Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[CH3:15][O-:16].[Na+]>C1COCC1>[CH3:15][O:16][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)cnc2c1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cnc2cc([N+](=O)[O-])ccc2n1
Yield: 68.3 %

Procedure:
Into 10 ml of THF was dissolved 1.16 g of 2-chloro-6-nitroquinoxaline, and then 1.0 g of sodium methoxide was added thereto, followed by heating under refluxing for 30 minutes. Then, the solvent was removed by evaporation. Water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline. After the solvent was removed by evaporation, the residue was crystallized from diethyl ether-hexane to obtain 776 mg of the title compound.
Reaction SMILES: [CH:1]([N:3]1[C:15]2[C:14]([O:16][CH3:17])=[CH:13][CH:12]=[C:11]([S:18](Cl)(=[O:20])=[O:19])[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([N:3]1[C:15]2[C:14]([O:16][CH3:17])=[CH:13][CH:12]=[C:11]([S:18]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:2]
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)c2c3ccccc3n(C=O)c12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(NS(=O)(=O)c2ccc(OC)c3c2c2ccccc2n3C=O)cc1
Yield: 65 %

Procedure:
Intermediate 63 (0.2 g, 0.62 mM) was dissolved in 40 ml of chloroform. To it was added p-anisidine (0.21 g, 1.66 mM), 0.19 g triethylamine and the reaction was refluxed for 18 hrs. Solvent was evaporated and the residue was extracted in ethyl acetate. The organic layer was washed with 10% HCl solution, brine and then dried over anhydrous Na2SO4. It was then evaporated to obtain the crude residue which was then purified over silica gel column using ethylacetate-hexane system to obtain the desired compound as beige solid with a yield of 65% (0.16 g); mp 190-192° C.
Reaction SMILES: [C:1]1([CH:7]([C:10]#[C:11][Si](C)(C)C)[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C#C>C(O)C.O.[N+]([O-])([O-])=O.[Ag+]>[C:1]1([CH:7]([C:10]#[CH:11])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)C#CC(CO)c1ccccc1
Agent: [Ag+]
Agent: C#C
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Solvent: O
Product: C#CC(CO)c1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
2-Phenyl-4-trimethylsilyl-but-3-yn-1-ol (Chem. Ber. (1988), 121, 1315-1320) (7.8 g) was dissolved in ethanol and the solution was cooled to -5° C. A solution of silver nitrate (8.9 g) in ethanol (60 ml) and water (21 ml) was added dropwise to the acetylene solution such that the temperature remained below 5° C. This precipitated the acetylene as the silver complex. A solution of potassium cyanide (17 g) in water (30 ml) was added dropwise to the stirred acetylene mixture and the resulting mixture was stirred at room temperature for 30 minutes. The mixture mainly dissolved and was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4) and evaporated. The residue was purified on silica using 10% ethyl acetate in hexane as eluant to afford the title compound (5 g) as a colourless oil.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([OH:20])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH:28]1[CH2:36][CH2:35][CH2:34][C@H:29]1[C:30]([O:32][CH3:33])=[O:31].Cl>C(Cl)Cl>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([N:28]1[CH2:36][CH2:35][CH2:34][C@H:29]1[C:30]([O:32][CH3:33])=[O:31])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Boc-Lys(Z)-OH (1 equivalent), Pro-OMe hydrochloride (1 equivalent) and TEA (1 equivalent) were dissolved in dry methylene chloride, and WSCD (1 equivalent) was added under cooling with ice. Thereafter, the mixture was stirred at room temperature for 20 hours, and the reaction mixture was washed successively with IN HCl, water, saturated aqueous sodium bicarbonate, water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under vacuum. The resulting crude product was purified by medium-pressure liquid column chromatography on silica gel to obtain the end compound. Boc-Lys(Z)-Pro-OMe (1 equivalent) thus obtained was dissolved in dry methylene chloride, and an excess of trifluoroacetic acid was added. The mixture was stirred (for about 6 hours), and the solvent was distilled off under vacuum to obtain the end compound (oil).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[CH:17]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccc(C2CCCN(CCCc3ccccc3)C2)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1cccc(C2CCCN(CCCc3ccccc3)C2)c1
Temperature: 120 °C
Yield: 27.6 %

Procedure:
To a stirred solution of 15.2 g (0.049 mole) of 1-(3-phenylpropyl)-3-(3-methoxyphenyl)piperidine from Preparation 1 in 75 ml of glacial acetic acid was added 150 g of 48% aqueous hydrobromic acid. The reaction mixture was heated at 120° C. for 2.5 hours and then it was poured onto ice. The resulting mixture was basified with sodium carbonate and then it was extracted with ethyl acetate. The extracts were washed with water, followed by sodium chloride solution, and then they were dried and evaporated to give 17.2 g of crude product as a tan solid. Purification by recrystallization from a mixture of ethyl acetate/hexane/triethylamine (5:5:0.5) gave 4.0 g (28%) of the title compound, m.p. 119°-120° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12]O)=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:34]I.N1C=CN=C1>C(Cl)Cl>[Cl:1][C:2]1[C:11]([CH2:12][I:34])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccc2cc(CO)c(Cl)nc12
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc2cc(CI)c(Cl)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a solution of (2-chloro-8-methylquinolin-3-yl)methanol (2.0 g, 10 mmol) in DCM (200 mL) were added triphenylphosphine (2.6 g, 10 mmol), iodine (2.6 g, 10 mmol) and imidazole (0.7 g, 10 mmol) and the reaction mixture was stirred for 2 h at r.t. The mixture was washed with water (50 mL) and the organic layer was separated, dried and concentrated in vacuo. Purification by column chromatography (SiO2, 50% Et2O in heptane) gave the title compound as a brown solid (2.2 g, 72%). δH (CDCl3) 8.17 (s, 1H), 7.62 (d, J 9 Hz, 1H), 7.55 (d, J 9 Hz, 1H), 7.45 (t, J 9 Hz, 1H), 4.68 (s, 2H), 2.75 (s, 3H). LCMS (ES+) 318.0, 320.0 (M+H)+, RT 4.53 minutes (Method 3).
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH:5]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:6][CH2:7][CH2:8][N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[S:10]([CH3:13])(=[O:12])=[O:11].C(O)(=O)C>CCOCC>[OH:4][CH:5]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:6][CH2:7][CH2:8][N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:3])=[O:21])[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: C=[N+]=[N-]
Reactant: CS(=O)(=O)N(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)CCCCCCN(CCCC(O)COc1ccc(F)cc1)S(C)(=O)=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approximately 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 7-{N-[4-hydroxy-5-(4-fluorophenoxy)pentyl]methanesulfonamido }heptanoic acid (12.3 g., 0.03 mole) (Example 1, Step E) in ether (50 ml.). The resulting solution is allowed to stand at room temperature for 4 hours. Acetic acid is then added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 7-{N-[4-hydroxy-5(4-fluorophenoxy)pentyl]methanesulfonamido }heptanoate as a viscous oil.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([C:37]#[N:38])[CH:3]=1.[CH:39]1(B(O)O)[CH2:41][CH2:40]1>>[C:37]([C:4]1[CH:3]=[C:2]([CH:39]2[CH2:41][CH2:40]2)[C:10]2[O:9][C:8]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([C:25]5[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=5)[CH2:23][CH2:24]4)=[O:16])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=1)#[N:38]
Reactant: N#Cc1cc(Br)c2oc(-c3ccc(C(=O)NCC4CCN(c5ccc(C(F)(F)F)cn5)CC4)cc3)nc2c1
Reactant: OB(O)C1CC1
Product: N#Cc1cc(C2CC2)c2oc(-c3ccc(C(=O)NCC4CCN(c5ccc(C(F)(F)F)cn5)CC4)cc3)nc2c1

Procedure:
The title compound was prepared from 4-(7-bromo-5-cyano-1,3-benzoxazol-2-yl)-N-({1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}methyl)benzamide (EXAMPLE 114, Step B) and cyclopropylboronic acid by a procedure analogous to that described in EXAMPLE 117. Mass spectrum (ESI) 546.3 (M+1). 1H NMR (500 MHz, CDCl3) δ: 8.38 (s, 1H), 8.33 (d, J=8.3 Hz, 2H), 7.95 (d, J=8.1 Hz, 2H), 7.86 (s, 1H), 7.60 (br d, J=8.9 Hz, 1H), 7.23 (s, 1H), 6.65 (d, J=8.9 Hz, 1H), 6.38 (br s, 1H), 4.46 (d, J=13.1 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 2.93 (t, J=12.1 Hz, 2H), 2.33 (m, 1H), 2.00 (m, 1H), 1.90 (d, J=12.3 Hz, 2H), 1.33 (m, 2H), 1.22 (m, 2H), 1.06 (m, 2H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][CH:35]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2nc(Sc3ccc(C(F)(F)F)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(C(F)(F)F)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.57 g of 4,5-bis(4-methoxyphenyl)-2-(4-trifluoromethylphenylthio)imidazole in 100 ml of dichloromethane. The mixture is agitated for 3 hours at room temperature, the solution is washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus producing 4.26 g of 4,5-bis(4-methoxyphenyl)-2-(4-trifluoromethylphenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]#[N:12].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:11]#[N:12]
Reactant: COc1ccc(F)c(C(C#N)=Cc2ccccc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(F)c(C(C#N)Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a suspension of 2-(2-fluoro-5-methoxy-phenyl)-3-phenyl-acrylonitrile (5.8 g, 22.90 mmol) in ethanol was added sodium borohydride (1.083 g, 28.6 mmol) and stirred at room temperature over night. The mixture was poured on ice-water and after addition of 5% citric acid extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to obtain an orange oil m=5.68 g (97%).
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[NH2:13][C:14]1[C:19]([C:20](OCC)=[O:21])=[C:18]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[C:17]([C:32]([O:34][CH3:35])=[O:33])=[C:16]([CH3:36])[N:15]=1>O1CCCC1>[NH2:13][C:14]1[C:19]([CH2:20][OH:21])=[C:18]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[C:17]([C:32]([O:34][CH3:35])=[O:33])=[C:16]([CH3:36])[N:15]=1
Reactant: CCOC(=O)c1c(N)nc(C)c(C(=O)OC)c1-c1ccc(C)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1c(C)nc(N)c(CO)c1-c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
An ice cold solution of Red-Al (65% in toluene) (3.55 ml, 11.63 mmol) in tetrahydrofuran (THF) (3.3 ml) was treated dropwise with a solution of 3-ethyl 5-methyl 2-amino-6-methyl-4-(p-tolyl)pyridine-3,5-dicarboxylate (1.91 g, 5.82 mmol) in tetrahydrofuran (THF) (23 ml). After stirring for 1 hour at 0° C., the reaction was quenched with water slowly, then diluted with EtOAc (10 mL) and 20% aq. NaOH (2 mL). The mixture was stirred for 20 min at rt, filtered, extracted with EtOAc, washed with brine, dried with Na2SO4, filtered, and concentrated to afford crude methyl 6-amino-5-(hydroxymethyl)-2-methyl-4-(p-tolyl)nicotinate (1.4679 g, 5.13 mmol, 88% yield) as brown solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.19 (d, J=7.8 Hz, 2 H), 7.03 (d, J=8.0 Hz, 2 H), 5.25 (s, 2 H), 4.42 (s, 2 H), 3.43 (s, 3 H), 2.42 (s, 3 H), 2.38 (s, 3 H); LCMS (m/z) ES+=287 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15].CCN(C(C)C)C(C)C>Cl[Pd]Cl.CN(C)C=O>[OH:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:15]=[CH:14]/[C:13]([O:17][CH2:18][CH3:19])=[O:16])=[C:3]([C:9]([F:12])([F:11])[F:10])[CH:4]=1
Reactant: Oc1ccc(Br)c(C(F)(F)F)c1
Reactant: C=CC(=O)OCC
Agent: Cl[Pd]Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1ccc(O)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-3-(trifluoromethyl)phenol (5 g, 20.75 mmol, 1.00 equiv), N,N-dimethylformamide (60 mL), ethyl prop-2-enoate (10.5 g, 104.88 mmol, 5.06 equiv), PdCl2 (370 mg, 2.09 mmol, 0.10 equiv), P(tolyl)3 (1.28 g, 4.21 mmol, 0.20 equiv), DIEA (16.25 g). The resulting solution was stirred for overnight at 90° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/8). This resulted in 2.6 g (42%) of ethyl (2E)-3-[4-hydroxy-2-(trifluoromethyl)phenyl]prop-2-enoate as a light yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6](F)[CH:5]=1.C(N(C(C)C)CC)(C)C.[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27]>CN(C=O)C>[CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([NH:28][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]=1
Reactant: CCCCN
Reactant: CNC(=O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCNc1cc(C(=O)NC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-methyl-3-fluoro-4-nitrobenzamide (300 mg, 1.64 mmol) and diisopropylethylamine (0.43 mL, 2.46 mmol) in DMF (7 mL) was added butylamine (0.203 mL, 2.05 mmol) and the solution was stirred at room temperature overnight. The solution was concentrated, the residue dissolved in ethyl acetate and washed with 1 N HCl. The organic phase was dried over MgSO4 and concentrated to give N-methyl-3-butylamino-4-nitrobenzamide as a yellow oil that was used without further purification (380 mg, 92%).
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6]C=C[CH:3]=1.[O:8]=[C:9]1[NH:17][CH:16]=[N:15][C:14]2[N:13]([CH2:18][CH2:19][C:20](OCC)=[O:21])[CH:12]=[N:11][C:10]1=2>C(#N)C>[O:8]=[C:9]1[NH:17][CH:16]=[N:15][C:14]2[N:13]([CH2:18][CH2:19][C:20]([NH:7][CH2:1][CH:2]([OH:6])[CH3:3])=[O:21])[CH:12]=[N:11][C:10]1=2
Reactant: NCc1ccco1
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CC#N
Product: CC(O)CNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 25 °C
Yield: 60.5 %

Procedure:
0.500 g (5.15 mmol) of furfurylamine and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) were heated at 120° C. for two hours with stirring. The solution was allowed to cool to room temperature and 10 ml acetonitrile was added and the solution was stirred. The precipitate was collected by filtration and the white solid was washed with acetonitrile and then with ether. Upon drying, 170 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-(2-hydroxypropyl)propanamide (AIT-0060) as a white solid was obtained.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[NH2:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>O1CCCC1>[N:48]1([CH2:47][CH2:46][O:45][C:19]2[CH:18]=[CH:17][C:16]([NH2:15])=[C:21]([N+:22]([O-:24])=[O:23])[CH:20]=2)[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: Nc1cc(O)ccc1[N+](=O)[O-]
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ccc(OCCN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diisopropyl azodicarboxylate (1.1 equivalents) was added dropwise to a stirred solution of 3-amino-4-nitrophenol (1.0 equivalent), triphenylphosphine (1.1 equivalents), and an alcohol, e.g. N-(2-hydroxyethyl)morpholine (1.0 equivalent), in tetrahydrofuran at 0° C. The mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was evaporated, and the product was purified by silica gel chromatography (98:2 CH2Cl2:methanol) to yield 4-(2-morpholin-4-ylethoxy)-2-nitrophenylamine as a dark reddish-brown oil. LC/MS m/z 268.0 (MH+), Rt 1.01 minutes. The nitroamine was reduced as in Method 1 to give the crude product which was used without further purification. LC/MS m/z 238.3 (MH+), Rt 0.295 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:7](=O)[NH:8][CH:9]=1)([O-:3])=[O:2].P(Br)(Br)([Br:17])=O.P(Br)(Br)Br.BrBr>>[Br:17][C:7]1[C:6]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: O=c1[nH]cc([N+](=O)[O-])cc1C(F)(F)F
Reactant: O=P(Br)(Br)Br
Agent: BrBr
Agent: BrP(Br)Br
Product: O=[N+]([O-])c1cnc(Br)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 88 %

Procedure:
A mixture of 5-nitro-3-(trifluoromethyl)pyridin-2(1H)-one 3, POBr3 (1.5 equivalents), PBr3 (4 equivalents), and Br2 (2 equivalents) is heated to about 90-110° C. and is then poured into ice water. The mixture is neutralized and extracted. The combined organic phases are dried over Na2SO4 and all solvents removed under reduced pressure to obtain 2-bromo-5-nitro-3-(trifluoromethyl)pyridine 21 in a yield of 88%.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([OH:25])[CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[I-].[Na+]>COCCOC>[OH:25][C:20]1[CH:19]=[C:18]([NH:17][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[C:6]([O:26][CH3:27])[CH:7]=3)[N:12]=[CH:11][C:10]=2[C:15]#[N:16])[CH:23]=[CH:22][C:21]=1[CH3:24]
Reactant: COc1cc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc2cc1OCCCl
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc2cc1OCCN1CCOCC1

Procedure:
A mixture of 1 g (2.38 mmol) of 7-(2-chloro-ethoxy)-4-(3-hydroxy-4-methyl-phenylamino)-6-methoxy-quinoline-3-carbonitrile, 3.4 g (39 mmol) of morpholine, and 0.08 g of sodium iodide in 22 ml ethylene glycol dimethyl ether refluxed for 34 hr. The solvent was removed and the residue was mixed with warm ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. Solvent was removed and the residue was chromatographed on silica gel eluting with ethyl acetate-methanol-triethylamine 70:30:2.5 giving 1.05 of the title compound as a light orange solid: mass spectrum (electrospray, m/e) M+H 435.0; (M+2H)+2 218.0.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:8]=2[C:7](=[O:17])[N:6]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:5][CH2:4]1)[CH3:2].C(O)C>[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]2[C:7](=[O:17])[N:6]([CH2:18][C:19]([N:21]([CH3:22])[CH3:23])=[O:20])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=2[CH:10]=1
Reactant: CCN1CCN(CC(=O)N(C)C)C(=O)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CCN1CCN(CC(=O)N(C)C)C(=O)c2ccc(N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
Into a Round bottom flask, 2-(1-ethyl-8-nitro-5-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-N,N-dimethyl-acetamide (0.27 g, 0.00084 mol;), Ethanol (20.0 mL, 0.342 mol;) and 10% Pd/C (10:90, Palladium:carbon black, 0.100 g) were added the reaction was evacuated and charged with hydrogen (3 times). The mixture was stirred at room temperature overnight under an atmosphere of Hydrogen via a balloon. The solid was filtered through Celite and washed with EtOH. The solvent was removed under vacuum to give 2-(8-amino-1-ethyl-5-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-N,N-dimethyl-acetamide as a white solid (0.24 g, 98%). LC/MS (ESI+) 291.19 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:9]1)=O)(C)(C)C.[ClH:26].O1CCOCC1>C(OCC)(=O)C>[ClH:26].[CH2:19]([O:18][C:16]([NH:15][CH2:14][CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(NCC1CCCNC1)OCc1ccccc1
Reaction time: 1.33 h
Yield: 84 %

Procedure:
A solution of 3-(benzyloxycarbonylaminomethyl)-piperidine-1-carboxylic acid tert-butyl ester (594 mg, 1.7 mmol) in ethyl acetate (10 mL) was stirred on an ice bath and treated with a solution of hydrogen chloride in dioxane (4.0 N, 10 mL, 40 mmol). The mixture was stirred for 80 minutes, then was concentrated under vacuum. The gummy residue was triturated repeatedly in ether to provide a white powder (408 mg, 84%)which was extremely hygroscopic and was used without further purification. 1H NMR (300 MHz, CD3OD) δ7.34 (m, 5H), 5.07 (s, 2H), 3.34 (m, 2H), 3.09 (m, 2H), 2.88 (m, 1H), 2.66 (m, 1H), 1.90 (m, 3H), 1.70 (m, 1H), 1.30 (m, 1H).