Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)=O.[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH2:17][CH3:18].Br[CH2:20][C:21](=[O:37])[CH2:22][C@H:23]1[C@H:28]([O:29][CH3:30])[CH2:27][CH2:26][CH2:25][N:24]1[C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32]>>[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[N:10]([CH2:20][C:21](=[O:37])[CH2:22][C@H:23]3[C@H:28]([O:29][CH3:30])[CH2:27][CH2:26][CH2:25][N:24]3[C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH2:17][CH3:18]
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Reactant: CCSc1cc2c(=O)[nH]cnc2cc1Br
Solvent: O=CO
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(Br)c(SCC)cc2c1=O

Procedure:
In the manner of Example 4, 0.743 g (0.00224 mol) of 7-bromo-6-ethylthioquinazolin-4(3H)-one formic acid salt and 0.750 g (0.00224 mol) of allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate were converted into the title compound. After flash chromatography on silica gel (eluant 3% methanol in chloroform) there was obtained the pure product: yield 0.61 g (51%) mass spectrum m/e 537 (molecular ion with expected isotope pattern), 41 (parent peak, CH2 =CH--CH2 +) among others. 1H--NMR(CDCl3) 1.4 ppm (triplet, 3H, SCH2CH3), 1.4-2.1 (multiplet, 4H, OCHCH2CH2CH2N), 2.8-3.4 (multiplet, 6H, NCH2, SCH2CH3, COCH2CH), 3.4 (singlet, 3H, OCH3), 4.0 (broad singlet, 1H, CHNCO), 4.6 (doublet, 2H, CH2CH=CH2), 5.0 (singlet, 2H, NCH2CO), 5.0-5.5 (multiplet, 2H, CH=CH2), 5.6-6.1 (octet, 1H, CH2 =CH), 7.3 (singlet, 1H, aromatic H), 7.9 (singlet, 2H, aromatic H, N=CH--N).
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[OH:5][C:6]1[CH:7]=[C:8]([CH:18]=[O:19])[CH:9]=[C:10]2[C:15]=1[O:14][C:13]([CH3:17])([CH3:16])[CH:12]=[CH:11]2.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:5][C:6]1[CH:7]=[C:8]([CH:18]=[O:19])[CH:9]=[C:10]2[C:15]=1[O:14][C:13]([CH3:16])([CH3:17])[CH:12]=[CH:11]2
Reactant: CC1(C)C=Cc2cc(C=O)cc(O)c2O1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cc(C=O)cc2c1OC(C)(C)C=C2

Procedure:
Chloromethyl methyl ether (4 mL, 5 mmol) was added to a solution of 9 (103 mg, 0.5 mmol) and N,N-diisopropylethylamine (0.2 mL, 1 mmol) in 4 mL of methylene chloride. The reaction mixture was refluxed overnight and concentrated in vacuo. 10 (48 mg, 38%) was purified with ethyl acetate/hexane (1/50). 1H NMR (CDCl3): δ 1.52 (s, 6H), 3.54 (s, 3H), 5.25 (s, 2H), 5.71 (d, J=9.67 Hz, 1H), 6.38 (d, J=9.96 Hz, 1H), 7.26 (d, J=1.76 Hz, 1H), 7.52 (d, J=1.76 Hz, 1H), 9.80 (s, 1H).
Reaction SMILES: C([CH:3]1[CH2:6][CH:5]([C:7]([OH:9])=[O:8])[CH2:4]1)C.CI.[CH:12]1(C(O)=O)[CH2:15][CH2:14][CH2:13]1.ICCCC>>[CH2:15]([C:5]1([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][CH2:6]1)[CH2:12][CH2:13][CH3:14]
Reactant: CCC1CC(C(=O)O)C1
Reactant: O=C(O)C1CCC1
Solvent: CCCCI
Solvent: CI
Product: CCCCC1(C(=O)O)CCC1

Procedure:
The title compound was prepared as in Example 2A by replacing 3-ethylcyclobutanecarboxylic acid and methyl iodide respectively with cyclobutanecarboxylic acid and 1-iodobutane (Aldrich Chemical Company; Beilstein 1: 123). The resultant product had the following physical characterisics:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:15][CH2:14][C@@H:13]3[C@H:16]([NH:17]C(=O)OC(C)(C)C)[C@H:9]2[CH2:10][CH2:11][CH2:12]3)=[CH:4][CH:3]=1.[H-].[Na+].[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37]([C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:48]=1[CH2:47][N:46]([C:49]1[S:50][C:51]([CH2:59][CH2:60][CH2:61]I)=[C:52]([C:54]([O:56]CC)=[O:55])[N:53]=1)[CH2:45][CH2:44]2)=[O:38].Cl.[OH-].[Na+]>CN(C=O)C>[NH2:17][C@H:16]1[C@@H:13]2[CH2:12][CH2:11][CH2:10][C@H:9]1[C@@H:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:61][CH2:60][CH2:59][C:51]3[S:50][C:49]([N:46]4[CH2:45][CH2:44][C:43]5[C:48](=[C:39]([C:37](=[O:38])[NH:36][C:28]6[S:27][C:31]7[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=7[N:29]=6)[CH:40]=[CH:41][CH:42]=5)[CH2:47]4)=[N:53][C:52]=3[C:54]([OH:56])=[O:55])=[CH:7][CH:6]=1)[CH2:15][CH2:14]2
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCI
Reactant: CC(C)(C)OC(=O)N[C@H]1[C@@H]2CCC[C@H]1[C@@H](c1ccc(O)cc1)CC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@H]1[C@@H]2CCC[C@H]1[C@@H](c1ccc(OCCCc3sc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)cc1)CC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 7 %

Procedure:
Tert-butyl (1S,2S,5R,9S)-2-(4-hydroxyphenyl)bicyclo[3.3.1]nonan-9-ylcarbamate 80A (40.5 mg, 0.11 mmol) in DMF (1 ml) was treated with NaH (12 mg, 0.3 mmol). After stirring at ambient temperature for 5 minutes, compound 2C (63 mg, 0.1 mmol) was added and stirring was continued for 1.5 hours. HCl (4N HCl in dioxane) (2.5 ml, 10 mmol) was added and the mixture was stirred overnight at room temperature and then at 60° C. for 6 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was slurried with 1N HCl, filtered, rinsed with water, slurried in Et2O, filtered and rinsed with additional Et2O. The solid was purified by column chromatography on silica gel using a gradient of 0 to 5% MeOH in CH2Cl2. The solid was dissolved in dioxane (2 ml), treated with NaOH (4N aqueous) (0.25 mL, 1 mmol) and stirred overnight at rt. The reaction mixture was acidified with 1N HCl to induce precipitation of the product. The solid was filtered, rinsed with water, slurried in Et2O, filtered and rinsed with additional Et2O. The solid was purified by HPLC (Preparative reverse phase HPLC was performed on an automated Gilson HPLC system, using a SymmetryPrep Shield RP18 prep cartridge, 250 mm×21.20 mm i.d., 10 um, and a flow rate of 25 mL/min; λ=214, 245 nm; mobile phase A, 0.1% TFA in H2O; mobile phase B, CH3CN; linear gradient 20-90% of B in 40 min) to provide the title compound 80 in 7% yield as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.85 (1H, s), 12.50 (1H, s), 8.03 (1H, d), 7.97 (2H, d), 7.97 (1H, d), 7.47 (2H, m), 7.37 (2H, m), 7.13 (2H, d), 6.88 (2H, m), 4.83 (2H, s), 3.95 (2H, t), 3.72 (2H, t), 3.17 (2H, m), 3.02 (2H, m), 2.19 (2H, m), 1.98 (5H, m), 1.80 (5H, m), 1.59 (2H, m), 1.40 (3H, m). MS (ESI(+)) m/e 708 (M+H).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I.[F:28][C:29]([C:34]([F:55])([F:54])[C:35]([F:53])([F:52])[C:36]([F:51])([F:50])[C:37]([F:49])([F:48])[C:38]([F:47])([F:46])[C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])=[CH:30][CH2:31][NH:32][CH3:33]>CN1CCCC1=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:32]([CH2:31][CH:30]=[C:29]([F:28])[C:34]([F:54])([F:55])[C:35]([F:52])([F:53])[C:36]([F:50])([F:51])[C:37]([F:48])([F:49])[C:38]([F:46])([F:47])[C:39]([F:44])([F:45])[C:40]([F:43])([F:42])[F:41])[CH3:33]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CCC2=O
Reactant: CNCC=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CN1CCCC1=O
Product: CN(CC=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
880 mg of 11β-fluoro-3-hydroxy-7α-(5-iodopentyl)-estra-1,3,5(10)-trien-17-one and 1.83 g of (3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-hexadecafluoro-dec-2-enyl)-methyl-amine are dissolved in 20 ml of N-methylpyrrolidone and stirred for 1 hour at a bath temperature of 80° C. After the reaction solution is cooled to room temperature, the batch is added to saturated common salt solution, extracted with diethyl ether, dried and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with ethyl acetate as an eluant, 1.2 g of 11β-fluoro-7α-{5-[(3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-hexadecafluoro-dec-2-enyl)-methyl-amino]-pentyl}-3-hydroxy-estra-1,3,5(10)-trien-17-one is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[BH4-].[Na+].O>C(O)C.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1ccc(Br)cn1
Yield: 95.1 %

Procedure:
To a solution of 5-bromopyridine-2-carbaldehyde (5.00 g, 26.9 mmol) dissolved in a mixture of ethanol (75 mL) and THF (25 mL) was added sodium borohydride (0.407 g, 10.8 mmol) in small portions. After 45 minutes 0.5 mL water was added and the mixture and evaporated to dryness. The oily residue was subjected to flash chromatography (silica, EtOAc/EtOH/Et3N 90:5:5) to give (5-bromo-pyridin-2-yl)-methanol (4.81 g, 86%) as pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[H-].[Na+].[Cl:12][C:13]1[C:18]([C:19]#[N:20])=[C:17](Cl)[N:16]=[C:15]([S:22][CH3:23])[N:14]=1>CS(C)=O.CCOC(C)=O>[Cl:12][C:13]1[C:18]([C:19]#[N:20])=[C:17]([NH:4][C:3]2[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=2[F:9])[N:16]=[C:15]([S:22][CH3:23])[N:14]=1
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Reactant: Nc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CSc1nc(Cl)c(C#N)c(Nc2c(F)cccc2F)n1
Reaction time: 3 h
Yield: 87 %

Procedure:
2,6-di-Fluoroaniline (2.66 mL, 24 mmol), DMSO (12 mL) and NaH (0.912 g, 22.8 mmol) were combined at 23°. When the foaming ceased 4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile [Santilli, et al., J. Heterocycl. Chem. 1971, 8, 445-453] (5.0 g, 22.82 mmol) was added in DMSO (12 mL). The reaction exothermed and the temperature was moderated with cold H2O bath, then stirred at 23° for 3 h. The reaction was diluted with EtOAc (300 mL) and washed with H2O (4×) and satd aq NaCl (1×). Dried (Na2SO4) and concentrated to afford 6.21 g (82%) of a tan foam. LC MS m/z=313 (MH+), Rt=2.37 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[CH:27]2>>[NH:29]1[C:30]2[C:26](=[CH:25][C:24]([O:23][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:32][CH:31]=2)[CH:27]=[CH:28]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Oc1ccc2[nH]ccc2c1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCCCN1CCCC1
Yield: 49.2 %

Procedure:
Using an analogous procedure to that described in Example 34, 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (110 mg, 0.34 mmol), (prepared as described for the starting material in Example 9), was reacted with 5-hydroxyindole (55 mg, 0.41 mmol). The crude product was purified by chromatography on alumina, eluting with methanol/ethyl acetate/methylene chloride (5/45/50) to give 4-(indol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (70 mg, 50%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]3([F:29])[C:23]([F:24])=[C:22]([O:25][CH2:26][CH3:27])[CH:21]=[CH:20][CH:19]3[CH3:28])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3([F:29])[C:23]([F:24])=[C:22]([O:25][CH2:26][CH3:27])[CH:21]=[CH:20][CH:19]3[CH3:28])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(-c2ccc(C=CC3(F)C(F)=C(OCC)C=CC3C)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2ccc(CCC3(F)C(F)=C(OCC)C=CC3C)cc2)cc1
Yield: 81.9 %

Procedure:
0.36 g of Pd/C was added to 7.29 g of the compound (20) having been dissolved in 100 mL of toluene and 100 mL of Solmix, and under a hydrogen atmosphere, the mixture was stirred at room temperature until hydrogen was not absorbed. Pd/C was removed by filtration, and the solvent was distilled off. The residue was purified by silica gel column chromatography and recrystallization to obtain 6.00 g of 2-(2-(4-(4-propylphenyl)phenyl)ethyl)-2,3-difluoro-4-ethoxytoluene (Compound 1-3-3-22) as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([NH:16][C:17]([CH3:28])=[CH:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14]Br)=[CH:8][CH:7]=1.[CH:30]1[C:42]2[NH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1.[OH-].[Na+]>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:28][C:17]([NH:16][CH:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][C:39]2[C:40]3[NH:41][C:42]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:35]=3[CH:36]=[CH:37][CH:38]=2)=[CH:10][CH:11]=1)[C:3]([OH:2])=[O:29])=[CH:18][C:19](=[O:27])[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1
Reactant: COC(=O)C(Cc1ccc(OCCBr)cc1)NC(C)=CC(=O)c1ccc(F)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=CC(=O)c1ccc(F)cc1)NC(Cc1ccc(OCCc2cccc3c2[nH]c2ccccc23)cc1)C(=O)O
Yield: 22.8 %

Procedure:
To a solution of 2-[1-methyl-3-oxo-3-(4-fluorophenyl)-propenylamino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid methyl ester (0.23 g, 0.49 mmol) and carbazole (0.082 g, 0.49 mmol) in benzene (10 ml) is added tetrabutyl ammonium bromide (0.08 g) and 50% NaOH aqueous solution (0.084 g, 1.08 mmol), then the mixture is heated to reflux for 10 h. After cooled, benzene (30 ml) is added, and the mixture is washed with water(3×30 ml). Then the solvent is evaporated under a vacuum. The crude product is purified by silica gel chromatography using CHCl3/MeOH (4:1) as eluent to give the title compound (0.06 g, 23%). HRMS calcd for C33H29FN2O4: 536.6027. Found: 536.6025. MA calcd for C33H29FN2O4: C, 73.86%; H, 5.45%; N, 5.22%. Found: C, 73.63%; H, 5.46%; N, 5.20%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:30][C:31]1([CH2:34][O:35][CH3:36])[CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]2([CH2:34][O:35][CH3:36])[CH2:33][CH2:32]2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: COCC1(CBr)CC1
Product: COCC1(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3cc(F)ccc34)c3ccc(Cl)cc32)CC1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with 1-bromomethyl-1-methoxymethyl-cyclopropane (described in WO 2001032633) gave the title compound.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:13][OH:14]>>[CH2:1]([N:5]1[CH2:10][CH2:9][C:8](=[N:13][OH:14])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: CCCCN1CCC(=NO)CC1

Procedure:
1-Butyl-4-piperidone oxime is prepared from 1-butyl-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[CH:16]C=CN=3)=[N:11][C:7]=2[CH:6]=1.[CH3:37][N:38]1C=CC(C(O)=O)=[N:39]1>>[F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[CH:16][N:38]([CH3:37])[N:39]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: Cn1ccc(C(=O)O)n1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccc(F)cc2F)cn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccn(C)n4)nc3cc2Oc2ccc(F)cc2F)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 203 or in accordance with the method or by combining it with an ordinary method but using 4-(2,4-difluoro-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 229 and 1-methyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([C:15]([OH:17])=O)[C:9]2=[O:18])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:23][C:24]1[CH:40]=[CH:39][C:27]([O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]([NH2:37])=[O:36])[C:30]=2[Cl:38])=[C:26]([F:41])[CH:25]=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.C1COCC1.CN(C=O)C>[Cl:38][C:30]1[C:31]([C:35]([NH2:37])=[O:36])=[N:32][CH:33]=[CH:34][C:29]=1[O:28][C:27]1[CH:39]=[CH:40][C:24]([NH:23][C:15]([C:10]2[C:9](=[O:18])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][C:11]=2[I:14])=[O:17])=[CH:25][C:26]=1[F:41]
Reactant: O=C(O)c1c(I)ccn(-c2ccc(F)cc2)c1=O
Reactant: NC(=O)c1nccc(Oc2ccc(N)cc2F)c1Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1nccc(Oc2ccc(NC(=O)c3c(I)ccn(-c4ccc(F)cc4)c3=O)cc2F)c1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.4 %

Procedure:
To 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (3.7 g, 10 mmol) in 6 mL of toluene was added thionyl chloride (10 mL, Aldrich ReagentPlus 99.5%). After stirring at rt for 2.5 h, the mixture became homogenous and was then concentrated in vacuo. Toluene (3 mL) was added to the residue and the mixture was concentrated in vacuo to remove excess thionyl chloride (performed twice). The crude acid chloride was then dried under high vacuum for 15 minutes. While the acid chloride was drying, 4-(4-amino-2-fluorophenoxy)-3-chloropicolinamide (2.5 g, 8.9 mmol) was dissolved in THF (50 mL) and DMF (3 mL). The solution was cooled to 0° C. and then N,N-diisopropylethylamine (3.1 mL, 18 mmol, Aldrich 99.5% redistilled) was added. The acid chloride was then added over 30 min as a solid. Upon completion of the addition, the cooling bath was removed and the reaction mixture was stirred at rt for 15 min before being quenched with saturated aqueous sodium bicarbonate solution (30 mL). Water was added (˜30 mL) to dissolve the salts and the mixture was extracted with ethyl acetate (1×100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (2% methanol/ethyl acetate) to give 4.9 g of the desired product along with a minor amount of 3-chloro-4-(4-(4-chloro-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-fluorophenoxy)picolinamide together as an off-white solid (89% based on iodide). 1H NMR (CD3OD) δ 8.34 (d, 1H, J=5.6 Hz), 7.92 (dd, 1H, J=12.4, 2.4 Hz), 7.51-7.47 (m, 4H), 7.37-7.29 (m, 3H), 6.99 (d, 1H, J=7.2 Hz), 6.86 (d, 1H, J=5.6 Hz); MS (ESI+) m/z 623.08 (M+H)+.
Reaction SMILES: [C:1]([C:3]([CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[CH2:22]1[O:32][C:31]2[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][C:24]=2[O:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:27][C:26]2[CH:29]=[CH:30][C:31]3[O:32][CH2:22][O:23][C:24]=3[CH:25]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCCNC1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)C1CCCN(Cc2ccc3c(c2)OCO3)C1

Procedure:
A mixture containing 3-(R,S)-(1-cyano-1,1-diphenylmethyl)piperidine (0.27 g), 3,4-methylenedioxybenzyl chloride (0.18 g), anhydrous potassium carbonate (0.3 g) and acetonitrile (10 ml) was heated under reflux for 16 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 2%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless solid, yield 0.2 g, m.p. 127°-130° C.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][C:11](=O)[CH2:10][NH:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:1]1([CH:7]2[CH2:8][NH:9][CH2:10][CH2:11][NH:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CNC(=O)C(c2ccccc2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(C2CNCCN2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
2.3 g of 3-phenyl-piperazine-2,5-dione were suspended in anhydrous THF under nitrogen and cooled in an ice-bath. 4 equiv. of lithium aluminium hydride were added. The reaction was stirred at 0° C. for 0.5 h, and then heated to reflux overnight. The reaction was quenched by the subsequent addition of 1 mL/gLiAlH4 of water, 1 mL/gLiAlH4 of 5% aqueous Sodium hydroxide solution and 3 mL/gLiAlH4 of water. The resulting solid were separated by filtration through Celite and rinsed with ethyl acetate. The filtrate was concentrated in vacuo to afford 2 g of 2-phenylpiperazine as brown oil. ES MS (+) m/z 163
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:28][S:27][C@@H:9]2[C@H:10]([NH:13]C(C(OC(C)=O)C3C=CC=CC=3)=O)[C:11](=[O:12])[N:8]2[C:7]=1[C:29]([OH:31])=[O:30])=O>O>[CH3:5][C:6]1[CH2:28][S:27][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:29]([OH:31])=[O:30]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(OC(C)=O)c3ccccc3)[C@H]2SC1
Solvent: O
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1

Procedure:
500 g of 7-phenylacetamido-desacetoxycephalosporanic acid were dissolved in 8.3 liters of water and split completely over the course of 4 hours at 38°C, by addition of 220 g of carrier-bound penicillinacylase (according to Example C), analogously to Example 2; the 7-amino-desacetoxycephalosporanic acid formed was precipitated and dried.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[S:26]1CC(O)S[CH2:28][CH:27]1O.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[NH2:5][C:4]1[S:26][CH:27]=[CH:28][C:3]=1[C:2]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)=[CH:10][CH:11]=1)=[O:1]
Reactant: OC1CSC(O)CS1
Reactant: COc1cc(CCc2ccc(C(=O)CC#N)cc2)cc(OC)c1OC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CCc2ccc(C(=O)c3ccsc3N)cc2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a solution of 1.35 g of the compound prepared in (a) above in 8 ml of dry N,N-dimethylformamide was added, successively and under a nitrogen atmosphere, 0.6 g (4 mmol) of 1,4-dithiane-2,5-diol and 0.14 ml (1 mmol) of triethylamine, and the resultant mixture was heated to 50° C. and maintained at this temperature for 4 hours. After cooling the reaction mixture to 25° C., it was diluted with ethyl acetate and the resultant solution was washed successively with water and a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to yield a crude product which was purified on silica gel employing a mixture of ethyl acetate and hexane in a 1:1 ratio as the eluent to yield a yellow foam.