Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C=O)C.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([CH:25]=[C:26]([C:28]3[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=3)[N:27]=2)[CH:24]=1.CCOC(C)=O>S(Cl)(Cl)=O.N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:32][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[N:27]=[C:22]3[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][N:23]3[CH:25]=2)=[CH:34][CH:33]=1)=[O:6]
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)cn2c1
Reactant: COc1ccc(C(=O)O)c(F)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)Nc2ccc(-c3cn4cc(C)ccc4n3)cc2)c(F)c1
Yield: 64.2 %

Procedure:
A stirred solution of 2-fluoro-4-methoxybenzoic acid (0.23 g, 1.34 mmol) in thionyl chloride (7 ml) containing a drop of DMF was heated under reflux for 4 h. The excess reagent was then removed under reduced pressure to give a crude solid. The amide was prepared as described in the Amide Coupling section using the crude solid and 4-(6-methylimidazo[1,2-a]pyridin-2-yl)aniline (0.30 g, 1.34 mmol) in dry pyridine (15 ml) to give the title compound (0.323 g, 80%) as a colourless solid after work-up and flash chromatography (EtOAc).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][Br:17])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(OCc2ccccc2)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 540 mg (2.51 mmol) 5-benzyloxy-2-pyridinemethanol (prepared according to J. Med. Chem. 1977, 20, 1258-1262), 536 mg N-bromo succinimide (3.01 mmol), and 1.2 g polymer bound triphenylphosphine (loading approx. 3 mmol/g, approx. 3.3 mmol) in dichloromethane (40 mL) was stirred overnight at room temperature. All solids were removed by filtration, and the filtrate was washed with aqueous sodium bicarbonate and water, and than concentrated in vacuo. The crude product (540 mg of a slightly pink solid, 79% crude yield) was used without further purification.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[C:25]([CH:27]=1)[OH:26].N1C=CN=C1>CN(C=O)C.O>[CH3:19][O:20][C:21]1[CH:27]=[C:25]([O:26][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=[C:23]([OH:28])[CH:22]=1
Reactant: COc1cc(O)cc(O)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(O)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reaction time: 0.17 h
Yield: 33 %

Procedure:
tert-Butyldiphenylsilylchloride (TBDPSCl) (1.8 mL, 1.96 g, 7.14 mmol) was added to a suspension of 5-methoxyresorcinol 18 (1.0 g, 7.14 mmol) and imidazole (729 mg, 10.71 mmol) in dry DMF (5 mL) under argon at −22° C. and the mixture was stirred for 10 min. The reaction mixture was diluted with H2O (25 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with aq 1M of HCl (2×25 mL), and brine (2×25 mL). The organic layer was then dried (Na2SO4) and concentrated in vacuo. The crude silyl phenol 19 was purified by FCC on silica gel (5% ethyl acetate in hexane) to afford pure silyl phenol 19 (892 mg, 33%): 1H NMR (300 MHz, CDCl3) δ 7.89-7.75 (4H, m, HAr), 7.48-7.34 (6H, m, HAr), 5.98 (2H, t, J=2.1 Hz, HAr), 5.92 (1H, t, J=2.1 Hz, HAr), 5.13 (1H, br, s, HO—), 3.56 (3H, s, H3CO), 1.14 (9H, s, [(H3C)3C]; 13C NMR (75 MHz, CDCl3) δ 161.1, 157.3, 156.8, 135.4, 132.8, 129.9, 127.7, 100.1, 98.5, 95.0, 55.0, 26.4, 19.4; LRMS (CI), m/z (relative intensity): 378([M+1]+, 30), 321 (100), 243 (30), 213 (10), 199 (29). This material was employed directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[C:5]([C:7]1[NH:12][C:11](=[O:13])[NH:10][C:9](=[O:14])[C:8]=1[CH:15]([CH3:17])[CH3:16])=[O:6].Cl[CH2:23][C:24]1[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([N:31]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]2=[O:41])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[C:5]([C:7]1[N:12]([CH2:23][C:24]2[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([N:31]3[C:39](=[O:40])[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]3=[O:41])[CH:25]=2)[C:11](=[O:13])[NH:10][C:9](=[O:14])[C:8]=1[CH:15]([CH3:16])[CH3:17])=[O:6]
Reactant: Cc1cc(Br)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Cc1cc(CCl)cc(N2C(=O)c3ccccc3C2=O)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(C)nc(N3C(=O)c4ccccc4C3=O)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To a mixture of (28) (351 mg, 1 mmol), (30) (287 mg, 1 mmol), anhydrous powdered potassium carbonate (138 mg, 1 mmol), and lithium iodide (134 mg, 1 mmol), was added DMF (5 ml). The mixture was stirred for overnight at room temperature. The mixture was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA: hexanes (from 1:2 to 1:1)) to afford 211 mg (35%) of a white solid; 1H NMR (200 MHz, CDCl3) δ 1.13 (3H, d, J=7.2 Hz), 1.20 (3H, d, J=7.2 Hz), 2.17-2.40 (4H, m), 2.47 (3H, s), 4.49 (1H, d, J=16.0 Hz), 5.15 (1H, d, J=16.0 Hz), 6.84 (1H, s), 6.91 (1H, s), 7.36 (1H, s), 7.53 (1H, s), 7.61 (1H, s), 7.77-7.96 (4H, m), 9.30 (1H, s).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7].[CH3:35]I>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH3:35])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1ccccc1N1C(=O)NCC12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: CI
Product: Cc1ccccc1N1C(=O)N(C)CC12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=500.2 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-2-one and methyl iodide.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([CH:25]=[O:26])=[N:22][C:23]=4[F:24])=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.[BH4-].[Na+]>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([CH2:25][OH:26])=[N:22][C:23]=4[F:24])=[C:13]([C:14]([F:16])([F:15])[F:17])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)c(F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: OCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)c(F)n1
Temperature: 0 °C

Procedure:
5-[1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-yl]-6-fluoropyridine-2-carbaldehyde (33 mg, 0.091) was dissolved in dichloromethane (2 mL) and cooled to 0° C. The mixture was treated with sodium borohydride (8.6 mg, 0.23 mmol, 2.5 equiv) and after 2 hours, the mixture was diluted with ethyl acetate (30 mL), washed with sodium bicarbonate (2×30 mL, aqueous saturated), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography, providing the titled compound.
Reaction SMILES: Cl.[CH3:2][O:3][C@H:4]1[C@@H:9]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7][NH:6][CH2:5]1.Cl[C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C>>[CH3:2][O:3][C@H:4]1[C@@H:9]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7][N:6]([C:22]2[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=2)[CH2:5]1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Reactant: Cc1cc(Cl)ncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1CN(c2cc(C)ncn2)CC[C@@H]1NC(=O)OCc1ccccc1

Procedure:
The same operation as in Example (158a) was performed using benzyl cis(±)-[3-methoxypiperidin-4-yl]carbamate hydrochloride obtained in Example (160a) (549 mg, 1.83 mmol), 4-chloro-6-methylpyrimidine (235 mg, 1.83 mmol) and diisopropylethylamine (709 mg, 5.48 mmol), to obtain the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]>[Pd]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCCCCCC=Cc1cccs1
Agent: [Pd]
Product: O=C(O)CCCCCCCCc1cccs1
Yield: 87.4 %

Procedure:
This compound was synthesized from 9-(2-thienyl)-8-nonenoic acid (1.19 g, 5 mmol) by a hydrogenation reaction using Pd/C. (120 mg). Crystallization afforded the product (1.05 g, 88%) as white crystals (mp 32-33° C.); IR: 3400-2500, 1715, 705 cm-1 ; 1H-NMR: 1.35 (m, 12H), 2.35 (t, 2H), 2.85 (t, 2H), 6.95 (m, 3H), 10.35 (bs, 1H). Anal. Calcd. for C13H20SO2 : C, 64.96, H, 8.39%; Found: C, 64.81, H, 8.43%.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[C:9]([C:17]3[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:21]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH:14]([F:16])[F:15])[CH2:4][CH2:3]1.[CH2:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH3:48])=[C:43]([CH:47]=1)[C:44](O)=[O:45])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH3:48])=[C:43]([C:44]([N:25]2[CH2:26][CH2:27][CH:22]([N:20]3[C:19](=[O:28])[C:18]([CH3:30])([CH3:29])[C:17]([C:9]4[CH:10]=[CH:11][C:12]([O:13][CH:14]([F:15])[F:16])=[C:7]([O:6][CH2:5][CH:2]5[CH2:3][CH2:4]5)[CH:8]=4)=[N:21]3)[CH2:23][CH2:24]2)=[O:45])[CH:47]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Agent: Cl
Product: Cc1ccc(OCc2ccccc2)cc1C(=O)N1CCC(N2N=C(c3ccc(OC(F)F)c(OCC4CC4)c3)C(C)(C)C2=O)CC1

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B3) and 5-(benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]([OH:21])=O)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:25])=O>C1COCC1>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]([Cl:25])=[O:21])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc2c(C(=O)O)cn(CC3CCCCC3)c12
Solvent: C1CCOC1
Product: COc1cccc2c(C(=O)Cl)cn(CC3CCCCC3)c12
Yield: 100.3 %

Procedure:
To a solution of 1-(cyclohexylmethyl)-7-methoxyindole-3-carboxylic acid (2.5 g, 8.8 mmol) in THF (30 ml) was added oxalyl chloride (4.5 g, 35.3 mmol), dropwise with stirring. The mixture was stirred at room temperature for 18 h. The volatile components were evaporated under reduced pressure to afford 1-(cyclohexylmethyl)-7-methoxyindole-3-carbonyl chloride (2.7 g) as a crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:19](=[CH:20][CH:21]=1)[C:9]1[O:10][C:11]3([CH2:17][S:18][C:8]=1[C:7](=[O:22])[C:6]2=[O:23])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3.[C:24]([C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C@H:34]2[CH2:36][O:35]2)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C@H:34]([OH:35])[CH2:36][N:14]2[CH2:15][CH2:16][C:11]3([O:10][C:9]4[C:19]5[C:5]([C:6](=[O:23])[C:7](=[O:22])[C:8]=4[S:18][CH2:17]3)=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=5)[CH2:12][CH2:13]2)=[CH:30][CH:29]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCNCC2)CS1
Reactant: CC(C)(C)c1ccc(OC[C@H]2CO2)cc1
Product: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCN(C[C@@H](O)COc3ccc(C(C)(C)C)cc3)CC2)CS1

Procedure:
Compound 201 was synthesized using 8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=188-190° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.73 (d, J=8.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31 (d, J=3.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 6.85 (d, J=9.0 Hz, 1H), 4.86 (d, J=4.7 Hz, 1H), 4.00-3.81 (m, 1H), 3.87 (s, 3H), 3.05 (s, 2H), 2.86-2.73 (m, 2H), 2.54-2.38 (m, 2H), 2.02-1.95 (m, 2H), 1.86-1.74 (m, 2H), 1.25 (s, 9H). LCMS: 538 [M+H].
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([N:11]=[C:12]([CH3:30])[C:13]([C:25](OCC)=[O:26])=[C:14]2[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([N:11]=[C:12]([CH3:30])[C:13]([CH2:25][OH:26])=[C:14]2[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)nc2cn(Cc3ccccc3)cc2c1-c1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc2cn(Cc3ccccc3)cc2c(-c2ccc(Cl)cc2Cl)c1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.4 %

Procedure:
To a solution of Example 7A (55 mg, 0.125 mmol) in THF (15 mL) was added LAH solution (0.4 mL, 1 M in THF, 0.4 mmol). The mixture was stirred at RT for 1.5 h and quenched with sat. NaHCO3 solution (1.5 mL) after which it was extracted with EtOAc (15 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (SiO2; EtOAc) to give the desired compound (32 mg; 64%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 2.78 (s, 3H), 4.43 and 4.52 (ABq, J=11.9 Hz, 2H), 5.28 (s, 2H), 6.55 (d, J=2.2 Hz, 1H), 7.06-7.38 (m, 2H), 7.20-7.38 (m, 6H), 7.53 (d, J=1.8 Hz, 1H). [M+H]+=397.17.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH2:10][CH2:9]1>C(Cl)Cl>[CH:8]1([CH2:11][N:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:16][CH2:17]2)[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(CC3CC3)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CC(N2CCN(CC3CC3)CC2)CCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5 mL TFA were added to a solution of 1.36 g (4.2 mmol) tert. butyl 4-(4-cyclopropylmethyl-piperazin-1-yl)-piperidine-1-carboxylate in 30 mL DCM and the reaction mixture was stirred for 4 h at RT. The reaction solution was evaporated down i.vac., the residue combined with diethyl ether, the precipitate was suction filtered and dried. The product was precipitated as the tris-trifluoroacetate salt.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1>O1CCCC1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:13](=[O:14])[CH2:12][C:11](=[O:15])[CH3:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=C1CC(=O)O1
Reactant: CC(=O)N1CCNCC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CCN(C(C)=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
A solution of 20.8 g (0.17 mol) 1-acetylpiperazine in 50 ml tetrahydrofuran were added dropwise to a solution of 13 g of diketene (0.16 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 27.2 g (0.13 mol, 83% yield) of a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH2:24][C:25]([OH:27])=[O:26])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:23][CH2:22]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[CH:30]=[N+:31]([O-:58])[CH:32]=[C:33]([Cl:57])[C:34]=1[CH2:35][C@@H:36]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH:49]([F:51])[F:50])=[C:44]([O:52][CH2:53][CH:54]2[CH2:56][CH2:55]2)[CH:43]=1)[O:37][C:38](=[O:41])[CH2:39]O.C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH2:24][C:25]([O:27][CH2:39][C:38]([O:37][C@H:36]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH:49]([F:51])[F:50])=[C:44]([O:52][CH2:53][CH:54]3[CH2:56][CH2:55]3)[CH:43]=2)[CH2:35][C:34]2[C:33]([Cl:57])=[CH:32][N+:31]([O-:58])=[CH:30][C:29]=2[Cl:28])=[O:41])=[O:26])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:22][CH2:23]1)[S:9]([CH3:12])(=[O:10])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CO)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CC(C)(C)OC(=O)N(c1cc(CC(=O)O)ccc1OCC1CC1)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(c1cc(CC(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)ccc1OCC1CC1)S(C)(=O)=O

Procedure:
To a solution of 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-(cyclopropylmethoxy)phenyl)acetic acid (0.200 g, 0.501 mmol) in DCM (5 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-hydroxyacetoxy)ethyl)pyridine 1-oxide (0.239 g, 0.501 mmol), EDC (0.288 g, 1.502 mmol), and DMAP (0.0306 g, 0.250 mmol) were added, and the mixture was reacted for 5 hours. A 1N solution of HCl was added, and the desired compound was extracted with DCM (3×) recovering the crude desired product (0.450 g, yield considered to be quantitative, MS/ESI+ 859.3 [MH]+) that was used in the following step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:13]2[C:14]3[C:6](=[C:7]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[NH:8][C:9]=3[CH:10]=[C:11]([NH:15][C:16](=[O:43])[CH2:17][CH2:18][C:19]3[N:20]=[CH:21][N:22](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:23]=3)[CH:12]=2)[CH:5]=[N:4][NH:3]1.[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51]>C(Cl)Cl>[F:53][C:52]([F:55])([F:54])[C:50]([OH:56])=[O:51].[NH:22]1[CH:23]=[C:19]([CH2:18][CH2:17][C:16]([NH:15][C:11]2[CH:12]=[C:13]3[C:2](=[O:1])[NH:3][N:4]=[CH:5][C:6]4=[C:7]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[NH:8][C:9]([CH:10]=2)=[C:14]34)=[O:43])[N:20]=[CH:21]1
Reactant: O=C(CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1c[nH]cn1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 62 %

Procedure:
Preparation of example 52 from the title compound of Example 51 (32 mg, 0.050 mmol) and 45% TFA in CH2Cl2 (1 mL) was carried out analogously to Example 20. (Deprotection of trityl group was effected using the same conditions as for tert-butoxycarbonyl deprotection.) Isolation, also in an analogous manner, additionally included recrystallization from methanol/ethyl acetate and diethyl ether to afford the title compound (16 mg, 0.031 mmol) as a yellow powder in 62% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]/I)[CH3:12].O>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]/[C:9]#[C:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([Cl:10])[CH:5]=1)[CH3:12]
Reactant: C#Cc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)/C=C/I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/C#Cc1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 1,3-dichloro-5-ethynyl-benzene (1.52 g, 8.9 mmol) in triethylamine (32.4 mL) was added PdC12(PPh3)2 (57.15 mg, 0.08 mmol), (E)-3-iodo-prop-2-enoic-acid ethyl ester (1.84 g, 8.1 mmol) and copper(l)iodide (7.7 mg, 0.04 mmol). The reaction mixture was stirred for 2 h at 50° C., whereafter the reaction mixture was cooled to room temperature, water (30 mL) added and the mixture extracted with diethyl ether (3×20 mL). The combined and dried organic phases were evaporated to give crude (E)-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl ester in 1.1 g yield.
Reaction SMILES: [Li][CH2:2]CCC.[C:6]([CH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:6]([CH:10]1[CH2:15][CH2:14][C:13](=[CH2:2])[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCC(C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (5.36 g, 15 mmol, 1.5 eq) in dried THF (40 mL) was added n-BuLi (2.5 M) (6 mL, 15 mmol, 1.5 eq) at −78° C. The mixture was stirred at room temperature for 1 h. The solution of 4-(tert-butyl)cyclohexanone (1.54 g, 10 mmol) in THF (10 mL) was added to the reaction mixture at −78° C. The mixture was stirred at 70° C. for 12 h. The solvent was removed and the residue was suspended in hexane. The mixture was filtered, and the filtrate was concentrated to give 1-(tert-butyl)-4-methylenecyclohexane as yellow oil (0.80 g, yield: 50%). 1HNMR (400 MHz, CDCl3) δ: 4.58 (s, 2H), 2.34-2.31 (m, 2H), 2.01-1.95 (m, 2H), 1.88-1.84 (m, 2H), 1.14-1.06 (m, 3H), 0.86 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:15][O:16]/[N:17]=[C:18](/[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)\[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]O)=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:15][O:16]/[N:17]=[C:18](/[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)\[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)=[CH:23][CH:22]=1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: CCOC(=O)COc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.3 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged 10 mL of Toluene. to the stirred solvent was added ethyl (4-hydroxyphenoxy)acetate (0.2 g, 1.030 mmol) and (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.22 g, 0.810 mmol) was added Tributyl phosphine (0.268 g, 1.32 mmol) and 1,1′(Azodicarbonyl)di-piperidene (0.33 g, 1.326 mmol). Then the reaction mixture was Stirred at RT for 3 hrs. After completion of the reaction (reaction monitored by TLC), reaction mixture was extracted with ethyl acetate. Then the organic layer was dried over anhydrous Na2SO4. Solvent was removed under reduced pressure, and the resulting crude compound was purified by column chromatography on silica gel using petroleum ether and ethyl acetate as eluent (0.13 g Yield: 28.3%): 1H NMR (300 MHz, CDCl3): δ 7.57-7.60 (m, 2H), 7.18-7.28 (m, 5H), 6.82-6.84 (d, 3H), 6.78-6.79 (d, 3H), 5.12 (s, 2H), 4.83 (s, 2H), 4.49 (s, 2H), 4.15-4.22 (m, 2H), 3.98 (s, 3H), 1.19-1.24 (t, 3H).