Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(N(CC)C(C)C)(C)C.Br[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[C:17]([Cl:25])[N:16]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:21]([C:19]1[CH:18]=[C:17]([Cl:25])[N:16]=[C:15]([CH2:14][N:2]([CH3:3])[CH3:1])[CH:20]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CNC
Reactant: CC(C)(C)c1cc(Cl)nc(CBr)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)Cc1cc(C(C)(C)C)cc(Cl)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
Stir a solution of 2N dimethylamine (9.00 mL, 18.08 mmol) in tetrahydrofuran, N,N-diisopropylethylamine (2.80 g, 3.80 mL, 21.69 mmol) while adding a solution of 2-bromomethyl-4-tert-butyl-6-chloro-pyridine (1.90 g, 7.23 mmol) in tetrahydrofuran (20 mL). Stir for 2.5 hours at ambient temperature, dilute the reaction with aqueous sodium bicarbonate (80 mL) and extract the aqueous layer with ethyl acetate (3×75 mL). Pool, desiccate, filter and concentrate the organics to yield the title compound (99%) (1.64 g, 7.23 mmol). MS(ES), m/z 227 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].N1C=CN=C1.C1COCC1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(OC)(C)C>[Si:18]([O:1][C@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7])([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1OCC[C@@H]1O
Agent: c1c[nH]cn1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](O[C@H]1CCOC1=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 94.9 %

Procedure:
To a stirred solution of (S)-3-hydroxydihydrofuran-2(3H)-one (5.24 g, 51.4 mmol), imidazole (3.8 g, 56 mmol), and THF (70 mL) at 0° C., under N2, was added t-butyldiphenylsilyl chloride (11.8 g, 43 mmol) dropwise. The mixture was stirred at 0° C. for 6 hours. TBME (150 mL) was added and the solution was washed with water (2×100 mL), brine (100 mL), dried over sodium sulfate, filtered, and evaporated to dryness under reduced pressure to afford (S)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (13.9 g, 95%) as a slightly yellow oil. 1H-NMR (400 MHz, CDCl3) δ 7.84-0.82 (m, 2H), 7.73-7.71 (m, 2H), 7.50-7.40 (m, 6H), 4.41-4.31 (m, 2H), 4.06-4.00 (m, 1H), 2.29-2.19 (m, 2H), 1.10 (s, 9H).
Reaction SMILES: Br[C:2]1[C:3]2C=C3[C@@H](CC(O)=O)CCN3C=2C=C(F)[CH:10]=1.[CH3:19][O:20][C:21](=[O:37])[CH2:22][C@@H:23]1[C:27]2=[CH:28][C:29]3[C:30](Br)=[CH:31][C:32]([F:35])=[CH:33][C:34]=3[N:26]2[CH2:25][CH2:24]1>>[CH3:19][O:20][C:21](=[O:37])[CH2:22][C@@H:23]1[C:27]2=[CH:28][C:29]3[C:30]([CH:2]([CH3:3])[CH3:10])=[CH:31][C:32]([F:35])=[CH:33][C:34]=3[N:26]2[CH2:25][CH2:24]1
Reactant: COC(=O)C[C@H]1CCn2c1cc1c(Br)cc(F)cc12
Reactant: O=C(O)C[C@H]1CCn2c1cc1c(Br)cc(F)cc12
Product: COC(=O)C[C@H]1CCn2c1cc1c(C(C)C)cc(F)cc12

Procedure:
Starting from [(1R)-8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetic acid (from Step 1 of Example 62A) which was converted to methyl[(1R)-8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate by addition of CH2N2, the title compound was synthesized following the procedures described in Steps 1 and 2 of Example 44.
Reaction SMILES: [CH2:1]([N:5]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:27]([C:29]1[C:30](=[C:45]([C:48]#[N:49])[C:46]#[N:47])[O:31][C:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:35]([F:38])([F:37])[F:36])[C:33]=1[CH3:34])#[N:28]>C(O)C.O1CCCC1>[CH2:23]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:34][C:33]3[C:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:35]([F:38])([F:36])[F:37])[O:31][C:30](=[C:45]([C:48]#[N:49])[C:46]#[N:47])[C:29]=3[C:27]#[N:28])=[CH:16][CH:15]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)s2)c(OC)c1
Temperature: 70 °C
Yield: 92.7 %

Procedure:
In 8 ml of ethanol and 2.5 ml of tetrahydrofuran were dissolved 226 mg (0.61 mmol) of 5-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]thiophene-2-carboaldehyde and 210 mg (0.62 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred with heating at 70° C. for 4 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 378 mg of a dark brown powdered crystal (yield: 92.9%; mp: 203-204° C.)
Reaction SMILES: C([O-])(O)=O.[Na+].C([O-])([O-])=O.[K+].[K+].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[C:22](=O)[C:21](=[CH:24]N(C)C)[CH2:20][C:19](=[O:28])[N:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:17]=2[CH:35]=1.[NH:36]([C:40]1[CH:48]=[CH:47][C:43]([C:44]([OH:46])=[O:45])=[CH:42][CH:41]=1)[C:37]([NH2:39])=[NH:38]>CCO.CN(C=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[C:22]3[N:38]=[C:37]([NH:36][C:40]4[CH:48]=[CH:47][C:43]([C:44]([OH:46])=[O:45])=[CH:42][CH:41]=4)[N:39]=[CH:24][C:21]=3[CH2:20][C:19](=[O:28])[N:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:17]=2[CH:35]=1
Reactant: CN(C)C=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2C1=O
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)c1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2N(c2ccccc2)C(=O)C3)cc1

Procedure:
In a manner similar to method I (DMF and NaHCO3 were used in place of EtOH and K2CO3), 8-chloro-4-dimethylaminomethylene-1-phenyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-1) and 4-guanidinobenzoic acid were converted to I-10 (61%): HRMS Calcd. for C25H17ClN4O3: 457.1067, Found 457.1076.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH:19][CH2:20][CH2:21][OH:22])(=[O:18])=[O:17])=[CH:15][C:9]=3[C:8]([N+:23]([O-:25])=[O:24])=[CH:7][C:6]=2[NH:5][CH2:4]1.[CH3:26][O:27][C:28]1[CH:38]=[CH:37][C:31](/[CH:32]=[CH:33]/[C:34](O)=[O:35])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.CC1C=CC(S(O)(=O)=O)=CC=1>CO.Cl.O.CC(N(C)C)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH:19][CH2:20][CH2:21][OH:22])(=[O:17])=[O:18])=[CH:15][C:9]=3[C:8]([N+:23]([O-:25])=[O:24])=[CH:7][C:6]=2[N:5]([C:34](=[O:35])/[CH:33]=[CH:32]/[C:31]2[CH:37]=[CH:38][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[CH2:4]1
Reactant: O=[N+]([O-])c1cc2c(c3ccc(S(=O)(=O)NCCO)cc13)C(CCl)CN2
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COc1ccc(/C=C/C(=O)N2CC(CCl)c3c2cc([N+](=O)[O-])c2cc(S(=O)(=O)NCCO)ccc32)cc1
Reaction time: 2 h
Yield: 65.5 %

Procedure:
(Scheme C). Amine 121 (75 mg, 0.19 mmol) was dissolved in MeOH/HCl(g) at room temperature and the solution was evaporated to dryness under reduced pressure. (E)-4-methoxycinnamic acid (41 mg, 0.23 mmol), EDCI (149 mg, 0.78 mmol), anhydrous TsOH (30 mg, 0.17 mmol) and dry DMA (3 mL) were then added and the mixture was sired at room temperature for 2 h. The mixture was poured into water and the precipitate was collected, washed with water, dried and dissolved in the minimum volume of DMW at room temperature. The solution was diluted with EtOAc, filtered and then diluted with hexane and refrigerated to give 37 (68 mg, 64%): mp 250-251° C.; 1H NMR [(CD3)2SO)] δ 9.35 (s, 1H), 8.83 (d, J=1.6 Hz, 1H), 8.38 (d, J=8.9 Hz, 1H) 8.00 (dd, J=8.9, 1.7 Hz, 1H), 7.90 (t, J=5.8 Hz, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.74 (d, J=15.3 Hz, 1H), 7.10 (d, J=15.3 z, 1H), 7.03 (d, J=8.81 Hz, 2H), 4.72-4.48 (m, 4 H), 4.13-4.06 (m, 2H), 3.83 (s, 3H), 3.38 (q, J=6.0 Hz, 2H), 2.87 (q, J=6.1 Hz, 2H). Anal. (C25H24ClN3O7S) C, H, N.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CN(C)C=O.[CH2:14]([C:21]1[C:22]2[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][C:23]=2[S:24][CH:25]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[Br:1][C:25]1[S:24][C:23]2[CH2:26][CH:27]([CH2:30][OH:31])[CH2:28][CH2:29][C:22]=2[C:21]=1[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCC1CCc2c(Cc3ccccc3)csc2C1
Solvent: O
Solvent: CN(C)C=O
Product: OCC1CCc2c(sc(Br)c2Cc2ccccc2)C1
Reaction time: 1 h

Procedure:
103 mg of N-bromosuccinimide was added little by little to a solution of 5.0 ml of N,N-dimethylformamide containing 136 mg of 3-benzyl-6-(hydroxymethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene under ice-cooling. After stirring for one hour, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, and the solvent was removed. Then, the residue was subjected to silica gel column chromatography and eluted with hexane and then with hexane/ethyl acetate (2:1), to give 164 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1([Cl:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[C:11]([CH:13]([OH:27])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)#[CH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1([Cl:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([O:27][CH:13]([C:11]#[CH:12])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:8]
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C(=O)Cl)C1(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C#CC(OC(=O)C1C(C)(C)C1(Cl)Cl)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,2-dichloro-3,3-dimethylcyclopropanoyl chloride (2.7g), alpha-ethynyl-3-phenoxybenzyl alcohol (3.0g) and triethylamine (3.0g) were dissolved in toluene (65 ml) at 10° C and the solution was stirred at room temperature for 16 hours. The mixture was filtered and the solvent was removed from the filtrate under reduced pressure. The residue was purified by chromatography on silica gel using toluene as eluant to give the desired product as an oil nD20 1.5660.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH3:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][SH:50]>>[CH2:49]([S:50][C:18](=[O:19])[CH2:17][S:14](=[O:16])(=[O:15])[NH:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:11])[CH3:12])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH3:38]
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: CCCCCCCCCCCCS
Product: CCCCCCCCCCCCSC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with dodecylthiol, mp 58°-60° C.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[C:5]1([N:11]2[C:15]([OH:16])=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[N:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCOCC1>[C:5]1([N:11]2[C:15]([OH:16])=[CH:14][C:13]([C:17]([O:19][C:2]([CH3:3])([CH3:1])[CH3:4])=[O:18])=[N:12]2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=C(C)C
Reactant: O=C(O)c1cc(O)n(-c2ccccc2)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1cc(O)n(-c2ccccc2)n1
Temperature: -78 °C
Reaction time: 6 h

Procedure:
To condensed isobutylene (1 ml) in a resealable glass tube was added 1-phenyl-3-carboxy-5-hydroxypyrazole (1 g; 4.9 mmol) in 30 ml of dioxane. The reaction mixture was cooled to -78° C. and 0.5 ml of conc. sulfuric acid was then added. The tube was sealed, stirred at room temperature for 6 hours, and cooled. The tube was opened, the mixture was neutralized and then basified (pH=12) with 2N NaOH solution, and extracted with ethyl acetate (3×). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 431 mg of 1-phenyl-3-(t-butyloxycarbonyl)-5-hydroxypyrazole as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH:8]([CH3:10])[NH:7][CH2:6][CH:5]1[CH3:11])[CH:2]=[CH2:3].C1(C)C=CC(C([C@](C(O)=O)(O)[C@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1.[OH-].[Na+].ClCCl>C(O)C>[CH2:1]([N:4]1[CH2:9][C@H:8]([CH3:10])[NH:7][CH2:6][C@H:5]1[CH3:11])[CH:2]=[CH2:3]
Reactant: C=CCN1CC(C)NCC1C
Agent: Cc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: C=CCN1C[C@H](C)NC[C@H]1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of racemic 1-allyl-2,5-dimethylpiperazine (3.82 g, 24.8 mmol, Example 42, infra) and (+)-di-p-toluoyl-D-tartaric acid (9.55 g, 24.8 mmol) in absolute ethanol (40 mL) was heated to reflux and allowed to cool gradually to room temperature. After standing for one day the salt was collected by filtration, washed with ethanol and dried to give 11.0 g. This was recrystallized four times from absolute ethanol to give the salt (4.5 g, 68% of theoretical for one enantiomer) as a white solid. The salt (3.3 g, 6.1 mmol) was partitioned between 2N sodium hydroxide solution and dichloromethane. The dichloromethane phase was separated, the alkali washed twice with dichloromethane, and the combined dichloromethane phases were dried with magnesium sulfate and evaporated to give (-)-(2R,5S)-1-allyl-2,5-dimethylpiperazine, (0.92 g, 98% recovery from the salt), [α]D20 =-55.7° (ethanol, c=1.8).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:26]=[C:27]([CH:39]=[CH:40][CH:41]=3)[O:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])OC(C)(C)C)=[O:24])[CH2:19][CH2:18]2)([CH3:15])[C:12](=[O:14])[N:13]=1.NCCOC1C=[C:48]([CH:73]=[CH:74]C=1)[C:49](N1CCC(CC2(C)SC(N[C@H]3CC4CC3CC4)=NC2=O)CC1)=[O:50].O1C=CC(C(O)=O)=C1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]([C:25]3[CH:26]=[C:27]([CH:39]=[CH:40][CH:41]=3)[O:28][CH2:29][CH2:30][NH:31][C:32]([C:73]3[CH:48]=[CH:49][O:50][CH:74]=3)=[O:38])=[O:24])[CH2:21][CH2:22]2)([CH3:15])[C:12](=[O:14])[N:13]=1
Reactant: CC1(CC2CCN(C(=O)c3cccc(OCCN)c3)CC2)SC(N[C@H]2CC3CCC2C3)=NC1=O
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(C(=O)N2CCC(CC3(C)SC(N[C@H]4CC5CCC4C5)=NC3=O)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)c1ccoc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CC1(CC2CCN(C(=O)c3cccc(OCCNC(=O)c4ccoc4)c3)CC2)SC(N[C@H]2CC3CCC2C3)=NC1=O

Procedure:
The title compound was prepared according to the procedure described in the preparation of tert-butyl 2-(3-(4-((2-((2S)-bicyclo[2.2.1]heptan-2-ylamino)-5-methyl-4-oxo-4,5-dihydrothiazol-5-yl)methyl)piperidine-1-carbonyl)phenoxy)ethylcarbamate by using 5-((1-(3-(2-aminoethoxy)benzoyl)piperidin-4-yl)methyl)-2-((2S)-bicyclo[2.2.1]heptan-2-ylamino)-5-methylthiazol-4(5H)-one (93 mg, 0.19 mmol), 3-furoic acid (Aldrich, 39 mg, 0.35 mmol), EDCI (Aldrich, 74 mg, 0.38 mmol), HOBt (Aldrich, 5.2 mg, 0.038 mmol) and triethylamine (Aldrich, 39 mg, 0.38 mmol, 2.0 eq). The title compound was obtained as an off-white solid (89 mg). MS (ESI, pos. ion) m/z. 579 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:12]=[C:13]([CH3:25])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cc(Br)cn12
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: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cc(C)cn12
Temperature: 25 °C

Procedure:
Under argon, 105 g (270 mmol) of ethyl 8-(benzyloxy)-6-bromo-2-methylimidazo[1,2-a]pyridine-3-carboxylate Example 15A were suspended in 4.2 l of 1,4-dioxane, 135.4 g (539 mmol, purity 50%) of trimethylboroxine, 31.2 g (27 mmol) of tetrakis(triphenylphosphine)palladium(0) and 78.3 g (566 mmol) of potassium carbonate were added in succession and the mixture was stirred under reflux for 8 h. The reaction mixture, cooled to RT, was filtered off from the precipitate over silica gel and the filtrate was concentrated. The residue was dissolved in dichloromethane and purified by silica gel chromatography (dichloromethane:ethyl acetate=9:1). This gave 74 g (84.6% of theory; purity 100%) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9](Cl)(=[O:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C(C)=CC=CC=1C.BrC1C=C(NC(=O)/C=C/C2C=CC=CC=2)C=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:9](=[O:18])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1cccc(F)c1
Agent: O=C(/C=C/c1ccccc1)Nc1cccc(Br)c1
Solvent: Cc1cccc(C)n1
Product: O=C(/C=C/c1ccccc1)Nc1cccc(F)c1

Procedure:
The compound was prepared from 3-fluoroaniline (5.8 mL, 60 mmol) and cinnamoylchloride (10 g, 60 mmol) in the presence of 2,6-lutidine (10.5 mL, 90 mmol) as described for Intermediate 18 to give a colorless solid, 13.9 g (96%), mp 110° C.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH:10]([CH2:12]Cl)[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:27][C:28]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:1]1([N:7]2[CH2:11][CH:10]([CH2:12][N:31]3[CH2:32][CH2:33][C:28]([OH:27])([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:29][CH2:30]3)[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=C1N(C2CCCCC2)CC(CCl)C1(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1N(C2CCCCC2)CC(CN2CCC(O)(c3ccccc3)CC2)C1(c1ccccc1)c1ccccc1
Temperature: 200 °C
Reaction time: 48 h

Procedure:
To 150 ml. of ethanol in a steel bomb was added 15.0 g. (0.041 mole) of 1-cyclohexyl-4-chloromethyl-3,3-diphenyl-2-pyrrolidinone, 7.23 g. (0.041 mole) of 4-hydroxy-4-phenyl piperidine and 17.0 g. (0.12 mole) of potassium carbonate. The bomb was heated in an oven at 200° C. with stirring for 48 hours. The mixture was concentrated in vacuo, and the residue was partitioned between dilute sodium hydroxide solution and chloroform. The chloroform layer was dried, filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate and treated with ethereal hydrogen chloride. The solid which precipitated was the hydrochloride of starting piperidine compound. A further precipitate from the filtrate of this material contained a by-product of the reaction. The by-product was separated by filtration and the filtrate concentrated. The residue was partitioned between chloroform and sodium hydroxide solution, and the chloroform, after drying, was concentrated in vacuo. The residue was placed on a magnesium silicate column using chloroform as the eluent. The product was obtained upon subsequent washings of 1 and 2 percent methanol in chloroform. The washings were concentrated in vacuo, and the residue crystallized using an isopropyl ether-ethyl acetate mixture. The solid (1.5 g.; m.p. 179°-184° C.) after recrystallizing from ethyl acetate weighed 1.0 g. and melted at 188°-190° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][C:20]([CH3:25])=[CH:19]4)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1>CS(C)=O.C(OCC)(=O)C>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([C:30]2[CH2:31][CH2:32][N:27]([CH2:12][CH:13]3[O:26][C:17]4=[C:18]5[C:22](=[CH:23][CH:24]=[C:16]4[O:15][CH2:14]3)[NH:21][C:20]([CH3:25])=[CH:19]5)[CH2:28][CH:29]=2)=[CH:34]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]c(C)cc4c3O2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc2c3c(ccc2[nH]1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3

Procedure:
A solution of 0.55 g (1.5 mmole) of [(2R)-8-methyl-2,3-dihydro-7H-[1,4]dioxino[2,3-e]indol-2-yl]methyl 4-methylbenzenesulfonate and 0.50 g (2.5 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1 H-indole in 6.0 mL of DMSO was heated at 65-7° C. for 4 hours. The mixture was diluted with 300 mL of ethyl acetate, washed with 200 ml portions of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 1% methanol in chloroform as eluant to give 0.21 g of the (S)-enantiomer of the title compound as a yellow solid, m.p. 212-215° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][C:42]1[C:43]([S:48](Cl)(=[O:50])=[O:49])=[N:44][CH:45]=[CH:46][CH:47]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:43]2[C:42]([CH3:41])=[CH:47][CH:46]=[CH:45][N:44]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cccnc1S(=O)(=O)Cl
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccnc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 20 mg) in tetrahydrofuran (2 mL) was added a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (161 mg), 15-crown-5 (110 mg), crude 3-methylpyridine-2-sulfonyl chloride (153 mg) in tetrahydrofuran (1.5 mL) at room temperature, and the mixture was stirred at room temperature for 72 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→11:9) to give the title compound as a colorless oil (yield 113 mg, 47%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:24][CH:25]([OH:28])[CH:26]=[CH2:27]>>[CH3:24][CH:25]([O:28][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)[CH:26]=[CH2:27]
Reactant: COc1cc(-c2cc3ncccc3c(Cl)n2)cc(OC)c1OC
Reactant: C=CC(C)O
Product: C=CC(C)Oc1nc(-c2cc(OC)c(OC)c(OC)c2)cc2ncccc12

Procedure:
5-(1-Methyl-allyloxy)-7-(3,4,5-trimethoxy-phenyl)-[1,6]naphthyridine (for Example 31) was prepared from 5-chloro-7-(3,4,5-trimethoxy-phenyl)-[1,6]naphthyridine and (R/S)-but-3-en-2-ol using an analogous procedure