Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].O[CH2:14][NH:15][C:16](=[O:19])[CH2:17][Cl:18]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:10]=[C:9]([CH2:14][NH:15][C:16](=[O:19])[CH2:17][Cl:18])[C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12]
Reactant: O=C(CCl)NCO
Reactant: Cc1ccc(O)c2c1CCC2=O
Agent: O=S(=O)(O)O
Product: Cc1cc(CNC(=O)CCl)c(O)c2c1CCC2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
9.3 Grams of 4-methyl-7-hydroxy-1-indanone and 30 g of N-hydroxymethyl-α-chloroacetamide were dissolved by adding 280 ml of concentrated sulfuric acid under a cooling condition. After the mixture was allowed to stand overnight, the mixture was poured into ice-water. The crystals formed in the mixture were collected by filtration and were recrystallized from ethanol to obtain 49 g of 4-methyl-6-α-chloroacetylaminomethyl-7-hydroxy-1-indanone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[O:31][N:30]=2)=[CH:25][C:21]=1[C:22](O)=[O:23]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:22](=[O:23])[C:21]3[CH:25]=[C:26]([C:29]4[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[O:31][N:30]=4)[CH:27]=[CH:28][C:20]=3[O:19][CH3:18])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: COc1ccc(-c2noc(C(F)(F)F)n2)cc1C(=O)O
Product: COc1ccc(-c2noc(C(F)(F)F)n2)cc1C(=O)NCC(C)(C)c1coc(-c2ccc(F)cc2)n1
Yield: 36 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 2-methoxy-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (40 mg, yield 36%). 1H NMR (400 MHz, MeOD) δ 8.64-8.63 (d, J=2.3 Hz, 1H), 8.45-8.42 (t, J=5.6 Hz, 1H), 8.24-8.21 (dd, J=8.8 Hz, 2.4 Hz, 1H), 8.11-8.07 (m, 2H), 7.83 (s, 1H), 7.34-7.32 (d, J=8.8 Hz, 1H), 7.27-7.23 (t, J=8.8 Hz, 2H), 3.91 (s, 3H), 3.72-3.71 (m, 2H), 1.41 (s, 6H). MS (ESI) m/z: Calculated for C24H20F4N4O4: 504.14. found: 505.2 (M+H)+.
Reaction SMILES: C(=O)([O-])N.Cl[C:6]([O:8][CH3:9])=[O:7].[CH3:10][O:11][C:12]([C:14]1[S:33][C:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([NH:25][CH2:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:23]=3[S:24][C:16]=2[C:15]=1[O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:13]>>[CH3:10][O:11][C:12]([C:14]1[S:33][C:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([N:25]([CH2:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:6]([O:8][CH3:9])=[O:7])[C:23]=3[S:24][C:16]=2[C:15]=1[O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:13]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(NCC3CCCCC3)cccc12
Agent: NC(=O)[O-]
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(N(CC3CCCCC3)C(=O)OC)cccc12
Yield: 63.7 %

Procedure:
Step B Carbamate Formation: Addition of methyl chloroformate (0.05 mL, 0.65 mmol) to 7-(Cyclohexylmethyl-amino)-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (60 mg, 0.13 mmol) was carried out following a procedure similar to that delineated in Step B, Example 27, affording 43 mg of 7-(Cyclohexylmethyl-methoxycarbonyl-amino)-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (63% yield).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.CCN(CC)CC.Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH2:26]([N:13]1[CH2:12][CH2:11][CH:10]([O:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([Br:1])[CH:17]=[CH:16][C:5]=3[N:6]=2)[CH2:15][CH2:14]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Brc1ccc2nc(OC3CCNCC3)sc2c1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Brc1ccc2nc(OC3CCN(Cc4ccccc4)CC3)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
To a solution of Compound 1B (4.32 g, 13.79 mmol) in THF (100 mL) was added Et3N (3.84 mL, 27.6 mmol) followed by (bromomethyl)benzene (1.64 mL, 13.8 mmol). Upon completion of addition, the reaction mixture was stirred at rt overnight. After this time, the reaction mixture was quenched with saturated aqueous NH4Cl (50 mL), and then extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (40 mL) and dried (MgSO4). The solvent was removed and the resulting residue was recrystallized from MeOH to give Compound 14A as a white solid (2.12 g, 5.26 mmol, 38% yield). LC/MS (m/z)=404 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[O:7])=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[O:7])=[CH:34][CH:35]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(N)cc1
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(NC(C)=O)cc1
Yield: 84.5 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2-methoxyphenyl)benzamide (2.65 g, 5.58 mmol) and acetic anhydride (0.79 ml, 8.37 mmol), the procedure of Inventive Example 94 was repeated to obtain 2.44 g (84.3%) of the title compound in a colorless amorphous form.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:44]([C:60]([N:62]2[CH2:68][CH2:67][CH2:66][N:65]([C:69](=[NH:84])[NH:70]C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:64][CH2:63]2)=[O:61])[CH2:43]1>>[C:69]([N:65]1[CH2:66][CH2:67][CH2:68][N:62]([C:60]([C@@H:44]2[CH2:43][C@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:46][NH:45]2)=[O:61])[CH2:63][CH2:64]1)(=[NH:70])[NH2:84]
Reactant: N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCCN(C(=N)N)CC4)C3)[C@H](C)[C@H]12

Procedure:
A procedure similar to that described in Example 101 was repeated, but using 4-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl -1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) and (2S,4S)-4-mercapto-1-(4-nitrobenzyl -oxycarbonyl)-2-[4-(4-nitrobenzyloxycarbonylamidino)homopiperazin -1-ylcarbonyl]pyrrolidine (prepared as described in Preparation 94) as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:16])([F:15])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[CH:4][CH:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1.C[Sn](C)C.C[Sn](C)C>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:15][C:8]([F:16])([C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=2)=[CH:3][CH:4]=1)[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10]
Reactant: CON(C)C(=O)C(F)(F)c1ccc(Br)cc1
Reactant: Fc1ccc(Br)nc1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CON(C)C(=O)C(F)(F)c1ccc(-c2ccc(F)cn2)cc1

Procedure:
Palladium tetrakis(triphenylphosphine) (236 mg, 0.20 mmol) was added to a degassed, ambient temperature solution of 2-(4-bromophenyl)-2,2-difluoro-N-methoxy-N-methylacetamide (600 mg, 2.05 mmol), 2-bromo-5-fluoropyridine (360 mg, 2.05 mmol) and hexamethylditin (670 mg, 2.05 mmol) in 1,4-dioxane (20 mL). After stirring at reflux overnight, the reaction mixture was diluted with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-60% ethyl acetate/hexane afforded 2,2-difluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]-N-methoxy-N-methylacetamide.
Reaction SMILES: C[Si](C)(C)[O:3][C@@H:4]1[C@@H:9]([O:10][Si](C)(C)C)[C@H:8]([O:15][Si](C)(C)C)[C@@H:7]([CH2:20][O:21][Si](C)(C)C)[O:6][C:5]1=[O:26].C([Mg]Cl)(C)C.[Li+].[Cl-]>CCCCCCC>[CH2:20]([OH:21])[C@H:7]1[O:6][C:5](=[O:26])[C@H:4]([OH:3])[C@@H:9]([OH:10])[C@@H:8]1[OH:15]
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCCC
Product: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
A 500 L glass-lined reactor was charged with (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (11.4 kg) and n-heptane (12.2 kg) and the mixture was cooled to −15° C. under nitrogen sparging for 1 h. iPrMgCl.LiCl (0.5 kg, 1.3 M in THF) was added dropwise and the mixture was stirred for 30 min at −15° C.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11](OS(C(F)(F)F)(=O)=O)=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:26]3[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=3[F:33])[C:5]2=[O:34])[CH2:3][CH2:2]1.[NH2:35][C:36]1[CH:37]=[C:38]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=1.CN(C)C(=O)C.N1C(C)=CC=CC=1C>CO>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11]([NH:35][C:36]4[CH:37]=[C:38]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=4)=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:26]3[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=3[F:33])[C:5]2=[O:34])[CH2:2][CH2:3]1
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: Cc1cccc(C)n1
Product: Cc1c(Nc2cccc(NS(C)(=O)=O)c2)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Temperature: 130 °C
Reaction time: 3.5 h
Yield: 96 %

Procedure:
To trifluoromethanesulfonic acid 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 43 (30.0 g) obtained in the same manner in Example 4-2, Step 6 to be mentioned later and N-(3-aminophenyl)methanesulfonamide 44 (10.9 g) were added N,N-dimethylacetamide (60.0 ml) and 2,6-lutidine (6.82 ml), and the mixture was stirred at 130° C. for 3.5 hrs. After allowing to cool to room temperature, methanol (60 ml) was added with stirring and the mixture was stirred for 2 hrs. The crystals were collected by filtration and dried is to give N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfonamide 45 (30.5 g, yield 96%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[C:8]3[CH:29]=[CH:28][CH:27]=[CH:26][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:32]([Cu])#[N:33]>CN(C=O)C>[C:32]([C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8]3[CH:29]=[CH:28][CH:27]=[CH:26][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:14][CH:13]=2)=[CH:30][CH:31]=1)#[N:33]
Reactant: Brc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Yield: 33.6 %

Procedure:
3-(4-Bromobenzyl)-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (300 mg, 0.61 mmol) in DMF (5 mL) was treated with CuCN (135 mg) at reflux for 3 h. The cooled reaction mixture was extracted with EtOAc (3×50 mL), with water (50 mL) washing. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:5:90) afforded the product (90 mg, 34%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16](=O)[CH3:17])=[CH:11][C:10]=1[CH3:19])([CH3:7])[CH3:6])[CH3:2].ClCC1[C:24]([CH:40]2[CH2:42][CH2:41]2)=[N:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)=[CH:27][CH:28]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[C:24]([CH:40]3[CH2:41][CH2:42]3)=[N:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:37])([F:39])[F:38])=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)=[CH:11][C:10]=1[CH3:19])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SC(C)=O)cc1C
Reactant: FC(F)(F)Oc1ccc(-c2ccc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(SCc2ccc(-c3ccc(OC(F)(F)F)cc3)nc2C2CC2)cc1C

Procedure:
In analogy to the procedure described in example 142D], 2-(4-acetylsulfanyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 142C]) was reacted with 3-chloromethyl-2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-pyridine (example 143F]) to give the title compound as colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[CH3:13][N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[CH3:12][O:11][C:4]1[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=[C:2]([C:17]2[CH:16]=[N:15][N:14]([CH3:13])[CH:18]=2)[CH:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(Br)cn2nccc12
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: C1COCCO1
Solvent: O
Product: COc1cc(-c2cnn(C)c2)cn2nccc12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
6-bromo-4-methoxypyrazolo[1,5-a]pyridine (500 mg, 2.20 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1375 mg, 6.61 mmol), tetrakis(triphenylphosphine)palladium (0) (254 mg, 0.220 mmol), and sodium carbonate (700 mg, 6.61 mmol) were suspended in a mixture of 1,4-dioxane (19.8 ml) and water (2.2 ml). The mixture was sparged with argon for 10 minutes, then heated to 90° C. After 2 h, the reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine as a tan solid contaminated with trace amounts of triphenylphosphine oxide. Analytically pure material could be obtained by purification by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:22])/[CH2:11][CH2:12]/[CH:13]=[C:14](\[CH3:21])/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH2:3][C:4](O)=[O:5].[OH-].[Na+].O1C=CN=C1[Cl:30]>C1C=CC=CC=1>[CH3:1][CH:2]([CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:22])/[CH2:11][CH2:12]/[CH:13]=[C:14](\[CH3:21])/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH2:3][C:4]([Cl:30])=[O:5]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC(C)CC(=O)O
Reactant: Clc1ncco1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC(C)CC(=O)Cl
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 97.4 %

Procedure:
At room temperature, 9.2 g of the compound obtained in step (c) above was dropped into a 55% benzene suspension containing 1.3 g of sodium hydroxide, and the mixture was stirred at 50° C. for 10 minutes. The liquid reaction mixture was cooled to room temperature, and 3.8 g of oxazolyl chloride was dropped into the liquid reaction mixture and the resulting mixture was stirred at 50° C. for 30 minutes. The liquid reaction mixture was filtered and the solvent was removed from the filtrate by distillation under reduced pressure at a temperature lower than 40° C. to obtain 9.5 g of the intended compound in the form of an oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)O1.Br[C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:41])[CH2:25][O:26][CH2:27][C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:32]=2[C:33]([OH:35])=[O:34])=[O:29])[CH:20]=[CH:21][CH:22]=1>>[Cl:40][C:37]1[CH:38]=[CH:39][C:31]([NH:30][C:28](=[O:29])[CH2:27][O:26][CH2:25][C:24]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:9]3[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=3)[CH:18]=2)=[O:41])=[C:32]([CH:36]=1)[C:33]([OH:35])=[O:34]
Reactant: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cn1cc(-c2cccc(NC(=O)COCC(=O)Nc3ccc(Cl)cc3C(=O)O)c2)cn1

Procedure:
Using the same method as in Example 5-(i), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-methylpyrazole was reacted with the 2-[((2-[(3-bromophenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester obtained in Example 19-(i) to give 5-chloro-2-([(2-([3-(1-methyl-1H-pyrazol-4-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 56%).
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[C:3]#[C:4][C:5]1([CH3:15])[CH2:14][CH2:13][C:8]2(OCC[O:9]2)[CH2:7][CH2:6]1.Cl>CC(C)=O.[Cl-].[Na+].O>[CH3:15][C:5]1([C:4]#[C:3][Si:2]([CH3:16])([CH3:1])[CH3:17])[CH2:14][CH2:13][C:8](=[O:9])[CH2:7][CH2:6]1
Reactant: CC1(C#C[Si](C)(C)C)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C#C[Si](C)(C)C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
To a solution of 6 (2.1 g, 8.3 mmol) in acetone (25 mL) was added 10% aqueous HCl solution (15 mL). The solution was cloudy. Thus, to the cloudy solution, was acetone dropwise (total 12 mL) until the solution was clear. The clear solution was stirred at room temperature for 5 h. The mixture was diluted with brine (250 mL). The aqueous mixture was extracted with methylene chloride/ether (1:2, 200 mL×3). The extract was washed with saturated aqueous bicarbonate solution (2×100 mL) and brine (100 mL×1), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo to give 7 as a crystalline solid (1.7 g, 98%): 1H NMR (CDCl3) δ 2.75, 2.29, 2.04, 1.65 (each 2H, m), 1.32 (3H, s), 0.17 (9H, s); 13C NMR (CDCl3) δ 211.8, 110.8, 86.9, 39.2, 38.8, 32.9, 28.8, 0.4.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15]Cl)[CH:10]=2)[NH:5][C:4](=[O:17])[CH:3]=1.[I-].[Na+].[CH2:20]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.CN(C)C=O.CC(C)=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:30]3[CH2:31][CH2:32][CH:27]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:28][CH2:29]3)[CH:10]=2)[NH:5][C:4](=[O:17])[CH:3]=1
Reactant: Cc1cc(=O)[nH]c2ccc(OCCCCl)cc12
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(=O)[nH]c2ccc(OCCCN3CCC(Cc4ccccc4)CC3)cc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
2.5 Grams of 4-methyl-6-(3-chloropropoxy)carbostyril, 1.8 g of sodium iodide were mixed with 50 ml of acetone and the mixture was stirred at 50° C. for 1 hour, then 50 ml of dimethylformamide was added and acetone was removed by distillation under a reduced pressure. To the residue thus obtained was added 1.5 g of triethylamine and 1.6 g of 4-benzylpiperidine and the mixture was heated at 70°-80° C. for 7 hours under stirring condition. The reaction mixture was then concentrated under a reduced pressure to dryness and to the residue thus obtained was added 60 ml of a 5%-sodium hydrogencarbonate aqueous solution and stirred to obtain the insoluble matters. The insoluble matters were collected by filtration, washed with water and then recrystallized from methanol to obtain 3.2 g (yield: 82%) of 4-methyl-6-[3-(4-benzyl-1-piperidyl)propoxy]-carbostyril as in the form of yellowish prism-like crystals. Melting point: 177°-178° C.
Reaction SMILES: [CH3:1][C@@:2]1([OH:21])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[CH:11]([CH2:12][CH:13]=[CH:14][CH2:15]1)[CH2:10][CH2:9]3.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>ClCCl>[CH3:1][C@@:2]1([OH:21])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[CH:11]([CH2:12][C@@H:13]2[O:30][C@@H:14]2[CH2:15]1)[CH2:10][CH2:9]3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@]12CC=CCC1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]2(C)O
Solvent: ClCCl
Product: C[C@]12C[C@H]3O[C@H]3CC1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]2(C)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
To a solution of compound 27 (120 mg, 0.43 mmol) in anhydrous dichloromethane (10 mL) was added m-CPBA (112 mg, 0.54 mmol) at 0° C. under an atmosphere of argon. The solution was stirred at 0° C. over a period of 3 h. The solution was subsequently diluted with dichloromethane (50 mL) and washed with an aqueous sodium bicarbonate solution (10%). The organic layer was dried with sodium sulfate and evaporated under reduced pressure. The crude compound was purified by flash chromatography (Hexanes/acetone: 95:5) to yield compound 28 (116 mg, 91%). 1H NMR (CDCl3) δ: 0.77 (s, 19-CH3), 0.83 (s, 18-CH3), 1.21 (s, 17α-CH3), 0.60-1.95 (residual CH and CH2), 3.11 (t, J=5.8 Hz, CH of epoxide) and 3.15 (broad s, 2×CH of epoxide).
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([CH3:10])[S:8][CH:9]=1)[CH2:3][NH2:4].[OH:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=1>>[OH:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([CH3:10])[S:8][CH:9]=2)[CH3:23])=[CH:17][CH:16]=1
Reactant: CC(=O)Cc1ccc(OCCO)cc1
Reactant: Cc1nc(C(O)CN)cs1
Product: Cc1nc(C(O)CNC(C)Cc2ccc(OCCO)cc2)cs1

Procedure:
Prepared by analogy to Example 13 by reaction of 2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with 1-[4-(2-hydroxyethoxy)phenyl)propan-2-one followed by purification on a silica gel column using methylene chloride/methanol=9:1 as eluant.
Reaction SMILES: N[C:2]1[C:3](=[O:12])[NH:4]C=[C:6]([C:8](OC)=O)[CH:7]=1.[Br:13][CH2:14]CCCCC(O)=O>>[Br:13][CH2:14][CH2:8][CH2:6][CH2:7][CH2:2][C:3]([NH2:4])=[O:12]
Reactant: COC(=O)c1c[nH]c(=O)c(N)c1
Reactant: O=C(O)CCCCCBr
Product: NC(=O)CCCCCBr

Procedure:
Solid phase synthesis has been employed in the preparation of certain pyridinones. In Solid Phase Synthesis of 1,3,5-Trisubstituted Pyridin-2-ones, Tetrahedron Letters, 40(1999) 2227-2230 authors James A. Linn et al. report the solid phase synthesis of 1,3,5-trisubstituted pyridin-2-ones via selective NH-alkylation of 3-amino-5-carbomethoxy-1H-pyridin-2-one using a solid supported halo-acid. The synthesis proceeds by the coupling of 6-bromohexanoic acid to a Rink amine macrocrown to form a solid-supported 6-bromohexanamide. The solid-supported 6-bromohexanamide was used to alklylate 3-amino-5-carbomethoxy-1H-pyridin-2-one which was then reacted with diphenylacetic acid. Saponification of the resulting ester yielded a solid supported carboxylic acid. Treatment of the solid supported carboxylic acid with pentafluorophenol provided the pentafluorophenyl ester, which when treated with benzylamine was cleaved from the macrocrown to give the pyridinone. However, a solid phase synthesis procedure to produce ring fused 2-pyridinones has not yet been reported.