Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[C:30]([O:31][C:32]2[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=2)=[CH:29][C:19]2[N:20]=[C:21]([C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)[NH:22][C:18]=2[CH:17]=1)=O>CO.O>[CH3:41][S:38]([C:35]1[CH:36]=[CH:37][C:32]([O:31][C:30]2[C:16]([CH:12]3[CH2:13][CH2:14][CH2:15][NH:11]3)=[CH:17][C:18]3[NH:22][C:21]([C:23]4[CH:28]=[N:27][CH:26]=[CH:25][N:24]=4)=[N:20][C:19]=3[CH:29]=2)=[CH:33][CH:34]=1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4cnccn4)[nH]c3cc2C2CCCN2C(=O)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4cnccn4)[nH]c3cc2C2CCCN2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
55 mg of potassium carbonate was added to a solution of 40 mg of 2,2,2-trifluoro-1-(2-(6-(4-methanesulfonyl-phenoxy)-2-pyrazin-2-yl-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone in a mixture of 1.6 ml of methanol and 0.4 ml of water, and the reaction liquid was stirred overnight at room temperature. The reaction liquid was concentrated under reduced pressure, and aqueous saturated ammonium chloride was added to the residue, then extracted with chloroform, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol/aqueous ammonia=90/10/1) to obtain the entitled compound as an oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][C:3]1=[O:13].C(N(CCC)CCC)CC.[C:24]1([CH:30]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][NH2:40])[CH2:33][CH2:32]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCOCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:40][CH2:39][CH2:38][CH2:37][N:34]2[CH2:33][CH2:32][N:31]([CH:30]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:36][CH2:35]2)=[N:4][C:3]1=[O:13]
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: Cn1c(=O)nc(Cl)c2ccccc21
Agent: CCCN(CCC)CCC
Solvent: C1COCCO1
Product: Cn1c(=O)nc(NCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.4 %

Procedure:
To a suspension of 1-methyl-4-chloro-2(1H)quinazolinone (4 g), tri(n-propyl)amine (7.2 g) and dioxane (20 ml) was added 3-[4-(diphenylmethyl)piperazin-1-yl]propylamine (3.5 g) and the mixture was stirred for 1.5 hours at ambient temperature. The reaction mixture was concentrated in vacuo and to the residue was added water. After the aqueous layer was made basic with 1N potassium hydroxide aqueous solution, the mixture was extracted twice with chloroform. The chloroform layer was washed with 0.2N potassium hydroxide aqueous solution, with water and with saturated sodium chloride aqueous solution respectively, dried over anhydrous magnesium sulfate and then concentrated in vacuo. After the residue was dissolved in toluene, remaining tri(n-propyl)amine was removed by evaporation in vacuo. This procedure was carried out further twice and then the residual oil was purified by subjecting to a column chromatography on silica gel (70 g) using 2% methanol in chloroform for elution to give a crystal, which was recrystallized from a mixture of ethyl acetate and hexane to give 1-methyl-4-[ 3-{4-(diphenylmethyl)piperazin-1-yl}propylamino]-2(1H)-quinazolinone (2.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[Li+].C[Si]([N-:14][Si](C)(C)C)(C)C.[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([NH2:14])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:5][CH:6]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=Cc1cc(Br)cs1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(Cc1ccccc1)c1cc(Br)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromothiophene-2-carboxaldehyde (10.1 g, 52.8 mmol) in anhydrous THF (150 mL) at 0° C. under N2 was added dropwise 1.0 M LiHMDS (58 mL) in THF. After 30 min, a solution of 2.0 M benzylmagnesium chloride (27 mL) in THF was added dropwise. The resulting mixture was stirred at rt for 50 min. The reaction mixture was quenched with sat. NH4Cl and most of the THF was evaporated. The residue was diluted with ethyl acetate (150 mL), washed with water and brine, and dried over MgSO4. Purification by flash chromatography gave 1A as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ: 1.5 (s, broad, 2H), 2.8 (m, 1H), 3.08 (m, 1H), 4.4 (m, 1H), 6.8 (s, 1H), 7.1-7.3 (m, 6H).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][C@H:8]([NH:11][S:12]([C:15]1[C:16]([O:23][CH2:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=[CH:28][CH:27]=2)=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:22][O:21][C:18]1[N:17]=[C:16]([O:23][CH2:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=[CH:28][CH:27]=2)[C:15]([S:12]([NH:11][C@H:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:36])=[O:5])(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: COc1ccc(S(=O)(=O)N[C@H](C=O)CC(=O)OC(C)(C)C)c(OCCc2ccnc3ccccc23)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N[C@H](C=O)CC(=O)O)c(OCCc2ccnc3ccccc23)n1

Procedure:
(S)-3-[6-Methoxy-2-(2-quinolin-4-yl-ethoxy)-pyridin-3-sulfonylamino]-4-oxo-butyric acid tert-butyl ester (0.18 g, 0.35 mmol) was stirred in 5 mL of a solution of 25% TFA in CH2Cl2 at room temperature for 2 h. Analytical HPLC indicated the reaction was complete. The reaction mixture was concentrated. Residual TFA was azeotroped with toluene. The crude product was purified by preparative-scale reverse phase HPLC (0 to 30% acetonitrile in H2O with 0.1% TFA over 2.5 hours at 15 mL/min on Vydac 2.5×25 cm C18 column) to give 0.053 g (0.12 mmol, 33%) of (S)-3-[6-methoxy-2-(2-quinolin-4-yl-ethoxy)-pyridin-3-sulfonylamino]-4-oxo-butryric acid as a fluffy white solid. MS (APCI) m/z 460.2 (M+1). 1H NMR (300 MHz) CD3OD 9.03 (m, 1H), 8.63 (d, J=8.4 Hz, 1H), 7.94-8.23 (m, 5H), 6.39 (d, J=8.4 Hz, 1H), 4.97 (m, 2H), 4.43 (dd, 1H), 3.96 (m, 2H), 3.88 (d, 3H), 3.48 (m, 1H), 2.46-2.60 (m, 1H), 2.24-2.38 (m, 1H)
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([S:5][C:6]1[NH:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)=[O:4].[CH3:18][N:19]([CH3:23])[C:20](Cl)=[O:21]>N1C=CC=CC=1>[CH3:18][N:19]([CH3:23])[C:20]([N:7]1[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=[C:6]1[S:5][C:3](=[O:4])[N:2]([CH3:17])[CH3:1])=[O:21]
Reactant: CN(C)C(=O)Cl
Reactant: CN(C)C(=O)Sc1nc(-c2ccccc2)c[nH]1
Solvent: c1ccncc1
Product: CN(C)C(=O)Sc1nc(-c2ccccc2)cn1C(=O)N(C)C
Temperature: 120 °C
Yield: 99.5 %

Procedure:
In 5 ml of pyridine was dissolved 0.70 g (2.84 millimoles) of 2-(N,N-dimethylcarbamoylthio)-4-phenylimidazole, and 0.26 ml (2.84 millimoles) of N,N-dimethylcarbamoyl chloride was added to the solution and the mixture was heated at 120° C. for 5 hours. The mixture was concentrated under reduced pressure and 20 ml of water and 20 ml of chloroform were added to the concentrate to effect extraction. The chloroform layer was dried and concentrated under reduced pressure to obtain 0.9 g (yield=100%) of intended 1-(N,N-dimethylcarbamoyl)-2-(N,N-dimethylcarbamoylthio)-4-phenylimidazole (compound No. 30) in the form of a light brown oil.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>C1(C)C(C)=CC=CC=1>[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]1=2)=[O:24]
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: O=C(Cl)CCCCCCl
Solvent: Cc1ccccc1C
Product: O=C1Nc2cccnc2N(C(=O)CCCCCCl)c2ccccc21

Procedure:
A solution of 5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one and 6-chloro-caproyl chloride in xylene was reacted to obtain 11-(6-chloro-caproyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one melting at 128°-130° C.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]2[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]2[CH2:8][NH:9][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(Br)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(OC2CNC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate (300 mg, 0.90 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give 3-(4-bromophenoxy)azetidine (207 mg, 100%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][N:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[S:24][C:23]4=[O:31])[CH2:15][CH2:14]3)[C:12](=[O:32])[N:11]([CH2:33][C:34]3[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=3)[C:37]([O:39]C)=[O:38])[CH2:10]2)=[CH:5][CH:4]=1.O.[OH-].[Li+]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][N:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[S:24][C:23]4=[O:31])[CH2:15][CH2:14]3)[C:12](=[O:32])[N:11]([CH2:33][C:34]3[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=3)[C:37]([OH:39])=[O:38])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(CN2CN(c3ccc(OC)cc3)C3(CCN(CCCn4c(=O)sc5ccccc54)CC3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(N2CN(Cc3cccc(C(=O)O)c3)C(=O)C23CCN(CCCn2c(=O)sc4ccccc42)CC3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
To a solution of methyl 3-((1-(4-methoxyphenyl)-4-oxo-8-(3-(2-oxobenzo[d]thiazol-3(2H)-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.19 g, 0.32 mmol) in methanol (3 mL) was added lithium hydroxide monohydrate (0.027 g, 0.63 mmol) in water (1 mL). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.11 g, 59%); 1H NMR (DMSO-d6): δ 1.64 (d, 2H, J=13.6 Hz), 1.79 (t, 2H, J=6.4 Hz), 1.88-1.95 (m, 2H), 2.38 (t, 2H, J=6 Hz), 2.50-2.66 (m, 4H), 3.69 (s, 3H), 3.97 (t, 2H, J=6.4 Hz), 4.53 (d, 4H, J=26.8 Hz), 6.86 (d, 2H, J=7.2 Hz), 6.94 (d, 2H, J=7.6 Hz), 7.16 (t, 1H, J=7.2 Hz), 7.30 (t, 1H, J=7.6 Hz), 7.38 (d, 1H, J=7.6 Hz), 7.47-7.53 (m, 2H), 7.58 (dd, 1H, J=8 and 1.2 Hz), 7.85-8.87 (m, 2H), 12.95 (br, 1H); MS for C32H34N4O5S m/z 587.02 (M+H)+.
Reaction SMILES: CC(O[C:6](=[O:22])[NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([NH:17][CH:18]2[CH2:20][CH2:19]2)=[O:16])[C:9]1=[O:21])(C)C.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:47][C:48]1[CH:57]=[C:56]2[C:51]([C:52]([N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)=[CH:53][C:54]([NH2:58])=[N:55]2)=[CH:50][CH:49]=1>>[NH2:58][C:54]1[CH:53]=[C:52]([N:59]2[CH2:60][CH2:61][N:62]([C:6]([NH:7][C@H:8]3[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([NH:17][CH:18]4[CH2:19][CH2:20]4)=[O:16])[C:9]3=[O:21])=[O:22])[CH2:63][CH2:64]2)[C:51]2[C:56](=[CH:57][C:48]([Cl:47])=[CH:49][CH:50]=2)[N:55]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(C(=O)NC2CC2)C1=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(C(=O)NC4CC4)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 213, [(3R)-1-[(cyclopropylamino)carbonyl]hexahydro-2-oxo-1H-azepin-3-yl]-carbamic acid-1,1-dimethylethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a white solid. LC-MS: 500 (M++1). 1H NMR (CDCl3): δ 0.50˜0.62 (m, 2H), 0.72–0.84 (m, 2H), 1.42 (m, 1H), 1.60 (m, 1H), 1.82˜2.02 (m, 3H), 2.13 (m, 1H), 2.76 (ddd, 1H), 3.12 (br.dd, 4H), 3.24 (br.dd, 1H), 3.66 (m, 4H), 4.82˜4.94 (m, 2H), 5.02 (br.s, 2H), 5.86 (d, 1H), 6.16 (s, 1H), 7.16 (dd, 1H), 7.60 (d, 1H), 7.72 (d, 1H), 9.10 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH:22]([CH2:23][O:24][CH2:25][C:26]([O-:28])=[O:27])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.[OH-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[C@H:22]([CH2:23][O:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2Cc3ccccc3CC2COCC(=O)[O-])c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N2Cc3ccccc3C[C@H]2COCC(=O)O)c(C)c1
Temperature: 25 °C

Procedure:
(S)-tert-butyl 2-((2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxyacetate (1.58 g, 3.32 mmol) was dissolved in tetrahydrofuran (10 ml), and sodium hydroxide solution (531 mg, 13.28 mmol in water (0.5 ml)) was added. The reaction mixture was refluxed for 2 h, then cooled to room temperature again, and water (20 ml) was added. The pH value of the aqueous phase was adjusted to pH 2 with 2 M hydrochloric acid, and extraction with ethyl acetate (3×20 ml) was carried out. The crude product was used in the next stage without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:16].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](=[NH:30])OCC)=[CH:21][CH:20]=1>C(O)C>[ClH:16].[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:26](=[NH:30])[CH2:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: CCOC(=N)Cc1ccc(OC)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(CC(=N)Nc2ncccc2OCc2ccccc2)cc1
Yield: 16.5 %

Procedure:
A mixture of 2-amino-3-benzyloxypyridine (4.0 g, 20 mmol) and ethyl 4-methoxyphenylacetimidate hydrochloride (5.04 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol) to give the product (1.27 g), m.p. 75°-78° C.
Reaction SMILES: [Si:1]([C:8]1[N:9]([S:17]([N:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:10]([CH:13]=[CH:14][C:15]#[N:16])=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)(Cl)Cl>C(O)C.C1COCC1.[Pt]=O>[Si:1]([C:8]1[N:9]([S:17]([N:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:10]([CH2:13][CH2:14][CH2:15][NH2:16])=[CH:11][N:12]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CN(C)S(=O)(=O)n1c(C=CC#N)cnc1[Si](C)(C)C(C)(C)C
Agent: O=[Pt]
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN(C)S(=O)(=O)n1c(CCCN)cnc1[Si](C)(C)C(C)(C)C

Procedure:
Compound 29 (2.1 mmol) is dissolved in absolute ethanol (75 mL) and THF (25 mL). Chloroform (1.5 mL) and platinum oxide (70 mg) are added and the mixture subjected to hydrogenation at 5 atmospheres in a Parr hydrogenation apparatus. After 4 hours the mixture is filtered through celite and the celite bed washed with absolute ethanol (2×20 mL). The filtrate and washings are evaporated in vacuo to give a product which is purified by column chromatography to provide the title compound 30.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:52]1[CH2:55][CH:54]([OH:56])[CH2:53]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([N:52]4[CH2:55][CH:54]([OH:56])[CH2:53]4)=[O:26])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: OC1CNC1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)N3CC(O)C3)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
To a DMF (0.4 mL) solution of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation K, 30 mg, 0.084 mmol) was added HATU (38 mg, 0.10 mmol) and azetidin-3-ol hydrochloride (11 mg, 0.10 mmol) at ambient temperature, followed by dropwise addition of DIEA (0.044 ml, 0.25 mmol) at 0° C. After stirring for 20 minutes at ambient temperature, the reaction was directly purified by reverse-phase chromatography (5 to 50% acetonitrile/water) to yield the final product as white solid (26 mg, 75%). LCMS (apci) m/z=413.1 (M+H).
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:20]1[O:22][CH:21]1[CH2:23][OH:24]>>[CH2:1]([S:19][CH2:20][CH:21]([OH:22])[CH2:23][OH:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCC1CO1
Reactant: CCCCCCCCCCCCCCCCCCS
Product: CCCCCCCCCCCCCCCCCCSCC(O)CO

Procedure:
The octadecyl mercaptan is then condensed with 4 moles glycidol per mole octadecyl mercaptan, first introducing a first molar equivalent of glycidol to obtain 3-octadecylthio-propane-1,2 diol at 80° C, the rest of the glycidol being introduced at 155° C in the course of 2 hours 20 minutes.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[CH:32]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[CH:32]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=2[C:39]2[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(C2c3ccccc3-c3ccccc32)[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc(C[C@@H]2C[C@@H](NCc3ccnc4ccccc34)CCN2C2c3ccccc3-c3ccccc32)cc1

Procedure:
130 mg (0.219 mmol) (2R*,4S*)-2-benzyl-1-(9-fluorenyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 40 with 500 μl (0.500 mmol) of 1N sodium hydroxide solution in 1 ml of tetrahydrofuran and 1 ml of methanol. The title compound ##STR77## is obtained (49 mg, 45%) as white foam. TLC:toluene/ethyl acetate (1:1) Rf =0.26; FD-MS:M+ =495.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1C=O.C1[O:19][C:14]([CH2:16][CH2:17][NH2:18])([CH3:15])OC1.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:6][C:7]([CH:20]2[CH2:15][C:14](=[O:19])[CH2:16][CH2:17][NH:18]2)=[C:8]([CH3:10])[CH:9]=1
Reactant: Cc1ccc(C=O)c(F)c1
Reactant: CC1(CCN)OCCO1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1C1CC(=O)CCN1
Temperature: 25 °C
Yield: 41.7 %

Procedure:
2-Fluoro-4-methyl-benzaldehyde (4 g) was added to a solution of 4-aminobutan-2-one ethylene acetal (3.8 g) in dry benzene (50 mL) and the solution was stirred at r.t. under a nitrogen atmosphere. After 1 hour the mixture was heated at reflux for 16 hours and then allowed to cool to r.t. This solution was slowly added to a refluxing solution of p-toluenesulphonic acid (10.6 g) in dry benzene (50 mL) previously refluxed for 1 hour with a Dean-Stark apparatus. After 3.5 hours the crude solution was cooled and made basic with a saturated potassium carbonate solution and taken up with AcOEt (50 mL). The aqueous phase was extracted with AcOEt (3×50 mL) and Et2O (2×50 mL). The organic layer was dried and concentrated in vacuo to a yellow thick oil as residue (7.23 g). A portion of the crude mixture (3 g) was dissolved in a 6N hydrochloric acid solution (20 mL) and stirred at 60° C. for 16 hours. The solution was basified with solid potassium carbonate and extracted with DCM (5×50 mL). The combined organic phases were washed with brine (50 mL), dried and concentrated in vacuo to give the title compound (2.5 g) as a thick yellow oil.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].[I:7][C:8]1[CH:9]=C(O)C(=C[CH:15]=1)C=O.[C:17]1(C)C=CC=C[CH:18]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[OH:4][C:2]1[CH:3]=[CH:9][C:8]([I:7])=[CH:15][C:1]=1[CH:17]=[CH2:18]
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccccc1
Reactant: O=Cc1ccc(I)cc1O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1cc(I)ccc1O
Temperature: 23 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
Haloorganic compound 15 was synthesized by a multi-step process. To a mixture of methyltriphenylphosphonium bromide (14.08 g, 39.4 mmol) in toluene at 23° C. was added a solution of potassium tert-butoxide (4.47 g, 39.8 mmol) in THF (60 mL) dropwise via cannula, and the resulting mixture was allowed to stir at 23° C. for 4 hours. The resulting yellow mixture was cooled to −78° C. and a solution of 4-iodo-salicylaldehyde (4.35 g, 17.5 mmol) in toluene (40 mL) was added dropwise via cannula. The resulting mixture was allowed to slowly warm to 23° C. and was stirred at that temperature for 12 hours. The reaction was then quenched with the addition of saturated aq. ammonium chloride (100 mL). The resulting mixture was then diluted with water (200 mL) and extracted with Et2O (3×100 mL). The combined organic fractions were then washed with brine (100 mL), dried over magnesium sulfate, and concentrated in vacuo. Purification by flash chromatography (SiO2, hexanes:ethyl acetate 7:1→1:1) yielded 2-hydroxy-5-iodostyrene as a colorless solid (4.0 g, 98%). See also Gligorich, K. M., 2006.
Reaction SMILES: [OH-].[Li+].[CH:3]1([CH2:6][O:7][C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=2/[CH:16]=[CH:17]/[C:18]2[N:19]=[C:20]3[N:24]([C:25]=2[C:26]([OH:28])=[O:27])[CH:23]=[CH:22][S:21]3)[CH2:5][CH2:4]1>>[CH2:6]([O:7][C:8]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:16]=[CH:17]/[C:18]1[N:19]=[C:20]2[N:24]([C:25]=1[C:26]([OH:28])=[O:27])[CH:23]=[CH:22][S:21]2)[CH:3]([CH3:5])[CH3:4]
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC1CC1
Agent: [Li+]
Agent: [OH-]
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC(C)C

Procedure:
Lithium hydroxide assisted hydrolysis of Step 1 intermediate (200 mg, 0.499 mmol) as described in Intermediate 1 gave 170 mg of the desired product as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.07 (d, J=6.3 Hz, 6H), 2.14-2.27 (m, 1H), 3.76 (d, J=6.3 Hz, 2H), 3.87 (s, 3H), 6.86 (d, J=7.8 Hz, 1H), 6.95 (d, J=4.5 Hz, 1H), 7.06 (t, J=7.8 Hz, 1H), 7.32 (d, J=7.2 Hz, 1H), 7.84 (d, J=16.2 Hz, 1H), 8.07 (d, J=16.2 Hz, 1H), 8.12-8.17 (m, 1H); APCI-MS (m/z) 373.07 (MH)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.I[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)=[CH:20][CH:21]=1
Reactant: COc1ccc(I)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: COc1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)cc1
Yield: 15 %

Procedure:
As described for Example 2b, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.44 mmol) using 4-iodoanisole instead of iodobenzene was converted to the title compound (22 mg, 15%) which was obtained as a yellow gum. MS: m/e=332.3 [M+H]+.