Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[S:17][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](=[O:11])[N:5]2[CH:4]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CN(C=O)C.C(Cl)Cl>[N:18]1([CH2:2][C:3]2[S:17][C:6]3=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](=[O:11])[N:5]3[CH:4]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cnc2sc(CBr)cn2c1=O
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cnc2sc(CN3CCOCC3)cn2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A mixture of ethyl 2-(bromomethyl)-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylate (Preparation 9, 159 mg) and morpholine (0.5 mL) in DMF (10 mL) is stirred for 4 h at rt. The mixture is diluted with CH2Cl2 (100 mL) and is washed with water. The organic layer is dried (MgSO4) and concentrated to afford 130 mg (80%) of the title compound as a white solid. Physical characteristics: MS (ESI+) m/z 324 (M+H)+. 1H NMR (DMSO) δ 8.62, 8.22,4.25, 3.75, 3.59, 2.49, 1.28.
Reaction SMILES: Cl.[C:2]1([CH:8]([CH3:11])[CH2:9][NH2:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:19][CH:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:2]1([CH:8]([CH3:11])[CH2:9][NH:10][S:22]([CH:20]([CH3:21])[CH3:19])(=[O:24])=[O:23])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(CN)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CNS(=O)(=O)C(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
To a solution of 2-phenyl-propylamine HCl salt (1.0 g, 5.8 mmol), DMAP (35 mg, 0.3 mmol) and Et3N (1.77 g, 17.5 mmol) in DCM (25 mL) was added propane-2-sulfonyl chloride (1.25 g, 8.7 mmol) dropwise at 0° C. The mixture was stirred at r.t. for 16 h, and was then concentrated under vacuum. The residue was partitioned between EtOAc (100 mL) and H2O (10 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous Na2SO4, filtrated and concentrated to give an oil residue. This residue was purified with silica gel column (Hexane/EtOAc=2/1 to 1/1) to obtain the desired product (1.2 g, 86%) as a pale yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.30-7.32 (m, 2H), 7.18-7.24 (m, 3H), 3.90-3.94 (m, 1H), 3.30-3.35 (m, 1H), 3.18-3.22 (m, 1H), 2.99-3.04 (m, 1H), 2.91-2.95 (m, 1H), 1.27 (d, 3H, J=7.2 Hz), 1.25 (d, H, J=7.8 Hz), 1.22 (d, 1H, J=7.2 Hz).
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:16][O:17][C:18](=[O:28])[C@H:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:20][C:21]([OH:23])=O.[CH2:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][NH:30]1.[Cl-].[Na+]>ClCCl>[CH3:16][O:17][C:18](=[O:28])[CH:19]([CH2:20][C:21]([N:30]1[CH2:31][CH2:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29]1)=[O:23])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: c1ccc2c(c1)CCNC2
Reactant: COC(=O)[C@@H](CC(=O)O)CC(C)C
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)C(CC(=O)N1CCc2ccccc2C1)CC(C)C
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
iso-Butyl chloroformate (33.64 mg, 0.2463 mmol) in dichloromethane (2 ml) and N-methyl morpholine (49.83 mg, 0.4927 mmol) in dichloromethane (2 ml) were simultaneously added to a stirred solution of (R)-2-isobutyl succinic acid 1-methyl ester (42.15 mg, 0.2239 mmol) in dichloromethane (2 ml) at −15° C. under argon over 5 minutes. The mixture was stirred at −15° C. for 15 minutes. A freshly prepared solution of 1,2,3,4-tetrahydro-isoquinoline (29.83 mg, 0.2239 mmol) in dichloromethane (2 ml) and N-methylmorpholine (24.92 mg, 0.2463 mmol) was then added dropwise. The mixture was then stirred at ambient temperature for 16 hours. The reaction mixture was poured into saturated aqueous sodium chloride solution (1 ml). The aqueous layer was extracted with diethyl ether (2×5 ml) which was discarded. The aqueous layer was acidified with 1M hydrochloric acid to pH (12), then the product was extracted into dichloromethane (3×5 ml). The combined dichloromethane layers were washed with water (2×5 ml), saturated aqueous sodium chloride solution (2×5 ml) then dried (Na2SO4). The solvent was removed in vacuo to give a residue which was purified over silica gel eluting with a gradient of n-heptane:ethyl acetate 4:1. Desired fractions were combined and reduced in vacuo to leave 2-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]-4-methyl-pentanoic acid methyl ester as a colourless oil (35 mg, 51.5% from starting acid). TLC (single UV spot, Rf=0.6, n-heptane:ethyl acetate 1:1), HPLC-MS (single UV peak with Rt=9.544 mins, 304.2 [M+H]+, 305.2 [M+2]+, 306.2 [M+3]+, 629.3 [2M+Na]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:21]([CH2:20][Cl:19])=[O:22])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(C(=O)CCl)CC1
Reaction time: 2 h
Yield: 383.5 %

Procedure:
To a solution of 1-ethoxycarbonylpiperazine (1.5 mL, 10 mmol) in 40 mL CH2Cl2, was added triethylamine (2 mL, 14 mmol) and chloroacetyl chloride (0.8 mL, 5.0 mmol) at 0° C. The resulting reaction mixture was stirred at amibent temperature for 2 hours. The reaction mixture was washed with water, 2N NaHSO4 and brine, and dried over sodium sulfate. The solvent was evaporated in vacuo to afford 1-ethoxycarbonyl-4-chloromethylcarbonylpiperazine (4.5 g) as an yellow oil, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([NH:29][CH3:30])=[O:28])[C:20]([Cl:34])=[CH:19][N:18]=1>>[Cl:34][C:20]1[C:21]([NH:23][C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([NH:29][CH3:30])=[O:28])=[N:22][C:17]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CNC(=O)c1cccc(Nc2nc(Cl)ncc2Cl)c1
Product: CNC(=O)c1cccc(Nc2nc(Nc3ccc4c(c3)C(C)(C)CCC(=O)N4)ncc2Cl)c1
Yield: 19 %

Procedure:
In an analogous procedure to Example 651, part c, 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide were combined to yield 3-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (19.47 mg, 19% yield) as a white amorphous solid. 1H-NMR (CDCl3) δ 8.10 (s, 1H), 8.01 (s, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.58 (d, J=8.60 Hz, 1H), 7.48 (m, 1H), 7.38 (m, 1H), 7.38 (m, 1H), 7.32 (s, 1H), 7.17 (d, J=14.9 Hz, 1H), 7.07 (s, 1H), 6.81 (d, J=7.8 Hz, 1H), 6.06 (br s, 1H), 2.97 (s, 3H), 2.37 (m, 2H), 2.07 (m, 2H), 1.33 (s, 6H). LC/MS (ESI+)=465 (M+H). MP=184.5° C.
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[NH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>O1CCCC1>[C:1]([NH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:23][CH:24]=1)(=[O:11])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=C(O)C=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
To a suspension of 0.33 g (2.01 mmol) of N,N′-carbonyldiimidazole in tetrahydrofuran (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of cinnamic acid at 0° C. Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 7. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give the title compound (0.51 g, 91%). HRMS calcd for C17H15NO3: 281.3242. Found: 281.3240. MA calcd for C17H15NO3: C, 72.58%; H, 5.38%; N, 4.98%. Found: C, 72.42%; H, 5.37%; N, 4.87%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1cccnc1-c1c(-c2ccc(Cl)cc2)c(C)n[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cccnc1-c1c(Cl)nnc(C)c1-c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
0.34 g of 5-(4-chlorophenyl)-6-methyl-4-(3-methyl-2-pyridyl)-2H-pyridazin-3-one and 3.6 g of phosphorus oxychloride were mixed. The mixture was stirred for 2 hours on an oil bath of 120° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.33 g of the resultant residue was subjected to silica gel column chromatograph, to obtain 0.21 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(3-methyl-2-pyridyl)pyridazine (hereinafter, described as compound (2) of the present invention.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:25][OH:26].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:25]\[OH:26])[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: O=C(CC(c1ccccc1)c1cccc(Br)c1)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O/N=C(\CC(c1ccccc1)c1cccc(Br)c1)c1ccncc1

Procedure:
In analogy to example 1, step 2, from 3-(3-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a colorless oil, MS (ESI+): m/z=381.0 ([M+H]+, 1Br).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([Cl:13])[CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=2)[CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC>>[Cl:13][C:7]1[CH:8]=[C:9]([OH:12])[CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=1)[CH:3]=[C:2]2[CH:22]=[CH2:23]
Reactant: Oc1cc(Cl)c2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Product: C=Cc1cc(-c2ccc(O)c(F)c2)nc2c(Cl)cc(O)cc12
Yield: 84 %

Procedure:
This compound was prepared from 45a based on method J using 1.1 equiv. of tributyl(vinyl)tin at 90° C. Red solid; Yield: 84%; mp 225° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 5.74 (dd, J=11.1, 1.0 Hz, 1H), 6.30 (dd, J=17.3, 1.1 Hz, 1H), 7.10 (dd, J=8.8, 8.8 Hz, 1H), 7.35 (d, J=2.6 Hz, 1H), 7.38 (dd, J=17.3, 11.1 Hz, 1H), 7.53 (d, J=2.5 Hz, 1H), 8.04 (dd, J=8.4, 1.7 Hz, 1H), 8.16 (dd, J=13.1, 2.1 Hz, 1H), 8.16 (s, 1H), 10.27 (s, 1H), 10.35 (s, 1H); 19F-NMR (400 MHz, DMSO-d6) δ −136.51 (dd, J=13.2, 9.3 Hz); MS (ESI) m/z 314/316 ([M−H]−), 316/318 ([M+H]+); Anal. Calcd for C17H11ClFNO2: C, 64.67; H, 3.51; N, 4.44. Found: C, 63.57; H, 3.61; N, 4.04.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:36])[CH2:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])=[CH:20][C:19]=3[F:37])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2].O=[C:39](NC1C=CC=CC=1)[CH2:40]C(O)=O>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH:26]4[CH2:40][CH2:39][N:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:27]4=[O:28])=[O:36])=[CH:20][C:19]=3[F:37])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)c1
Reactant: O=C(O)CC(=O)Nc1ccccc1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)C5CCN(c6ccccc6)C5=O)cc4F)c3s2)c1
Yield: 40 %

Procedure:
Following the procedure described above for the synthesis of compound 5d (scheme 4), but replacing acid 1 with the acid 205, title compound 204 was obtained in 40% yield. 1HNMR (DMSO-d6) δ(ppm): 10.72 (s, 1H), 8.49 (d, J=5.7 Hz, 1H), 8.06 (d, J=1.0 Hz, 1H), 7.96-7.90 (m, 2H), 7.72 (s, 1H), 7.67-7.65 (m, 2H), 7.53-7.49 (m, 2H), 7.41-7.37 (m, 2H), 7.16 (t, J=7.2 Hz, 1H), 6.70 (d, J=5.5 Hz, 1H), 4.06 (q, 2H), 3.93 (m, 2H), 3.77 (t, J=8.2 Hz, 1H), 4.42 (m, 2H), 1.40 (t, 3H). MS (m/z): 542.0 (M+H).
Reaction SMILES: BrN1C(=[O:7])CCC1=O.Br.[C:10]([O:18][CH:19]([CH3:33])[CH2:20][CH:21]1[CH2:26][O:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:23][CH2:22]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[C:24]([O:25][CH2:26][CH:21]([CH2:20][CH:19]([O:18][C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:33])[CH2:22][OH:7])(=[O:23])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(CC1COC(c2ccccc2)OC1)OC(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(CC(CO)COC(=O)c1ccccc1)OC(=O)c1ccccc1
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a stirred and ice cooled suspension of 9.344 g (52.5 mM) of N-bromosuccinimide in 250 ml of water are added a drop of conc. hydrobromic acid and 17.125 g of the crude 5-(2-benzoyloxypropan-1-yl)-2-phenyl-1,3-dioxane m4 obtained in the previous reaction dropwise. After standing at 0° C. for another 1 hour, 22 g (260 mM) of sodium bicarbonate is added to the reaction mixture and the product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated. Purification of the product by column silica gel chromatography using n-hexane-ethyl acetate (1:1) as an eluent gives 7.401 g (29.7% yield from the compound m2) of the titled compound m5 as an oily product.
Reaction SMILES: [C:1]([CH:3]=[C:4](OC)[O:5][CH3:6])#[N:2].[CH3:9][C:10]1[N:11]=[CH:12][NH:13][C:14]=1[CH2:15][S:16][CH2:17][CH2:18][NH2:19]>>[C:1]([CH:3]=[C:4]([O:5][CH3:6])[NH:19][CH2:18][CH2:17][S:16][CH2:15][C:14]1[NH:13][CH:12]=[N:11][C:10]=1[CH3:9])#[N:2]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: COC(=CC#N)OC
Product: COC(=CC#N)NCCSCc1[nH]cnc1C

Procedure:
Reaction of 1-cyano-2,2-bis methoxyethylene (J.A.C.S., 1949, 71, 47) with 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole by the procedure of Example 8(i) yields 1-cyano-2-methoxy-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene.
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[OH:12])=[O:4].[C:13](OCC)(=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>C(O)C>[OH:11][C:9]1[CH:10]=[C:5]2[C:6](=[CH:7][CH:8]=1)[O:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:2][C:3]2=[O:4]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cc(O)ccc1O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2cc(O)ccc2o1
Temperature: 25 °C

Procedure:
1.1 3.8 g of sodium are dissolved in portions in 300 ml of ethanol with stirring. A solution of 5.0 g of 2,5-dihydroxyacetophenone and 17.8 ml of diethyl oxalate in 25 ml of ethanol is subsequently added dropwise. The reaction mixture is then heated at 800 for 3 hours and cooled to room temperature, and 10 ml of 32% HCl are added dropwise. The mixture is heated at 90° for 30 minutes and cooled, and the solvent is removed. Conventional work-up gives 5.6 g of 6-hydroxy-2-ethoxycarbonylchromen-4-one (“AA”).
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([CH3:13])[CH:11]([NH2:14])[CH:10]([CH3:15])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)Cl>[C:16]1([CH:9]2[CH:10]([CH3:15])[CH:11]([NH:14][C:29](=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:12]([CH3:13])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:8]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC1C(c2ccccc2)NC(c2ccccc2)C(C)C1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)NC1C(C)C(c2ccccc2)NC(c2ccccc2)C1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
To a stirred 0° C. solution of 12.7 g (45.3 mmol) of 2,6-diphenyl-3,5-dimethyl-4-aminopiperidine and 5.1 g (50 mmol) of triethylamine in 150 ml of methylene chloride is added dropwise a solution of 9.9 g (45.3 mmol) of lauroyl chloride. After stirring for 30 minutes at 0° C., the reaction mixture is washed with water (2×200 ml) followed by a saturated aqueous sodium bicarbonate solution (300 ml). The organic phase is separated, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting solid is recrystallized from ethanol to give 15.4 g (73% yield) of the title compound as a white solid melting at 112°-114° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([NH:8][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(NCc2ccccc2)c1
Temperature: 25 °C
Yield: 107.7 %

Procedure:
A solution of benzylamine (0.77 mL, 7.0 mmol), ethyl 3-fluoro-4-nitrobenzoate (1.0 g, 4.7 mmol) and TEA (2 mL) was heated in DMF (10 mL) for 18 hr at 70° C. The solution was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed with H2O (2×100 mL) then 1N HCl (2×100 mL). The organic layer was dried (MgSO4), filtered and then concentrated to provide 1.52 g (˜100%) of crude ethyl 3-(benzylamino)-4-nitrobenzoate as an orange solid. This material was used without further purification.
Reaction SMILES: [CH3:1]I.[Li+].[BH4-].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:20][CH3:21])[C:16]=1[CH:17]([CH3:19])[CH3:18])[C:10]([O:12]C)=O.Cl>CCOCC.O>[CH3:21][O:20][C:15]1[CH:14]=[C:9]([CH:10]([OH:12])[CH3:1])[CH:8]=[C:7]([O:6][CH3:5])[C:16]=1[CH:17]([CH3:19])[CH3:18]
Reactant: CI
Reactant: COC(=O)c1cc(OC)c(C(C)C)c(OC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COc1cc(C(C)O)cc(OC)c1C(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of Mg (2 g, 82.2 mmol) in dry ether (100 mL) was added CH3I (5 mL, 80.4 mmol) in dry ether (100 mL). After the addition was completed, the reaction mixture was refluxed for 1 hour and then cooled to 0° C. LiBH4 (2.0M in THF, 25 mL, 50 mmol) was added followed by addition of methyl 3,5-dimethoxy-4-i-propylbenzoate (10.0 g, 42.0 mmol) in dry ether (300 mL). The reaction was stirred at 0° C. overnight. Water (50 mL) was added dropwise followed by 2N HCl (100 mL). The organic layer was separated and the aqueous extracted with ether (4×200 mL). The extract was dried over anhydrous sodium sulfate. Evaporation of the solution yielded a liquid mixture. This was used directly in the next step without purification.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:8]=2)[N:3]=1.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>O1CCOCC1.CCOC(C)=O>[CH2:20]([NH:24][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:8]=2)[N:3]=[C:2]([NH:3][CH2:4][CH2:5][CH2:6][CH3:7])[N:11]=1)[CH2:21][CH2:22][CH3:23]
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(Cl)c3c2)cc1
Reactant: CCCCN
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCCNc1nc(NCCCC)c2cc(-c3ccc(F)cc3)ccc2n1
Temperature: 60 °C
Yield: 64.2 %

Procedure:
To a solution of 2,4-Dichloro-6-(4-fluoro-phenyl)-quinazoline (20 mg, 0.068 mmol) in 1,4-dioxane was added n-butylamine (20 mg). The solution was heated to 60° C. for 2 hours, and subsequently cooled, diluted with EtOAc and washed with brine. The organic layer was dried and purified by RP HPLC with a gradient of H2O, 0.1% TFA-acetonitrile, to provide the desired product (8 mg). The product was characterized as follows: MS (m/z): 367 ([M+H]+, 100); HPLC Rt=1.69 minutes (Method A).
Reaction SMILES: [CH2:1]([C:3]1[S:30][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:15]=3[O:28][CH3:29])[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[O:34].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:30][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:15]=3[O:28][CH3:29])[C:8](=[O:12])[N:9]([CH2:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)=[O:34])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3OC)c2s1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3OC)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-3′-methoxybiphenyl-2-carbonitrile (1.9 g), 2-bromo-1-(4-methoxyphenyl)ethanone (1.3 g) and N,N-dimethylformamide (19 mL) was added 60% sodium hydride (0.28 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as pale-yellow crystals (1.2 g, 46%).