Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:19][NH:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15]2)=[O:13])=[CH:7][C:6]=1[OH:24])([CH3:4])([CH3:3])[CH3:2].[OH:25]O>C(O)(=O)C.CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[S:15](=[O:25])[C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[NH:18][CH2:19]2)=[O:13])=[CH:7][C:6]=1[OH:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: OO
Reactant: CC(C)(C)c1ccc(NC(=O)C2CNc3ccccc3S2)cc1O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(NC(=O)C2CNc3ccccc3S2=O)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
A solution of N-(4-tert-butyl-3-hydroxy-phenyl)-3,4-dihydro-2H-1,4-benzothiazine-2-carboxamide (20 mg, 0.058 mmol) in acetic acid (500 μL) was treated with hydrogen peroxide (12 μL of aq. 30% w/w, 0.12 mmol) and stirred at room temperature for 2 h. The reaction was diluted with DMF and purified by HPLC (10-99% CH3CN/5 mM HCl) to provide N-(4-tert-butyl-3-hydroxy-phenyl)-1-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-2-carboxamide (8 mg, 38% yield). LC/MS m/z 359.2 [M+H]+.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].Cl[S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8].[NH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([NH:13][S:7](=[O:9])(=[O:8])[NH:10][C:11]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:12])[CH:15]=1
Reactant: CC(C)(C)O
Reactant: Nc1cccnc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NS(=O)(=O)Nc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
tert-Butanol (2.0 mL, 21.1 mmol) was added to a solution of chlorosulfonyl- isocyanate (1.8 mL, 21.1 mmol) in CH2Cl2 (40 mL). The reaction mixture was stirred at ambient temperature for 0.5 hours and then treated with a solution of 3-aminopyridine (2.00 g, 21.1 mmol) and triethylamine (4.4 mL, 31.6 mmol) in CH2Cl2 (20 mL) via canula. The reaction mixture was stirred at ambient temperature for an additional 1.5 hours and then filtered through a 0.25 inch silica gel plug. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (elution with EtOAc) to provide 1.17 g of the title compound as a white solid.
Reaction SMILES: C(O[C:5]([O:9]C(=O)C)(C)[CH:6]=[CH2:7])(=O)C.[C:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:16][CH3:17])([CH3:15])[CH3:14].B(F)(F)F.[CH3:28]COCC>[Ti](Cl)(Cl)(Cl)Cl.Cl>[C:13]([C:18]1[CH:19]=[CH:20][C:21]([CH2:28][CH:5]([CH3:9])[CH:6]=[O:7])=[CH:22][CH:23]=1)([CH2:16][CH3:17])([CH3:14])[CH3:15]
Reactant: CCOCC
Reactant: C=CC(C)(OC(C)=O)OC(C)=O
Reactant: CCC(C)(C)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: FB(F)F
Product: CCC(C)(C)c1ccc(CC(C)C=O)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 172 g of α-methyl-allylidene diacetate and 160 g of p-tert.amyl-benzene is allowed to drop in to a mixture, cooled to -10° C., of 637 g of p-tert.amyl-benzene, 211 g of titanium tetrachloride and 3 g of boron trifluoride etherate while stirring over a period of 1.5 hours. The mixture is subsequently stirred at -10° C. for 45 minutes and then poured on to a mixture of 800 ml of ice-water and 140 ml of concentrated hydrochloric acid in order to hydrolyse the titanium tetrachloride. The organic layer is separated, washed neutral with water and 5% sodium bicarbonate solution, dried over sodium sulphate and the excess p-tert.amyl-benzene is distilled in a water-jet vacuum. (Boiling point 108° C./20 Torr). The residue, crude 3-(p-tert.amyl-phenyl)-2-methyl-1-propenyl acetate, is taken up in 190 ml of methanol, treated with a solution of 80 g of potassium carbonate in 145 ml of water and heated at reflux with intensive stirring until the saponification has been completed. The methanol is distilled and the organic phase is separated and distilled. There is obtained pure 3-(p-tert.amyl-phenyl)-2-methyl-propionaldehyde of boiling point 109°-111° C./0.06 Torr.
Reaction SMILES: O1C2C=CC=CC=2C=C1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=2)[N:12]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[N:11]=1.[NH2:27][NH:28][C:29](=O)[CH2:30][N:31]([CH3:33])[CH3:32].[CH3:35][O-:36].[Na+]>CO.ClCCl>[O:36]1[C:15]2[CH:14]=[CH:13][CH:18]=[CH:17][C:16]=2[CH:19]=[C:35]1[CH:26]1[CH2:25][CH2:24][CH2:23][O:22][CH:21]1[N:12]1[C:13]2[C:18](=[CH:17][C:16]([C:19]3[NH:27][N:28]=[C:29]([CH2:30][N:31]([CH3:33])[CH3:32])[N:20]=3)=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: CN(C)CC(=O)NN
Reactant: C[O-]
Reactant: N#Cc1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN(C)Cc1n[nH]c(-c2ccc3c(cnn3C3OCCCC3c3cc4ccccc4o3)c2)n1
Temperature: 100 °C
Yield: 7 %

Procedure:
To a suspension of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (167 mg, 0.49 mmol) and N-amino-2-(dimethylamino)acetamide (171 mg, 1.46 mmol) in anhydrous methanol (1.0 mL) in a screw-top pressure tube was added sodium methoxide (445 μL of a 25% w/w in methanol). The tube was sealed and heated in a 100° C. oil bath for 21 h. An additional amount of N-amino-2-(dimethylamino)acetamide (171 mg, 1.46 mmol) was added and the reaction heated for an additional 2 days. The reaction was cooled, evaporated to dryness and partitioned between ethyl acetate and satd. ammonium chloride. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo to give a yellow solid. Purification of the residue by flash chromatography on silica gel using 5% methanol in dichloromethane then 20% methanol in dichloromethane gave the desired product (15 mg, 7% yield) as a pale yellow foam. ES-MS (m/z) 443 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]([F:11])([F:10])[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:12][O:13][C:14](=[O:17])[CH2:15]Br.C(N(CC)CC)C>C1COCC1.O>[CH3:12][O:13][C:14](=[O:17])[CH2:15][N:7]1[CH2:8][CH2:9][CH:4]([C:3]([F:11])([F:10])[F:2])[CH2:5][CH2:6]1
Reactant: FC(F)(F)C1CCNCC1
Reactant: COC(=O)CBr
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CN1CCC(C(F)(F)F)CC1
Yield: 99.7 %

Procedure:
To a solution of 4-trifluoromethylpiperidine hydrochloride (1 g, 5.3 mmol) in THF (20 mL) was added methylbromoacetate (0.52 mL, 5.5 mmol) and triethylamine (2.2 mL, 15.8 mmol). The reaction was heated at reflux for 4 h and then diluted with water (50 mL) and the product extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield (4-trifluoromethylpiperidin-1-yl)acetic acid methyl ester as a brown oil (1.19 g, 98%). MS 226 (M+H)+. To a solution of (4-trifluoromethylpiperidin-1-yl)acetic acid methyl ester (1.19 g, 5.3 mmol) in THF (15 mL) at 0° C. was added portion wise lithium aluminium hydride (0.4 g, 10.6 mmol). Once the effervescence had ceased the reaction was heated at 60° C. for 1.5 h. The reaction was quenched with water (10 mL) followed by sodium hydroxide solution (2N, 10 mL) then water (10 mL). The reaction was filtered and the filtrate extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield 2-(4-trifluoromethylpiperidin-1-yl)-ethanol as a brown oil (1.0 g, 99%). MS 198 (M+H)+. To a solution of diisopropylazodicarboxylate (0.58 mL, 2.28 mmol) in DCM (20 mL) was added polymer supported triphenylphosphine (1.14 g, 3.4 mmol). The reaction was stirred at RT for 10 mins. 5-Hydroxybenzofuran-2-carboxylic acid ethyl ester (0.47 g, 2.3 mmol) and 2-(4-trifluoromethylpiperidin-1-yl)-ethanol (0.45 g, 2.28 mmol) were added and the reaction stirred at RT for 16 h. The reaction was filtered and the filtrate concentrated in vacuo. The product was purified on silica eluting with 50% tert-butyl methyl ether in n-heptane to yield 5-[2-(4-trifluoromethylpiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester as a yellow solid (548 mg, 62%). MS 386 (M+H)+. To a solution of 5-[2-(4-trifluoromethylpiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester (548 mg, 1.42 mmol) in THF (5 mL) and water (1 mL) was added lithium hydroxide (45 mg, 2.84 mmol). The reaction was stirred at RT for 16 h. The THF was removed in vacuo and the remaining aqueous solution dried overnight in a freeze dryer to yield the crude title compound as a brown solid. MS 358 (M+H)+ which was used directly for coupling with H2N-Leu-P1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:13]([CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)=[O:14])[CH:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Product: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Yield: 37 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with ethyl 1-(6-chloronaphth-2-ylsulphonyl)piperazine-3-carboxylate to give 4-(6-chloronaphth-2-ylsulphonyl)-2-ethoxycarbonyl-1-[1-(4-pyridyl)-piperidin-4-ylcarbonyl]piperazine in 37% yield;
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:27][N:28]([C:30](=[O:33])[CH2:31][CH3:32])[NH2:29].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>ClCCCl.CN(C1C=CN=CC=1)C.O>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:14]([F:17])([F:15])[F:16])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][N:28]([CH3:27])[C:30](=[O:33])[CH2:31][CH3:32])=[O:5]
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: CCC(=O)N(C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCCl
Product: CCC(=O)N(C)NC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-1-enyl)benzoic acid (200 mg, 0.41 mmol) in 1,2-dichloroethane (DCE) (10 mL) was added N-methylpropionohydrazide (WO 2009110510) (50 mg, 0.49 mmol), DMAP (55 mg, 0.45 mmol), EDC.HCl (60 mg, 0.41 mmol) and DIPEA (0.20 mL, 1.1 mmol). The reaction mixture was stirred at 25° C. for 12 h, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh) eluting with 30% EtOAc in hexane afforded the title compound as an off white solid (86 mg, 34%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(CCCCI)CC(OC)=[O:17].[O:25]1CCC[CH2:27][CH:26]1[O:31][CH:32]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:33][CH2:34][CH2:35][N:36]([CH2:40][CH2:41][CH2:42]CC(C)CC(OC)=O)C(=O)C>>[C:26]([O:31][CH:32]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:33][CH2:34][CH2:35][N:36]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:40](=[O:17])[CH:41]=[CH2:42])(=[O:25])[CH3:27]
Reactant: COC(=O)CC(C)CCCCI
Reactant: CCOC(=O)CCCCCCBr
Reactant: CCCCCC(CCCN(CCCCC(C)CC(=O)OC)C(C)=O)OC1CCCCO1
Product: C=CC(=O)N(CCCCCCC(=O)OCC)CCCC(CCCCC)OC(C)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the ethyl 7-bromoheptanoate is replaced by an equimolar amount of methyl 3-methyl-7-iodoheptanoate. The product of Step A is methyl 7-{N-[4-(2-tetrahydropyranyloxy)nonyl]acetamido}-3-methylheptanoate. The subsequent step yields 7-[N-(4-hydroxynonyl)acetamido]-3-methylheptanoic acid (B).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][C@H:11]([CH2:13]I)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[NH:23][C:22]2=[O:30])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][C@H:11]([CH2:13][N:15]3[CH2:16][CH2:17][CH:18]([N:21]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[NH:23][C:22]4=[O:30])[CH2:19][CH2:20]3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: Fc1ccc([C@H]2C[C@H](CI)CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1C1CCN(C[C@@H]2CO[C@@H](c3ccc(F)cc3)C2)CC1
Reaction time: 42 h
Yield: 79 %

Procedure:
A mixture of 5.0 g of trans-2-(4-fluorophenyl)-4-(iodomethyl)tetrahydrofuran, 4.2 g of 1-(4-piperidyl)benzimidazolin-2-one and 2.5 g of potassium carbonate in 80 ml of dimethylformamide is heated with stirring at 60°-70° C. for 42 hours. The reaction mixture is then poured into water and extracted with ethyl acetate. The extract is washed three times with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. Isopropyl ether is added to the residue, and the crystals precipitated are collected by filtration and recrystallized from ethanol to give 5.1 g of 1-[1-(trans-2-(4-fluorophenyl)-tetrahydro-4-furylmethyl)-4-piperidyl]benzimidazolin-2-one as colorless needles, melting at 154°-155° C. The corresponding hydrochloride melts at 239° C. with decomposition.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[N:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:9][CH:10]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: Clc1ncccc1-c1ccncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Oc2ncccc2-c2ccncn2)cc1
Temperature: 200 °C

Procedure:
A mixture of 4-(2-chloro-pyridin-3-yl)-pyrimidine, 4-hydroxy-benzoic acid and Cs2CO3 in DMSO was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 200° C. for 10 minutes. The reaction mixture was cooled to RT and diluted with 60 mL of EtOAc. The product was precipitated from the solution. The mixture was then washed with 20 mL of water twice. The solid was collected by filtration and dried in an oven at 50° C. to afford off white solid as desired product. MS m/z=294 [M+1]+. Calc'd for C16H11N3O3: 293.28.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:8][CH:9]=1.I[CH2:22][C:23]([NH2:25])=[O:24]>CN(C)C=O.C(OCC)(=O)C.O>[F:3][C:4]1[CH:5]=[CH:6][C:7](=[N:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:8]([CH2:22][C:23]([NH2:25])=[O:24])[CH:9]=1
Reactant: NC(=O)CI
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(F)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(F)cn2CC(N)=O)cc1
Reaction time: 0.33 h

Procedure:
Sodium hydride (5.0 g, 0.21 mol) in N,N-Dimethylformamide (370 mL) was treated portion wise with N-(5-Fluoro-pyridin-2-yl)-4-methyl-benzenesulfonamide (compound a, 50 g, 0.2 mol). After stirring for 20 minutes, iodoacetamide (30 g, 0.2 mol) was added in one portion. The reaction stirred overnight at room temperature. The solvent was removed to give a brown solid. The crude material was diluted with 500 ml of ethyl acetate and 100 mL of water and stirred for 2 hours. The solid was collected by filtration and dried to afford 36 g of 2-(5-fluoro-2-(tosylimino)pyridin-1(2H)-yl)acetamide. Rf 0.37, neat ethyl acetate MS m/z 324 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[O:10])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.CN(C1C=CC=CN=1)C.[N+:47]([C:50]1[CH:55]=[CH:54][C:53]([CH2:56][C:57](O)=[O:58])=[CH:52][CH:51]=1)([O-:49])=[O:48]>C(OCC)(=O)C.O.CN(C=O)C>[CH3:16][N:14]([CH3:15])[CH2:13][CH2:12][NH:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:57](=[O:58])[CH2:56][C:53]2[CH:52]=[CH:51][C:50]([N+:47]([O-:49])=[O:48])=[CH:55][CH:54]=2)=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)CCNC(=O)Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)CCNC(=O)Cc1ccc(NC(=O)Cc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 4 h
Yield: 20.8 %

Procedure:
2-(4-Aminophenyl)-N-[2-(dimethylamino)ethyl]acetamide (221 mg), WSC (free form: 0.23 ml), 1-hydroxybenzotriazole (199 mg), and dimethylaminopyridine (244 mg) were added to a DMF (5 ml) solution of 4-nitrophenylacetic acid (181 mg), which was stirred for 4 hours. The reaction mixture was poured into water, and extraction was conducted using ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over sodium sulfate, and then concentrated. The residue was recrystallized from methanol, to give the titled compound (80 mg).
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH2:16][C:17]([OH:19])=O)=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:32]([NH:35][CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34]>O1CCCC1>[C:1]1([C:7]2[C:15]([CH2:16][C:17]([N:35]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:33][CH3:34])=[O:19])=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCNCCC
Reactant: O=C(O)Cc1c(-c2ccccc2)nn2cccnc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cc1c(-c2ccccc2)nn2cccnc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
A mixture of 3.5 g (0.013 mole) of 2-phenylpyrazolo[1,5-a]pyrimidine-3-acetic acid and 2.24 g (0.013 mole) of 1,1'-carbonyldiimidazole in 150 ml of anhydrous tetrahydrofuran was stirred for 4 hours at room temperature while nitrogen was bubbled through the mixture. After additional stirring, a solution of 4.19 g (0.041 mole) of di-n-propylamine in 10 ml of anhydrous tetrahydrofuran was added dropwise and the mixture was stirred for about 17 hours under a nitrogen atmosphere. The solvent was evaporated under reduced pressure and the residue (7.3 g) was recrystallized from ethanol-water to give 3.3 g of product (72%), mp 103°-105° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C@@H:10]([CH2:24][OH:25])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](=O)=O.CC(C)=O.B(F)(F)F.CCOCC.[N+](=C)=[N-]>ClCCl>[CH2:1]([O:8][C:9](=[O:26])[C@@H:10]([CH2:24][O:25][CH3:27])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=O
Reactant: COc1ccc(COC(=O)N[C@H](CO)C(=O)OCc2ccccc2)cc1
Agent: C=[N+]=[N-]
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: ClCCl
Product: COC[C@@H](NC(=O)OCc1ccc(OC)cc1)C(=O)OCc1ccccc1
Yield: 70 %

Procedure:
The N-p-methoxybenzyloxycarbonyl-D-serine benzyl ester (720 mg, 2.00 mmol) is dissolved in dry dichloromethane (20 ml) and the solution cooled to dry ice/acetone. Boron trifluoride etherate (100 μl) is added followed by the portionwise addition of diazomethane (30 mmol in 20 ml CH2Cl2). After about 30 minutes the solution is filtered and washed once with water (10 ml), then dried (MgSO4) and evaporated to dryness. The resulting residue is chromatographed on silica gel using chloroform as eluant to give the pure title compound as an oil (520 mg, 70%) which crystallises on standing to give a colourless solid of m.p. 68°-69° C.; [α]D20 -1.3° (c 4.0, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[CH2:27]([CH2:29][NH2:30])[OH:28].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:30][CH2:29][CH2:27][OH:28])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: NCCO
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCCO)c(Cl)c32)c(F)cc1F
Temperature: 50 °C
Reaction time: 15.5 h
Yield: 85 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg), ethanolamine (35 mg) and triethylamine (200 mg) were added to pyridine (600 mg), and the mixture was stirred at 50° C. for 15.5 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (3 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethanol (1 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (188 mg) as a pale brown powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Na].[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(OCC)(=O)C>CN(C)C=O>[N:10]1([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: Brc1ccc(Br)nc1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc(-n2cncn2)nc1
Yield: 92.6 %

Procedure:
In 20 ml of dimethylformamide, 1 g of 2,5-dibromopyridin was reacted with 0.58 g of 1,2,4-triazole sodium at 80° C. for 10 hours with stirring. Following the addition of ethyl acetate, the organic layer thus separated was washed with brine, dehydrated, filtered, and concentrated in vacuo to give 880 mg of 2-(1,2,4-triazol-1-yl)-5-bromopyridine. This compound was dissolved, along with 1.4 g of (S)-[N-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide, in 50 ml of dimethylformamide and then added with 1.2 ml of triethyl amine and 1.1 g of dichlorobistriphenylphosphine palladium (II) at room temperature. Reaction was conducted at 100° C. for 3 hours. Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer thus separated was washed with brine, dehydrated, filtered, and concentrated in vacuo. Purification of the concentrate with column chromatography provided the title compound. 320 mg. Yield 23%.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7](=[O:31])[N:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([CH:18]([NH:23][C:24](=[O:30])OC(C)(C)C)[CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])[CH2:12][CH2:11]3)[CH2:9][C:5]2=[CH:4][N:3]=1.[ClH:32].[CH2:33](O)[CH3:34]>>[Cl:32][C:34]1[CH:33]=[CH:15][C:10]([NH:8][C:24]([NH:23][CH:18]([C:16]([N:13]2[CH2:12][CH2:11][CH:10]([N:8]3[CH2:9][C:5]4=[CH:4][N:3]=[C:2]([CH3:1])[N:6]4[C:7]3=[O:31])[CH2:15][CH2:14]2)=[O:17])[CH2:19][CH2:20][CH2:21][CH3:22])=[O:30])=[CH:11][CH:12]=1
Reactant: CCCCC(NC(=O)OC(C)(C)C)C(=O)N1CCC(N2Cc3cnc(C)n3C2=O)CC1
Reactant: Cl
Reactant: CCO
Product: CCCCC(NC(=O)Nc1ccc(Cl)cc1)C(=O)N1CCC(N2Cc3cnc(C)n3C2=O)CC1
Reaction time: 15 h
Yield: 51 %

Procedure:
To tert-butyl 1-((4-(5-methyl-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl)-1-piperidinyl)carbonyl)pentylcarbamate (0.65 g) obtained in Example 80b) was added concentrated hydrochloric acid (5 ml), and mixed for 15 minutes. To the reaction solution was added ethanol, and then concentrated under reduced pressure. The residue and DBU (0.69 g) were dissolved in acetonitrile (15 ml), and a solution of 4-chlorophenyl isocyanate (0.25 g) in acetonitrile (15 ml) was added dropwise thereto. After reacting for 15 hours, the solvent was distilled off under reduced pressure, and the residue was purified with silica gel column (ethyl acetate to ethyl acetate/methanol=5/1). The product was recrystallized from ethyl acetate-diisopropyl ether to obtain the title compound as colorless powder (0.37 g, 51%).