Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:23][CH3:24])[NH:20][C:21](=[O:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I>COCCOC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:23][CH3:24])[N:20]([CH3:31])[C:21](=[O:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CSc1nc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CSc1nc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)n1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.4 %

Procedure:
Under argon gas, 7-[4-(4-chlorobenzoyl)benzyl]-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (82 mg) was dissolved in anhydrous DME (10 ml)-anhydrous DMF (4 ml). Then, 60% sodium hydride-oil (9.6 mg) was added with ice-cooling and, after 30 minutes of agitation, methyl iodide (34 mg) was added. Then, at room temperature, the mixture was stirred for 2.5 hours. This reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by flash column chromatography (hexane: ethyl acetate=4:1) to provide the title compound (30 mg). 1H-NMR (CDCl3) δ: 2.58(3H,s), 3.60(3H,s), 5.37(2H,s), 6.67(1H,d,J=3.4Hz), 6.75(1H,d,J=3.4Hz), 7.30(2H,d,J=8.OHz), 7.45(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.74(2H,d,J=8.OHz).
Reaction SMILES: ClC1N=CC(C2C=CC3N(C=C(NC(=O)C)N=3)N=2)=CC=1NS(C1C=CC(C(O)(C)C)=CC=1)(=O)=O.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[CH:45][C:46]3[N:47]([CH:49]=[C:50]([NH:52][C:53](=[O:55])[CH3:54])[N:51]=3)[N:48]=2)O1.Br[C:58]1[CH:59]=[C:60]([NH:65][S:66]([C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][C:70]=2[Cl:76])(=[O:68])=[O:67])[C:61]([Cl:64])=[N:62][CH:63]=1>>[Cl:64][C:61]1[N:62]=[CH:63][C:58]([C:43]2[CH:44]=[CH:45][C:46]3[N:47]([CH:49]=[C:50]([NH:52][C:53](=[O:55])[CH3:54])[N:51]=3)[N:48]=2)=[CH:59][C:60]=1[NH:65][S:66]([C:69]1[CH:74]=[CH:73][C:72]([F:75])=[CH:71][C:70]=1[Cl:76])(=[O:68])=[O:67]
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(F)cc1Cl
Reactant: CC(=O)Nc1cn2nc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Agent: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(C(C)(C)O)cc4)c3)ccc2n1
Product: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4Cl)c3)ccc2n1
Yield: 15.2 %

Procedure:
Following the procedure described for compound N-(6-(6-chloro-5-(4-(2-hydroxypropan-2-yl)phenylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 35), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (200 mg, 662 μmol) (Example 35, Step 3) was reacted with N-(5-bromo-2-chloropyridin-3-yl)-2-chloro-4-fluorobenzenesulfonamide (265 mg, 662 μmol) to afford the title compound as a grey solid (50 mg, 25% yield). MS (ESI positive ion) m/z: 495 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.12 (s, 3H), 7.33-7.43 (m, 1H), 7.77 (dd, J=8.61, 2.15 Hz, 1H), 7.83 (d, J=9.39 Hz, 1H), 7.99 (dd, J=8.80, 6.06 Hz, 1H), 7.99 (dd, J=8.80, 6.06 Hz, 1H), 8.12 (d, J=9.39 Hz, 1H), 8.33 (d, J=8.41 Hz, 2H), 8.91 (s, 1H), 10.82-10.92 (br s, 1H), 10.96 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([CH3:12])=[CH:10][S:11][C:5]=2[N:4]=[C:3]1[SH:13].[OH-].[Na+].CN(C=O)C.[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>CO.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][S:13][C:3]3[N:2]([CH3:1])[C:7](=[O:8])[C:6]4[C:9]([CH3:12])=[CH:10][S:11][C:5]=4[N:4]=3)=[CH:30][CH:29]=2)=[O:27])=[CH:36][CH:37]=1
Reactant: Cc1csc2nc(S)n(C)c(=O)c12
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1csc2nc(SCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To a solution of 3,5-dimethyl-2-mercaptothieno[2,3-d]pyrimidin-4(3H)-one (1.06 g) and sodium hydroxide (205 mg) in 50% methanol (16 ml)-DMF (4 ml) was added 4-(4-chlorobenzoyl)benzyl bromide (1.69 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water, and recrystallized from ethyl acetate to provide the title compound as colorless solid (878 mg).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][CH:9]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OC(F)(F)F)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Oc1ccc(OC2CCNC2)cc1
Yield: 82.2 %

Procedure:
To a solution of tert-butyl 3-(4-(trifluoromethoxy)phenoxy)pyrrolidine-1-carboxylate (325 mg, 0.936 mmol) in CH2Cl2 (3.7 mL) was added TFA (360 μL, 4.68 mmol). The colorless solution was dried under reduced pressure and the crude oil obtained purified with a 5 g SCX-2 column washing first with MeOH, then with 2M NH3 in MeOH leading to elution of basic materials to afford 3-(4-(trifluoromethoxy)-phenoxy)pyrrolidine (190 mg, 0.769 mmol, 82% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24](=[O:26])[CH3:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:25][C:24]([C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=2)=[O:26])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: COc1ccc(C(C)=O)cc1OC
Solvent: CO
Product: COc1ccc(C(=O)C=Cc2cc(O)c(O)c([N+](=O)[O-])c2)cc1OC

Procedure:
The procedure described in Example 8 was repeated using 1.8 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 18 g of 3',4'-dimethoxyacetophenone in 20 ml of methanol. Yield 1.7 g (50%), m.p. 206°-208° C.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:31])[N:4]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=2)[CH:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]=1[C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1>[O-2].[Mn+2].CC(C)=O>[CH:29]([C:26]1[CH:27]=[CH:28][C:23]([N:4]2[CH:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]([C:7](=[O:16])[C:8]3[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=3)=[C:2]([OH:1])[C:3]2=[O:31])=[CH:24][CH:25]=1)=[O:30]
Reactant: COc1ccc(C(=O)C2=C(O)C(=O)N(c3ccc(CO)cc3)C2c2ccccc2)cc1
Agent: [Mn+2]
Agent: [O-2]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)C2=C(O)C(=O)N(c3ccc(C=O)cc3)C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 3-hydroxy-1-(4-hydroxymethylphenyl)-4-(4-methoxy-benzoyl)-5-phenyl-1,5-dihydropyrrol-2-one (0.125 g, 0.3 mmol) and acetone (20 mL) was added manganese oxide (IV) (0.625 g, 7.18 mmol). The mixture was stirred at r.t. for 2.5 hr. Manganese oxide (IV) (0.625 g, 7.18 mmol) was added to the mixture, and the mixture was stirred at r.t. for 4.5 hr. The mixture was filtrated by celite, the filtrate was concentrated under reduced pressure to give a crude product of 1-(4-formylphenyl)-3-hydroxy-4-(4-methoxybenzoyl)-5-phenyl-1,5-dihydropyrrol-2-one. Methanol was added to prepare a 0.1M methanol solution of the crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[C:11]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)([OH:13])=[O:12].CC1C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[N:23][S:20]([C:17]2[CH:16]=[CH:15][C:14]([C:11]([OH:13])=[O:12])=[CH:19][CH:18]=2)(=[O:21])=[O:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: COc1ccc(C=NS(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
In a similar manner to Example 2, 1.28 g (9 mmol) of anisaldehyde, 1.89 g (9 mmol) of 4-carboxybenzenesulfonamide and 20 mg of TsOH in 150 mL of chlorobenzene and under nitrogen were heated for 4.5 hours to yield 2.86 g (96%) of SULF-8 as a white powder: IR (Nujol) 3300-2700 (br), 1693, 1601, 1584, 1155 cm-1 ; 1H NMR (DMSO-d6, TMS ext std)δ 8.91 (s, 1), 8.4-7.7 (m, 8), 3.92 (s, 3).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[C@H:31]([OH:32])[CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[C@H:31]([OH:32])[CH2:30][N:29]([C:37](=[O:36])[CH2:38][OH:39])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CNC[C@H]1O
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CN(C(=O)CO)C[C@H]1O

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f10) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)=O.[C:10]([CH2:12]C(O)=O)#[N:11].[OH-].[NH4+].CN(C)C=O>C1C=CC=CC=1>[C:10]([CH2:12][CH:1]=[C:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)#[N:11]
Reactant: O=CC1CC2C=CC1C2
Reactant: N#CCC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: N#CCC=C1CC2C=CC1C2
Yield: 72.1 %

Procedure:
A stirred solution of 100 g (0.82 mol) of 2-formyl-5-norbornene (Aldrich Chemical Co.), 65 g (0.76 mol) of cyanoacetic acid, 2 ml of ammonium hydroxide (58%), 132 ml of dimethylformamide, and 170 ml benzene was heated to reflux and the water removed with a Dean-Stark trap. The reaction was allowed to continue until the evolution of carbon dioxide ceased (approx. 24 hrs.). Upon completion, the reaction was cooled and the solvent removed under reduced pressure. The residual oil was distilled under vacuum to give 79.6 g (68% yield) of 2-(2-cyanoethylidene)-bicyclo[2.2.1]hept-5-ene: b.p. 76°-78° C./1 mm; ir 3060, 2260, 1420, 1330, 915, 840, 755, 720; nmr 1.3-2.5 (4H, m), 2.9-3.4 (4H, m), 5.0-5.5 (1H, m), 5.9-6.2 (2H, m); ms 145.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][C:10]([CH:12]=O)=[CH:11][C:5]=2[NH:4][C:3]1=[O:20].[CH:21]1([NH:24][C:25](=[O:38])[C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[CH2:23][CH2:22]1>>[CH:21]1([NH:24][C:25](=[O:38])[C:26]2[CH:27]=[CH:28][C:29]([N:32]3[CH2:33][CH2:34][N:35]([CH2:12][C:10]4[CH:9]=[C:8]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[C:6]5[O:7][CH:2]([CH3:1])[C:3](=[O:20])[NH:4][C:5]=5[CH:11]=4)[CH2:36][CH2:37]3)=[CH:30][CH:31]=2)[CH2:23][CH2:22]1
Reactant: CC1Oc2c(cc(C=O)cc2-c2ccccc2)NC1=O
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)cc1
Product: CC1Oc2c(cc(CN3CCN(c4ccc(C(=O)NC5CC5)cc4)CC3)cc2-c2ccccc2)NC1=O

Procedure:
Using 349A and N-cyclopropyl-4-(piperazin-1-yl)benzamide 284 in the general procedure for reductive aminations, the title compound was obtained as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.48-0.59 (m, 2H) 0.59-0.69 (m, 2H) 1.40 (d, J=6.82 Hz, 3H) 2.51-2.56 (m, 4H) 2.75-2.82 (m, 1H) 3.19-3.29 (m, 4H) 3.48 (s, 2H) 4.70 (q, J=6.74 Hz, 1H) 6.92 (m, 4H) 7.32-7.37 (m, 1H) 7.41-7.46 (m, 2H) 7.51-7.57 (m, 2H) 7.69 (d, J=9.09 Hz, 2H) 8.13 (d, J=4.04 Hz, 1H) 10.71 (s, 1H). ESI-MS: m/z 497.3 (M+H)+. mp=217.0-223.5° C.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][C@H:6]([CH2:9][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][OH:12])[CH2:5][O:4]2)[CH2:2]1.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:28][C:27]1[CH:29]=[CH:30][C:24]([S:21]([O:12][CH2:11][C@@H:10]([NH:13][C:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:20])[CH2:9][C@H:6]2[CH2:7][CH2:8][C:3]3([CH2:2][CH2:1]3)[O:4][CH2:5]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C[C@H]1CCC2(CC2)OC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](C[C@H]2CCC3(CC3)OC2)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The tert-butyl (S)-1-((R)-4-oxaspiro[2.5]oct-6-yl)-3-hydroxypropan-2-ylcarbamate (1.70 g, 5.92 mmol) and tosyl chloride (4.5 g, 23.7 mmol, 4.0 equiv) were dissolved in pyridine (30 mL) and the mixture stirred at room temperature for 17 hr. The pyridine was removed in vacuo and the residue partitioned between EtOAc and 1.0 M HCl. The layers were separated and the organic layer washed with brine, dried over Na2SO4, filtered and evaporated. The (S)-2-(tert-butoxycarbonylamino)-3-((R)-4-oxaspiro[2.5]oct-6-yl)propyl 4-methylbenzenesulfonate was purified by flash chromatography on silica eluting with 0-29% EtOAc in hexanes. The fractions were evaporated and used directly in the next step. MS ESI +ve m/z 464 (M+Na).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:21][CH:22]=2)[CH:8]=[CH:9][C:10]=1[O:11]COC.Cl.O.[OH-].[Na+]>CO>[OH:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:21][CH:22]=2)[CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: COCOc1ccc(C=Cc2ccc(-c3ccccn3)nc2)cc1OCOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Oc1ccc(C=Cc2ccc(-c3ccccn3)nc2)cc1O
Yield: 85.3 %

Procedure:
A solution of 5-{2-[3,4-bis(methoxymethoxy)phenyl]vinyl}-[2,2′]bipyridinyl (0.85 g, 2.246 mmol), concentrated hydrochloric acid (5 mL) and water (2 mL) in methanol (100 mL) was stirred under argon atmosphere at room temperature for 15 hoursw. Water (50 mL) was added to the mixture and methanol was rotary evaporated. More water (100 mL) was added and the resulting mixture was neutralized to pH 7 with sodium hydroxide solution. The solid precipitate was collected by filtration and washed with water and a mixed solvent of hexane and EtOAc (3:1, v/v). The resulting orange solid was dried under high vacuum giving 0.5559 g of 5-{2-[3,4-dihydroxyphenyl]vinyl}-[2,2′]bipyridinyl (1.915 mmol, yield 85.3%) as a Z/E mixture. 1H NMR (MeOH, 300.16 MHz): 8.71 (d, J=1.7 Hz, 0.70H), 8.65-8.62 (m, 1.56H), 8.51 (d, J=1.4 Hz, 1.03H), 8.31-8.23 (m, 2.29H), 8.16 (d, J=8.3 Hz, 1.00H), 8.0 (dd, J=2.0 Hz, 0.78H), 7.94-7.89 (m, 1.63H), 7.80 (dd, J=8.2 & 2.0 Hz, 1.04H), 7.44-7.40 (m, 1.52H), 7.23 (d, J=16.4 Hz, 0.74H), 7.08 (d, J=1.8 Hz, 0.71H), 7.00 (d, J=16.4 Hz, 0.74H), 6.95 (dd, J=8.2 & 1.8 Hz, 0.70H), 6.77 (d, J=8.2 Hz, 0.74H), 6.72-6.67 (m, 2.80H), 6.61 (dd, J=8.1 & 1.5 Hz, 1.01H), 6.47 (d, J=12.1 Hz, 1.00H). UV-Vis (MeOH): Emax=252 nm, 288 nm and 352 nm. MS (ESI) m/z: 291 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:14]([F:17])([F:16])[F:15])(O)[O:10][N:9]=2)=[CH:4][CH:3]=1.C1(C2CC(O)(C(F)(F)F)ON=2)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:14]([F:16])([F:15])[F:17])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OC1(C(F)(F)F)CC(c2ccc(F)cc2)=NO1
Agent: OC1(C(F)(F)F)CC(c2ccccc2)=NO1
Product: Fc1ccc(-c2cc(C(F)(F)F)on2)cc1
Yield: 97.5 %

Procedure:
As described for example 128b, rac-3-(4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-5-ol (35.6 g, 142.9 mmol), instead of 3-phenyl-5-hydroxy-5-(trifluoromethyl)isoxazoline, was converted to the title compound (32.2 g, 98%) which was obtained as a light brown solid. MS: m/e=298.1 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]([CH3:15])=[CH:12][CH2:13]Br.[CH3:16][N:17]1[C:25]2[N:24]=[C:23]([Br:26])[NH:22][C:21]=2[C:20](=[O:27])[NH:19][C:18]1=[O:28]>CN(C)C=O.O>[CH3:16][N:17]1[C:25]2[N:24]=[C:23]([Br:26])[N:22]([CH2:13][CH:12]=[C:11]([CH3:15])[CH3:10])[C:21]=2[C:20](=[O:27])[NH:19][C:18]1=[O:28]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: CC(C)=CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C

Procedure:
15.37 ml of Hünig base and 9.98 ml of 3,3-dimethylallylbromide are added to 20.00 g of 3-methyl-8-bromo-xanthine in 200 ml of N,N-dimethylformamide. The reaction mixture is stirred for about half an hour at ambient temperature and then diluted with 500 ml of water. The precipitate formed is suction filtered, washed with water and dried.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH2:10])=[O:9])[C:3]1=[O:11].O[C@H]1CCN(CC(OCC)=O)C1>>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH2:10])=[O:9])[C:3]1=[O:11]
Reactant: NC(=O)CN1CCC(O)C1=O
Agent: CCOC(=O)CN1CC[C@H](O)C1
Product: NC(=O)CN1CC[C@H](O)C1=O

Procedure:
According to the process described in paragraph (b) of Example 1, from ethyl (S)-(-)-2-(3-hydroxy-1-pyrrolidinyl)acetate there is obtained (S)-(-)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide which has a melting point of 197°-198°; [α]D20 =-82°, [α]54620 =-99°, [α]35620 =-313° (dimethylformamide c=1.00).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](O)([CH3:17])([CH3:16])[CH3:15].CCCCCC>C1(C)C=CC=CC=1>[C:14]([C:11]1[CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]=1[OH:13])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)O
Reactant: Oc1ccc(-c2ccccc2)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
Into a 300 ml reactor thoroughly dried and purged with nitrogen, 34.04 g (200.0 mmol) of 4-phenylphenol, 3.40 g of Umberist-15E (trade name, available from Organo Co.) and 150 ml of toluene were introduced. To the reactor, a solution containing 48.20 g (200.0 mmol) of t-butyl alcohol diluted with 10 ml of a toluene was dropwise added at 105° C., followed by stirring for 16 hours. After the system was cooled to room temperature, the solution was introduced into 500 ml of hexane and filtered with washing with hexane. After concentration, the resulting liquid was purified by silica gel column chromatography to obtain 31.15 g (yield: 69%) of 2-t-butyl-4-phenylphenol.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7](OCC)(=[O:12])[CH2:8][C:9]([CH3:11])=O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH3:11][C:9]1[N:1]=[C:2]2[S:3][CH:4]=[CH:5][N:6]2[C:7](=[O:12])[CH:8]=1
Reactant: Nc1nccs1
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(=O)n2ccsc2n1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
To a stirred solution of 2-aminothiazole (5.0 g, 49.930 mmol) in acetic acid (40 ml) was added ethyl acetoacetate (9.746 g, 74.90 mmol) at room temperature. The reaction mixture was heated to reflux for 12 h under nitrogen. The reaction mixture was allowed to cool to room temperature. The residue obtained after concentration of the reaction mixture was basified with saturated solution of sodium bicarbonate and diluted with ethyl acetate (500 ml). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to afford a crude product which was purified by silica gel column chromatography using 1% methanol in chloroform to give 4.20 g of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 6.15 (s, 1H), 6.95 (d, J=4.8 Hz, 1H), 7.94 (d, J=4.8 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8](OC)=[O:9])[C:5]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.[CH:23]1(B(O)O)[CH2:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>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].C1(C)C=CC=CC=1>[CH:23]1([C:2]2[CH:7]=[C:6]([CH2:8][OH:9])[C:5]([O:12][CH:13]([CH3:14])[CH3:15])=[CH:4][C:3]=2[C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH2:25][CH2:24]1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1cc(Br)c(-c2ccc(F)cc2)cc1OC(C)C
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)Oc1cc(-c2ccc(F)cc2)c(C2CC2)cc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
A mixture of methyl 2-bromo-4′-fluoro-5-isopropoxybiphenyl-4-carboxylate (7.53 g), cyclopropylboronic acid (4.40 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (1.26 g), a 2 M aqueous sodium carbonate solution (30.8 mL), tris(dibenzylideneacetone)dipalladium(0) (1.31 g), and toluene (150 mL) was stirred overnight at 100 C in an argon atmosphere. The reaction mixture was allowed to cool to room temperature. Then, the organic layer was separated, washed with saturated saline, and passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. A THF (50 mL) solution of the obtained residue was added to a THF (50 mL) suspension of lithium aluminum hydride (2.00 g) under ice cooling in a nitrogen atmosphere. After stirring at the same temperature as above for 30 minutes, water (2 mL) and a 15% aqueous sodium hydroxide solution (2 mL) were added thereto, and the mixture was stirred for 5 minutes. Water (6 mL) was further added to the reaction mixture, and the mixture was stirred for 30 minutes and then filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (5.75 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][O:31][C:32](=[O:35])[CH2:33]Cl.CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[O:14][CH2:33][C:32]([O:31][CH3:30])=[O:35])=[CH:4][C:3]=1[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: Nc1ncc(-c2cccc(O)c2)cc1-c1nc2ccccc2s1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[6-amino-5-(1,3-benzothiazol-2-yl)pyridin-3-yl]phenol (80 mg, 0.20 mmol), potassium carbonate (100 mg, 0.700 mmol) and chloroacetic acid methyl ester (33 mg, 0.30 mmol) in DMF was left to stir at rt overnight. To the mixture was added EtOAc (10 mL), which was left to stir at rt for 10 min. Then, the mixture was washed with NaHCO3 aq. soln. (2×). The combined organic extracts were treated with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. Purification via silica gel chromatography (5% MeOH in DCM) afforded the title compound as a yellow solid. MS (ES+): m/z=392.02 (100) [MH+]. HPLC: tR=3.63 min (ZQ3, polar—5 min).