methylthio)phenyl)ethanol (1.375 g). 1H NMR (CDCl3, 400 MHz) δ 8.26 (d, J=2.35 Hz, 1H), 7.82-7.76 (m, 1H), 7.35-7.30 (m, 2H), 7.25-7.20 (m, 2H), 6.86 (dd, J=8.61 Hz, 2.93 Hz, 1H), 2.48 (s, 3H), 2.30 (s, 1H), 1.96 (s, 3H). m/z (ESI, +ve ion) 264 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[I:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[CH3:27])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[I:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([NH:4][CH:1]2[CH2:3][CH2:2]2)[CH3:27])=[CH:22][CH:21]=1
Reactant: NC1CC1
Reactant: CC(=O)c1ccc(I)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(NC1CC1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
Cyclopropylamine (0.85 g), acetic acid (0.89 g), and sodium triacetoxyborohydride (3.2 g) were added to a chloroform (20 mL) solution of 1-(4-iodophenyl)ethanone (1.2 g), and the mixture was stirred in a nitrogen atmosphere for 24 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and then the mixture was extracted with chloroform. Then, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. Then, the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel chromatography (hexane/ethyl acetate=80/20) to obtain N-[1-(4-iodophenyl)ethyl]cyclopropylamine (colorless oil) (1.3 g, 95%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[S:20][C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29].[OH-].[Na+]>C(Cl)Cl>[O:30]([C:28]([N:8]1[CH2:9][CH2:10][C:11]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[S:20][C:21]3[C:26]2=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:12][CH2:13]1)=[O:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: c1ccc(CN2CCC3(CC2)c2ccccc2Sc2ccccc23)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC2(CC1)c1ccccc1Sc1ccccc12
Reaction time: 18 h

Procedure:
To a stirred solution of 1'-benzylthioxanthene-9-spiro-4'-piperidine (2 g.) in methylene chloride (25 ml.) is added dropwise a solution of phenyl chloroformate (0.88 g.) in methylene chloride (15 ml.) at room temperature during 10 minutes. Stirring is continued for 18 hours, the methylene chloride is shaken with 1.ON sodium hydroxide solution, washed with water and dried (Na2SO4). The solution is filtered, the solvent evaporated and the residual oily product is crystallised from ethanol to give 1'-phenoxycarbonyl-thioxanthene-9-spiro-4'-piperidine, m.p. 149°-151° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([C:16]([OH:18])=O)[CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:19][C:20]1([CH:26](C)[C:27]([O:29][CH2:30][CH3:31])=[O:28])C=CC=NC1.[CH:33]1[CH:38]=[N:37][C:36]2N(O)N=N[C:35]=2[CH:34]=1.CCN(C(C)C)C(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([C:16]([NH:19][CH:20]([C:35]3[CH:36]=[N:37][CH:38]=[CH:33][CH:34]=3)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:18])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: On1nnc2cccnc21
Reactant: CCOC(=O)C(C)C1(N)C=CC=NC1
Reactant: O=C(O)C1CC(=O)N(c2cccc([N+](=O)[O-])c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(NC(=O)C1CC(=O)N(c2cccc([N+](=O)[O-])c2)C1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(3-nitrophenyl)-5-oxopyrrolidine-3-carboxylic acid (5 g, 0.02 mol), ethyl 3-amino-3-pyridylpropanoate (HCl salt) (0.03 mol) and HOAt (0.02 mol) in DMF (80 mL) at 0° C. was added i-Pr2NEt (0.03 mol), followed by 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) (0.04 mol), in portions. The reaction mixture was then warmed up to room temperature and stirred overnight. The reaction solution was diluted with EtOAc (150 mL) and the organic phase was washed with saturated NaHCO3 and NaCl aqueous solution. The organic layer was dried over Na2SO4, concentrated in vacuo. The crude product was purified by flash column with 10% MeOH/EtOAc as eluent. Yellow solid was obtained. MS (ES+): 427.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13]>C(O)(C)(C)C>[CH3:16][O:15][C:11](=[O:14])[CH2:12][CH2:13][C:8]([C:9]#[N:10])([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:13][CH2:12][C:11]([O:15][CH3:16])=[O:14]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: C=CC(=O)OC
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(Cl)cc1
Yield: 71.4 %

Procedure:
A mixture of 25 g. (0.165 mole) of the known compound (p-chlorophenyl)acetonitrile and 77 ml. of methyl acrylate in 80 ml. of t-butyl alcohol is heated to reflux. The heat is removed and 25 ml. of 40% methanolic Triton B in 37 ml. of t-butyl alcohol quickly added. After about 4 hours of heating at reflux the mixture is allowed to cool and taken up in water and benzene. The organic layer is washed successively with 2.5 N hydrochloric acid, water and brine and then evaporated to dryness. The residue is distilled under vacuum, first at 40 mm. of mercury to remove excess methyl acrylate and then at 0.35 mm. to give 38.06 g. (71.4% yield) of dimethyl-4-cyano-4-(4-chlorophenyl)pimelate, having a boiling point of 186° to 191°C. The nuclear magnetic resonance (NMR) spectrum of the compound confirms its expected structure.
Reaction SMILES: [CH:1]([C:3]1[C:9](=[O:10])[C:8]([OH:11])=[CH:7][C:6]([CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1)=[O:2].[CH2:15]([Li])[CH2:16][CH2:17]C>O1CCCC1.CCCCCC>[OH:2][CH:1]([C:3]1[C:9](=[O:10])[C:8]([OH:11])=[CH:7][C:6]([CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1)[CH2:15][CH2:16][CH3:17]
Reactant: [Li]CCCC
Reactant: CC(C)c1ccc(C=O)c(=O)c(O)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC(O)c1ccc(C(C)C)cc(O)c1=O
Temperature: -78 °C

Procedure:
7-formyl-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one (1.95 g, 10 mmol) was dissolved in tetrahydrofuran (30 ml) and the resultant was cooled to -78° C. in a dry ice/acetone bath. A solution of n-butyllithium in hexane (1.6M, 14 ml) was added dropwise to the solution, then, the dry ice/acetone bath was removed and the resultant was stirred until insoluble matter was dissolved. An aqueous saturated ammonium chloride was added to the reaction mixture and the resultant was extracted with methylene chloride. The methylene chloride layer was washed with water, then dried over anhydrous sodium sulfate. Solvent was distilled off to give 2.72 g of 7-(α-hydroxybutyl)-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one as a reddish brown oil (yield: quantitative).