Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(C)(C)C.[K+].[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Br[C:19]1[C:20](=[O:37])[N:21]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:26]=2[CH2:34][O:35][CH3:36])[CH:22]=[CH:23][CH:24]=1>O1CCOCC1.C(OCC)(=O)C.Cl>[CH2:16]([O:15][C:7](=[O:14])[CH:8]([C:19]1[C:20](=[O:37])[N:21]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:26]=2[CH2:34][O:35][CH3:36])[CH:22]=[CH:23][CH:24]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:17]
Reactant: COCc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1cccn(-c2ccc([N+](=O)[O-])cc2COC)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, a suspension of 49.3 g (513 mmol) of potassium tert-butanolate was introduced as initial charge at RT in 360 ml of dioxane, and 82.2 g (513 mmol) of diethyl malonate were added such that the temperature remained below 30° C. The reaction mixture was stirred for 1 h at RT, 3.4 g (11.0 mmol) of bis(2-pyridinecarboxylato)copper(II) complex and 49.7 g (147 mmol) of 3-bromo-1-[2-(methoxymethyl)-4-nitrophenyl]pyridin-2(1H)-one were added and the mixture was stirred for 4.5 h at 95° C. A further 2.0 g (6.5 mmol) of bis(2-pyridinecarboxylato)copper(II) complex were added and the reaction mixture was stirred overnight at 95° C. After cooling to RT, the mixture was diluted with 0.9 l of ethyl acetate, 1.8 l of 3N hydrochloric acid were added and the mixture was stirred for 15 min at RT. The aqueous phase was extracted with 0.9 l of ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution. After drying over sodium sulphate, filtration and removal of the solvent on a rotary evaporator, the residue was dried in vacuo. This gave 115 g of crude product, which was reacted further without purification.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2cc(F)cc(F)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (66 mg, 82%), MS (ISN) m/z=324.5 [(M+H)+], mp 264° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 3,5-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]#[N:19].[OH-:20].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]([NH2:19])=[O:20]
Reactant: [OH-]
Reactant: CC(C)c1nn(-c2c(Cl)cccc2Cl)c(N)c1C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)c1nn(-c2c(Cl)cccc2Cl)c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
5-Amino-1-(2,6-dichlorophenyl)-3-isopropyl-1H-pyrazole-4-carbonitrile (15 g, 50 mmol) was taken up in conc. H2SO4 (45 mL) and stirred at room temp for 16 h. The reaction was then poured onto 3 N NaOH (850 mL) at 0° C. The resulting solid was then filtered and washed with H2O (1 L). The product was then dried under vacuum to yield the desired amide (14 g, 88%).
Reaction SMILES: [CH2:1]([O:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:7]1(/[CH:30]=[CH:31]/[C:32]([OH:34])=O)[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4].Cl.C([N:38]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[CH2:1]([O:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][CH:18]2[CH2:19][CH2:20]2)[C:7]1(/[CH:30]=[CH:31]/[C:32]([NH2:38])=[O:34])[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC1c2ccccc2C(=O)N(CC2CC2)C1(/C=C/C(=O)O)CNC(=O)OC(C)(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC1c2ccccc2C(=O)N(CC2CC2)C1(/C=C/C(N)=O)CNC(=O)OC(C)(C)C
Yield: 94.7 %

Procedure:
A solution of (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenic acid (0.71 g, 1.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.58 g, 3 mmol) and 1-hydroxybenzotriazole ammonium salt (0.46 g, 3 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenamide (0.67 g, 95.7%) as crystals.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20]>>[C:18]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)(=[O:21])[CH:19]=[CH2:20]
Reactant: C=CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(NCc2ccccc2)cc1
Product: C=CC(=O)N(Cc1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-benzylamino-nitrobenzene and acrylic acid chloride
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].ClCC1([C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=2[CH3:23])OCC(C)(C)CO1.[OH-].[Na+]>C(O)CO.O>[CH3:23][C:17]1[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=1[CH2:2][C:1]([OH:4])=[O:3]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(C)c(C2(CCl)OCC(C)(C)CO2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1ccc(C)c(CC(=O)O)c1
Temperature: 182.5 °C
Yield: 94.4 %

Procedure:
A mixture of 4.1 g [0.05 mol] of sodium acetate and 10.75 g [0.04 mol] of 2-chloromethyl-5,5-dimethyl-2-(2,5-dimethylphenyl)-[1,3]dioxane in 50 ml of ethylene glycol is heated at 180 to 185° C. for 5 hours. It is then allowed to cool to 90 to 95° C., 20 ml of 30% strength sodium hydroxide solution are added, and the mixture is heated at 100 to 105° C. for 1 hour. The reaction mixture is diluted with 80 ml of water at room temperature and extracted twice with 10 ml of methylene chloride each time. The aqueous phase is then adjusted to pH 1 with conc. hydrochloric acid, and the solid is filtered off with suction, washed twice with 20 ml of water each time and dried. 6.20 g of white solid are obtained with a purity of 99.3% (GC). The yield is thus 93.7% of theory.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19](C(=O)C)[CH2:18][CH2:17]4)=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.CO>Cl>[CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]4)=[CH:14][CH:15]=3)[CH2:6][CH2:7]2)[CH2:3]1
Reactant: CC(=O)N1CCN(c2ccc(N3CC[C@@H]4CN(C)C[C@@H]43)cc2)CC1
Agent: Cl
Solvent: CO
Product: CN1C[C@H]2CCN(c3ccc(N4CCNCC4)cc3)[C@H]2C1

Procedure:
The product of Example 49A (300 mg, 0.91 mmole) was dissolved in 6 ml of 2N hydrochloric acid and 3 ml of methanol and stirred at 60° C. for 3 hours. The mixture was concentrated to dryness under reduced pressure, diluted with water and extracted with dichloromethane (4×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure and purified by column chromatography (eluting with a mixture of 10% methanol and 1% ammonium hydroxide in dichloromethane) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 6.84-6.94 (m, 2H) 6.53-6.60 (m, 2H) 4.00-4.07 (m, 1H) 3.44-3.51 (m, 1H) 3.11-3.20 (m, 1H) 2.99-3.09 (m, 9H) 2.88-2.96 (m, 1H) 2.68 (dd, J=9.66, 2.54 Hz, 1H) 2.48-2.59 (m, 2H) 2.31 (s, 3H) 2.09-2.19 (m, 1H) 1.89 (m, 1H). MS: (M+H)+=287.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:33]([C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([CH3:26])[CH:28]=4)(=[O:35])=[O:34])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=O)=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].[N+:23]([CH3:26])([O-:25])=[O:24]>CCOCC>[N+:23]([CH:26]=[CH:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1)([O-:25])=[O:24]
Reactant: O=Cc1cn(-c2ccccc2)c2ccccc12
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOCC
Product: O=[N+]([O-])C=Cc1cn(-c2ccccc2)c2ccccc12

Procedure:
120 g 1-phenylindole-3-carboxaldehyde and 16.2 g ammonium acetate are heated under reflux in 406 ml nitromethane for 5 hours. The mixture is cooled, diluted with ether to give 3-(2-nitroethenyl)-1-phenylindole, m.p. 154°-155°.
Reaction SMILES: C1C[N:4]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:34]([O:38][C:39]([N:41]1[CH2:44][CH:43]([CH2:45][C:46]([OH:48])=O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C>[NH2:4][C:46](=[O:48])[CH2:45][CH:43]1[CH2:44][N:41]([C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[CH2:42]1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(CC(N)=O)C1
Yield: 57.5 %

Procedure:
PyBOP (1.946 g, 3.74 mmol) was added to a solution of [1-(tert-Butoxycarbonyl)azetidin-3-yl]acetic acid (0.805 g, 3.74 mmol) in DMF (10 mL). The mixture was stirred in an ice-bath, ammonia gas was bubbled in for 3 mins and then the mixture was stirred at rt overnight. The reaction mixture was concentrated, water (15 mL) and saturated, aqueous NaHCO3 (5 mL) were added, and the mixture was extracted with EtOAc (20 mLx3). The extracts were combined, washed with water (20 mL) and brine (10mL), dried (Na2SO4) and evaporated. Column chromatography of the residue (ISOLUTE SI, 50 g/150 ml), eluting with EtOAc and heptane (50:50), then EtOAc and then MeOH and EtOAc (1:99, 2:98 and 5:95), gave the title compound (0.461 g, 57.5%) as a white solid. 1H NMR (400 MHz, CDCl3): 1.42 (s, 9H), 2.53 (d, 2H), 2.85-2.96 (m, 1H), 3.60 (dd, 2H), 4.09 (t, 2H), 5.78 (s, br, 2H); 13C NMR (100 MHz, CDCl3): 25.4, 28.3, 39.7, 54.3 (br), 79.4, 156.3, 173.2.
Reaction SMILES: Cl[C:2](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1C=CC=CC=1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[CH2:29])=[CH:26][CH:25]=1>C(N(CC)CC)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[CH:28]([C:27]3[CH:30]=[CH:31][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH2:29][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]2)=[CH:11][CH:12]=1
Reactant: C=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cl)=NNc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C1=NN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)C1
Reaction time: 1 h

Procedure:
The compound of Example 6 (5.0 gm) was heated in refluxing benzene (30 ml) containing 4-chlorostyrene (7.0 ml). Addition of a benzene (10 ml) solution of triethylamine(7.5 ml) was followed by one hour of continued heating. The cooled mixture was filtered, rotovapped, and dried on the vacuum pump to remove excess styrene. The residual solid was recrystallized from hexane/benzene (charcoal) to give the title compound (6.3 gm); m.p.: 128° to 130° C. NMR (CDCl3) 7.3-6.9 (m, 8H, ArH), 5.4 (dd, 1H, CH), 4.3 (q, 2H, OCH2), 3.8 (m, 1H, CH), 3.0 (m, 1H, CH), 1.38 (t, 3H, CH3).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc(N)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)OCCc1ccc(NC(=O)OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
To an ethyl acetate (100 ml) suspension of 4-aminophenylethyl acetate (10 g), saturated aqueous sodium bicarbonate solution (100 ml) was added, and further, benzyloxycarbonyl chloride (12.3 ml) was added dropwise under ice-cooling. After stirring for 1 hour, hydrochloric acid was added to the reaction mixture to make it acidic, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was recrystallized from ethyl acetate-hexane, to give the titled compound (17.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:14])[CH2:5][CH:6]([CH3:13])[NH:7]2.[S:15]([N:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27](Cl)=[O:28])([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>N1C=CC=CC=1.ClCCl>[Cl:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:14])[CH2:5][CH:6]([CH3:13])[N:7]2[C:27](=[O:28])[C@@H:26]1[CH2:30][CH2:31][CH2:32][N:25]1[S:15]([C:18]1[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=1)(=[O:17])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)Cl)cc1
Reactant: CC1CC(=O)c2c(ccc(F)c2Cl)N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N2c3ccc(F)c(Cl)c3C(=O)CC2C)cc1
Reaction time: 0.33 h

Procedure:
36.7g of (+)-5-chloro-6-fluoro-2-methyl-4-oxo1,2,3,4-tetrahydroquinoline was dissolved in 34.3 g of pyridine and 400 ml of dichloromethane. Then, a solution of N-tosyl-L-prolyl chloride (prepared from 92.4 g of N-tosyl-L-proline and 74.5 ml of thionyl chloride) in 70 ml of dichloromethane was added thereto at room temperature over a period of 20 minutes. After completion of the addition, the resulting mixture was stirred for 15 minutes and then heated under reflux for 20 minutes. This reaction mixture was allowed to cool, washed successively with dilute hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water, and then dried. Thereafter, the solvent was evaporated under reduced pressure to obtain a residue comprising a mixture diastereomers of 5-chloro-6-fluoro-2-methyl-4-oxo-1-(N-tosyl-L prolyl)-1,2,3,4-tetrahydroquinoline. This residue was subjected to silica gel column chromatography using chloroform-ethyl acetate (10:1) as the eluent, and then subjected to thin-layer chromatography [using chloroform-ethyl acetate (10:1) as the developing solvent]. Fractions having an Rf value of 0.47 were collected and concentrated under reduced pressure to obtain 36.8 g of (+)-5-chloro-6-fluoro-2-methyl-4-oxo-1-(N-tosyl-L-prolyl)-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.[NH2:18][NH2:19]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:19][N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(F)c1
Reactant: NN
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccc(F)c2)n[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a solution of Intermediate 4A (100 g, 420 mmol) in ethanol (250 mL) was added hydrazine (13.83 mL, 441 mmol) in ethanol (250 mL) to give a brown solution. The reaction mixture was stirred at 80° C. for 2 h. Ethanol was removed under reduced pressure and the residue was diluted with water and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with water (2×100 mL), brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The brown solid thus obtained was purified by ISCO using 20% ethyl acetate in hexane as eluent. The combined fractions were concentrated to afford Intermediate 4B (85 g, 86%) MS(ES): m/z=233 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 14.06 (bs, 1H), 7.68-7.75 (m, 2H), 7.45-7.55 (m, 1H), 7.36 (s, 1H), 7.20 (t, J=7.53 Hz, 1H), 4.34 (q, J=7.03 Hz, 2H), 1.34 (t, J=7.03 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH2:24][CH2:25][C:26]2([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[O:31][C:30](=[O:32])[CH2:29][C:28](=[O:33])[CH2:27]2)[CH:12]=[C:13]([CH2:22][CH3:23])[C:14]=1[O:15]COCCOC>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:24][CH2:25][C:26]2([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[O:31][C:30](=[O:32])[CH2:29][C:28](=[O:33])[CH2:27]2)[CH:12]=[C:13]([CH2:22][CH3:23])[C:14]=1[OH:15]
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OCOCCOC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (0.07 mL, 0.88 mmol) was added to a solution of 6-{2-[3-Chloro-5-ethyl-4-(2-methoxy-ethoxymethoxy)-phenyl]-ethyl}-6-cyclopentyl-dihydro-pyran-2,4-dione (0.2 g, 0.44 mmol) dissolved in CH2Cl2 (4 mL). The reaction mixture was stirred for 2 hours at room temperature and then partitioned between H2O and EtOAc. The organic extracts were washed with brine, dried over Na2SO4 and concentrated to an oil. The oil was purified by flash column chromatography (0% to 30% EtOAc in hexanes) to give the title compound as a solid. (0.12 g, 75%). 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J=7.6 Hz, 3 H), 1.58–173 (br m, 8 H), 1.92 (m, 2 H), 2.26 (m, 1 H), 2.57 (m, 2 H), 2.65 (q, J=7.6 Hz, 2 H), 2.76 (s, 2 H), 3.43 (s, 2 H), 5.47 (s, 1 H), 6.81 (s, 1 H), 6.95 (s, 1 H). MS: C20H24O4Cl (M−H) 363.10.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[CH:3]=1.[CH3:10][C:11]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][Si:14]([C:11]([CH3:13])([CH3:12])[CH3:10])([CH3:16])[CH3:15])[CH:3]=1
Reactant: Cc1cc(Br)cc(O)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(O[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-6-methylpyridin-2-ol (376 mg, 2 mmol) in dry DMF (20 mL) is stirred under N2. TBDMS-Cl (600 mg, 4 mmol) is added, followed by triethylamine (0.97 mL, 7.00 mmol), and the mixture is stirred at rt for 1 h. The solution is poured into ice-water (170 mL) and extracted with diethyl ether (5×50 mL). The combined extracts are dried over Na2SO4 and the solvent is evaporated under reduced pressure. The residue is taken up in pentane (50 mL), dried over Na2SO4 and the solvent evaporated again, to afford the crude title compound as a yellow oil. This is used without further purification.
Reaction SMILES: C1(O[C:8](=[O:24])[NH:9][C:10]2[S:14][N:13]=[C:12]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:11]=2[C:21](=[O:23])[NH2:22])C=CC=CC=1.[NH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.[OH-].[Na+]>O1CCCC1>[CH2:16]([S:15][C:12]1[C:11]([C:21]([NH2:22])=[O:23])=[C:10]([NH:9][C:8]([NH:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:24])[S:14][N:13]=1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: NCCCN1CCCC1
Reactant: CCCCCSc1nsc(NC(=O)Oc2ccccc2)c1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCSc1nsc(NC(=O)NCCCN2CCCC2)c1C(N)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.4 %

Procedure:
To a mixture of (4-carbamoyl-3-pentylsulfanyl-isothiazol-5-yl)-carbamic acid phenyl ester (0.10 g, 0.27 mmol) and 1 mL of tetrahydrofuran was added N-3-aminopropylpyrollidine (0.175 g, 1.4 mmol). After stirring for 72 hours at ambient temperature, the mixture was poured into 1M NaOH, extracted twice with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated. Purification of the residue by radial chromatography (2 mm plate, 3% ethanol-CH2Cl2−30% ethanol-CH2Cl2 containing 0.5% NH4OH), followed by concentration and trituration of the residue with ether-hexane afforded 0.076 g (78%) of 3-pentylsulfanyl-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylic acid amide as a colorless solid 1H NMR (400 MHz, CDCl3) δ 7.57 (bs, 1H), 7.06 (bs, 2H), 3.35 (m, 2H), 3.26(m, 2H), 2.53 (t, 2H, J=6.8 Hz), 2.47(m, 4H), 1.73 (m, 8H), 1.4-1.2 (m, 4H), 0.88 (t, 3H, J=7.2 Hz) ppm; MS (APCl, m/z): 400 [M+H]+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[C:9](=[CH:10][C:11]([Br:19])=[CH:12][CH:13]=2)[CH:8]=1)=[O:6]>O.C(O)C>[Br:19][C:11]1[CH:10]=[C:9]2[C:14]([CH:15]=[C:16]([O:17][CH3:18])[C:7]([C:5]([OH:6])=[O:4])=[CH:8]2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc2cc(Br)ccc2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc2ccc(Br)cc2cc1C(=O)O
Yield: 94.8 %

Procedure:
A solution of sodium hydroxide (1.6 g, 40 mmol) in water (30 mL) was added to a solution of 7-bromo-3-methoxy-naphthalene-2-carboxylic acid methyl ester (5.9 g, 20 mmol) in ethanol (100 mL) and the resulting mixture was heated at reflux for 2 hours. The reaction mixture was then cooled and concentrated under reduced pressure. The residue was acidified until pH 3 ca. by addition of an aqueous solution of hydrochloric acid. The resulting mixture was extracted twice with dichloromethane and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 5.329 g of 7-bromo-3-methoxy-naphthalene-2-carboxylic acid as a cream colored solid.