Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[C:14]([N+:20]([O-:22])=[O:21])[CH2:15][S:16][CH2:17][CH:18]=[CH2:19])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[CH3:27]I>CN(C)C=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][N:11]([CH3:27])[C:10]2=[C:14]([N+:20]([O-:22])=[O:21])[CH2:15][S:16][CH2:17][CH:18]=[CH2:19])=[CH:4][CH:3]=1
Reactant: C=CCSCC(=C1NCCN1Cc1ccc(Cl)nc1)[N+](=O)[O-]
Reactant: [H][H]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCSCC(=C1N(C)CCN1Cc1ccc(Cl)nc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
0.5 g of 1-(6-chloro-3-pyridylmethyl)-2-(1-nitro-2-allylthioethylidene)imidazolidine was dissolved in 10 ml of N,N-dimethylformamide, and 0.06 g of sodium hydride (60% oil suspension) was then gradually added thereto at room temperature. The resultant reaction liquor was continuously stirred for about 15 minutes until the generation of hydrogen gas stopped, and thereafter 0.18 g of methyl iodide was gradually added dropwise to the reaction liquor. The reaction liquor was further continuously stirred for 2 hours at room temperature, and the solvent was then distilled off under reduced pressure to obtain a residue. The residue thus obtained was purified by silica gel column chromatography (eluting solution: ethyl acetate/methanol =2/1) to obtain 0.26 g of the desired compound (Compound No. 63) having a refractive index of nD39.0 =1.6205.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=O)[NH:12][C:13]2[CH:18]=[C:17]([F:19])[C:16]([Cl:20])=[CH:15][C:14]=2[NH2:21])=[CH:6][CH:5]=1>CC(O)=O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][C:13]3[CH:18]=[C:17]([F:19])[C:16]([Cl:20])=[CH:15][C:14]=3[N:21]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC(=O)Nc2cc(F)c(Cl)cc2N)cc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Cc2nc3cc(Cl)c(F)cc3[nH]2)cc1
Yield: 94.1 %

Procedure:
Compound 72 (333 mg, 0.99 mmol) was dissolved in AcOH (10 ml) and the solution was refluxed, for 24 h. AcOH was evaporated and the residue was dissolved in AcOEt, washed with aqueous NH4Cl, NaHCO3 and brine, and dried over MgSO4. Evaporation of EtOAc provided the title compound 73 as a brownish powder (297 mg, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH:14]=[O:15])[N:4]=1.[CH3:20]ON>CO>[CH3:20][C:12]1([O:11][C:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:13]1[CH:14]=[O:15]
Reactant: COc1cc(OC)nc(Oc2ccccc2C=O)n1
Reactant: CON
Solvent: CO
Product: COc1cc(OC)nc(OC2(C)C=CC=CC2C=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.3 %

Procedure:
In 100 ml of methanol, 5.2 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldehyde and 1.0 g of methoxyamine were dissolved. The solution was stirred at room temperature for 2 hours. After the methanol was distilled out under reduced pressure, the resulting residue was purified by silica gel chromatography (developer: n-hexane:ethyl acetate=10:1) to obtain 5.7 g of 0-methyl-2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldehyde as an oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([CH2:27][CH:28]=C)([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][B:10]1[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]1)[CH3:2].[O:31]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4](=[O:30])[C:5]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])([CH2:27][CH:28]=[O:31])[CH2:6][CH2:7][CH2:8][CH2:9][B:10]1[O:11][C:12]([CH3:17])([CH3:18])[C:13]([CH3:15])([CH3:16])[O:14]1)[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=CCC(CCCCB1OC(C)(C)C(C)(C)O1)(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(CC=O)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 93 %

Procedure:
A solution of Ethyl-2-allyl-2-(tert-butoxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (650 mg, 1.53 mmol) in dichloromethane (30 mL,) was cooled to −78° C. and treated with ozone until a pale blue-gray color appeared. After TLC indicated the absence of starting material, the ozone inlet tube was replaced with nitrogen and nitrogen was bubbled through the solution for 20 min to remove any excess ozone. Triphenylphosphine (1.20 g, 4.59 mmol, 3 equiv) was added in one portion, the cooling bath was removed and the mixture was stirred for 4 h. The solution was concentrated and purified by MPLC (0-40% ethyl acetate in heptane) gave the title compound as a colorless oil (608 mg, 93%). Rf 0.25 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz): δ 9.64 (s, CHO, 1H), 5.60 (br, s, NH, 1H), 4.19 (q, J=7.5 Hz, 2H), 3.56 (d, J=17 Hz, 1H), 2.93 (d, J=17.5 Hz, 1H), 2.20 (m, 1H), 1.62 (m, 1H), 1.38 (s, 9H), 1.28-1.43 (m, 4H), 1.23 (t, J=7 Hz, 3H), 1.21 (s, 12H) and 0.72 (t, J=7.5 Hz, 2H).
Reaction SMILES: C(O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].P(N=[N+]=[N-])(=O)([O:29][C:30]1C=CC=CC=1)OC1C=CC=CC=1.C([N:42](CC)CC)C.CCOCC>C1(C)C=CC=CC=1>[CH2:2]([N:42]=[C:30]=[O:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CCN(CC)CC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCN=C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 50 ml of toluene is dissolved 5.68 g of stearic acid, followed by addition of 5.5 g of diphenyl phosphoroazidate ##STR19## and 3.0 ml of triethylamine. The mixture is stirred at room temperature for 2 hours. The reaction mixture is cooled, 100 ml of ether is added and the ether layer is washed with ice-water. The organic layer is taken, dehydrated with a dehydrating agent and refluxed for 2 hours, whereby 5.3 g of the above-indicated compound is obtained as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>ClCCl>[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:8]([C:7]2[C:2]([Cl:1])=[N:3][C:4]([S:11][CH3:12])=[N:5][CH:6]=2)=[O:9])=[CH:16][CH:15]=1
Reactant: Nc1ccc(F)cc1
Reactant: CSc1ncc(C(=O)Cl)c(Cl)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(Cl)n1
Reaction time: 0.25 h

Procedure:
To a mixture of 4-chloro-2-methylsulfanylpyrimidine-5-carbonyl chloride prepared above (113 mg, 0.54 mmol) in dichloromethane was added 4-fluoroaniline (56 μL, 0.59 mmol). This was followed by the dropwise addition of DIPEA. The mixture was stirred for 15 min, the mixture was diluted with dichloromethane, washed with water and saturated aqueous sodium bicarbonate and was dried over sodium sulfate. Filtration and concentration afforded a residue that was purified by trituration from ethyl acetate with hexanes. The resulting off-white solid (122 mg, 0.41 mmol, 76%) was sufficiently pure to use without further purification. 1H NMR (300 MHz, DMSO-d6) δ 10.7 (s, 1H), 8.86 (s, 1H), 7.69 (m, 2H), 7.23 (m, 2H), 2.56 (s, 3H); MS (EI) m/z 296.2 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:13][CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].S(Cl)([Cl:25])(=O)=O>ClCCl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:13][CH:12]=2)[C:10]=1[Cl:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cnc(-c3ccccc3)s2)n[nH]1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]nc(-c2cnc(-c3ccccc3)s2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 25 mg (0.084 mmol) of the above-prepared 5-(2-phenyl-thiazol-5-yl) -2H-pyrazole-3-carboxylic acid ethyl ester in dichloromethane was added 23 mg (0.168 mmol) of sulfuryl chloride and allowed to stir overnight at room temperature. The solution was diluted with ethyl acetate, washed once with aqueous sodium bicarbonate, once with water once with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 7:93 ethyl acetate:hexanes as eluant to give 23 mg of the title compound (82%). 1H NMR (500 MHz, CDCl3) δ 8.39 (s, 1H) 7.94 (d, 2H) 7.40 (m, 2H) 4.40 (q, 2H) 1.38 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](=[O:21])([O-])[O-].[K+].[K+].ClC1[C:34]2[C:29](=[CH:30][C:31]([O:37][CH2:38][CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][N:26]=1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:36][O:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][C:31]=1[O:37][CH2:38][CH2:39][CH2:40][N:41]1[CH2:42][CH2:43][O:44][CH2:45][CH2:46]1)[N:28]=[CH:27][N:26]=[C:18]2[O:21][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10][CH2:11]2
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccccc21
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc4c(c3)CCCN4C(=O)OC(C)(C)C)ncnc2cc1OCCCN1CCOCC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
6-Hydroxy-4-(1-tertbutoxycarbonyl-1,2,3,4-tetrahydroquinoline (82 mg, 0.32 mmol) was dissolved in anhydrous dimethylformamide under argon, with potassium carbonate (61 mg, 0.44 mmol) and 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (100 mg, 0.3 mmol), (prepared as described for the starting material in Example 1). No reaction occurred after 2 hours at 60° C. Sodium hydride (12 mg, 0.3 mmol) was added and the reaction mixture was heated at 120° C. for 90 minutes. The cooled mixture was poured into water and ethyl acetate. The organic phase was washed with water, brine, dried (MgSO4), filtered and the solvent evaporated. The residue was purified by flash chromatography using first dichloromethane/methanol (97/3) as solvent. Evaporation of the solvent gave 6-methoxy-7-(3-morpholinopropoxy)-4-((1-tertbutoxycarbonyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy)quinazoline (115 mg, 71%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=O)C.O.[NH2:13][NH2:14]>C(O)C>[N:7]1[CH:8]=[CH:9][CH:10]=[N:11][C:6]=1[C:4]([NH:13][NH2:14])=[O:3]
Reactant: CCOC(=O)c1ncccn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ncccn1
Yield: 68.8 %

Procedure:
A mixture of pyrimidine-2-carboxylic acid ethyl ester (Ann. Chim., 5, 351 (1960)) (0.866 g, 5.7 mmol) and hydrazine hydrate (0.332 mL, 6.8 mmol) in ethanol (20 mL) was heated under reflux for 3 hours, then concentrated under reduced pressure. The residue was triturated with diethyl ether, collected by filtration and washed with ethyl acetate to give the title compound (0.542 g, 69%) as a yellow solid, mp 173-175° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.N[C:30]1[CH:31]=[C:32]2[C:36](=CC=1)[CH2:35]N(C(NC1C=CC(C(=O)NCCC)=CC=1)=O)[CH2:33]2>>[CH3:33][C:32]1[CH:36]=[CH:35][C:2]([C:1]([N:5]2[CH2:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]4[CH2:21][C:22]5[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:28]4)=[O:19])=[CH:13][CH:12]=3)[CH2:9][CH2:10]2)=[O:3])=[CH:30][CH:31]=1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: CC(=O)Cl
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccccc2C1
Product: Cc1ccc(C(=O)N2CC=C(c3ccc(NC(=O)N4Cc5ccccc5C4)cc3)CC2)cc1

Procedure:
The title compound was prepared as described in Example 278, substituting 4-methylbenzoyl chloride for acetyl chloride and N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (s, 1H), 7.55-7.58 (m, 2H), 7.20-7.39 (m, 10H), 6.01-6.21 (m, 1H), 4.77 (s, 4H), 3.93-4.36 (m, 2H), 3.43-3.90 (m, 2H), 2.48-2.57 (m, 2H), 2.36 (s, 3H); MS (ESI(+)) m/e 438 (M+H)+.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[I:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH2:28].[CH3:29][O:30][C:31](=[O:37])[CH:32]([CH3:36])[C:33](O)=[O:34].CCN(CC)CC.[OH-].[Na+]>CCOC(C)=O>[I:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH:28][C:33](=[O:34])[CH:32]([CH3:36])[C:31]([O:30][CH3:29])=[O:37]
Reactant: COC(=O)C(C)C(=O)O
Reactant: NCCc1ccccc1I
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)C(=O)NCCc1ccccc1I
Temperature: 25 °C
Reaction time: 144 h
Yield: 78.5 %

Procedure:
A solution of T3P in AcOEt (50%, 26.2 mL, 44.0 mmol) was added dropwise at 0° C. under N2 to a clear solution of 2-(2-iodophenyl)ethanamine (9.45 g, 38.2 mmol), 3-methoxy-2-methyl-3-oxopropanoic acid (5.05 g, 38.2 mmol) and Et3N (10.7 mL, 76.0 mmol) in AcOEt (350 mL). The mixture was stirred at RT for 6 days. A 2N aqueous solution of NaOH (50 mL) was then added to the reaction and the mixture was extracted with AcOEt. The combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The yellow oil obtained was purified by flash chromatography (SiO2, cHEx/AcOEt 100:0 to 50:50) to afford the title compound (10.83 g) as a clear oil. UPLC-MS: MS 362.2 (M+H+); UPLC rt 0.95 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[N:9][N:8]=2)[CH:7]=1
Reactant: CN1CCN(CCC(=O)NNc2ccc(F)cn2)CC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(CCc2nnc3ccc(F)cn23)CC1
Reaction time: 18 h
Yield: 72.4 %

Procedure:
Intermediate 2a (458 mg, 1.63 mmol) was dissolved in THF (15 mL) and cooled in an ice/water bath. Triphenylphosphine (854 mg, 3.26 mmol) was added followed by triethylamine (907 μL, 6.52 mmol) and hexachloroethane (773 mg, 3.26 mmol). The reaction was stirred for 18 h and then loaded onto an SCX-2 cartridge, which was washed with MeOH and product eluted with 2M NH3 in MeOH. Further purification by FCC, using 0-10% [2M NH3 in MeOH] in DCM, afforded the title compound (310 mg, 1.18 mmol, 72%). LCMS (Method 4): Rt 0.28 min, m/z 264 [MH+].
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][CH2:30][O:31][C:24]=3[CH:23]=2)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:11]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Product: Cc1nccn1-c1nc(NCc2ccc3c(c2)OCCO3)c2cc([N+](=O)[O-])sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-nitro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-nitro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[F:19][C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=1.[ClH:27]>C(O)C.CN(C)C=O>[ClH:27].[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(F)cc1
Reactant: [H][H]
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Fc1ccc(OC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
86.4 g of 1-benzyl-4-piperidinol in 200 ml. and dimethylformamide are added dropwise to a stirred suspension of 34.7 g of a 50% oil dispersion of sodium hydride in 900 ml. of dimethylformamide at 60°-70° C. When no more hydrogen gas is liberated, a mixture of 68.4 g of p-difluorobenzene in 200 ml. of dimethylformamide is added slowly, and the temperature is raised to 80° C. Stirring and heating is continued for 48 hours, the reaction is cooled, poured into 2 l. of water, and the aqueous suspension is extracted with benzene. The benzene extracts are dried and the benzene is removed under reduced pressure, leaving a thick brown oil. The oil solidifies on standing. The solid is dissolved in 95% ethanol, the solution is filtered and the solvent is removed from the filtrate, leaving a yellow oil. The oil is dissolved in absolute ethanol, the solution is stirred, and saturated ethereal-HCl is added. A resultant hydrochloride salt precipitates out of solution and is collected and dried. The salt is recrystallized from an ethanol and ether mixture to give 1-benzyl-4-(p-fluorophenoxy)piperidine hydrochloride.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.O>CN(C)C=O>[C:13]([C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])=[CH:10][CH:11]=1)([OH:15])=[O:14]
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)/C=C\C(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
One molar equivalent of maleic anhydride and p-amino benzoic acid are dissolved in N,N-dimethylformamide (DMF), and the mixture stirred at room temperature for five hours under nitrogen atmosphere. The resulting solution is poured into a sufficient water to precipitate crude N-(4-carboxyphenyl)maleamic acid. This is filtered, dried, and recrystallized three times from water to obtain pure N-(4-carboxyphenyl)maleamic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([N:13]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.C(OC([N:30]1[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH:17]3[CH2:18][CH2:19][N:20]([C:36]([CH:33]4[CH2:34][CH2:35][NH:30][CH2:31][CH2:32]4)=[O:37])[CH2:21][CH2:22]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CCCN(C1CCNCC1)[C@@H]1CCc2ccc(OC)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(C1CCN(C(=O)C2CCNCC2)CC1)[C@@H]1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 104.5 %

Procedure:
Under an inert atmosphere was combined ((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine (7.0 g, 23.14 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (5.3 g, 23.14 mmol), EDCI (4.43 g, 23.14 mmol), HOBT (3.13 9, 23.14 mmol), and triethylamine (65 mL, 46.3 mmol) in dichloromethane (140 mL). The mixture was stirred at room temperature for 48 h then concentrated in vacuo. The residue was taken-up in EtOAc (150 mL) and washed with water (100 mL), 1N NaOH (30 mL), and brine (30 mL), then dried (MgSO4). The solution was filtered, and concentrated. This was flash chromatographed on silica gel eluting with 20% acetone in hexanes to afford the protected amine (10.0 g), which was deprotected with 10 mL trifluoroacetic acid as described herein to afford {4-[((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone 39 (6.5 g), [M+H]+=450.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=[O:3].[C:11](=O)([O:15]CC)[O:12][CH2:13][CH3:14].[H-].[Na+].Cl>C(O)C>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][C:11]([O:12][CH2:13][CH3:14])=[O:15])=[CH:5][CH:6]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 4-bromoacetophenone (80 g, 0.40 mol), ethanol (1 ml) and diethyl carbonate (350 ml) was added sodium hydride (32 g, 60% in oil) by small portions under ice-cooling and the mixture was stirred at room temperature for 4 hrs. The reaction solution was cooled to 0° C. and 6N hydrochloric acid (200 ml) was added. The mixture was extracted with ethyl acetate (200, 100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1-5:1) to give the objective substance (108.9 g, quantitative) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[Li]CCCC.CCCCCC.CON(C)[C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]>C1COCC1>[Cl:1][C:2]1[C:3]([F:8])=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1ccccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2F)C1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a stirred solution of 1-chloro-2-fluoro-benzene (13.0 g, 0.1 mol) in THF (250 mL) at −75° C. was added dropwise 2.5 M BuLi in hexane (40 mL, 0.1 mol) during 45 min. After additional stirring for 30 min at −75° C., a solution of (R)-tert-butyl 3-(methoxy(methyl)-carbamoyl)piperidine-1-carboxylate (21.76 g, 0.08 mol) in THF (100 mL) was added dropwise over 30 min. The mixture was allowed to warm from −70° C. to 0° C. The mixture was quenched with sat'd aq NH4Cl, extracted with EtOAc (3×) and the combined organic layers were dried over Na2SO4. Solvent removal and flash column chromatography, eluting with 5% EtOAc/PE afforded (R)-tert-butyl 3-(3-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (19.2 g, 70%). 1H NMR (400 MHz, CDCl3): 1.45 (s, 9H), 1.63 (m, 2H), 1.76 (m, 1 H), 2.06 (m, 1H), 2.87 (m, 1H), 3.15 (m, 1H), 3.25 (m, 1H), 3.9 (m, 1H), 4.2 (m, 1H), 7.18 (m, 1H), 7.60 (m, 2H). MS (E/Z): 342 (M+H+).
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)=O.O.[NH2:19][NH2:20].[CH2:21](O)C>>[C:12]1([C:11]2[C:9]([C:4]3[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:21][NH:20][N:19]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NN
Reactant: CCO
Reactant: O=Cc1ccccc1C(=O)Cc1ccccc1
Solvent: O
Product: c1ccc(-c2c[nH]nc2-c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
Formyldeoxybenzoin (10 g) was suspended in ethanol (50 ml ) and hydrazine hydrate (5 ml) added giving an orange solution which warmed to 40° C. This solution was stirred at room temperature for 3 hours and the solvent evaporated. The resulting oil was taken up in dichloromethane and washed with dilute hydrochloric acid (pH 2) and water, dried over potassium carbonate and evaporated to an orange solid. This was boiled in ether, cooled and filtered giving 3,4-diphenylpyrazole (5.64 g, 57%) as pale yellow crystals, m.p. 155°-6° C.