Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[Mg].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16](Br)[CH:17]=[CH:18][CH:19]=1.[Cl-].[NH4+]>CCOCC>[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[C:1]([CH2:2][CH3:3])([OH:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CCC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC(O)(c1ccccc1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 37.5 g. of propiophenone in 200 ml. of dry ether is added dropwise to a -10° C Grignard solution prepared from 13.6 g. of magnesium turnings and 126 g. of 3-trifluoromethyl-bromobenzene in 182 ml. of dry ether. The reaction mixture is stirred at 0° C for 30 minutes, thereafter refluxed for 1 hour. The mixture is cooled to 0° C, and the Grignard complex is decomposed with a 10% aqueous ammonium chloride solution. The ethereal phase is separated, washed until neutral, and dried over anhydrous sodium sulfate. The solvent is evaporated, and the residual oil is subjected to fractional distillation in vacuo. This way 57.3 g. of 3-trifluoromethyl-α-ethyl-benzhydrol are obtained: b.p.: 106°-108° C/0.03mmHg.
Reaction SMILES: N1C(C)=CC=CC=1C.[CH2:9]([C:11]([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:38]2([OH:44])[CH2:43][CH2:42][S:41][CH2:40][CH2:39]2)=[C:32]([CH3:45])[CH:31]=1)([C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:16]([CH3:29])[CH:15]=1)[CH2:12][CH3:13])[CH3:10].O([Si:54]([CH3:57])([CH3:56])[CH3:55])S(C(F)(F)F)(=O)=O.O>ClCCl>[CH2:9]([C:11]([C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][C:23]([CH3:25])([CH3:26])[C:22]([CH3:27])([CH3:28])[O:21]2)=[C:16]([CH3:29])[CH:15]=1)([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:38]2([O:44][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH2:39][CH2:40][S:41][CH2:42][CH2:43]2)=[C:32]([CH3:45])[CH:31]=1)[CH2:12][CH3:13])[CH3:10]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCSCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: O
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCSCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reaction time: 4 h
Yield: 86.3 %

Procedure:
2,6-Lutidine (0.76 mL, 5 mmol) was added to a solution of 4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenylethynyl)-tetrahydro-thiopyran-4-ol (Example 136-(3); 0.53 g, 1 mmol) in dichloromethane (5 mL). Trimethylsilyl triflate (0.32 mL, 2.5 mmol) was added at 0° C., and the mixture was stirred at the same temperature for four hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (0.51 g, 84%).
Reaction SMILES: Cl.Cl.C([O:6][C@@H:7]1[C@@H:48]([O:49]C(=O)C)[C@H:47]([O:53]C(=O)C)[C@@H:46]([CH2:57][O:58]C(=O)C)[O:45][C@H:8]1[O:9][C:10]1[C:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][C:28]4([CH2:36][CH2:35][N:34]([C:37](=[O:40])[CH2:38][NH2:39])[CH2:33][CH2:32]4)[CH2:27]3)=[CH:18][C:17]=2[CH3:41])=[C:13]([CH:42]([CH3:44])[CH3:43])[NH:12][N:11]=1)(=O)C.C(N(C(C)C)CC)(C)C.[CH2:71]([N:75]=[C:76]=[O:77])[CH:72]([CH3:74])[CH3:73].N>ClCCl.C(#N)C>[C@@H:8]1([O:9][C:10]2[C:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][CH2:29][C:28]5([CH2:36][CH2:35][N:34]([C:37](=[O:40])[CH2:38][NH:39][C:76]([NH:75][CH2:71][CH:72]([CH3:74])[CH3:73])=[O:77])[CH2:33][CH2:32]5)[CH2:27]4)=[CH:18][C:17]=3[CH3:41])=[C:13]([CH:42]([CH3:44])[CH3:43])[NH:12][N:11]=2)[O:45][C@H:46]([CH2:57][OH:58])[C@@H:47]([OH:53])[C@H:48]([OH:49])[C@H:7]1[OH:6]
Reactant: CC(C)CN=C=O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CCCC4(CCN(C(=O)CN)CC4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(/C=C/CCN2CCCC3(CCN(C(=O)CNC(=O)NCC(C)C)CC3)C2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 67.9 %

Procedure:
A mixture of 4-(4-{(1E)-4-[9-(aminoacetyl)-2,9-diazaspiro[5.5]undec-2-yl]but-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside dihydrochloride (11.70 g; 13.04 mmoles) in dichloromethane (33 mL) and diisopropylethylamine (13.65 mL; 78.27 mmoles) is stirred for 10 minutes to dissolve. The mixture is cooled to 5° C. and isobutyl isocyanate (2.59 g, 26.09 mmoles) is added dropwise over 5 minutes. When the addition is complete the cooling bath was removed. After 15 minutes, the mixture is concentrated under reduced pressure. The residue is treated with ammonia (2M in methanol; 35.00 mL, 70.00 mmoles) and stirred at ambient temperature for 1.5 hours. Further ammonia (2M in methanol; 35.00 mL, 70.00 mmoles) is added and the reaction is stirred overnight. The mixture is warmed to 40° C. and ammonia (2M in methanol; 35.00 mL, 70.00 mmoles) is added. The mixture is stirred for 160 minutes, and then concentrated. The residue is purified by reverse phase (C18) flash column chromatography eluting with 20:80 to 80:20 10 mM ammonium bicarbonate in water:acetonitrile to give the title compound (6.686 g, 68% yield). Mass spectrum (m/z): 755.5 (M+1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1>O>[Cl-:1].[CH2:2]1[N+:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: ClCCCN1CCCC1
Solvent: O
Product: C1CC[N+]2(C1)CCC2
Product: [Cl-]
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
An aqueous solution of 4-azoniaspiro[3,4]octane chloride was prepared by adding 1-(3-Chloropropyl)pyrrolidine (128 ml) to water (100 ml) at 94° C. over 25 minutes. The mixture was stirred for a further 5 minutes to give a clear yellow solution. This was cooled to 20° C. and stored in a bottle. Line washes of water (2×25 ml) were applied.
Reaction SMILES: [CH3:1][C:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[C:3]([CH:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:4].C1(C(CCC)(CCC)C(C(C(OCC)=O)C(OCC)=O)=O)C=CC=CC=1>>[OH:13][C:11]1[C:18]2[C:17](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:2]([CH3:16])([CH3:1])[C:3](=[O:4])[C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccccc1
Agent: CCCC(CCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccccc1
Product: CCOC(=O)C1=C(O)c2ccccc2C(C)(C)C1=O

Procedure:
The title compound was prepared according to the procedure of Example 1F, substituting the product of Example 9D for the product of Example 1E. 1H NMR (300 MHz, CDCl3): δ 15.16, 15.03 (two s, 1 H), 8.18 (m, 1 H), 7.52 (m, 3 H), 4.47 (m, 2 H), 1.66 (s, 3 H), 1.51 (s, 3 H), 1.45 (t, J=6.62 Hz, 3 H).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[Br:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CCOCC>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:32][CH:31]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
Diisopropyl azodicarboxylate (9.1 mL, 46.27 mmol) in THF (15 mL) was added dropwise to a solution of 1-methylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate (7.76 g, 38.56 mmol), 4-bromophenol (6.67 g, 38.56 mmol) and Ph3P (13.15 g, 50.12 mmol) in THF (85 mL) at −20° C. The reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature overnight. The mixture was concentrated, and the residue was purified by chromatography on a silica gel column using 0 to 25% EtOAc/hexane to give the crude product. The crude product was taken up in Et2O (250 mL) and washed with 1N NaOH (aq). The organic extracts were dried over MgSO4, filtered, and the filtrate was concentrated to give 7.5 g (55%) of 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CDCl3): δ7.35 (d, 2H, J=8.9 Hz), 6.75 (d, 2H, J=8.9 Hz), 4.96-4.83 (m, 1H), 4.24-4.14 (m, 2H), 3.75 (d, 2H, J=6.4 Hz), 2.81-2.71 (m, 2H), 2.02-1.87 (m, 1H), 1.85-1.75 (m, 2H), 1.33-1.13 (m, 8H); LRMS (ESI), m/z 356/358 (M+H).
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[O:6][C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.Br[C:19]1[S:23][C:22]([C:24]#[N:25])=[N:21][N:20]=1>>[F:17][C:3]([F:2])([F:16])[C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[O:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:19]2[S:23][C:22]([C:24]#[N:25])=[N:21][N:20]=2)[CH2:8]1
Reactant: FC(F)(F)c1ccccc1O[C@H]1CCNC1
Reactant: N#Cc1nnc(Br)s1
Agent: Cl
Product: N#Cc1nnc(N2CC[C@H](Oc3ccccc3C(F)(F)F)C2)s1

Procedure:
The title compound was prepared according to the procedure described for Example 6, step 2 from (3S)-3-[2-(trifluoromethyl)phenoxy]-pyrrolidine hydrochloride and 5-bromo-1,3,4-thiadiazole-2-carbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42](O)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl.C1C=CC=CC=1>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([O:12][C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1ccc(F)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: COC(=O)c1ccc(F)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 60.8 %

Procedure:
A mixture of methyl 4-fluoro-2-hydroxybenzoate (5.1 g, 30 mmol), triphenylphosphine (9.5 g, 36 mmol), 1-tert-butoxycarbonyl-4-hydroxypiperidine (6 g, 30 mmol), and benzene (10 mL) was heated until all solids dissolved. The solution was cooled to 0° C., then sonicated while adding diethyl azodicarboxylate (6.3 g, 36 mmol) dropwise. After the addition was complete, the reaction mixture was sonicated for an additional 60 min, diluted with CH2Cl2 (25 mL), and purified by flash chromatography, eluting with 10% EtOAc in hexanes to yield the title compound (6.45 g, 61%) as a white solid.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[CH:7]1[C:17]2[C:16](=[O:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[C:13](=[O:23])[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.C(Br)C#C.C(O)(=O)C>CN(C)C=O.O>[CH2:3]([N:12]1[C:13](=[O:23])[C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16](=[O:18])[C:17]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]1=2)[C:2]#[CH:1]
Reactant: O=c1[nH]c2ccccc2c(=O)c2ccccc12
Reactant: CC(C)(C)[O-]
Agent: C#CCBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: C#CCn1c(=O)c2ccccc2c(=O)c2ccccc21
Reaction time: 0.5 h

Procedure:
potassium tert.-butoxide, 2.5 g, was added to a suspension of 4.5 g of 5H-dibenz[b,e]azepine-6,11-dione in 50 ml of dimethylformamide. After stirring under nitrogen for 30 minutes, 2 ml of propargyl bromide was added and stirring was continued for I hour at room temperature. The reaction mixture was acidified with acetic acid and diluted with water. The precipitate was filtered off and sucked dry. The solids were dissolved in methylene chloride. The solution was dried and evaporated and the residue was chromatographed over 120 g of silica gel using methylene chloride. The combined clean fractions containing product were evaporated and the residue was crystallized from ether/hexane to give colorless crystals of 5-(2-propynyl)-5H-dibenz[b,e]azepine-6,11-dione with m.p. 117°-118°.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[O:14]1[C@H:16]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15]1.Cl>CO>[CH2:19]([O:18][CH2:17][C@H:16]([OH:14])[CH2:15][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)Cc1ccc(OC[C@@H](O)COCc2ccccc2)cc1

Procedure:
Sodium (2.3 g; 0.1 mol) was dissolved in 500 ml anhydrous MeOH and to this was added a solution of 194.3 g (1.17 mol) 4-hydroxyphenylacetic acid, methyl ester in 250 ml MeOH followed by a solution of 167.3 g. (1.018 mol) (S)-1,2-epoxy-3-benzyloxypropane in 250 ml MeOH. The solution was stirred under reflux for 12 hours. The cooled solution was treated with 8.3 ml (0.1 mol) of concentrated HCl and the methanol was removed in vacuo. The crude product was dissolved in benzene and washed with 2×200 ml portions of cold 1 N NaOH solution and with H2O (1×300 ml). The aqueous layers were backwashed with benzene (2×500 ml). The combined organic layers were dried (Na2SO4) and evaporated in vacuo to give crude (S)-4-(3-benzyloxy-2-hydroxypropoxy)phenyl acetic acid, methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:30][C:29]3[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reactant: Nc1ccc(F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(Nc3ccc(F)cc3)nc21
Temperature: 180 °C
Yield: 36.8 %

Procedure:
A mixture of 100 mg (0.26 mmol) of 3-(2,6-dichlorophenyl)-7-methane-sulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 0.25 ml (2.6 mmol) of 4-fluoroaniline was heated at 180° C. for 30 minutes and then cooled. 30 ml of ethyl acetate and 30 ml of 2M hydrochloric acid were added to the residue. The phases were separated and the organic phase was washed with 20 ml of brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel using ethyl acetate/hexane (2:3) for the elution. Product-containing fractions were combined and evaporated to give 40 mg (37%) of 3-(2,6-dichlorophenyl)-7-(4-fluoroanilino)-3,4-dihydro-1-methylpyrimido[4,5-d]-pyrimidin-2(1H)-one as a light grey solid of melting point 208-211° C.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:13]=2)[CH:10]=1)=[O:4].[CH3:38][NH2:39]>CO>[C:28]([O:27][C:25](=[O:26])[NH:24][C:20]1([C:17]2[CH:18]=[CH:19][C:14]([C:12]3[N:13]=[C:8]4[CH:7]=[CH:6][C:5]([C:3](=[O:4])[NH:39][CH3:38])=[CH:10][N:9]4[C:11]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:15][CH:16]=2)[CH2:23][CH2:22][CH2:21]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)c1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Reactant: CN
Solvent: CO
Product: CNC(=O)c1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Reaction time: 1.5 h

Procedure:
A mixture of 2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (100 mg) and a solution of methylamine in methanol (2M, 1.4 mL) was heated at 100° C. under microwave irradiation for 90 minutes followed by a further 90 minutes. On cooling, the reaction mixture was concentrated in vacuo to give the title compound which was used without further purification in the next step.
Reaction SMILES: CI.[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12](=[O:18])[NH:13][C:14](=[S:17])[NH:15][CH:16]=2)=[CH:6][CH:5]=1.[OH-].[Na+].[C:21](O)(=O)C>O.C(O)C>[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12](=[O:18])[NH:13][C:14]([S:17][CH3:21])=[N:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Solvent: CCO
Product: CSc1ncc(Cc2ccc(C)nc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (13.79 g) was added to a stirred solution of 5-(6-methyl-3-pyridylmethyl)-2-thiouracil (22.66 g) and sodium hydroxide (8.0 g) in water (250 ml) and ethanol (250 ml), and the mixture was heated at 70° for 1 hour and stirred at room temperature overnight. Acetic acid was added to pH 5 and the volume of the mixture was evaporated to a volume of 50 ml. The solid was filtered off and was recrystallised from ethanol-acetic acid to give 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone (10.16 g) m.p. 197°-197.5°.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]([CH3:26])=[CH:5][C:4]=1[OH:27].[CH3:28][O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[S:42](Cl)(=[O:44])=[O:43].O1CCCC1.Cl>N1C=CC=CC=1>[CH3:28][O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[S:42]([NH:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]([CH3:26])=[CH:5][C:4]=1[OH:27])(=[O:44])=[O:43]
Reactant: COCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCOc1cc(N)c(O)cc1C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc([N+](=O)[O-])ccc2OCCOC)c(O)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20 g of 2-amino-4-hexadecyloxy-5-methylphenol hydrochloride and 18 g of 4-(2-methoxyethoxy)nitrobenzene-3-sulfonyl chloride prepared as described in Step (a) above were added to a mixture of 100 ml of tetrahydrofuran and 10 ml of pyridine and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to a mixture of 300 ml of ice water and 50 ml of concentrated hydrochloric acid (35 wt%) with stirring. The crystals thus-precipitated were recovered by filtration, washed with water, air-dried and recrystallized from 100 ml of acetonitrile. Yield: 35 g; Melting Point: 85.5° to 86° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]1[N:14]=[CH:13][O:12][N:11]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.[OH-].[Na+]>O>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:9][C:10]2[N:14]=[CH:13][O:12][N:11]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccccc1SCc1ncon1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1ccccc1SCc1ncon1)c1ccc(Cl)cc1
Reaction time: 4 h

Procedure:
A mixture of 3-(2-aminophenylthiomethyl)1,2,4-oxadiazole (4.14 g), 4-chlorobenzoyl chloride (3.68 g), sodium hydroxide (0.8 g) and water (15 ml) was stirred at 25° for 4 hours. Crude product was recovered by filtration and crystallised from ethanol to give 3-[2-(4-chlorobenzamido)phenylthiomethyl]-1,2,4-oxadiazole, m.p. 103°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[N:27]=[CH:26][CH:25]=[C:24]3[N:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][OH:37])[CH2:31][CH2:30]2)=[CH:15][CH:14]=1.CCN(CC)CC>C(Cl)Cl>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[N:27]=[CH:26][CH:25]=[C:24]3[N:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH:36]=[O:37])[CH2:31][CH2:30]2)=[CH:38][CH:39]=1
Reactant: COc1ccc(COc2cccc3c(N4CCN(CCO)CC4)ccnc23)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(COc2cccc3c(N4CCN(CC=O)CC4)ccnc23)cc1
Reaction time: 0.17 h
Yield: 76.9 %

Procedure:
To a stirred solution of oxalyl chloride (1.8 mL, 20.33 mmol) in CH2Cl2 (40 mL) at −78° C. was added DMSO (2.8 mL, 40.66 mmol). The reaction mixture was stirred for 10 minutes followed by addition of compound 26 (4.0 g, 10.16 mmol, solution in 10 mL of CH2Cl2). The reaction mixture was stirred at the same temperature for 12 minutes. Then Et3N (8.4 mL, 60.98 mmol) was added and stirring was continued for another 1 hour and 20 minutes allowing the reaction mixture to come to room temperature. The reaction mixture was quenched by addition of water and extracted with CH2Cl2 (3×75 mL). The combined organic layer was washed with water and brine and finally purified by silica gel column chromatography (EtOAc/MeOH, 9.5:0.5) to yield 3.06 g (77%) of compound 27 as thick oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.45-2.90 (m, 4H), 3.02-3.40 (m, 4H), 3.34 (s, 2H), 3.69 (s, 3H), 5.25 (s, 2H), 6.64-7.04 (m, 4H), 7.16-7.56 (m, 4H), 8.60-8.76 (m, 1H), 9.68 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:41])([F:40])[C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:27])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][NH:17][C:18]([C:19]2[CH:24]=[CH:23][C:22]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([F:41])([F:40])[F:28])=[CH:31][CH:32]=3)=[CH:21][CH:20]=2)=[O:26])[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CNC(=O)c2ccc(Br)cc2)cs1
Reactant: OB(O)Oc1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CNC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1
Yield: 86.4 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{[(4-bromobenzoyl)amino]methyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (600 mg) synthesized in Example 455-1 and 4-trifluoromethylphenylboric acid (363 mg) were dissolved in dioxane (8 mL) and 2 M aqueous sodium carbonate solution (4 mL), tetrakis(triphenylphosphine)palladium (73 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1) to give the title compound (590 mg) as a white solid.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>C(O)(=O)C.C1COCC1.O>[OH:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: c1cc(SCCOC2CCCCO2)ccn1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: OCCSc1ccncc1
Yield: 81.4 %

Procedure:
A solution of 4-(2-(tetrahydropyran-2-yloxy)ethylthio)pyridine (2.73 g, 11 mmol) in acetic acid (8 ml), THF (4 ml) and water (2 ml) was heated at 50° C. for 4 hours. The volatiles were removed by evaporation and the residue azeotroped with toluene to give 4-(2-hydroxyethylthio)pyridine (1.39 g, 79%) as an off-white solid.