Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].I[CH2:11][CH2:12][CH3:13].[K+].[Br-].[Br:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1>C(#N)C>[Br-:16].[CH2:11]([C:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]([CH3:17])[C:27]=1[N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[NH:5][CH:4]=1)[CH2:12][CH3:13]
Reactant: Clc1nc[nH]c1Cl
Reactant: CCCI
Reactant: BrCc1ccc2ccccc2c1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCc1c(-[n+]2c[nH]c(Cl)c2Cl)c(C)cc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) was dissolved into 27 mL of acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) was added and the mixture was allowed to stir for 0.5 h. 1-iodopropane (0.88 mL, 9 mmol) was added and the solution was allowed to reflux overnight. The solution was filtered hot to remove a white precipitate (presumed to be KBr) and 2-bromomethylnaphthalene (1.98 g, 9 mmol) was added and the mixture was returned to reflux overnight. The mixture was then allowed to cool to room temperature, resulting in a yellow precipitate (1.125, 31% yield). 1H NMR (500 MHz, DMSO-d6) 9.58 (1H, s, NCHN), 8.02 (4H, m, Ar), 7.57 (3H, m, Ar), 5.66 (2H, s, NCH2), 4.21 (2H, t, NCH2), 1.85 (2H, tq, CH2), 0.94 (3H, t, CH3). 13C{1H} NMR (125 MHz, DMSO-d6) 136.4 (NCN), 132.8 (Ar), 132.6 (Ar), 130.0 (Ar), 128.8 (Ar), 127.8 (Ar), 127.7 (Ar), 127.6 (Ar), 126.9 (Ar), 126.8 (Ar), 125.5 (Ar), 119.1 (Ar), 118.8 (Ar), 51.6 (CH2), 50.0 (CH2), 21.7 (CH2), 10.3 (CH3). MS: m/z=318.8 (theor for C17H17Cl2N2Br1=399.13).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].ClC(Cl)(Cl)S(O[CH2:18][C:19]([F:22])([F:21])[F:20])(=O)=O>C1(C)C=CC=C(C)C=1>[F:20][C:19]([F:22])([F:21])[CH2:18][NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9]
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: COC(=O)c1ccccc1N
Solvent: Cc1cccc(C)c1
Product: COC(=O)c1ccccc1NCC(F)(F)F

Procedure:
A solution of methyl anthranilate (98.3 g) and trifluoroethyl trichloromethanesulphonate (91.5 g) in m-xylene (200 ml) was heated at reflux for 3 h under nitrogen. The reaction mixture was allowed to cool overnight, then filtered from a white solid, washing well with diethyl ether. The combined filtrates were evaporated in vacuo and the residual oil purified by flash chromatography (silica gel, 10% diethyl ether/hexane) to give methyl 2-[N-(2,2,2-trifluoroethyl)]aminobenzoate, contaminated with trifluoroethyl trichloromethanesulphonate. To a solution of this mixture (35.8 g) in dichloromethane (150 ml), cooled to 1° C. under nitrogen, was added dropwise bromoacetyl bromide (10.1 ml), keeping the temperature below +3° C. The reaction mixture was stirred at 0°±3° C. for 12 min, then 4N NaOH solution (33.4 ml) was added dropwise over 18 min. The cooling bath was removed and the reaction mixture was stirred at room temperature for 4 h. More bromoacetyl bromide (1.6 ml) was added dropwise and the mixture was stirred for a further 6 h. After leaving to stand overnight, the organic layer was separated, washed with 10% citric add (30 ml), brine (30 ml), saturated potassium carbonate solution (30 ml) and brine (30 ml), dried (Na2SO4) and evaporated in vacuo to leave a yellow oil. This was purified by flash chromatography (silica gel, 20-25% EtOAc/petroleum ether) to afford the title compound (27.4 g). 1H NMR (CDCl3) δ3.58 (1H, d, J=11.4 Hz), 3.64 (1H, d, J=11.3 Hz), 3.83 (1H, m), 3.90 (3H, s), 4.79 (1H, m), 7.49 (1H, d, J=7.8 Hz), 7.57 (1H, t of d, J=7.6 and 1.3 Hz), 7.68 (1H, t of d, J=7.6 and 1.7 Hz), 8.09 (1H, dd, J=7.8 and 1.6 Hz). MS (CI+, NH3) m/e 373/371 (M+NH4)+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]=[O:22])=[CH:15][CH:14]=1
Reactant: COc1ccc(CCCO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(CCC=O)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 50.8 %

Procedure:
A solution of dimethyl sulfoxide (5.1 mL) in dichloromethane (10 ml) was added to a stirred solution of oxalyl chloride (3.0 mL, 36 mmol) in dichloromethane (40 ml) at −78° C. over 30 min. Upon completion of the addition, the mixture was stirred at −78° C. for 5 min, followed by addition of a solution of 4-methoxybenzenepropanol (3.0 g, 18 mmol) in dichloromethane (20 ml) at −78° C. over 30 min. The resulting mixture was stirred at −78° C. for 40 min. Next, triethylamine (15 mL, 110 mmol) was added dropwise over 10 min. The resulting mixture was allowed to warm to 0° C. and stirred at this temperature for 1 hour. It was diluted with dichloromethane (30 mL) and quenched with water (15 mL). The organic extracts were separated, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in hexanes (gradient: 3 min: 0/100 to 23 min: 20/80) to afford the desired product (1.50 g, 51%).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].CN(C)C=O.Cl[C:18]([F:23])([F:22])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[F:22][CH:18]([F:23])[O:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc(C)c1OC(F)F
Temperature: 120 °C
Reaction time: 4.5 h
Yield: 94.9 %

Procedure:
To a mixture of 4-hydroxy-3,5-dimethylbenzaldehyde (2.00 g), N,N-dimethylformamide (54.0 mL) and water (6.00 mL), sodium chlorodifluoroacetate (6.09 g) and potassium carbonate (3.68 g) were added and the mixture was stirred at 120° C. for 4.5 hours. After cooling the reaction mixture to room temperature, water was added to it and two extractions were conducted with ethyl acetate. The combined organic layers were washed with water four times and thereafter washed with saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was removed by filtration and the filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=97:3-88:12) to give the titled compound as a colorless solid (2.53 g).
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[CH2:3][C:2]1=[O:7].[C:8]([NH:13][C:14]([NH2:16])=[O:15])([CH2:11][CH3:12])([CH3:10])[CH3:9].O>C1C=CC=CC=1>[C:8]([NH:13][C:14]([NH:16][C:4]1[CH2:5][O:1][C:2](=[O:7])[CH:3]=1)=[O:15])([CH2:11][CH3:12])([CH3:10])[CH3:9]
Reactant: O=C1COC(=O)C1
Reactant: CCC(C)(C)NC(N)=O
Solvent: O
Solvent: c1ccccc1
Product: CCC(C)(C)NC(=O)NC1=CC(=O)OC1
Yield: 39.3 %

Procedure:
To a solution of 3 g of 2,4-furandione in 100 ml of benzene is added 4 g of tert-amylurea. The solution is heated under nitrogen at reflux for three hours with water removal. At the end of that period the solution is cooled and concentrated. The residual material is recrystallized from acetonitrile to give 2.5 g of 1-tert-amyl-3-(2,5-dihydro-5-oxo-3-furyl)urea, m.p. 169°-171° C. The infrared and n.m.r. spectra are consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[S:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C([C:28]1[C:29]([N:35]=[CH:36][N:37]([CH3:39])C)=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1)#N.NC1C=C(C=CC=1SC1C=CC(O)=CC=1)C(NC1C=CC(Br)=CC=1)=O>>[CH2:8]([NH:7][C:5](=[O:6])[C:4]1[CH:15]=[CH:16][C:17]([S:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[C:2]([NH:1][C:39]2[C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[N:30][C:29]=3[N:35]=[CH:36][N:37]=2)[CH:3]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccc1Sc1ccc(O)cc1
Agent: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(C(=O)NCc4ccccc4)ccc3Sc3ccc(O)cc3)ncnc2n1
Yield: 54 %

Procedure:
The product of Example 35A was reacted with the product of Example 9B using the procedure of Example 22C substituting the product of Example 35A for the product of Example 22B and substituting the product of Example 9B for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (50 mg, 54%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.67 (s, 3 H) 4.45 (d, J=5.88 Hz, 2 H) 6.78-6.96 (m, 1 H) 6.83 (d, J=8.46 Hz, 2 H) 7.15-7.40 (m, 7 H) 7.55 (d, J=7.35 Hz, 1 H) 7.73 (d, J=5.88 Hz, 1 H) 7.90 (s, 1 H) 8.56 (s, 1 H) 8.80 (d, J=8.09 Hz, 1 H) 9.01 (s, 1 H) 9.94 (s, 1 H) 10.14 (s, 1 H); MS (ESI+) m/z 494(M+H)+, (ESI−) m/z 492 (M−H)−.
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.[I-].[Na+].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH2:27]Cl)[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>ClCCl.CO.C(OCC)C>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH2:27][NH2:2])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1cc(OCc2ccccc2)ccn1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: NCc1cc(OCc2ccccc2)ccn1

Procedure:
1.5 g (10.78 mmol) of hexamethylenetetramine and then 1.3 g of sodium iodide are added to 2.1 g (8.99 mmol) of 4-(benzyloxy)-2-(chloromethyl)pyridine (described in stage A) in 60 ml of dichloromethane. The reaction medium is heated at reflux for 12 hours and then concentrated under reduced pressure. The residue obtained is taken up in 45 ml of methanol. 7.5 ml (89.90 mmol) of a 12N hydrochloric acid solution are added. The reaction medium is heated at reflux for 16 hours. After addition of ethyl ether, the precipitate obtained is filtered off and then taken up in a saturated aqueous sodium carbonate solution. The aqueous phase is extracted with ethyl acetate, dried over sodium sulfate and then concentrated under reduced pressure. 1.1 g of a beige oil are collected. Mass spectrometry (ES+Mode): MH+=215
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]3[NH:21][N:22]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[C:23](=O)[CH:24]=3)=[C:9]2[CH3:32])=[O:7])=[CH:4][CH:3]=1.[C:35](=[O:38])([O-])[O-].[K+].[K+].[CH3:41]I>CC(C)=O>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]3[C:24]([CH3:41])([CH3:23])[C:35](=[O:38])[N:22]([CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)[N:21]=3)=[C:9]2[CH3:32])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2c(c1)c(Cc1cc(=O)n(C3CCCCC3)[nH]1)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CI
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2c(c1)c(CC1=NN(C3CCCCC3)C(=O)C1(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Pyrazolone from Example 9 (300 mg, 0.62 mmol) was dissolved in dry acetone (5 mL) to which was added anhydrous potassium carbonate (100 mg, 0.7 mmol) and CH3I (500 mg, 3 mmol). The reaction was stirred at room temperature for 5 hours under nitrogen. The reaction was filtered and solvent removed under reduce pressure. The residue was chromatographed on silica gel. The title compound elutes with 25% EtOAc/hexane. 1H-NMR (CDCl3) δ=7.67 (d, 2H, J=8.49 Hz), δ=7.49 (d, 2H, J=8.43 Hz), δ=6.93 (d, 1H, J=2.37 Hz), δ=6.84 (d, 1H, J=5.61 Hz), δ=6.69 (dd, 1H, J=2.43, 8.91 Hz), δ=4.05 (m, 1H), δ=3.81 (s, 3H), δ=3.78 (s, 2H), δ=2.40 (s, 3H), δ=1.9 (d, 6 H), δ=1.83-1.45 (m, 10H); 13C-NMR (CDCl3) δ=171.77, 168.65, 156.89, 156.34, 135.77, 133.56, 131.73, 130.63, 129.52, 115.38, 114.09, 112.07, 101.24, 56.05, 52.56, 40.81, 31.44, 27.40, 25.93, 25.74, 13.62; LRMS (FAB) 506.4 (M+H+); Rf 0.6 (EtOAc/hexanes 1:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:6]=[C:5]2[C:15]([OH:17])=[O:16].[F:18][C:19]([F:30])([F:29])[C:20]([O:22]C(=O)C(F)(F)F)=[O:21].C(O)(C(F)(F)F)=O.[N:38]12[CH2:45][CH2:44][C:41](O)([CH2:42][CH2:43]1)[CH2:40][CH2:39]2>C1(C)C=CC=CC=1>[F:18][C:19]([F:30])([F:29])[C:20]([OH:22])=[O:21].[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:6]=[C:5]2[C:15]([O:17][C:41]12[CH2:44][CH2:45][N:38]([CH2:43][CH2:42]1)[CH2:39][CH2:40]2)=[O:16]
Reactant: OC12CCN(CC1)CC2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)n1cc(C(=O)O)c2cc(F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CS(=O)(=O)n1cc(C(=O)OC23CCN(CC2)CC3)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a vial containing 5-fluoro-1-(methylsulfonyl)-1H-indole-3-carboxylic acid (20 mg, 0.078 mmol; see Reference 10 for the synthesis) and trifluoroacetic anhydride (10.98 μl, 0.078 mmol) in toluene (259 μl) was added TFA (64.8 μl). After 30 min, quinuclidin-4-ol (8.24 mg, 0.065 mmol) was added and the mixture was stirred at RT overnight. Direct HPLC purification (after dilution with DMF and filtration) gave the title compound as a clear film. MS (ESI, pos. ion) m/z: 367.2 (M+1).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:76][CH:77]5[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]5)=[O:28])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 47.4 %

Procedure:
To a mixture of 0.040 g (0.0899 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-benzoic acid (I-194) and 6 mL of dimethylformamide was added 0.0182 g (0.135 mmole) of 1-hydroxybenzotriazole, 0.0520 g (0.135 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.060 g (0.463 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0153 g (0.134 mmole) of 4-amino-1-methylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0231 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-N-(1-methyl-piperidin-4-yl)-benzamide (I-195) as a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][S:7][CH2:6][CH2:5]1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>O1CCOCC1>[S:7]1[CH2:8][CH2:9][CH:4]([O:3][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:5][CH2:6]1
Reactant: OC1CCSCC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccccc1OC1CCSCC1
Temperature: 90 °C
Yield: 83.7 %

Procedure:
To 50 ml of a dioxane suspension containing 0.96 g of 60% sodium hydride was added 3.6 g of 4-hydroxytetrahydrothiopyran at room temperature, and the mixture was stirred on heating at 90° C. with stirring for 6 hours. The temperature of the mixture was returned to room temperature, then 10 ml of a dioxane solution of 4.5 g of 2-fluoronitrobenzene was added dropwise, and the mixture was stirred overnight. The reaction solution was poured into ice water and extracted with ethyl ether, and the ethyl ether layer was washed, in turn, with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated, and 1.1 g of the resulting oil was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=10:1 ) to give 6.1 g of 2-(tetrahydro-4H-thiopyran-4-yloxy)nitrobenzene as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:46][C@@H:47]1[CH2:51][NH:50][C@H:49]([C:52]#[N:53])[CH2:48]1.CN1CCOCC1>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([N:50]3[CH2:51][C@@H:47]([F:46])[CH2:48][C@H:49]3[C:52]#[N:53])=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)[C@H](C(=O)N1C[C@@H](F)C[C@H]1C#N)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 15.5 %

Procedure:
(R)-2-(6-Chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol)), HATU (15 mg, 0.039 mmol), (2S,4S)-4-fluoropyrrolidine-2-carbonitrile (4 mg, 0.032 mmol), and N-methylmorpholine (90 μL, 0.097 mmol) were combined in THF (0.5 mL). The reaction mixture was stirred under nitrogen at 40° C. for 10 min and then at room temperature for 30 min. The solution was concentrated and purified by preparative HPLC (10-50% AcCN/H2O with 0.035% TFA) to afford the title compound as a white solid (2 mg, 12%). 1H NMR (500 MHz, CD3OD) δ 0.94 (d, J=6.3 Hz, 3H), 1.05 (d, J=6.3 Hz, 3H), 1.03-1.15 (m, 1H), 2.56-2.65 (m, 3H), 23.89-3.91 (m, 1H), 4.25-4.30 (m, 1H), 4.83-4.87 (m, 1H), 5.09-5.13 (m, 1H), 5.39-5.41 (m, 1H), 5.47-5.66 (m, 1H), 7.87 (s, 1H), 8.27 (s, 1H). [M+H] calc'd for C19H19ClFN5O2, 404; found, 404.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([Cl:12])[N:3]=1.[CH2:13]([CH:15]([NH2:18])[CH2:16][CH3:17])[CH3:14]>C1COCC1>[Cl:12][C:4]1[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:18][CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CCC(N)CC
Solvent: C1CCOC1
Product: CCC(CC)Nc1nc(C)nc(Cl)c1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 4 h
Yield: 35.9 %

Procedure:
A mixture of 2-methyl-5-nitro-4,6-dichloro-pyrimidine (208 mg, 1.00 mmol) and 1-ethyl-propyl-amine (87 mg, 1.03 mmol) in 2 ml of dry THF was stirred at −78° C. for 4 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give a green oil. The oil was purified through silica gel column chromatography using chloroform to 1:1 hexane/chloroform as eluent to give the title compound (93 mg, 35%). 1H NMR (CDCl3) δ 7.50 (brs, 1H), 4.29 (m, 1H), 2.51 (s, 3H), 1.4–1.8 (m, 4H), 0.92 (t, 6H) ppm.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[CH:23]=[CH:22][C:13]([CH2:14][C:15]2[C:20](O)=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:12]([F:24])[CH:11]=1.C(OCC)(=O)C>CN(C)C=O>[Br:9][C:10]1[CH:23]=[CH:22][C:13]([CH2:14][C:15]2[C:20]([O:4][CH3:1])=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:12]([F:24])[CH:11]=1
Reactant: Oc1cccnc1Cc1ccc(Br)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1cccnc1Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
Potassium carbonate (38.7 mg, 0.280 mmol) and methyl iodide (10.5 μl, 0.168 mmol) were added to a solution of the compound of Example B245 (15.8 mg, 0.0560 mmol) in dimethylformamide (1 ml), and this reaction mixture was stirred at room temperature for 2 hours. After ethyl acetate was added, the reaction mixture was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (14.0 mg).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=C([F:35])C=2)=CSC=1C(OC)=O.C([O:47][CH2:48]C)(OCC)OCC.COC1C=CC(N)=CC=1>C(O)(=O)C>[F:35][C:21]1[CH:22]=[C:17]([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C:1]4[CH:6]=[CH:5][C:4]([O:47][CH3:48])=[CH:3][CH:2]=4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2cccc(F)c2)c1N
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: COc1ccc(N)cc1
Product: COc1ccc(-n2cnc3c(-c4cccc(F)c4)csc3c2=O)cc1
Yield: 39 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(3-fluorophenyl)thiophene-2-carboxylate (56.2 mg, 0.22 mmol), triethyl orthoformate (0.42 ml), p-anisidine (50.5 mg, 0.41 mmol), and acetic acid (0.05 ml) were used to give 30.3 mg (0.086 mmol, 39% yield) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[CH:11][C:12]([OH:14])=O)([O-:3])=[O:2].C(N(CC)CC)C.ClC(OCC)=O.[CH2:28]([NH2:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[CH2:28]([NH:36][C:12](=[O:14])[CH:11]=[CH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCN
Reactant: O=C(O)C=Cc1ccccc1[N+](=O)[O-]
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCNC(=O)C=Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 9.7 g. of 3-(2-nitrophenyl)propenoic acid, 5.6 g. of triethylamine and 240 ml. of dichloromethane was stirred at room temperature for 20 minutes, and then it was cooled in an ice-bath. To the mixture was then added, dropwise, during 15 minutes, a solution of 6.0 g. of ethyl chloroformate in 20 ml. of dichloromethane. After 15 minutes of stirring, a solution of 7.1 g. of octylamine in 20 ml. of dichloromethane was added dropwise, during 10 minutes. The reaction mixture was allowed to warm to room temperature, and then it was washed successively with 1 N potassium carbonate, 1 N hydrochloric acid, water and saturated sodium chloride. The resulting solution was dried and evaporated in vacuo, leaving 14.5 g. (95%) yield of the title compound as a tan solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][O:28][CH2:29][C:30](O)=[O:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][O:28][CH3:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: COCC(=O)O
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (84 mg, 84%), MS (ISP) m/z=401.5 [(M+H)+], mp 156° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and methoxy-acetic acid.