Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:37]=[CH:36][C:30]([C:31]([O:33]CC)=[O:32])=[C:29]([F:38])[CH:28]=2)=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=1)(=[O:44])=[O:43])([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.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:37]=[CH:36][C:30]([C:31]([OH:33])=[O:32])=[C:29]([F:38])[CH:28]=2)=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=1)(=[O:44])=[O:43])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1F
Yield: 93.2 %

Procedure:
Ethyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino)-ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoate (0.11 g, 0.14 mmol), THF (0.5 mL), MeOH (0.5 mL), and 1N NaOH (0.5 mL) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and extracted with ethyl acetate. The extract was dried over sodium sulfate, and evaporated. The resulting residue was triturated with a mixture of ether and hexanes to give 0.10 g of 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoic acid as a white solid; mp 117-119° C.; HRMS: calcd for C39H32Cl3FN2O5S, 764.1082; found (ESI+), 787.09794
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30]C)[O:7][C:8]1[C:9]([CH3:26])=[CH:10][C:11]([NH:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12]2[C:16]=1[CH2:15][CH2:14][CH2:13]2)(=[O:3])[CH3:2].B(Cl)(Cl)Cl.C(O)C>ClCCl>[C:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[OH:30])[O:7][C:8]1[C:9]([CH3:26])=[CH:10][C:11]([NH:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12]2[C:16]=1[CH2:15][CH2:14][CH2:13]2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(OC)c(C(C)=O)c2)c2c1CCC2
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(O)c(C(C)=O)c2)c2c1CCC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.6 %

Procedure:
To a solution of ethyl N-[7-(3-acetyl-4-methoxyphenoxy)-6-methylindan-4-yl]malonamate (268 mg) in dichloromethane (15 mL) was added a 1 mol/L solution of boron trichloride in dichloromethane (1.9 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 days. Ethanol was added to the reaction mixture, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1−1/1) to give the title compound (183 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]=2[CH:16]=1.CN(C)[C:19]1[O:20][C:21](=[O:29])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:24]=1>C(O)(=O)C>[O:20]=[C:19]1[NH:24][C:23]([C:25]([F:26])([F:27])[F:28])=[CH:22][C:21](=[O:29])[N:1]1[C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]=2[CH:16]=1
Reactant: CCOC(=O)Cc1nsc2ccc(N)cc12
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc12

Procedure:
A mixture of ethyl 5-amino-1,2-benzisothiazole-3-acetate (0.748 g, 3.16 mmol) and 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (0.660 g, 3.17 mmol) in acetic acid is refluxed for three hours, concentrated in vacuo, and diluted with saturated sodium hydrogen carbonate solution. The resultant mixture is extracted with methylene chloride. The combined organic extracts are washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a tan solid which is identified by NMR spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[C:19](=S)=[S:20].C1(N=C=NC2CCCCC2)CCCCC1.Cl>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[N:5]=[C:19]=[S:20]
Reactant: COc1ccc(OC)c(N)c1
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(OC)c(N=C=S)c1
Reaction time: 3 h
Yield: 57.6 %

Procedure:
To a solution of 2,5-dimethoxyaniline (61.2 g, 0.4 mol) and triethylamine (75 ml, 0.48 mol) in 300 ml of tetrahydrofuran was added carbon disulfide (91.2 g, 0.48 mol) at 5° C. and stirring was continued for 3 hours. To the reaction mixture kept at 5° C. was added N,N'-dicyclohexylcarbodiimide (99 g, 0.48 mol) and stirring was continued for another 3 hours. To the reaction mixture were added 2N HCl solution (100 ml) and hexane (100 ml) and an aqueous layer was separated. n-Hexane (100 ml) was further added to an organic layer and precipitates were filtered off. The solvents were distilled off under reduced pressure and a crude oily product was obtained. Separation and purification by chromatography using a silica gel column gave oily 2,5-dimethoxyphenylisothiocyanate (45 g, yield 57%).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)/[C:5](/[F:22])=[C:6](\[F:21])/[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1.[S-:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Na+]>C(O)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH:4]([CH2:3][CH2:2][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)/[C:5](/[F:22])=[C:6](\[F:21])/[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)=[CH:24][CH:25]=1
Reactant: F/C(Cc1cccc(Oc2ccccc2)c1)=C(/F)C(CCBr)c1ccc(Cl)cc1
Reactant: [S-]c1ccccc1
Agent: [Na+]
Solvent: CCO
Product: F/C(Cc1cccc(Oc2ccccc2)c1)=C(/F)C(CCSc1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a stirred solution of 1-[(2E)-6-bromo-4-(4-chlorophenyl)-2,3-difluoro-2-hexenyl]-3-phenoxybenzene (0.308 g, 0.64 mmol) in ethanol (9.6 ml) under nitrogen was added sodium thiophenoxide (0.253 g, 1.91 mmol) and the resulting mixture was stirred at room temperature for two hours. The reaction mixture was concentrated in vacuo, diluted with water (25 ml) and extracted with methylene chloride (3×25 ml). The combined organic extracts were washed with water (2×25 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to a colorless oil (0.187 g). Chromatography on a preparative thin layer silica gel plate eluting with ethyl acetate:hexane (5:95) afforded the title compound as a colorless oil (0.176 g) which was characterized by IR, 1HNMR and mass spectral analysis.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([O:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH2:11][CH2:12][CH3:13]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:17]=[CH:16]/[C:15]([O:14][CH2:10][CH2:11][CH2:12][CH3:13])=[O:18])=[CH:3][CH:4]=1
Reactant: COc1ccc(I)cc1
Reactant: C=CC(=O)OCCCC
Product: CCCCOC(=O)/C=C/c1ccc(OC)cc1

Procedure:
4-Iodoanisole (58 mg, 0.25 mmol) and n-butylacrylate (54 μL, 0.375 mmol) were coupled using the procedure described above to give 74% conversion to (E)-n-butyl 3-(4-methoxyphenyl)acrylate by GC analysis.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1Br.[Cu][C:16]#[N:17]>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[C:16]#[N:17]
Reactant: N#C[Cu]
Reactant: COC(=O)Cc1ccc(OC)cc1Br
Solvent: CN1CCCC1=O
Product: COC(=O)Cc1ccc(OC)cc1C#N
Temperature: 170 °C
Yield: 75.9 %

Procedure:
To a microwave vial was added (2-bromo-4-methoxy-phenyl)-acetic acid methyl ester (200 mg, 0.77 mmol), copper (I) cyanide (138 mg, 1.54 mmol), a stir bar and 1 mL of N-methyl-pyrrolidinone. The vial was capped and heated at 170° C. for 15 minutes in a microwave reactor. The resulting dark solution was purified directly on an ISCO (Teledyne Isco Inc., Lincoln Nebr.) 12 g column using a 0-20% MeOH in dichloromethane gradient. The desired product eluted in 100% dichloromethane to give 120 mg (76%) of (2-cyano-4-methoxy-phenyl)-acetic acid methyl ester as an orange oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5](CC2C=CC(OC)=CC=2)[C:4](=[O:26])[C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>FC(F)(F)C(O)=O>[OH:1][C:2]1[C:11]2[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][C:4](=[O:26])[C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cccc2c1c(O)c(-c1ccccc1)c(=O)n2Cc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cccc2[nH]c(=O)c(-c3ccccc3)c(O)c12
Yield: 40.4 %

Procedure:
A mixture of ethyl 4-hydroxy-1-(4-methoxybenzyl)-2-oxo-3-phenyl-1,2-dihydroquinoline-5-carboxylate (298 mg, 2 mmol) in trifluoroacetic acid was heated to reflux for 48 h. After the removal of the solvents, the residue was washed by ethyl acetate to obtain the title compound as a white solid (250 mg, yield 32%). LC-MS (ESI) m/z: 310 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.25 (t, J=7.2 Hz, 3H), 4.23 (q, J=7.2 Hz, 2H), 7.08 (d, J=7.2 Hz, 1H), 7.31-7.43 (m, 6H), 7.52 (t, J=8 Hz, 1H), 10.39 (s, 1H), 11.64 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][CH:12]=[N:11][C:10]=2[C:14]([O:16]CC)=[O:15])[CH:5]=[C:6]([F:8])[CH:7]=1>O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=[O:15])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)c1ncsc1-c1cc(F)cc(F)c1
Solvent: O
Product: O=C(O)c1ncsc1-c1cc(F)cc(F)c1
Yield: 97 %

Procedure:
The ethyl 5-(3,5-difluorophenyl)-4-thiazolecarboxylate was saponified in an analogous manner to that described in Example 1(D). whereby after acidification there was obtained 5-(3,5-difluorophenyl)-4-thiazolecarboxylic acid in 97% yield, melting point 200° (from water).
Reaction SMILES: C1(C2C3C=CC4C(=O)NCCC=CCCNC(=O)CN(C=3C=4)C=2C2C=CC(OCC3C=C([N+]([O-])=O)C=CC=3N3CCN(S(C)(=O)=O)CC3)=CC=2)CCCCC1.[CH2:56]([NH:60][C:61]([C:63]1[CH:71]=[C:70]2[C:66]([C:67]([CH:106]3[CH2:111][CH2:110][CH2:109][CH2:108][CH2:107]3)=[C:68]([C:80]3[CH:85]=[CH:84][C:83]([O:86][CH2:87][C:88]4[CH:93]=[C:92]([N:94]5[CH2:98][CH2:97][CH2:96][C:95]5=[O:99])[CH:91]=[CH:90][C:89]=4[N:100]4[CH2:105][CH2:104][O:103][CH2:102][CH2:101]4)=[CH:82][CH:81]=3)[N:69]2[CH2:72][C:73](=[O:79])[NH:74][CH2:75][CH2:76][CH:77]=[CH2:78])=[CH:65][CH:64]=1)=[O:62])[CH2:57]C=C>>[CH:106]1([C:67]2[C:66]3[CH:65]=[CH:64][C:63]4[C:61](=[O:62])[NH:60][CH2:56][CH2:57][CH:78]=[CH:77][CH2:76][CH2:75][NH:74][C:73](=[O:79])[CH2:72][N:69]([C:70]=3[CH:71]=4)[C:68]=2[C:80]2[CH:85]=[CH:84][C:83]([O:86][CH2:87][C:88]3[CH:93]=[C:92]([N:94]4[CH2:98][CH2:97][CH2:96][C:95]4=[O:99])[CH:91]=[CH:90][C:89]=3[N:100]3[CH2:105][CH2:104][O:103][CH2:102][CH2:101]3)=[CH:82][CH:81]=2)[CH2:107][CH2:108][CH2:109][CH2:110][CH2:111]1
Reactant: C=CCCNC(=O)Cn1c(-c2ccc(OCc3cc(N4CCCC4=O)ccc3N3CCOCC3)cc2)c(C2CCCCC2)c2ccc(C(=O)NCCC=C)cc21
Agent: CS(=O)(=O)N1CCN(c2ccc([N+](=O)[O-])cc2COc2ccc(-c3c(C4CCCCC4)c4ccc5cc4n3CC(=O)NCCC=CCCNC5=O)cc2)CC1
Product: O=C1Cn2c(-c3ccc(OCc4cc(N5CCCC5=O)ccc4N4CCOCC4)cc3)c(C3CCCCC3)c3ccc(cc32)C(=O)NCCC=CCCN1
Yield: 25 %

Procedure:
The target product 17-cyclohexyl-18-[4-[2-morpholin-4-yl-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1,4,11-triaza-tricyclo[11.5.2.016,19]icosa-7,13 (20),14,16(19),17-pentaene-3,12-dione 11 was synthesized in 25% yield, following the procedure reported for the synthesis of compound 3 and using intermediate 10-11 instead of intermediate 3-11; m/z=730 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29]Br)=[CH:25][C:24]=1[N+:33]([O-:35])=[O:34])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:29][CH2:28][O:27][C:26]3[CH:31]=[CH:32][C:23]([O:22][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[C:24]([N+:33]([O-:35])=[O:34])[CH:25]=3)[CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Reactant: O=[N+]([O-])c1cc(OCCBr)ccc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(CC2CCN(CCOc3ccc(OCc4ccccc4)c([N+](=O)[O-])c3)CC2)cc1
Yield: 82.4 %

Procedure:
From a mixture of 4-(4-methylbenzyl)piperidine (1.96 g, 30.36 mmol), 2-(4-benzyloxy-3-nitrophenoxy)ethyl bromide (1.825 g, 5.18 mmol) and KI (100 mg) in toluene (50 mL) was obtained 1.965 g (80%) of 4-(4-methylbenzyl)-1-(2-(4-benzyloxy-3-nitrophenoxy)ethyl)piperidine as yellow solid, mp. 176-7° C. 1H NMR (CDCl3) 1.25-1.39 (m, 2H), 1.46-1.54 (m, 1H), 1.60-1.66 (m, 2H), 2.00-2.07 (m, 2H), 2.320 (s, 3H), 2.500 (d, 2H, J=9), 2.754 (t, 2H, J=6), 2.93-2.97 (m, 2H), 4.068 (t, 2H, J=6), 5.179 (s, 2H), 7.02-7.10 (m, 4H), 7.33-7.46 (m, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14](=O)([O:18]CC)[O:15]CC.CC[O-].[K+].Cl>O>[CH:1]1[C:13]2[CH:12]([C:14]([OH:18])=[O:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)OCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: CC[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)C1c2ccccc2-c2ccccc21
Temperature: 20 °C
Reaction time: 5 h
Yield: 70.1 %

Procedure:
A solution of 332 g (1.9 moles) of fluorene and 974 g (8.2 moles) of diethyl carbonate was added with cooling to keep the temperature no higher than 40° C. to a mixture of 584 g (4.6 moles) of diethyl carbonate and 186 g (2.2 moles) of potassium ethylate in a reaction vessel and the mixture was stirred at 65°-70° C. for 5 hours and was cooled to 20° C. The mixture was slowly poured into a solution of 220 g (2.2 moles) of hydrochloric acid and 500 g of water with cooling to keep the temperature at a maximum of 40° C. The product was then treated as in Example 1 to obtain 280 g of fluorene-9-carboxylic acid in the form of light-beige crystals melting at 227°-229° C. (72.7% yield based on fluorene).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21]C)=[CH:15][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[Cl:1][C:2]1[C:3]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([OH:21])=[CH:15][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:8]
Reactant: COc1cc2sc(C(=O)N3CCOCC3)c(Cl)c2cc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c(Cl)c(C(=O)N3CCOCC3)sc2cc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(3-Chloro-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (11.8 g) from Example 8 was slurried in dichloromethane (250 ml) and aluminum chloride (33 g) was gradually added. The reaction mixture was stirred at room temperature for 24 hours. Then 6M hydrochloric acid (96 ml) was gradually added. The organic layer was dried with sodium sulphate, evaporated and dried in vacuum. The product was a mixture of two compounds and was used for the next step without any purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH2:13][CH2:14][O:15][CH2:16][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C2=CCOCC2)C1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CC(C2CCOCC2)C1
Temperature: 25 °C
Reaction time: 36 h
Yield: 92.2 %

Procedure:
A mixture of 3-(3,6-dihydro-2H-pyran-4-yl)azetidine-1-carboxylic acid tert-butyl ester (28.6 g, 0.12 mol) and 10% palladium on charcoal (5.0 g) in IMS (500 mL) was stirred under hydrogen (4 bar) at room temperature for 36 hours. The reaction mixture was filtered through a bed of Celite® which was washed with IMS. The filtrates were combined and concentrated to give a residue which was reacted as above for 18 hours. The reaction mixture was worked up as above to give a residue which was dried under reduced pressure to give 3-(Tetrahydropyran-4-yl)azetidine-1-carboxylic acid tert-butyl ester as a beige solid (26.7 g, 92%). 1H NMR (300 MHz, CHCl3-d): δ 4.03-3.90 (m, 4 H); 3.63 (dd, J=8.6, 5.7 Hz, 2 H); 3.37 (td, J=11.8, 2.0 Hz, 2 H); 2.32-2.19 (m, 1 H); 1.63-1.48 (m, 3 H); 1.44 (s, 9 H); 1.29-1.12 (m, 2 H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:33]=[CH:32][C:11]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[CH:21][C:16]=3[N:15]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:14]2=[O:31])=[C:10]([O:34][CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37](C)[CH2:38]C(N)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:25]1([N:15]2[C:16]3[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[CH:19]=[CH:18][C:17]=3[N:13]([CH2:12][C:11]3[CH:32]=[CH:33][C:8]([C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:2])[CH2:3][N:37]([CH3:38])[CH3:36])=[CH:9][C:10]=3[O:34][CH3:35])[C:14]2=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CN(C)CC(C)(C)N
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2Cc1ccc(C(=O)NC(C)(C)C)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2Cc1ccc(C(=O)NC(C)(C)CN(C)C)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.2 %

Procedure:
A mixture of 1.5 g of the compound obtained in Example 15 Step B, 1 g of 2-dimethylamino-1,1-dimethylethylamine (synthesized according to J. Am. Chem. Soc., 1946, 68, 12-14), 1.6 g of BOP and 2 g of DIPEA in 20 ml of DCM is left stirring for 1 hour at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with 1N NaOH solution, with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with a DCM/MeOH mixture (98/2; v/v). 0.15 g of the expected product is obtained after crystallization from iso ether, mp=161° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15](=[O:17])[CH3:16])=[C:13]([OH:18])[C:12]([O:19][C:20]2[C:28]([CH3:29])=[CH:27][C:26]([N+:30]([O-:32])=[O:31])=[C:25]3[C:21]=2[CH2:22][CH2:23][CH2:24]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](=O)([O-])[O-].[Cs+].[Cs+].CI>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15](=[O:17])[CH3:16])=[C:13]([O:18][CH3:33])[C:12]([O:19][C:20]2[C:28]([CH3:29])=[CH:27][C:26]([N+:30]([O-:32])=[O:31])=[C:25]3[C:21]=2[CH2:22][CH2:23][CH2:24]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Agent: [Cs+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1c(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)ccc(OCc2ccccc2)c1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of 1-[6-benzyloxy-2-hydroxy-3-(5-methyl-7-nitroindan-4-yloxy)phenyl]ethanone (10.0 g) in tetrahydrofuran (15 mL) was added cesium carbonate (7.53 g) under ice-cooling, and then was added dropwise methyl iodide (2.88 mL). After stirring at room temperature overnight, the reaction mixture was evaporated under reduced pressure to dryness. Adding ethyl acetate (30 mL), the mixture was stirred for 30 min. The insoluble material was removed by filtration. The filtrate was evaporated under reduced pressure to dryness to give the title compound (10.2 g).
Reaction SMILES: [C:1]1([C:6]2[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.C1(C2C=CN([Si](C(C)C)(C(C)C)C(C)C)C=2)CCCC=1.[C:41]([C:47]([O:49][CH3:50])=[O:48])#[C:42][C:43]([O:45][CH3:46])=[O:44]>CCOCC>[CH:12]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[N:7]1[C:6]2[C:10](=[C:41]([C:47]([O:49][CH3:50])=[O:48])[C:42]([C:43]([O:45][CH3:46])=[O:44])=[C:2]3[CH2:3][CH2:4][CH2:5][C:1]3=2)[CH:9]=[CH:8]1)([CH3:13])[CH3:14]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1C1=CCCC1
Agent: CC(C)[Si](C(C)C)(C(C)C)n1ccc(C2=CCCC2)c1
Solvent: CCOCC
Product: COC(=O)c1c2c(c3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c1C(=O)OC)CCC2
Temperature: 110 °C
Yield: 5.3 %

Procedure:
A 2:1 mixture of 2-(cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole and 3-(cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole (6.2 g, 21.4 mmol) and dimethyl acetylenedicarboxylate (6.2 g, 43.7 mmol) were heated to 110° C. for 22 h. More dimethyl acetylenedicarboxylate (6.2 g, 43.7 mmol) was added and heating was continued for 6 more h. The resulting orange-brown oil was dissolved in ether (25 mL) then treated with hexanes (50 mL). The same process was repeated 3 more times on the precipitate. The combined ether-hexane soluble fractions were evaporated in vacuo, then heated in vacuo to remove excess dimethyl acetylenedicarboxylate. The residue (3.3 g) was chromatographed (hexanes-ether 75:25) to give 490 mg (5.3% yield) product as a light orange oil. The same product was obtained in 10% yield from pure 2-(cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole. NMR (CDCl3) δ 7.44 (d, 1H), 7.05 (d, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.20 (t, 2H), 3.11 (t, 3H), 2.09 (quintet, 2H), 1.70 (septet, 3H), 1.14 (d, 18H). MS m/e 430 (M+H)+. Anal. Calcd for C24H35NO4Si-0.5H2O: C, 65.71; H, 8.27; N, 3.19. Found: C, 65.51; H, 8.14; N, 2.83.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:17])=[C:6]([C:9]([CH2:15][OH:16])=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:7]#[N:8])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].Cl>C1(C)C=CC=CC=1.COCCOC>[CH3:25][S:26]([O:16][CH2:15][C:9]1[CH:10]=[C:11]([O:12][CH2:13][CH3:14])[C:4]([O:3][CH2:1][CH3:2])=[C:5]([F:17])[C:6]=1[C:7]#[N:8])(=[O:28])=[O:27]
Reactant: CCOc1cc(CO)c(C#N)c(F)c1OCC
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: CCOc1cc(COS(C)(=O)=O)c(C#N)c(F)c1OCC
Temperature: 20 °C

Procedure:
3,4-Diethoxy-2-fluoro-6-(hydroxymethyl)benzonitrile (4.50 kg, 18.81 mol) and 1,2-dimethoxyethane (45 L) were loaded into a reaction vessel, followed by stirring. The reaction solution was cooled, and the system was placed under nitrogen atmosphere. At an internal temperature of 8.4° C., triethylamine (2.47 kg, 24.45 mol) was added. Furthermore, methanesulfonyl chloride (2.59 kg, 22.61 mol) was added dropwise without warming the internal temperature over 20° C. After stirring for 34 minutes, the system was placed under a stream of nitrogen gas, and the cooling was stopped. Toluene (45 L) and 0.5 N hydrochloric acid (9 L) were added, and the solution was separated. The obtained organic layer was washed with water (18 L), 10% aqueous sodium hydrogen carbonate solution (18 L), 10% brine (18 L), and water (18 L), and the organic layer was concentrated under reduced pressure. After adding toluene (45 L) to the concentrated solution, this was concentrated again under reduced pressure. The concentrated solution was cooled and diluted with toluene (40 L), and the diluted solution from the reaction vessel was equally divided into two containers. The walls of the reaction vessel were rinsed with toluene (5 L). This rinsing solution was divided in half and mixed with the aforementioned diluted solutions to give toluene solutions of 2-cyano-4,5-diethoxy-3-fluorobenzyl methanesulfonate. They were named solution A and solution B, and after measuring the weight of the solutions (solution A; 32.16 kg, solution B: 32.24 kg), the solutions were sampled and quantified by HPLC.