Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:12][CH:13]=C)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=C.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH2:21][CH:20]([NH2:25])[CH2:19]2.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH2:21][CH:20]([N:25]1[CH2:2][CH2:1][N:4]([C:5]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:11])[CH2:12][CH2:13]1)[CH2:19]2
Reactant: NC1Cc2ccc(Br)cc2C1
Reactant: C=CCN(CC=C)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C2Cc3ccc(Br)cc3C2)CC1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
In a 100 mL round bottom flask, tert-butyl di(prop-2-en-1-yl)carbamate (0.74 mL, 3.4 mmol) was dissolved in dichloromethane (10 mL). The solution was cooled to −78° C. To above solution was bubbled ozone for 15 min. The solution turned into light blue and the color stayed. To above solution was bubbled nitrogen to remove excess ozone until the solution turned into colorless. To above solution was added (5-bromo-2,3-dihydro-1H-inden-2-amine (1.0 g, 3.4 mmol), triethylamine (0.48 mL, 3.4 mmol) followed by sodium triacetoxyborohydride (4.3 g, 20 mmol). The reaction was allowed to warm up to room temperature and stirred at this temperature overnight. HPLC-MS showed product was formed as major peak. To above solution was added water (5 mL), extracted with dichloromethane (10 mL×3). The organic phase was dried over MgSO4, filtered and concentrated. The product was obtained as white solid after purification by flash column chromatography. LC-MS (IE, m/z): 381.2 [M+1]+. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.30 (1H, s), 7.25 (d, J=8.0 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 2.0-4.0 (m, 13H), 1.5 (s, 9H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)C=O>[C:8]1([S:14]([N:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cccc1
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To a suspension of 1.056 g of prewashed sodium hydride in 50 ml of dimethylformamide at 0° C. was added dropwise a solution of 1.34 g of pyrrole in 50 ml of dimethylformamide. The mixture was stirred for 30 minutes, then a solution of 3.89 g of benzenesulfonyl chloride in dimethylformamide was added. This mixture was stirred at room temperature for 18 hours, then slowly quenched with water and extracted several times with ether. The extracts were combined, washed with water, dried and evaporated, giving 2.9 g of 1-(phenylsulfonyl)-1H-pyrrole.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:11](=[O:12])[C:10](Br)=[C:9]([CH3:14])[N:8]([CH:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH3:16])[CH:7]=1)=[O:5])[CH3:2].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CO>[CH2:1]([NH:3][C:4]([C:6]1[C:11](=[O:12])[C:10]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=2)=[C:9]([CH3:14])[N:8]([CH:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH3:16])[CH:7]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCNC(=O)c1cn(C(C)c2ccc(C#N)cc2)c(C)c(Br)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: CCNC(=O)c1cn(C(C)c2ccc(C#N)cc2)c(C)c(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 75 °C
Reaction time: 24 h

Procedure:
To a solution of 5-bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid ethylamide (preparation 10, 50 mg, 0.129 mmol), 3-trifluoromethyl-phenylboronic acid (29 mg, 0.155 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 0.012 mmol) in acetonitrile (1 mL) is added 2 M aqueous K2CO3 solution (0.20 mL, 0.40 mmol). After stirring for 24 h at 75° C., the reaction mixture is diluted with methanol and purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.1% NH4OH, 60° C.). Yield: 56 mg (96% of theory); ESI mass spectrum: [M+H]+=454; Retention time HPLC: 0.93 min (Z011_S03).
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:5]1=[O:34].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:6]([C@@H:24]([CH2:32][CH3:33])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:5](=[O:34])[C@:4]([CH2:3][C:2]#[N:1])([CH3:35])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@@](C)(CC(N)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@@](C)(CC#N)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of (S)-tert-butyl 2-((3R,5R,6S)-3-(2-amino-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate (105 mg, 0.197 mmol; Example 128, Step A) and triethylamine (137 μL, 0.984 mmol) in THF (3.3 mL) was treated with 2,2,2-trifluoroacetic anhydride (69.8 μL, 0.492 mmol) at 0° C. After being stirred at 0° C. for 3 h, the reaction was quenched (10% citric acid), extracted (2×EtOAc) and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (12 g SiO2, 20 to 50% EtOAc/Hex, a gradient elution) provided the title compound as a colorless foam.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:13]2[CH:12]=[C:11]3[CH2:14][CH2:15][O:16][C:10]3=[CH:9][C:8]=2[CH2:7][C:6]1=[O:17])[CH3:4].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1.[Cl-].[Na+]>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([CH:7]2[C:8]3[CH:9]=[C:10]4[O:16][CH2:15][CH2:14][C:11]4=[CH:12][C:13]=3[N:5]([CH2:3][CH3:4])[C:6]2=[O:17])=[O:27])=[CH:21][CH:20]=1
Reactant: CCN1C(=O)Cc2cc3c(cc21)CCO3
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C(=O)Nc2ccc(Cl)cc2)c2cc3c(cc21)CCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 6 %

Procedure:
To a slurry of 18 mg. (0.803 mmole) of sodium hydride in 740 ul. of dimethylformamide cooled to -10° C. was added 150 mg. (0.739 mmole) of 5-ethyl-6-oxo-2,3,6,7-tetrahydro-furo[2,3-f]indole. After the evolution of gas ceased, 125 mg. (0.813 mmole) of 4-chlorophenylisocyanate was added and the reaction mixture allowed to warm to 25° C. and stir for 16 hours. The reaction mixture was poured into a saturated solution of sodium chloride--1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to dryness in vacuo. The residue was purified by chromatographing on 20 g. of silica gel using ethyl acetate-hexane (1:2, v:v) as the eluant. The final product was recrystallized from diethyl etherdichloromethane, 15 mg. (6% yield), m.p. 175°-176° C.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[CH3:18])=[CH:12][CH:11]=1>C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[C@H:17]([CH3:18])[C@H:3]2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C/C=C/c1ccc(Cl)cc1
Agent: [Rh+3]
Agent: CC(=O)[O-]
Product: CCOC(=O)[C@@H]1[C@@H](C)[C@@H]1c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 5.9 %

Procedure:
Ethyl diazoacetate (1.61 g, 12 mmol) was added over 90 minutes to a mixture of rhodium acetate (44 mg) in E-1-(4-chlorophenyl)-1-propene (2.243 g, 12 mmol) at 90° C. with stirring. Heating was continued for 60 minutes. On cooling the mixture was chromatographed with EtoAc/hexane to yield 170 mg of racemic ethyl (1R,2S,3S)-2-(4-chlorophenyl)-3-methyl-cyclopropanecarboxylate. (Another isomer was also isolated.)
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:5][CH2:4]1)=O.ClC1C=CC(C(F)(F)F)=CC=1C(N[C@H]1CC[C@H](C=O)CC1)=O.[NH2:44][C:45]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:46]=1[CH:47]=[CH:48][CH:49]=[N:50]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[N:50]1[C:51]2[C:46](=[C:45]([NH:44][CH2:1][C@H:3]3[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:21])[C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=4)[CH2:5][CH2:4]3)[CH:54]=[CH:53][CH:52]=2)[CH:47]=[CH:48][CH:49]=1
Reactant: Nc1cccc2ncccc12
Reactant: O=C[C@H]1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(N[C@H]1CC[C@H](CNc2cccc3ncccc23)CC1)c1cccc(C(F)(F)F)c1
Temperature: 140 °C

Procedure:
To a solution of trans-N-(4-formyl-cyclohexyl)-3-trifluoromethyl-benzamide (prepared analogously to trans-2-chloro-N-(4-formyl-cyclohexyl)-5-trifluoromethyl-benzamide (Ex. 1 step 3) from the appropriate starting compounds) (100 mg, 0.33 mmol) and 5-aminoquinoline (48 mg, 0.33 mmol) in dry 1,2-dichloroethane (2 mL) in a 2-5 mL capacity microwave tube, is added acetic acid (0.06 mL, 1.0 mmol) and sodium triacetoxyborohydride (178 mg, 0.84 mmol). The tube is sealed with a septum and the mixture is heated at 140° C. for 10 minutes in a Biotage Initiator microwave. After cooling to room temperature, the solvents are removed under reduced pressure and the residue is purified by chromatography on a pre-packed reverse phase column. [MH+428.45].
Reaction SMILES: Cl[C:2]1[C:3]([C:18]([O:20]CC2C=CC=CC=2)=[O:19])=[N:4][CH:5]=[C:6]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH:7]=1.[CH3:28][S-:29].[Na+].O>CS(C)=O>[CH3:28][S:29][C:2]1[C:3]([C:18]([OH:20])=[O:19])=[N:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1
Reactant: O=C(OCc1ccccc1)c1cnc(C(=O)OCc2ccccc2)c(Cl)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1cc(C(=O)O)cnc1C(=O)O
Temperature: 140 °C
Yield: 109.4 %

Procedure:
4.6 g (12 mmol) of dibenzyl 3-chloropyridine-2,5-dicarboxylate were dissolved, at 20° C. and while stirring, in 30 ml of dimethyl sulfoxide, and after that 5.0 g (70 mmol) of sodium thiomethoxide were added, in association with which the temperature rose to 80° C. The reaction mixture was heated at 140° C. for 1 h and then cooled down, after which water was added to it; the oily layer was separated off and cone. hydrochloric acid (pH 1) was added to the aqueous DMSO phase, and the precipitated product was filtered off with suction. 2.8 g of yellow crystalline product were obtained, m.p. 223° C. (with decomposition).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][C:14]([C:16]1[S:17][C:18](Br)=[CH:19][CH:20]=1)=[O:15]>C(#N)C.CCOC(C)=O.[Cu]I.C(N(CC)CC)C>[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([C:10]#[C:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])=[CH:19][CH:20]=1)=[O:15]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(Br)s1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Yield: 63406.2 %

Procedure:
A mixture of prop-2-ynyl-carbamic acid tert-butyl ester (1.67 g, 0.011 mmol), 5-bromo-thiophene-2-carboxylic acid methyl ester (2.50 g, 0.011 mmol), tetrakistriphenylphosphine(0) palladium (0.622 g, 0.0538 mmol), CuI (0.102 g, 0.538 mmol) and triethylamine (1.57 mL, 0.011 mmol) in 50 mL acetonitrile under nitrogen was heated at reflux for 16 h. The reaction was cooled to room temperature, diluted with 75 mL EtOAc, washed with 5.5% HCl, water and brine, dried over MgSO4, filtered and concentrated in vacuo to an oil. The product was purified via flash chromatography (9:1 to 4:1 hexanes:EtOAc) to afford the title compound as an oil (2.06 g). MS 313 (M+18).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[P:11](Cl)(Cl)(Cl)=[O:12].[C:16]([Mg]Cl)([CH3:19])([CH3:18])[CH3:17]>BrCCBr.O1CCCC1>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([P:11](=[O:12])([C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][CH:5]=1
Reactant: CC(C)(C)[Mg]Cl
Reactant: COc1ccc(Br)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1ccc(P(=O)(c2ccc(OC)cc2)C(C)(C)C)cc1
Temperature: 67 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Magnesium (30.1 g, 1.24 mol), tetrahydrofuran (400 mL), and 1,2-dibromoethane (1 drop) were stirred under nitrogen for 1 h. The mixture was then heated to reflux and the heating stopped. 4-Bromoanisole (224.4 g, 1.20 mol) was added as a mixture at a rate to maintain a slow reflux (67° C.) over a period of 4 h. The reaction mixture was then held for a further 3h at 70° C. To a tetrahydrofuran (500 mL) solution of phosphorus oxychloride (92.0g, 0.60 mol) was added by drop tert-butylmagnesium chloride (300 mL, 2.0 M, 0.60 mole) over 5.5 h and held at 40° C. for 1 h. Then the 4-methoxy-phenylmanesium bromide solution prepared above was added by drop over 2 h at a rate to maintain 40° C. The mixture was allowed to stir for 2 days at rt. The reaction mixture was worked up to yield a pale-yellow sticky solid (135.6 g, 71%). 31P NMR (d6-DMSO): δ 44.7 (s, 43.0%), 37.8 (s, 7.0%), 26.5 (s, 7.6%), 25.4 (s, 36.4%), 14.9 (s, 6.0%).
Reaction SMILES: C1(=O)OC(=O)C=C1.C(N)CCC.[CH2:13](/[C:17](=[CH:21]/[C:22]([NH2:24])=[O:23])/[C:18](O)=[O:19])[CH2:14][CH2:15][CH3:16].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH2:13]([C:17]1[C:18]([NH:24][C:22](=[O:23])[CH:21]=1)=[O:19])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC/C(=C/C(N)=O)C(=O)O
Agent: CC(=O)[O-]
Agent: O=C1C=CC(=O)O1
Agent: [Na+]
Solvent: CCCCN
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCCCC1=CC(=O)NC1=O
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 92.3 %

Procedure:
Maleic anhydride is reacted with n-butylamine under the conditions reported by L. E. Coleman et al., in J. Org. Chem., 24: 135, (1959). A mixture containing the thus-formed n-butylmaleamic acid (12.0 g, 0.07 mol), anhydrous sodium acetate (2.7 g) and acetic anhydride (29 mL) is heated at 85° C. to 90° C. for 30 minutes. The solution is cooled to 40° C. and poured into 55 mL of water. The layers are stirred at room temperature for 15 minutes, the diluted to 275 mL. A dark oil precipitates. Extraction with 100 mL of CH2Cl2, then another 25 mL of CH2Cl2, and evaporation of solvent gives 9.9 g of n-butylmaleimide as an oil, ir, 1735 (sh) and 1700 cm-1. A solution of 9.9 g (0.065 mol) of the n-butylmaleimide and 35 mL of acetic acid is treated with 6.51 g (0.07 mol) of aniline, with the resulting solution heated at 120° C. for 30 minutes. The solution is cooled and poured into 280 mL of water. The amorphous material is collected and recrystallized from isopropyl alcohol to give 9.3 g of n-butyl anilinosuccinimide as off-white crystals, m.p. 97°-100° C., ir, 3350, 1720 (sh), 1680, 1600 cm-1; mass spec, (ci) m/e 247. Anal. Calcd. for C14H18N202: C, 68.29; H, 7.32; N, 11.38. Found: C, 68.46; H, 7.28; N, 11.25.
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[C:5]1=[O:24].CSC(SC)=C1C(=O)C(CCCC)(CCCC)C2C(=CC=CC=2)C1=O.[NH2:52][C:53]1[CH:58]=[CH:57][C:56]([I:59])=[CH:55][C:54]=1[S:60]([NH2:63])(=[O:62])=[O:61]>>[CH2:15]([C:12]1([CH2:19][CH2:20][CH2:21][CH3:22])[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[C:5]([OH:24])=[C:4]([C:3]2[NH:52][C:53]3[CH:58]=[CH:57][C:56]([I:59])=[CH:55][C:54]=3[S:60](=[O:62])(=[O:61])[N:63]=2)[C:13]1=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC1(CCCC)C(=O)C(=C(SC)SC)C(=O)c2cc(F)ccc21
Reactant: Nc1ccc(I)cc1S(N)(=O)=O
Agent: CCCCC1(CCCC)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)c2cc(F)ccc21

Procedure:
The title compound was prepared according to the procedure of Example 5D, substituting the compound of Example 18G for the compound of Example 5C, and substituting the compound of Example 20A for the compound of 2D. 1H NMR (300 MHz, CDCl3): δ 0.56 (m, 2 H) 0.77 (m, 6 H) 0.90 (m, 2 H) 1.18 (m, 4 H) 1.90 (m, 2 H) 2.30 (m, 2 H) 7.08 (dd, J=8.46, 4.41 Hz, 2 H) 7.43 (m, 2 H) 7.93 (m, 2 H) 8.28 (d, J=1.84 Hz, 1 H) 16.58 (s, 1 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:3][CH:2]=1.[CH:18]([N-]C(C)C)(C)C.[Li+].IC.O>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][C:10]([CH3:18])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:3][CH:2]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCN(c2ccncn2)CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CCOC(=O)C1(C)CCN(c2ccncn2)CC1
Reaction time: 8 h

Procedure:
1-(4-pyrimidinyl)-4-(ethoxycarbonyl)piperidine (400 mg) in 4 ml tetrahydrofuran was cooled to -70° C and treated with a solution of lithium diisopropylamide (1.0 ml in THF), under an argon atmosphere. After stirring 1.5 hours 1.2 ml of a solution of 1 ml iodomethane in 10 ml THF was added and reaction mixture left to reach room temperature overnight. Water added and extracted twice with ethyl acetate. Organic extract washed with brine and dried over magnesium sulphate, filtered and evaporated to give 1-(4-pyrimidinyl)-4-methyl-4-(ethoxycarbonyl)piperidine (370 mg) as an oil; NMR (CDCl3): 1.24 (s, 3H), 1.28 (t, 3H), 1.38-1.51 (m,2H), 2.14-2.26 (m, 2H), 3.12-3.26 (m, 2H), 4.03-4.14 (m, 2H), 4.2(q,2H), 6.5 (dd, 1H), 8.17 (d. 1H), 8.57 (s, 1H)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([Cl:11])[N:6]=1)=O.[O:12]=[C:13]1[CH2:29][C:28](=O)[C:16]2([CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][CH2:17]2)[CH2:15][NH:14]1.C([O-])(=O)C.[NH4+:35]>CCO>[Cl:11][C:7]1[N:6]=[C:5]([C:3]2[NH:35][C:28]3[C:16]4([CH2:17][CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20]4)[CH2:15][NH:14][C:13](=[O:12])[C:29]=3[CH:2]=2)[CH:10]=[CH:9][N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CNC(=O)CC2=O)C1
Reactant: [NH4+]
Reactant: O=C(CBr)c1ccnc(Cl)n1
Agent: CC(=O)[O-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CNC(=O)c3cc(-c4ccnc(Cl)n4)[nH]c32)C1
Yield: 26.2 %

Procedure:
A solution of 2-bromo-1-(2-chloropyrimidin-4-yl)ethanone (1.04 mmol, 0.24 g), D6 (1.04 mmol, 0.28 g) and ammonium acetate (4.15 mmol, 0.32 g) in EtOH (20 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was taken up in water (20 mL) and brought to pH 7 with 5% aqueous NaHCO3. The precipitate was filtered off and purified by flash silicagel chromatography (100% DCM to 10% MeOH) yielding 0.11 g of a yellow solid (26%). 1H-NMR (400 MHz, CDCl3, 300K): δ=1.49 (9H, s), 2.28 (2H, m), 3.55 (6H, m), 5.70 (1H, br s), 7.30 (1H, s), 7.39 (1H, d, J=5.3 Hz), 8.50 (1H, d, J=5.3 Hz), 9.84 (1H, br s); MS (ES) C19H22ClN5O3 requires: 403. found: 404.2 [M+H]+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([O-])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][CH:7]=1.ONC(=O)CCC(N)=O>CN(C)C=O>[OH:2][CH2:1][CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][CH:7]=1
Reactant: NCCO
Reactant: O=C([O-])c1cccnc1
Agent: NC(=O)CCC(=O)NO
Solvent: CN(C)C=O
Product: O=C(NCCO)c1cccnc1
Yield: 73 %

Procedure:
The ethanolamine was dissolved in dried N,N-di-methyl formamide (DMF) and chilled in an ice bath. The nicotinate derivative, also dissolved in DMF, was added to the DMF-amine mixture, dropwise under a nitrogen atmosphere. As the nicotinate derivative was added, the mixture turned milky and was slurried for at least one half hour. The milky substance was the N-hydroxy-succinamide precipitating, which was filtered off. The DMF-mixture was washed with ether to remove any precipitant. The solvent mixture was removed under high vaccum. The oily residue was triturated with ether, yielding a precipitant, N-(2-hydroxyethyl)-nicotinamide, which was recrystallized from ethyl acetate/petroleum ether. This compound had a melting point of 86°-87° C.; and Rf value of 0.30 (TLC: silica: chloroform/methanol (10:1)); and a yield of 73%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:20][CH:21]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[S:31][CH:32]=[CH:33][C:23]=2[NH:22]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:22]2[C:23]3[CH:33]=[CH:32][S:31][C:24]=3[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[CH:21]2[CH3:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CC1Nc2ccsc2-c2ccccc21
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2c3ccsc3-c3ccccc3C2C)cc1
Yield: 55.9 %

Procedure:
A solution of 4-Methoxybenzenesulfonyl chloride (16 g, 77 mmol), triethylamine (25 mL, 180 mmol), and 4-dimethylaminopyridine (0.20 g, 1.6 mmol) in methylene chloride (100 mL) was de-gassed with nitrogen and treated with a de-gassed methylene chloride (100 mL) solution of 5-Methyl4,5-dihydrothieno[3,2-c]isoquinoline (16 g obtained above) at 23° C. After 21 h the reaction mixture was quenched with 1 N aqueous sodium hydroxide (200 mL). The organic layer was separated and the aqueous phase was extracted with methylene chloride (2×200 mL). The combined extracts were washed with 1 N aqueous sodium hydroxide, 1 N aqueous hydrochloric acid, and brine (200 mL each), dried (K2CO3), and concentrated in vacuo to give the crude product (21 g) as a dark oil. The oil was taken up in methylene chloride (ca. 80 mL) and pre-adsorbed on silica gel (80 g). Flash chromatography on silica gel (400 g) eluting 25-, then 50-, and then 75% methylene chloride-hexane gave the product (16 g) as a yellow solid. Further elution with methylene chloride, then 10-, and then 20% ethyl acetate-methylene chloride gave recovered 5-methylthieno[3,2-c]isoquinoline (1.7 g, 14%) from the previous step. Recrystallization of the product from hot ethyl acetate-hexane provided the title compound (15 g, 79% overall based on recovered starting material from Step 1, m.p. 135-36° C.) as shiny yellow-orange prisms.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[CH2:21]Cl)[CH2:13][CH2:12]1)[CH3:3].[C:26]1(=[O:32])[NH:31][CH:29]([CH3:30])[CH2:28][CH2:27]1.[Li]CCCC.CCCCCC>C1COCC1>[CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:21][N:31]3[CH2:29][CH2:30][CH2:28][CH2:27][C:26]3=[O:32])[CH:23]=[CH:24][CH:25]=2)[CH2:13][CH2:12]1)[CH3:3]
Reactant: CC1CCC(=O)N1
Reactant: CC(C)Oc1ccccc1N1CCC(Cc2cccc(CCl)c2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)Oc1ccccc1N1CCC(Cc2cccc(CN3CCCCC3=O)c2)CC1

Procedure:
A solution of 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperidinyl]methyl]benzyl chloride (5.25 g, 0.0147 mol) in THF (90 mL) was added dropwise to a solution of γ-valerolactam (2.06 g, 0.02 mol) in THF (50 mL) which had been treated at 0° C. with 1.6M n-BuLi/hexane (12 mL, 1 mol equiv). The resulting solution was heated to reflux for 3 h, cooled, and quenched with MeOH (20 mL). The solution was evaporated to dryness to give a yellow oil. The residue was chromatographed on silica gel using 99:1/CHCl3 :MeOH as eluant to give 1-[[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperidinyl]methyl]phenyl]methyl]-piperidin-2-one as a light yellow oil, 1.41 g (23%). MS (Cl CH4): m/e 421 (MH+). 1H NMR (CDCl3): δ1.3 (d, 6H), 1.8 (m, 4H), 2.0 (m, 2H), 2.4 (s, 1H), 2.9 (m, 3H), 3.2 (m, 2H), 3.6 (s, 1H), 3.7 (d, 1H), 4.6 (m, 3H), 5.0 (s, 1H), 6.9 (m, 2H), 7.1 (m, 2H), 7.3-7.6 (m, 4H).