Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH2:19][CH2:20][N:21]([N:30]2[CH:34]=[N:33][N:32]=[CH:31]2)[C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C1COCC1.C(O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH2:19][CH2:20][N:21]([N:30]2[CH:31]=[N:32][N:33]=[CH:34]2)[C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(N(CCCS(=O)(=O)c2ccc(OCc3ccccc3)cc2)n2cnnc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1ccc(N(CCCS(=O)(=O)c2ccc(O)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Palladium on charcoal (50 mg, 10% Pd) was added to a solution of 4-{[3-(4-Benzyloxy-benzenesulfonyl)-propyl]-[1,2,4]triazol-4-yl-amino}-benzonitrile (CAB02168, 118 mg, 0.25 mmol) in THF (10 mL) and ethanol (10 mL). The mixture was stirred under hydrogen atmosphere (balloon) for 18 h at room temperature. The reaction mixture was filtered through celite and the clear colourless filtrate was concentrated under reduced pressure. The residue was crystallised from acetone/water. Yield: 68 mg (71%) colourless crystals. 1H-NMR (400 MHz, d6-DMSO) δ=1.68-1.76 (m, 2H), 3.38 (t, J=7.6 Hz, 2H), 3.92 (t, J=7.2 Hz, 2H), 6.57 (d, J=9.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 7.68 (d, J=9.0 Hz, 2H), 7.73 (d, J=9.0 Hz, 2H), 8.97 (s, 2H), 10.64 (s, 1H, —OH). LRMS (FAB+): 384.0 (100, [M+H]+). HRMS (FAB+): 384.11248 C18H18N5O3S requires 384.11304.
Reaction SMILES: O.[CH3:2][C:3]([CH3:19])([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])[CH3:4].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[C:28](=[O:37])[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH2:30]>C(O)C>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[C:28](=[O:37])[CH:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:30][N:13]1[CH:14]=[N:15][C:11]([CH2:10][C@@H:9]([C:16]([OH:18])=[O:17])[NH:8][C:6]([O:5][C:3]([CH3:19])([CH3:2])[CH3:4])=[O:7])=[CH:12]1
Reactant: C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cn(CC(C(=O)c2ccc(Cl)cc2Cl)c2ccccc2)cn1)C(=O)O
Reaction time: 18 h
Yield: 100.2 %

Procedure:
Water was added to a stirred suspension of N-[(1,1-dimethylethoxy)carbonyl]-L-histidine (13.26 g) in ethanol (100 ml) and 1-(2,4-dichlorophenyl)-2-phenylpropen-1-one (14.5 g) until a clear solution was obtained. The clear solution was allowed to stand for 18 hours, and was then concentrated under reduced pressure to yield a foam which was triturated with hexane. The resulting mixture was filtered to yield 1-[3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[(1,1-dimethylethoxy)carbonyl]-L-histidine (27.7 g), as a mixture of diastereoisomers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C@@H:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[F:28])[CH2:19][OH:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:16])[NH:17][C@@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[F:28])[CH2:19][OH:20])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@H](CO)c1cccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)N[C@H](CO)c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (750 mg, 3.30 mmol), (2S)-2-amino-2-(3-chloro-2-fluorophenyl)ethan-1-ol (746 mg, 3.30 mmol) and HBTU (1.75 g, 4.62 mmol) in CH2Cl2 (30 mL) was added under nitrogen DIPEA (2.31 mL, 13.20 mmol). The reaction mixture was stirred at RT overnight. CH2Cl2 and water were added, the layers were separated and the aqueous one back-extracted with CH2Cl2 (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1 to EtOAc) to give the desired compound as a colorless oil. MS (UPLC/MS): 399.3/401.3 [M+H]+, 443.4/445.3 [M+HCOO]−; tR (HPLC conditions a): 3.28 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]([F:12])[C:7]=1[O:8][CH:9]([F:11])[F:10].[CH2:14]([Si:21]1(C2C=CC=CC=2)[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:14]([Si@H:21]1[CH2:22][CH2:23][C@H:24]([C:27]([O:13][C:4]2[CH:3]=[C:2]([F:1])[C:7]([O:8][CH:9]([F:11])[F:10])=[C:6]([F:12])[CH:5]=2)=[O:28])[CH2:25][CH2:26]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Reactant: Oc1cc(F)c(OC(F)F)c(F)c1
Product: CCCCCCC[Si@H]1CC[C@H](C(=O)Oc2cc(F)c(OC(F)F)c(F)c2)CC1

Procedure:
The general procedure of Example 3 was repeated using 3,5-difluoro-4-difluoromethoxyphenol and 4-n-heptyl-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[CH2:25]([N:27]([CH2:39][CH3:40])[CH2:28][CH2:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1)[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:36][CH2:35][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:27]([CH2:39][CH3:40])[CH2:25][CH3:26])=[CH:38][CH:37]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: CCN(CC)CCOc1ccc(CN)cc1
Reactant: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Product: CCN(CC)CCOc1ccc(CNc2ncc3c(n2)N(C)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 170 °C
Yield: 29.1 %

Procedure:
A mixture of 100 mg (0.26 mmol) of 3-(2,6-dichlorophenyl)-3,4-dihydro-7-methanesulfonyl-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 238 mg (1.07 mmol) of 4-(2-diethylaminoethoxy)benzylamine was heated at 170° C. for 30 minutes. The product was purified by flash column chromatography using dichloromethane/methanol/water/acetic acid (120:14:3:2) for the elution. Product-containing fractions were combined and evaporated to give 40 mg (29%) of 3-(2,6-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]benzylamino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 137-138° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:20]O>>[OH:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH3:20])=[O:6]
Reactant: CO
Reactant: Cc1c(O)cc(O)cc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc(O)cc(O)c1C
Temperature: 25 °C

Procedure:
To 168.2 g of 3,5-dihydroxy-2-methylbenzoic acid in 0.6 l of methanol were added 10 ml of 98% sulfuric acid, and the mixture was heated at reflux for 18 hours. The solution was cooled to room temperature and neutralized by the addition of about 30 ml of 28% sodium hydroxide solution. The solvent was evaporated in vacuo, and the residue was taken up in 0.7 l of ethyl acetate. The solution was washed successively with saturated sodium carbonate solution and brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was crystallized from ethyl acetate/hexane to yield 162.9 g of methyl 3,5-dihydroxy-2-methylbenzoate, m.p. 136°-138° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Br:15][C:16]1[O:20][C:19]([C:21](O)=[O:22])=[CH:18][CH:17]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:21]([C:19]2[O:20][C:16]([Br:15])=[CH:17][CH:18]=2)=[O:22])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2ccc(Br)o2)C1

Procedure:
59.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 5-bromo-furan-2-carboxylic acid to give (R)-3-{[(5-bromo-furan-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. Pale yellow solid. MS373.1 ([M−H]−)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[N+:18]([C:21]1[CH:32]=[CH:31][C:24]([O:25][CH:26]([CH3:30])[C:27](Cl)=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:27](=[O:28])[CH:26]([O:25][C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:32][CH:31]=2)[CH3:30])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a mixture of 4-nitrophenol (21.8 g) and triethylamine (33 ml) in ethyl acetate (360 ml) at 0° C. was added 2-(4-nitrophenoxy)-propionyl chloride (36 g) dropwise, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was filtered to remove the salts, washed with 5% sodium bicarbonate, followed by water, and the ethyl acetate layer was dried over anhydrous sodium sulphate. The solvent was distilled off under vacuum and the compound was precipitated by adding cold methanol. Filtration and drying gave pure 2-(4-nitrophenoxy)-propionic acid-4-nitrophenyl ester (35 g) as white powder. The product had a melting point of 136-139° C., with a purity of 99%. The product was characterized by 1H NMR (CDCl3) δ 1.85 (d, 3H, CH3), 5.15 (q, 1H, CH), 7.05 (d, 2H, Ar), 7.28 (d, 2H, Ar), 8.30 (m, 4H, Ar).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[CH3:13][C:14]1[CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:17][CH:18]=1.[OH-].[Na+]>C(Cl)Cl>[Cl:9][C:7]1[CH:6]=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[C:3]([CH:8]=1)[CH2:2][N:17]1[CH:18]=[C:14]([CH3:13])[CH:15]=[C:16]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1cc(C)c[nH]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)cn1Cc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Vigorously stir a solution of 2-(bromomethyl)-4-chloro-1-nitro-benzene (25.02 g, 99.88 mmoles) in DCM (200 mL), and to this add a solution of ethyl 4-methyl-1H-pyrrole-2-carboxylate (15 g, 97.92 mmoles) in DCM (200 mL). Then add 30-hydrated tetra-n-butylammonium hydroxide (0.508 g) and cool the stirred mixture under nitrogen to 5° C. using an external ice-bath. Add 25% aq. sodium hydroxide (200 mL) dropwise over 15 minutes observing the internal temperature rise to 10° C. Stir and allow to warm to room temperature. Stir at room temperature for 3.5 h. Add further 50% aq. sodium hydroxide (20 mL) and stir at room temperature for a further 1 h. Stop the stirring and allow the layers to separate. Transfer to a separating funnel and wash the organic layer with 1N hydrochloric acid (200 mL), observing the pH of this layer to be acidic using indicator paper. Next wash the organic layer with water (600 mL) and then brine (600 mL) and finally dry over Na2SO4. Filter the mixture and remove the solvent in vacuo at 40° C. to give an orange oil. Purify by passing through a silica gel pad with iso-hexane/ethyl acetate (gradient eluting from 10 to 20%) to give ethyl 1-(5-chloro-2-nitrobenzyl)-4-methyl-1H-pyrrole-2-carboxylate as a yellow oil (33 g, quantitative). MS (m/z): 322.98 (M+1).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].C([O-])(=O)C.[Na+].O.[CH2:14]([O:18][CH2:19][CH:20]=O)[CH2:15][CH:16]=[CH2:17]>C(O)C>[CH2:14]([O:18][CH2:19][CH:20]=[N:6][OH:7])[CH2:15][CH:16]=[CH2:17]
Reactant: NO
Reactant: C=CCCOCC=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCCOCC=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
Hydroxylamine sulfate (20.5 g), sodium acetate (12.8 g) and water (20 ml) were added to a solution of 3-butenyloxyacetaldehyde (17.8 g; J. Chem. Soc., Perkin Trans. 1, 1999, 3143-3155) in ethanol (200 ml). The mixture was stirred at room temperature overnight and then water was added. The excess of ethanol was evaporated under reduced pressure and the resulting residue was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (6.20 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[N:18]=[N:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH3:12])=[N:9][N:10]=2)[CH:7]=1.Br[CH2:21][C:22]#[N:23].C([O-])(O)=O.[Na+]>CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:21]=[C:22]([NH2:23])[N:19]=4)[N:18]=3)[CH3:12])=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(c1ccc(N)nn1)c1nnc2ccc(Br)cn12
Reactant: N#CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(c1ccc2nc(N)cn2n1)c1nnc2ccc(Br)cn12
Temperature: 100 °C
Yield: 55.3 %

Procedure:
A mixture of 6-(1-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)pyridazin-3-amine (1.0 g, 3.13 mmol), 2-bromoacetonitrile (0.251 ml, 3.76 mmol) and NaHCO3 (0.053 g) in IPA (10 mL) was heated at 100° C. in a sealed tube for 2 hrs. The solid was filtered off, rinsed with IPA, and stripped to dryness via rotary evaporation. The resulting residue was purified by LCMS and lyophilized as a TFA salt to provide the title compound, 6-(1-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)imidazo[1,2-b]pyridazin-2-amine 48G (0.62 mg, 1.73 mmol, 55%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85 (d, J=7.07 Hz, 3 H) 5.17 (d, J=7.07 Hz, 1 H) 7.38-7.57 (m, 3 H) 7.80 (d, J=9.60 Hz, 1 H) 7.99 (d, J=9.09 Hz, 1 H) 8.78 (s, 1 H). ESI-MS:m/z 358.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1.[CH3:14][NH:15][NH2:16]>>[CH3:14][N:15]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH2:16]
Reactant: Clc1cc2c(nn1)CCCCCC2
Reactant: CNN
Product: CN(N)c1cc2c(nn1)CCCCCC2
Reaction time: 24 h

Procedure:
A suspension of 9.8 g of 3-chloro-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine in 50 cc of methylhydrazine is stirred in an oil bath of 45° for 24 hours. The material dissolves completely during heating. After the reaction is complete, the mixture is evaporated to dryness, and the crude crystalline title compound is recrystallized twice from ether. The title compound has a
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH2:18]([S:34](Cl)(=[O:36])=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O1CCCC1>[CH2:18]([S:34]([NH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1)(=[O:36])=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Reactant: CC(=O)c1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1cccc(C(C)=O)c1
Reaction time: 2 h

Procedure:
To a mechanically stirred solution of 31.2 g (0.23 M) of m-aminoacetophenone and 35.4 ml (0.254 M) of triethylamine in 1 liter of tetrahydrofuran was added 75 g (0.23 M) of 1-hexadecanesulfonyl chloride at room temperature. The mixture was stirred for 2 hours and the suspended salt was removed. The filtrate was treated on a rotary evaporator to give a solid which was recrystallized from hexane: mp 95.5°-100° C.
Reaction SMILES: [CH:1]1[C:2]([CH2:19][C:20]([OH:22])=[O:21])=[CH:3][C:4]([I:18])=[C:5]([O:8][C:9]2[CH:10]=[C:11]([I:17])[C:12]([OH:16])=[C:13]([I:15])[CH:14]=2)[C:6]=1[I:7].O=S(Cl)Cl.O.[CH3:28]O>>[CH3:28][O:21][C:20](=[O:22])[CH2:19][C:2]1[CH:1]=[C:6]([I:7])[C:5]([O:8][C:9]2[CH:10]=[C:11]([I:17])[C:12]([OH:16])=[C:13]([I:15])[CH:14]=2)=[C:4]([I:18])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Yield: 61 %

Procedure:
In anhydrous conditions, Tetrac (5.0 g, 6.7 mmol, 1.0 eq.) was dissolved in anhydrous methanol (200 mL). To the solution was then added dropwise SOCl2 (485 μL, 6.7 mmol, 1.0 eq.). The reaction was set to reflux for 2 days. Water was then added to the reaction medium (200 mL) and then the solution was concentrated to yield a precipitate. The precipitate was then collected by vacuum filtration and then recrystallized to give orange crystals (3.10 g, 4.0 mmol) of methyl-2-(4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl)acetate in 61% yield.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([OH:23])=O)[C:12]=3[CH:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1.C(N1C=CN=C1)([N:28]1C=CN=C1)=O.N>CN(C=O)C.C(Cl)Cl>[F:24][C:3]([F:2])([F:25])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([NH2:28])=[O:23])[C:12]=3[CH:13]=[N:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of (rac)-2-(4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yloxy)acetic acid hydrochloride (example 99) (34.6 mg, 0.093 mmol) in DMF (1 mL) was added N,N-triethylamine (31 μL, 0.22 mmol) and 1,1′-carbonyldiimidazole (18.0 mg, 0.11 mmol). The reaction was stirred at room temperature for 2 h, cooled (0°) and treated with aq. 25% ammonia solution (0.87 mL, 5.55 mmol) and evaporated after 30 min to give a 1:1 mixture of starting material and product. The residue was dissolved in CH2Cl2, dried (Na2SO4) and evaporated. The oil was again dissolved in DMF (1 mL) and N,N-triethylamine (15.5 μL, 0.11 mmol) and 1,1′-carbonyldiimidazole (18.0 mg, 0.11 mmol) were added. The reaction was stirred at room temperature for 2 h, cooled (0°) and treated with aq. 25% ammonia solution (0.87 mL, 5.55 mmol) and evaporated after 30 min at room temperature. The solution was evaporated, dried in vacuo and purified by flash chromatography (20 g SiO2, Telos-cartridge, 3% MeOH in CH2Cl2) to give the title compound (15 mg, 48%) as off-white solid. MS: 337.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][CH2:9][CH:10](O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)=[CH:5][CH:4]=1.S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:23]=[C:22]2[C:6](=[CH:5][CH:4]=1)[CH2:7][NH:8][CH2:9][CH:10]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1
Reactant: COc1ccc(CNCC(O)c2ccc(OC)c(OC)c2)cc1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C(c1ccc(OC)c(OC)c1)CNC2
Yield: 88.2 %

Procedure:
α-[[(4-methoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol (950 mg) was dissolved in 7.2 ml of trifluoroacetic acid, and after adding thereto 0.22 ml of conc. sulfuric acid under cie cooling, the reaction was allowed to react for 45 minutes. The reaction solution was concentrated, and subjected to azeotropic distillation with toluene 2 times. After adding chloroform, the mixture was basified by addition of 28% aqueous ammonia under ice cooling. By a separating procedure, the chloroform layer was collected, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue obtained was subjected to silica gel column chromatography (chlroform-methanol-28% aqueous ammonia=15:1:0.1), giving 790 mg of 6-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline as oily matter.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([NH2:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[C:27]=1[C:28](Cl)=[O:29]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([NH:23][C:28](=[O:29])[C:27]2[C:31]([C:39]([F:41])([F:42])[F:40])=[CH:32][C:33]([C:35]([F:36])([F:37])[F:38])=[CH:34][C:26]=2[O:25][CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1(c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)Cl
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1(c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1

Procedure:
In analogy to the procedure described for the synthesis of example 16, the title compound was prepared from rac-3-amino-3-phenyl-piperidine-1-carboxylic acid benzyl ester and 2-methoxy-4,6-bis-trifluoromethyl-benzoyl chloride (CAS: 886503-47-5).
Reaction SMILES: C(O[CH:5]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:19][CH3:20])[CH:16]=3)[N:11]=[CH:10][C:9]=2[O:8][CH:7]([O:21][C:22](=[O:24])[CH3:23])[CH:6]1[C@H:25]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]1)(=O)C>[Pd].CO>[C:35]([O:34][C:32]([NH:31][C@H:28]1[CH2:27][CH2:26][C@H:25]([CH:6]2[CH2:5][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:19][CH3:20])[CH:16]=4)[N:11]=[CH:10][C:9]=3[O:8][CH:7]2[O:21][C:22](=[O:24])[CH3:23])[CH2:30][CH2:29]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COc1ccc2ncc3c(c2c1)C(OC(C)=O)C([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)C(OC(C)=O)O3
Agent: [Pd]
Solvent: CO
Product: COc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)C(OC(C)=O)O3
Temperature: 25 °C
Reaction time: 72 h

Procedure:
10% Palladium on activated carbon (500 mg, 4.70 mmol, 1.09 eq) is added at room temperature to a stirred solution of acetic acid 4-acetoxy-3-(trans-4-tert-butoxycarbonylamino-cyclohexyl)-6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-2-yl ester (2.3 g, 4.29 mmol, 1.0 eq) in methanol (60 mL). The reaction mixture is stirred at room temperature under hydrogen flow (10 bars) for 72 hours. The catalyst is then removed by filtration and the solution is concentrated to afford acetic acid 3-(trans-4-tert-butoxycarbonylamino-cyclohexyl)-6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-2-yl ester as a yellow semisolid (1.45 g, 71% yield) which is directly engaged in the next step.