Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Cl[CH2:10][C:11]1[CH:15]=[CH:14][S:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:10][C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)=[CH:4][N:3]=1
Reactant: ClCc1ccsc1
Reactant: Oc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncc(OCc2ccsc2)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A mixture of 2-chloro-5-hydroxypyrimidine (200 mg), 3-chloromethylthiophene (610 mg), potassium carbonate (635 mg) and dimethylformamide (3 ml) is stirred at 50° C. for one hour. After the reaction is complete, to the reaction mixture is added water, and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; n-hexane/ethyl acetate=20:1→20:3), and evaporated to remove the solvent to give 2-chloro-5-(3-thienylmethoxy)pyrimidine (345 mg) as colorless needles.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)N=1.BrC1C=CC2[O:21][CH2:22][O:23]C=2C=1C(O)=O.ClC1N=C(C)C=CC=1C(O)=O>>[N:12]1[N:11]([C:4]2[CH:1]=[CH:2][C:10]3[O:21][CH2:22][O:23][C:9]=3[C:5]=2[C:6]([OH:8])=[O:7])[N:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(C(=O)O)c(-n2nccn2)n1
Reactant: O=C(O)c1c(Br)ccc2c1OCO2
Agent: Cc1ccc(C(=O)O)c(Cl)n1
Product: O=C(O)c1c(-n2nccn2)ccc2c1OCO2

Procedure:
The title compound was prepared in a manner analogous to Intermediate 70 substituting 5-bromobenzo[1,3]dioxole-4-carboxylic acid for 2-chloro-6-methylnicotinic acid. MS (ESI): mass calculated for C10H7N3O4, 233.18; m/z found 234.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.85 (s, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.16 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)[C:3]=1[CH3:14].[CH3:15][S:16]SC.N(OCCCC)=O.Cl>[Cu].O>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)[C:5]([S:16][CH3:15])=[CH:7][CH:8]=1
Reactant: CSSC
Reactant: Cc1c(Br)ccc(N)c1C1=NOCC1
Agent: [Cu]
Agent: CCCCON=O
Agent: Cl
Solvent: O
Product: CSc1ccc(Br)c(C)c1C1=NOCC1
Reaction time: 1 h
Yield: 89 %

Procedure:
114.7 g (0.45 mol) of 4-bromo-2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline, 857 mg of copper powder and 1000 ml of dimethyl disulfide are initially charged. Over a period of one hour, 49.2 g of n-butyl nitrite are metered in at 58-65° C., and the mixture is stirred until the reaction has gone to completion (about 1-3 hours). At 20-25° C., 130 ml of conc. hydrochloric acid are added, and the mixture is stirred for 20-30 minutes. 130 ml of water are added, and the phases are then separated. Washing is repeated twice. The organic phase is concentrated, giving 114.4 g of product (yield: 89%).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.CCN(C(C)C)C(C)C.[CH2:51]([O:53][C:54](=[O:75])[C@H:55]([OH:74])[CH2:56][N:57]([CH2:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[C:70]([Cl:72])[CH:69]=[CH:68][C:67]=2[F:73])=[CH:62][CH:61]=1)[NH2:58])[CH3:52]>>[CH2:51]([O:53][C:54](=[O:75])[C@H:55]([OH:74])[CH2:56][N:57]([CH2:59][C:60]1[CH:61]=[CH:62][C:63]([C:66]2[CH:71]=[C:70]([Cl:72])[CH:69]=[CH:68][C:67]=2[F:73])=[CH:64][CH:65]=1)[NH:58][C:9]([C:7]1[NH:6][N:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:8]=1)=[O:11])[CH3:52]
Reactant: CCOC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(C(C)=O)n[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Acetyl-1H-pyrazole-5-carboxylic acid (168 mg, 1.1 mmol) and HCTU (451 mg, 1.1 mmol) were combined in DMF (6.8 mL, 87.2 mmol), and stirred at room temperature. After 15 minutes, DIPEA (570 μL, 3.3 mmol) and (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid ethyl ester (400 mg, 1.1 mmol) were added. The mixture was stirred for 20 minutes at room temperature, then evaporated under reduced pressure to yield the title compound. MS m/z [M+H]+ calc'd for C24H24ClFN4O5, 503.14. found 503.2.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O>>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1/[CH:18]=[N:8]/[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1Br
Product: Brc1ccccc1/C=N/C(c1ccccc1)c1ccccc1

Procedure:
This material was prepared from diphenylmethanamine and 2-bromobenzaldehyde using the methods described by G. Cainelli et al, J. Org. Chem., 1996, 51, 5134.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C@@H:15]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:16][S:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:11]([F:30])=[CH:10][N:9]=1>CO.O>[C:22]([O:21][C:19](=[O:20])[CH2:18][S@:17]([CH2:16][CH:15]([NH:14][C:12]1[C:11]([F:30])=[CH:10][N:9]=[C:8]([Cl:7])[N:13]=1)[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:1])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)CSC[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C[S@@](=O)CC(Nc1nc(Cl)ncc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Oxone (1.04 g, 1.69 mmol) was added to a stirring solution of (S)-tert-Butyl 2-(2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethyl-butylthio)ethanoate, 168a, (0.53 g, 1.41 mmol) in methanol (20 mL). The solution was stirred for 15 minutes at room temperature. The solution was concentrated to give white residue which was dissolved in water (50 mL). The aqueous layer was extracted with EtOAc (3×25 mL) and the organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 540 mg of the desired product as a white solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.05 minutes (M+H) 394.28.
Reaction SMILES: [C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[N:17]=[CH:18][S:19][CH:20]=3)[C@@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH2:34][CH:35]([CH3:37])[CH3:36])[C:27]([O:29]C(C)(C)C)=[O:28])=[O:10])=[CH:7][C:6]=1[O:40][CH3:41])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[N:17]=[CH:18][S:19][CH:20]=3)[C@@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH2:34][CH:35]([CH3:36])[CH3:37])[C:27]([OH:29])=[O:28])=[O:10])=[CH:7][C:6]=1[O:40][CH3:41])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(C(=O)N2[C@@H](c3cscn3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)OC(C)(C)C)ccc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N2[C@@H](c3cscn3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)O)ccc1C(C)(C)C

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1, to afford the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([S:4]([NH:6][C:7]1(/[C:11](=[N:13]/[OH:14])/[NH2:12])[CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:3].[CH3:16]OC(OC)N(C)C>O1CCOCC1>[O:14]1[CH:16]=[N:12][C:11]([C:7]2([NH:6][S:4]([C:2]([CH3:15])([CH3:1])[CH3:3])=[O:5])[CH2:10][CH2:9][CH2:8]2)=[N:13]1
Reactant: CC(C)(C)S(=O)NC1(/C(N)=N/O)CCC1
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: CC(C)(C)S(=O)NC1(c2ncon2)CCC1
Temperature: 70 °C
Yield: 14.7 %

Procedure:
(Z)-1-(1,1-dimethylethylsulfinamido)-N′-hydroxycyclobutanecarboximidamide (300 mg, 1.29 mmol) was taken up in dioxane (6 ml) and treated with N,N-Dimethylformamide dimethyl acetal (2.6 ml, 19 mmol) at rt. The reaction was then heated to 70° C. for 4 h. LCMS showed that starting material had been consumed. The expected M+H of 244 was observed in one of the minor peaks. The reaction was concentrated under high vacuum and the residue was purified by preparative reverse phase HPLC on a C18 column using a NH4OAc buffered H2O/CH3CN gradient, and concentrated to give N-(1-(1,2,4-oxadiazol-3-yl)cyclobutyl)-2-methylpropane-2-sulfinamide (45 mg, 0.19 mmol, 14% yield) as a light brown oil consistent by LCMS. LC-MS retention time: 1.31 min; m/z (MH+): 244. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([NH:24][C:25](=S)[NH:26][C:27]1[CH:32]=[CH:31][C:30](/[N:33]=[CH:34]/[N:35](C)C)=[C:29]([C:38]#N)[CH:28]=1)([CH3:23])[CH2:21][OH:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:41]1[CH:42]=[N:43][N:44]2[CH:49]=[CH:48][C:47]([O:50][C:51]3[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][C:52]=3[CH3:58])=[CH:46][C:45]=12>>[N:41]1[CH:42]=[N:43][N:44]2[CH:49]=[CH:48][C:47]([O:50][C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:38]4[C:29]5[C:30](=[CH:31][CH:32]=[C:27]([NH:26][C:25]6[O:22][CH2:21][C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]7[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=7)[C:2]7[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=7)([CH3:23])[N:24]=6)[CH:28]=5)[N:33]=[CH:34][N:35]=4)=[CH:53][C:52]=3[CH3:58])=[CH:46][C:45]=12
Reactant: Cc1cc(N)ccc1Oc1ccn2ncnc2c1
Reactant: CN(C)/C=N/c1ccc(NC(=S)NC(C)(CO)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1C#N
Product: Cc1cc(Nc2ncnc3ccc(NC4=NC(C)(CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CO4)cc23)ccc1Oc1ccn2ncnc2c1

Procedure:
Prepared according to the method of Example 1, using (E)-N′-(4-(3-(1-(tert-butyldiphenylsilyloxy)-3-hydroxy-2-methylpropan-2-yl)thioureido)-2-cyanophenyl)-N,N-dimethylformimidamide in place of 1-(3-cyano-4-((dimethylamino)methyleneamino)phenyl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea and 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylbenzenamine in place of 4-(imidazo[1,2-a]pyridin-7-yloxy)-3-methylaniline.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[C:10]([N:17]1[CH2:21][CH2:20][CH:19]=[CH:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:2]([O:3][C:4]([C:6]1[C@@H:19]2[CH2:18][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:21][C@@H:20]2[O:8][N:7]=1)=[O:5])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1C=CCC1
Reactant: CCOC(=O)/C(Cl)=N\O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=NO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]12
Reaction time: 8 h

Procedure:
The title compound was prepared using commercially available ethyl chloro oximidoacetate (5). N-Boc-pyrroline (1.0 g; 5.91 mmol), ethyl chloro oximidoacetate (2.55 g; 16.8 mmol) and sodium bicarbonate (1.77 g; 21.06 mmol) in ethyl acetate (15 mL) were stirred for 54 hours. An additional amount of chloro oxime (2.6 g; 17.28 mmol) and sodium bicarbonate (2.1 g; 25.00 mmol) was added and the reaction mixture stirred overnight. The addition of reagents was repeated again and the reaction mixture stirred for 36 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with water, brine, dried (MgSO4), filtered and evaporated. Cycloadduct 6 was isolated as a clear oil after chromatography with 20% ethyl acetate/hexanes.
Reaction SMILES: C(NC([O:8][CH2:9][CH3:10])=O)CCC.C(NC(OCC)=O)CCC.[CH2:21](O)[C:22]#[C:23][C:24]#[C:25][CH2:26][OH:27].C(NC(OCC)=O)C.C(NC(OCC)=O)C.C(O)C#CC#CCO>>[CH2:9]([OH:8])[CH2:10][C:21]#[C:22][C:23]#[C:24][CH2:25][CH2:26][OH:27]
Reactant: OCC#CC#CCO
Reactant: CCCCNC(=O)OCC
Agent: CCNC(=O)OCC
Product: OCCC#CC#CCCO

Procedure:
2,4-hexadiyn-1,6-diol bis(n-butylurethane) plus 2,4-hexdiyn-1,6-diol bis(ethylurethane)
Reaction SMILES: OCC[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].NC1C=CC([CH2:50][CH2:51][NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=CC=1>>[C:33]([C:26]1[CH:27]=[N:28][C:29]2[C:24]([C:25]=1[NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=1)=[CH:23][C:22]([S:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:11]([NH:10][C:9]1[CH:4]=[CH:5][C:6]([CH2:50][CH2:51][NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:7][CH:8]=1)=[O:12])(=[O:21])=[O:20])=[CH:31][C:30]=2[CH3:32])(=[O:34])[NH2:35]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCNC(=O)OC(C)(C)C)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 27 in place of 8-aminooctanol. 1H NMR (400 MHz, DMSO-d6) δ510.80 (s, 1H), 10.46 (s, 1H), 9.09 (s, 1H), 8.25-8.39 (m, 3H), 8.21 (d, J=7.9 Hz, 1H), 8.04 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.72-7.80 (m, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.11 (t, J=8.0 Hz, 1H), 6.88 (t, J=5.4 Hz, 1H), 6.60-6.68 (m, 2H), 6.52 (d, J=8.3 Hz, 1H), 3.60 (s, 3H), 3.08-3.18 (m, 2H), 2.65-2.73 (m, 5H), 1.40 (s, 9H); ES/MS calcd. for C38H40N6O7S+ 710.3. Found m/z=710.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7](C=O)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:26])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].[OH-].[Na+].Cl>C(Cl)Cl>[CH2:1]([N:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([OH:26])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c2c(cc(C=O)c1=O)CCCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCn1c2c(cc(O)c1=O)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
1-Butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboaldehyde (1-015-04) (160 mg, 0.69 mmol) was dissolved in methylene chloride (10 mL), and to the reaction mixture were added NaH2PO4.H2O (190 mg, 1.38 mmol) and meta-chloroperbenzoic acid (237 mg, 1.38 mmol). The reaction mixture was stirred at room temperature for 30 min, and to the reaction mixture was added 5% aqueous sodium thiosulfate solution (20 mL). The reaction mixture was extracted with ethyl acetate (50 mL), washed with aqueous saturated sodium hydrogen carbonate solution (20 mL) and brine (20 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in ethanol (5 mL), 2 mol/L aqueous sodium hydroxide solution (0.35 mL, 0.7 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 30 min. To the reaction mixture was added 0.2 mol/L diluted hydrochloric acid (7 mL), and the reaction mixture was extracted with ethyl acetate (25 ml), washed brine (10 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene/ethyl acetate) to give 1-butyl-3-hydroxy-5,6,7,8-tetrahydro-1H-quinoline-2-one (1-015-05) (82 mg, 54%) as a pale brown color crystal.
Reaction SMILES: Cl.OO.[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][CH:13]=[O:14].[O-:15]Cl=O.[Na+]>O.CC#N.[O-]Cl=O.[Na+]>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]([OH:15])=[O:14]
Reactant: O=CC#Cc1ccccc1F
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)C#Cc1ccccc1F
Yield: 86 %

Procedure:
A mixture of NaH2PO4 (37 g, 0.3 mol, 0.3 equiv) in water (330 mL) buffered to pH 2 with conc. HCl and H2O2 (30%, 112 mL, 1.1 mol, 1.1 equiv) was added to a solution of 3-(2-fluorophenyl)prop-2-ynal (151 g, 1.02 mol) in CH3CN (830 mL). The resulting mixture was cooled in an ice bath and was treated slowly with a solution of NaClO2 (102 g, 1.1 mol, 1.1 equiv) in water (1.1 L), keeping the temperature below 10° C. After 30 min a solution of NaClO2 (5.8 g, 64 mmol, 0.06 equiv) in water (50 mL) was added. After another 30 min the layers were separated and the aqueous layer was washed with EtOAc (3×500 mL). The organic layers were combined and back-extracted with a saturated NaHCO3 solution (3×500 mL). The aqueous layers were combined, acidified to pH 1 with conc. HCl and extracted with EtOAc (3×500 mL). The combined organic layers were washed with a saturated NaCl solution (1 L), dried (Na2SO4) and concentrated under reduced pressure to give 3-(2-fluorophenyl)prop-2-ynoic acid (144 g, 86%) as a yellow solid: TLC (1% AcOH/CH2Cl2) Rf 0.34; 1H NMR (CDCl3+d4-MeOH) δ 6.98-7.08 (m, 2H), 7.29-7.48 (m, 2H), 12.77 (br s, 1H); 13C NMR (CDCl3+d4-MeOH) δ 78.3, 85.7 (d, JC−F=2.5 Hz, 1C), 108.3 (d, JC−F=15.8 Hz, 1C), 115.4 (d, JC−F=20.7 Hz, 1C), 124.0, 132.1 (d, JC−F=7.3 Hz, 1C), 134.1 (d, JC−F=9.8 Hz, 1C), 135.2, 154.8, 163.1 (d, JC−F=256.1 Hz, 1C).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:7]([C:16]2[N:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[N:6]=1)=[O:4].Cl.C(Cl)(Cl)Cl.CO>CO.O1CCCC1.[OH-].[Na+]>[CH3:23][O:22][C:19]1[N:18]=[N:17][C:16]([N:7]2[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[CH:9][C:5]([C:3]([OH:4])=[O:2])=[N:6]2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1cc(-c2ccccn2)n(-c2ccc(OC)nn2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-n2nc(C(=O)O)cc2-c2ccccn2)nn1
Reaction time: 2.5 h
Yield: 67.6 %

Procedure:
1-(6-Methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid methyl ester (2.20 g) obtained in Method B step 3) of Referential Example 139 was dissolved in a solvent mixture of methanol (30 mL) and tetrahydrofuran (30 mL), and 1N aqueous sodium hydroxide (15 mL) was added to the solution at room temperature, followed by stirring for 2.5 hours. Under cooling with ice, 1N aqueous hydrochloric acid (15 mL) and a solvent mixture of chloroform-methanol (10:1) were added to the reaction mixture for partitioning the mixture. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and isopropyl ether was added to the residue, and then the precipitated solid was recovered by filtration, to thereby give the title compound (1.42 g, 47.6%).
Reaction SMILES: O[CH2:2][C@H:3]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:4][C:5](=[O:21])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C:14]2=[O:19])=[CH:9][C:8]=1[F:20].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[F:20][C:8]1[CH:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C:14]2=[O:19])[CH:11]=[CH:12][C:7]=1[N:6]1[C:5](=[O:21])[CH2:4][C@@H:3]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:2]1
Reactant: O=C(C[C@H](CO)NC(=O)OCc1ccccc1)Nc1ccc(N2CCOCC2=O)cc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CC(=O)N(c2ccc(N3CCOCC3=O)cc2F)C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
310 mg (0.7 mmol) benzyl (2-hydroxy-(1R)-1-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-methyl}-ethyl)-carbamate are dissolved in 3.5 ml THF. While cooling with ice a mixture of 205 mg (0.89 mmol) di-tert.-butyl azodicarboxylate and 210 μl (0.83 mmol) tributylphosphine in 6 ml THF is added. The mixture is slowly heated to ambient temperature and stirred for 16 hours. The mixture is then evaporated to dryness. The residue is purified by reversed-phase chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)[CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.I[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)[CH2:9][N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Ic1ccccc1
Reactant: Brc1cccc(C2(c3cccc(Br)c3)CNC2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Brc1cccc(C2(c3cccc(Br)c3)CN(c3ccccc3)C2)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 56.9 %

Procedure:
A mixture of 3,3-bis(3-bromophenyl)azetidine (200 mg, 0.545 mmol), iodobenzene (222 mg, 1.090 mmol), xantphos (31.5 mg, 0.054 mmol), Pd2(dba)3 (12.47 mg, 0.014 mmol) and sodium tert-butoxide (62.8 mg, 0.654 mmol) in dioxane (3 ml) was stirred for 12 h at 100° C. After cooling to room temperature, water (15 mL) and dichloromethane (15 mL) was added. The aqueous layer was extracted with dichloromethane (15 mL×3). The combined organic layers were dried and concentrated. The residue was purified by prep-TLC (eluent with dichloromethane: EtOAc=5:1) to afford 140 mg of the title compound (0.31 mmol, 58%). LC/MS: [M+1]=444, Ret. Time: 2.69 min. 1HNMR (CDCl3), 400 MHz: 4.42 (s, 4H), 6.54 (d, 2H, J=7.6 Hz), 7.09-7.11 (m, 2H), 6.79 (t, 1H, J=7.2 Hz), 7.17-7.26 (m, 6H), 7.37-7.45 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[N:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].[N:22]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:32])[C:26]=2[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:18]([O:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][O:32][C:27]3[CH:28]=[CH:29][CH:30]=[C:31]4[C:26]=3[CH:25]=[CH:24][CH:23]=[N:22]4)[CH2:6][CH2:7]2)[CH:16]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: Oc1cccc2ncccc12
Reactant: CC(C)COc1cc(N2CCN(C(=O)CCl)CC2)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)COc1cc(N2CCN(C(=O)COc3cccc4ncccc34)CC2)ncn1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-1-(4-(6-isobutoxypyrimidin-4-yl)piperazin-1-yl)ethanone (20 mg, 0.064 mmol), quinolin-5-ol (10.2 mg, 0.070 mmol), and potassium carbonate (18 mg, 0.13 mmol) in DMF was (0.5 mL) was stirred at 90° C. for 3 h. After cooling to rt, the mixture was poured onto water, and the aqueous later was extracted with dichloromethane (three times). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 9.3 mg (34% yields) of the title compound.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][C:16]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[C:17]([C:19]([NH:21][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)=[O:20])[N:18]=2)=[CH:10][CH:9]=1)(=O)C.[OH-].[Na+]>>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:16]2[NH:15][C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][OH:4])=[CH:13][CH:12]=3)=[N:18][C:17]=2[C:19]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])=[CH:32][CH:31]=1
Reactant: CC(=O)OCCOc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(Cl)cc3)[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1nccs1)c1nc(-c2ccc(OCCO)cc2)[nH]c1-c1ccc(Cl)cc1

Procedure:
2-(4-(2-Acetoxyethyloxy)phenyl)-5-(4-chlorophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide is hydrolyzed with sodium hydroxide to give 5-(4-chlorophenyl)-2-(4-(2-hydroxyethyloxy)-phenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.