Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH3:6][O:7][CH2:8][CH2:9][N:10]([CH3:24])[C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][C:12]=1[C:20]([F:23])([F:22])[F:21].C([BH3-])#[N:26].[Na+]>CO>[NH2:26][CH:17]([C:14]1[CH:15]=[CH:16][C:11]([N:10]([CH2:9][CH2:8][O:7][CH3:6])[CH3:24])=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:13]=1)[CH3:18]
Reactant: [BH3-]C#N
Reactant: COCCN(C)c1ccc(C(C)=O)cc1C(F)(F)F
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COCCN(C)c1ccc(C(C)N)cc1C(F)(F)F
Yield: 26.9 %

Procedure:
Ammonium acetate (1.53 g, 19.8 mmol) was added to a solution of the compound from step 1 (545 mg, 1.98 mmol) in MeOH (8 mL). After stirring at RT overnight sodium cyanoborohydride (149 mg, 2.38 mmol) was added and the reaction was refluxed for 6 h. The solvent was evaporated and the solid, redissolved in ethyl acetate, was extracted with water. The organic layer was separated, washed with brine, dried over sodium sulphate, filtered, evaporated and purified by preparative HPLC. The relevant fractions were lyophilized to give 147 mg (yield: 19%) of the pure product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][CH2:29][CH2:30][CH2:31][OH:32]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([O:15][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: Cc1cn2c3ccc(Br)cc3c3cc(O)cc(c1=O)c32
Reactant: OCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cn2c3ccc(Br)cc3c3cc(OCCCCO)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
10-bromo-2-hydroxy-5-methyl-4H-pyrido[3,2,1-jk]carbazole-4-one (250 mg) obtained in Example 49 was suspended in dimethyl sulfoxide (10 ml), and potassium carbonate (210 mg) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and 4-chloro-1-butanol (0.09 ml) was added to the mixture. The mixture was stirred at 80° C. in a hot water bath for 14 hours, and the reaction mixture was poured into ice water (500 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride containing 4% methanol) to obtain the title compound (80 mg, 26%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14]OS(C)(=O)=O)[N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].CC1C=CC(S(O)(=O)=O)=CC=1.[F:40][CH2:41][C@H:42]1[CH2:46][CH2:45][NH:44][CH2:43]1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:44]3[CH2:45][CH2:46][C@H:42]([CH2:41][F:40])[CH2:43]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Reactant: FC[C@H]1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CC[C@H](CF)C1
Yield: 100.6 %

Procedure:
Prepare using the method of Example 102 with 2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]ethyl methanesulfonate (See Intermediate 13) (0.17 g, 0.46 mmole), anhydrous acetonitrile (2 mL), potassium carbonate (0.25 g, 1.84 mmol), potassium iodide (0.008 g, 0.05 mmol) and (3S)-3-(fluoromethyl)pyrrolidine 4-methylbenzenesulfonate (salt) (See Intermediate 55) (0.19 g, 0.69 mmol) to give the title compound as a pale orange oil (0.17 g): MS (m/e): 367, 369(M+1)
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]([C:7]1[CH:8]=[CH:9][C:10]2[NH:16][C:15]3[N:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:14]=3[CH2:13][N:12]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:11]=2[CH:38]=1)([CH3:6])[CH3:5].[Li+].[OH-]>O.C1COCC1.C(#N)C>[C:34]([C:31]1[CH:30]=[CH:29][C:28]([S:25]([N:12]2[C:11]3[CH:38]=[C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:39])=[O:2])[CH:8]=[CH:9][C:10]=3[NH:16][C:15]3[N:17]=[C:18]([C:21]([F:23])([F:22])[F:24])[CH:19]=[CH:20][C:14]=3[CH2:13]2)(=[O:26])=[O:27])=[CH:33][CH:32]=1)([CH3:35])([CH3:36])[CH3:37]
Reactant: COC(=O)C(C)(C)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(C)(C)C(=O)O)cc32)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To the methyl ester (92 mg, 0.16 mmol) of Example 373 in 3 mL of H2O/THF/acetonitrile (1:1:1) was added LiOH (16 mg, 0.65 mmol). After stirring at rt for 48 hrs, the reaction was quenched with aqueous NH4Cl (25 mL) and the product was extracted with EtOAc (60 mL). The extracts were washed with water (30 mL) and brine (30 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified on silica gel column eluting with 20-50% EtOAc in hexanes to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.61 (1H, d), 7.46 (1H, s), 7.24 (1H, d), 7.17 (2H, d), 7.03 (1H, d), 6.93 (1H, d), 6.91 (2H, d), 1.58 (6H, s), 1.22 (9H, s). LCMS: m/e 548.2 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.Br[C:13]([F:20])([F:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].[Cl-].[NH4+].C(OCC)(=O)C>CS(C)=O.[Cu]>[CH2:17]([O:16][C:14](=[O:15])[C:13]([F:20])([F:19])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)[CH3:18]
Reactant: Ic1ccc2ncccc2c1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)c1ccc2ncccc2c1
Temperature: 55 °C
Reaction time: 15 h
Yield: 50.5 %

Procedure:
To a suspension of 6-Iodoquinoline (10.2 g, 40 mmol) and Copper (0) (nanopowder, 5.59 g, 88 mmol) in dry DMSO (97 mL) was added 8.93 g (44 mmol) of ethyl bromodifluoroacetate. The reaction mixture was stirred under nitrogen at 55° C. for 15 hours. The reaction was allowed to reach room temperature and the mixture was poured over a solution of ammonium chloride. Ethyl acetate was added and the resulting mixture filtered over Celite. The organic layer was collected, dried (MgSO4), filtered and concentrated in vacuum. The crude mixture was chromatographied over silica gel with CH2Cl2 100% and CH2Cl2/MeOH:95/5 to yield 5.07 g of Difluoro-quinolin-6-yl-acetic acid ethyl ester as light yellow oil (50%).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)C1C=CC=CC=1>[Pd].C(O)C>[C:28]1([NH:27][C:25](=[O:26])[NH:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][C:14]3[CH:13]=[CH:12][C:11]([NH2:10])=[CH:16][CH:15]=3)=[CH:19][CH:20]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Nc1ccccc1)Nc1ccc(Cc2ccc(NC(=O)OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Cc2ccc(NC(=O)Nc3ccccc3)cc2)cc1
Reaction time: 12 h
Yield: 83.2 %

Procedure:
A mixture of 4-[4-(3-phenylureido)benzyl]phenyl-carbamic acid benzyl ester (1.3 g) and 10% palladium on carbon (0.35 g) in ethanol (150 mL) was hydrogenated at 50 psi in a Parr apparatus for 12 hours. The reaction mixture filtered through a Celite pad to remove catalyst. The filtrate on concentration gave 4-[4-(3-phenylureido)benzyl]-phenylamine (0.76 g) as white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH2:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])=[CH:15][CH:14]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])=[CH:15][CH:14]=2)[N:3]=1
Reactant: Nc1ccc(C(=O)Nc2ccccc2)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: O=C(Nc1ccccc1)c1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Yield: 95.7 %

Procedure:
The procedure is carried out as in Example 1, starting with 195 mg of 2,6-dichloropurine, 5 ml of butanol and 272 mg of 4-amino-N-phenylbenzamide. 360 mg of the expected product are thus obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.C(N(CC)CC)C.Cl.[CH2:35]1[CH:39]2[CH2:40][NH:41][CH2:42][CH2:43][N:38]2[C:37](=[O:44])[O:36]1.CN(C)C=O>O>[CH3:26][N:17]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]([C:6]1[S:7][C:3]([CH2:2][N:41]3[CH2:42][CH2:43][N:38]4[C:37](=[O:44])[O:36][CH2:35][CH:39]4[CH2:40]3)=[CH:4][N:5]=1)=[CH:16]2)[S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:20]
Reactant: O=C1OCC2CNCCN12
Reactant: CN(c1cccc2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(c1cccc2cc(-c3ncc(CN4CCN5C(=O)OCC5C4)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A mixture of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (150 mg), triethylamine (150 μL), hexahydro[1,3]oxazolo[3,4-a]pyrazin-3-one hydrochloride (125 mg) and N,N-dimethylformamide (2 ml) was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (103 mg, yield 56%) as a colorless amorphous form from a fraction eluted with ethyl acetate. MS 530 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][Si:5]([CH3:11])([CH3:10])[O:6][SiH:7]([CH3:9])[CH3:8].[CH2:14]([O:17][CH2:18][CH:19]1[CH2:21][O:20]1)[CH:15]=[CH2:16]>>[CH3:11][Si:5]([CH3:10])([CH2:4][CH2:3][Si:2]([CH3:1])([CH3:13])[CH3:12])[O:6][Si:7]([CH3:9])([CH3:8])[CH2:16][CH2:15][CH2:14][O:17][CH2:18][CH:19]1[CH2:21][O:20]1
Reactant: C=CCOCC1CO1
Reactant: C[SiH](C)O[Si](C)(C)CC[Si](C)(C)C
Product: C[Si](C)(C)CC[Si](C)(C)O[Si](C)(C)CCCOCC1CO1
Temperature: 90 °C

Procedure:
1-(2-trimethylsilylethyl)-1,1,3,3-tetramethyldisiloxane (18.8 g) and chloroplatininc acid catalyst (ethanolic solution, 30 ppm Pt) were charged to a 100 ml round-bottomed (RB) flask equipped with a magnetic stirrer, reflux condenser, and N2 inlet. The mixture was stirred and heated to 90° C. 2-Allyloxymethyl-oxirane (10 g) was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 90° C. for an additional 4 hours. Reaction progress was followed by NMR spectroscopy. Upon reaction completion, excess 2-allyloxymethyl-oxirane was removed by vacuum distillation.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[CH2:13][CH2:12]1.[H][H]>CO.[Pd]>[NH:14]1[CH2:13][CH2:12][CH:11]([N:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:10][C:2]2=[O:1])[CH2:16][CH2:15]1
Reactant: O=C(OCc1ccccc1)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2ncccc2n1C1CCNCC1

Procedure:
690 g (1.96 mol) benzyl 4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidine-1-carboxylate were dissolved in 5.4 L methanol and hydrogenated with the addition of 46 g Pd/C (10%; 6.6% by weight) at 60° C. under a hydrogen pressure of 60 psi until all the hydrogen had been taken up. The catalyst was filtered off. 4 L methanol were distilled off from the filtrate. 2 L methylcyclohexane were added and a further 1.5 L solvent were distilled off. The suspension thus obtained was suction filtered, the residue was washed with methylcyclohexane and dried at 40° C.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[N+:16]([C:19]1[CH:34]=[CH:33][C:22]([CH2:23][O:24][C:25]([NH:27][CH2:28][CH2:29][C:30](O)=[O:31])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].S.[S:36](=O)(=O)(O)O>C(Cl)Cl>[N+:16]([C:19]1[CH:34]=[CH:33][C:22]([CH2:23][O:24][C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:31])=[S:36])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)CCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CC(C)COC(=O)Cl
Agent: S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCC(O)=S)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.4 g (40 mmol) of triethylamine and a solution of 2.8 ml (2 mmol) of isobutyl chloroformate in 20 ml of dry methylene chloride are added dropwise, in succession, to a solution, cooled to -10°, of 5.36 g (20 mmol) of 3-p-nitrobenzyloxycarbonylaminopropionic acid in 100 ml of dry methylene chloride. The reaction mixture is stirred for one hour at -18°, then for 11/2 hours a strong current of hydrogen sulphide is passed through and the mixture allowed to heat up to room temperature. After acidifying with 2N sulphuric acid, again in the cold, the organic phase is separated, dried and concentrated in vacuo. The 3-p-nitrobenzyloxycarbonylaminothiopropionic acid obtained can be used without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([NH:46][CH2:47][CH3:48])=[O:45])=[CH:40][CH:39]=3)[C:11]=2/[CH:12]=[CH:13]/[C:14]2[CH:15]=[N:16][N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:18]=2)=[O:6])[CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:38]3[CH:39]=[CH:40][C:41]([C:44]([NH:46][CH2:47][CH3:48])=[O:45])=[CH:42][CH:43]=3)[C:11]=2/[CH:12]=[CH:13]/[C:14]2[CH:15]=[N:16][NH:17][CH:18]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2cn[nH]c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-[(E)-2-(1-trityl-1H-pyrazol-4-yl)vinyl]-1H-1,2,3-triazole-4-carboxamide (910 mg) obtained in Example 325a) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the obtained residue was triturated with water to give the title compound as a white powder (470 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:38]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:38][N:32]1[CH:31]=[CH:30][N:29]=[C:28]1[CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2cc(F)cc(F)c2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (40 mg, 0.085 mmol), 3,5-difluoro benzyl bromide (11.5 μL, 0.089 mmol, 1.05 equiv) and potassium carbonate (23.5 mg, 0.17 mmol) in dimethylformamide (1.0 mL) was stirred at room temperature for 16 h. The solvents were removed and the residue purified by column chromatography to afford 40.0 mg (79%). Mass spec.: 598.4 (MH)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[NH:16][C:17](=[O:23])OC(C)(C)C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:25](Cl)(=O)[CH2:26][CH2:27]C>>[CH2:1]([NH:8][C:9]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[NH:16][C:17](=[O:23])[CH2:25][CH2:26][CH3:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1sccc1C(=O)NCc1ccccc1
Agent: Cl
Product: CCCC(=O)Nc1sccc1C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 3-[(benzylamino)carbonyl]thien-2-ylcarbamate (2-2, 500 mg, 1.50 mmol, 1 equiv) was saturated with HCl gas at 0° C., and the resulting solution was stirred at 0° C. for 1 h, then allowed to warm to 23° C. and stirred for 1 h. The reaction mixture was concentrated and the residue was dissolved in pyridine (10 mL). The resulting solution was cooled to 0° C., and butyryl chloride (420 μL, 4.04 mmol, 2.69 equiv) was added in three equal portions over 1 h. The reaction mixture was partitioned between aqueous sodium bicarbonate solution and ethyl acetate (50 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column (hexanes initially, grading to 100% ethyl acetate) to give N-benzyl-2-(butyrylamino)thiophene-3-carboxamide (2-3) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 7.36 (m, 5H), 6.92 (d, 1H, J=6.1 Hz), 6.76 (d, 1H, J=5.8 Hz), 6.23 (s, 1H), 4.62 (d, 2H, J=5.8 Hz), 2.47 (t, 2H, J=7.3 Hz), 1.80 (sextet, 2H, J=7.3 Hz), 1.01 (t, 3H, J=7.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:17])[CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:18][C:19]1([CH3:28])[CH2:24][C:23](=O)[CH2:22][C:21]([CH3:27])([CH3:26])[O:20]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:23]2[CH2:22][C:21]([CH3:27])([CH3:26])[O:20][C:19]([CH3:28])([CH3:18])[CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:17])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)CC(C)(C)O1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(O)c(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(Br)cc2)c2ccc(O)c(F)c2)CC(C)(C)O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
To a stirred suspension of zinc powder (0.54 g, 8.13 mmol) in THF (20 mL) was slowly added TiCl4 (0.45 mL, 4.07 mmol) via syringe at room temperature under a nitrogen atmosphere. The mixture was heated at reflux for 2 h. A solution of (4-bromophenyl)(3-fluoro-4-hydroxyphenyl)methanone (82) (0.30 g, 1.02 mmol) and 2,2,6,6-tetramethyl tetrahydro-4H-pyran-4-one (0.49 g, 3.05 mmol) in THF (6 mL) was added to the mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 1.5 h. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added 10% aqueous K2CO3 (20 mL). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with EtOAc (25 mL). The combined organic phase washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as yellow oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 15% EtOAc:hexanes to give 0.40 g (94%) of compound 136 as a yellow foam. 1H NMR (400 MHz, CDCl3): δ 1.20 (s, 6H), 1.22 (s, 6H), 2.18 (s, 2H), 2.23 (s, 2H), 5.04 (d, J=4.0 Hz, 1H), 6.80-6.88 (m, 2H), 6.93 (t, J=8.6 Hz, 1H), 7.02 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H). LCMS (ES): m/z 417 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[N:7](C(O)=O)[CH:6]([C:11]([OH:13])=[O:12])[CH:5]=[CH:4][CH:3]=1.[C:14](O)(=[O:16])C.N1C=CC=CC=1.CCCCCC>COCCOC.CCOCC>[CH3:1][C:2]1[N:7]=[C:6]2[C:11](=[O:12])[O:13][C:14](=[O:16])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: CC1=CC=CC(C(=O)O)N1C(=O)O
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CCCCCC
Product: Cc1ccc2c(n1)C(=O)OC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
A solution of 6-methyl-1,2-pyridine dicarboxylic acid (25 g, 138 mmol) and acetic acid (42 mL, 733 mmol) in DME (150 mL) is treated with pyridine (22 mL, 272 mmol) and stirred at room temperature for 2 h. The pale yellow solution is diluted with ether (250 mL) and then hexane (1250 mL) is added slowly. A white precipitate is formed. The solution is cooled to 0° C. for 30 min and the white solid is collected by filtration. The solid is washed with hexane and dried to give the title compound as a white solid (16.7 g, 74%).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Na+].[I-].Cl[CH2:26][CH2:27][OH:28]>CN(C=O)C.CCOC(C)=O>[OH:28][CH2:27][CH2:26][O:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(O)cc1)c1ccc(OCCO)cc1
Temperature: 80 °C
Yield: 36.2 %

Procedure:
To a solution of 4,4′-dihydroxybenzophenone (3.0 g, 13.9 mmol) in DMF (30 mL) was added Cs2CO3 (13.55 g, 41.6 mmol). The mixture was heated at 80° C. under nitrogen for 1 h. Cooled to room temperature, NaI (2.08 g, 13.9 mmol) was added, followed by dropwise addition of a solution of 2-chloroethanol (1.03 mL, 15.3 mmol) in DMF (7 mL) with stirring. The reaction mixture was heated at 80° C. under nitrogen overnight. The mixture was cooled to room temperature and quenched with saturated aqueous NH4Cl (100 mL), then extracted with EtOAc (3×60 mL). The organic layers were combined and washed with water, brine and dried over Na2SO4. Concentration gave a reddish brown oil which was further purified by chromatography on a silica gel column eluted with a gradient from hexanes to 80% EtOAc:hexanes yielded a pale white solid. Trituration with 10% EtOAc:hexanes afforded 1.30 g (36%) of 96 as a white solid. mp 146-147° C. 1H NMR (400 MHz, CD3OD): δ 3.85-3.95 (m, 2H), 4.10-4.20 (m, 2H), 6.87 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 7.67 (d, J=8.6 Hz, 2H), 7.73 (d, J=8.8 Hz, 2H). LRMS (ESI): m/z 259 (M+H)+, 257 (M−H)−.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH2:14][CH:15]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH:27]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:10]1[O:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCCCC1CC(c2ccccc2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1N1CCNCC1CCCCC1CC(c2ccccc2)=NO1
Yield: 74.5 %

Procedure:
4-(3-Phenyl-4,5-dihydroisoxazol-5-yl)butanal (20.9 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.6 mg, 0.262 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 25.5 mg (69.2%) of the target compound was obtained.