Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[C:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=3)(=[O:15])=[O:14])=[CH:11][C:10]([C:23](OCC)=[O:24])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([N:8]2[C:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=3)(=[O:15])=[O:14])=[CH:11][C:10]([CH2:23][OH:24])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cc(S(=O)(=O)c2cccc(C)c2)n(-c2cccnc2F)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cccc(S(=O)(=O)c2cc(CO)nn2-c2cccnc2F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A solution of ethyl 1-(2-fluoropyridin-3-yl)-5-[(3-methylphenyl)sulfonyl]-1H-pyrazole-3-carboxylate (384 mg) in tetrahydrofuran (5 mL) was cooled to −78° C., a 1.5 mol/L solution (2.6 mL) of diisobutylaluminum hydride in toluene was added dropwise. The reaction mixture was stirred for 1 hr at 0° C., treated with 1 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a colorless oil (yield 320 mg, yield 94%)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:20][CH3:21])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.ClC(O[CH2:31][CH3:32])=O>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:20][CH3:21])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:31][CH3:32])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cl
Reactant: CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C2CC2)c2cc(N3CCN(CC)CC3)c(F)cc2c1=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
100 parts by weight of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethyl-1-piperazinyl)-3-quinoline-carboxylic acid were dissolved in 300 parts by volume of anhydrous chloroform, and 33.2 parts by weight of triethylamine were added. A solution of 37.7 parts by weight of ethyl chloroformate in 100 parts by volume of anhydrous chloroform was added dropwise to this mixture at -20° C. in the course of 30 minutes, and the mixture was stirred for a further 30 minutes at -20° C. and was then stirred overnight at room temperature. After extraction with twice 300 parts by volume of water, 400 parts by volume of water were added to the organic phase. The pH was adjusted to 5 with glacial acetic acid (consumption approximately 15 parts by volume), and the chloroform was removed by distillation under a water pump vacuum. The pH of the aqueous solution was adjusted to 8.9 with half-concentrated potassium hydroxide solution (consumption approximately 70 parts by volume), and the mixture was stirred overnight at room temperature. The product was filtered off with suction, washed with 500 parts by volume of water and dried overnight at 70° C. in a vacuum drying cabinet.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=[C:8]2[C:16]([O:18]CC)=O)[CH:2]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[S:29][C:28]([CH3:30])=[N:27][C:26]=2[CH:31]=1>>[CH3:30][C:28]1[S:29][C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:16]([C:8]3[N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[C:11]4=[N:12][CH:13]=[CH:14][CH:15]=[C:10]4[CH:9]=3)=[O:18])=[CH:31][C:26]=2[N:27]=1
Reactant: CCOC(=O)c1cc2cccnc2n1-c1cccnc1
Reactant: Cc1nc2cc(N)ccc2s1
Product: Cc1nc2cc(NC(=O)c3cc4cccnc4n3-c3cccnc3)ccc2s1

Procedure:
This compound was prepared according to the experimental protocol described in Example 6.2, starting with ethyl 1-(3-pyridyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate obtained according to the protocol described in step 7.1 and 5-amino-2-methylbenzothiazole. A yellow solid is obtained.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]([OH:14])=O)[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:38]([CH2:40][NH2:41])[OH:39]>CN(C=O)C.C(Cl)(Cl)Cl.C(Cl)Cl.CO.CC(O)=O.C(Cl)Cl.CO>[C:1]([NH:8][C@H:9]([C:12]([NH:41][CH2:40][CH2:38][OH:39])=[O:14])[CH2:10][OH:11])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)NCCO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution comprising 6.15 g (30 mmol) of N-Boc-L-serine (1, Fluka) and 3.45 g of N-hydroxysuccinimide (30 mmol) in 80 ml of DMF is stirred at 0° C. and 6.2 g (30 mmol) of DCC are added. The reaction mixture is maintained at 0° C. for 15 min, then it is allowed to return to ambient temperature and stirring is continued for 1 h 30. 2.75 ml (60 mmol) of ethanolamine are subsequently added. After stirring for 12 h, the DCU formed is filtered off and washed with 2×15 ml of DMF. The combined organic phases are evaporated to dryness under vacuum. The product is isolated from the residual paste by flash chromatography on a silica gel column (Kieselgel Merck 60, 230-400 mesh; eluent: CH2Cl2/MeOH 6%). The expected compound is collected in the form of a gum which crystallizes from an AcOEt/hexane mixture to provide 5.21 g (Yd=70%) of colorless needles. Rf (CH2Cl2/MeOH, 9.3/0.7): 0.23; (CH2Cl2/MeOH/AcOH, 9/0.9/0.1): 0.47. M.p.=74-76° C. [α]D20=−2.2° (c 0.9, CHCl3).
Reaction SMILES: OC1C(C2C=CC(O)=CC=2)CCN(C(OC(C)(C)C)=O)C1.BrCCCC1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[OH:38][CH:39]1[CH:44]([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:47][CH:46]=2)[CH2:43][CH2:42][N:41]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:40]1.Br[CH2:69][C:70]1[CH:79]=[CH:78][C:77]2[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=2)[CH:71]=1>>[CH:71]1[C:72]2[C:77](=[CH:76][CH:75]=[CH:74][CH:73]=2)[CH:78]=[CH:79][C:70]=1[CH2:69][O:38][CH:39]1[CH:44]([C:45]2[CH:46]=[CH:47][C:48]([O:51][CH2:52][CH2:53][CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)=[CH:49][CH:50]=2)[CH2:43][CH2:42][N:41]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCc3ccccc3)cc2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Agent: BrCCCc1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Agent: O=C([O-])[O-]
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 44(e), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate [Example 46(b)] with 1-bromo-3-phenyl-propane in the presence of potassium carbonate, tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(3-phenyl-propoxy)-phenyl]-piperidine-1-carboxylate, alkylation of which analogously to Example 1(g) with 2-bromomethyl-naphthalene yielded tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(3-phenyl-propoxy)-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 551 (M)+.
Reaction SMILES: C([O-])(=[O:3])C.[C:5]1([Sn+:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Sn]>>[OH-:3].[C:18]1([Sn+:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)[O-]
Agent: [Sn]
Agent: c1ccc([Sn+](c2ccccc2)c2ccccc2)cc1
Product: [OH-]

Procedure:
triphenyl tin acetate (FENTINACETAT) and further organic tin compounds
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].Cl[C:31]1[S:32][C:33]2[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:34]=2[N:35]=1>>[Cl:40][C:38]1[CH:37]=[CH:36][C:34]2[N:35]=[C:31]([N:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:17][CH2:16][C:13]3[CH:12]=[CH:11][C:10]([O:9][C:2]([CH3:8])([CH3:1])[C:3]([OH:5])=[O:4])=[CH:15][CH:14]=3)[S:32][C:33]=2[CH:39]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2nc3ccc(Cl)cc3s2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate and 2,6-dichloro benzothiazole. 1H NMR (CDCl3) δ 7.55 (d, 2H, J=8.0), 7.52 (d, 1H, J=2.0), 7.47 (d, 1H, J=8.0), 7.32 (d, 2H, J=8.0), 7.24 (dd, 1H, J=8.0; 2.0), 7.07 (d, 2H, J=8.6), 6.86 (d, 2H, J=8.6), 4.67 (s, 2H), 3.65 (t, 2H, J=7.2), 2.93 (t, 2H, J=7.2), 1.53 (s, 6H). MS: m/z 549 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([O:11][CH3:12])=[CH:4][C:5](=[O:10])[C:6]([Cl:9])([Cl:8])[Cl:7].[C:13]([O-:16])(=[O:15])[CH3:14].[K+].C(O)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:13]([O:16][CH2:2][C:3]([O:11][CH3:12])=[CH:4][C:5](=[O:10])[C:6]([Cl:9])([Cl:8])[Cl:7])(=[O:15])[CH3:14]
Reactant: COC(=CC(=O)C(Cl)(Cl)Cl)CBr
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=CC(=O)C(Cl)(Cl)Cl)COC(C)=O

Procedure:
29.6 g (0.1 mol) of 5-bromo-1,1,1-trichloro-4-methoxypent-3-en-2-one, 17 g of potassium acetate, 5 g of tetrabutylammonium bromide and 8 g of acetic acid were stirred at 40° C. in 300 ml of acetonitrile for 16 h. The mixture was concentrated under reduced pressure, and the water was added to the residue. The product was extracted with ethyl acetate, the organic phase was washed with water and the solvent was removed completely under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:33])[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[CH2:57]([O:59][C:60](=[O:64])[CH2:61][CH2:62][NH2:63])[CH3:58].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O.C(N(CC)CC)C>[CH2:57]([O:59][C:60](=[O:64])[CH2:61][CH2:62][NH:63][C:30]([C:27]1[CH:26]=[CH:25][C:24]([C:21]2[CH:20]=[CH:19][C:18]([CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[CH2:9][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[O:33])=[CH:23][CH:22]=2)=[CH:29][CH:28]=1)=[O:31])[CH3:58]
Reactant: Cc1cc(C(=O)CC(c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccccc2C)ccn1
Reactant: CCOC(=O)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 117.3 %

Procedure:
To a solution of 4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid (50 mg) in THF (1 mL) was added TBTU (41 mg) and triethylamine (0.048 mL) and the resulting mixture was stirred at room temperature for 10 min. Beta-alanine ethyl ester hydrochloride (21.2 mg) was added and the reaction mixture was stirred at rt overnight. A saturated solution of NH4Cl and EtOAc were added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to yield the title compound (72 mg) as a light yellow oil, MS (ESI+): m/z=535.3 ([M+H]+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[C:16]([F:17])=[CH:15][C:12]([C:13]#[N:14])=[C:11]([NH:18][C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)[CH:10]=1.CC[OH:32]>CS(C)=O.[OH-].[Na+].OO>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[C:16]([F:17])=[CH:15][C:12]([C:13]([NH2:14])=[O:32])=[C:11]([NH:18][C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)[CH:10]=1
Reactant: N#Cc1cc(F)c(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cc(-c2ccccc2)no1
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: NC(=O)c1cc(F)c(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-((1R,2S)-2-aminocyclohexylamino)-5-fluoro-2-(3-phenylisoxazol-5-ylamino)benzonitrile in EtOH (1 mL) and DMSO (0.5 mL), 1N aq. NaOH (0.5 mL) and H2O2 (50% aq., 0.5 mL) were added. After being stirred at room temperature for 1 h, the mixture was concentrated in vacuo. The residue was acidified with HOAc (0.5 mL), and then was purified by HPLC to give the titled compound (33 mg). MS 410.3 (M+H); UV 204.7, 246.1, 287.8 nm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[OH:38]>CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:38][C:32]4[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:31]=4[Cl:30])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(Cl)cc4Cl)ncnc32)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 14.4 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 42 mg, 0.12 mmol), anhydrous potassium carbonate (22 mg, 0.16 mmol) and 2,4-dichlorophenol (26 mg, 0.16 mmol) in N-methylpyrrolidinone (0.5 mL) was heated to 100° C. in a sealed scintillation vial. After 18 hr, the mixture was allowed to cool to room temperature and the reaction mixture purified by reverse phase HPLC to give 4-[4-(2,4-dichloro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (8 mg, 14%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 1.97-2.05 (m, 2H), 2.18-2.33 (m, 2H), 2.90-3.04 (m, 2H), 4.24-4.40 (m, 2H), 4.90-5.02 (m, 1H), 7.23-7.25 (m, 1H), 7.36 (dd, 1H, J=8.6, 2.6 Hz), 7.64 (d, 1H, J=2.1 Hz), 8.12 (s, 1H), 8.49 (s, 1H). Mass spectrum MH+=464.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N=C1CC(C)CCN1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH:13]=[C:14]1[CH2:19][CH2:18][CH2:17][CH:16]([C:20]([F:22])([F:21])[F:23])[NH:15]1
Reactant: Nc1cccc(C(F)(F)F)n1
Agent: CC1CCNC(=N)C1
Solvent: CC(=O)O
Product: N=C1CCCC(C(F)(F)F)N1

Procedure:
The method of preparation of 2-imino-4-methylpiperidine acetate was used to convert 2-amino-6-(trifluoromethyl)pyridine to the title compound. Product was crystallized from EtOAc to give a white solid. The analysis of the product was found to be consistent with the proposed structure. MH+=167; 1H NMR (D2O): δ4.20-4.00 (m, 1H); 2.60-2.50 (m, 2H); 2.05-1.50 (m, 4H); 1.80 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][SH:7])[CH3:3].CO.[OH-].[Na+].Br[CH2:15][CH2:16][OH:17]>O>[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][S:7][CH2:15][CH2:16][OH:17])[CH3:3]
Reactant: CCN(CC)CCS
Reactant: OCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(CC)CCSCCO
Temperature: 25 °C
Yield: 87.5 %

Procedure:
2-(Diethylamino)ethanethiol hydrochloride (5.0 g, 29 mmol) was added to a 250 mL round-bottom flask, 20 mL methanol was added, and the solution cooled in an ice bath with stirring. Sodium hydroxide (2.34 g, 58 mmol), dissolved in water (15 mL), was added, followed by slow addition of 2-bromoethanol (5.9 g, 47 mmol). Stirring was continued while the reaction mixture was allowed to warm to room temperature overnight. The methanol and water were removed under reduced pressure, and the residue dissolved in ethyl acetate (100 mL), washed with water (3×20 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give 2-[2-(diethylamino)-ethylthio]ethanol as a yellow oil (4.5 g, 87% yield). LC-MS (ES+): m/z=178 [C8H19NOS+H+] for product peak. A 1.0 g aliquot of the crude 2-[2-(diethylamino)ethylthio]ethanol was purified by flash chromatography on silica cartridges, eluting with a gradient of 100% hexane to 100% ethyl acetate over 5 minutes, to give 0.78 g pure 2-[2-(diethylamino)ethylthio]ethanol as a colorless oil after evaporation of the solvents, and the remaining 3.5 g similarly purified, eluting with a gradient of 100% hexane to 100% ethyl acetate over 20 minutes, to give an additional 3.11 g pure 2-[2-(diethylamino)ethylthio]ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14][CH:15]=[CH:16][OH:17])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([CH:21]([CH3:23])[CH3:22])[C:9]=2[C:24]([OH:26])=O)=[CH:4][CH:3]=1.O[N:28]1[C:32]2C=CC=[CH:36][C:31]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.C(N)CC>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14][CH:15]=[CH:16][OH:17])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([CH:21]([CH3:22])[CH3:23])[C:9]=2[C:24]([NH:28][CH2:32][CH2:31][CH3:36])=[O:26])=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)c1nc(C(C)C)c(C(=O)O)c(-c2ccc(F)cc2)c1CC=CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCCN
Solvent: CCOC(C)=O
Product: CCCNC(=O)c1c(C(C)C)nc(C(C)C)c(CC=CO)c1-c1ccc(F)cc1
Reaction time: 0.42 h
Yield: 37 %

Procedure:
To a stirring solution of 4-(4-fluorophenyl)-5-(3-hydroxy-2-propenyl)-2,6-bis(1-methylethyl)-3-pyridinecarboxylic acid (4.0 g, 0.0112 mol) was added 1.51 g of 1-hydroxybenzotriazole (0.0112 mol) followed by 2.31 g of DCC (0.0112 mol). The resulting mixture was stirred 25 minutes, then 1.84 ml of n-propylamine (0.0224 mol) was added. The resulting mixture was stirred for 72 hrs and then was taken up in ethyl acetate (500 ml), filtered, washed with water (2×250 ml), washed with 30% saturated NaHCO3 (1×150 ml), washed with brine (1×150 ml), dried (MgSO4), concentrated under reduced pressure, and chromatographed on silica (1:1 hexane:ethyl acetate) to yield 1.65 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.[OH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.CNCCNC.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cu]I.C(O)CCC.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[O:9])=[N:4][CH:3]=1
Reactant: Oc1ccccn1
Reactant: Nc1ccc(Br)nc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CCCCO
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-n2ccccc2=O)nc1
Temperature: 110 °C
Yield: 33.8 %

Procedure:
A mixture of 3-amino-6-bromopyridine (865 mg, 5.00 mmol), 2-hydroxypyridine (475 mg, 5.00 mmol), N,N′-dimethylethylenediamine (0.215 mL, 2.00 mmol) and K2CO3 (1.38 g, 10.0 mmol) in dioxane (8 mL) was degassed with Argon before being charged with CuI (190 mg, 1.00 mmol). The mixture in a sealed tube was heated at 110° C. overnight. After being cooled down, H2O and nBuOH were added. The organic phase was separated, and concentrated in vacuo to give 1-(5-aminopyridin-2-yl)pyridin-2(1H)-one (316 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:40][C:41]([CH3:44])([OH:43])[CH3:42].ClCCl>CN(C)C=O.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:30][CH2:31]6)=[O:28])[CH2:23]5)=[N:19][N:18]([CH2:40][C:41]([OH:43])([CH3:44])[CH3:42])[C:17]4=[O:32])=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)(O)CCl
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)Cn1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.233 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (100 mg, 0.724 mmol, 3.1 eq) and 1-chloro-2-methyl-2-propanol (50 mg, 0.461 mmol, 2 eq). The vial was capped and purged with nitrogen gas, and the reaction mixture was stirred for 16 h at 80° C. Analysis by LC/MS displayed no reaction. The solution was then irradiated in the microwave at 185° C. for 60 min. Analysis by LC/MS displayed the reaction was complete. The reaction mixture was poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extractions were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 25-55% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (56 mg, 48%). MS(ES)+ m/e 501.1 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:16]2[O:15][C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:9][C:8]=2[C:7]([C:17]2[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:21]=2)=[CH:6][CH:5]=1.[CH3:31][C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>>[CH3:2][O:3][C:4]1[C:16]2[O:15][C:10]3([CH2:11][CH2:12][CH2:13][CH2:14]3)[CH2:9][C:8]=2[C:7]([C:17]2[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH:22]3[CH2:27][CH2:26][N:25]([S:38]([C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([CH3:31])[CH:33]=4)(=[O:40])=[O:39])[CH2:24][CH2:23]3)[N:21]=2)=[CH:6][CH:5]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C)c4)CC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(7-methoxy-3H-spiro[1-benzofuran-2,1′-cyclopentan]-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B6*HCl) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.