Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:6][CH:5]=1.[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][N:18]([CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:8][CH:9]=1
Reactant: O=C1CCCC1
Reactant: COC(=O)c1ccc(COc2ccc3c(c2)CCNCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(2,3,4,5-Tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoic acid methyl ester (D4) (2.83 g, 9.1 mmol) and cyclopentanone (1.6 ml, 18.2 mmol) were dissolved in dichloromethane (30 ml) and acetic acid (0.5 ml). Sodium triacetoxy borohydride (3.85 g, 18.2 mmol) was added and the solution was stirred at room temperature for 4 hours. The reaction mixture was washed with a saturated solution of sodium carbonate, the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (E88); MS (ES+) m/e 380 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N:21]5[C:30](=[O:31])[C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=[CH:22]5)[C:16]=4[CH3:32])=[C:13]([CH3:33])[N:12]=[C:11]([C:34]([NH2:36])=[O:35])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:42]([O:44]CC)=[CH2:43])CCC.C(N(CC)CC)C>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:42]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N:21]5[C:30](=[O:31])[C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=[CH:22]5)[C:16]=4[CH3:32])=[C:13]([CH3:33])[N:12]=[C:11]([C:34]([NH2:36])=[O:35])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1)(=[O:44])[CH3:43]
Reactant: Cc1nc(C(N)=O)c2[nH]c3cc(Br)ccc3c2c1-c1cccc(-n2cnc3ccccc3c2=O)c1C
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)nc(C)c(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a well degassed mixture of 7-bromo-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (0.101 g, 0.188 mmol) and Bis(triphenylphosphine)palladium(II) chloride (0.018 g, 0.026 mmol) in 1,4-dioxane (2.0 mL) in a sealed tube was added tributyl(1-ethoxyvinyl)stannane (0.148 mL, 0.450 mmol) followed by triethylamine (0.052 mL, 0.375 mmol). The resulting mixture was evacuated and charged with nitrogen (2×), immersed in an oil bath at 100° C., and stirred overnight. The mixture was diluted with ethyl acetate, filtered through a pad of CELITE®, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL) and stirred with 1 N aqueous hydrochloric acid (2 mL) for 2 h. The solution was concentrated under reduced pressure, and the residue was suspended in water. The pH was adjusted to ˜6 with 1 N sodium bicarbonate, and the suspension was extracted with ethyl acetate (3×). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a mixture of ethyl acetate and hexane (50%-62%-75%-88%) afforded 7-acetyl-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (0.051 g, 0.102 mmol, 54% yield) as a pale yellow solid. LC/MS M+1=502.1.
Reaction SMILES: [C:1]1([C@@H:7]([OH:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:10][CH2:9][CH2:8][C@H:7]([OH:11])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: OCC[C@H](O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC[C@H](O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a solution of (S)-1-phenylpropane-1,3-diol (500 mg, 3.28 mmol) and triethylamine (399 mg, 3.94 mmol) in CH2Cl2 (5 mL) was added 4-methylbenzene-1-sulfonyl chloride (626 mg, 3.28 mol) slowly at 0° C., and the reaction mixture was stirred at rt for 2 h. The reaction solution was dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC (3:1 Petroleum ether/EtOAc) to give (S)-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate (576 mg, 57%). 1H NMR (400 MHz, CDCl3): δ=1.91-2.00 (m, 3H), 2.48 (s, 2H), 4.00 (m; 1H), 4.22 (m, 1H), 4.75 (m, 2H), 7.25-7.30 (m, 7H), 7.75 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][C:25]4[CH2:26][NH:27][CH:28]([CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])[CH2:29][C:30]=4[N:31]=3)=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][C:25]4[CH2:26][NH:27][CH:28]([CH2:32][C:33]([OH:35])=[O:34])[CH2:29][C:30]=4[N:31]=3)=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)sc2CN1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)sc2CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In methylene chloride (1 ml) was dissolved tert-butyl [2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-6-yl)acetate (200 mg), followed by the addition of trifluoroacetic acid (2 ml). The resulting mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, diethyl ether was added to the residue. The precipitate so formed was collected by filtration, whereby the title compound (193 mg) was obtained as a colorless foam.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13]>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:14]/[CH:12]=[O:13]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc2ccccc2o1
Solvent: ClCCl
Product: O=C/C=C/c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A solution of benzofuran-2-carboxaldehyde (2.2 g, 15.1 mmol) and formylmethylenetriphenylphosphorane (4.6 g, 15.1 mmoles) in CH2Cl2 (150 mL) was refluxed for 6 hours. Another aliquot of formylmethylenetriphenylphosphorane (1.5 g, 4.93 mmol) was then added and the reflux continued overnight. The reaction mixture was cooled to RT, the solvent concentrated at reduced pressure and the residue was chromatographed on silicagel (n-heptane/EtOAc 4/1). The collected fractions were pooled and concentrated and the residue triturated with isopropyl ether to give, after drying, pure title compound (1.3 g, 7.55 mmol, yield 50.0%) as pale yellow crystals, m.p.=67°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](S(C)(=O)=O)[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[CH3:28][S:29]([CH2:32][CH2:33][NH2:34])(=[O:31])=[O:30].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:34][CH2:33][CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: CS(=O)(=O)CCN
Reactant: Cc1cc(-c2cnc3c(S(C)(=O)=O)cc(Br)nn23)ccc1C(=O)NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2cnc3c(NCCS(C)(=O)=O)cc(Br)nn23)ccc1C(=O)NC1CC1
Temperature: 160 °C

Procedure:
To a stirred solution of 1.12 g (2.5 mmol) 4-[6-bromo-8-(methylsulfonyl)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methyl benzamide which was prepared according to intermediate example 516b in 15 mL NMP is added 924 mg (7.5 mmol) 2-(methylsulfonyl)ethanamine and 1.94 g (15 mmol) DIPEA and the mixture is heated at 160° C. for 4 h in a heating block. After working up and without further purification 1.18 g (96%) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:26][C:27]([OH:44])([CH3:43])[CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>>[CH3:26][C:27]([OH:44])([CH3:43])[CH2:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:31]=[N:30]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 193. MS(ESI+) 491.1. 1H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 8.27 (d, J=8.3, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.45 (dd, J=8.3, 1.8, 1H), 7.31 (d, J=1.7, 1H), 5.86 (q, J=8.7, 2H), 4.71 (s, 1H), 4.39 (t, J=5.0, 2H), 4.03 (s, 2H), 3.47 (t, J=5.0, 2H), 1.10 (s, 6H)
Reaction SMILES: [CH3:1][NH:2][C:3](NC)=[O:4].[CH2:7]([NH:10][CH2:11][CH2:12][CH3:13])[CH2:8][CH3:9]>C1(C(C)C)C=CC=CC=1>[CH2:7]([N:10]([CH2:11][CH2:12][CH3:13])[C:3]([NH:2][CH3:1])=[O:4])[CH2:8][CH3:9]
Reactant: CCCNCCC
Reactant: CNC(=O)NC
Solvent: CC(C)c1ccccc1
Product: CCCN(CCC)C(=O)NC
Temperature: 137 °C
Yield: 104.9 %

Procedure:
To a 250 ml, 3-neck flask, with an agitator and condenser were added 22.0 g (0.25 mol) of 1,3-dimethylurea, 25.3 g (0.25 mol) of dipropylamine and 100 ml of cumene. The solution was heated at reflux (about 137° C.) for about 12 hours, cooled to 100° C., and the solvent was removed using vacuum distillation to provide a residue. The residue was dried in a vacuum oven at 60° C. to provide 41.5 g of 1,1-dipropyl-3-methylurea.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH2:16])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[C:23](Cl)(=[O:25])[CH3:24]>O.ClCCl>[CH3:24][C:23]([NH:16][CH2:15][CH2:14][C:11]1[C:12]2[CH:13]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1)=[O:25]
Reactant: COc1ccc2cccc(CCN)c2c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2cccc(CCNC(C)=O)c2c1
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
The compound V (6.0 g, 0.03 mol) produced as described above and potassium carbonate (5 g) were added to 20 ml of water and 40 ml of dichloromethane, and stirred for 30 minutes. The aqueous layer was removed. The organic layer was cooled to the temperature of 0° C., and acetyl chloride (7.8 g, 0.1 mol) was added dropwise. A reaction was allowed to proceed at room temperature for 1 hour. 100 ml water was then added, and the reaction solution was extracted with dichloromethane (50 ml*3). The organic phases were combined, dried with anhydrous magnesium sulfate, and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure, to give a solid. The solid was recrystallized in a 2:1 toluene/n-hexane mixture, to produce 4.8 g of agomelatine. The yield was 78.5%. The melting point was 107-108° C. (in Literature [2], 109° C.).
Reaction SMILES: [CH2:1]1[CH:4]2[CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH:3]2[C:2]1=[O:12].[OH:13]O.[Na]>C(O)(=O)C.O>[O:13]1[C:2](=[O:12])[CH2:1][CH:4]2[CH2:5][CH:6]3[C:11]([CH:10]=[CH:9][CH:8]=[CH:7]3)=[C:3]12
Reactant: OO
Reactant: O=C1CC2Cc3ccccc3C12
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC2CC3C=CC=CC3=C2O1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
A solution of 1,2a,7,7a-tetrahydro-2H-Cyclobut[a]inden-2-one (Example I4, 0.377 mg, 2.383 mmol) in acetic acid (5 mL) and water (0.5 mL) was cooled at 0° C. and hydrogen peroxide (30% in water, 0.810 mL, 7.14 mmol) was added. The solution as stirred for 3 h at 0° C. and the reaction mixture was poured into saturated solution of sodium hydrogenocarbonate. The solution was extracted with ethyl acetate and the combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography eluting with cyclohexane and ethyl acetate (4/1) to give rac-Tetrahydroindeno[1,2-b]furan-2-one (Colourless oil, 383 mg, 92%), that solidified upon cooling (data match with litt data, CAS 4471-33-4). C11H10O2; MW: 174.20; LCMS (method A) RT 1.32 min; ES: 175 (60%, MH+), 129 (100%); IR: 1769 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.50 (1H, d), 7.25-7.39 (4H, m), 5.91 (1H, d), 3.28-3.45 (2H, m), 2.86-2.97 (2H, m), 2.41 (1H, dd) ppm.
Reaction SMILES: CS(O[CH2:6][C:7]#[C:8][C:9]1[CH:21]=[CH:20][C:12]2[N:13]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[N:14]=[N:15][C:11]=2[C:10]=1[Cl:22])(=O)=O.[CH3:23][N:24]1[C:28](=[O:29])[CH2:27][NH:26][C:25]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Cl:22][C:10]1[C:11]2[N:15]=[N:14][N:13]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:12]=2[CH:20]=[CH:21][C:9]=1[C:8]#[C:7][CH2:6][N:26]1[CH2:27][C:28](=[O:29])[N:24]([CH3:23])[C:25]1=[O:30]
Reactant: CS(=O)(=O)OCC#Cc1ccc2c(nnn2CC2CC2)c1Cl
Reactant: CN1C(=O)CNC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1C(=O)CN(CC#Cc2ccc3c(nnn3CC3CC3)c2Cl)C1=O
Temperature: 50 °C

Procedure:
3-[4-Chloro-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]prop-2-yn-1-yl methanesulfonate (30 mg, 0.088 mmol), 3-methylimidazolidine-2,4-dione (20.15 mg, 0.177 mmol), and potassium carbonate (36.6 mg, 0.265 mmol) were combined in acetonitrile (1 ml) and heated at 50° C. for 24 hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic extract was dried with sodium sulfate, filtered, concentrated in vacuo. The residue was purified by silica gel gradient chromatography (0-5% acetone/dichloromethane) to provide the titled compound: 1H NMR (500 MHz, d6-DMSO) δ 7.97 (d, J=8.6 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 4.64 (d, J=7.3 Hz, 2H), 4.53 (s, 2H), 4.13 (s, 2H), 2.88 (s, 3H), 1.42-1.34 (m, 1H), 0.56 (m, 2H), 0.47 (m, 2H) ppm. LRMS m/z (M+H) 358.0 [calculated for C17H17ClN5O2: 358.8].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2NN=[N:27][N:26]=2)=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:17][C:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[N:26][N:27]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: Fc1ccc(-c2nnn[nH]2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)N1CCCCC1Cc1nnc(-c2ccc(F)cc2)o1
Yield: 74.2 %

Procedure:
The title compound (1.34 g) was prepared from 2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (1.22 g), 5-(4-fluorophenyl)tetrazole (0.82 g) and dicyclohexylcarbodiimide (1.05 g) according to the method of description 1.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[CH:8][C:7]=1[OH:14].[CH3:16][O:17][CH2:18][CH2:19]Br.O>CN(C)C=O>[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[CH:8][C:7]=1[O:14][CH2:19][CH2:18][O:17][CH3:16]
Reactant: COCCBr
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc(N)c(Cl)cc1C(=O)OC
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
A suspension of 60% sodium hydride/oil dispersion (1.00 g, 25 mmol) in anhydrous dimethylformamide (40 ml) under nitrogen was treated with 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester (4.03 g, 20 mmol), stirred for 30 minutes, then treated with 2-bromoethyl methyl ether (3.48 g, 25 mmol). The mixture was heated to 95±5° C. for 1.5 hours, then cooled and added to water (250 mL). The aqueous suspension was filtered, and the solid was washed with water, air dried, collected, and recrystallized from ether/hexane to afford 2.75 g (53%) of the tile compound; mp 121.0°-122.5° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[CH:19]=O)[CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:32]=[CH:31][C:26]2[C:27](=[O:30])[CH2:28][O:29][C:25]=2[C:24]=1[CH2:33][N:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1.N1CCCCC1>CO>[CH3:21][O:22][C:23]1[CH:32]=[CH:31][C:26]2[C:27](=[O:30])/[C:28](=[CH:19]/[C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([O:9][CH2:8][CH2:7][N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:11]=4)[NH:15][N:14]=3)/[O:29][C:25]=2[C:24]=1[CH2:33][N:34]1[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]1
Reactant: O=Cc1n[nH]c2ccc(OCCN3CCOCC3)cc12
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccc(OCCN4CCOCC4)cc13)C2=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
A solution of 5-(2-morpholinoethoxy)-1H-indazole-3-carboxaldehyde (0.0163 g, 0.0592 mmol) in methanol (0.5 mL) was added with tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0172 g, 0.0493 mmol) and piperidine (0.00335 g, 0.0394 mmol), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-[(6-methoxy-2-{[5-(2-morpholinoethoxy)-1H-indazol-3-yl]methylene}-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0303 g, 99%).
Reaction SMILES: C1(C([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)/[C:27]([O-:29])=O)[N:25]=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Na+].CS(Cl)(=O)=O.[NH2:57][C@@H:58]1[C:88](=[O:89])[N:60]2[C:61]([C:72]([O:74]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:73])=[C:62]([CH2:65][CH:66]3[O:70][C:69](=[O:71])[CH:68]=[CH:67]3)[CH2:63][S:64][C@H:59]12>CN(C=O)C>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[OH:31])/[C:27]([NH:57][C@@H:58]2[C:88](=[O:89])[N:60]3[C:61]([C:72]([OH:74])=[O:73])=[C:62]([CH2:65][CH:66]4[O:70][C:69](=[O:71])[CH:68]=[CH:67]4)[CH2:63][S:64][C@H:59]23)=[O:29])[N:25]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC3C=CC(=O)O3)CS[C@H]12
Reactant: O=C([O-])/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CC4C=CC(=O)O4)CS[C@H]23)cs1
Yield: 82.8 %

Procedure:
Sodium 2-(2-triphenylmethylaminothiazol-4-yl)-2-Z-triphenylmethoxyiminoacetate (1.33 g) in DMF (5 mls) was activated with methanesulphonyl chloride (0.148 mls) as described in example 7(a). Treatment with diphenylmethyl 7β-amino-3-[(5RS)-2,5-dihydro-2-oxofuran-5-ylmethyl]ceph-3-em-4-carboxylate (0.737 g) in DMF (5 mls), work up and purification by repeated flash, silica gel chromatography afforded major isomer of the title compound, (0.614 g, 35%), νmax 3380(w), 1785, 1770 (shoulder), 1755 (shoulder), 1725, 1685, 1510 and 1370cm-1 ; δH (CDCl3) 2.25 (1H, dd, J 9.9, 13.7Hz), 3.16 (1H, dd, J 2.9, 13.7Hz), 3.49 and 3.53 (2H, ABq, J 18.7Hz), 5.03 (1H, d, J 4.9Hz), 5.22 (1H, J 7.9Hz), 6.05 (1H, dd, J 1.9, 5.7Hz), 6.14 (1H, dd, J 4.9, 9.1Hz), 6.45 (1H, s), 6.76 (1H, broad s, exch.), 6.90 (1H, s), 7.07 (1H, d, J 9.1Hz, exch.), 7.19 (1H, dd, J 1.4, 5.7Hz) and 7.24 to 7.50 (40H, m); [mass spectrum: +ve ion (NOBA, Na+) MNa+ 1138]. The minor isomer was not progressed.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(C(C)C)C(C)C)C>C(O)C>[NH2:9][C:4]1[N:3]=[C:2]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)[CH:7]=[C:6]([Cl:8])[N:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)nc(N)n2)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 68.3 %

Procedure:
A mixture of 4,6-dichloropyrimidin-2-amine (1.500 g, 0.0091 mole), tert-butyl piperazine-1-carboxylate (2.044 g, 0.0110 mole), and N-ethyl-N-isopropylpropan-2-amine (11.1 mL, 0.0637 mole) in ethanol (20 mL) was magnetically stirred in a sealed tube at 80° C. for 18 hours. After cooling to ambient temperature, the seal was broken and volatiles were removed under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a crude, white solid that was crystallized from hot methanol. The crystals were collected by filtration and dried under vacuum to provide tert-butyl 4-(2-amino-6-chloropyrimidin-4-yl)piperazine-1-carboxylate (1.95 g, 68.3% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 3.46-3.52 (m, 4H), 3.55-3.61 (m, 4H), 4.90 (sbr, 2H), 5.96 (s, 1H). MS (DCl—NH3) m/z=314 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:14][CH3:15])[CH:3]=1.C(Cl)(=O)OCC.[NH2:22][C@H:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][C@H:24]1[O:34][CH3:35]>ClC(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH:22][C@H:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][C@H:24]2[O:34][CH3:35])=[O:8])=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: CCOC(=O)N1CC[C@H](N)[C@H](OC)C1
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CC[C@H](NC(=O)c2cc([N+](=O)[O-])c(Cl)cc2OC)[C@H](OC)C1
Reaction time: 1 h
Yield: 75 %

Procedure:
To a stirred and cooled (5° C.) suspension of 81 parts of 4-chloro-2-methoxy-5-nitrobenzoic acid in 1350 parts of trichloromethane were added first 35.4 parts of N,N-diethylethanamine and then 38 parts of ethyl carbonochloridate at a temperature below 5° C. The whole was stirred for 2 hours in an ice bath. A solution of 65 parts of ethyl cis-4-amino-3-methoxy-1-piperidinecarboxylate in 1125 parts of trichloromethane was added while the temperature was kept below 10° C. Stirring was continued first for 1 hour in an ice bath and then overnight at room temperature. The mixture was washed successively once with water, twice with a sodium hydroxide solution 5% and three times with water, dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 100 parts (75%) of ethyl cis-4-[(4-chloro-2-methoxy-5-nitro-benzoyl)amino]-3-methoxy-1-piperidinecarboxylate; mp. 181.3° C. (interm. 13).