Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:65](=[O:73])[NH:66][S:67]([CH:70]([CH3:72])[CH3:71])(=[O:69])=[O:68])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]4[N:49]([CH:50]5[CH2:52][CH2:51]5)[N:48]=[C:47]([CH:53]([CH3:55])[CH3:54])[C:46]=4[C:56]([OH:58])=O)=[CH:42][C:41]4[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:40]=4[C:39]=23)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.Cl.Cl.[CH3:76][N:77]1[C@H:82]([CH3:83])[CH2:81][NH:80][CH2:79][C@@H:78]1[CH3:84].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:65]([NH:66][S:67]([CH:70]([CH3:71])[CH3:72])(=[O:68])=[O:69])=[O:73])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]4[N:49]([CH:50]5[CH2:51][CH2:52]5)[N:48]=[C:47]([CH:53]([CH3:54])[CH3:55])[C:46]=4[C:56]([N:80]4[CH2:81][C@H:82]([CH3:83])[N:77]([CH3:76])[C@H:78]([CH3:84])[CH2:79]4)=[O:58])=[CH:42][C:41]4[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:40]=4[C:39]=23)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: COc1ccc2c(c1)C=C(c1c(C(=O)O)c(C(C)C)nn1C1CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Reactant: C[C@@H]1CNC[C@H](C)N1C
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: COc1ccc2c(c1)C=C(c1c(C(=O)N3C[C@@H](C)N(C)[C@@H](C)C3)c(C(C)C)nn1C1CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Reaction time: 2 h
Yield: 28.9 %

Procedure:
HATU (65.0 mg, 0.171 mmol) was added to a stirring solution of 5-(13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1-cyclopropyl-3-isopropyl-1H-pyrazole-4-carboxylic acid (78 mg, 0.114 mmol), (2S,6R)-1,2,6-trimethylpiperazine dihydrochloride (46 mg, 0.23 mmol), DIEA (80 μL, 0.456 mmol) in DMF (1 mL) at room temperature. The reaction was allowed to stir for 2 hours. The reaction was purified by preparative reverse phase HPLC on a C18 column using a TFA buffered H2O/CH3CN gradient, and concentrated to give the titled compound (31 mg, 0.033 mmol, 29% yield) consistent by LCMS and NMR, with sufficient purity by HPLC.
Reaction SMILES: [CH3:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[N:6]([CH2:10][C:11]([OH:13])=O)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:54]1([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:59]=[CH:58][C:57]([CH:60]([NH:67][CH3:68])[CH2:61][N:62]2[CH2:66][CH2:65][CH2:64][CH2:63]2)=[CH:56][CH:55]=1>C(Cl)Cl>[C:54]1([C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[CH:59]=[CH:58][C:57]([CH:60]([N:67]([CH3:68])[C:11](=[O:13])[CH2:10][N:6]2[C:5]3[CH:14]=[C:15]([O:16][CH3:17])[C:2]([CH3:1])=[CH:3][C:4]=3[O:8][C:7]2=[O:9])[CH2:61][N:62]2[CH2:66][CH2:65][CH2:64][CH2:63]2)=[CH:56][CH:55]=1
Reactant: COc1cc2c(cc1C)oc(=O)n2CC(=O)O
Reactant: CNC(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1C)oc(=O)n2CC(=O)N(C)C(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
[6-Methyl-5-(methyloxy)-2-oxo-1,3-benzoxazol-3(2H)-yl]acetic acid (59 mg, 0.25 mmol) and BOP reagent (133 mg, 0.30 mmol) were dissolved in CH2Cl2 (1 mL), and diisopropylethylamine (32 mg, 0.25 mmol) was added to it. The resulting mixture was stirred at room temperature for 5 min, then 1-(4-biphenylyl)-N-methyl-2-(1-pyrrolidinyl)ethanamine (70 mg, 0.25 mmol) was added. Stirring was continued for 16 h and then the mixture was concentrated. The residue was dissolved in CH3OH, and purified by preparative HPLC (YMC CombiPrep ODS-A, 50×50 mm, 50 mL/min, A: acetonitrile B: water with NH4OH at pH=10, A: 20% to 70% during 12 min, UV detection at 214 nm) to give 92 mg (74%) of the title compound as a white solid. MS (ES) m/e 500 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]([OH:13])=O)=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.Cl.[CH3:40][NH:41][O:42][CH3:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.ClCCl>[CH3:43][O:42][N:41]([CH3:40])[C:11]([C:10]1[N:2]([CH3:1])[C:3]2[C:8]([N:9]=1)=[C:7]([N:14]1[CH2:15][CH2:16][CH:17]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[NH:22][C:21]3=[O:29])[CH2:18][CH2:19]1)[N:6]=[CH:5][N:4]=2)=[O:13]
Reactant: CNOC
Reactant: Cn1c(C(=O)O)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9-Methyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxylic acid (450 mg, 1.14 mmol) was dissolved in dimethylacetamide (3 mL) and DIPEA (0.57 mL, 3.43 mmol). N,O-Dimethylhydroxylamine hydrochloride salt (123 mg, 1.26 mmol) was added to the solution, followed by dichloromethane (3 mL) and HATU (522 mg, 1.37 mmol). The reaction was stirred at room temperature for 1 hour. The crude reaction mixture was concentrated, diluted with 80 mL of dichloromethane, was washed with 2×50 mL of water and 3×50 mL of saturated potassium carbonate. The organic layer was collected, dried over magnesium sulfate, was filtered and was concentrated to afford N-methoxy-N,9-dimethyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxamide (quantitative yield) as an oil. 1H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 8.32 (s, 1H), 7.18-7.12 (m, 1H), 6.96-6.88 (m, 3H), 5.38 (br s, 2H), 4.55 (tt, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.49-3.09 (m, 5H), 2.40-2.23 (m, 2H), 1.83 (br d, 2H). MS (EI) for C21H24N8O3: 437 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:16])[NH:11][C:12](=[S:15])[NH:13][CH:14]=2)=[CH:4][N:3]=1.[CH3:17]C[O-].[Na+].CI>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][C:9]2[C:10](=[O:16])[N:11]=[C:12]([S:15][CH3:17])[NH:13][CH:14]=2)=[CH:6][N:7]=1
Reactant: CC[O-]
Reactant: Cc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CSc1nc(=O)c(Cc2cnc(C)nc2)c[nH]1
Yield: 38 %

Procedure:
5-(2-Methyl-pyrimidin-5-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (210 mg, 234.28 gmol−1, 0.90 mmol, 1 eq) and NaOEt (2 eq, 128 mg) were stirred in 5 ml of absolute ethanol at room temperature for 30 minutes. In the suspension was then added methyl iodide (2.5 eq, 140 μl) and the mixture was stirred for 35 hours. Solvent was then evaporated. In the mixture was added 3 ml of water and pH was adjusted to 5-6 range using 3N HCl water solution. The resulting precipitate was collected and dried to afford 5-(2-methyl-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (85 mg, yield=36.6%, purity=96%) in form of white powder. MS: [M+H]+=249.22 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.45 (s, 3H), 2.54 (s, 3H), 3.57 (s, 2H), 7.87 (br.s., 1H), 8.56 (s, 2H), 12.79 (br.s., 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[C:30]12([CH2:40][NH2:41])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:41][CH2:40][C:30]34[CH2:39][CH:34]5[CH2:33][CH:32]([CH2:38][CH:36]([CH2:35]5)[CH2:37]3)[CH2:31]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NCC34CC5CC(CC(C5)C3)C4)n2)cc1
Yield: 73 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 μL of triethylamine and 1-Adamantanemethylamine (19 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (40 mg, 73% yield.) MS/ES+: m/z=479
Reaction SMILES: [C:1]([O:6]CC)(=[O:5])C(C)=O.[CH2:9](O)[CH2:10]O.B(F)(F)F.[C:17]([OH:20])(=[O:19])[CH3:18]>ClCCl>[CH3:18][C:17]1([C:1]([OH:6])=[O:5])[O:20][CH2:10][CH2:9][O:19]1
Reactant: OCCO
Reactant: CCOC(=O)C(C)=O
Reactant: CC(=O)O
Agent: FB(F)F
Solvent: ClCCl
Product: CC1(C(=O)O)OCCO1
Temperature: 40 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
To a stirred mixture containing ethyl pyruvate (11.1 mL, 0.1 mol) and ethylene glycol (5.6 mL, 0.1 mol) in anhydrous dichloromethane (100 mL) at 0° C. was added boron trifluoride dietherate (6.4 mL, 0.05 mol) and catalytic amount of acetic acid. The resulting mixture was stirred at 40° C. for 16 h and then diluted with 100 mL of dichloromethane. The organic solution was washed successively with saturated sodium chloride solution (2×80 mL). The organic layer was separated and the combined organic extracts were concentrated. The residue was treated with 1N sodium hydroxide at room temperature. After stirring at room temperature for 3 h (monitored by TLC), citric acid was added to adjust the pH to 4. The product was extracted with dichloromethane, dried over Na2SO4 and concentrated to afford 5.1 g (38%) of the title compound (129) as a clear liquid. This material was used in the next reaction without further purification. 1H NMR (CDCl3, 400 MHz): δ 1.55 (s, 3H), 4.03 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[OH:20][CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C.[I-].[K+]>CN(C)C=O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11][N:26]2[CH2:27][CH2:28][CH:23]([CH2:22][CH2:21][OH:20])[CH2:24][CH2:25]2)=[CH:4][CH:3]=1
Reactant: OCCC1CCNCC1
Reactant: Fc1ccc(C(CCCBr)c2ccc(F)cc2)cc1
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OCCC1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
20 g (62 mmol) of 4,4-bis(4-fluorophenyl)butyl bromide, 8.8 g (68 mmol) of 4-hydroxyethylpiperidine, 12.5 g (124 mmol) of triethylamine and 0.1 g of potassium iodide were stirred in 200 ml of absolute dimethylformamide at 80° C. for 4.5 hours. The solvent was stripped off in vacuo, the residue was taken up in methylene chloride, the mixture was extracted by shaking with 2N HCl, water and NaCl solution and the extract was dried and concentrated.
Reaction SMILES: [C:1]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C1(C(OCC)=O)CCCCCCCCCCC1>>[C:1]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1=CCCCCCCCCCC1
Agent: CCOC(=O)C1CCCCCCCCCCC1
Product: CCOC(=O)C1=CC=CCCCCCCCC1

Procedure:
The major ester product of hydrogenation is a mixture of ethyl cyclododecenecarboxylate and ethyl cyclododecanecarboxylate.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9]3[C:14]([NH:15][C:4]2=[CH:3][CH:2]=1)=[CH:13][C:12]1[C:16]([C:18]2[C:23]([NH:24][C:11]=1[CH:10]=3)=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[O:8].[OH-:25].[K+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[OH2:39]>>[CH:20]1[CH:19]=[C:18]2[C:16]([C:12]3[C:13](=[O:39])[C:14]4[NH:15][C:4]5[C:5]([C:7](=[O:8])[C:9]=4[C:10](=[O:25])[C:11]=3[NH:24][C:23]2=[CH:22][CH:21]=1)=[CH:6][CH:1]=[CH:2][CH:3]=5)=[O:17]
Reactant: O
Reactant: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Reactant: [OH-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: O=C1c2[nH]c3ccccc3c(=O)c2C(=O)c2[nH]c3ccccc3c(=O)c21
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Quinacridone (50 grams) was dispersed in water (1000 grams) and potassium hydroxide (50 grams) was added. The resulting slurry was then heated to 65° C. and sodium peroxydisulfate (200 grams) was added over a 6 hour period. The resulting slurry was stirred continuously for 8 hours at 65° C. then filtered. The resulting presscake was washed with water to neutral and dried. 55 grams of bright yellow highly pure quinacridonequinone was produced.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N:10]1([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:10]1([CH:16]2[CH2:21][CH2:20][N:19]([C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=3)[CH2:18][CH2:17]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1ccc(F)cc1
Reactant: C1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(N2CCC(N3CCCCC3)CC2)cc1
Temperature: 100 °C

Procedure:
A mixture of 4-fluorobenzaldehyde (1 mL), {1,4′}bipiperidinyl (829.6 mg), and potassium carbonate (0.72 g) in DMF (3 mL) was heated to 100° C. for 6 h. The cooled reaction mixture was poured into water (200 mL) and then extracted with DCM. Removal of the solvent and chromatography of the residue on silica gel (1-7% 2 M methanolic ammonia/DCM) gave the title compound (838.3 mg).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)[CH3:2].S1C=C[CH:13]=[C:12]1C(O)=O.ICCCC>>[CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)[CH2:2][CH2:12][CH3:13]
Reactant: CCc1ccc(C(=O)O)s1
Reactant: O=C(O)c1cccs1
Solvent: CCCCI
Product: CCCCc1ccc(C(=O)O)s1

Procedure:
The title compound is prepared in analogy to 5-ethyl-thiophene-2-carboxylic acid starting from 2-thiophenecarboxylic acid and 1-iodobutane; LC-MS: tR=0.92 min.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].Cl[C:32](OC1C=CC([N+]([O-])=O)=CC=1)=[O:33].N.[NH2:45][CH2:46][CH2:47][C:48]1[N:52]=[CH:51][NH:50][CH:49]=1.[OH-].[Na+]>ClCCl.CN(C=O)C>[C:17]([C:8]1([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:32]([NH:45][CH2:46][CH2:47][C:48]2[N:52]=[CH:51][NH:50][CH:49]=2)=[O:33])[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH2:6][CH2:7]1)(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: NCCc1c[nH]cn1
Reactant: CCCC(=O)C1(C2CCCCC2)CCN(C(=O)[C@H](N)Cc2ccc(OC)cc2)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)NCCc2c[nH]cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
1.24 g (3 mmol) of 1-{1-[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexyl-piperidin-4-yl}butan-1-one and 660 mg (3.3 mmol) of para-nitrophenyl chloroformate are dissolved in 40 mL of dichloromethane at 0° C. The reaction mixture is stirred for 1 hour at room temperature and the reaction is then stopped by adding 20% aqueous ammonia solution and the organic products are extracted with dichloromethane. The organic phase is washed with water and then dried over sodium sulfate, filtered and concentrated. The white solid obtained is dissolved in 20 mL of DMF, the mixture is heated to 80° C., 0.367 g (3.3 mmol) of histamine is then added and the solution is stirred for 5 minutes at 80° C. and for 10 minutes at room temperature. The reaction is stopped by adding aqueous 1N NaOH solution and the reaction medium is extracted with DCM. The organic phase is washed with water and then dried over sodium sulfate, filtered and concentrated. The crude product obtained is chromatographed on silica gel (eluent: 80/20 DCM/MeOH). 1.1 g of 1-[(R)-2-(4-butyryl-4-cyclo-hexylpiperidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1H-imidazol-4-yl)ethyl]urea in the form of a white powder are obtained in a yield of 67%.
Reaction SMILES: [C:1](=[S:19])([O:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:14])=[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=1)[NH2:2].Cl[CH2:21][C:22](=O)[CH3:23].O>C(O)(=O)C>[C:15]([C:6]1[CH:5]=[C:4]([O:3][C:1]2[S:19][CH:21]=[C:22]([CH3:23])[N:2]=2)[CH:9]=[C:8]([C:10]([CH3:11])([CH3:12])[CH3:13])[C:7]=1[OH:14])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(=O)CCl
Reactant: CC(C)(C)c1cc(OC(N)=S)cc(C(C)(C)C)c1O
Solvent: CC(=O)O
Solvent: O
Product: Cc1csc(Oc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Yield: 58.7 %

Procedure:
O-(3,5-Di-tert-butyl-4-hydroxyphenyl) thiocarbamate (1.5 g) and 1.3 g of chloroacetone were dissolved in 60 ml of acetic acid, and the solution was heated at 90°-100° C. for 15 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product obtained was purified by silica gel column chromatography (diethyl ether-hexane =1:4) to give 1.0 g of the desired compound as a colorless solid.
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:21][CH2:20][C:12]3([S:16][CH2:15][C@@H:14]([C:17]([OH:19])=[O:18])[NH:13]3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>C(Cl)Cl>[C:31]([N:13]1[C:12]2([CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:23][CH:22]=3)[CH2:21][CH2:20]2)[S:16][CH2:15][C@H:14]1[C:17]([OH:19])=[O:18])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)c1ccc(OC2CCC3(CC2)N[C@H](C(=O)O)CS3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(OC2CCC3(CC2)SC[C@@H](C(=O)O)N3C(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
In 50 ml of methylene chloride were dissolved 2.40 g of (3R)-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-carboxylic acid and 2.23 ml of triethylamine. To the solution thus obtained was dropwise added 1.41 g of benzoyl chloride at 0-5° C., and the resulting mixture was stirred at the same temperature as above for 3 hours. The reaction mixture was poured into ice water, pH was adjusted to 1.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl ether was added to the residue thus obtained, and the deposited crystal was collected by filtration. Thus, 2.10 g of (3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-carboxylic acid was obtained as a colorless crystalline product.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[C:33]1([C:39]2[O:40][C:41]([C:47]([F:50])([F:49])[F:48])=[C:42]([C:44](Cl)=[O:45])[N:43]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.C(OCC)(=O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:44]([C:42]4[N:43]=[C:39]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[O:40][C:41]=4[C:47]([F:49])([F:50])[F:48])=[O:45])=[CH:17][N:16]=3)[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: Nc1ccc(N2CCC(c3cccc(C(F)(F)F)c3)CC2)nc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(N2CCC(c3cccc(C(F)(F)F)c3)CC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ylamine (400 mg, 1.24 mmol) in methylene chloride (10 mL) was added diisopropylethylamine (0.60 mL, 3.30 mmol) followed by 2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl chloride (300 mg, 1.10 mmol). The reaction was stirred at room temperature for 24 hours and then diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated to dryness under vacuum. The residue was purified by HPLC to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(3-trifluoromethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-amide as a light purple solid. The NMR spectrum obtained on the sample is compatible with its structure. LCMS calcd for C28H22F6N4O2 (m/e) 560, obsd 561 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.Br[C:36]1[N:41]([CH3:42])[C:40](=[O:43])[CH:39]=[CH:38][CH:37]=1>>[OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:36]3[N:41]([CH3:42])[C:40](=[O:43])[CH:39]=[CH:38][CH:37]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: Cn1c(Br)cccc1=O
Product: C[C@@H](c1ccc(-c2cccc(=O)n2C)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 6-bromo-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 30 Step 2. LC-MS Method 2 tR=1.088 min, m/z=447; 1H NMR (CDCl3) 1.38 (m, 1H), 1.56 (d, 3H), 1.70 (m, 1H), 1.95-2.08 (m, 2H), 2.23 (m, 1H), 2.37 (s, 2H), 3.05 (m, 1H), 3.33 (s, 3H), 3.58 (m, 2H), 5.73 (m, 1H), 6.29 (d, 1H), 6.89 (d, 1H), 7.01-7.09 (m, 4H), 7.21-7.39 (m, 5H), 7.53 (t, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH3:25]
Reactant: CCNCc1ccc(O)cc1
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Product: CCN(Cc1ccc(O)cc1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with 4-ethylaminomethyl-phenol
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8](C)[C:9](O)=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:11]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O.[CH2:24](Cl)[Cl:25]>>[ClH:1].[ClH:22].[Cl:1][C:2]1[S:6][C:5]([C:7]2[NH:8][C:9]([CH2:24][Cl:25])=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccc(Cl)s2)nc(-c2cccnc2)c1O
Reactant: ClCCl
Reactant: O=S(Cl)Cl
Product: Cl
Product: ClCc1[nH]c(-c2ccc(Cl)s2)nc1-c1cccnc1

Procedure:
To a solution of 2-(5-chlorothiophen-2-yl)-5-hydroxy-methyl-4-(3-pyridyl) imidazole (200 mg) in methylene chloride (5 ml) was added thionyl chloride (5 ml), and the mixture was refluxed for one hour. After cooling, the reaction mixture was concentrated under reduced pressure to obtain a crude product of 2-(5-chlorothiophen-2-yl)-5-chloromethyl-4-(3-pyridyl)-imidazole dihydrochloride (260 mg) as yellowish powder.