Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:12][C:13]1[CH:22]=[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>CN(C=O)C>[Cl:12][C:13]1[CH:22]=[C:21]([N:23]([CH2:2][CH2:3][O:4][CH3:5])[S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COCCBr
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCN(c1ccc(C(=O)OC)c(Cl)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 5 g of methyl 2-chloro-4-nitrobenzoate in 100 mL of EtOH was added 20 g of Tin (II) Chloride in portions. The reaction was heated to 55° C. and monitored by TLC until complete. Solvent was concentrated and extraction was performed in Ethyl Acetate and water with TEA to reduce emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give 3.9 g of methyl 4-amino-2-chlorobenzoate. 1 g of methyl 4-amino-2-chlorobenzoate was cooled to 0° C. in DCM with 485 μL of Pyridine before Methanesulfonyl Chloride was added dropwise. The reaction was allowed to warm to room temperature and stir overnight. Solvent was concentrated and the crude material was dissolved in Ethyl Acetate and extracted with saturated bicarbonate 10′ solution and then brine. The crude material was dried over Magnesium Sulfate, filtered and concentrated to give 1.54 g of methyl 2-chloro-4-(methylsulfonamido)benzoate. 107 μL of 1-bromo-2-methoxyethane and 556 mg of Cesium Carbonate were added to 150 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in DMF and stirred at room temperature for 16 hours. The reaction mixture was extracted in Ethyl Acetate twice with saturated bicarbonate and once with brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate. 182 mg of methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate was hydrolyzed via Procedure M to yield 169 mg of crude 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid. 65 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-methoxyethyl)methylsulfonamido)benzamide. MS (Q1) 494 (M)+.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[O:23][C:22]([F:21])([F:32])[F:33])[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccccc1OC(F)(F)F
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccccc1OC(F)(F)F

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 2-(trifluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.91 min.; [M+H]+: 410.01 g/mol.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:35][CH:34]([N:36]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[N:37]2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:35][CH:34]([N:36]2[CH:40]=[C:39]([C:2]3[CH:24]=[CH:23][C:5]4[C:6]5[N:7]=[C:8]([C:14]6[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=6)[S:9][C:10]=5[CH2:11][CH2:12][O:13][C:4]=4[CH:3]=3)[CH:38]=[N:37]2)[CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)C)n1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4cnn(C5CN(C(=O)OC(C)(C)C)C5)c4)ccc2-3)n(C(C)C)n1

Procedure:
Following the procedure for 114, 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 3-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-azetidine-1-carboxylic acid tert-butyl ester to give 3-{4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidine-1-carboxylic acid tert-butyl ester which was treated with acid via General Procedure F to give 8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]=[CH2:5].Br[CH2:18][C:19]#[CH:20]>CN(C=O)C.CCOCC>[CH2:3]([C:6]([CH2:20][C:19]#[CH:18])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]=[CH2:5]
Reactant: C#CCBr
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CCC(CC=C)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaH (60%, 0.480 g) was added to a cold (0° C.) solution of diethyl 2-allylmalonate (2.002 g) in DMF (10 mL) and the mixture was allowed to warm to rt over 30 min. Then a solution of 3-bromoprop-1-yne (1.487 g) in DMF (3 mL) was added dropwise at 0° C. and the mixture was allowed to warm to rt and stirred at rt overnight. The reaction mixture was diluted with ether and then quenched with sat. NH4Cl, washed with water, brine and dried (Na2SO4). The crude product was purified by silica gel FCC (1:1 DCM-hexane) to afford diethyl 2-allyl-2-(prop-2-ynyl)malonate as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]3[C:20](=[O:23])[O:21][CH2:22][C:18]=3[C:17]=2[CH:26]=[CH2:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]3[C:20](=[O:23])[O:21][CH2:22][C:18]=3[C:17]=2[CH2:26][CH3:27])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1c(CCN2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1COC2=O
Agent: [Pd]
Solvent: CO
Product: CCc1c(CCN2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1COC2=O
Reaction time: 16 h

Procedure:
To a solution of tert-butyl-4-[2-(1-oxo-4-vinyl-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate (30 mg, 0.081 mmol) in MeOH (10 mL) was added palladium on carbon (4.3 mg, 0.040 mmol). The mixture was allowed to stir under an atmosphere of hydrogen for 16 hours. LC showed complete reaction. The crude reaction was filtered through a pad of Celite®, concentrated to deliver tert-butyl-4-[2-(4-ethyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=2)=[CH:4][C:3]=1[C@:18]12[O:26][CH2:25][CH2:24][C@H:23]1[CH2:22][S:21][C:20]([NH:27]C(=O)OC(C)(C)C)=[N:19]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][C:20]1[S:21][CH2:22][C@@H:23]2[CH2:24][CH2:25][O:26][C@:18]2([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=3)[CH:6]=[CH:7][C:2]=2[F:1])[N:19]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(F)cn4)ccc3F)OCC[C@H]2CS1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1=N[C@@]2(c3cc(NC(=O)c4ccc(F)cn4)ccc3F)OCC[C@H]2CS1
Yield: 149.4 %

Procedure:
A solution of tert-butyl ((4aR,7aR)-7a-(2-fluoro-5-(5-fluoropicolinamido)phenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (6 mg, 0.012 mmol) and TFA (18.85 μL, 0.245 mmol) in DCM (122 μL) was stirred at rt for 3 h. The solvents were removed to give N-(3-((4aR,7aR)-2-amino-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-fluoropicolinamide (7 mg) as its TFA salt. 1H NMR (500 MHz, CHLOROFORM-d) δ 9.83 (s, 1H), 8.48 (d, J=2.7 Hz, 1H), 8.35 (dd, J=8.7, 4.6 Hz, 1H), 8.00-7.96 (m, 1H), 7.70 (dd, J=6.9, 2.7 Hz, 1H), 7.62 (td, J=8.3, 2.7 Hz, 1H), 7.08 (dd, J=10.9, 8.8 Hz, 1H), 4.11 (t, J=7.2 Hz, 3H), 3.16 (dd, J=13.0, 4.0 Hz, 1H), 2.98 (ddd, J=12.9, 7.5, 1.8 Hz, 1H), 2.78 (dd, J=7.1, 4.0 Hz, 1H), 2.22-1.99 (m, 2H). MS (M+H)+: 391.2.
Reaction SMILES: [PH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[O:23]S(C(F)(F)F)(=O)=O)=O>C(N(CC)CC)C>[PH2:1][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[OH:23]
Reactant: O=[PH2]c1ccc2ccccc2c1-c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Solvent: CCN(CC)CC
Product: Oc1ccc2ccccc2c1-c1c(P)ccc2ccccc12

Procedure:
More specifically, following Tetrahedron Letters, 31, 6321-6324 (1990), trifluoromethanesulfonic anhydride (4) is reacted with 1,1-bi-2-naphthol (3) to form 2,2'-bis(trifluoromethanesulfonyloxy)-1,1'-binaphthyl (5). This compound (5) is reacted with phosphine oxide (6) in the presence of a palladium catalyst to form 2-phosphinyl-2'-trifluoromethanesulfonyloxy-1,1'-binaphthyl (7). Compound (7) is then reduced in the presence of triethylamine, followed by hydrolysis of the reduction product to form 2-phosphino-2'-hydroxy-1,1'-binaphthyl (8). Further, this compound (8) is reacted with chlorophosphine (9) in the presence of triethylamine, whereby the phosphine compound (I) of the present invention is prepared.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]2[N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1(O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:10]2[N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16][CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C2C1CCN2C(=O)OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccccc2)C2C1CCN2C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 47 %

Procedure:
To a solution of 11 (600 mg, 1.65 mmol) in THF (10 mL) was added phenol (186 mg, 1.98 mmol) and Ph3P (520 mg, 1.98 mmol). DIAD (459 mg, 2.31 mmol) was then added and the reaction mixture was immersed into a preheated (75° C.) oil bath. After 16 h, the reaction mixture was concentrated in vacuo and the residue was passed through a short column of silica gel (4:1 hexanes/EtOAc). The crude product was then purified by reverse-phase HPLC (2″ Dynamax® C18, 10-70% ACN/water containing 0.1% HOAc over 30 min; Flow: 40 mL/min) to afford 340 mg (46%) of 12 as a white solid. 1H NMR (CDCl3, 300 MHz), mixture of rotomers: δ7.37-7.27 (m, 6H), 7.22 (m, 1H), 7.04 (m, 1H), 6.96-6.88 (m, 1H), 6.81 (d, J=8.4 Hz, 1H), 5.27-5.13 (m, 2H), 5.01 (dd, J=3.3, 6.3 Hz, 0.5H), 4.77 (d, J=2.7 Hz, 0.5H), 4.57-4.45 (m, 1H), 4.43-4.32 (m, 1H), 3.99-3.89 (m, 1H), 3.85-3.73 (m, 1H), 3.37 (m, 1H), 3.21 (dt, J=5.7, 11.7 Hz, 1H), 2.38 (m, 0.5H), 2.23 (dd, J=5.7, 13.2 Hz, 0.5H), 1.91-1.83 (m, 1H), 1.47 (m, 9H) ppm. Mass spectrum, m/z [339.2] (M−Boc)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4C=CC=CC=4)[CH2:23][CH2:22]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH3:28])[CH2:23][CH2:22]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OCCCNC3CCN(Cc4ccccc4)CC3)c2c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1oc2cccc(OCCCNC3CCN(CC)CC3)c2c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(3-(1-benzyl-piperidin-4-ylamino)-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (the compound in Example 100, 14 mg) in ethanol (3 ml) was added 5% Pd on charcoal catalyst (10 mg) under N2. The nitrogen atmosphere was replaced by hydrogen (1 atom) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered through a pad of celite and the pad of celite was rinsed with methanol and dichloromethane. The filtrate combined was concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane-MeOH) to give 4-[3-(1-ethyl-piperidin-4-ylamino)-propoxy]-3-methyl-benzofuran-2-carboxylic acid ethyl ester (5 mg) as a colorless oil. EI-MS: m/z 388 (M+); 1H-NMR (CDCl3): δ 1.13 (3H, t, J=7 Hz), 1.44 (3H, t, J=7 Hz), 1.54 (2H, m), 1.98-2.22 (6H, m), 2.53 (2H, q, J=7 Hz), 2.61 (1H, m), 2.74 (3H, s), 2.89 (2H, t, J=7 Hz), 3.02 (2H, m), 4.16 (2H, t, J=6 Hz), 4.44 (2H, q, J=7 Hz), 6.62 (1H, d, J=8 Hz), 7.12 (1H, d, J=8 Hz), 7.30 (1H, t, J=8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C@H:12]3[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:18])[CH2:13]3)[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C1C(=O)N([Cl:26])C(=O)C1>C1COCC1>[Cl:26][N:15]1[CH2:16][CH2:17][C@H:12]([C:9]2[S:8][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=3[CH:10]=2)[CH2:13][C@@H:14]1[CH3:18]
Reactant: COc1cccc2sc([C@H]3CCN[C@@H](C)C3)cc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: COc1cccc2sc([C@H]3CCN(Cl)[C@@H](C)C3)cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A solution of cis-(±)-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine in THF (35 mL) was cooled to 0° C. (ice-water bath), then treated with NCS (2.26 g, 16.94 mol). After stirring 15 minutes, the ice-water bath was removed and the mixture was stirred at room temperature for 45 minutes. The mixture was then concentrated under reduced pressure and diluted with Et2O (100 mL), saturated aqueous NaHCO3 (50 mL) and H2O (50 mL). The mixture was shaken and partitioned in a separatory funnel. The aqueous layer was separated and extracted once with Et2O. The combined organic layers were washed once with H2O (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give the cis-(±)-N-chloro-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine as a yellow oil (4.78 g, 99%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([NH:13][C:14](=[O:35])[CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)(=[O:24])=[O:23])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN(C)C(=O)C>[N:36]1([CH2:1][C:3]2[CH:12]=[C:11]3[C:6]([C@H:7]([NH:13][C:14](=[O:35])[CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][N:17]4[S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=4)(=[O:24])=[O:23])[CH2:8][CH2:9][O:10]3)=[CH:5][CH:4]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=Cc1ccc2c(c1)OCC[C@H]2NC(=O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCOc2cc(CN3CCCCC3)ccc21
Reaction time: 14 h

Procedure:
N-(7-Formyl-chroman-4-(R)-yl)-2-[1-(3-trifluoromethyl-benzenesulfonyl)-piperidin-2-yl]-acetamide (135 mg, 0.26 mmol) and piperidine (28 mg, 0.33 mmol) were added to N,N-dimethyl-acetamide (1.5 mL) solution, followed by NaBH(OAc)3 (115 mg, 0.52 mmol) and the reaction was stirred overnight (14 h). The reaction was quenched with dilute NaHCO3—H2O (10 mL), and the mixture was extracted with CH2Cl2 (2×10 mL), and the organic phase was washed with dilute NaHCO3—H2O and H2O, and dried over MgSO4. After filtration and concentration in vacuo, the crude was purified by precipitation and crystallization as the HCl salt in Et2O to provide a white solid (of the title compound as a mixture of diastereomers (ca. 1:1 by 1H NMR). MS (ESI) 580 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:21])[N:10]=[C:11]([C:12]3[CH:17]=[C:16]([F:18])[C:15]([OH:19])=[C:14]([Br:20])[CH:13]=3)[C:6]2=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][OH:31]>CN(C=O)C.CO>[NH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:21])[N:10]=[C:11]([C:12]3[CH:17]=[C:16]([F:18])[C:15]([O:19][CH2:29][CH2:30][OH:31])=[C:14]([Br:20])[CH:13]=3)[C:6]2=[CH:5][N:4]=1
Reactant: Cn1nc(-c2cc(F)c(O)c(Br)c2)c2cnc(N)nc21
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1nc(-c2cc(F)c(OCCO)c(Br)c2)c2cnc(N)nc21
Temperature: 120 °C

Procedure:
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-6-fluoro-phenol hydrochloride (Example 42b) (30 mg, 0.08 mmol) is dissolved in DMF (1 ml) then treated with K2CO3 (24 mg, 0.18 mmol) and 2-bromoethanol (5.7 μL, 0.08 mmol). The reaction mixture is heated at 120° C. for 3 hours then cooled to room temperature, diluted with MeOH and concentrated onto silica. Purification by flash column chromatography on silica using iso-hexanes:EtOAc (50% EtOAc to 100% EtOAc) followed by recrystallisation from MeOH afforded the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][OH:29])[CH:23]=4)[C:14]3=[O:30])[CH:10]=[N:9]2)=[C:5]([CH3:31])[O:4][N:3]=1.[H-].[Na+].I[CH3:35]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][CH3:35])[CH:23]=4)[C:14]3=[O:30])[CH:10]=[N:9]2)=[C:5]([CH3:31])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)N(Cc3cccc(CO)c3)C(C)(C)C2=O)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCc1cccc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
To a solution of 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-(hydroxymethyl)benzyl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-34) (559 mg, 1.32 mmol) in anhydrous dimethylformamide (10 mL) at 0° C., was added sodium hydride (53 mg, 1.32 mmol), followed by iodomethane (99 ul, 1.58 mmol). The reaction was allowed to warm to room temperature and stirred for about 4 hours. The resulting mixture was diluted with ethyl acetate (40 mL) and ice water (10 mL), The organic phase was collected, dried over anhydrous MgSO4, filtered and then concentrated on the rotovap. The residue was purified by reverse phase HPLC (gradient 10% to 100% methanol/water) and further purified by column chromatography (60% EtOAc in hexane). Yield 36%, colorless gel. 1H NMR (DMSO-d6, 400 MHz): δ1.29 (s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 3.25 (s, 3H), 4.37 (s, 2H), 4.55 (s, 2H), 5.18 (s, 2H), 7.19 (t, 1H) 7.30 (d, 2H), 7.32 (s, 1H), 7.82 (s, 1H) 8.20 (s, 1H). MS 438 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.13 μM.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][N:18]=[CH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24](O)[CH3:25]>[Pt]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][CH2:17][N:18]([CH2:24][CH3:25])[CH2:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3cnccc23)CC1
Agent: [Pt]
Product: CCN1CCc2c(cccc2N2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
The compound of Step 2 (200 mg, 0.64 mmol) is dissolved in absolute ethanol (50 mL), and Pt/C 10% catalyst (200 mg) is added. The mixture is pressurized to 45 psi under hydrogen and shaken for about 4 hours at r.t. The mixture is filtered over celite, concentrated and chromatographed on silica gel to give about 68 mg of 5-(4-t-butyloxycarbonylpiperazin-1-yl)-2-ethyl-1,2,3,4-tetrahydroisoquinoline (30%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:4]=[N:3]1.O=P(Cl)(Cl)Cl.CN([CH:24]=[O:25])C>>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH:24]=[O:25])=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:4]=[N:3]1
Reactant: CN1CCN(c2cnn(C)c(=O)c2)CC1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(c2cnn(C)c(=O)c2C=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-methyl-5-(4-methylpiperazin-1-yl)pyridazin-3(2H)-one (416 mg, 2 mmol) in dry DMF (6.7 ml) was cooled to 5° C., then a solution of POCl3 (0.41 ml, 4.4 mmol) in dry DMF (1 ml) was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 10 min. Then, the temperature was raised to 70° C. and stirring was continued for 75 min. After cooling, the volatile components were removed under reduced pressure and the residue was treated with crushed ice (15 g). The mixture was adjusted to pH 7-8 with aqueous NaOH. Then it was extracted with dichloromethane (4×40 ml) and the combined extracts were washed with water, dried (Na2SO4) and evaporated. Residual volatile material was removed at 10−2 mbar to leave an oily residue which slowly solidified on storage in a refrigerator.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36](O)=[O:37])=[CH:26][CH:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:37])=[CH:28][CH:29]=1)[CH3:23]
Reactant: CCc1ccc(-c2sc(C)nc2C(=O)O)cc1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: CCc1ccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)cc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(4-ethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH2:4][NH:5][C:6](=[O:18])[CH2:7][N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:9]1=[O:17])[CH3:2]>CO.[Pd]>[NH2:14][C:10]1[C:9](=[O:17])[N:8]([CH2:7][C:6]([NH:5][CH2:4][CH:3]([CH2:19][CH3:20])[CH2:1][CH3:2])=[O:18])[CH:13]=[CH:12][CH:11]=1
Reactant: CCC(CC)CNC(=O)Cn1cccc([N+](=O)[O-])c1=O
Agent: [Pd]
Solvent: CO
Product: CCC(CC)CNC(=O)Cn1cccc(N)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg (0.36 mmol) of N-(2-ethylbutyl)-2-(3-nitro-2-oxopyridin-1(2H)-yl)acetamide are suspended under nitrogen atmosphere in 7 mL of methanol. To this solution 10 mg of Pd/C (10%) is added and stirred under hydrogen atmosphere at atmosphere pressure for 2 h at RT. The catalysis is separated by filtration over silica gel, before the solvent is removed in vacuo. Green-gray solid is obtained and it is suitable for further processing without purification.