Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=2)[CH:20]=1)=O.O=P(Cl)(Cl)[Cl:35].P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:35][C:6]1[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]2[NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[C:24]([F:32])[CH:23]=4)[CH:20]=3)=[N:1][C:2]=2[N:7]=1
Reactant: CCCn1c(=O)[nH]c(N)c(NC(=O)c2cnn(Cc3ccc(C(F)(F)F)c(F)c3)c2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccc(C(F)(F)F)c(F)c4)c3)[nH]c2c1=O
Temperature: 127.5 °C
Yield: 50 %

Procedure:
A mixture of 1-(3-fluoro-4-trifluoromethyl-benzyl)-1H-pyrazole-4-carboxylic acid (6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (0.8 g, 1.76 mmol), POCl3 (25 ml) and PCl5 (0.2 g) were heated at 125-130° C. for 20 hours. Reaction mixture was cooled to 20-25° C. and it was concentrated under vacuum. To this reaction mixture brine (50 ml) was added and extracted with ethyl acetate (3×2 ml). The combined organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 2 to 4% methanol in DCM as an eluent to obtain 2-Chloro-8-[1-(3-fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one (0.4 g, 50%) as a pale brown solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9]1([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)[O:8][CH2:7]2)(=[O:3])[CH3:2].[F:23][C:24]([F:37])([F:36])[C:25]([C:27]1[CH:32]=[C:31]([Cl:33])[C:30](Cl)=[C:29]([Cl:35])[CH:28]=1)=O.C([O-])([O-])=O.[Cs+].[Cs+].[F:44]C(F)(F)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:35][C:29]1[CH:28]=[C:27]([C:25]([C:24]([F:37])([F:36])[F:23])=[CH:2][C:1]([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9]2([CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]2)[O:8][CH2:7]3)=[O:3])[CH:32]=[C:31]([Cl:33])[C:30]=1[F:44]
Reactant: CC(=O)c1ccc2c(c1)COC21CN(C(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1ccccc1
Reactant: O=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc12
Temperature: 110 °C
Yield: 80.64 %

Procedure:
In 100 mL two neck RBF equipped with dean-stark apparatus a stirred solution of tert-butyl 5′-acetyl-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 1, 4.5 g, 14.851 mmol) in toluene (13.5 mL) and trifluorotoluene (13.5 mL) was added 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)-ethanone (4.44 g, 17.079 mmol) and Cs2CO3 (0.483 g, 1.485 mmol) at room temperature. Resulting reaction mixture was heated at 110° C. for 16 hours. After complete consumption of starting material, reaction mixture was diluted with ter-butylmethyl ether (30 mL) and filtered through celite bed. Filtrate was concentrated under vacuum to afford brown sticky oil (9.01 g, crude). Crude compound was purified by column chromatography using silica gel (230-400 mesh). Desired compound was eluted in 20% ethyl acetate in n-hexane to give light yellow solid (6.54 g, 80.64%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 4.10 (d, J=9.52 Hz, 2H), 4.32 (d, J=9.36 Hz, 2H), 5.12 (s, 2H), 7.20 (d, J=9.76 Hz, 2H), 7.39 (s, 1H), 7.56 (d, J=7.96 Hz, 1H), 7.67 (s, 1H), 7.84 (d, J=7.96 Hz, 1H). LC-MS (m/z): 374.1 (M+H).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=O)[CH:22]([F:24])[F:23])[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>>[F:23][CH:22]([F:24])[C:21](=[S:38])[NH:20][CH2:19][C@@H:17]1[O:16][C:15](=[O:26])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([N:5]3[CH2:6][CH2:7][S:2](=[O:28])(=[O:1])[CH2:3][CH2:4]3)=[C:9]([F:27])[CH:10]=2)[CH2:18]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(NC[C@H]1CN(c2ccc(N3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(F)F
Product: O=C1O[C@@H](CNC(=S)C(F)F)CN1c1ccc(N2CCS(=O)(=O)CC2)c(F)c1

Procedure:
Following the procedure described in Example 1 for the preparation of 1 the reaction of 15 with Lawesson's Reagent provides the title compound (13), which is purified by silica gel chromatography with 2.5% MeOH—CH2Cl2 and crystallization from EtOAc-hexane.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:59][NH:60][CH2:61][C:62]1[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=1>CN(C=O)C.O>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:60]([CH3:59])[CH2:61][C:62]3[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCc1ccncc1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccncc1)C(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1
Yield: 63.5 %

Procedure:
A solution of 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid (60 mg, 0.17 mmol), HATU (76 mg, 0.20 mmol), DIEA (0.035 mL, 0.20 mmol) and N-methyl-1-(pyridin-4-yl)methanamine (20.39 mg, 0.17 mmol) in DMF (1 mL) was stirred at room temperature for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (solvent gradient; 5→80% ethyl acetate/hexane) to give the title compound (50 mg, 0.108 mmol, 65%) as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([OH:32])=O)=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2)[C:3]1=[O:33].C1C=CC2N(O)N=[N:40]C=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([NH2:40])=[O:32])=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:20])([F:22])[F:21])[CH2:6][CH2:5]2)[C:3]1=[O:33]
Reactant: On1nnc2ccccc21
Reactant: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C(N)=O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.5 %

Procedure:
To a solution of (E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylic acid (15 mg, 0.05 mmol) in anhydrous CH2Cl2 (4 mL) was added HOBt (15 mg, 4 mL), EDCI (22 mg, 0.11 mmol) and DIEA (32 mg, 0.25 mmol) at 0° C. and the mixture was stirred overnight under NH3 at rt. The reaction mixture was washed with 1 N aq HCl and the aqueous phase was extracted with CH2Cl2 (2×). The combined organic phases were dried, filtered and concentrated to give (E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxamide (2.4 mg, 10%). 1H NMR (CD3OD): 1.94 (m, 4H), 3.27 (s, 3H), 4.01 (m, 1H), 4.28 (m, 3H), 7.10 (d, 1H), 7.26 (d, 1H), 7.55 (m, 1H), 7.66 (m, 1H), 7.76 (m, 1H), 8.00 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[Br:11]N1C(=O)CCC1=O>C(O)(=O)C>[Br:11][C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[Cl:1])[NH:8][N:9]=1
Reactant: Clc1ccnc2[nH]ncc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: Clc1ccnc2[nH]nc(Br)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.3 %

Procedure:
4-chloro-1H-pyrazolo[3,4-b]pyridine (6) 1 g (6.53 mmoles) in acetic acid (100 mL) cooled to 0° C. was added N-bromosuccinimide 2.31 g (13.06 mmol and the resulting RM was stirred for 4 hr at rt. After completion of the SM, the RM was quenched with ice water and extracted with dichlromethane (2×10 mL). The combined organic layer was dried over sodium sulphate, and the solvent evaporated to yield compound 7 (Yield: 0.9 g, 60%). 1H NMR (400 MHz, CDCl3): δ 13.19 (br s, 1H), 8.21 (s, 1H), 7.39 (m, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1([CH3:34])[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:14]([CH2:23][CH2:24][C:25]([N:27]2[C@H:31]([CH3:32])[CH2:30][O:29][C:28]2=[O:33])=[O:26])[CH2:13][O:12]1.[C:35]([O:39][C:40](=[O:43])[CH:41]=[CH2:42])([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:35]([O:39][C:40](=[O:43])[CH2:41][CH2:42][C@@H:24]([C:25]([N:27]1[C@H:31]([CH3:32])[CH2:30][O:29][C:28]1=[O:33])=[O:26])[CH2:23][C@H:14]1[CH2:13][O:12][C:11]([CH3:10])([CH3:34])[N:15]1[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])([CH3:38])([CH3:37])[CH3:36]
Reactant: C[C@@H]1COC(=O)N1C(=O)CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1COC(=O)N1C(=O)[C@H](CCC(=O)OC(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
At 0° C., 1.0M TiCl4 in CH2Cl2 solution (8.55 mL, 0.7 eq) was added to CH2Cl2 (100 mL) followed by the addition of 1.0M TiCl(Oi-Pr)3 in hexanes solution (4.28 mL, 0.35 eq) and stirred 5 min DIPEA (2.87 mL, 1.35 eq) was added and stirred 15 min. A solution of (S)-tert-butyl 2,2-dimethyl-4-(3-((R)-4-methyl-2-oxooxazolidin-3-yl)-3-oxopropyl)oxazolidine-3-carboxylate (5.28 g, 12.22 mmol) in CH2Cl2 (50 mL) was added. The reaction mixture was stirred 1 hr at 0° C. To the solution, t-butylacrylate (2.22 mL, 1.25 eq) was added and the mixture was left stirred over 48 hr with concomitant warming to rt. The mixture was concentrated, partitioned between EtOAc (300 mL) and 1% HCl solution (100 mL). The organic layer was washed with sat. NaHCO3 solution (60 mL), brine (60 mL), dried over Na2SO4. After filtration and concentration, the residue was purified by ISCO (120 g column, 0→35% EtOAc in Hexanes gradient) to afford 4.12 g (60%) (S)-tert-butyl 4-((R)-5-tert-butoxy-2-((R)-4-methyl-2-oxooxazolidine-3-carbonyl)-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate as a yellowish solid. MS ESI +ve m/z 583 (M+Na).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][C:13]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8][CH:7]=1.[OH-].[K+]>CO.C1COCC1>[C:23]1([C:13]2[CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:12]=2[C:9]2[CH:8]=[CH:7][C:6]([CH:5]=[CH:4][C:3]([OH:29])=[O:2])=[CH:11][CH:10]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of ester (2d) (4.2 g, 11.0 mmol) in methanol (370 mL) and THF (225 mL) was added 1N KOH (188 mL). After stirring overnight the mixture was heated to 50° C. for 0.5 h and was allowed to cool to room temperature. After stirring 2 h the solvent was partially removed under reduced pressure, the mixture was acidified with 1N HCl, and was extracted with EtOAc. The combined organic layers were washed with water, brine and were dried (MgSO4). The solvent was removed under reduced pressure and the residue was triturated (EtOAc) to give the acid (2e) as a white solid (3.86 g, 96%): 1H NMR (CD3OD) δ 7.54 (d, J=15.7 Hz, 1H), 6.28 (d, J=8.1 Hz, 2H), 7.27-7.08 (m, 8H), 6.89 (d, J=8.1 Hz, 2H), 6.76 (dd, J=7.3, 1.1 Hz, 1H), 6.34 (d, J=15.7 Hz, 1H), 2.83 (t, J=7.0 Hz, 2H), 2.37 (t, J=7.0 Hz, 2H), 2.14 (m, 2H); ESI m/z: 365 (M−H−, 100%).
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:8][NH:9][C:10]1[C:15]([CH2:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:18][CH3:19].C(=O)(O)[O-].[Na+].O1CCOCC1.[Cl:31][CH2:32][C:33](Cl)=[O:34]>CCOCC.O>[Cl:31][CH2:32][C:33]([N:9]([CH2:8][CH:2]1[O:3][CH2:4][CH2:5][CH2:6][CH2:7][O:1]1)[C:10]1[C:15]([CH2:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:18][CH3:19])=[O:34]
Reactant: CCc1cccc(CC)c1NCC1OCCCCO1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: CCc1cccc(CC)c1N(CC1OCCCCO1)C(=O)CCl
Reaction time: 0.25 h

Procedure:
N-(1,3-dioxepan-2-ylmethyl)-2,6-diethylaniline (26.3 grams), sodium bicarbonate (15 grams), dioxane (30 ml) and water (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0°C and chloroacetyl chloride (15 grams) is added, with stirring, over a period of about 15 minutes. After the addition is completed stirring is continued for a period of about 1 hour. After this time ether (100 ml) is added to the mixture and the resulting solution is washed with water. The washed solution is then dried over anhydrous magnesium sulfate and stripped of solvents leaving a solid residue. The residue is recrystallized to yield the desired product N-α-chloroacetyl-N-(1,3-dioxepan-2-ylmethyl)-2,6-diethylaniline.
Reaction SMILES: [OH:1]O.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[C:7]([CH3:14])[N:6]=1.O>ClCCl>[CH3:3][O:4][C:5]1[N:6]=[C:7]([CH3:14])[C:8]([OH:1])=[CH:9][CH:10]=1
Reactant: COc1ccc(B(O)O)c(C)n1
Reactant: OO
Solvent: ClCCl
Solvent: O
Product: COc1ccc(O)c(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
Add hydrogen peroxide (7.69 mL, 89.8 mmol) to a stirred mixture of 2-methoxy-6-methyl-5-pyridylboronic acid (5.0 g, 30 mmol) in dichloromethane (100 mL) kept under nitrogen at room temperature. Stir overnight at ambient temperature, add water and extract the mixture with dichloromethane. Combine the organic phases, dry (MgSO4), filter and concentrate to afford 2.6 g (62%) of the title compound. MS (m/z)=140 [M+1]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:22]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[K+].[K+]>>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)[C@H](Cc1ccc(OCc2ccc(C(C)(C)C)cc2)cc1)NC(=O)OC(C)(C)C
Yield: 46.9 %

Procedure:
(S)-2-Tert-butoxycarbonylamino-3-[4-(4-tert-butyl-benzyloxy)-phenyl]-propionic acid methyl ester (290 mg) was prepared from (S)-2-tert-butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionic acid methyl ester (425 mg, 1.4 mmol) and 4-tert-butylbenzyl bromide (1.6 mmol) with K2CO3 (398 mg, 2.9 mmol) as described in Procedure H and purified over silica gel (8:2, DCM-hexanes).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C:14]2[N:13]=[CH:12][N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[C:9](=[O:22])[NH:8][C:7]1=[O:23])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)C=O>C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C:14]2[N:13]=[CH:12][N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[C:9](=[O:22])[N:8]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:7]1=[O:23])[CH3:2]
Reactant: CCOC(=O)Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(CCc2ccccc2)c(=O)c2c1ncn2Cc1ccccc1
Temperature: 50 °C

Procedure:
A mixture of (7-benzyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl)acetic acid ethyl ester (300 mg), anhydrous potassium carbonate (250 mg), 2-bromoethylbenzene (0.25 ml), and N,N-dimethylformamide (5 ml) was stirred with heating in an oil bath of 50° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 10–20% (20% 2-propanol/ethyl acetate)/hexane to give 366 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[CH:14]=[N:13][C:12]([C:17]([O:19]C)=O)=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([C:34]([NH:36][C@@H:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C@@H:38]1[NH2:43])=[O:35])=[CH:28]2>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[CH:14]=[N:13][C:12]([C:17]([NH:43][C@@H:38]3[CH2:39][CH2:40][CH2:41][CH2:42][C@@H:37]3[NH:36][C:34]([C:29]3[NH:30][C:31]4[C:27]([CH:28]=3)=[CH:26][C:25]([Cl:24])=[CH:33][CH:32]=4)=[O:35])=[O:19])=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@H]1CCCC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)c1ncc2c(n1)CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1Cc2cnc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)nc2C1

Procedure:
After 6-(tert-Butoxycarbonyl)-5,7-dihydro-2-methoxycarbonylpyrrolo[3,4-d]pyrimidine was hydrolyzed with lithium hydroxide, it was reacted with (±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine hydrochloride in a similar manner to Example 2 to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.C([Li])CCC.O>O1CCCC1.CCCCCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9][C:3]=2[CH:4]=1
Reactant: BrCCCCOc1cc(Br)ccc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)OCCCC2
Reaction time: 5 h
Yield: 102.7 %

Procedure:
To a solution of 12.7 g (33 mmol) of 1,4-dibromo-2-(4-bromobutoxy)benzene in 220 mL of anhydrous tetrahydrofuran and 55 mL of hexane under nitrogen cooled in a dry ice/acetone bath was added dropwise 14.5 mL (36.3 mmol, 1.1 equiv) of 2.5M n-butyllithium in tetrahydrofuran, keeping the internal temperature <−70° C. The mixture was stirred with cooling for 30 minutes, then at ambient temperature. After 5 hours, 220 mL of water was added and the layers were separated. The aqueous layer was extracted with 2×160 mL of ether. The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 7.7 g of a yellow oil. Purification by flash chromatography (5-20% ethyl acetate in hexanes) gave the product as a yellow oil. MS (m+1)=228.1; 1H NMR (400 MHz, CDCl3) 7.15 (d, 1H, J 2 Hz), 7.09 (m, 1H), 6.99 (d, 1H, J 8 Hz), 4.01 (m, 2H), 2.76 (m, 2H), 1.96 (m, 2H), 1.71 (m, 2H).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11]([Cl:14])[CH:12]=2)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>N1C=CC=CC=1>[ClH:14].[F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:12]=2)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]1
Reactant: O=C(O)c1cn(CCF)c2cc(Cl)c(F)cc2c1=O
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: Cl
Product: O=C(O)c1cn(CCF)c2cc(N3CCNCC3)c(F)cc2c1=O
Yield: 26.8 %

Procedure:
A mixture of 1-(2-fluoroethyl)-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.87 g) (3 millimole), piperazine (1.3 g) (15 millimole) and pyridine (4 ml) piperazine was heated at 135° to 145° C. for 12 hours. After cooling, the reaction mixture was evaporated under vacuum, the residue was acidified with acetic acid, the undissolved matter was filtered off. The filtrate was neutralized in an aqueous solution of caustic soda. The precipitate was filtered, washed, dried and dissolved in diluted HCl. Ethanol was added and the solution was ice cooled. The precipitate was filtered, washed with ethanol and dried and recrystallized from ethanol to obtain 0.30 g (27%) of 1-(2-fluoroethyl)-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride in powder form.
Reaction SMILES: [N:1]([CH2:8][CH2:9][OH:10])([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:11]([Br:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br-:18].[CH2:11]([N+:1]([CH2:8][CH2:9][OH:10])([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: OCCN(CCO)CCO
Product: OCC[N+](CCO)(CCO)Cc1ccccc1
Product: [Br-]

Procedure:
A] Benzyl tris(hydroxyethyl)ammonium bromide was synthesized from triethanolamine and benzyl bromide using the procedure of Rengan et al (J.Chem.Soc.Chem.Commun., 10, 1992, 757).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[ClH:9].[CH2:10]([OH:12])[CH3:11]>C(Cl)(Cl)Cl>[ClH:9].[CH2:10]([O:12][C:1](=[NH:2])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:11]
Reactant: CCO
Reactant: CCOC(=O)CC#N
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=N)CC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 2-cyanoacetate (100 mL, 94 mmol) in chloroform (100 mL) and ethanol (6.5 mL) is bubbled with HCl at −10° for 4 h. The reaction mixture is allowed to warm to RT slowly and then stirred at RT overnight. The mixture is concentrated in vacuo to remove the solvent. The residue is suspended in diethyl ether (100 mL) and stirred for 30 min. The resulting solid is collected by filtration and rinsed with diethyl ether to afford ethyl 3-ethoxy-3-iminopropanoate hydrochloride (Z-1) as a white solid.
Reaction SMILES: [CH:1]1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:14][C:15]([C:17]1[C:18](=[O:34])[C:19]2[CH:24]=[N:23][C:22](SC)=[N:21][C:20]=2[N:27]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:28]=1)=[O:16])[CH3:13].[O-:35][S:36]([O-:38])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:12]([O:14][C:15]([C:17]1[C:18](=[O:34])[C:19]2[CH:24]=[N:23][C:22]([S:36]([CH3:1])(=[O:38])=[O:35])=[N:21][C:20]=2[N:27]([CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33]2)[CH:28]=1)=[O:16])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])[O-]
Reactant: CCOC(=O)c1cn(C2CCCC2)c2nc(SC)ncc2c1=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cn(C2CCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Reaction time: 2 h

Procedure:
m-CPBA (0.45 g, 2.05 mmol of a 77% powder) was added to a solution of 8-cyclopentyl-2-methylsulfanyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.27 g, 0.82 mmol) in DCM (5 mL). After 2 hours, a 10% solution of Na2SO3 (2 mL) was added and the mixture was partitioned between sat. NaHCO3 and DCM. The organic layer was dried (MgSO4) and concentrated to provide the title compound. Mass Spectrum (LCMS, ESI pos.) Calcd. For C16H19N3O5S: 365.10, found: (M+H) 366.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:24][CH:23]([CH2:25][CH:26]=[CH:27][CH3:28])[C:11]3=[C:12]4[C:17](=[CH:18][CH:19]=[C:10]3[C:6]=2[C:7]=1[O:8][CH3:9])[NH:16][C:15]([CH3:21])([CH3:20])[CH:14]=[C:13]4[CH3:22].[I-].[CH:30]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:24][CH:23]([CH2:25][CH:26]=[C:27]([CH3:30])[CH3:28])[C:11]3=[C:12]4[C:17](=[CH:18][CH:19]=[C:10]3[C:6]=2[C:7]=1[O:8][CH3:9])[NH:16][C:15]([CH3:20])([CH3:21])[CH:14]=[C:13]4[CH3:22]
Reactant: CC=CCC1Oc2ccc(O)c(OC)c2-c2ccc3c(c21)C(C)=CC(C)(C)N3
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Product: COc1c(O)ccc2c1-c1ccc3c(c1C(CC=C(C)C)O2)C(C)=CC(C)(C)N3

Procedure:
The intermediate aldehyde from Example 282 and isopropyltriphenylphosphonium iodide were processed according to Example 282 to give the desired compound. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.91 (d, J=9 Hz, 1H), 6.62 (d, J=9 Hz, 1H), 6.60 (d, J=9 Hz, 1H), 6.46 (d, J=9 Hz, 1H), 6.14 (s, 1H), 5.60 (dd, J=9, 3 Hz, 1H), 5.43 (s, 1H), 5.15 (m, 1H), 3.64 (s, 3H), 2.45-2.18 (m, 2H), 2.15 (s, 3H), 1.63 (s, 3H), 1.32 (s, 3H), 1.17 (s, 3H), 1.16 (s, 3H); MS (APCI) m/e (M+H)+ 392, (M−H)− 390.