Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11]([C:13]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:14]=2[O:15][CH2:16][C@H:17]2[CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)=[O:12])/[N:7]([CH2:36][C@H:37]2[CH2:41][CH2:40][CH2:39][O:38]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH:18]1[CH2:19][CH2:20][C@@H:17]1[CH2:16][O:15][C:14]1[CH:28]=[CH:29][C:30]([C:32]([F:34])([F:33])[F:35])=[CH:31][C:13]=1[C:11](/[N:10]=[C:8]1\[S:9][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][N:7]\1[CH2:36][C@H:37]1[CH2:41][CH2:40][CH2:39][O:38]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@H]2CCN2)s1
Yield: 84.1 %

Procedure:
The mixture of Example 1B (472 mg, 0.79 mmol) and 2,2,2-trifluoroacetic acid (608 μL, 7.9 mmol) in CH2Cl2 (10 mL) was stirred at room temperature overnight. Saturated aqueous Na2CO3 (20 mL) and CH2Cl2 (20 mL) were added. The organic layer was washed with brine and concentrated. Purification by gradient flash chromatography (silica gel, 5-30% solvent A in EtOAc, solvent A: MeOH (10):Et3N (1)) afforded 330.5 mg (84%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (s, 9 H), 1.56-2.00 (m, 4 H), 2.03-2.34 (m, 2 H), 3.23-3.35 (m, 2 H), 3.59-3.71 (m, 2 H), 3.74-3.83 (m, 2 H), 4.03-4.34 (m, 5 H), 7.27 (s, 1 H), 7.32 (d, J=8.81 Hz, 1 H), 7.75 (dd, J=8.98, 2.20 Hz, 1 H), 7.98 (d, J=2.37 Hz, 1 H); MS (ESI) m/z 498 (M+H)+.
Reaction SMILES: [K].[C:2]([CH:10]([CH2:34][CH3:35])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[S:22](=[O:24])(=[O:23])[NH:21][C:20](=[O:25])[CH2:19]2)=[C:14]([O:26]CC2C=CC=CC=2)[CH:13]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCO.O.[Pd]>[C:2]([CH:10]([CH2:34][CH3:35])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[S:22](=[O:24])(=[O:23])[NH:21][C:20](=[O:25])[CH2:19]2)=[C:14]([OH:26])[CH:13]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCC(Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)c1ccccc1
Agent: [Pd]
Agent: [K]
Solvent: O
Solvent: CCO
Product: CCC(Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1)C(=O)c1ccccc1

Procedure:
A solution of 5-[4-(2-benzoylbutyl)-2-benzyloxyphenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one potassium salt (45 mg) in 4 mL of EtOH/water (1:1) is hydrogenated over Degussa 5% Pd/C (7 mg) at 1 atm for 6 h. The catalyst is filtered and the solvent is removed under reduced pressure to give the title compound: (M−1)−=387. HPLC retention time=0.60 min (Method C).
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.O[CH2:53][CH2:54][C:55]([CH3:61])([CH3:60])[C:56]([O:58][CH3:59])=[O:57].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:53][CH2:54][C:55]([CH3:61])([CH3:60])[C:56]([O:58][CH3:59])=[O:57])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COC(=O)C(C)(C)CCO
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCC(C)(C)C(=O)OC)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.1 M) was added methyl 4-hydroxy-2,2-dimethylbutanoate (appendage 5) (2 eq.) and cesium carbonate (2 eq.). The reaction was heated to 80° C. and stirred for 18 h. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 20% EtOAc in toluene) to afford the title compound as an oil.
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH2:9][CH2:10][NH2:11])=[CH:7][O:8][C:4]=2[CH:3]=1.[O:14]1[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15]1.[OH-].[Na+]>FC(F)(F)C(O)=O>[I:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]3[CH2:9][CH2:10][NH:11][C:16]4([CH2:17][CH2:18][CH2:19][O:14][CH2:15]4)[C:7]=3[O:8][C:4]=2[CH:3]=1
Reactant: NCCc1coc2cc(I)ccc12
Reactant: O=C1CCCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Ic1ccc2c3c(oc2c1)C1(CCCOC1)NCC3

Procedure:
A solution of 2-(6-iodo-benzofuran-3-yl)-ethylamine (1.00 g, 3.48 mmol) and dihydro-pyran-3-one (1.05 g, 10.4 mmol) in trifluoroacetic acid (4.00 mL) was heated at 80° C. for 15 h. The reaction mixture was cooled down, 1M aqueous NaOH was added and the mixture was extracted with DCM. The solvent was evaporated and the residue was purified by silica gel chromatography eluting with DCM-MeOH—NH4OH to afford the title product. mp 131-137° C. dec.; MS m/z 370 [M+H]+
Reaction SMILES: [CH:1]1(/[CH:4]=[N:5]/[S:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[CH2:3][CH2:2]1.[CH:12]1([Mg]Br)[CH2:14][CH2:13]1.[NH4+].[Cl-]>C(Cl)Cl>[CH:1]1([CH:4]([CH:12]2[CH2:14][CH2:13]2)[NH:5][S:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[CH2:2][CH2:3]1
Reactant: Br[Mg]C1CC1
Reactant: CC(C)(C)S(=O)/N=C/C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)S(=O)NC(C1CC1)C1CC1
Temperature: 25 °C

Procedure:
To a stirred solution of N-[(1E)-cyclopropylmethylene]-2-methylpropane-2-sulfinamide (35 g, 202 mmol) in DCM (800 mL) was added cyclopropylmagnesium bromide (1 M in THF, 404 mL, 404 mmol) at −78° C. The reaction mixture was allowed to warm to room temperature as the bath did (2 h). The mixture was treated with sat'd NH4Cl solution, and extracted with EtOAc. The organic layer was washed with brine, dried (sodium sulfate), concentrated, and purified by flash chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH2:28][CH2:29][OH:30])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].[NH2:31][C:32]1[CH:36]=[C:35]([CH3:37])[NH:34][N:33]=1>>[NH2:31][C:32]1[CH:36]=[C:35]([CH3:37])[N:34]([C:5]([C:4]2[CH:8]=[CH:9][C:10]([N:11]([CH2:28][CH2:29][OH:30])[C:12]([C:14]3[S:27][C:17]4[C:18]5[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=5[O:20][CH2:21][CH2:22][C:16]=4[CH:15]=3)=[O:13])=[C:2]([Cl:1])[CH:3]=2)=[O:6])[N:33]=1
Reactant: O=C(O)c1ccc(N(CCO)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Reactant: Cc1cc(N)n[nH]1
Product: Cc1cc(N)nn1C(=O)c1ccc(N(CCO)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Yield: 25 %

Procedure:
Following Example 91, 3-chloro-4-(N-(2-hydroxyethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and 3-amino-5-methylpyrazole were reacted to give 116. Yield 25% of theoretical. MS: (ESI+) 523.1
Reaction SMILES: [CH3:1][C:2]12[CH2:7][CH:6]1[CH2:5][CH:4]([CH2:8][CH:9]=O)[C:3]2([CH3:12])[CH3:11].C[O-].[Na+].[CH:16](=[O:19])[CH2:17][CH3:18].C(O)(=O)C>CO>[CH3:18][C:17](=[CH:9][CH2:8][CH:4]1[CH2:5][CH:6]2[C:2]([CH3:1])([CH2:7]2)[C:3]1([CH3:12])[CH3:11])[CH:16]=[O:19]
Reactant: CC1(C)C(CC=O)CC2CC21C
Reactant: CCC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C=O)=CCC1CC2CC2(C)C1(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.1 %

Procedure:
30 g (0.18 mol) of (1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)ethanal was added to 5.0 ml (24 mmol) of stirred 5.4 M methanolic solution of sodium methylate diluted with 40 ml of methanol. 35 g (0.61 mol) of propionaldehyde was added at 25° C. with cooling during 10 minutes, the reaction mixture stirred at room temperature for 1.5 hours, neutralized with acetic acid and the solvent removed in vacuo. The residue was dissolved in 100 ml of ether, washed with 3×80 ml of water, dried (MgSO4) and evaporated in vacuo. Purification by Kugelrohr distillation at 94° C./0.1 Torr followed by flash chromatography on silica gel (eluent: hexane/MTBE 4:1) gave 16.0 g (43% yield) of 2-methyl-4-(1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)but-2-enal.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([N:18]2[CH:24]3[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]3)[CH2:20][CH2:19]2)=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[O:5].[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH:31]=O>C(O)C.C(O)(=O)C.CO.[O-2].[O-2].[Mn+4]>[N:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[N:18]([C:15]1[CH:14]=[C:3]3[C:2](=[CH:17][CH:16]=1)[N:1]=[C:31]([C:30]1[CH:33]=[C:34]([F:36])[CH:35]=[C:28]([Cl:27])[CH:29]=1)[N:6]([CH2:7][C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])[C:4]3=[O:5])[CH2:19][CH2:20]2
Reactant: CC(C)NC(=O)CNC(=O)c1cc(N2CCN3CCC2CC3)ccc1N
Reactant: O=Cc1cc(F)cc(Cl)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCO
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)NC(=O)Cn1c(-c2cc(F)cc(Cl)c2)nc2ccc(N3CCN4CCC3CC4)cc2c1=O
Temperature: 95 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
2-Amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-(2-(isopropylamino)-2-oxoethyl)benzamide (Intermediate 7A) (70 mg, 0.20 mmol) was dissolved in ethanol (2 mL) before addition of 3-chloro-5-fluorobenzaldehyde (46.3 mg, 0.29 mmol) followed by 2 drops of acetic acid. The resulting solution was sealed in a Reactivial® and heated at 95° C. for 24 hours. Reaction mixture was then cooled to room temperature and diluted with methanol before loading directly onto a 1 g SCX cartridge. The crude material was purified by SCX and concentrated under reduced pressure. The resultant product was re-dissolved in dichloromethane (2 mL), manganese dioxide (33.8 mg, 0.39 mmol) was added and reaction stirred overnight. The sample was then washed with water (5 mL) and extracted into dichloromethane. The organics were separated using a hydrophobic frit. The solvent was removed under reduced pressure and then re-dissolved in methanol (1 mL) and purified by preparative-HPLC. Purified sample was free-based using 500 mg SCX cartridge to afford 2-(6-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chloro-5-fluorophenyl)-4-oxoquinazolin-3(4H)-yl)-N-isopropylacetamide (9.0 mg, 0.018 mmol) 9% yield.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:7](=[O:8])[CH2:6][N:5]([CH2:9][C:10]#[CH:11])[C:4]1=[O:12].[CH2:13]([O:16][N:17]=[CH:18]/[C:19](/[CH3:29])=[CH:20]/[C@@H:21]1[C@@H:23]([C:24](O)=[O:25])[C:22]1([CH3:28])[CH3:27])[CH:14]=[CH2:15].C(Cl)(Cl)Cl.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.[Cl-].[Na+].O>[CH2:13]([O:16][N:17]=[CH:18]/[C:19](/[CH3:29])=[CH:20]/[C@@H:21]1[C@@H:23]([C:24]([O:1][CH2:2][N:3]2[C:7](=[O:8])[CH2:6][N:5]([CH2:9][C:10]#[CH:11])[C:4]2=[O:12])=[O:25])[C:22]1([CH3:28])[CH3:27])[CH:14]=[CH2:15]
Reactant: C=CCON=C/C(C)=C/[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: C#CCN1CC(=O)N(CO)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: C#CCN1CC(=O)N(COC(=O)[C@@H]2[C@@H](/C=C(\C)C=NOCC=C)C2(C)C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
Under nitrogen atmosphere, to a mixture of 0.17 g of 3-hydroxymethyl-1-(2-propynyl)imidazolidine-2,4-dione, 0.24 g of (1R)-trans-3-[(E)-3-(2-propenyloxyimino)-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylic acid, catalytic amount of 4-dimethylaminopyridine and 3 ml of anhydrous chloroform was added 0.19 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the mixture was stirred at room temperature for 3 hours. Thereafter, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, then, filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.24 g of 2,5-dioxo-3-(2-propynyl)imidazolidin-1-ylmethyl (1R)-trans-3-[(E)-3-(2-propenyloxyimino)-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate (hereinafter, referred to as the present compound (3)) represented by the formula (3):
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:19])([F:18])[F:17])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([Cl:21])[C:3]=1[NH:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([N+:32]([O-])=O)[CH:25]=1.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[NH2:32][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[C:30]#[N:31])[C:23]([NH:22][C:3]1[C:4]([Cl:21])=[CH:5][C:6]([C:8]([F:20])([C:16]([F:17])([F:18])[F:19])[C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13])=[CH:7][C:2]=1[Br:1])=[O:35]
Reactant: N#Cc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc2Br)cc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])S(=O)[O-]
Agent: [Br-]
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc2Br)cc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
To a solution of N-[2-bromo-6-chloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethyl-propyl)phenyl]-4-cyano-3-nitrobenzamide (Example 1.1) (92.7 g, 154.8 mmol) in tetrahydrofuran (800 ml) was added aqueous sodium hydroxide (0.1 M) (270 ml), sodium hydrosulfite (80.9 g, 464.4 mmol) and tetrabutylammonium bromide (“TBAB”) (4.99 g, 15.5 mmol). The reaction mixture was stirred at ambient temperature for 90 minutes. The phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were washed with water, aqueous sodium hydrogen carbonate (10% w/v) (400 ml) and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent:cyclohexane/ethyl acetate 5:1) to give 3-amino-N-[2-bromo-6-chloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)phenyl]-4-cyanobenzamide (69 g, 78.4% yield). 1H NMR (400 MHz, CDCl3): 7.82 (s, 1H), 7.75 (s, 1H), 7.71 (s, 1H), 7.51 (m, 1H), 7.35 (s, 1H), 7.21 (m, 1H), 4.7 (s, 2H).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:28])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])C1C=CC=CC=1>C(O)(=O)C>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][C:19]2[C:19](=[O:20])[CH:18]=[C:15]([CH3:14])[O:28][C:18]=2[C:15]2[CH:14]=[CH:13][C:12]([S:9]([NH2:8])(=[O:10])=[O:11])=[CH:17][CH:16]=2)=[CH:26][CH:25]=1
Reactant: O=C(COc1ccc(Cl)cc1)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccccc2)cc1
Solvent: CC(=O)O
Product: Cc1cc(=O)c(Oc2ccc(Cl)cc2)c(-c2ccc(S(N)(=O)=O)cc2)o1
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 6.2 %

Procedure:
To a solution of N,N-dibenzyl-4-[2-(4-chlorophenoxy)acetyl]benzenesulfonamide (11.7 g, 23 mmoles) in acetic acid(105 ml), polyphosphoric acid (75 g) was added and the resulting solution was heated at 140° C. for 5 hours. After cooling, the reaction mixture was poured into ice-water, extracted with ethyl acetate (3×150 ml), and the organic solution was dried (Na2SO4). The solvent was removed under reduced pressure and the resulting oil was solved in H2SO4 (33 ml). The mixture was stirred at room temperature for 15 minutes, and poured into ice-water. The solid was filtered off and purified by column chromatography silica gel and ethyl acetate/methylene chloride/acetic acid (78:10:1) as eluent. 4-[3-(4-chlorophenoxy)-6-methyl-4-oxo-4H-pyran-2-yl]benzenesulfonamide (0.28 g) was obtained. m.p. 221° C. (Compound 57 in Table 4).
Reaction SMILES: [Cl:1][C:2]1[C:3](/[C:9](=[N:24]/[O:25][CH:26]([CH3:28])[CH3:27])/[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C>[Cl:1][C:2]1[C:3](/[C:9](=[N:24]\[O:25][CH:26]([CH3:28])[CH3:27])/[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:20])[F:22])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)O/N=C(\CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CC(C)O/N=C(/CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Yield: 89.5 %

Procedure:
To 258 mg of (E)-N-[2-(3,5-dichloropyridin-2-yl)-2-(isopropoxyimino)ethyl]-2-(trifluoromethyl)benzamide in 4 ml of acetonitrile, 2 mg of benzophenone was added, and the mixture was irradiated with light for 12 hours in a quartz cell (manufactured by Fine, 4 clear windows for spectroscopy) using a 100 W high-pressure mercury lamp (manufactured by USHIO INC., lamp: UM-102, power supply: UM-103B-B). After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 231 mg of the desired product as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[F:9].[Li]CCCC.B(F)(F)F.CCOCC.[CH2:24]([N:31]1[CH2:38][CH2:37][C:34]2([O:36][CH2:35]2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH2:24]([N:31]1[CH2:38][CH2:37][C:34]([CH2:35][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[F:9])([OH:36])[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1ccc(F)c(Br)c1
Reactant: c1ccc(CN2CCC3(CC2)CO3)cc1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(F)c(CC2(O)CCN(Cc3ccccc3)CC2)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-1-fluoro-4-methylbenzene (0.76 g, 4 mmol) in THF (15 ml) at −70° C. under Ar a solution of n-BuLi (1.6 M in hexane, 2.5 ml, 4 mmol) was added dropwise. The reaction mixture was stirrred at −70° C. for 1 h, then BF3.Et2O (0.5 ml, 4 mmol) was added. After stirring for 20 min at −70° C., a solution of 6-benzyl-1-oxa-6-azaspiro[2.5]octane (0.41 g, 2 mmol) in dry THF (5 ml) was added dropwise. The stirring was continued for 2 h at −70° C., then the reaction mixture was quenched with sat. aq. NH4Cl (20 ml). The layers were separated, the aqueous layer extracted with THF. The combined organic layers were dried over Na2SO4. The solvent was removed in vacuo. Diethyl ether (50 ml) was added to the residue, folowed by a 2 M HCl in Et2O (5 ml). The precipitate was collected, washed with Et2O, and dissolved in minimal volume of methanol (ca. 5 ml). Water (50 ml) was added, and pH adjusted to 10 by addition of 2 M aq. NaOH. The mixture was extracted with ethyl acetate (2×25 ml), and the combined organic extracts were dried with Na2SO4. Evaporation of solvent afforded brownish oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([Cl:14])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(C(=O)O)cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Cl)cn1

Procedure:
To a stirred solution of 6-methylpyridine-3-carboxylic acid (100 mg, 0.73 mmol) in DCM (2 mL) was added oxalyl chloride (120 μL, 1.46 mmol) and DMF (2 drops). After 2 hours the reaction mixture was concentrated at reduced pressure and the crude product used in subsequent steps without further purification.
Reaction SMILES: C1SSO[C:4]([C:7]2[NH:8][CH:9]=[C:10]([C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:11]=2)([O:5]C)[O:3][CH2:2]1>[Ni].C(O)C>[CH2:12]([C:10]1[CH:11]=[C:7]([C:4]([O:3][CH3:2])=[O:5])[NH:8][CH:9]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCC(=O)c1c[nH]c(C2(OC)OCCSSO2)c1
Agent: [Ni]
Solvent: CCO
Product: CCCCCCCCCCCCCc1c[nH]c(C(=O)OC)c1
Temperature: 30 °C
Yield: 91.8 %

Procedure:
Methyl 4-tridecanoylpyrrole-2-carboxylate dithioethylene ketal (15.06 g, 37.9 mmol) prepared in Synthetic Example 8 was added to a mixed solution of 750 ml of ethanol and 150 ml of Raney-nickel (activated type, manufactured by Aldrich Co.) which was washed with water and ethanol successively. The mixture was heated under reflux for 30 minutes. After cooling it to ca. 30° C., the Raney-nickel was filtered off and the filtrate was concentrated under reduced pressure. Recrystallization of the residue from ethanol gave 10.70 g (91.8% yield) of methyl 4-tridecylpyrrole-2-carboxylate as white crystals, m.p. 80°-82° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:23]2[CH:28]=[CH:27][C:26]([C:30]#[N:31])=[CH:25][CH:24]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: Cc1cccc(OC(c2ccc(Br)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cccc(OC(c2ccc(C#N)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 130 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
To a solution of 4-[(4-bromo-phenyl)-(6-methyl-pyridin-2-yloxy)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (2.00 g, 4.33 mmol) and zinc cyanide (305 mg, 2.60 mmol) in DMF (20 mL) under nitrogen was added DPPF (48 mg, 0.087 mmol) and Pd2(dba)3 (40 mg, 0.043 mmol). The resulting suspension was warmed to 130° C. and stirred for 5 hours. Standard work-up and purification gave 4-[(4-cyano-phenyl)-(6-methyl-pyridin-2-yloxy)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (1.4 g, 79%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][C:12]([OH:14])=O.[Cl-].[Al+3].[Cl-].[Cl-]>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[CH2:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][C:12]2=[O:14]
Reactant: COc1ccccc1CC(CC(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cccc2c1CC(c1ccccc1)CC2=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
4-(2'-Methoxyphenyl)-3-phenylbutyric acid (29.1 g, 108 mmol), from Step 5, was dissolved in 50 mL of thionyl chloride and heated to 60° C. for 10 min. After stirring an additional 30 min at ambient temperature, the solvent was removed in vacuo. The crude product was dissolved in 60 mL of methylene chloride and the resultant solution was added dropwise to 15.8 g (118 mmol) of aluminum chloride in 240 mL of methylene chloride precooled to 0° C. After the addition, the reaction was allowed to proceed at 0° C. for 1 h, and then quenched by the addition of 500 g of ice. The methylene chloride layer was separated and washed with 3×200 mL of water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 9.84 g (36% yield) of 5-methoxy-3-phenyl-1,2,3,4-tetrahydro-1-naphthalenone as a clear yellow oil; 1H NMR (CDCl3 )δ2.48 (dd, 1H), 2.65-2.8 (m, 2H), 3.20 (dd, 1H), 3.7-3.85 (m, 1H), 3.82 (s, 3H), 6.85-6.95 (m, 2H), 7.08 (dd, 1H), 7.2-7.3 (m, 1H), 7.35-7.4 (m, 2H), 7.57 (dt, 1H), 7.73 (d, 1H); DCl MS M/Z: 270 (M+NH4)+, 253 (M+H)+.