Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH:22]([O:23][CH2:24][CH3:25])[CH2:21][CH2:20][C:19]2=[O:26])(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH:22]([O:23][CH2:24][CH3:25])[CH2:21][CH2:20][C:19]2=[O:26])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CCOC1CCC(=O)N1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Solvent: CCO
Product: CCOC1CCC(=O)N1S(=O)(=O)c1ccc(O)cc1
Yield: 52.2 %

Procedure:
At 20° C., and under 1000 mbar, 6.3 g of 1-(4-benzyloxyphenylsulphonyl)-5-ethoxypyrrolidin-2-one is hydrogenated in the presence of 1.2 g of catalyst (Pd at 10%), in 150 cm3 of 96° ethanol. After filtering, concentrating the filtrate, and crystallizing the residue from 96° ethanol, 2.5 g of the expected product is obtained, m.p. 162°-163° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[N:9][OH:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:19]([N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])[CH2:20][C:21]#[CH:22]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[C:21]([CH2:20][CH2:19][N:23]3[C:27](=[O:28])[C:26]4[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:24]3=[O:33])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: ON=C(Cl)c1ccc(F)cc1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCc1cc(-c2ccc(F)cc2)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.9 %

Procedure:
Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride (31 g, 180 mmol), prepared as described in Parts A through C of Example 11, was added dropwise to a solution of anhydrous triethylamine (19 mL, 210 mmol) and N-(3-butynyl)phthalimide (19.04 g, 95.58 mmol) in dichloromethane (1 L). The reaction was stirred at room temperature for 24 hours and then diluted with dichloromethane, washed sequentially with aqueous potassium carbonate, water, and brine; dried over potassium sulfate; filtered; and concentrated under reduced pressure. The resulting solid was triturated with ethanol, isolated by filtration, and washed with diethyl ether to provide 29.87 g of 2-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-1H-isoindole-1,3(2H)-dione. A portion of the product was recrystallized from isopropyl alcohol and dried to provide an analytically pure sample as white crystals, mp 155.0-156.0° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CC#N.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:22][CH:19]2[CH2:21][CH2:20]2)[CH2:15][CH2:16][O:17][CH3:18])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COCCN(CC1CC1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of 4-(2-methoxy-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (525 mg), cyclopropylmethyl bromide (218 μL) and potassium carbonate (340 mg) was heated to reflux in MeCN for 16 h. After cooling the reaction mixture was diluted with chloroform, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-[cyclopropylmethyl-(2-methoxy-ethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (475 mg). Removal of the BOC group with HCl yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:29](OCC)C.[H-].[Na+].CI>C1COCC1>[CH3:29][N:12]1[CH:13]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:4]=2)[N:10]=[C:11]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cc(-c2cccc(C(F)(F)F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Add tert-butyl 4-(4-(3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (540 mg, 1.36 mmol) to diethyl ether (100 mL) and cool to 0° C. Add sodium hydride (55 mg, 1.5 mmol, 60% in mineral oil) to the mixture followed by methyl iodide (0.142 mL, 2.72 mmol). Stir the mixture for 1 h at 0° C. and warm to room temperature. Add THF (40 mL) and stir the mixture for 12 h. Concentrate the mixture, and purify the residue by silica gel chromatography (120 g RediSep column, elute with a gradient of 0% to 100% ethyl acetate:hexane, over 40 min, 85 mL/min) to provide tert-butyl 4-(1-methyl-4-(3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (425 mg, 76%).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:11]=2)[N:6]=[C:5]([N:20]2[CH:24]=[C:23]([C:25]([O:27]CC)=[O:26])[CH:22]=[N:21]2)[N:4]=1.[OH-].[K+]>C1COCC1>[CH3:1][N:2]([CH3:30])[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][CH:11]=2)[N:6]=[C:5]([N:20]2[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[CH:22]=[N:21]2)[N:4]=1
Reactant: CCOC(=O)c1cnn(-c2nc(N(C)C)c3ccc(Oc4ccccc4)cc3n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(Oc3ccccc3)ccc12
Temperature: 40 °C
Yield: 65.1 %

Procedure:
A mixture of ethyl 1-(4-(dimethylamino)-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylate (35 mg, 0.09 mmol), 1M aqueous KOH (0.43 mL, 0.43 mmol), and THF (1.3 mL) was heated to 40° C. for 48 h with rapid stirring. The mixture was then concentrated, cooled in an ice bath, and 1M aqueous HCl was added until the mixture was slightly acidic (pH ca 5-6). The resulting precipitate was collected by filtration, washed with water, and dried to furnish the titled compound (22 mg, 68%). MS (ESI): mass calcd. for C20H17N5O3, 375.1; m/z found, 376.3 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 12.73 (s, 1H), 8.98 (d, J=0.6 Hz, 1H), 8.31 (d, J=9.3 Hz, 1H), 8.07 (s, 1H), 7.52 (ddd, J=7.6, 5.9, 2.2 Hz, 2H), 7.36-7.28 (m, 1H), 7.28-7.20 (m, 2H), 7.17 (dd, J=9.3, 2.7 Hz, 1H), 6.97 (d, J=2.7 Hz, 1H), 3.46 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:29][NH:30][CH3:31].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:29][N:30]([CH3:31])[C:25]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([C:14]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:24])[CH:11]=1)=[O:26]
Reactant: CNC
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) were added dimethylamine hydrochloride (60 mg, 0.74 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.87 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction solution was purified by preparative HPLC to afford the final product as a light brown solid.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:14](Br)([CH3:16])[CH3:15]>>[CH3:15][CH:14]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH3:16]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CC(C)Br
Product: CC(C)n1c2ccccc2c2ccccc21

Procedure:
Carbazole (5 g; 0.03 mol) was reacted with isopropyl bromide (5.61 ml; 0.06 mol) by working in a manner similar to that described in Example 1a).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][C:13]3[N:17]4[N:18]=[C:19]([C:22]#[N:23])[CH:20]=[CH:21][C:16]4=[N:15][CH:14]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][C:13]3[N:17]4[N:18]=[C:19]([C:22]#[N:23])[CH:20]=[CH:21][C:16]4=[N:15][CH:14]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)=[O:32]
Reactant: CSc1nc2ccc(Cc3cnc4ccc(C#N)nn34)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cc3cnc4ccc(C#N)nn34)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a solution of 3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile (0.7 g, 2.1 mmol) in DCM (30 mL) at 0° C. was slowly added m-CPBA (0.4 g, 2.1 mmol). The reaction mixture was stirred at 0° C. for 2 h, then aq Na2SO3 (25 mL) was added and the mixture was stirred for 0.5 h. The organic layer was separated and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile as a yellow solid (0.7 g, 96%). 1H NMR (300 MHz, CDCl3) δ 8.11 (d, J=9.3 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31 (d, J=9.3 Hz, 1H), 4.54 (s, 2H), 3.07 (s, 3H). LCMS (ESI) m/z 354 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[Cl:27]N1C(C)(C)C(=O)N(Cl)C1=O.[OH-].[Na+]>O1CCCC1.CCCCC>[Cl:27][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Br)nc2)CC1
Agent: [Li]C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)nc2)CC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 1-(6-Bromo-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine (3.6 g, 10 mmol) in tetrahydrofuran (200 ml) was cooled to −78° C. Tert-butyllithium (14.7 ml, 1.5 M) in pentane was added during 10 min, followed by stirring for 5 min at −78° C. 1,3-Dichloro-5,5-dimethylhydantoin (1.97 g, 10 mmol) was added in small portions. The mixture was stirred for 0.5 min. Aqueous sodium hydroxide was added (100 ml, 4 M), and the reaction was allowed reach room temperature. The mixture was extracted twice with diethyl ether (100 ml) Chromatography on silica gel with a mixture of petroleum:ethyl acetate (1:1) gave the title compound as free base. Yield 1.7 g, 55%.
Reaction SMILES: [CH3:1][N:2]1[S:6](=[O:8])(=[O:7])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.C(O)C.C(OCC)(=O)C.[ClH:28]>[Pd].O>[ClH:28].[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[S:6]2(=[O:8])=[O:7])=[CH:15][CH:14]=1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)S1(=O)=O
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CN1CCN(Cc2ccc(N)cc2)S1(=O)=O
Yield: 99.5 %

Procedure:
A suspension of the product from Step 1 (20 g, 74.72 mmol) in a mixture of absolute ethanol (300 ml), ethyl acetate (150 ml), 2N hydrochloric acid (39 ml) and water (25 ml), was hydrogenated at 30 psi for 7 minutes over 10% palladium on carbon (2 g). The catalyst was removed by filtration, washed with ethanol (2×30 ml) and solvents were removed under vacuum. The remaining residue was azeotropically dried with absolute ethanol (1×150 ml) and further dried at high vacuum to give 20.36 g (99.5%) of the required title compound as a white solid. A sample recrystallised from absolute ethanol showed: mp 153°-156° C. (white needles); δH (250 MHz, DMSO-d6) 7.42 (2H, d, J=8.4 Hz, Ar--H), 7.29 (2H, d, J=8.4 Hz, Ar--H), 4.15 (2H, s, Ar--CH2 --N), 3.27--3.17 (4H, m, N--CH2CH2 --N), 2.62 (3H, s, --NMe); m/z (CI) 240 (M+ -1).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21])([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1.CO>C(Cl)Cl.CN(C)C=O>[C:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:17][CH3:1])=[O:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(C(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.8 %

Procedure:
13 ml (0.15 mol) of oxalyl chloride were added, with ice-cooling, to a solution of 20.9 g (0.094 mol) of 4-t-butyl-3-nitrobenzoic acid in 200 ml of methylene chloride, and then 0.3 ml of dimethylformamide was added to the resulting mixture. After this addition, the temperature of the reaction mixture was allowed to rise to room temperature, and the mixture was then stirred at room temperature for 4 hours. At the end of this time, any excess of the reagent and the solvent were removed by distillation under reduced pressure, and the residue was again dissolved in 150 ml of methylene chloride. 19 ml (0.25 mol) of pyridine and 6.0 ml (0.15 mol) of methanol were then added, with ice-cooling, to the solution, and the resulting mixture was stirred for 30 minutes with ice-cooling and then at room temperature for 30 minutes. At the end of this time, the reaction was quenched by adding water, the solvent was removed by distillation under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with 2 N aqueous hydrochloric acid, with water, with a saturated aqueous solution of sodium hydrogencarbonate and with water, in that order, and the solvent was removed by distillation under reduced pressure, to give 22.7 g of the title compound as an oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:16])[CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl.[Ag]=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:16])[CH2:14][O:15][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)CO)C1
Reactant: BrCc1ccccc1
Agent: O=[Ag]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)COCc2ccccc2)C1
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a solution of (S)-3-((S)-1,2-dihydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (294.0 mg, 1.3 mmol) in DCM (6.3 mL) at room temperature, was added benzyl bromide (181.4 μL, 1525 μmol) followed by silver(II) oxide (472.4 mg, 3.8 mmol). The resulting mixture was stirred overnight. The mixture was filtered and the filtrate was subjected to same amount of silver (II) oxide and benzyl bromide and stirred overnight. The mixture was concentrated and the residue was purified by flash chromatography (12 g silica gel, 0-50% EtOAc/Hexanes). Desired fractions were combined and concentrated to yield the title compound as a colorless oil (165.6 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[C:4]([N+:22]([O-])=O)[CH:3]=1.O.NN>C(O)C.[Ni]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH2:12][CH2:11]2)=[C:4]([NH2:22])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
N-(4,5-Dichloro-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D38) (320 mg) was dissolved in ethanol (20 ml) and Raney nickel (50% aqueous suspension, 0.5 ml) was added at room temperature; the mixture was heated to 40° C. and hydrazine monohydrate (0.4 ml) was added over 20 min. After 30 min more, the reaction mixture was cooled to room temperature, filtered through Celite and the solvent was evaporated. Chromatography on silica gel eluting with methanol-dichloromethane mixtures yielded the title compound, 150 mg.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH3:7][N:8]([CH3:13])[S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>ClCCl>[CH3:7][N:8]([CH3:13])[S:9]([N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1])(=[O:11])=[O:10]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1ncc[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nccn1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution of 2-methyl-1H-imidazole (10 g, 121.8 mmol) in dichloromethane (100 mL) was added N,N-dimethylsulfamoyl chloride (14.4 mL, 133.7 mmol) and triethylamine (34 mL, 244.1 mmol). The reaction mixture was stirred overnight at room temperature, then quenched with 10 mL of water and extracted with 1×50 mL of DCM. The organic layer was washed with 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2) as the eluent to furnish 20 g (87%) of the title compound as a yellow oil.
Reaction SMILES: C1([C@@H](N[C:10](=[O:39])[CH2:11][C@H:12]([OH:38])[CH2:13][C@H:14]([OH:37])/[CH:15]=[CH:16]/[C:17]2[C:18]([CH:34]3[CH2:36][CH2:35]3)=[N:19][C:20]3[C:25]([C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)C)C=CC=CC=1.[OH2:40].[OH-].[Na+].Cl>C(O)C>[CH:34]1([C:18]2[C:17](/[CH:16]=[CH:15]/[C@@H:14]([OH:37])[CH2:13][C@@H:12]([OH:38])[CH2:11][C:10]([OH:39])=[O:40])=[C:26]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:36][CH2:35]1
Reactant: O
Reactant: C[C@H](NC(=O)C[C@H](O)C[C@H](O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C[C@H](O)C[C@H](O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 52.5 °C
Reaction time: 0.25 h

Procedure:
(E)-(3R,5S)-7-[2-Cyclopropyl-4-(4-fluoro-phenyl)quinolin-3-yl]-3,5-dihydroxy-hept-6-enoic acid ((S)-1-phenyl-ethyl)-amide (4.0 g, 6.53 mmol) is dissolved in ethanol (40 mL). Water (40 mL) and sodium hydroxide powder (2.64 g, 66 mmol) are added and the mixture is heated at 50-55° C. for 26 h, until an in-process control (HPLC) indicated complete conversion. Hydrochloric acid (59 mL of a 1M solution, 59 mmol) is added slowly over a time period of 15 minutes. The solvent is distilled under reduced pressure and the residue is dissolved in water (80 mL). The water solution is extracted with tert-butyl-methyl ether (3×80 mL) and the organic phase is removed. The water phase is evaporated under reduced pressure and the residue is re-dissolved in water (176 mL). Hydrochloric acid (6.53 mL of a 1M solution, 6.53 mmol) is added to precipitate the acid, followed by the addition of ethyl acetate (176 mL). The mixture is stirred for 15 min. and the layers are separated. The organic layer is washed with water (90 mL). Charcoal (0.5 g) is added to the organic layer and the mixture is stirred at 30-35° C. for several hours. Filter-aid (Cellflock, 1.0 g) is added and stirring is continued for additional 30 min. The charcoal is removed by filtration on a filter-aid to obtain a clear solution and the solvent is evaporated at 30-35° C. under reduced pressure, to obtain (E)-(3R,5S)-7-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoic acid as a white solid. For the formation of the calcium salt, the acid (2.55 g, 6.05 mmol) is suspended in water (40.5 mL) and sodium hydroxide (0.260 g, 6.5 mmol) is added to obtain a clear solution of the corresponding sodium salt. A solution of calcium chloride (0.399 g, 3.49 mmol) in water (2 mL) is added dropwise to the solution of the sodium salt. A suspension is formed immediately upon addition of calcium chloride. The suspension is stirred for 4 hours at 20-25° C. and for 2 hours at 15-17° C. The product is isolated by filtration, the filter cake is washed with cold water and dried in vacuo at 20-25° C. to obtain
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:18])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([OH:15])[C:7]=1[CH:16]=[O:17])[CH:2]=[CH2:3].[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:4][C:5](=[O:18])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25])[C:7]=1[CH:16]=[O:17])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCOC(=O)c1c(C)c(OC)cc(O)c1C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
To a solution of 15 g of 2-formyl-3-hydroxy -5-methoxy-6-methylbenzoic acid allyl ester in 0.12 l of N,N-dimethylformamide were added 13.8 g of tert-butyl-dimethylchlorosilane and 12.0 g of triethylamine. The mixture was stirred for 3 h at room temperature and then evaporated in vacuo. The residue was taken up in 0.4 l of ethyl acetate and the solution was washed successively with 1N hydrochloric acid, water and brine. The organic layer was dried over sodium sulfate. The solvent was evaporated in vacuo and the solid residue was recrystallized from hexane to give 20.5 g of 2-formyl-3-(tert-butyl-dimethylsilanyloxy)-5-methoxy-6-methylbenzoic acid allyl ester as white crystals of m.p. 94°-95° C.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[CH2:29][CH:30]([CH3:32])[CH3:31]>CN(C=O)C>[CH3:31][CH:30]([CH3:32])[CH2:29][CH2:28][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 80 °C
Yield: 71.8 %

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 50.7 mg, 0.18 mmol), K2CO3 (49.5 mg, 0.36 mmol), and isoamyl bromide (32 uL, 0.27 mmol) in DMF (1.0 mL). Heat at 80° C. for 6 hours. Pass through an SCX column, washing with methanol and then eluting with 2.0 M NH3 in MeOH. Concentrate the eluant and purify by flash chromatography, eluting with 70:22:8 EtOAc/CH2Cl2/2.0 M NH3 in MeOH to afford the title compound (45.7 mg, 72%): MS ES+ 354.0 (M+H)+, HRMS calcd for C21H28N3O2 354.2182 (M+H)+, found 354.2182, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.39 min, 100% purity; Anal. Calcd for C21H27N3O2.0.2CH2Cl2.0.1MeOH: C, 69.59; H, 5.98; N, 11.43. Found: C, 69.47; H, 6.25; N, 11.30.