Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([C:13](=[O:16])[NH:14][CH3:15])[C:6]=2[CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.Cl.[CH3:53][NH:54][O:55][CH3:56]>CN(C=O)C>[Br:1][C:2]1[C:3]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:4][C:5]2[O:9][C:8]([C:10]([N:54]([O:55][CH3:56])[CH3:53])=[O:12])=[C:7]([C:13]([NH:14][CH3:15])=[O:16])[C:6]=2[CH:17]=1
Reactant: CNC(=O)c1c(C(=O)O)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(C(=O)N(C)OC)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A mixture of 5-bromo-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylic acid (1 g, 2.47 mmol), HOBT (500 mg, 3.70 mmol) and EDCI (946 mg, 4.94 mmol) in DMF (20 mL) was stirred at room temperature under N2 for 2 h. Et3N (1.25 g, 12.34 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.03 g, 12.34 mmol) were added, then the mixture was stirred for 18 h. The mixture was concentrated, diluted with water, extracted with EA, the organic layers were washed with Na2CO3 (a.q.), brine, dried over Na2SO4, concentrated. The residue was purified by column chromatography (DCM:EA=20:1) to get product 5-bromo-N2-methoxy-N2,N3-dimethyl-6-(N-methylmethylsulfonamido)benzofuran-2,3-dicarboxamide (0.68 g, yield: 62%). 1H-NMR (CDCl3, 400 MHz) δ 8.83 (s, 1H), 8.74 (s, 1H), 7.72 (s, 1H), 3.89 (s, 3H), 3.42 (s, 3H), 3.34 (s, 3H), 3.08 (s, 3H), 2.98 (d, J=4.8 Hz, 3H). MS (M+H)+: 448/450.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([CH2:10][NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=2[CH3:18])=[CH:4][N:3]=1.C(N(CC)CC)C.ClC(Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:42])[N:11]([C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:10][C:5]2=[CH:4][N:3]=1
Reactant: CNc1nc(Cl)ncc1CNc1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N1Cc2cnc(Cl)nc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 185.6 %

Procedure:
To a stirred solution of N-{3-[(2-chloro-4-methylaminopyrimidin-5-ylmethyl)amino]-4-methylphenyl}-3-trifluoromethylbenzamide (559 mg, 1.24 mmol) and triethylamine (693 μL, 4.97 mmol) in THF (15 mL) is added triphosgene (147 mg, 0.49 mmol) in THF (5 mL) at 0° C., and the mixture is stirred for 30 minutes at room temperature. The precipitate is filtered off and the filtrate is stirred for 3 hours at 110° C. The reaction mixture is then diluted with EtOAc and washed with saturated NaHCO3. The organic layer is dried over MgSO4 and concentrated under reduced pressure to give crude oil which is purified by flash column chromatography (SiO2, EtOAc/hexane=1/2) to give N-[3-(7-chloro-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-4-methylphenyl]-3-trifluoromethylbenzamide (420 mg, 71%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[CH:18]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([Cl:30])=[C:25]([Cl:31])[CH:24]=2)[C:19]([F:22])([F:21])[F:20])=[CH:12][C:11]=1[C:32]([F:35])([F:34])[F:33].CCN(CC)CC.[CH:43]1([C:46](Cl)=[O:47])[CH2:45][CH2:44]1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[CH:18]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([Cl:30])=[C:25]([Cl:31])[CH:24]=2)[C:19]([F:22])([F:21])[F:20])=[CH:12][C:11]=1[C:32]([F:35])([F:34])[F:33])[C:46]([CH:43]1[CH2:45][CH2:44]1)=[O:47]
Reactant: FC(F)(F)c1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1CNCc1ccccn1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CC1)N(Cc1ccccn1)Cc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 482.4 %

Procedure:
(E)-1-(Pyridin-2-yl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzyl)methanamine (0.27 g, 0.05 mmol) was taken up in CH2Cl2 (3 mL). To this was added Et3N (0.14 mL, 0.1 mmol). The reaction mixture was stirred for 10 min After 10 min, the reaction mixture was cooled to 0° C., and cyclopropylcarbonyl chloride (0.08 mL, 0.075 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 h and then was washed with H2O and satd aq NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and evaporated to obtain pale yellow gummy material (0.15 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=4.6 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 8.0 Hz, 1H), 5.02 (s, 1H), 4.8 (s, 1H), 4.8 (d, J=10 Hz, 2H), 4.10 (m, 1H), 1.8 (m, 1H), 1.2 (m, 2H), 0.6 (m, 2H); ESIMS m/z 620.86 ([M−H]−); IR (thin film) 1645, 1115, 808 cm−1.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:9][S:10][CH3:11])[NH:5][C:6](=[O:8])[CH3:7].[CH3:13][NH:14][NH2:15]>C(O)C>[CH3:13][N:14]([C:3](=[O:2])[C@H:4]([CH2:9][S:10][CH3:11])[NH:5][C:6](=[O:8])[CH3:7])[NH2:15]
Reactant: CNN
Reactant: COC(=O)[C@H](CSC)NC(C)=O
Solvent: CCO
Product: CSC[C@H](NC(C)=O)C(=O)N(C)N
Reaction time: 3 h
Yield: 51 %

Procedure:
In 20 ml of ethyl alcohol was dissolved 1.91 g (10 mmole) of S-methyl-N-acetyl-L-cysteine methylester and 5.4 ml (100 mmole) of methylhydrazine was added. The mixture was stirred for 3 hours at boiling temperature and then allowed to stand for 1 day at room temperature. After the precipitate was removed, the ethyl alcohol and the excess methylhydrazine were distilled off in vacuo to leave crystals. Thus, 1.05 g (5.1 mmole) of N-methyl-N-(S-methyl-N-acetylcysteinyl)-hydrazine was obtained in 51% yield.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=O)(C)(C)C.[Br:31][C:32]1[CH:33]=[CH:34][C:35]([O:40][CH2:41][CH3:42])=[C:36]([CH:39]=1)[CH:37]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[NH2:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:37][C:36]2[CH:39]=[C:32]([Br:31])[CH:33]=[CH:34][C:35]=2[O:40][CH2:41][CH3:42])[CH2:23][CH2:24]1)=[O:16])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: CCOc1ccc(Br)cc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOc1ccc(Br)cc1CN1CCC(CNC(=O)CNC(=O)c2cc(F)c(F)cc2N)CC1
Temperature: 50 °C
Reaction time: 13 h

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 5-bromo-2-ethoxybenzaldehyde (0.15 mmol), methanol (1.2 mL), and acetic acid (0.030 mL) was added NaBH3CN (0.25 mmol) in methanol (0.50 mL). The reaction mixture was stirred at 50° C. for 13 h. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×3). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting material were added dichloromethane (1 mL) and trifluoroacetic acid (TFA) (0.50 mL) and the solution was stirred at room temperature for 10 min. The reaction mixture was concentrated, and the residue was dissolved in methanol, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. Preparative TLC (SiO2, ethyl acetate/methanol=10/1) gave 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(5-bromo-2-ethoxybenzyl)piperidine (Compound No. 2052) (10.2 mg, 38%): The purity was determined by RPLC/MS (96%); ESI/MS m/e 539.2 (M++H, C24H29BrF2N4O3).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3([CH2:12][CH2:11]3)[C:6]=2[C:5]([O:13][C:14]2[N:19]=[CH:18][C:17]([NH:20][C:21]([C@H:23]([NH:26]C(=O)OC(C)(C)C)[CH2:24][CH3:25])=[O:22])=[CH:16][N:15]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:26][C@H:23]([CH2:24][CH3:25])[C:21]([NH:20][C:17]1[CH:16]=[N:15][C:14]([O:13][C:5]2[C:6]3[C:10]4([CH2:9][O:8][C:7]=3[C:2]([CH3:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11]4)=[N:19][CH:18]=1)=[O:22]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](N)C(=O)Nc1cnc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a solution of tert-butyl N-[(1R)-1-[[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]carbamoyl]propyl]carbamate (Intermediate 163, 42 mg) in dry DCM (3 ml) at 0° C. TFA (1 ml) was slowly added and the reaction mixture was stirred for 3 hours at the same temperature. The solvent and the excess of TFA were removed under reduced pressure and the residue was diluted with DCM (10 ml) and an aqueous saturated solution NaHCO3 was added while the pH was allowed to reach ˜8. Two phases were separated and the organic layer was dried (Na2SO4), filtered and evaporated affording the title compound (25 mg) as light yellow gum.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[F:22])[C:16](O)=O)#[N:12].N>>[F:22][C:21]1[CH:20]=[CH:19][C:15]([C:16]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[CH:14][C:13]=1[C:11]#[N:12]
Reactant: N#Cc1cc(C(=O)O)ccc1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: N#Cc1cc(-c2nc(-c3cccnc3)no2)ccc1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-cyano-4-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ ppm 7.62-7.71 (m, 2H), 8.54-8.63 (m, 2H), 8.69 (dd, J=5.9, 2.2 Hz, 1H), 8.75 (dd, J=4.9, 1.5 Hz, 1H), 9.30 (dd, J=2.0, 1.0 Hz, 1H); MS (DCl/NH3) m/z 267 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[F:12][C:13]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:14]=1[C:15]([NH:17][C:18]1[S:19][C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[C:21](C2C=CC=CN=2)[N:22]=1)=[O:16]>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][C:6]([C:21]2[N:22]=[C:18]([NH:17][C:15](=[O:16])[C:14]3[C:13]([F:12])=[CH:42][CH:41]=[CH:40][C:39]=3[F:43])[S:19][C:20]=2[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=2)=[CH:5][CH:4]=1
Reactant: O=C(Nc1nc(-c2ccccn2)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Reactant: CN(C)c1ccc([Mg]Br)cc1
Product: CN(C)c1ccc(-c2nc(NC(=O)c3c(F)cccc3F)sc2-c2cccc(C(F)(F)F)c2)cc1

Procedure:
Compound 110 was prepared from 22a and N,N-dimethyl-4-aminophenylmagnesium bromide as described for the preparation of Compound 107.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C(O[C:27](=[O:29])[CH3:28])(=O)C>>[C:17]([N:1]([C:27](=[O:29])[CH3:28])[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[N:10]([C:16](=[O:21])[CH3:15])[N:9]=2)=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC1Cc2cc3c(cc2C(c2ccc(N)cc2)=NN1)OCO3
Product: CC(=O)N(C(C)=O)c1ccc(C2=NN(C(C)=O)C(C)Cc3cc4c(cc32)OCO4)cc1
Yield: 84.6 %

Procedure:
2.0 g (6.7 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine were refluxed with 40 ml of acetic anhydride for 3 hours, then it was evaporated to dryness under reduced pressure. The crystalline residue was transferred with 25 ml of water to a filter and washed with 5×3 ml of water. After drying 2.79 g of the raw triacetyl derivative were obtained. After washing with 20 ml of isopropanol and drying at 100° C. 2.39 g (84.6%) of the pure aimed product were obtained, m.p. 224°-227° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:21][CH:22]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[NH:8][S:25]([CH3:24])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(CCN2CCN(c3ccc(N)c(F)c3)CC2)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(CCN2CCN(c3ccc(NS(C)(=O)=O)c(F)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 334.1 %

Procedure:
1-(3-Fluoro-4-aminophenyl)-4-(4-aminophenethyl)piperazine (0.06 g) was dissolved in pyridine (4.5 ml) and methanesulphonyl chloride (0.13 g) was added. The mixture was stirred at room temperature overnight, the pyridine removed by evaporation, and the residue chromatographed over silica, developing and eluting with 10% methanol in dichloromethane. The fractions containing the product were evaporated to give a residue (0.30 g) which was crystallized from methanol, yielding the pure title compound, (0.016 g), m.p. 232°-4°.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[N:20][NH2:21])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][C:34](O)=[O:35])=[CH:32][C:27]=2[O:26][CH2:25]1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[CH:19]=[N:20]/[NH:21][C:34](=[O:35])[CH2:33][C:31]2[CH:30]=[CH:29][C:28]3[O:24][CH2:25][O:26][C:27]=3[CH:32]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: NN=Cc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1ccc2c(c1)OCO2)N/N=C/c1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
A solution of 2-[hydrazonomethyl]phenyl 4-(trifluoromethyl)benzenesulfonate (150 mg, 0.44 mmol) and 1,3-benzodioxol-5-ylacetic acid (1.2 equiv) in DMF (1 mL) is treated with a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (167 mg, 0.87 mmol) and 4-dimethylaminopyridine (DMAP) (106 mg, 0.87 mmol) in CH2Cl2 (10 mL). The solution is shaken overnight on an orbital shaker. The solution is evaporated to dryness using a speed. Water is added to the mixture, which is then sonicated to give a solid. The solid is filtered and washed with a large amount of water. A small amount of methanol is added and the mixture sonicated. The resulting solid is filtered and washed with more methanol to yield pure 2-((E)-{2-[2-(1,3-benzodioxol-5-yl)acetyl]hydrazono}methyl)phenyl 4-(trifluoromethyl)benzenesulfonate. The yield is 169 mg, 77%. 1H NMR (400 MHz, DMSO) □ 11.48 (2s, 1H), 8.01 (m, 6H), 7.12 (m, 6H), 5.99 (2s, 2H), 3.62 (2s, 2H). ESI− for C23H17F3N2O6S, m/z 505, (M−H)−.
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3([C:30]4[C:21](=[CH:22][C:23]5[O:28][CH2:27][CH2:26][O:25][C:24]=5[CH:29]=4)[O:20][CH2:19]3)[C:11]2=[O:31])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1>ClCCl>[O:31]=[C:11]1[C:12]2([C:30]3[C:21](=[CH:22][C:23]4[O:28][CH2:27][CH2:26][O:25][C:24]=4[CH:29]=3)[O:20][CH2:19]2)[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]1[CH2:9][C:4]1[C:3]([NH:2][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Agent: Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.5 %

Procedure:
A 50 mL round-bottom flask was charged with 1′-[(3-aminopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one hydrobromide (0.56 g, 1.0 mmol), methanesulfonyl chloride (0.12 g, 1.1 mmol), pyridine (0.25 g, 3.0 mmol) and dichloromethane (20 mL). The reaction mixture was stirred under nitrogen at ambient temperature for 16 h and diluted with dichloromethane (50 mL). The organic phase was washed with water (2×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 0% to 100% gradient of ethyl acetate in dichloromethane, followed by recrystallization from methanol (10 mL) to afford N-{2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-yl}methanesulfonamide (0.18 g, 38%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.27 (dd, J=4.6, 1.2 Hz, 1H), 7.78 (dd, J=8.0, 1.4 Hz, 1H), 7.34 (dd, J=8.0, 4.7 Hz, 1H), 7.21-7.10 (m, 2H), 6.96 (t, J=7.4 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.48 (s, 1H), 6.46 (s, 1H), 5.17 (ABq, 2H), 4.73 (ABq, 2H), 4.18-4.05 (m, 4H), 3.14 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.6, 154.9, 151.0, 147.1, 144.5, 143.2, 138.1, 134.5, 132.6, 132.2, 132.1, 129.0, 123.8, 123.2, 122.2, 112.3, 109.4, 99.0, 79.6, 64.6, 64.1, 57.8, 41.8, 40.6; MS (ES+) m/z 479.9 (M+1).
Reaction SMILES: CC(C)(C)C([O:5][C:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:8][C:7]=1[C:19]([O:21]C)=O)=O.OC1C(O)=C(C(OC)=O)N=C(C(O)=O)N=1.[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH2:46])=[CH:43][CH:42]=1.CCOC(C)=O>CN(C=O)C>[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH:46][C:19]([C:7]2[N:8]=[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]([CH3:13])[C:11](=[O:12])[C:6]=2[OH:5])=[O:21])=[CH:43][CH:42]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc(C(=O)OC)c(OC(=O)C(C)(C)C)c(=O)n1C
Agent: COC(=O)c1nc(C(=O)O)nc(O)c1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
2-Ethyl 4-methyl 5-[(2,2-dimethylpropanoyl)oxy]-1-methyl-6-oxo-1,6-dihydropyrimidine-2,4-dicarboxylate (made by protection and alkylation of the starting material of Example 4, Step 1 using procedures similar to those set forth in Examples 1 or 2) was dissolved in DMF, 4-fluorobenzylamine (3.1 eq.) was added and the mixture was stirred at 90° C. overnight. After concentration of the solvent, the residue was taken into EtOAc, washed with 1 N HCl, dried over Na2SO4 and evaporated to obtain crude N-(4-fluorobenzyl)-2-ethoxycarbonyl-1-methyl-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide. To this crude product was added 2-picolylamine (8 eq.), and the reaction was stirred at 90° C. overnight. The title product was obtained as its trifluoroacetic salt by preparative RP-HPLC purification (C18 gradient of CH3CN/H2O+0.01% TFA).
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4]([OH:6])=[O:5].[CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>S(=O)(=O)(O)O.O>[Br:1][CH2:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)C(=O)CBr
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C(CBr)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3-Bromopyruvic acid (170 g) is suspended in cold sulfuric acid (0.85 L) and maintained at 0° C. while benzene (0.255 L) is added over 1.5 hours. The temperature is allowed to warm to 35°-36° C. and then kept at 25° C. for three hours. Pouring over crushed ice (4 L) followed by trituration in cold water and recrystallization from 95% ethanol affords 76 g of 3-bromo-2,2-diphenylpropionic acid (mp 201°-202° C.). This acid (75 g) is suspended in benzene and thionyl chloride (55 ml) is added. After refluxing, the mixture is filtered, and the filtrate affords 40 g of the acid chloride (mp 98°14 100° C.). The acid chloride is added portionwise to aqueous ammonium hydroxide with stirring and left overnight, with filtration yielding 3-bromo-2,2-diphenylpropionamide. The amide (10 g) is added portionwise with stirring to a solution of sodium (1.5 g) in absolute ethanol (0.2 L), and the resulting solution is heated for one hour on a steam bath. Dilution with water affords a solid (mp >310° C.), 2,2-diphenyl azetidin-2-one. The azetidinone (2 g) is heated at reflux in methanol saturated with HCl (50 ml) affording the title compound after crystallization from methanol/ether (mp 207°-208° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]1([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][CH2:5][N:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:25])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:7][CH2:8]1
Reactant: O=C(CCCCCBr)c1ccccc1
Reactant: COC1(CNC(=O)OC(C)(C)C)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC1(CNC(=O)OC(C)(C)C)CCN(CCCCCC(=O)c2ccccc2)CC1
Yield: 85 %

Procedure:
4-Methoxy-4-tert-butoxycarbonylaminomethylpiperidine (2.3 g), 6-bromo-1-phenyl-1-hexanone (2.52 g) and potassium carbonate (2.6 g) were reacted and treated in the same manner as in Preparation Example 138(1) to give 3.35 g of 4-methoxy-1-(6-oxo-6-phenylhexyl)-4-tert-butoxycarbonylaminomethylpiperidine.
Reaction SMILES: [H-].[Na+].C(O)C.[C:6]([O:14]CC)(=[O:13])[CH2:7][C:8](OCC)=O.[Br:17][C:18]1[CH:25]=[CH:24][C:21](CBr)=[CH:20][CH:19]=1>C1COCC1>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:8][CH2:7][C:6]([OH:14])=[O:13])=[CH:20][CH:19]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.9 %

Procedure:
Sodium hydride (60% dispersion in oil; 4 g) was added portionwise to an ethanol (100 ml) solution of diethyl malonate (16 g) under ice-cooling. The reaction mixture was stirred at room temperature for 10 minutes, to which was added dropwise a THF (50 ml) solution of p-bromobenzylbromide (12 g) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and concentrated. Acetic acid (200 ml) and6N hydrochloric acid (100 ml) were added to the residue. The reaction mixture was stirred under heating at 90° C. for 18 hours, and concentrated. Water was added to the residue, which was extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1), which was recrystallized from IPE to obtain the entitled compound (1.2 g).