Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[N:9]=[CH:10][NH:11][C:12]=1[CH3:13].[H-].[Na+].[C:16]([NH:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1)(OCC)=[O:17].C(O)C>N1C=CC=CC=1>[CH3:13][C:12]1[NH:11][CH:10]=[N:9][C:8]=1[CH2:7][S:6][CH2:5][CH2:4][NH:3][C:16]([NH:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1)=[O:17]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CCOC(=O)Nc1nc(C)cs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1csc(NC(=O)NCCSCc2nc[nH]c2C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
To 3.40 g (13.9 mmole) of 4-[(2-aminoethyl)thiomethyl]-5-methylimidazole dihydrochloride stirred under flowing nitrogen in 100 ml of dry pyridine is added 1.27 g (ca. 27.9 mmole) of a 50 percent dispersion in oil of sodium hydride. After approximately 90 min. 24.3 g (13.1 mmole) of 2-carbethoxyamino-4-methylthiazole is added, and the resultant mixture is heated at reflux for 1 day. After cooling to room temperature, the mixture is filtered to remove insolubles, and the filtrate is concentrated at reduced pressure. The resultant gum is repeatedly dissolved in aqueous ethanol and dried in vacuo, triturated with pentane to remove mineral oil, and purified by column chromotography* on silica gel. Fractions containing the product are combined, partially concentrated, filtered and finally dried by concentration in vacuo, giving 2.40 g (7.2 mmole) of the desired product as an ethanol solvate. Structure assignment and solvation by one-half mole of ethanol per mole of product are supported by nmr.
Reaction SMILES: C([C@:3]([O:8]S(C(F)(F)F)(=O)=O)([CH3:7])[C:4]([OH:6])=[O:5])C.[H-].[Na+].O[CH:19]1[CH:24]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])=[CH:27][CH:26]=2)[CH2:23][CH2:22][N:21]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:20]1.O1CC[CH2:54][CH2:53]1>>[CH2:53]([O:6][C:4]([C@@H:3]([O:8][CH:23]1[CH:24]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])=[CH:27][CH:26]=2)[CH2:19][CH2:20][N:21]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[CH2:22]1)[CH3:7])=[O:5])[CH3:54]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: CC[C@@](C)(OS(=O)(=O)C(F)(F)F)C(=O)O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)[C@H](C)OC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.32 ml of ethyl 2(R)-trifluoromethanesulphonyloxypropionic acid and 0.075 g of sodium hydride dispersion (55%) are added at −45° C. to the solution of 0.733 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 5 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature over 5 hours and subsequently poured onto water. The mixture is extracted with ethyl acetate (2×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.26 (1:3 EtOAc-heptane); Rt=6.01.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23].[Cl-].[Al+3].[Cl-].[Cl-].COC1C=C(C(C2C=CC(OC)=CC=2)=CC#N)C=CC=1OC>>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([C:6]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=2)=[O:7])[CH:19]=[CH:18][C:17]=1[O:22][CH3:23]
Reactant: COc1ccccc1OC
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Agent: COc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2)c1
Yield: 71.9 %

Procedure:
3,5-Dimethoxybenzoyl chloride (10.28 g, 51.24 mmol), 1,2-dimethoxybenzene (6.53 ml, 51.24 mmol), and aluminum chloride (7.52 g, 56.37 mmol) were treated in the same manner as described above for the synthesis of 3-(3,4-dimethoxy-phenyl)-3-(4-methoxy-phenyl)-acrylonitrile. The crude was purified via flash column chromatography (10% EtOAc in hexane gradient to 50% EtOAc in hexane in 50 min.) to give (3,4-dimethoxy-phenyl)-(3,5-dimethoxy-phenyl)-methanone as a light yellow solid (11.14 g, 72%); 1HNMR (DMSO-d6) δ 7.38-7.33 (m, 2H, Ar), 7.09 (d, J=8 Hz, 1H, Ar), 6.77 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.79 (s, 6H, 2OCH3). The product was carried over to the next step.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].N[C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12]>COCCO>[F:18][C:16]1[CH:17]=[C:9]2[C:10]([C:11]([OH:12])=[N:6][CH:5]=[N:7]2)=[CH:14][CH:15]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: N=CN
Solvent: COCCO
Solvent: CC(=O)O
Product: Oc1ncnc2cc(F)ccc12
Reaction time: 1 h
Yield: 65.2 %

Procedure:
Formamidine acetate (20.13 g, 193.4 mmol) was added to a solution of 2-amino-4-fluorobenzoic acid (15 g, 96.7 mmol) in 2-methoxyethanol (97 ml) and the mixture heated to reflux for 18 hours. The reaction was cooled, concentrated and the residue stirred in aqueous ammonium hydroxide (0.01 M, 250 ml) for 1 hour. The suspension was filtered, washed with water and dried over phosphorus pentoxide to yield 7-fluoroquinazolin-4-ol as an off-white solid (10.35 g, 65% yield):
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH2:18])=[CH:15][CH:14]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:10][C:7]1[CH:8]=[CH:9][C:2](/[CH:18]=[CH:17]/[C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: C=Cc1ccc(OC)cc1
Reactant: O=Cc1cc(F)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(/C=C/c2ccc(F)cc2C=O)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
A solution of 10 g (49.26 mmol) of 2-bromo-5-fluorobenzaldehyde in 200 ml of dry DMF is mixed with 7.27 g (54.18 mmol) of 4-methoxystyrene, 1.5 g (4.93 mmol) of tri-2-tolylphosphine, 330 mg (1.48 mmol) of palladium(II) acetate and 10.3 ml (73.89 mmol) of triethylamine under argon and stirred at 100° C. for 12 hours. After reaction is complete, the reaction solution is cooled to room temperature and concentrated to dryness. The resulting residue is taken up in 100 ml of water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases are dried over sodium sulfate. After filtration, the solution is concentrated to dryness, and the residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 7.79 g (55% yield) of a colorless solid are obtained.
Reaction SMILES: C([Cu])#N.[C:4]([Mg]Cl)([CH3:7])([CH3:6])[CH3:5].Br[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:15][CH:16]=1>C1COCC1>[C:4]([C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:15][CH:16]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cn1
Reactant: CC(C)(C)[Mg]Cl
Agent: N#C[Cu]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C(C)(C)C)cn1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 21 %

Procedure:
To a mixture of anhydrous CuCN (2.7 g, 30.4 mmol) in 100 mL of THF was added a solution of tert-butylmagnesium chloride (30.4 mL, 60.2 mmol, 2M solution in THF) under N2 at −78° C. After 20 minutes, tert-butyl 5-bromopyridin-2-ylcarbamate (2.1 g, 7.6 mmol, Aldrich) was added. The reaction mixture was stirred for 2 hours at −78° C. and then at room temperature for 12 hours. The mixture was quenched with saturated aqueous NH4OH and basified to pH 7 with 20% aqueous NaOH. The solid was filtered through a pad of Celite. The filtrate was extracted with ether and washed with water. The organic extract was dried over MgSO4 and concentrated. Purification by column chromatography (SiO2: 0-15% hexanes/ethyl acetate gradient) afforded 0.4 g of the title compound. MS (ESI+) m/z 251 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:8]=1)[NH2:5].C([Sn](CCCC)(CCCC)[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>C1(C)C=CC=CC=1.O1CCOCC1.CCOC(C)=O.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>[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:8]=1)[NH2:5]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: Nc1cc(Br)cc(-c2ncccn2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Nc1cc(-c2ncccn2)cc(-c2ncccn2)c1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
The mixture of 3-bromo-5-(pyrimidin-2-yl)aniline (140 mg, 0.56 mmol),), 2-tributylstannylpyrimidine (420 mg, 1.12 mmol), Pd(Ph3P)4 (65 mg, 0.056 mmol) in 20 mL toluene and 5 mL dioxane was degassed with argon stream and stirred at 110° C. in argon atmosphere for two days. It was cooled to RT, diluted with EtOAc, filtered through celite, concentrated in vacuo, and subjected to silica flash column to isolate 3,5-di(pyrimidin-2-yl)aniline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([NH:8][C:9](=[O:20])[CH:10]([NH2:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:5]([CH3:7])[CH3:6].O.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25].CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:21])[CH:4]([NH:8][C:9](=[O:20])[CH:10]([NH:19][C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25])[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:5]([CH3:6])[CH3:7]
Reactant: COC(=O)C(NC(=O)C(N)CCc1ccccc1)C(C)C
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C(NC(=O)C(CCc1ccccc1)NC(=O)Oc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a mixture of the crude compound obtained in step b above (1400 mg) in dioxane (18 mL) and water (2 mL) was added phenyl chloroformate (0.9 mL, 7.16 mmol) and DIEA (1.6 mL, 8.95 mmol). The mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc, the combined organic phases were dried and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as a white solid (1165 mg, 79% yield, three steps).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[CH2:18]([NH2:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[H][H]>C(O)C.[Pd]>[CH2:12]([O:11][C:9](=[O:10])[C:8]([O:7][C:6]1[CH:16]=[CH:17][C:3]([CH2:1][NH:25][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:4][CH:5]=1)([CH3:15])[CH3:14])[CH3:13]
Reactant: [H][H]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1
Reactant: CCCCCCCN
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCNCc1ccc(OC(C)(C)C(=O)OCC)cc1
Yield: 92.6 %

Procedure:
The product from step (a) (4.72 g) was dissolved in absolute ethanol (140 ml) and n-heptylamine (2.3 g, Aldrich) added. The resulting solution was refluxed for one hour, 10% Pd/C added and the suspension placed on a Paar hydrogenation apparatus--uptake of hydrogen ceased after approximately ten minutes. The suspension was filtered and the filtrate evaporated in vacuo to give the desired product as a clear oil (6.2 g).
Reaction SMILES: C1([C:7]([CH3:12])([OH:11])[C:8]([OH:10])=O)C=CC=CC=1.[N+]([O-])(O)=O.Cl.C(O[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=1C)(=O)C(C)O.[CH2:34]([NH2:37])[CH2:35][NH2:36]>S(=O)(=O)(O)O.CO>[N+:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:12][CH:7]([OH:11])[C:8]([NH:36][CH2:35][CH2:34][NH2:37])=[O:10])=[CH:29][CH:28]=1)([O-:32])=[O:31]
Reactant: Cc1cc([N+](=O)[O-])ccc1OC(=O)C(C)O
Reactant: CC(O)(C(=O)O)c1ccccc1
Reactant: NCCN
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Solvent: CO
Product: NCCNC(=O)C(O)Cc1ccc([N+](=O)[O-])cc1

Procedure:
Phenyl-lactic acid (available from Aldrich Chemical Co., Milwaukee, Wis.) is nitrated with nitric acid in sulfuric acid. P-nitrophenyl lactic acid is esterified with methanol and gaseous hydrochloric acid. Methyl-p-nitrophenyl lactate is condensed with ethylene diamine to provide the amide adduct, 3-(4-nitrophenyl)-2-hydroxy-N-(2-aminoethyl)propionamide.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:6][N:7]([C@H:26]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:28]2[CH:37]=[C:38]([C:42]([F:45])([F:44])[F:43])[C:39]([CH3:41])=[CH:40][C:27]1=2)[C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[N:12]=1.O.NN>CO>[NH2:15][CH2:14][CH2:13][N:11]1[N:10]=[N:9][C:8]([N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:53])[F:54])[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=2)[C@H:26]2[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:28]3[CH:37]=[C:38]([C:42]([F:44])([F:45])[F:43])[C:39]([CH3:41])=[CH:40][C:27]2=3)=[N:12]1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CC1CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(CC1CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCN)n1

Procedure:
Heat the mixture of (S)-2-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopropylmethyl-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino]-tetrazol-2-yl}-ethyl)-isoindole-1,3-dione (0.140 g, 0.183 mmol) and hydrazine hydrate (0.114 mL, 3.66 mmol) in methanol (2 mL) at 60° C. overnight. Evaporate the solvents.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:9]=[C:10]([NH2:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:19])[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:2]2[C:3]3[N:4]([N:9]=[C:10]([NH2:12])[N:11]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH:23]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCc1cccc(B(O)O)c1
Reactant: Cc1cc(Br)c2nc(N)nn2c1
Product: Cc1cc(-c2cccc(CNC(=O)OC(C)(C)C)c2)c2nc(N)nn2c1

Procedure:
Prepared in analogy to example 160b, starting from 8-bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine and 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid. The title compound was obtained as an off-white solid (yield: 99%) after precipitation from diethyl ether. MS ISP (m/e): 354.4 (80) [(M+H)+], 298.4 (100), 237.2 (99).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:15]([NH:25][C:12]([C@@H:9]1[CH2:10][CH2:11][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Reactant: CCCCCCCCCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)[C@@H]1CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
N-(tert-Butoxycarbonyl)-(S)-(−)-2-azetidinecarboxylic acid (1) (90 mg; 0.447 mmol) is dissolved in methylene chloride (3 mL) at ambient temperature. n-Decylamine (72 mg; 0.470 mmol), N,N-diisopropylethylamine (116 mg; 0.895 mmol) and PyBOP (244 mg; 0.470 mmol) are added sequentially. The reaction is stirred for 4 days at room temperature, then concentrated under reduced pressure. The crude product is purified via silica gel chromatography using a gradient elution (10%→60% ethyl acetate in hexanes) affording the desired product (285). ISMS: MH+ 341.4
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=O)=O)=CC=1.[CH:24]([NH2:27])([CH3:26])[CH3:25].O.C(Cl)(Cl)Cl>O1CCOCC1>[CH3:25][CH:24]([NH:27][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)[CH3:26]
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(C)N
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)NCCCc1ccc([N+](=O)[O-])cc1

Procedure:
3-(4-nitrophenyl)propyl p-toluenesulfonate (1 g) and 5 ml of isopropylamine were dissolved in 15 ml of dioxane, and the solution was stirred under heating with reflux for 4 hours. To the solution were added 100 ml of water and 100 ml of chloroform, and the mixture was thoroughly mixed for extraction. The chloroform-layer fraction was taken, washed with water and dried over sodium sulfate anhydrous. The solvent was removed in vacuo, and thus 0.61 g of an oil of N-(1-methylethyl)-3-(4-nitrophenyl)propylamine was obtained.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[Cl:21][C:22]1[N:27]=[CH:26][C:25]([NH:28][C:29](=O)[O:30]C2C=CC([N+]([O-])=O)=CC=2)=[CH:24][CH:23]=1.CS(C)=O>C1(C)C=CC=CC=1>[Cl:21][C:22]1[N:27]=[CH:26][C:25]([NH:28][C:29]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:30])=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc(Cl)nc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)nc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1

Procedure:
A solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (50 mg, 180 μmol, example 87, Step 3) and 4-nitrophenyl 6-chloropyridin-3-yl-carbamate (119 mg, 406 μmol) in toluene (1.0 mL) was subjected to a microwave irradiation at 180° C. for 30 min. Then, DMSO (1.0 mL) was added and the solution mixture was filtered. The filtrate was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound, which was dissolved in MeOH (1.0 mL). Then, the solution was washed through PL-HCO3 MP-Resin (200 mg per 6 mL tube) and the resin was washed with MeOH (2×0.3 mL). The combined washings were concentrated and dried under vacuum to give the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 432 (M+H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:34])=[C:5]([C:21]([O:23][CH2:24]/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:34])=[C:5]([C:21]([O:23][CH2:24]/[CH:25]=[CH:26]/[C:27]2[CH:28]=[CH:29][C:30]([O:33][C:35](=[O:37])[CH3:36])=[CH:31][CH:32]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(O)cc2)C1c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(OC(C)=O)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
0.5 Gram of methyl 3-(4-hydroxyphenyl)-2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate was dissolved in 5 ml of pyridine, then to this solution was added 0.5 ml of acetic anhydride under an ice-cooling condition. The reaction mixture was allowed to stand overnight, then poured into an ice-water, and extracted with ether. The ether layer was washed with a diluted hydrochloric acid, 10%-sodium bicarbonate aqueous solution and water in this order, then dried with anhydrous sodium sulfate. The ether extract was concentrate, and the residue thus obtained was purified by means of a silica gel column chromatography (eluent: methanol:chloroform=1:100) to yield 0.4 g of methyl 3(4-acetyloxyphenyl)-2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate in the form of light yellow indefinite form crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:21])=O.[OH:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH2:27]>CN(C=O)C.CC(O)C>[ClH:21].[CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:27][C:26]1[CH:28]=[CH:29][C:30]([CH3:31])=[C:24]([OH:23])[CH:25]=1
Reactant: Cc1ccc(N)cc1O
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nc[nH]c(=O)c2c([N+](=O)[O-])c1OC
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(C)c(O)c3)c2c([N+](=O)[O-])c1OC
Product: Cl
Yield: 81 %

Procedure:
A mixture of 6,7-dimethoxy-5-nitro-3,4-dihydroquinazolin-4-one (1.75 g, 7.0 mmol) and thionyl chloride (25 ml) and DMF (3 drops) was heated at reflux for 2 hours. Excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene. 3-Hydroxy-4-methylaniline (0.94 g, 7.6 mmol) in 2-propanol (40 ml) was added to the residue and the mixture heated at reflux for 2 hours. The mixture was allowed to cool, the precipitate collected by filtration, washed with 2-propanol and dried to give 6,7-dimethoxy-4-(3-hydroxy-4-methylanilino)-5-nitroquinazoline hydrochloride (2.02 g, 81%).
Reaction SMILES: [C:1]([C:9]1[CH:20]=[C:19]([Cl:21])[C:12]2[O:13][CH:14]([C:16]([OH:18])=[O:17])[CH2:15][C:11]=2[C:10]=1[Cl:22])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25].Cl>N1C=CC=CC=1>[Cl:22][CH:10]1[C:11]2[C:12]([O:13][CH:14]([C:16]([OH:18])=[O:17])[CH:15]=2)=[C:19]([Cl:21])[CH:20]=[C:9]1[C:1](=[N:24][OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)c2c(c1Cl)CC(C(=O)O)O2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)C1C=C2C(=C(Cl)C=C(C(=NO)c3ccccc3)C2Cl)O1
Reaction time: 18 h
Yield: 99.6 %

Procedure:
A mixture of 5-benzoyl-4,7-dichloro-2,3-dihydrobenzo[b]furan-2-carboxylic acid (2.5 g), hydroxylamine hydrochloride (5.2 g) and pyridine (50 ml) was stirred for 18 hours at 90°-100° C. After cooling, the mixture was rendered acidic with HCl and subjected to extraction with ether. Ether was distilled off and the residual water was removed by azeotropic distillation with benzene, yielding 2.6 g of 4,7-dichloro-2,4-dihydro-5-(α-hydroxyiminobenzyl)benzo[b]furan-2-carboxylic acid. This compound (2.6 g) was dissolved in 20 ml of anhydrous dimethylformamide, and to the ice-cooled solution, 0.9 g of 60% sodium hydride was added in small portions under stirring. After continuing the agitation for 7 hours at room temperature, the mixture was left to stand overnight. After addition of water, the mixture was rendered acidic with HCl and subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized with acetonitrile-benzene, yielding 0.9 g of 5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. The physical data of this compound were in agreement with those of the product obtained in Example 3.