Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:25]([CH:29]=1)[C:26](Cl)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:38]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][N:38]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:26](=[O:27])[C:25]1[CH:29]=[C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:22]=[CH:23][C:24]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:44]
Reactant: O=C(Cl)c1cc(OCCCCCCCCCCCCOc2ccccc2)ccc1OCc1ccccc1
Reactant: CCOC(=O)CNCC(=O)OCC
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cc(OCCCCCCCCCCCCOc2ccccc2)ccc1OCc1ccccc1
Yield: 56 %

Procedure:
The reaction of 5-[(12-phenoxydodecyl)oxy]-2-(phenylmethoxy) benzoic acid chloride with diethyl iminodiacetate under conditions described in Example 80 gave N-(2-ethoxy-2-oxoethyl)-N-[5-[(12-phenoxydodecyl)oxy]-2-(phenylmethoxy)benzoyl]glycine ethyl ester (56% yield, mp 49°-50° ). The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [CH:1]1([NH2+:7][CH:8]2[CH2:13]CCCC2)CCCCC1.[C:14]([NH:24][C@H:25]([C:35]([O-:37])=[O:36])[CH2:26][CH:27]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O-:30])=[O:29])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[CH:38]1([NH2+]C2CCCCC2)CCCCC1.C(Cl)Cl>C1(C)C=CC=CC=1>[CH3:38][N:7]([CH3:1])[CH:8]([O:36][C:35](=[O:37])[C@H:25]([CH2:26][CH:27]([C:31]([CH3:32])([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[NH:24][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:13]
Reactant: C1CCC([NH2+]C2CCCCC2)CC1
Reactant: CC(C)(C)C(C[C@H](NC(=O)OCc1ccccc1)C(=O)[O-])C(=O)[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(OC(=O)[C@H](CC(C(=O)O)C(C)(C)C)NC(=O)OCc1ccccc1)N(C)C
Temperature: 50 °C
Yield: 89.1 %

Procedure:
To 1.20 g N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-dicyclohexyl ammonium salt, 20 ml methylene chloride and 2.1 ml solution of dimethylamioethyl-chloride in the amount of 0.5 g, which stoichiometrically corresponds to two times molar volume, in toluene were added to be subjected to reflux in oil bath at 50° C. for 35 hrs. After cooling down to the room temperature, the reaction mixture was similarly treated as in Step Example 1 to obtain N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-α-dimethylaminoethyl ester in the amount of 842 mg (yield; 89.1%).
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[CH2:14]([O:21][C:22]([NH:24][CH2:25][CH:26]([NH:30][C:31]([O:33]C(C)(C)C)=O)[C:27]([OH:29])=[O:28])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(=O)O[C:41](=[O:42])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12>ClCCl.Cl.C1(C)C=CC=CC=1>[CH2:14]([O:21][C:22]([NH:24][CH2:25][C@H:26]([N:30]1[C:31](=[O:33])[C:39]2=[CH:47][CH:46]=[CH:45][CH:44]=[C:40]2[C:41]1=[O:42])[C:27]([OH:29])=[O:28])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NC(CNC(=O)OCc1ccccc1)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(NC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of (2S) 3-benzyloxycarbonylamino-2-tert-butoxycarbonylaminopropionic acid dicyclohexylamine salt (3 g, 5.8 mmol) in dichloromethane (200 ml) was washed four times with 1M HCl solution, dried (MgSO4) and concentrated. The resulting oil was dissolved in dry dichloromethane (35 ml), cooled to 0° C. and treated with trifluoroacetic acid (35 ml). This solution was stirred at 0° C. for 1.5 h then evaporated to dryness. Dichloromethane (50 ml) was added to the residue then removed under vacuum. This process repeated six times to afford a white solid. The white solid was suspended in toluene (50 ml), treated with powdered phthalic anhydride (940 mg, 6.35 mmol) and refluxed for 18 h. The resulting solution was concentrated to afford an oil which was purified by flash chromatography (2-10% methanol/dichloromethane) to afford 266, 2.01 g (94%) as a white powder: IR (KBr) 3600-2500br, 1776, 1714, 1530, 1469, 1455, 1392, 1263, 1131, 722; 1H NMR (CDCl3) δ 7.83 (2H, m), 7.72 (2H, m), 7.29 (5H, m), 5.41 (1H, m), 5.03 (2H, s), 3.90 (2H, m); MS (ES-), 367 (M-1).
Reaction SMILES: [CH:1]1[C:18]2[C:19]3[C:4]([C:5]4[CH:6]=[CH:7][CH:8]=[C:9]5[C:24]=4[C:13]([C:14]=3[C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[CH:17]=2)=[C:12]2[CH:25]=[CH:26][CH:27]=[CH:28][C:11]2=[CH:10]5)=[CH:3][CH:2]=1.[Br:29]Br>C(Cl)(Cl)(Cl)Cl>[Br:29][C:10]1[C:9]2[C:24]3[C:13]([C:14]4[C:15]5[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=5[CH:17]=[C:18]5[C:19]=4[C:4]([C:5]=3[CH:6]=[CH:7][CH:8]=2)=[CH:3][CH:2]=[CH:1]5)=[C:12]2[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=12
Reactant: BrBr
Reactant: c1ccc2c(c1)cc1cccc3c4cccc5cc6ccccc6c(c54)c2c13
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c2c3c1cccc3c1cccc3cc4ccccc4c2c31

Procedure:
After dibenzo[a,o]perylene dissolved in carbon tetrachloride was brominated with cooling for four hours by adding one molar equivalent of bromine, the reaction product was refined in accordance with an ordinary method to obtain 7-bromodibenzo[a,o]perylene. Di-p-tolylamine, potassium carbonate and copper powder were added to the thus obtained 7-bromodibenzo[a,o]perylene and were allowed to react for 30 hours at 200° C. After the reaction solution was diluted with water, the reaction product was extracted with chloroform. Thereafter, it was refined in accordance with an ordinary method to obtain a target compound expressed in Formula 32.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11]Cl)=[C:6]([CH3:13])[C:5](=[O:14])[N:4]([CH3:15])[C:3]1=[O:16].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CCC)CCC)CC>COCCOCCOC>[CH3:1][N:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][N:31]2[CH2:32][CH2:33][N:28]([C:20]3[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=3[O:18][CH3:17])[CH2:29][CH2:30]2)=[C:6]([CH3:13])[C:5](=[O:14])[N:4]([CH3:15])[C:3]1=[O:16]
Reactant: Cc1c(NCCCCl)n(C)c(=O)n(C)c1=O
Reactant: COc1cc([N+](=O)[O-])ccc1N1CCNCC1
Agent: CCCN(CCC)CCC
Solvent: COCCOCCOC
Product: COc1cc([N+](=O)[O-])ccc1N1CCN(CCCNc2c(C)c(=O)n(C)c(=O)n2C)CC1
Yield: 79 %

Procedure:
Analogously to Example 13, 1,3,5-trimethyl-6-(3-chloropropylamino)-2,4(1H,3H)-pyrimidinedione (130 mmol) is refluxed for 14 h with 1-(2-methoxy-4-nitrophenyl)piperazine (100 mmol) and tripropylamine (75 ml) in 300 ml of diglyme. After removing the solvent in vacuo, the mixture is worked up in the customary manner, and after purification by column chromatography, the title compound is obtained in 79% yield (m.p. 131-133° C.).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1CCCCC1=O>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CN1CCCCC1=O
Product: O=[N+]([O-])c1cc(F)ccc1NC1CCN(Cc2ccccc2)CC1
Yield: 86.9 %

Procedure:
2,5-Difluoro-nitrobenzene (21.5 g), 1-benzyl-4-amino-piperidine (52.3 g) and N-methyl-piperidone (100 ml) were stirred at 100° C. for 3 h. After cooling the mixture was partitioned between water and ethyl acetate and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were extracted 5 times with water, and the solvent was evaporated in vacuo. The target compound was crystallized from methanol to yield 38.7 g of the title compound as orange crystals (mp. 86-87° C.).
Reaction SMILES: [NH2:1][OH:2].[OH-].[Na+].[C:5](#[N:14])[C:6]1[CH:13]=[CH:12][CH:11]=[C:8]([C:9]#[N:10])[CH:7]=1>C(O)C>[C:9]([C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[C:5](=[N:1][OH:2])[NH2:14])#[N:10]
Reactant: NO
Reactant: N#Cc1cccc(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cccc(C(N)=NO)c1
Temperature: 25 °C

Procedure:
Hydroxylamine (Aldrich, 7.65 g, 100 mmol) in ethanol (100 mL) was treated with 10 N sodium hydroxide (10 mL, 100 mmol). To this solution, isophthalonitrile (Aldrich, 12.8 g, 100 mmol) in 100 mL ethanol was added. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed under vacuum and the residue was purified with flash column chromatography (5% methanol/dichloromethane) to provide the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 5.98 (bs, 2H), 7.59 (t, J=7.4 Hz, 1H), 8.06-8.0 (m, 2H), 9.89 (s, 1H) ppm; MS (DCI/NH3) m/z 162 (M+H)+.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.[C:13](Cl)(=[O:16])[CH2:14][CH3:15]>C(N(CC)CC)C>[C:1]1([CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[O:7][C:13](=[O:16])[CH2:14][CH3:15]
Reactant: Cc1ccccc1O
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(=O)Oc1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
At 0° C., to a mixture of o-cresol 10 g and chloroform 100 ml was added propionyl chloride 10 g and triethylamine 28 g. The resulting mixture was raised to room temperature and was stirred for two hours. Then the reaction mixture was extracted with chloroform and the organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give propionic acid o-tolyl ester 14 g.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH2:8][CH2:9][O:10][C:11]([CH2:13][NH:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[NH2:26])[C:19]([O:21][CH3:22])=[O:20])=[O:12])=[O:7])=[CH:4][CH:3]=1.[N:29]1([C:34]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[O:35])[CH2:33][CH:32]=[CH:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH2:8][CH2:9][O:10][C:11]([CH2:13][NH:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[NH:26][CH2:40][C:39]2[CH:38]=[CH:37][C:36]([C:34]([N:29]3[CH2:33][CH:32]=[CH:31][CH2:30]3)=[O:35])=[CH:43][CH:42]=2)[C:19]([O:21][CH3:22])=[O:20])=[O:12])=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C(=O)N2CC=CC2)cc1
Reactant: COC(=O)c1ccc(N)c(CNCC(=O)OCCC(=O)c2ccc(Cl)cc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(NCc2ccc(C(=O)N3CC=CC3)cc2)c(CNCC(=O)OCCC(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
660 mg (1.63 mmol) of methyl 3-[((4-chlorobenzoyl)ethoxycarbonylmethylamino)methyl]-4-aminobenzoate and 431 mg (2.1 mmol) of 4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzaldehyde were dissolved in 10 ml of dichloromethane. 0.185 ml (3.26 mmol) of acetic acid was added to the solution, and they were stirred at room temperature for 30 minutes. 860 mg (4.1 mmol) of sodium triacetoxyborohydride was added to the obtained mixture, and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]1([CH:30]2[CH:39]3[CH:34]([CH2:35][CH2:36][CH2:37][NH:38]3)[CH2:33][CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:38]2[CH:39]3[CH:34]([CH2:33][CH2:32][CH2:31][CH:30]3[N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:35][CH2:36][CH2:37]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CNC2C(C1)CCCC2N1CCCC1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCCC2CCCC(N3CCCC3)C21
Temperature: 25 °C
Reaction time: 4 h
Yield: 113.6 %

Procedure:
A solution of 873 mg of 3,4-dichlorophenyl-acetic acid and 690 mg of carbonyldiimidazole in tetrahydrofuran was stirred for 1 hour at 20° to 25° C. and then 645 mg of the product of Step C in solution in 3 ml of tetrahydrofuran was added. After stirring for 4 hours at ambient temperature, the tetrahydrofuran was eliminated under reduced pressure at less than 40° C. and the residue was taken up in 20 ml of ether. The solution was washed with a saturated solution of sodium bicarbonate, then with water saturated with sodium chloride and the etheral phase was dried and distilled to dryness under reduced pressure to obtain 1.39 g of the crude product.
Reaction SMILES: C(Cl)(Cl)Cl.[NH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[F:29])[C:23](Cl)=[O:24].C([O-])(O)=O.[Na+]>CCN(CC)CC>[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[F:29])[C:23]([NH:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1)=[O:24]
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(F)c(Cl)c2)CC1
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
To a CHCl3 (350 mL) solution of tert-butyl 4-aminopiperidine-1-carboxylate (35.0 g), Et3N (122 mL) and 3-chloro-4-fluorobenzoyl chloride (37.1 g) were added under ice cooling and the mixture was stirred at the same temperature for 1.5 hours. To the reaction mixture, a saturated aqueous NaHCO3 solution was added and the solution was extracted three times with CHCl3. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to obtain tert-butyl 4-[(3-chloro-4-fluorobenzoyl)amino]piperidine-1-carboxylate (62.0 g). To an EtOAc (300 mL) suspension of the compound obtained, a 4 M HCl/EtOAc solution (300 mL) was added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and 1 M aqueous NaOH solution (300 mL) was added to the residue and the solution was extracted three times with CHCl3. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was suspended in EtOAc/hexane (200 mL, 1/1; v/v) and the mixture was stirred for one hour. The precipitate was filtrated to obtain 3-chloro-4-fluoro-N-piperidin-4-ylbenzamide (37.7 g, a colorless solid).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN1C(=O)N(C)CCC1.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[CH2:47]I>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:47][C:46]2[CH:49]=[CH:50][C:51]([O:52][CH3:53])=[C:44]([O:43][CH3:42])[CH:45]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1ccc(CI)cc1OC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)cc1OC

Procedure:
In analogy with Example 44c), 1 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one [Example 2b)] in 4 ml of abs. THF is deprotonated (-75° C.) with 6.42 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, with the addition of 0.66 ml of DMPU, and alkylated with 911 mg of 3,4-dimethoxybenzyl iodide. Chromatography on silica gel (eluents D, C and J) gives the pure title compound. TLC Rf (C)=0.42. MS M+ =455.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([CH:6]=[C:7]2[C:16]3[N:15]=[C:14]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][N:13]4[C:12](=[O:24])[C:11]=3[CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].N1C=CC=CC=1>CN(C)C=O>[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]2[C:16]3[N:15]=[C:14]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][N:13]4[C:12](=[O:24])[C:11]=3[CH2:10][CH2:9][CH2:8]2)=[CH:25][CH:26]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C=C2CCCc3c2nc2ccc(C(=O)O)cn2c3=O)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C=C2CCCc3c2nc2ccc(C(=O)O)cn2c3=O)cc1

Procedure:
4-(4-amino-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid (1 g) in dimethylformamide (40 ml) was reacted with acetic anhydride (4 ml) in the presence of pyridine (8 ml) at 60° C. for 7 hours. After cooling and dilution with ice water, the precipitate was filtered and washed with water: crystallization from dimethylformamide-ethanol gave 0.7 g of 4-(4-acetylamino-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH:8]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=O>C(Cl)Cl>[C:2]([S@@:5](/[N:7]=[CH:8]/[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]1)=[O:6])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CC(C)(C)[S@@](N)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(/C=N/[S@@](=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
To a round bottomed flask charged with a magnetic stir bar was added (S)-2-methylpropane-2-sulfinamide (20.46 g, 169 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (30 g, 141 mmol), DCM (300 mL), and Ti(OEt)4 (59.0 ml, 281 mmol). The solution was stirred at room temperature for 3 h before it was quenched with brine (80 mL). The solution was stirred for 30 minutes before filtering. The filter cake was washed with DCM and the filtrate was placed in a separatory funnel and washed with water. The organics layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue solidified to the title compound (29 g, 92 mmol, 65.1% yield) m/z 217.
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[C:10]([CH3:12])([CH3:11])[O:9][C:8](=[O:13])[N:7]([CH2:14][CH3:15])[C:6]=2[CH:16]=1.[F:18][C:19]([F:33])([F:32])[O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][C:22]=1B(O)O.C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:14]([N:7]1[C:6]2[CH:16]=[C:2]([C:26]3[CH:25]=[C:24]([CH:23]=[CH:22][C:21]=3[O:20][C:19]([F:18])([F:32])[F:33])[CH:27]=[O:28])[C:3]([CH3:17])=[CH:4][C:5]=2[C:10]([CH3:12])([CH3:11])[O:9][C:8]1=[O:13])[CH3:15]
Reactant: CCN1C(=O)OC(C)(C)c2cc(C)c(Br)cc21
Reactant: O=Cc1ccc(OC(F)(F)F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN1C(=O)OC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OC(F)(F)F)cc21
Temperature: 80 °C
Yield: 51.4 %

Procedure:
A round bottom flask was charged with 0.5 g (1.67 mmol) of Compound 14D, 0.58 g (2,5 mmol) of 2-trifluoromethoxy-5-formylphenylboronic acid and 0.083 g of tetrakis(triphenylphosphine)palladium(0). The flask was sealed with a septa and 8.5 mL of toluene and 2.5 mL of ethanol was added. The resulting solution was stirred to dissolve the reactants and then 1.7 mL of 2M K2CO3 was added via syringe. The reaction mixture was heated to 80° C. for 4 hours. After cooling, the reaction mixture was partitioned between ethyl acatate (20 mL) and water (8 mL). The water layer was further extracted (2×10 mL) and the combined organic layers were washed with water (10 mL) followed by brine (10 mL), dried over magnesium sulfate, filtered and excess solvent removed on the rotary evaporator. The crude product was purified by flash chromatography (EtOAc/Hexanes; gradient 20% to 40%) to give 0.35 g (52%) of 3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-7-yl)-4-trifluoromethoxy-benzaldehyde as yellow solid. MS (electrospray): mass calculated for C21H20F3NO4, 407.13; m/z found 408 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.S(Br)([Br:27])=O.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][Br:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCN(Cc1ccccc1)Cc1ccccc1
Reactant: O=S(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: BrCCN(Cc1ccccc1)Cc1ccccc1
Reaction time: 15 h
Yield: 55 %

Procedure:
To N,N-dibenzyl-2-aminoethanol (18.47 g) was added hexane (150 ml) and DMF (0.3 ml), and thereto was added dropwise thionyl bromide (15.91 g) at 0° C. The mixture was stirred for 15 hours, and to the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution in an ice-bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (×2) and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane) to give the title compound (12.80 g).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:23]=[CH:22][O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:8]1)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+].CCOC(C)=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[N:24]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:23]=[CH:22][O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:8]1)=[N+:25]=[N-:26]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(-c3ccon3)cc2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(-c3ccon3)cc2)C(=O)O1
Temperature: 60 °C

Procedure:
[(5R)-3-(4-Isoxazol-3-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl methanesulfonate (Intermediate 7,400 mg, 1.18 mmol), sodium azide (99 mg, 1.53 mmol), 18 crown-6 (23.6 mg, 0.089 mmol) and tetrabutylammonium iodide (28.2 mg, 0.076 mmol) were combined in DMF (5 ml) and heated to 60° C. for 4 hours. EtOAc (20 ml) was added and the organic layers were washed with brine (3×20 ml), dried over Na2SO4 and concentrated under vacuum to yield (5R)-5-(azidomethyl)-3-(4-isoxazol-3-ylphenyl)-1,3-oxazolidin-2-one. (5R)-5-(Azidomethyl)-3-(4-isoxazol-3-ylphenyl)-1,3-oxazolidin-2-one (300 mg, 1.045 mmol) was added to CH2Cl2:MeOH:THF:H2O 10:10:10:2 and then polystyrene triphenylphosphine resin (2650 mg, 4.18 mmol) was added. The reaction was allowed to stir overnight and then the resin was filtered and washed multiple times with dichloromethane and methanol. The filtrate was concentrated in vacuo and then dissolved in dichloromethane (10 ml) followed by addition of 2N HCl in ether (0.5 ml). The precipitate was collected and washed with ether (2×20 ml) and then dried under vacuum to yield the title product (300 mg).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]=O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[O:12]1[CH2:15][CH:14]([NH2:16])[CH2:13]1>>[Cl:11][C:6]1[C:7]2[CH:8]=[CH:9][N:16]([CH:14]3[CH2:15][O:12][CH2:13]3)[C:2]=2[N:3]=[CH:4][N:5]=1
Reactant: NC1COC1
Reactant: O=CCc1c(Cl)ncnc1Cl
Product: Clc1ncnc2c1ccn2C1COC1

Procedure:
The title compound was prepared according to the method described for Preparation 1 using (4,6-dichloropyrimidin-5-yl)acetaldehyde (Preparation 208) and oxetan-3-amine to afford the title compound as a yellow solid in 67% yield, 2.81 g.