Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])=[O:9].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:31](I)[CH3:32]>CC(C)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH2:31][CH3:32])=[O:14])=[O:9]
Reactant: O=C(C=Cc1cccs1)Nc1ccccc1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOC(=O)c1ccccc1NC(=O)C=Cc1cccs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
To a suspension of 2-[3-(2-thienyl)acrylamido]benzoic acid (273 mg, 1 mmol) in acetone (2 ml) were added potassium carbonate (194 mg, 1.4 mmol) and dry dimethylformamide (1 ml). To the resulting solution, ethyl iodide (218 mg, 1.4 mmol) and dry dimethylformamide (2 ml) were added and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was poured into ice water. The precipitated solid was collected by suction, and recrystallized from methanol to give pale yellow crystals of the desired compound (197 mg, yield, 65%). m.p., 120°-122° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[CH2:5][N:6]=[C:7]=[O:8].[N+:15](=[C:17]1[N:21]=[CH:20][N:19]=[C:18]1[C:22]([NH2:24])=[O:23])=[N-:16]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[CH2:5][N:6]1[C:7](=[O:8])[N:21]2[CH:20]=[N:19][C:18]([C:22]([NH2:24])=[O:23])=[C:17]2[N:15]=[N:16]1
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: COc1ccc(CN=C=O)c(OC)c1
Solvent: CS(C)=O
Product: COc1ccc(Cn2nnc3c(C(N)=O)ncn3c2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-dimethoxybenzyl isocyanate (0.717 g, 4.4 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.548 g, 4 mmol) in dry dimethylsulfoxide (5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product (purple) removed by filtration, washed with water and ethyl acetate and recrystallised from chloroform/hexane to give the title compound. Yield: 0.613 g, 46%. IR vmax/cm−1 3473, 3121, 1734, 1697, 1605, 1589. 1H NMR δH (DMSO-d6) 3.76 (3H, s, OMe), 3.80 (3H, s, OMe), 5.37 (2H, s, CH2Ar), 6.48 (1H, dd, J=8.4, 2.4, ArH), 6.60 (1H, d, J=2.4, ArH), 7.22 (1H, d, J=8.4, ArH), 7.68 (1H, br s, NH), 7.80 (1H, br s, NH), 8.81 (1H, s, 6-H). δC (DMSO-d6) 47.5, 55.8, 56.1, 98.9, 105.1, 115.9, 129.3, 130.7, 131.2, 134.8, 139.4, 158.5, 161.1, 162.0.
Reaction SMILES: C[O:2][C:3](=[O:40])[C@@H:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][C:34]([Br:37])=[C:33]([O:38][CH3:39])[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1>[Br:37][C:34]1[CH:35]=[CH:36][C:29]2[O:28][C:27]([C:25]([NH:24][C:21]3[CH:20]=[CH:19][C:18]([C:15]4[CH:14]=[CH:13][C:12]([S:9]([NH:8][C@@H:4]([CH:5]([CH3:6])[CH3:7])[C:3]([OH:40])=[O:2])(=[O:10])=[O:11])=[CH:17][CH:16]=4)=[CH:23][CH:22]=3)=[O:26])=[C:31]([CH3:32])[C:30]=2[C:33]=1[O:38][CH3:39]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4ccc(Br)c(OC)c4c3C)cc2)cc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(Br)ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 144 h
Yield: 45.5 %

Procedure:
To 18 mg of (S)-2-{4′-[(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester was added 0.5 mL of THF and 0.5 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature for 6 days. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried under vacuum to give 8 mg (39% yield) of (S)-2-{4′-[(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.9, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.7 (s, 3 H) 3.6 (dd, J=9.0, 5.9 Hz, 1 H) 3.9 (s, 3 H) 7.5 (d, J=8.8 Hz, 1 H) 7.7 (d, J=8.8 Hz, 1 H) 7.8 (d, J=8.6 Hz, 2 H) 7.9 (m, 4 H) 8.0 (d, J=8.8 Hz, 2 H) 8.1 (d, J=9.1 Hz, 1 H) 10.6 (s, 1 H) 12.6 (s, 1 H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([Cl:18])=[C:7]([CH:14]=[C:15]([Br:17])[CH:16]=1)[C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])C=C.BrC1C(OC)=C(OC)C(Cl)=C(C=1)[C:25](O)=[O:26]>>[Br:17][C:15]1[C:16]([O:26][CH3:25])=[C:5]([O:4][CH3:1])[C:6]([Cl:18])=[C:7]([CH:14]=1)[C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9]
Reactant: C=CCOc1cc(Br)cc(C(=O)N(C)OC)c1Cl
Reactant: COc1c(Br)cc(C(=O)O)c(Cl)c1OC
Product: COc1c(Br)cc(C(=O)N(C)OC)c(Cl)c1OC

Procedure:
Similar procedure with preparation of 182 proceeded except for using compound 158 to obtain the compound 195.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].[CH2:17]1COCC1>>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH3:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(O)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
To this reaction mixture was added dropwise a liquid mixture of 182.22 g (1.1 mol) of benzophenone (3a; R1,R2 =H) and 364 ml of dry THF at 35° to 40° C. over a period of 30 minutes. This mixture was stirred first at that temperature for 2 hours and then at that temperature for 13 hours to complete the reaction. The resulting solution was added to 1,400 g of cooled 10% aqueous ammonium chloride solution with cooling with ice. The mixture was stirred for 30 minutes, allowed to stand, and then subjected to liquid separation, followed by washing with aqueous common salt solution, drying with magnesium sulfate, and concentration to obtain 200.23 g of crude 1,1-diphenylethanol (theoretical yield based on the benzophenone, 98.6%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]([C:11](SC)=[CH:12][N+:13]([O-:15])=[O:14])[CH2:8][CH2:9][CH3:10])[CH2:2]1.[CH2:18]([NH2:20])[CH3:19]>>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]([C:11]([NH:20][CH2:18][CH3:19])=[CH:12][N+:13]([O-:15])=[O:14])[CH2:8][CH2:9][CH3:10])[CH2:2]1
Reactant: CCN
Reactant: CCCN(CC1CCOC1)C(=C[N+](=O)[O-])SC
Product: CCCN(CC1CCOC1)C(=C[N+](=O)[O-])NCC
Temperature: 25 °C

Procedure:
A mixture comprising 0.25 g of 1-[N-{(tetrahydro-3-furanyl)methyl}-N-propylamino]-1-methylthio-2-nitroethylene and 1 ml of 70% aqueous ethylamine solution was stirred for an hour at room temperature. After concentration of the mixture under a reduced pressure, the reaction fluid was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=7/1) to obtain 0.25 g of 1-[N-{(tetrahydro-3-furanyl)methyl}-N-propylamino]-1-ethylamino-2-nitroethylene.
Reaction SMILES: CC1[C@H]2C(C)(C)C(C2)CC=1.C1OC2C=C([N+]([O-])=O)C(C=O)=CC=2O1.B(Br)(Br)Br.C(OC(=O)CN)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].S(Br)(Br)=O.C(OC(=O)CN)(C)(C)C.NO.[CH:57]1[C:62]([OH:63])=[C:61]([OH:64])[CH:60]=[C:59](F)[C:58]=1[CH:66](O)[CH2:67][NH2:68]>>[NH2:68][CH2:67][CH2:66][C:58]1[CH:59]=[CH:60][C:61]([OH:64])=[C:62]([OH:63])[CH:57]=1
Reactant: NCC(O)c1cc(O)c(O)cc1F
Agent: BrB(Br)Br
Agent: CC(C)(C)OC(=O)CN
Agent: CC1=CCC2C[C@@H]1C2(C)C
Product: NCCc1ccc(O)c(O)c1

Procedure:
(1S)-(-)-α-pinene, 6-nitropiperonal, boron tribromide, glycine ethyl ester, lithium aluminum hydride (1M in diethyl ether) and thionyl bromide were obtained from Aldrich. Glycine t-butyl ester was purchased from Sigma Chemical Company. Hydroxylamine (free base) was obtained from Southwestern Analytic Chemicals, Inc. 6-Fluoronorepinephrine was purchased from RBI (Research Biochemicals Inc.). Dopamine and dopamine β-hydroxylase was obtained from the Sigma Chemical Co. 1H NMR spectra were also recorded with a Brucker 300 MHz in CDCl3 as a solvent using TMS as internal reference. Mass spectra were recorded with a Finnegan-Mat GC-MS 5100 mass spectrometer using electron impact ionization at 70 eV. HPLC analyses were carried out with a Perkin-Elmer liquid chromatograph equipped with a radioactivity monitor and UV detector. Optical rotation analysis was performed by Rudolph Instruments, Inc.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:24][CH:25]=[CH:26][C:27]=1B(O)O)(=[O:19])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O.O.C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(Br)cc(Nc2cnccn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cnccn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with 5-bromo-1-methyl-3-(pyrazin-2-ylamino)pyridin-2(1H)-one 162a (210 mg, 0.70 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (560 mg, 1.4 mmol), Pd(dppf)Cl2 (70 mg, 0.035 mmol), K3PO4 (320 mg, 1.4 mmol), sodium acetate trihydrate (210 mg, 1.4 mmol), acetonitrile (10 mL), and water (6 drops). The system was evacuated and refilled with N2. The reaction mixture was stirred at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 25:1 of dichloromethane/methanol to afford 188a (150 mg, 40%) as a yellow brown solid. MS-ESI: [M+H]+ 554.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:29][C:30](O)=[O:31].ClC(OC)=O.O.[NH2:39][NH2:40]>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:18][CH2:19]2)[CH:5]=[CH:4][C:3]=1[CH2:29][C:30]([NH:39][NH2:40])=[O:31]
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)nc1
Reactant: NN
Agent: COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)NN)c(F)c3)CC2)nc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution [2-fluoro-4-(2-{(1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl}ethoxy)phenyl]acetic acid (500 mg, 1.152 mmol) in 5 mL of THF was cooled to −10° C. TEA (0.177 mL, 1.268 mmol) and methyl chloroformate (0.098 mL, 1.268 mmol) were added and the mixture stirred for 30 minutes at −10° C. The precipitate was filtered and the filtercake washed with 10 mL of THF. The filtrate was collected, concentrated under reduced pressure. The residue (265 mg, 0.539 mmol) was dissolved in 1 mL of DMF and hydrazine monohydrate (0.052 mL, 1.077 mmol) added. The resulting mixture was stirred overnight at room temperature, diluted with ethyl acetate (3 mL), washed with water (2 mL), and brine (2 mL). The organic fractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via preparative TLC (1000 μM, silica gel) developing with 5% methanol in DCM. The band containing the product was collected and the silica washed with 10% methanol in DCM. The filtrate was collected and concentrated under reduced pressure to afford the title compound. HPLC/MS; 1.31 min(2 minute run), 458 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:54][O:55][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([NH2:62])[CH:57]=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:62][C:58]3[CH:59]=[CH:60][CH:61]=[C:56]([O:55][CH3:54])[CH:57]=3)=[O:17])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Reactant: COc1cccc(N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)c2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 72.8 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (41 mg, 0.15 mmol), N,N-diisopropylethylamine (0.105 mL, 0.60 mmol), and HBTU (63 mg, 0.165 mmol) in 1.5 mL DMF was briefly warmed to approx. 50° C. to dissolve solids, then continued stirring at room temperature. After 10 minutes meta-anisidine (0.025 mL, 0.225 mmol) was added and the reaction continued at room temperature for 4 hours. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with an acetone/hexane mixture to give the title compound as a light beige solid (41 mg, 73%). 1H NMR (DMSO-d6) δ: 10.13 (s, 1H), 8.13 (s, 1H), 7.46-7.51 (m, 2H), 7.31-7.41 (m, 3H), 7.19-7.28 (m, 2H), 6.68 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 6.41 (s, 2H), 4.29 (s, 2H), 3.75 (s, 3H), 3.65 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[N:20]=[CH:19][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:17]=3)=[O:15])[C:10]([CH3:28])([CH3:27])[CH2:9]2)=[O:7])=[CH:4][C:3]=1[NH:31][CH3:32].[CH:33]1([CH2:38][C:39](O)=O)[CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C=O)C>[CH:33]1([CH2:38][C:39]2[N:31]([CH3:32])[C:3]3[CH:4]=[C:5]([C:6]([N:8]4[CH2:13][CH2:12][N:11]([C:14]([C:16]5[N:20]=[CH:19][N:18]([C:21]6[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=6)[N:17]=5)=[O:15])[C:10]([CH3:27])([CH3:28])[CH2:9]4)=[O:7])[CH:29]=[CH:30][C:2]=3[N:1]=2)[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CNc1cc(C(=O)N2CCN(C(=O)c3ncn(-c4ccccc4)n3)C(C)(C)C2)ccc1N
Reactant: O=C(O)CC1CCCC1
Solvent: CN(C)C=O
Product: Cn1c(CC2CCCC2)nc2ccc(C(=O)N3CCN(C(=O)c4ncn(-c5ccccc5)n4)C(C)(C)C3)cc21
Temperature: 200 °C
Reaction time: 0.5 h

Procedure:
A mixture of 123 mg (0.284 mmol) [4-(4-amino-3-methylamino-benzoyl)-2,2-dimethyl-piperazin-1-yl]-(1-phenyl-1H-[1,2,4]-triazol-3-yl)-methanone and 500 μL (3.99 mmol) cyclopentylacetic acid was stirred at 200° C. for 30 min. The reaction mixture was diluted with DMF and purified by HPLC.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][CH2:11][CH2:12][NH2:13].[N+](N[C:22]1[NH:27][C:26](=[O:28])[C:25]([CH2:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[CH:24][N:23]=1)([O-])=O>N1C=CC=CC=1>[CH3:17][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][CH2:11][CH2:12][NH:13][C:22]1[NH:27][C:26](=[O:28])[C:25]([CH2:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[CH:24][N:23]=1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: CN(C)CCOc1cccc(OCCCN)c1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCOc3cccc(OCCN(C)C)c3)[nH]c2=O)cn1

Procedure:
Equimolar amounts of 3-(3-(2-(dimethylamino)ethoxy)phenoxy)propylamine and 2 -nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone are heated under reflux in dry pyridine for 24 hours to give 2-[3-(3-(2-dimethylaminoethoxy)phenoxy)propylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[C:3]([N:8]1[C@H:11]([CH2:12][CH:13]=[CH2:14])[CH2:10][C:9]1=[O:15])[C:4]([O:6][CH3:7])=[O:5].[CH3:17][C:18]([CH3:20])=[O:19].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]([CH3:16])=[C:3]([N:8]1[C@H:11]([CH2:12][CH:13]=[CH2:14])[C@@H:10]([C:18]([OH:19])([CH3:20])[CH3:17])[C:9]1=[O:15])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=CC[C@@H]1CC(=O)N1C(C(=O)OC)=C(C)C
Reactant: CC(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@@H]1[C@@H](C(C)(C)O)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
1.55M Butyl lithium-hexane solution (2.82 ml) was added to a solution of N-isopropylcyclohexylamino (0.72 ml) in tetrahydrofuran (6 ml) at -70° C., and the mixture was stirred for 20 minutes at -70° C. This mixture was added to a solution of methyl 3-methyl-2-[(4R)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (247 mg) in tetrahydrofuran (6 ml) at -70° C. and the mixture was stirred for 1 hour at -70° C., and for 30 minutes at -30° C. Acetone (0.12 ml) was added to the reaction mixture at -70° C., and the mixture was stirred for 1 hour at -70° C. and for 30 minutes at -30° C.--15° C. 3N Hydrochloric acid was added to the reaction mixture at -70° C. and the mixture was diluted with ethyl acetate (200 ml). The solution was washed with water, brine, aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. Triethylamine (0.15 ml) was added to a solution of the residue in dichloromethane (3 ml) at 0° C. and the mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate (20 ml) and the solution was washed with 0.1N hydrochloric acid (15 ml) brine, aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (10 g) eluting with a mixture of benzene and acetone (10:1-2:1) to give methyl 3-methyl-2-[(3S,4R)-3-(1hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (100 mg);
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][N:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:10]=[CH:9][N:8]=[C:7]2[N:6]([S:17]([C:14]3[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=3)(=[O:19])=[O:18])[CH:5]=[CH:4][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1ccnc2[nH]ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ccnc32)cc1
Reaction time: 8 h

Procedure:
To a suspension of 4-chloro-7-azaindole (2.32 g, 15.2 mmol) and p-toluenesulfonyl chloride (3.04 g, 15.96 mmol) in toluene (60 mL) and tetrabutylammonium sulfate (0.175 mL, 0.152 mmol, 50% solution in water) was added a solution of sodium hydroxide (0.913 g, 22.8 mmol) in water (36 mL). The biphasic mixture was stirred vigorously overnight, and was partitioned between ethyl acetate and brine. The aqueous layer was separated and extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Teledyne CombiFlash Rf, 0-20% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 307 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:11](=[O:16])[NH:12][CH:13]=[CH:14][N:15]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CC([O-])(C)C.[K+].CS(O[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])(=O)=O.O>C1COCC1>[F:39][C:32]1[CH:33]=[C:34]([F:38])[C:35]([F:37])=[CH:36][C:31]=1[O:30][CH2:29][CH2:28][N:12]1[CH:13]=[CH:14][N:15]=[C:10]([N:7]2[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]2)[C:11]1=[O:16]
Reactant: CC(C)N1CCN(c2ncc[nH]c2=O)CC1
Reactant: CS(=O)(=O)OCCOc1cc(F)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1CCN(c2nccn(CCOc3cc(F)c(F)cc3F)c2=O)CC1
Temperature: 60 °C

Procedure:
A mixture of 3-(4-isopropyl-1-piperazinyl)-2(1H)-pyrazinone (0.58 g, 2.6 mmol; from Step 2) and t-BuOK (440 mg, 3.90 mmol) in THF (40 mL) was stirred until the mixture became thick (about 10 min), and then a solution of 2-(2,4,5-trifluorophenoxy)ethyl methanesulfonate (0.90 g, 2.2 mmol; from Example 54, Step 4) in THF (10 mL) was added. After being stirred for 5 days at ambient temperature, HPLC showed only 25% conversion. The reaction solution was then heated to 60° C. overnight which gave almost full conversion. The reaction was worked up according to the following: water was added, THF was evaporated off and the aqueous mixture was extracted twice with EtOAc, dried and concentrated to yield 1.18 g of the crude product as a yellow oil. Purification by chromatography on silica gel (eluent: 2.5% MeOH in CHCl3+NH3 (g)) gave the title compound as a colourless oil, which solidified upon cooling. Yield: 120 mg (14%). HPLC purity: 99%. MS m/z 397 (M+H)+. HRMS m/z calcd for C19H23F3N4O2 (M)+ 396.1773, found 396.1771.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[CH2:8][C:9]#[N:10].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)=O>C(O)C>[C:14]1(=[C:8]([C:7]2[CH:6]=[C:5]([CH3:4])[CH:13]=[CH:12][CH:11]=2)[C:9]#[N:10])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1cccc(CC#N)c1
Reactant: O=C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=CO
Product: Cc1cccc(C(C#N)=C2CCCCC2)c1
Temperature: 85 °C
Yield: 57.7 %

Procedure:
Sodium methylate (5.40 g, 0.10 mol) is dissolved in ethanol (70 ml) and 3-methyl benzylcyanide (1310 g, 0.10 mol) is added over 2 min. Cyclohexanone (9.80 g, 0.10 mol) is added to the white suspension. The resulting mixture is heated to 85° C. (bath) for 4.5 h. Under icecooling, formic acid (5.0 ml) is added dropwise, upon which the mixture turns colourless. Standard aqueous workup as described in example 1, followed by a short path distillation at 0.05 mbar/157-165° C. yields 12.2 g of product (58% yield), which is further purified by a fine distillation at 0.05 mbar/183° C. to yield 3.95 g (19%) of product as a colourless oil.