Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH:20]([CH3:27])[CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH:20]([CH3:27])[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: CC(CCl)CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(COc1ccc(C2(CN(C)C)CCOCC2)cc1)CN1CCCC1
Yield: 41.5 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (0.91 g, 3.87 mmol), 1-(3-chloro-2-methyl-propyl)-pyrrolidine (500 mg, 3.10 mmol), DMF (5 ml) and K2CO3 (2.14 g, 15.50 mmol) were reacted together according to general procedure B. The organic phase was washed with 2M NaOH (3×20 ml), water (2×20 ml), dried over MgSO4, fitered and concentrated in vacuo at 35° C. The crude material was subjected to chromatography on silica eluting with DCM:MeOH:NH3 (97:2:1) to provide the title compound (464 mg, 42%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.88 (d, 2H), 4.00 (dd, 1H), 3.80-3.70 (m, 3H), 3.55 (td, 2H), 2.59-2.43 (m, 5H), 2.40 (s, 2H), 2.33 (dd, 1H), 2.21-2.04 (m, 3H), 1.97 (s, 6H), 1.88 (ddd, 2H), 1.82-1.70 (m, 4H), 1.08 (d, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([Cl:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CN1C(=O)CCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Cl:16])[N:12]=[C:13]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)n1
Solvent: CN1CCCC1=O
Product: Clc1cc(OCc2ccccc2)cc(N2CCOCC2)n1
Temperature: 130 °C

Procedure:
A mixture of 4-(benzyloxy)-2,6-dichloropyridine (1.0 equiv.) and morpholine (1.2 equiv.) in NMP (2 M) were heated to 130° C. for 1 h in the microwave. The reaction mixture was partitioned between water and EtOAc. The organic phase was washed with brine and dried over sodium sulfate. The solution was concentrated and dried under vacuo to give crude 4-(4-(benzyloxy)-6-chloropyridin-2-yl)morpholine and was used in the next step without further purification. LCMS (m/z) (M+H)=305.0, Rt=1.10 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][C:4]=1[O:21][CH2:22][CH2:23][NH2:24].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:13])=[O:14])=[CH:5][C:4]=1[O:21][CH2:22][CH2:23][NH:24][C:32](=[O:34])[CH3:33]
Reactant: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1OCCN
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1OCCNC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
2-{[6-Methoxy-1-(phenylsulfonyl)-1H-indol-5-yl]oxy}ethanamine (Intermediate 32, 2.0 g, 5.8 mmol) in DCM (100 mL) was treated with triethylamine (2.4 mL, 17 mmol) and 4-dimethylaminopyridine (0.35 g, 2.9 mmol). The solution was cooled to 0° C. and acetyl chloride (0.82 mL, 12 mmol) was added. The mixture was stirred at room temperature for 1 hour, washed with aqueous saturated NaHCO3 (20 mL) and 1 M HCl (2×20 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (1.2 g). MS m/z 389 [M+H]+.
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]([CH2:16][CH:17]([CH:25]2[CH2:28][CH2:27][CH2:26]2)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=1[Cl:15])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:8][C:9]1[CH:10]=[C:11]([CH2:16][CH:17]([CH:25]2[CH2:26][CH2:27][CH2:28]2)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: CC(C)(C)OC(=O)C(Cc1ccc(Cl)c(NCc2ccccc2)c1)C1CCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(Cc1ccc(Cl)c(N)c1)C1CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.1 %

Procedure:
1.85 g (4.63 mmol) of (+/−)-tert-butyl 3-[3-(benzylamino)-4-chlorophenyl]-2-cyclobutylpropanoate were dissolved in 10 ml of ethyl acetate and deoxygenated with argon, and 98 mg (0.093 mmol) of palladium on carbon (10%) were added. The reaction mixture was stirred at RT under an atmosphere of hydrogen at atmospheric pressure for 4 h and then allowed to stand over the weekend. The mixture was filtered through celite, the residue was washed with ethyl acetate, the filtrate was concentrated under reduced pressure and the residue of the filtrate was dried under high vacuum. This residue (about 1:1 mixture of starting material and target product) was once more dissolved in about 10 ml of ethyl acetate and deoxygenated with argon, and once more 98 mg (0.093 mmol) of palladium on carbon (10%) were added. Again, the reaction mixture was stirred at RT under an atmosphere of hydrogen at atmospheric pressure for 4 h. The mixture was then filtered through celite, the residue was washed with ethyl acetate, the filtrate was concentrated under reduced pressure and the residue was dried under high vacuum. Chromatographic purification on silica gel (mobile phase cyclohexane/ethyl acetate 20:1) gave 1.12 g of the target product (78.2% of theory).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[NH:26][N:27]=1.N1NC(=O)C=CC=1>>[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[N:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@@H:14]5[CH3:18])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)[N:27]=1
Reactant: Cc1ccc(=O)[nH]n1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: O=c1cccn[nH]1
Product: Cc1ccc(=O)n(-c2ccc3nc([C@H]4C[C@H](N5CCC[C@@H]5C)C4)sc3c2)n1

Procedure:
The title compound was prepared according to the procedure described in Example 22, substituting the product of Example 11A for the product of Example 1E, and substituting 6-methyl-3(2H)-pyridazinone for 3(2H)-pyridazinone. 1H NMR (500 MHz, CDCl3) δ ppm 8.12 (m, 1H) 8.00 (m, 1H) 7.67 (dd, J=8.73, 1.87 Hz, 1H) 7.16 (m, 1H) 7.01 (m, 1H) 3.57-3.67 (m, 1H) 3.15-3.24 (m, 1H) 3.02-3.11 (m, 1H) 2.73-2.86 (m, 1H) 2.56-2.68 (m, 1H) 2.45-2.55 (m, 2H) 2.41 (s, 3H) 2.30-2.37 (m, 1H) 1.92-2.04 (m, 1H) 1.77-1.87 (m, 1H) 1.67-1.74 (m, 1H) 1.44-1.61 (m, 2H) 1.15 (s, 3H). MS: (M+H)+=381.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[O:9]=[C:10]1[N:17]2[C:12]([CH3:20])([CH2:13][CH2:14][O:15][C:16]2([CH3:19])[CH3:18])[CH:11]1[CH3:21].[CH2:22]=[O:23].[Cl-].[Na+]>O1CCCC1.O>[O:23]=[C:22]1[N:17]2[C:12]([CH3:20])([CH2:13][CH2:14][O:15][C:16]2([CH3:19])[CH3:18])[C:11]1([CH3:21])[CH2:10][OH:9]
Reactant: C=O
Reactant: CC1C(=O)N2C(C)(C)OCCC12C
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OCCC2(C)N1C(=O)C2(C)CO
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
To a solution of 1.1 equivalents of freshly prepared lithium diisopropylamide in anhydrous tetrahydrofuran under a nitrogen atmosphere at -78° is added a solution of 8-oxo-2,2,6,7-tetramethyl-3-oxa-1-azabicyclo-[4.2.0]octane in anhydrous tetrahydrofuran which has been cooled to -78° C. After two minutes, the resulting lithium enolate is treated with excess formaldehyde, introduced as a gas just above the surface of the stirred solution. The solution is stirred for 30 minutes at -78° and then poured into water. The aqueous phase is saturated with sodium chloride and extracted with ethyl acetate. The combined ethyl acetate solutions are dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give the crude product. Purification by chromatography on silica gel using ethyl acetate/benzene gives 8-oxo-2,2,6,7-tetramethyl-7-(hydroxymethyl)-3-oxa-1-azabicyclo[4.2.0]octane.
Reaction SMILES: [N+](C1C=CC=CC=1[Se]C#N)([O-])=O.[CH2:13]([O:20][C@@H:21]([C@@H:28]([CH2:45][CH2:46]O)[CH:29]=[CH:30][C@@H:31]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.OO>O1CCCC1>[CH2:13]([O:20][C@@H:21]([C@@H:28]([CH:45]=[CH2:46])[CH:29]=[CH:30][C@@H:31]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCC[C@@H](C=C[C@H](CCO)[C@@H](CC(OC)OC)OCc1ccccc1)OCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: N#C[Se]c1ccccc1[N+](=O)[O-]
Agent: OO
Solvent: C1CCOC1
Product: C=C[C@@H](C=C[C@H](CCCCC)OCc1ccccc1)[C@@H](CC(OC)OC)OCc1ccccc1
Temperature: 0 °C
Yield: 91 %

Procedure:
To a suspension of 997 mg (3.67 mM) of o-nitrophenylselenium cyanide in 12 ml of anhydrous tetrahydrofuran was dropwise added 886 mg (1.83 mM) of (3R,4S,7S) 3,7-dibenzyloxy-4-(2'-hydroxyethyl)-1,1-dimethoxydodeca-5-ene [7] described above. The mixture was stirred for several minutes and 0.91 ml (3.67 mM) of tri-n-butylphosphine was dropwise added to the mixture. The reaction solution was stired for ten minutes then, cooled to 0° C. and 35% hydrogen peroxide aqueous solution was dropwise added thereto at the same temperature while stirring. After stirring for 3 hours, the aqueous phase was extracted with a solvent mixture of diethyl ether : hexane=7:3. The extracts were combined and washed sequentially with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The precipitated crystals were taken from the residue by filtration to give 776 mg (1.67 mM) of (3 R,4S,7S) 3,7-dibenzyloxy-4-vinyl-1,1-dimethoxydodeca-5-ene [8]. Yield, 91%.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][O:6][B:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17](O)=O)=[CH:10][CH:9]=2)[O:4][CH2:3]1.BrC1C=CC(CCCC[C:32]([OH:34])=[O:33])=CC=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1>>[CH3:1][C:2]1([CH3:20])[CH2:7][O:6][B:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:32]([OH:34])=[O:33])=[CH:10][CH:9]=2)[O:4][CH2:3]1
Reactant: O=C(O)CCCCc1ccc(Br)cc1
Reactant: CC1(C)COB(c2ccc(CCCC(=O)O)cc2)OC1
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Product: CC1(C)COB(c2ccc(CCCCC(=O)O)cc2)OC1
Yield: 71 %

Procedure:
Using a procedure analogous to that used to prepare 2A, 5-(4-bromophenyl)pentanoic acid (537 mg, 2.09 mmol) was reacted with 5,5,5′,5′-Tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to afford 5A (429 mg, 71%) as a white solid. 1H NMR (400 MHz, tetrahydrofuran-d8) δ 0.99 (s, 6H), 1.55-1.70 (m, 4H), 2.24 (t, J=7.5 Hz, 2H), 2.61 (t, J=7.0 Hz, 2H), 3.73 (s, 4H), 7.12 (d, J=7.9 Hz, 2H), 7.65 (d, J=7.9 Hz, 2H).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]#[N:15])[CH2:9]1)C1C=CC=CC=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH3:38])=[O:36]>C(Cl)Cl>[C:14]([C:13]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:10]1[CH2:11][CH2:12][N:8]([C:35]([O:37][CH3:38])=[O:36])[CH2:9]1)#[N:15]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCN(Cc2ccccc2)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N1CCC(C(C#N)(c2ccccc2)c2ccccc2)C1
Reaction time: 5 h
Yield: 68.7 %

Procedure:
To a solution of 36.5 g (0.10 mole) of α-(1-benzyl-3-pyrrolidinyl)-α,α-diphenylacetonitrile and 8.7 g (0.11 mole) of pyridine in methylene chloride was added dropwise at 25° C., 10.4 g (0.11 mole) of methyl chloroformate. The solution was refluxed for 16 hr. To the refluxing solution was added 26.1 g (0.33 mole) of pyridine and 31.2 g (0.33 mole) additional methyl chloroformate. Heating at reflux was continued for 5 hr. The mixture was cooled and washed four times with water. The methylene chloride layer was dried and concentrated in vacuo. The residual oil was crystallized twice from a mix of petroleum ether (30°-60° ) and isopropanol to give 22 g (68%) of title product, m.p. 133°-135° C.
Reaction SMILES: NC1SC(CC)=CN=1.C(OC=C(C(OCC)=O)C(OCC)=O)C.[C:24]([CH:29]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:30][NH:31][C:32]1[S:33][C:34]([CH2:37][CH3:38])=[CH:35][N:36]=1)([O:26][CH2:27][CH3:28])=[O:25].C(Cl)(Cl)Cl>C(OCC)(=O)C.CCCCCC>[C:24]([C:29]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:30][NH:31][C:32]1[S:33][C:34]([CH2:37][CH3:38])=[CH:35][N:36]=1)([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(CNc1ncc(CC)s1)C(=O)OCC
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CCc1cnc(N)s1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1ncc(CC)s1)C(=O)OCC

Procedure:
2-Amino-5-ethylthiazole (11.7 g., 91.3 mmoles) and diethyl ethoxymethylenemalonate (21.7 g., 100.43 mmoles) were combined and heated on a steam bath for 45 minutes. 2-(2,2-Dicarbethoxyethylamino)-5-ethylthiazole (27.2 g., Rf 0.6 and 0.7 respectively, on silica gel thin layer chromatography, with chloroform/1% ethanol and with 2:1 hexane:ethyl acetate as eluant) was obtained as an oil by cooling and used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH3:26])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[CH2:27]([O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)[CH2:28][CH2:29][CH3:30].N1C=CC=CC=1>O1CCCC1>[CH2:27]([O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH3:26])=[C:6]([C:8]3[NH:13][C:12](=[O:14])[C:11]4=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:10]4[N:9]=3)[CH:7]=2)(=[O:40])=[O:39])=[CH:34][CH:33]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)Nc2ccc(OCC)c(-c3nn4c(C5CCCC5)nc(C)c4c(=O)[nH]3)c2)cc1

Procedure:
150 mg (0.424 mmol) of the compound from example 42A are reacted with 186 mg (0.747 mmol) of 4-(n-butoxy)-benzenesulfonyl chloride and 0.34 g (4.30 mmol) of pyridine in 6 ml of tetrahydrofuran.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:28][CH2:29][CH2:30][N:31]1C(=O)C2=CC=CC=C2C1=O.O.NN>>[NH2:31][CH2:30][CH2:29][CH2:28][N:10]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]
Reactant: O=C(c1ccccc1)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: NN
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: NCCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1[N+](=O)[O-]

Procedure:
[2-[(3-Nitro-2-pyridinyl)amino]phenyl]phenylmethanone is reacted with (a) sodium hydride in solvent followed by N-(3-bromopropyl)phthalimide. The product of (a) is reacted with alcholic hydrazine hydrate and acid to give the title compound.
Reaction SMILES: [N:1]([C:4]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]2[C:5]=1/[C:6](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1)/[C:7](=[O:16])[NH:8]2)=[N+]=[N-].[OH-].[NH4+].[H][H]>C1COCC1.[Pt]>[NH2:1][C:4]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]2[C:5]=1/[C:6](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1)/[C:7](=[O:16])[NH:8]2
Reactant: [H][H]
Reactant: [N-]=[N+]=Nc1c([N+](=O)[O-])ccc2c1/C(=C/c1ccc[nH]1)C(=O)N2
Agent: [Pt]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1N)/C(=C/c1ccc[nH]1)C(=O)N2

Procedure:
(Z)-4-Azido-1,3-dihydro-5-nitro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (340 mg, 1.15 mmol)(from Example 11) was dissolved in THF at rt (30 mL). Ammonium hydroxide was added (0.36 ml), followed by a catalytic amount of poisoned platinum on carbon (5% Pt/C.1/2S, 50 mg) (Engelhard Industries). The reaction mixture was hydrogenated in a Parr bomb under 50 psi of hydrogen for 2.5 h. The mixture was filtered through a cake of Celite®, and the cake was washed twice with THF. The hydrogenation was repeated with a fresh batch of catalyst, solvent and ammonium hydroxide (50 psi, 2 h). After filtration through Celite®, the mixture was concentrated under reduced pressure. The crude material was purified by flash chromatography on Silica Gel (230-400 mesh, eluted with 75% ethyl acetate in hexanes) to yield (Z)-4,5-diamino-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 160 mg, 58%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.Cl.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(CC)CC>CN(C=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:24]2[CH2:23][CH2:22][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:26][CH2:25]2)=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)c([N+](=O)[O-])c2)CC1
Temperature: 70 °C
Yield: 96.8 %

Procedure:
To a solution of a mixture of compound 17 (3 g, 13.27 mmol) and 1-boc-piperazine hydrochloride (3.53 g, 15.92 mmol) in DMF (30 mL) was added Et3N (4.4 mL, 31.8 mmol), and the mixture was heated at 70° C. for 6 h. The mixture was cooled to room temperature, extracted with ethyl acetate (100 mL), and the organic layer was washed with brine (20 mL), dried over Na2SO4 and evaporated. Trituration with diethyl ether afforded 4.27 g (97%) of compound 18 as bright yellow solid, m.p. 138-139° C.; IR (KBr) νmax. cm−1: 3042 (Ar—H), 2252 (CN), 1690 (C═O), 1610, 1520, 1412 (C═C). 1H NMR (500 MHz, DMSO-d6) δ=1.39 (s, 9H, (CH3)3C); 3.44 (br. s, 4H, 2 CH2); 7.19 (dd, 1H, J=2.6, 9.4 Hz, H-5); 7.46 (d, 1H, J=2.7 Hz, H-2); 8.17 (d, 1H, J=2.7 Hz, H-6); 13C NMR (125.7 MHz, DMSO-d) δ=28.11 (CH3)3C), 45.92 (CH2), 46.02 (CH2), 79.56 (CH3)3C), 109.24 (C-4), 115.61 (C-2), 116.46 (CN), 119.03 (C-6), 128.09 (C-5), 135.85 (C-3), 153.30 (C-1), 154.13 (C═O). Calculated (%) for C16H20N4O4(332.15); C, 57.82; H, 6.07; N, 16.86. found (%); C, 57.76; H, 6.11; N, 16.80.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:7](Cl)[N:6]=[CH:5][N:4]=1>C(O)C>[NH2:1][C:7]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:3]([Cl:2])[N:4]=[CH:5][N:6]=1
Reactant: N
Reactant: COc1ccccc1Oc1c(Cl)ncnc1Cl
Solvent: CCO
Product: COc1ccccc1Oc1c(N)ncnc1Cl
Temperature: -78 °C
Reaction time: 50 h

Procedure:
105 ml of ammonia were passed into a solution of 7 g of 4,6-dichloro-5-(o-methoxyphenoxy)pyrimidine in 140 ml of ethanol at -78° C. The reaction mixture was stirred for 15 hours at -78° C. and for 50 hours at room temperature and then concentrated. The residue was distributed between ethyl acetate and water and the organic phase worked up. There were obtained 6.45 g of 4-amino-6-chloro-5-(o-methoxyphenoxy)pyrimidine as white crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:13][C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](=O)([O-])[O-].[Li+].[Li+].S(OC)(OC)(=O)=O>C(#N)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]([CH3:29])[C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(CCCOCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [Li+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: CC(C)c1nc(CCCOCc2ccccc2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 70 °C
Yield: 60 %

Procedure:
In 25 ml of dry acetonitrile was dissolved 5.0 g (11.5 mmol) of imidazole (101e), followed by addition of 1.7 g (23 ml) of lithium carbonate and 2.2 g (17.4 mmol) of dimethyl sulfate. The mixture was stirred under heating at 70° C. for 2 hours. The reactLion mixture was diluted with ice-water and extracted with diethyl ether. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to provide 3.1 g (yield 60%) of 2-(3-benzyloxypropyl)-5-(3,5-dichlorophenyl-thio)-4-isopropyl-1-methyl-1H-imidazole (136a) as oil.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(C(C)C)C(C)C)C.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C(Cl)Cl>[C:12]([O:11][C:9]([N:2]1[CH2:3][CH:4]2[CH:5]([CH2:6][N:7]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([Br:25])=[CH:27][CH:28]=3)[CH2:8]2)[CH2:1]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccc(Br)cc3)CC2C1
Temperature: 0 °C
Reaction time: 14 h
Yield: 90.9 %

Procedure:
1.1 tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.65 g; 3.06 mmol) is dissolved in 20 ml of DCM. N-Ethyldiisopropylamine for synthesis (1.56 ml; 9.19 mmol) is added and the mixture cooled to 0° C. Now 4-bromobenzoyl chloride for synthesis (0.74 g; 3.37 mmol) is dissolved in 10 ml of DCM and added dropwise to the reaction, followed by stirring at RT for 14 h. The reaction mixture is extracted with 50 ml of water. The organic layer is separated, dried over MgSO4, filtered off and then reduced to dryness under vacuo to afford 1.10 g (90.9%) 5-(4-bromo-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester 1 as a slight orange oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[S:23][N:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:29]2[CH2:28][CH2:27][N:26]([C:24]3[S:23][N:22]=[C:21]([C:17]4[S:16][CH:20]=[CH:19][CH:18]=4)[N:25]=3)[CH2:31][CH2:30]2)=[O:15])[CH:2]=1
Reactant: c1csc(-c2nsc(N3CCNCC3)n2)c1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3cccs3)ns2)CC1
Yield: 36.9 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (235 mg, 0.872 mmol), 1-[3-(2-thienyl)-1,2,4-thiadiazol-5-yl]piperazine (200 mg, 0.793 mmol) and diisopropylethylamine (0.152 ml, 0.872 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 109 mg (37.1%) of the desired product as a solid.