Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:17][CH2:16][C@@:10]3([NH:14][C:13](=[O:15])[O:12][CH2:11]3)[CH2:9]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[C:29]([O:33][C:34](=[O:37])[CH2:35][Zn+])([CH3:32])([CH3:31])[CH3:30]>O1CCOCC1.C(OCC)(=O)C.C1([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[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]>[O:15]=[C:13]1[O:12][CH2:11][C@:10]2([CH2:16][CH2:17][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([CH2:35][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:37])=[CH:3][CH:4]=3)[CH2:9]2)[NH:14]1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: O=C1N[C@@]2(CC[C@H](c3ccc(Br)cc3)C2)CO1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Cc1ccc([C@H]2CC[C@]3(COC(=O)N3)C2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a mixture of (5R,7S)-7-(4-bromophenyl)-3-oxa-1-azaspiro[4.4]nonan-2-one (I-3, 1 g, 3.38 mmol) in dioxane (10 mL) at room temperature was added lithium bis(trimethylsilyl)amide (3.71 mL, 3.71 mmol). The mixture was stirred for 30 minutes, then 1,2,3,4,5-pentaphenyl-1′-(di-t-butylphosphino)ferrocene (0.121 g, 0.169 mmol), Pd2(dba)3 (0.155 g, 0.169 mmol) and (2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride (8.10 mL, 4.05 mmol) were added. The reaction mixture was heated at 80° C. for 2 hours, then cooled to room temperature, diluted with ethyl acetate and washed with 1M HCl. The organic layer was dried with MgSO4, filtered and concentrated. The crude material was purified on a silica gel cartridge (40 g) using an EtOAc/hexane gradient (0-100% EtOAc over 20 minutes) to afford 950 mg of tert-butyl 2-(4-((5R,7S)-2-oxo-3-oxa-1-azaspiro[4.4]nonan-7-yl)phenyl)acetate. HPLC retention time=0.93 min (Condition G); LC/MS M+1=332.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=1.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(N)c1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
A solution of 20.0 g (0.065 mol) of 5-methyl-4-[(3-nitrophenoxy)methyl]-2-phenyloxazole and 73.0 g (0.325 mol) of stannous chloride dihydrate in 600 ml of ethanol is heated to 70° C. for 3 hours. The solution is allowed to cool to room temperature, and poured into 2 L of ice water. The mixture is made alkaline by the addition of solid sodium bicarbonate, and extracted twice with 500 ml of ethyl acetate. The combined ethyl acetate solution is concentrated in vacuo to obtain crystals. Recrystallization from acetone gives 8.5 g (47%) of crystals, m.p. 89°-90° C., MS (CI) 281 (M+H). The product is used without further purification in subsequent reactions.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][CH2:10][CH:11]([CH2:13][OH:14])[O:12][C:7]=2[C:6]=1[CH3:17])=[O:4].O.[OH-].[Ba+2].[OH-]>CO>[OH:14][CH2:13][CH:11]1[CH2:10][O:9][C:8]2[CH:15]=[CH:16][C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:17])[C:7]=2[O:12]1
Reactant: COC(=O)c1ccc2c(c1C)OC(CO)CO2
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)ccc2c1OC(CO)CO2
Yield: 79.9 %

Procedure:
To a round bottom flask equipped with magnetic stirring was added 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester (6.40 g, 26.9 mmol), barium hydroxide monohydrate (25.44 g, 134.3 mmol), and methanol (108 mL). This mixture was stirred at room temperature for 24 hours. The methanol was evaporated. The resulting slurry was taken up in water and washed once with ether. The aqueous layer was acidified by pouring into iced concentrated HCl. This was extracted twice with ethyl acetate. The ethyl acetate extracts were combined, dried over magnesium sulfate, filtered and evaporated to give a yellow solid, 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid, (4.82 g, 21.5 mmol) in 80% yield. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 2.45 (s, 3H), 3.85 (m, 2H), 4.12 (m, 1H), 4.24 (m, 1H), 4.41 (m, 1H), 6.76 (d, 1H), 7.51 (d, 1H); TLC: Rf=0.32 (1:1 ethyl acetate/hexane).
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[N:8]=[CH:7][C:6]([C@@H:9]([OH:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.O>C(Cl)Cl>[Si:14]([O:11][CH2:10][C@@H:9]([C:6]1[CH:7]=[N:8][C:3]([CH:2]([F:1])[F:13])=[CH:4][CH:5]=1)[OH:12])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: OC[C@H](O)c1ccc(C(F)F)nc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccc(C(F)F)nc1
Reaction time: 16 h
Yield: 75 %

Procedure:
To a stirred solution of (R)-1-(6-(difluoromethyl)pyridin-3-yl)ethane-1,2-diol (2.5 g, 13.2 mmol) in dry CH2Cl2 at room temperature were added tert-butyldimethylsilyl chloride (2.19 g, 14.5 mmol) and imidazole (0.99 g, 14.5 mmol). The resulting reaction mixture was stirred for 16 h. After completion of the reaction, the reaction mixture was treated with water and extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated in vacuo. The residue was purified by column chromatography (SiO2, 20% EtOAc/pet. ether) to afford the title compound (3g, 75% yield). MS: 304 [M+1]+; 1H-NMR (300 MHz, CDCl3): 8.63 (s, 1H), 7.89 (d, 1H, J=8.2 Hz), 7.63 (d, 1H, J=8.2 Hz), 6.64 (t, 1H, J=55.4 Hz), 4.82-4.86 (m, 1H), 3.82 (dd, 1H, J=10.1, 3.7 Hz), 3.58 (dd, 1H, J=10.1, 7.8 Hz), 0.9 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][C@@H:11]2[N:12]([CH3:22])[C:13]3[C:14]([C:20]#[N:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[Br-].[CH3:26][CH:27]([CH3:31])[CH2:28][CH2:29][Zn+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][N:12]1[C:13]2[C:18](=[CH:17][C:16]([CH2:29][CH2:28][CH:27]([CH3:31])[CH3:26])=[CH:15][C:14]=2[C:20]#[N:21])[C@@H:10]2[CH2:9][NH:8][CH2:24][CH2:23][C@H:11]12
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: CC(C)CC[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CC(C)CCc1cc(C#N)c2c(c1)[C@@H]1CNCC[C@@H]1N2C

Procedure:
Following the general procedure for Example 127–146, the title compound was prepared (11 mg, 39%) as a light yellow oil using (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 40 mg, 0.10 mmol), 3-methyl-butylzinc bromide (0.5 M in THF, 2.5 mole equivalent) and Pd(PPh3)4 (0.06 mole equivalent).: MS (ESI): 284 (base, M+H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[CH3:21][S:22]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])(=[O:24])=[O:23]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: CS(=O)(=O)Cl
Product: CCOC(=NS(C)(=O)=O)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and methanesulfonyl chloride, there is obtained ethyl N-(methylsulfonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 136.5°-138° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16](O)=[O:17])=[CH:13][CH:14]=3)[C:9]([CH3:19])=[C:8]2[CH3:20])=[CH:4][C:3]=1[O:23][C@@H:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].Cl.[CH:31]([C:34]1[CH:35]=[C:36]([C@@H:40]([NH2:42])[CH3:41])[CH:37]=[CH:38][CH:39]=1)([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCN(C(C)C)C(C)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16](=[O:17])[NH:42][C@H:40]([C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([CH:31]([CH3:33])[CH3:32])[CH:35]=4)[CH3:41])=[CH:13][CH:14]=3)[C:9]([CH3:19])=[C:8]2[CH3:20])=[CH:4][C:3]=1[O:23][C@@H:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1Cl
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)ccc1Cl
Reaction time: 15 h

Procedure:
The (S)-1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid (55 mg, 0.13 mmol), the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride (37 mg, 0.19 mmol) and HATU (61 mg, 0.16 mmol) were dissolved in DMF (3 mL) and DIEA (0.1 mL). It was stirred for 15 h. The solution was filtered and purified by preparative HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:11]=1)[CH3:2].[CH2:27]([O:29][CH2:30][C:31](O)=[O:32])[CH3:28]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[CH2:22][N:23]([C:31](=[O:32])[CH2:30][O:29][CH2:27][CH3:28])[CH2:24][CH3:25])[CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Reactant: CCOCC(=O)O
Product: CCOCC(=O)N(CC)Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1

Procedure:
[5-(2-ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester and ethoxyacetic acid were reacted as described in Example 8, Step 6 to provide [5-(2-{[N-(2-ethoxy-acetyl)-N-ethyl-amino]-methyl}-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester. The ester was hydrolyzed to the acid as described in Example 30, Step 2.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O-])=[O:14].C(O)(=O)C>CO.O>[OH:14][N:13]=[C:16]1[CH:21]=[CH:20][C:19](=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=2)[C:11]#[N:12])[CH:18]=[CH:17]1
Reactant: Cc1ccc(CC#N)cc1
Reactant: O=[N+]([O-])c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1ccc(C(C#N)=C2C=CC(=NO)C=C2)cc1
Temperature: 55 °C
Reaction time: 2.5 h

Procedure:
40 g of KOH are dissolved in 200 ml of methanol and heated up to 55° C. To the solution are added 25 g (0.19 mol) of 4-methylphenylacetonitrile, followed by 18 ml (0.17 mol) of nitrobenzene. The reaction mixture is stirred at 55° C. for 2.5 hrs. After cooling, 400 ml of water are added with stirring. The resulting solution is acidified by addition of 110 ml of acetic acid in 100 ml of water, leading to a yellow precipitate. The mixture is then filtered, and the solid is washed with a mixture of methanol and water, and methanol. After the solid is dried in air, 29.6 g (74%) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-(4-methylphenyl)-acetonitrile are obtained in the form of a yellow powder having a melting point of 148-151° C. (dec.).
Reaction SMILES: [N+](C1C=CC(C(OO)=O)=CC=1)([O-])=[O:2].C(O)(C)(C)C.[C:19]([O:22][C:23]1[CH:41]=[CH:40][C:39]2[C@@H:38]3[C@H:28]([C@H:29]4[C@@:33]([CH2:36][CH2:37]3)([CH2:34][CH3:35])[CH:32]=[CH:31][CH2:30]4)[CH2:27][CH2:26][C:25]=2[CH:24]=1)(=[O:21])[CH3:20]>C(Cl)CCl>[C:19]([O:22][C:23]1[CH:41]=[CH:40][C:39]2[C@@H:38]3[C@H:28]([C@H:29]4[C@@:33]([CH2:36][CH2:37]3)([CH2:34][CH3:35])[C@@H:32]3[O:2][C@@H:31]3[CH2:30]4)[CH2:27][CH2:26][C:25]=2[CH:24]=1)(=[O:21])[CH3:20]
Reactant: O=C(OO)c1ccc([N+](=O)[O-])cc1
Reactant: CC[C@@]12C=CC[C@H]1[C@@H]1CCc3cc(OC(C)=O)ccc3[C@H]1CC2
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: CC[C@]12CC[C@@H]3c4ccc(OC(C)=O)cc4CC[C@H]3[C@@H]1C[C@H]1O[C@H]12
Reaction time: 18 h

Procedure:
At room temperature, a solution of 460 mg. of p-nitroperbenzoic acid in 3 ml. of tert.-butanol and 0.6 ml. of ethylene chloride is gradually added to 600 mg. of 3-acetoxy-18-methyl-1,3,5(10),16-estratetraene in 20 ml. of ethylene chloride. After 18 hours, the crude product is worked up as described in (A) and purified by preparative layer chromatography (eluent: hexane/ethyl acetate = 7 : 3). In this way, 490mg. of 3-acetoxy-16α,17α-epoxy-18-methyl-1,3,5(10)-estratriene is isolated as an oily product.
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7].C([O-])=O.[NH4+:20]>[Pd].O.CO>[CH3:1][Si:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:20])[CH2:10][CH2:9]1)=[O:7]
Reactant: C[Si](C)(C)CCOC(=O)N1CCC(=O)CC1
Reactant: [NH4+]
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOC(=O)N1CCC(N)CC1
Reaction time: 8 h
Yield: 40.1 %

Procedure:
A slurry of 10% palladium on carbon (200 mg) in water was added to 4-oxo-piperidine-1-carboxylic acid-2-trimethylsilanyl-ethyl ester (2.42 g, 10 mmol) in 100 mL of methanol. Ammonium formate (6.0 g, 95 mmol) in water was added dropwise, and the mixture stirred vigorously overnight. The mixture was filtered and the filtrate concentrated in vacuo to leave the crude product. Chromatography (elution with methanol-dichloromethane) provided 0.98 g of product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].Cl[CH:20]([C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=1[CH3:35])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:9][C:2]=1[O:1][CH:20]([C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=1[CH3:35])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:5]
Reactant: CCOC(=O)CCC(Cl)c1cc(C)ccc1C
Reactant: N#Cc1ccc(OCc2ccsc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C#N)c1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.1 %

Procedure:
2-Hydroxy-4-(3-thienylmethoxy)benzonitrile (1.5 g) is added portionwise to a stirred suspension of sodium hydride (440 mg, 60% dispersion in mineral oil) in dry DMF(50 mL). After stirring at ambient temperature for 30 minutes, ethyl (RS)-4-chloro-4-(2,5-dimethylphenyl)butanoate (2.5 g) is added in one portion and the reaction stirred for 48 hours at 90° C. The reaction is concentrated in vacuo and the residue partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer is extracted twice with ethyl acetate (50 mL). The combined organic phases are dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:2 v/v). Fractions homogeneous in the required product are combined and evaporated to give ethyl (RS)-4-(2-cyano-5-(3-thienylmethoxy)phenoxy)-4-(2,5-dimethylphenyl)butanoate (500 mg) as a pale brown oil.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:11]([C:15]1[O:19][C:18](S(C)(=O)=O)=[N:17][N:16]=1)([CH3:14])([CH3:13])[CH3:12]>CS(C)=O>[C:11]([C:15]1[O:19][C:18]([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)=[N:17][N:16]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1nnc(S(C)(=O)=O)o1
Reactant: Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)c1nnc(Oc2ccc(N)cc2)o1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
7.3 g of pulverised KOH are added to 10.9 g of 4-aminophenol in 100 ml of dimethyl sulfoxide, and the mixture is stirred for 15 minutes. Then 20.4 g of 5-tert-butyl-2-methylsulfonyl-1,3,4-oxadiazole are added, the reaction mixture is stirred for 12 hours at room temperature and poured into ice water. The mixture is extracted with diethyl ether and the combined extracts are dried and concentrated by evaporation. Petroleum ether is added to the oily residue, whereupon the product crystallises. The product is then isolated by filtration and dried. Yield: 16.5 g (71% of theory). Melting point: 80°-81° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([OH:16])=[CH:11][CH:12]=2)[CH:7]=1.[H-].[Na+].[Br:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34]Br>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([O:16][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][Br:23])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: BrCCOCCOCCOCCBr
Reactant: COC(=O)COc1ccc2ccc(O)c(C(C)=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2ccc(OCCOCCOCCOCCBr)c(C(C)=O)c2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 80.1 %

Procedure:
Under an argon atmosphere, 2 g of [(8-acetyl-7-hydroxy-2-naphthalenyl)oxy]acetic acid methyl ester was added to a suspension of 0.32 g of 60% sodium hydride in 30 ml of anhydrous dimethylformamide. The mixture was stirred at room temperature for 40 minutes and then 11.6 g of bis[2-[2-bromoethoxy)ethyl]ether was added and the mixture was stirred at room temperature for 20 hours. The resulting dark mixture was concentrated in vacuo to an oil which was dissolved in methylene chloride, washed with water and concentrated to give an oil. Purification by high pressure liquid chromatography (35% ethyl acetate-toluene) gave 3.0 g (80%) of [[8-acetyl-7-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester as an oil.
Reaction SMILES: C[Si](C)(C)[C:3]1[C:4]2[C:9](C=C3[C:16]=1[C:15](C#C)=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:21]1[CH2:25]O[CH2:23][CH2:22]1>CO.[OH-].[K+].O>[C:22]([C:21]1[C:25]2[C:16]([CH:3]=[C:4]3[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)#[CH:23]
Reactant: C1CCOC1
Reactant: C#Cc1cccc2cc3ccccc3c([Si](C)(C)C)c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#Cc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.8 %

Procedure:
27 g (0.098 mol) of 9-trimethylsilyl ethynyl anthracene was put into a 1 L round-bottomed flask equipped with a stirrer and dissolved in a mixture of 100 ml of THF and 200 ml of methanol. A solution in which 0.7 g of KOH was dissolved in 7 ml of water was dropped into the resulting solution. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, THF and methanol were removed under a reduced pressure. The reaction mixture was then extracted with methylene chloride. The organic layer was washed with water several times and then dried with anhydrous magnesium sulfate. The solvent was removed to obtain yellow viscous liquid, which was then purified by silica gel column chromatography using hexane as an eluent, to give 17 g (85.8% yield) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:28][CH2:27][CH:26]([CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].O1CCOCC1.O.[OH-].[Li+]>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:28][CH2:27][CH:26]([CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(COc4cccc(F)c4)C3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(COc4cccc(F)c4)C3)CC2)cc1
Reaction time: 0.08 h
Yield: 51 %

Procedure:
To a solution of methyl 4-(1-(5-chloro-2-(3-((3-fluorophenoxy)methyl)pyrrolidin-1-yl)nicotinamido)cyclopropyl)benzoate (D200) (37 mg, 0.070 mmol) in a mixture 1,4-dioxane and water (3:1) (2 ml) lithium hydroxide monohydrate (10 mg, 0.238 mmol) was added and the mixture was stirred 20 min (4 cycles of 5 min each) under microwaves irradiation. After solvent evaporation the residue was diluted with water (5 ml) and 1M HCl (5 ml) and extracted with ethylacetate (3×10 ml). Collected organics after solvent evaporation afforded a residue that was purified by ISOLUTE Spe-Si (1 g) eluting with a mixture dichloromethane/methanol 98:2. Collected fractions after solvent evaporation afforded the title compound (E76) (18.2 mg)
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:32])[CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[CH:20]=[C:19]([S:22][CH:23]([C:29](=O)[CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:18]=[CH:17]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O>>[CH:1]1([NH:7][C:8](=[O:32])[CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:20]2[C:29]([CH3:30])=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[S:22][C:19]=2[CH:18]=[CH:17]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(Sc1ccc2cccc(CCCC(=O)NC3CCCCC3)c2c1)C(C)=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1sc2ccc3cccc(CCCC(=O)NC4CCCCC4)c3c2c1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
The product obtained in Step A (18 mmol) is added all at once to 5 ml of sulphuric acid (d=1.81). The temperature of the reaction mixture rises rapidly to approximately 80° C. After stirring for 5 minutes, the mixture is poured into 100 ml of ice-cold water and is then extracted with dichloromethane. The organic phase is then washed with water, then with saturated sodium hydrogen carbonate solution and then again with water. The organic phase is then dried over magnesium sulphate and is then concentrated under reduced pressure. The residue is chromatographed to yield the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][C:9]2[C:10]([NH:16][C:17]([O:19][CH:20]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[O:18])=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43].CO>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[C:10]([NH:16][C:17]([O:19][CH:20]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)=[O:18])=[CH:11][C:12]([NH:15][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:13][CH:14]=2)=[O:7])=[CH:33][CH:34]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(NC(=O)c2ccc(Cl)cc2)c(NC(=O)OC(c2ccncc2)C2CCNCC2)c1
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(NC(=O)c2ccc(Cl)cc2)c(NC(=O)OC(c2ccncc2)C2CCNCC2)c1
Reaction time: 16 h
Yield: 44.8 %

Procedure:
A solution of N1-(4-chlorobenzoyl)-N2-[1-(4-pyridyl)piperidin-4-ylmethoxycarbonyl)-1,2,4-benzenetriamine (40 mg, 0.08 mmol) in 5 mL of CH2Cl2 was treated with pyridine (1 mL) and methanesulfonyl chloride (0.008 mL, 0.09 mmol). After 16 h, the mixture was treated with MeOH (1 mL) and then concentrated. The residue was partitioned between EtOAc and NaOH (aq). The organic layer was dried (MgSO4) concentrated, and purified by chromatography (17:3 CH2Cl2:MeOH) affording 20 mg (40%) of the title compound.