Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[Br:12][C:13]1[CH:17]=[CH:16][N:15]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:14]=1[C:27](OC)=[O:28].O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Br:12][C:13]1[CH:17]=[CH:16][N:15]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:14]=1[C:27]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:28]
Reactant: COC(=O)c1c(Br)ccn1S(=O)(=O)c1ccccc1
Reactant: Nc1ccccc1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1ccccc1)c1c(Br)ccn1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 114.7 %

Procedure:
In a three-necked round-bottom flask aniline (1.57 mL, 17.20 mmol) was dissolved in 80 mL of toluene under inert atmosphere. To this solution was added trimethy aluminium (7.82 mL, 15.64 mmol) and the mixture was stirred at room temperature during 10 minutes. Afterwards, a solution methyl 3-bromo-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate (2.0 g, 5.81 mmol) in 20 mL of toluene were added and the reaction mixtures was heated at 80° C. for 3 h. Next, the mixture was allowed to cool to room temperature and 20-30 mL of water was added to hydrolyze unreacted trimethyl aluminium and a 0,5M aqueous solution of disodium tartrate dihydrate was also added. After stirring for a while, the two layers were separated and the aqueous phase was extracted with ethyl acetate. The organic mixture was washed with the same 0,5M aqueous solution of disodium tartrate dehydrate (200 mL), water and brine, dried and concentrated in vacuum to afford 2.7 g of a residue that was used in the following step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]([O:19][CH3:20])=[O:18])[C:6]2[CH:7]=[CH:8][C:9](=[O:16])[N:10]([CH2:13][CH:14]=O)[C:11]=2[CH:12]=1.[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:32]([CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:35]([O:34][C:33]([N:32]([CH2:31][C:29]1[CH:28]=[CH:27][C:26]2[O:21][CH2:22][CH2:23][O:24][C:25]=2[CH:30]=1)[CH:40]1[CH2:45][CH2:44][N:43]([CH2:14][CH2:13][N:10]2[C:11]3[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([C:17]([O:19][CH3:20])=[O:18])[C:6]=3[CH:7]=[CH:8][C:9]2=[O:16])[CH2:42][CH2:41]1)=[O:39])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)c1cc(OC)cc2c1ccc(=O)n2CC=O
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To 10 mL of a chloroform solution containing 472 mg of methyl 7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-5-carboxylate and 374 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 62 μL of acetic acid was added and stirred at room temperature for 1 hour. To the reaction mixture, 352 mg of sodium triacetoxyborohydride was added and stirred for 30 min. Aqueous saturated sodium hydrogen carbonate solution was added and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate:hexane=2:1], to give 493 mg of methyl 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-5-carboxylate as a white solid.
Reaction SMILES: Cl.Br[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[CH:17]=1)=[O:14].[N:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13]([C:8]2[C:9]3[C:4](=[C:3]([C:34]4[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=4)[CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:6][CH:7]=2)=[O:14])=[CH:17][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1
Reactant: COc1ccc(NC(=O)c2cccc3c(Br)cccc23)cc1N1CCN(C)CC1
Reactant: OB(O)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(NC(=O)c2cccc3c(-c4ccncc4)cccc23)cc1N1CCN(C)CC1
Yield: 17.1 %

Procedure:
A stirred suspension of 5-bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]naphth-1-yl carboxamide hydrochloride salt (E2, 0.35 g, 0.71 mmole) and 4-pyridylboronic acid (85 mg, 0.71 mmole) in 1,2-dimethoxyethane (30 ml) and water (30 ml) containing sodium carbonate (0.38 g, 3.5 mmole) was de-gassed by bubbling argon through for 15 minutes. Tetrakis (triphenylphosphine)palladium (0) (80 mg) was added and the mixture heated at reflux for 30 h. The mixture was concentrated in vacuo to approx. 30 ml volume, then diluted with water (50 ml) and extracted with dichloromethane. The organic extract was dried (Na2SO4) and concentrated in vacuo to a dark solid. Purification by column chromatography on silica gel eluting with 0-20% methanol/dichloromethane afforded the title compound as a pale yellow oil (55 mg, 17%). This was converted to its hydrochloride salt and solidified from acetone.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH2:6].Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:12])[C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH:6][C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H](NC(=O)Oc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
L-aspartic acid dimethyl ester hydrochloride (2.0 g, 10 mmol) was dissolved in dichloromethane (30 ml), phenyl chloroformate (1.3 mL, 11 mmol) and N,N-diisopropylethylamine (4.4 mL, 25 mmol) were added at 0° C., and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[C:11]([C:26]([F:29])([F:28])[F:27])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].Cl.[CH2:38](OCC)C>C(Cl)Cl>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:38])[CH2:33][CH2:32]2)=[C:11]([C:26]([F:28])([F:27])[F:29])[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC2CCNCC2)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1
Reactant: CCOCC
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-5-trifluoromethyl-pyridazine dihydrochloride (0.14 mmol, 0.075 g) and aqueous formaldehyde (37%, 0.68 mmol, 0.070 mL) in dry DCM (1.2 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 0.82 mmol, 0.35 g). The mixture was shaken for 12 hours. The reaction was filtered and the resin was washed with DCM (10 mL). The solvent was removed under reduced pressure. The crude product was purified on a 4 g SiO2 cartridge with 4-6% (2N NH3 in MeOH) in DCM to give 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-5-trifluoromethyl-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (0.5 mL) and DCM (0.5 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.05 g). LCMS: m/z 493 [M+1]; 1H NMR (400 MHz, CD3OD) δ 7.10-7.19 (2 H, m), 7.00-7.09 (2 H, d), 5.54-5.82 (1 H, m), 4.38-4.43 (1 H, m), 3.66 (1 h, d), 3.54 (1 H, d), 3.10-3.35 (2 H, m), 2.89-2.98 (3 H, m), 2.64-2.73 (2 H, m), 2.58 (1 H, d), 2.46 (1 H, d), 2.27 (1 H, t), 1.96-2.13 (3 H, m), 1.78-1.83 (2 H, m), 1.14-1.66 (10 H, m), 0.77 (3 H, t).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]#[C:12][CH2:13]Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([O:9][CH2:10][C:11]#[C:12][CH2:13][N:25]1[CH2:26][CH2:27][CH:22]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][CH2:24]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(OCC#CCBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(OCC#CCN1CCC(Cc2ccccc2)CC1)c1ccccc1
Yield: 31.7 %

Procedure:
A mixture of 1-benzoyloxy-4-bromobut-2-yne (1.26 g, 5.00 mmol), 4-benzylpiperidine (0.964 g, 5.50 mmol) and K2CO3 (1.52 g, 11.0 mmol) in 50 mL of CH3CN was refluxed under N2 for 24 hr. The inorganic salt was removed through a short column of silica gel and was washed with EtOAc (3×30 mL). The filtrate was evaporated in vacuo to give a residue, which was purified by flash chromatography to give the product as a brown oil (0.55 g, 32%): 1H NMR (CDCl3) d 1.34 (m, 2 H), 1.50 (m, 1 H), 1.63 (m, 2 H), 2.11 (m, 2 H), 2.51 (d, J=6.9 Hz, 2 H), 2.78 (m, 2 H), 2.86 (d, J=11.1 Hz, 2 H), 3.31 (s, 2 H), 4.94 (s, 2 H), 7.12-7.52 (m, 8 H); MS (m/z) 348 (M++1, 20), 347 (M+, 100), 346 (M+−1, 60), 226 (30), 105 (100).
Reaction SMILES: [CH3:1][S:2]([CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([NH:15][C:16](=[O:22])OC(C)(C)C)[N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1)(=[O:4])=[O:3].N1C=CC=CC=1.ClC([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1)=O>Cl.O1CCOCC1>[CH3:1][S:2]([CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([NH:15][C:16]([C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)=[O:22])[N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)Nc1cc2c(ccn2CS(C)(=O)=O)cn1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2cc3c(ccn3CS(C)(=O)=O)cn2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 30.8 %

Procedure:
A mixture of tert-butyl 1-(methylsulfonylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamate (8D, 420 mg, 1.3 mmol) in 4M HCl in dioxane (3 ml) was stirred at 50° C. for 3 h. The mixture was concentrated in vacuo and the resulting residue was dissolved in pyridine (3 ml, 37.1 mmol). To the mixture, methyl 4-(chlorocarbonyl)benzoate (385 mg, 1.936 mmol) was added and stirred at room temperature for 3 h. The mixture was extracted with EtOAc/H2O. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by chromatography (NH—SiO2, EtOAc) to give methyl 4-(1-(methylsulfonylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamoyl)benzoate (8E, 160 mg, 0.40 mmol, 31% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.02 (s, 3H) 3.90 (s, 3H) 5.88 (s, 2H) 6.73 (d, J=2.78 Hz, 1H) 7.49 (d, J=3.28 Hz, 1H) 8.01-8.12 (m, 2H) 8.12-8.19 (m, 2H) 8.46 (s, 1H) 8.70 (s, 1H) 10.93 (s, 1H).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:22])[CH3:21])[CH:17]=2)[N:12]=[C:11]([CH3:23])[CH:10]=1>C1(C)C=CC=CC=1>[CH3:5][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:22])[CH3:21])[CH:17]=2)[N:12]=[C:11]([CH3:23])[CH:10]=1
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)Nc1ccc2nc(C)cc(O)c2c1
Solvent: Cc1ccccc1
Product: COc1cc(C)nc2ccc(NC(C)=O)cc12
Temperature: 25 °C

Procedure:
Dimethyl sulfate (294 g, 2.33 mol) was charged to a suspension of hydroxyquinoline 4 (287 g, 1.33 mol) in toluene (1.5 L) and the mixture was refluxed for 6 h. After cooling to ambient temperature, the resulting dark yellow solids were collected by filtration and washed with toluene. The dry solid was dissolved in water (2.5 L) and the pH adjusted to 14 using 35% aqueous NaOH (290 g). The resulting tan precipitate was collected by filtration, washed with copious amounts of water and dried in vacuo at 60° C. to give methoxyquinoline 5 as light tan solid (259 g, 85% yield); 1H NMR (DMSO) δ 10.18 (s, 1H), 8.46 (s, 1H), 7.76 (m, 2H), 6.84 (s, 1H), 3.99 (s, 3H), 2.55 (s, 3H), 2.09 (s, 3H); 13C NMR (DMSO) δ 168.36, 160.99, 158.07, 144.86, 135.87, 128.27, 122.78, 119.26, 108.80, 101.20, 55.69, 25.08, 23.97.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:17])[CH2:14][CH2:15]2)=[CH:3][C:2]=1[NH:1][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1Nc1ccccc1
Reaction time: 12 h
Yield: 80.7 %

Procedure:
To a stirred solution of (4-(3-amino-4-methoxyphenyl)piperazin-1-yl) (phenyl)methanone (2 g, 6.4 mmol) and phenylboronic acid (2.34 g, 19.2 mmol) in DCM (100 mL) was added triethylamine (2.7 mL, 19.2 mmol) and Cu(OAc)2 (1.74 g, 9.6 mmol). The mixture was stirred for 12 h. It was then filtered through celite, evaporated under vacuum. Flash column chromatography gave (4-(4-methoxy-3-(phenylamino) phenyl)piperazin-1-yl)(phenyl)methanone (2.0 g), 80% yield. 1H NMR (500 MHz, CDCl3): δ 3.0 (bs, 2H), 3.15 (bs, 2H), 3.59 (bs, 2H), 3.89 (s, 3H), 3.95 (bs, 2H), 6.18 (s, 1H), 6.46 (dd, J=2.5, 3 Hz 1H), 6.85 (d, J=9 Hz, 1H), 7.01 (m, 2H), 7.19 (d, J=7.5 Hz, 2H), 7.34 (m, 2H), 7.49 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:24]1[CH2:25][O:26][CH2:27][CH:28]=1)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:24]3[CH2:25][O:26][CH2:27][CH:28]=3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOC1
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3=CCOC3)cc2C1

Procedure:
Prepared in analogy to Example A49(a) from 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and tributyl-(2,5-dihydro-furan-3-yl)-stannane. Off-white solid. MS (m/e): 268.3 ([{37Cl} M+H−Me2C═CH2]+, 32%), 266.1 ([{35Cl}M+H−Me2C═CH2]+, 100%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:17])[CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Tl].I[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]>C(Cl)(Cl)Cl>[CH3:23][CH:22]([CH3:24])[CH2:21][CH2:20][O:1][C:2]1[C:7]2[C:8](=[O:17])[CH:9]=[C:10]([C:12]([OH:14])=[O:13])[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCI
Reactant: CCOC(=O)c1cc(=O)c2c(O)cccc2o1
Agent: [Tl]
Solvent: ClC(Cl)Cl
Product: CC(C)CCOc1cccc2oc(C(=O)O)cc(=O)c12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A stirred mixture of 21.67 parts of ethyl 5-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate, thallium salt and 99 parts of 1-iodo-3-methylbutane was refluxed for one hour. After cooling, chloroform was added to the reaction mixture and the insoluble thallium salts were removed by filtration. The chloroform filtrate was washed with cold N sodium hydroxide solution, then washed with water and the volatile components were removed by evaporation. Sodiumbicarbonte soluton was added to the oily residue obtained and the mixture was stirred at 100° C for 2 hours. After cooling, the solution ws extracted with chloroform and the aqueous layer was separated. This aqueous extract was acidified with 2H hydrochloric acid and the solid which precipitated was collected by filtration, washed with water and dried to give 6.16 parts of 5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid, m.p. 181°-183° C (after crystallistion from ethyl acetate/light petroleum.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH3:3].S(Cl)([Cl:23])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([Cl:23])=[O:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCCOC[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCOC[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1

Procedure:
4-(Trans-4-(propoxymethyl)cyclohexyl)benzoic acid (2.0 g, 7.2 mmol) was mixed with thionyl chloride (1.3 g, 10.9 mmol), pyridine (0.1 ml) and toluene (4 ml), followed by reacting them at 80° C. for 2 hours, and distilling off superfluous thionyl chloride and toluene under reduced pressure, to obtain raw 4-(trans-4-(propoxymethyl)cyclohexyl) benzoyl chloride.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11](=[O:19])[CH:12]=[C:13]([CH2:17]Cl)[N:14]([CH3:16])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:20][C@H:21]([C:23]([NH:25][CH3:26])=[O:24])[CH3:22].Cl.C(N(C(C)C)CC)(C)C>CC#N>[CH2:2]([O:9][C:10]1[C:11](=[O:19])[CH:12]=[C:13]([CH2:17][NH:20][C@@H:21]([CH3:22])[C:23]([NH:25][CH3:26])=[O:24])[N:14]([CH3:16])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cn1cc(OCc2ccccc2)c(=O)cc1CCl
Reactant: CNC(=O)[C@H](C)N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNC(=O)[C@H](C)NCc1cc(=O)c(OCc2ccccc2)cn1C
Temperature: 85 °C
Yield: 87.1 %

Procedure:
A mixture of 5-(benzyloxy)-2-(chloromethyl)-1-methylpyridin-4(1H)-one hydrochloride (7.55 g, 25.0 mmol), H-Ala-NHMe.HCl (5.14 g, 37.0 mmol) and diisopropylethylamine (12.5 mL, 72.0 mmol) in CH3CN (50 mL) was heated at 85° C. under a nitrogen atmosphere for overnight. Volatiles were removed in vacuo, and the residue was pre-purified by column chromatography on silica gel using a mixture of MeOH and ethyl acetate as eluant (solvent gradient of 10, 15 and 20% MeOH in ethyl acetate). The fractions rich in product were combined and evaporated to dryness. Further purification by column chromatography on silica gel using a mixture of H2O and CH3CN (1-5% H2O content) and then a 10% MeOH in dichloromethane solution afforded (S)-2-((5-(benzyloxy)-1-methyl-4-oxo-1,4-dihydropyridin-2-yl)methylamino)-N-methylpropanamide (7.17 g) in 87% yield. MS m/z 352 [M+Na]+, 330 (100%) [M+1]+, 228, 138, 91.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:13]([N:21]=[C:22]=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:13]([NH:21][C:22](=[S:23])[NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCNC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To an ice cold solution of tert-butyl 3-aminopropylcarbamate (3.56 g, 20.43 mmol) in CH2Cl2 (80 mL) is added dropwise benzoyl isothiocyanate (3.50 g, 21.45 mmol). The reaction mixture is stirred at room temp for 2 h after which the solvent is removed in vacuo. The resulting residue is partitioned with CH2Cl2 and water, the water layer is extracted with CH2Cl2, the organic layers are combined, washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give 6.89 g (quantitative yield) of the title compound. LC/MS (Condition A): ret. T=3.56 min, (M+H)+ 338.26.
Reaction SMILES: [O-]CC.[Na+].C1(C)C=CC=CC=1.C([O:14][C:15](=[O:31])[CH2:16][C:17](=[N:24][N:25]1[CH2:29][CH2:28][CH2:27][C:26]1=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)C.Cl>O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[C:16]([C:15]([OH:14])=[O:31])=[C:29]2[CH2:28][CH2:27][CH2:26][N:25]2[N:24]=1
Reactant: CCOC(=O)CC(=NN1CCCC1=O)c1ccccn1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1c(-c2ccccn2)nn2c1CCC2
Temperature: 100 °C
Yield: 93.2 %

Procedure:
Add sodium ethoxide (145 g, 2.03 mol), followed by toluene (7 L) and 3-(2-oxo-pyrrolidin-1-ylimino)-3-(pyridin-2-yl)-propionic acid ethyl ester (Preparation 3, Part B; 280 g, 1.02 mol) to a 22 L flask equipped with mechanical stirrer, nitrogen inlet and a reflux condenser. Heat the mixture at 100° C. for 21 h. Cool to room temperature, add water (6 L), and adjust to pH 5 with concentrated hydrochloric acid. Separate the organic layer and extract the aqueous layer with 10% isopropyl alcohol in chloroform (2×9 L). Combine the organic layers, dry (sodium sulfate), filter, and concentrate in vacuo to yield 218 g (93%) of the title compound as a yellow solid MS (ES) m/z=230 (M+H).
Reaction SMILES: [CH:1]1([N:4]2[C:8](=[O:9])[N:7]([CH2:10][C:11]3[C:12]([Cl:21])=[C:13]([CH:17]=[CH:18][C:19]=3[Cl:20])[C:14](Cl)=[O:15])[N:6]=[N:5]2)[CH2:3][CH2:2]1.[CH2:22]([N:24]1[C:28]([OH:29])=[CH:27][CH:26]=[N:25]1)[CH3:23].C(N(CC)CC)C>ClCCCl>[CH:1]1([N:4]2[C:8](=[O:9])[N:7]([CH2:10][C:11]3[C:12]([Cl:21])=[C:13]([CH:17]=[CH:18][C:19]=3[Cl:20])[C:14]([C:27]3[CH:26]=[N:25][N:24]([CH2:22][CH3:23])[C:28]=3[OH:29])=[O:15])[N:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc(Cl)c(Cn2nnn(C3CC3)c2=O)c1Cl
Reactant: CCn1nccc1O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCn1ncc(C(=O)c2ccc(Cl)c(Cn3nnn(C4CC4)c3=O)c2Cl)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.6 %

Procedure:
A 1,2-dichloroethane solution of 3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorobenzoyl chloride (0.70 g) was added drop by drop to the solution of 1-ethyl-5-hydroxypyrazole (0.24 g) and triethylamine (0.24 g) in 1,2-dichloroethane (4 ml) at 5° C. and the mixture was stirred at room temperature for 6 hours. After reaction it was extracted with dichloromethane (100 ml), washed with diluted hydrochloric acid and aqueous solution of sodium hydrogen carbonate and then dried with anhydrous magnesium sulfate. The residue, obtained by distilling off the solvent, was dissolved in 1,4-dioxane (8 ml), added with potassium carbonate (0.38 g) and refluxed by heating for 3 hours. After the solvent was distilled off, the residue was teated with an aqueous solution of potassium carbonate and washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate (150 ml). The organic layer was washed with saturated salt water and dried with anhydrous magnesium sulfate. By distilling off the ethyl acetate, the objective 4-{3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorobenzoyl}-5-hydroxy-1-ethylpyrazole (0.73 g, 88% yield from 3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorobenzoic acid) was obtained. nD20: 1.5510.