Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]=[N+]=[N-])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCCCN1CCC(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: NCCCN1CCC(Cc2ccccc2)CC1
Reaction time: 4 h
Yield: 59.8 %

Procedure:
To a solution of 4-benzyl-1-(3-azidopropyl)piperidine (0.14 g, 0.54 mmol) in methanol (5 mL) was added Pd/C 5% (6 mg) and the resulting heterogeneous mixture was hydrogenated at 1 atm for 4 h. then filtered through a celite pad and concentrated in vacuum. The crude compound was purified by trituration with diethyl ether (5 mL) to give the title compound as a white solid (0.075g, 60%), mp 140-141° C. 1H-NMR (DMSO): 1.05-1.21 (m, 2H), 1.35-1.55 (m, 3H), 1.55-1.70 (m, 2H), 1.746 (t, J=11.1Hz, 2H), 2.281 (t, J=6.6Hz, 2H), 2.4-2.5 (m, 2H), 2.5-2.85 (m, 4H), 7.06-7.18 (m, 3H), 7.23 (t, J=7.2Hz, 2H), 7.8 (bs, 2H).
Reaction SMILES: [CH2:1]1OC(O)C[O:3][CH:2]1O.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1.[BH3-][C:23]#N.[Na+]>CC#N>[OH:3][CH2:2][CH2:1][NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH3:21])[C:17]([O:19][CH2:20][CH3:23])=[O:18])=[CH:14][CH:15]=1
Reactant: OC1COC(O)CO1
Reactant: [BH3-]C#N
Reactant: COC(=O)C(C)c1ccc(N)cc1
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C(C)c1ccc(NCCO)cc1
Reaction time: 1 h

Procedure:
Following the procedure of Himmelsbach, et. al., EP 0587134, Example V, glycolaldehyde dimer (Aldrich) (1 mmol) is added to a solution of methyl 2-(4-aminophenyl)propionate (1 mmol) in aqueous CH3CN (pH 6-7) (10 mL), followed by NaBH3CN (1.2 mmol), and the mixture is allowed to stir for 1 h. The mixture concentrated to an oil, and the residue is dissolved in a mixture of ice water and EtOAc. The aqueous layer is neutralized with 4N NaOH and washed with EtOAc. The organic phase is concentrated to an oil. A solution of the oil in EtOAc is chromatographed (silica gel, gradient, 5-30% CH3OH/CH2Cl2 -0.1% HOAc). The fractions containing the product are combined and concentrated to give the title compound.
Reaction SMILES: O=[O+][O-].[CH2:4]([C:7]1([C:23]([O:25][CH3:26])=[O:24])[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1)[CH:5]=C.S(OC)(OC)(=O)=[O:28].C(N(CC)CC)C>C(Cl)Cl>[O:28]=[CH:5][CH2:4][C:7]1([C:23]([O:25][CH3:26])=[O:24])[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH2:9][CH2:8]1
Reactant: COS(=O)(=O)OC
Reactant: C=CCC1(C(=O)OC)CCN(C(=O)OCc2ccccc2)CC1
Agent: O=[O+][O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(CC=O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ozone was passed through a solution of 1-benzyl 4-methyl 4-allylpiperidine-1,4-dicarboxylate (10.0 g, 0.0315 mol) in methylene chloride (200.0 mL) at −78° C. until the color of the solution turned to steel blue. The reaction mixture was flushed with an atmosphere of nitrogen. Then to the solution was added dimethyl sulfate (6.0 mL, 0.063 mol) followed by triethylamine (8.8 mL, 0.063 mol). The mixture was stirred at room temperature for overnight, and then concentrated. The residue was dissolved in ethyl acetate, and the resulting solution was washed with saturated NH4Cl solution, NaHCO3 (7.5%), brine, dried over Na2SO4, filtered and concentrated to give 1-benzyl 4-methyl 4-(2-oxoethyl)piperidine-1,4-dicarboxylate.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:16]([NH:19][C:20](=[CH2:25])[C:21]([O:23][CH3:24])=[O:22])(=[O:18])[CH3:17].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:16]([NH:19][C:20](=[CH:25][C:5]1[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[C:21]([O:23][CH3:24])=[O:22])(=[O:18])[CH3:17]
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC(C)=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere 50.0 g (171 mmol) 3,5-bis-(trifluoromethyl)-bromobenzene, 25.0 g (171 mmol) methyl 2-acetylamino-acrylate in 475 mL triethylamine and 250 mL acetonitrile were combined with 3.9 g (12.4 mmol) tri-o-tolyl-phosphane and 2.8 g (12.5 mmol) Pd(OAc)2 and stirred for 18 h at 80° C. After the reaction had ended the reaction mixture was evaporated down i. vac. to approx. 200 mL, combined with 400 mL EtOAc and 400 mL water, the precipitate was suction filtered and the phases were separated. The organic phase was dried over Na2SO4, combined with activated charcoal, filtered and evaporated to dryness. The residue was stirred with DIPE, suction filtered and dried i. vac.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[CH:8]([NH2:11])([CH3:10])[CH3:9].[OH-].[Na+]>>[CH:8]([NH:11][CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1)([CH3:10])[CH3:9]
Reactant: BrCC1OCCO1
Reactant: CC(C)N
Agent: [Na+]
Agent: [OH-]
Product: CC(C)NCC1OCCO1
Reaction time: 0.5 h

Procedure:
2-Bromomethyl-1,3-dioxolane (15 grams; 0.09 mole) and isopropylamine (38 ml; 0.45 mole) were charged into a Parr Shaker. The shaker was sealed and was heated with an infrared lamp to a pressure of about 50 p.s.i. Heating was stopped and the reaction mixture was shaken for a period of about 1/2 hour. After this time aqueous sodium hydroxide (12 ml; 50% concentration) was added to the reaction mixture with stirring. The organic phase was then separated from the aqueous phase, was dried over anhydrous magnesium sulfate and distilled under reduced pressure to yield the desired product N-isopropyl-N-(1,3-dioxolan-2-ylmethyl)amine as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:25])=[C:8]([C:16]([C:18]2[CH:19]=[N:20][N:21]([CH3:24])[C:22]=2[OH:23])=[O:17])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13].C(N(CC)CC)C.[CH3:33][CH2:34][S:35][C:36](Cl)=[O:37].C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:25])=[C:8]([C:16]([C:18]2[CH:19]=[N:20][N:21]([CH3:24])[C:22]=2[O:23][C:36]([S:35][CH2:34][CH3:33])=[O:37])=[O:17])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C)c2O)c1C
Reactant: CCSC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSC(=O)Oc1c(C(=O)c2ccc(S(C)(=O)=O)c(OCCOC)c2C)cnn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude 5-hydroxy-1-methylpyrazol-4-yl 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)phenyl ketone obtained in the same manner as the above step (3) was dissolved in anhydrous THF (10 mL), and triethylamine (190 mg) and 96% S-ethyl chlorothiolformate (151 mg) were added, followed by stirring for 1 hour at room temperature. Ethyl acetate (200 mL) was added to the reaction mixture, and the mixture was washed twice with a saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the desired product (250 mg).
Reaction SMILES: [CH2:1]1[CH2:6][O:5][C:3]([C:7]2([OH:25])[CH2:16][C:15]3[C:10](=[C:11]([O:19][CH3:20])[CH:12]=[CH:13][C:14]=3[O:17][CH3:18])[C:9]3(SCCS3)[CH2:8]2)([CH3:4])[O:2]1.C([O:28]CC)C>O1CCCC1.CO.O>[CH2:6]1[CH2:1][O:2][C:3]([C:7]2([OH:25])[CH2:16][C:15]3[C:10](=[C:11]([O:19][CH3:20])[CH:12]=[CH:13][C:14]=3[O:17][CH3:18])[C:9](=[O:28])[CH2:8]2)([CH3:4])[O:5]1
Reactant: CCOCC
Reactant: COc1ccc(OC)c2c1CC(O)(C1(C)OCCO1)CC21SCCS1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(OC)c2c1CC(O)(C1(C)OCCO1)CC2=O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 89 %

Procedure:
2.0 g of rac-3'-(1,1-ethylenedioxyethyl)-1',2',3',4'-tetrahydro-3'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] in 20 ml of tetrahydrofuran were added over a period of 10 minutes to a suspension of 6.4 g of mercuric oxide and 6.4 g of mercuric chloride in 200 ml of methanol and 18 ml of water. The resulting suspension was stirred at room temperature for 1.25 hours and then ca 100 ml of solvent were removed by evaporation under reduced pressure. 300 ml of dichloromethane were added and the suspension obtained was filtered to remove insoluble mercury salts. The filtrate was washed with three 200 ml portions of water, dried over magnesium sulphate and evaporated to give a solid residue. Tituration with diethyl ether gave 1.42 g (89%) of rac-3-(1,1-ethylenedioxyethyl)-1,2,3,4-tetrahydro-3-hydroxy-5,8-dimethoxy-1-oxo-naphthalene in the form of an off-white powder of melting point 177.5°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:27]([N:34]1[CH2:39][CH2:38][O:37][CH:36]([CH2:40]Cl)[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:34]1[CH2:39][CH2:38][O:37][CH:36]([CH2:40][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7]2)[CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Product: O=C(c1cn(CC2CN(Cc3ccccc3)CCO2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with commercially available 4-benzyl-2-(chloromethyl)morpholine gave the title compound. ES-MS m/e (%): 556.3 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][C:11]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=3)=[C:12]([CH3:14])[N:13]=2)[CH:5]=[N:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[S:10][C:9]([NH:8][C:6]3[N:7]=[C:2]([N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)[CH:3]=[N:4][CH:5]=3)=[N:13][C:12]=2[CH3:14])=[CH:16][C:17]=1[C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:22]
Reactant: Cc1nc(Nc2cncc(Cl)n2)sc1-c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Reactant: CN1CCNCC1
Product: Cc1nc(Nc2cncc(N3CCN(C)CC3)n2)sc1-c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1

Procedure:
The titled compound is prepared from (6-chloro-pyrazin-2-yl)-[5-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-amine (65) and 1-methyl piperazine following the procedure described in Example 13.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][N:8]=[C:9]3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:4][C:3]=2[O:2]1.[CH2:20]1[CH2:33][O:32][C:31]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][N:27]=[C:28]3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:23][C:22]=2[O:21]1>>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][NH:8][CH:9]3[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:4][C:3]=2[O:2]1.[CH2:20]1[CH2:33][O:32][C:31]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][NH:27][CH:28]3[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:23][C:22]=2[O:21]1
Reactant: c1ccc(C2=NCCc3cc4c(cc32)OCCO4)cc1
Reactant: c1ccc(C2=NCCc3cc4c(cc32)OCO4)cc1
Product: c1ccc(C2NCCc3cc4c(cc32)OCCO4)cc1
Product: c1ccc(C2NCCc3cc4c(cc32)OCO4)cc1

Procedure:
Substitution of an equivalent quantity of 6,7-methylenedioxy-1-phenyl-3,4-dihydroisoquinoline or 6,7-ethylenedioxy-1-phenyl-3,4-dihydroisoquinoline for the substituted 3,4-dihydroisoquinoline called for in the first paragraph of this example and substantial repetition of the procedure there detailed affords 6,7-methylenedioxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline, melting at about 94°-96°C., or 6,7-ethylenedioxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline, melting at about 89°-91°C., respectively.
Reaction SMILES: O=C[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6]C)[CH:4]=1.[CH3:12]COCC>>[OH:6][CH2:5][CH:8]([OH:9])[CH2:10][CH2:11][CH2:3][CH2:4][CH3:12]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCOCC
Product: CCCCCC(O)CO

Procedure:
A solution of the title B ketal (1.87 g, 11.8 mmol) in methanol (30 ml) and concentrated HCl (2.5 ml) was stirred at room temperature 3 hours. The solution was basified by adding concentrated NH4OH solution (10 ml) and the solvent was removed in vacuo. Saturated NaCl solution (50 ml) was added to the residue and the product was extracted into ether (4×50 ml). The combined ether extracts were washed with saturated NaCl solution (50 ml), dried (MgSO4) and freed of solvent in vacuo leaving the title C diol as a yellow oil (1.13 g, 81%) 13-C NMR consistent. TLC:silica gel, Et2O, vanillin, Rf =0.25.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH:19]=3)[O:14]2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>>[CH2:2]([N:9]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:29][O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][O:32]4)=[O:27])[CH:19]=3)[O:14]2)[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2
Agent: Cl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2)NOC1CCCCO1

Procedure:
(+)-(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid hydrochloride salt (33 mg, 0.083 mmol) was reacted with NH2OTHP following the procedure described in Example 1, Step C, giving (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (24 mg) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH3:12]>CO>[NH2:12][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: N
Solvent: CO
Product: Cc1ccc(C(=O)O)c(N)n1
Yield: 54 %

Procedure:
A solution of 2-Chloro-6-methyl-nicotinic acid (3.00 g, 17.5 mmol) in ammonia in MeOH (7M, 60 mL) in a bomb was heated to 120° C. overnight. After cooling, the solvent was removed and the residue was neutralized with 2N HCl. The precipitate was filtered, washed with water and dried to afford 2-Amino-6-methyl-nicotinic acid (1.44 g, 54%). 1H NMR (CD3OD, 400 MHz) δ 8.21 (d, J=7.6 Hz, 1H), 6.60 (d, J=7.6 Hz, 1H), 2.41 (s, 3H). MS (APCI+) [M+H]+153.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[Na+].[Na+].[NH2:16][C:17](=[NH:22])S(O)(=O)=O>O>[NH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:17]([NH2:22])=[NH:16]
Reactant: N=C(N)S(=O)(=O)O
Reactant: NCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N=C(N)NCCCCCC(=O)O
Reaction time: 20 h

Procedure:
6.5 g (50 mmol) 6-aminohexanoic acid and 6.9 g (50 mmol) sodium carbonate were dissolved in 50 mL water. 6.2 g (50 mmol) amino-iminomethane sulphonic acid was added under stirring to the solution. After 20 hours, the product was filtered and washed with acetic acid, methanol and then ether. Yield: 6.6 g (76%).
Reaction SMILES: C([O:9][CH2:10][C:11]1[CH:16]=[C:15]([C@H:17]2[C@H:22]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:21]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:20]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:19]([CH2:47][O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[O:18]2)[CH:14]=[CH:13][C:12]=1[Cl:56])(=O)C1C=CC=CC=1>C1COCC1.CO.O>[Cl:56][C:12]1[CH:13]=[CH:14][C:15]([C@H:17]2[C@H:22]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:21]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:20]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C@@H:19]([CH2:47][O:48][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[O:18]2)=[CH:16][C:11]=1[CH2:10][OH:9]
Reactant: O=C(OCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.5 %

Procedure:
To a solution of benzoate 104 (6.13 g, 7.97 mmol) in THF/MeOH/H2O (150 mL/5 mL/5 mL) was added LiOH monohydrate (1.0 g, 23.9 mmol) at room temperature. The mixture was stirred at room temperature for 15 hours. The mixture was extracted with EtOAc/aq. saturated NH4Cl solution (100 mL/100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield the title compound 105 (5.33 g, 10%), which was carried on to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH2:31][C@@H:32]([O:34][CH3:35])[CH3:33])(=O)=O)=CC=1>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:31][C@@H:32]([O:34][CH3:35])[CH3:33])[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)c(O)cc2n1
Reactant: CO[C@@H](C)COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CO[C@@H](C)COc1cc2nc(C)ccc2cc1F
Temperature: 80 °C

Procedure:
To a stirred mixture of 6-fluoro-2-methylquinolin-7-ol (0.200 g, 1.13 mmol), Cs2CO3 (0.552 g, 1.69 mmol) and NMP (2.3 mL) was added (S)-2-methoxypropyl 4-methylbenzenesulfonate (0.303 g, 1.24 mmol). The reaction mixture was heated at 80° C. for 1 hour. After cooling, the reaction was partitioned between toluene and water. The aqueous layer was extracted with toluene. The combined organic layers were washed with water and brine, dried and concentrated to give the crude product, which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>O1CCCC1>[C:19]([N:4]1[C:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:1][N:2]=[N:3]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)Cc1nnn[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 51.2 %

Procedure:
To a stirred suspension of 0.969 g of ethyl (1H-tetrazol-5-yl)acetate in 9mL of tetrahydrofuran were added successively 0.932 mL of triethylamine and 1.68 g of trityl chloride at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and 1 mol/L hydrochloric acid, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 1.23 g of ethyl (1-trityl-1H-tetrazol-5-yl)acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:27][CH3:28])([CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH2:30]([O:37][NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:30]([O:37][NH:38][C:14](=[O:15])[CH2:13][C:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:10])=[O:11])([CH2:27][CH3:28])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NOCc1ccccc1
Reactant: CCC(CCCCc1ccccc1)(CC(=O)O)S(=O)(=O)c1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(CCCCc1ccccc1)(CC(=O)NOCc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.8 %

Procedure:
To a solution of 0.4 g (0.99 mmol) of 3-(4-methoxyphenylsulfonyl)-3-ethyl-7-phenylheptanoic acid in 50 mL of methylene chloride is added 0.47 g (2.96 mmol, 3 eq) of O-benzyl-hydroxylamine hydrochloride, 0.13 g (0.247 mmol) of HOBT, 0.54 mL (4.94 mmol, 5 eq) of n-Methylmorpholine (NMM), and 0.25 g (1.28 mmol, 1.3 eq) of EDCl. After stirring for 18 hours at 25° C. the reaction is partitioned between methylene chloride and 1 N HCl. The organic layer is dried over anhydrous Na2SO4 then concentrated in vacuo. Purification by flash silica gel chromatography afforded 0.463 g (92%) of N-benzyloxy-3-(4-methoxyphenylsulfonyl)-3-ethyl-7-phenylheptanamide in the form of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]([C:12]([O:14]C)=O)[C:9]([OH:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH2:28])(=[O:20])=[O:19]>CO>[Br:1][C:2]1[N:11]=[C:10]([C:12]([NH:28][CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:18]([CH3:17])(=[O:20])=[O:19])=[O:14])[C:9]([OH:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CS(=O)(=O)c1ccccc1CN
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Solvent: CO
Product: CS(=O)(=O)c1ccccc1CNC(=O)c1nc(Br)c2cccnc2c1O
Reaction time: 96 h

Procedure:
Methyl 5-bromo-8-hydroxy-1,6-naphthyridine-7-carboxylate (500 mg, 1.77 mmol, prepared as in Example 113) and 1-[2-(methylsulfonyl)phenyl]methanamine (491 mg, 2.65 mmol) were suspended in 10 mL methanol in an oven-dried Schlenck tube. The solution was purged with Argon for 1 minute and capped. The solution was heated to 80 deg C. with stirring over 4 days. Upon cooling a white solid precipitated out of the methanol. LCMS analysis indicated that the precipitate was the desired product. Filtration and subsequent washing with methanol (10 mL) afforded the desired material as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:13][CH2:14][CH3:15])=[C:10]([SH:12])[CH:11]=1.[OH-].[K+].[K+].[C:20]([C:25]([O-:27])=[O:26])#[C:21][C:22]([OH:24])=[O:23]>O>[CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:13][CH2:14][CH3:15])=[C:10]([S:12]/[C:21](=[CH:20]\[C:25]([OH:27])=[O:26])/[C:22]([OH:24])=[O:23])[CH:11]=1
Reactant: O=C([O-])C#CC(=O)O
Reactant: CCCc1ccc(OCCC(C)C)cc1S
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCc1ccc(OCCC(C)C)cc1S/C(=C\C(=O)O)C(=O)O

Procedure:
A solution of 95.7 parts of 5-(3-methylbutoxy)-2-propylthiophenol, 54 parts of potassium hydroxide and 73 parts of acetylene dicarboxylic acid mono potassium salt in 350 parts of water was refluxed for 40 minutes and cooled. The mixture was filtered through Whatman 54 filter paper to remove an oil residue and the filtrate was acidified to pH 1 with concentrated hydrochloric acid. The resulting yellow precipitate was collected, washed with water and dried in vacuo to give 67.8 parts of the desired product as a yellow powder, mp 121° - 129°C Crystallization from 15% ethanol-water afforded pure [5-(3-methylbutoxy)-2-propylphenylthio] fumaric acid, m.p. 131° - 133°C.