Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([N:12]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:8]=[CH:7]2.CCCCCC.C([Li])CCC.[CH3:38][N:39]1[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40]1>O1CCCC1>[CH2:20]([N:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][CH:3]=[C:2]2[C:42]2([OH:45])[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]2)=[CH:7][CH:8]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Brc1cccc2ccc(N(Cc3ccccc3)Cc3ccccc3)cc12
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCC(O)(c2cccc3ccc(N(Cc4ccccc4)Cc4ccccc4)cc23)CC1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 138.8 %

Procedure:
The following reaction was run in two side by side reactions and the crude products were combined for work up and purification. A mechanically stirred solution of 8-bromo-2-(dibenzylamino)-naphthalene (10.0 g, 24.9 mmol from Preparation 4) in tetrahydrofuran (200 mL) was cooled to -95° C. (hexane/liquid nitrogen) and butyllithium (10.39 mL, 24.9 mmol, 2.4 M) was added dropwise. The orange solution was stirred 7 min, then 1-methyl-4-piperidone (2.82 g, 24.9 mmol) was added dropwise over 10 minutes with a 10 mL tetrahydrofuran rinse. The orange color faded while stirring was continued 20 minutes at -100° C. The reaction was allowed to warm to room temperature and quenched with water. The solvent was removed and the residue was partitioned between methylene chloride and water (at this point the two reactions were combined). The phases were separated and the organic layer was washed with brine, dried, and concentrated onto silica gel. Flash chromatography (4×4 inches silica gel) proceeded as follows: methylene chloride (1 L) and 2% methanol/methylene chloride (1.6 L) unweighed white solid 7-dibenzylaminonaphthalene; 15% methanol / methylene chloride (1 L), 25% methanol/methylene chloride (1 L) and 30% methanol/methylene chloride/0.2% ammonium hydroxide (4 L) product contaminated with water. The combined eluents were concentrated and redissolved in methylene chloride. The solution was dried and concentrated to afford 15.09 g (69%) of 7-dibenzylamino-1-(4-hydroxy-1-methyl-4-piperidinyl)-naphthalene as a light tan foam. A sample recrystallized from ethyl acetate had mp 173°-174° C. Analysis calculated for C30H32N2O: C, 82.53; H, 7.39; N, 6.42. Found: C, 82.42; H, 7.44; N, 6.38.
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][NH:18][C:19]1[CH:23]=[CH:22][NH:21][C:20]=1[C:24]([O:26]CC)=O>C(Cl)Cl.CO>[NH:14]1[CH:15]=[CH:16][N:12]=[C:13]1[CH2:17][N:18]1[C:19]2[CH:23]=[CH:22][NH:21][C:20]=2[C:24](=[O:26])[NH:9][C:10]1=[S:11]
Reactant: CCOC(=O)c1[nH]ccc1NCc1ncc[nH]1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]c(=S)n(Cc2ncc[nH]2)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
Benzoyl isothiocyanate (0.19 mL, 1.41 mmol) was added to a stirred solution of ethyl 3-[(1H-imidazol-2-ylmethyl)amino]-1H-pyrrole-2-carboxylate (0.3 g, 1.28 mmol) in CH2Cl2 (4 mL) and methanol (2 mL) and the mixture was stirred at r.t. for 1 h. The solvent was evaporated in vacuo and the residue was dissolved in ammonia (7N in methanol, 7 mL) and heated at 80° C. for 1 h. The crude product was filtrated and purified by preparative HPLC, obtaining 0.110 g, (35%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]([CH3:15])=[CH2:14])[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].[Pt].CCO>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(C)c1ccnc(-c2ccccc2)c1
Agent: [Pd]
Agent: [Pt]
Solvent: CCO
Product: CC(C)c1ccnc(-c2ccccc2)c1
Reaction time: 2 h
Yield: 73.4 %

Procedure:
2-Phenyl-4-(prop-1-en-2-yl) pyridine (13.5 g, 69.1 mmol) was added to a hydrogenator bottle containing EtOH (150 mL). The reaction mixture was degassed by bubbling with nitrogen for 10 min. Pd/C (0.736 g, 6.9 mmol) and Pt/C (0.674 g, 3.5 mmol) was added to the reaction mixture. The reaction mixture was placed on the Parr hydrogenator for 2 h. The reaction mixture was filtered on a tightly packed Celite® bed and washed with dichloromethane. The solvent was removed on a rotary evaporator and GC/MS confirmed complete conversion. The crude product was adsorbed on Celite® for column chromatography. The crude product was chromatographed on silica gel with 10% EtOAc in hexane to yield 10 g (75%) of 2-phenyl-4-isopropylpyridine (HPLC purity: 99.8%). The product was confirmed by GC/MS.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.Cl[CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:46][N:45]([CH3:47])[C:43](=[O:44])[CH2:42][NH:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CN(C)C(=O)CCl
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C
Yield: 51.8 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (50 mg, 0.092 mmol), 2-chloro-N,N-dimethylacetamide (33.5 mg, 0.276 mmol), potassium phosphate (78 mg, 0.368 mmol) and potassium iodide (36.6 mg, 0.221 mmol) in acetonitrile (1 mL) was heated at 120° C. for 33 h in a sealed tube. The reaction mixture was quenched with distilled water (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a pale yellow solid (30 mg, 52%). LCMS: m/e 629.51 (M+H)+, 3.03 min (method 10). The product was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22]([OH:24])=[O:23])[C:18]([OH:20])=[O:19]>>[C:12]([C:11]1[C:2]([NH:16][CH:17]([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([OH:24])=[O:23])[C:18]([OH:20])=[O:19])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:15])=[CH:6][CH:5]=2)([OH:14])=[O:13]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(C(=O)O)C(C(=O)O)c1ccccc1
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(C(=O)O)C(C(=O)O)c1ccccc1

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-phenyl-succinic acid [J. Med. Chem. 1973, 16, 1277-1280] to provide the title compound in moderate yield.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1([CH3:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][NH:11][CH2:10]1>ClCCl>[CH3:8][C:9]1([CH3:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][N:11]([C:5](=[O:7])[CH3:6])[CH2:10]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CNCc2ccccc21
Solvent: ClCCl
Product: CC(=O)N1Cc2ccccc2C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A solution of acetic anhydride (1.17 ml, 12.4 mmol) was added dropwise to a stirred, ice-cooled solution of 4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline (1.0 g, 6.2 mmol) (for preparation see J. Org. Chem., 1983, 48, 5348) in dry dichloromethane (5 ml). The cooling bath was removed and the solution was stirred for 2 h at room temperature. The reaction mixture was then concentrated in vacuo to give the title compound (D2) as an oil (1.1 g, 87%), δH (CDCl3, rotamers observed)/ppm 1.28, 1.32 (6H, 2×s), 2.20, 2.22 (3H, 2×s), 3.43, 3.61 (2H, 2×s), 4.66, 4.77 (2H, 2×s), 7.07-7.37 (4H, m).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][N:19]=[C:18]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][C:39]([F:42])([F:41])[F:40])[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][N:19]=[C:18]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][C:39]([F:41])([F:42])[F:40])[N:17]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2C#Cc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2C#Cc2ccccc2)CC1
Reaction time: 2 h
Yield: 57 %

Procedure:
(trans-4-{[5-Bromo-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester (100 mg, 0.174 mmol), CuI (0.97 mg, 0.005 mmol), and Pd(PhCN)2Cl2 (1.96 mg, 0.005 mmol) were dissolved in degassed dioxane (0.5 mmol). To this solution was added tri-(tert)-butylphosphine tetrafluoroborate (2.4 mg, 0.010 mmol) followed by diisopropylamine (0.029 mL, 0.2 mmol) and phenylacetylene (0.022 mL, 0.2 mmol). The reaction was stirred at 25° C. for 18 h. The reaction was worked up by the addition of EtOAc and filtered through a plug of SiO2. The filtrate was concentrated and purified via flash chromatography (SiO2, 25% EtOAc-Hexanes) to yield (4-{[5-phenylethynyl-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester. (4-{[5-Phenylethynyl-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester was dissolved in CH2Cl2 (0.5 mL) and TFA (0.5 mL) was added. The solution was stirred for 2 h and the volatiles were removed and the crude residue was purified via preparative thin layer chromatography (SiO2, 2000 micron thickness, 1:9:90 NH4OH:CH3OH:CH2Cl2) to afford 49 mg (57%) of N4-[(trans-4-aminocyclohexyl)methyl]-5-(phenylethynyl)-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine, m/z 496.58 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[CH3:11][CH2:12][C:13](=[O:19])[CH2:14][C:15](=[O:18])[CH2:16][CH3:17]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[C:14]([C:13](=[O:19])[CH2:12][CH3:11])[C:15](=[O:18])[CH2:16][CH3:17])[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CCC(=O)CC(=O)CC
Product: CCC(=O)C(=Cc1cccc(C#N)c1)C(=O)CC

Procedure:
The procedure described in Example 19 was repeated by using 1.82 g 3-cyanobenzaldehyde and 3.5 g 3,5-heptanedione. Yield 0.4 g, mp 51°-52° C.
Reaction SMILES: O1CCOCC1.[ClH:7].C([NH:11][CH:12]([CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[CH:30][C:29]=3[O:36][CH3:37])[CH:24]=2)[CH:19]=1)[C:13]([O:15]C)=[O:14])(=O)C>C(OCC)C>[ClH:7].[NH2:11][CH:12]([CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[C:29]([O:36][CH3:37])=[CH:30][CH:31]=[CH:32][C:33]=3[O:34][CH3:35])[CH:24]=2)[CH:19]=1)[C:13]([OH:15])=[O:14]
Reactant: COC(=O)C(Cc1ccc2cc(-c3c(OC)cccc3OC)ccc2c1)NC(C)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1cccc(OC)c1-c1ccc2cc(CC(N)C(=O)O)ccc2c1
Yield: 81 %

Procedure:
To a solution of 1,4-dioxane (1 ml) are added successively 6 N HCl (3 ml) and methyl 2-(acetylamino)-3-[6-(2,6-dimethoxyphenyl)-2-naphthyl]propanoate 207 (0.135 g). The solution is stirred and heated at reflux for 4 hours, then cooled, and diethyl ether (5 ml) is added. The aqueous phase is extracted with diethyl ether (35 ml). The organic phase is concentrated under vacuum. The resulting residue is dried overnight under high pression to give 2-amino-3-[6-(2,6-dimethoxyphenyl)-2-naphthyl]propanoic acid hydrochloride 208.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:16](=[S:19])[NH:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].S(OC)(O[CH3:24])(=O)=O.[OH-].[Na+]>O>[CH3:24][S:19][C:16]1[N:8]2[C:9](=[O:15])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2=[N:18][N:17]=1
Reactant: COS(=O)(=O)OC
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(=S)[nH]nc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(SC)nnc12
Yield: 85.1 %

Procedure:
A solution of 9-pentyl-3-thioxo-2,3,6,9-tetrahydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (1.90 g, 6.83 mmol), dimethyl sulfate (1.03 g, 8.19 mmol) and 1 M of sodium hydroxide in water (25 ml) was stirred at room temperature for 1 hour. The mixture was nutralized to pH=7. The solid formed was filtered and dried to provide the desired product (1.70 g, 85.2%). 1HNMR (300 MHz, CD3OD): δ 4.29 (t, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.89 (m, 2H), 1.40 (m, 4H), 0.92 (m, 3H). LCMS calculated for: C12H17N6OS (M+H) 294.1; found: 294.1.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N:14]([CH3:24])[C:15](=[O:19])[O:16][CH2:17][CH3:18])=[CH:20][CH:21]=1
Reactant: CI
Reactant: CCOC(=O)Nc1c(Oc2ccc(N)cc2)ccnc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(C)c1c(Oc2ccc(N)cc2)ccnc1N
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 52.9 %

Procedure:
Method O1. Ethyl 4-(4-aminophenoxy)-2-aminopyridin-3-yl-carbamate (72 mg, 0.25 mmol) was dissolved in dry THF (3 mL) and cooled at 0° C. Sodium hydride (11 mg, 0.28 mmol) was added, and the reaction mixture was stirred for 25 minutes. Methyl iodide (18 μL, 0.25 mmol) was added. The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1.5 hours. The solvent was evaporated and the residue extracted between DCM and saturated Na2CO3. The organic layer was dried and evaporated, and the residue purified by column chromatography (eluent AcOEt) to afford the title compound (40 mg, 53%). 1H-NMR (δ, ppm, DMSO-d6): 1.10 (t, 3H, CH3,Et, J=7.04 Hz), 3.01 (s, 3H, CH3N), 3.90-4.10 (m, 2H, CH2,Et), 5.06 (s, 2H, NH2,Ph), 5.78 (d, 1H, HPy,5, J=6.68 Hz), 5.97 (s, 2H, NH2,Py2), 6.59 (d, 2H, Harom,Ph,3+5, J=8.76 Hz), 6.73 (d, 2H, Harom,Ph,2+6, J=8.79 Hz), 7.67 (d, 1H, HPy,6, J=5.73 Hz). LC-MS (m/z): 302 (M+, 100). Acc. mass (C15H19N4O3): calculated 303.1457, found 303.1453.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[Br:16][C:17]1[C:22]([O:23][CH2:24][C:25](O)=[O:26])=[CH:21][CH:20]=[C:19]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:18]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CCN(CC)CC>C1COCC1>[Br:16][C:17]1[C:22]([O:23][CH2:24][C:25]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:26])=[CH:21][CH:20]=[C:19]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:18]=1
Reactant: CC(C)(C)c1ccc(OCC(=O)O)c(Br)n1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)c(Br)n1
Yield: 65.5 %

Procedure:
3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (72 mg, 0.25 mmol) was reacted with (2-bromo-6-tert-butyl-pyridin-3-yloxy)-acetic acid (64 mg), DMTMM (1.2 eq, 83 mg) and NEt3 (2.5 eq, 90 μl) in THF to give the title compound (71 mg, 58.2%) after purification by column chromatography (Hex/EtOAc=1/1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[CH:12]([CH3:14])[CH3:13].Cl[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1>O1CCCC1>[CH3:13][C:12]([CH3:14])([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[C:11]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(C)C
Reactant: ClCc1ccc2ccccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1ccc2ccccc2c1
Yield: 169.6 %

Procedure:
Lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 25.3 mL, 25.3 mmol) was added to a mixture of ethyl isobutyrate (2.67 g, 23.0 mmol) in tetrahydrofuran (25 mL) at −78° C. After stirring for 30 m, a solution of 2-(chloromethyl)naphthalene (400 mg, 2.30 mmol) in tetrahydrofuran (10 mL) was added to the reaction mixture dropwise. The mixture was stirred at −78° C. for another hour and then at room temperature overnight. The mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over sodium sulfate and concentrated under vacuum to give ethyl 2,2-dimethyl-3-(naphthalene-2-yl)propanoate (1.00 g) as a yellow oil, which was used without further purification.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[F:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[OH:24].[OH-].[K+].Cl>CS(C)=O>[N+:14]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:20]1[CH:21]=[CH:22][C:23](=[O:24])[C:18]([F:17])=[CH:19]1)[NH:9][C:8](=[O:12])[C:7](=[O:13])[NH:6]2)([O-:16])=[O:15]
Reactant: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2[nH]c1=O
Reactant: Oc1ccncc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=c1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2[N+](=O)[O-])cc1F
Temperature: 130 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
First, 127 mg of 7-fluoro-6-nitro-1,4-dihydroquinoxaline-2,3-dione, 96 mg of 3-fluoro-4-hydroxypyridine, and 55 mg of powdered potassium hydroxide were added to 12 ml of dry dimethylsulfoxide. The mixture was stirred at 130° C. for 3 hours in a nitrogen atmosphere. Then, 50 ml of ice water was added to the reaction mixture, and the mixture was neutralized with 2N hydrochloric acid. The resultant precipitate was filtered and washed with water. The precipitate was dissolved in 3 ml of 1N sodium hydroxide. The solution was treated with activated carbon and filtered. The filtrate was neutralized with conc. hydrochloric acid. The precipitated crystals were filtered and dried to give 147 mg of 6-nitro-7-(3-fluoro-4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: [N:1]1[CH2:2][O:3][C:4](=[O:11])[C:5]2[C:6]=1[S:7][C:8](=O)[CH:9]=2.[CH2:12]1[C@@H:15](C(O)=O)[NH:14][CH2:13]1>CN(C)C=O.C(O)(=O)C>[S:7]1[C:6]2[NH:1][C:2](=[O:3])[C@@H:13]3[CH2:12][CH2:15][N:14]3[C:4](=[O:11])[C:5]=2[CH:9]=[CH:8]1
Reactant: O=C1C=C2C(=O)OCN=C2S1
Reactant: O=C(O)[C@@H]1CCN1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1Nc2sccc2C(=O)N2CC[C@@H]12
Yield: 72.6 %

Procedure:
A solution of 7.23 g (42.75 mmol) of 6H-thieno[2,3-d]-[1,3]oxazine-4,6(7H)-dione (J. chem. Res. (M), 1986, 1459) and 1.99 g (24.75 mmol) of L-azetidine-2-carboxylic acid in 30 ml of dimethylformamide and 6 ml of acetic acid was stirred at 120° for 16 hours. The brown solution was evaporated and the brown residue obtained was crystallized from ethanol. There were obtained 3.74 g (42%) of (S)-7,7a-dihydroazeto[1,2-a]thieno[2,3-e][1,4]diazepine-4,8(6H,9H)-dione as colourless needles of m.p. 272°-274°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[N:18][C:19]#[N:20])OC2C=CC=CC=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(#N)C>[C:19]([NH:18][C:10]([NH:26][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[N:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)#[N:20]
Reactant: NC1CCCC1
Reactant: N#CN=C(Nc1cc(Cl)cc(Cl)c1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#CNC(=Nc1cc(Cl)cc(Cl)c1)NC1CCCC1
Temperature: 82 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of N-(3,5-dichlorophenyl)-N'-cyano-O-phenylisourea (0.8 mmol, 250 mg) in dry acetonitrile (2 ml), cyclopentylamine (0.9 mmol, 0.089 ml) and triethylamine (0.125 ml) were added. The mixture was stirred for 21/2 h at 82° C. under nitrogen. After concentration the residue was purified by flash chromatography (ethyl acetate/heptane 1:2) to give the title compound (160 mg, 66%) as crystals. Mp 147.5-148.5° C.; 1H-NMR (CDCl3): δ 1.45 (m, 2H), 1.65 (m, 4H), 2.05 (m, 2H), 4.11 (sextet, 1H), 5.1 (br, 1H), 7.2 (m, 3H), 8.02 ppm (br, 1H); EI SP/MS: 296 (M+), 298 (M+2), 300 (M+4). MA calc for C13H14Cl2N4 : C, 52.54%; H, 4.75%; N, 18.85%. Found: C, 52.17%; H, 4.71%; N, 18.50%.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(N2CCNCC2)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A solution of t-butyl 4-phenylpiperazine-1-carboxylate (500 mg, 1.91 mmol, 1.00 equiv) in DCM/CF3COOH (10/3 mL) was placed in a 50-mL round bottom flask and stirred for 1 h at 30° C. in an oil bath. The pH value of the solution was adjusted to 9 with aqueous sodium hydroxide (1 M), and the solution was extracted with 3×10 mL of dichloromethane, the organic layers combined and dried over anhydrous sodium sulfate. Solids were removed via filtration, and the resulting solution concentrated under vacuum yielding 300 mg (97%) of 1-phenylpiperazine as yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12](=[O:20])[CH2:13][C:14](=NN(C)C)[CH3:15])[CH3:2].CC1(C)[O:27][C:26](=O)[CH:25]=[C:24]([CH3:29])[O:23]1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:13]1[C:26](=[O:27])[CH:25]=[C:24]([CH3:29])[O:23][C:14]=1[CH3:15])=[O:20])[CH3:2]
Reactant: CCc1cccc(CC)c1NC(=O)CC(C)=NN(C)C
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1NC(=O)c1c(C)oc(C)cc1=O
Yield: 74.3 %

Procedure:
A mixture of 25.0 g (90.8 m mol) of N-(2,6-diethylphenyl)-3-(N,N-dimethylhydrazono)butyramide and 130 ml of toluene was refluxed, to which a solution of 28.4 g (200 m mol) of 2,2,6-trimethyl-4H-1,3-dioxin-4-one was dropwise added over a period of 30 minutes. The mixture was further refluxed for 2 hours. After distilling off the solvent, 200 ml of ethyl ether was added to the residue. The mixture was well stirred and filtered to remove insoluble material. The filtrate was concentrated and subjected to chromatography to remove high polar impurities. The resultant product was recrystallized from hexane to obtain 20.2 g (Yield 74%) of the title compound.