Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:13][C@@H:14]([C@@H:16]2[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH3:23])[CH2:17]2)[CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[C:11]([C:10]1[CH:9]=[N:8][N:6]2[CH:7]=[C:2]([C:48]3[CH:47]=[CH:46][C:45]([N:42]4[CH2:41][CH2:40][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:44][CH2:43]4)=[CH:50][CH:49]=3)[N:3]=[C:4]([O:13][C@@H:14]([C@@H:16]3[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[CH3:23])[CH2:17]3)[CH3:15])[C:5]=12)#[N:12]
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cn4ncc(C#N)c34)CC2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cn4ncc(C#N)c34)CC2=O)cc1
Temperature: 100 °C

Procedure:
Intermediate 5.64 (218 mg, 0.496 mmol), (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (303 mg, 0.99 mmol), K3PO4 (420 mg, 2.0 mmol) and Bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium (II) (18 mg, 0.025 mmol) were taken up in 1,4-dioxane (7 mL) and water (0.72 mL). The stirred reaction mixture was heated to 100° C. Once complete, the reaction mixture was partitioned between EtOAc, water, and brine. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography to provide tert-butyl 4-(4-(3-cyano-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazin-6-yl)phenyl)piperazine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C37H44N7O5: 666.3; found: 666.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-(4-Fluoro-benzyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.25 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.33 mmol of 4-fluoro-benzylamine. LC/MS [6.99 min; 466 (M+1)]
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][N:4]([S:9]([C:12]2[CH:25]=[CH:24][C:23]3[N:22]([CH3:26])[C:21]4[C:16](=[CH:17][C:18]([S:27]([N:30]5[CH2:35][CH:34]([CH3:36])[CH2:33][CH:32]([CH3:37])[CH2:31]5)(=[O:29])=[O:28])=[CH:19][CH:20]=4)[C:15](=S)[C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH2:3]1.Cl.[NH2:40][OH:41]>N1C=CC=CC=1>[CH3:37][CH:32]1[CH2:33][CH:34]([CH3:36])[CH2:35][N:30]([S:27]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([CH3:26])[C:23]4[C:14](=[CH:13][C:12]([S:9]([N:4]5[CH2:5][CH:6]([CH3:8])[CH2:7][CH:2]([CH3:1])[CH2:3]5)(=[O:11])=[O:10])=[CH:25][CH:24]=4)[C:15](=[N:40][OH:41])[C:16]=3[CH:17]=2)(=[O:28])=[O:29])[CH2:31]1
Reactant: CC1CC(C)CN(S(=O)(=O)c2ccc3c(c2)c(=S)c2cc(S(=O)(=O)N4CC(C)CC(C)C4)ccc2n3C)C1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC1CC(C)CN(S(=O)(=O)c2ccc3c(c2)c(=NO)c2cc(S(=O)(=O)N4CC(C)CC(C)C4)ccc2n3C)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of 2,7-bis(3,5-dimethylpiperidin-1-ylsulfonyl)-10-methylacridine-9(10H)-thione (290 mg, 0.5 mmole) in pyridine (5 mL) was added hydroxylamine hydrochloride (210 mg, 30 mmole) and the mixture was stirred at 100° C. for 8 hrs. Solvent was removed and the residue was treated with water to remove excess of hydroxylamine. Crude material was crystallized from methanol-water to give 245 mg (85%) of the title compound. MS 575 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C:3]([O:5][C@H:6]([O:10][C:11](ON1C(=O)[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C2C=CC=CC=2)C1=O)=[O:12])[CH:7]([CH3:9])[CH3:8])=[O:4].[NH2:40][CH2:41][CH2:42][CH2:43][P:44]([CH2:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)(=[O:46])[OH:45].C1COCC1>O>[C:3]([O:5][C@H:6]([O:10][C:11]([NH:40][CH2:41][CH2:42][CH2:43][P:44]([CH2:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)(=[O:45])[OH:46])=[O:12])[CH:7]([CH3:8])[CH3:9])(=[O:4])[CH:2]([CH3:39])[CH3:1]
Reactant: NCCCP(=O)(O)CC1CCCCC1
Reactant: CC(C)C(=O)O[C@H](OC(=O)ON1C(=O)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)C1=O)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)O[C@H](OC(=O)NCCCP(=O)(O)CC1CCCCC1)C(C)C
Temperature: 19 °C
Reaction time: 4 h

Procedure:
To a 3 L three necked round bottom flask fitted with a mechanical stirrer, temperature probe, and nitrogen inlet is added compound (25) (100 mmol), 3-aminopropyl(cyclohexylmethyl)phosphinic acid (100 mmol), THF (1 L), and water (100 mL). The suspension is stirred under a nitrogen atmosphere at 18-20° C. for 4 h during which time the reaction mixture becomes homogeneous. The THF is removed in vacuo and the reaction mixture is diluted with methyl tert-butyl ether (250 mL) and washed with 1N HCl (1×500 mL) and water (2×200 mL). The organic phase is separated and concentrated in vacuo to leave a white solid. The solid is purified by flash chromatography to afford the product (99) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28](O)=[O:29])[CH:25]=[CH:24][CH:23]=[N:22]1>>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:14][CH:15]4[CH:19]([CH2:18][N:17]([C:28]([C:27]5[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=5[N:21]5[CH:25]=[CH:24][CH:23]=[N:22]5)=[O:29])[CH2:16]4)[CH2:20]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1-n1cccn1
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Product: O=C(c1ccccc1-n1cccn1)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2-pyrazol-1-yl-benzoic acid. MS (ESI) mass calcd. for C26H24N6, 436.52; m/z found, 437.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[NH2:21][C:22]1[C:26]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:25][NH:24][N:23]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[C:22]3[N:21]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C(F)(F)F
Reactant: Nc1n[nH]cc1-c1cccnc1
Product: Cc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)cc1C(F)(F)F
Yield: 75.8 %

Procedure:
Reaction of 1-(4-methyl-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (149 mg, 0.5 mmol), prepared from 4-methyl-3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (160 mg, 76%). MS (ISP) 423.2 [(M+H)+]; mp 182° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a stirred solution of 1-t-butoxycarbonyl-3-pyrrolidinone (0.57 g, 3.23 mmol) in THF (10 mL) was added 4-chlorophenyl magnesium bromide (1.0 M, 5.2 mL) under the protection of argon at 0° C. The reaction was stirred at room temperature for 1 hour then quenched by the addition of saturated aqueous NH4OH (8 mL). The aqueous layer was extracted with EtOAc (50 mL×2), dried over MgSO4 and concentrated in vacuo. Chromatographic purification on silica gel (Hexane/EtOAc=3/1) provided 0.57 g 1-t-butoxycarbonyl-3-(4-chlorophenyl)-3-hydroxypyrrolidine (60%). m/z 298 (m+1)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[CH:4]=1.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[OH-].[Na+].O>C(O)C>[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:2][C:3]2[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[CH:4]=2)=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: Cc1cc(C)cc(CCl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)cc(COc2ccc(S(C)(=O)=O)cc2)c1
Yield: 74.7 %

Procedure:
To a solution of 2.9 g (18.9 mmol) of 1-chloromethyl-3,5-dimethylbenzene and 3.9 g (22.7 mmol) of 4-methylsulfonylphenol in ethanol (10 mL) was added 10 mL (20.0 mmol) of 2 N aqueous sodium hydroxide solution, followed by heating under reflux for 2 hours. After standing to cool, water was added and the precipitates were collected by filtration and dried under a reduced pressure to obtain 4.1 g (yield 75.3%) of 1-(4-methanesulfonylphenoxymethyl)-3,5-dimethylbenzene (VI-5). Its physical properties are shown below.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][NH:27][C:28]2=[O:33]>[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:11]([NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=1[CH:25]=[N:26][NH:27][C:28]3=[O:33])[C:10]([OH:17])([C:13]([F:14])([F:15])[F:16])[CH2:9][C:8]2([CH3:19])[CH3:18]
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2c(=O)[nH]ncc12
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1c(F)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)[nH]ncc12
Yield: 12.3 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 200 mg of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 105 mg of 5-amino-phthalazin-1-one. As in Example 3, 50 mg of imine is reacted by reaction with 0.22 ml of titanium tetrachloride, and 36 mg of the title compound is obtained.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[C:20]([F:21])=[CH:19][C:15]([C:16](O)=O)=[C:14]([F:22])[CH:13]=1.N>>[Cl:11][C:12]1[C:20]([F:21])=[CH:19][C:15]([C:16]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[C:14]([F:22])[CH:13]=1
Reactant: O=C(O)c1cc(F)c(Cl)cc1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1cc(-c2nc(-c3cccnc3)no2)c(F)cc1Cl

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 4-chloro-2,5-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.73 (dd, J=9.7, 5.9 Hz, 1H), 8.18 (dd, J=8.8, 6.1 Hz, 1H), 8.57 (dt, J=8.1, 1.9 Hz, 1H), 8.75 (dd, J=4.7, 1.7 Hz, 1H), 9.30 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 294 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:24]=1[NH2:25].Cl>CC(O)CCC.C(O)(C)C>[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:24]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: COCCOCCOc1cc2nncc(Cl)c2cc1OC
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cl
Solvent: CCCC(C)O
Solvent: CC(C)O
Product: COCCOCCOc1cc2nncc(Nc3cc(O)c(C)cc3F)c2cc1OC

Procedure:
A solution of 4-chloro-6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]cinnoline (130 mg, 0.41 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (70 mg, 0.5 mmol), (prepared as described for the starting material in Example 11), in 2-pentanol (3 ml) containing 5M hydrogen chloride in isopropanol (2 drops) was heated at reflux for 45 minutes. After cooling the solid was filtered off, washed with isopropanol followed by ether to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]cinnoline as an hydrochloride salt (159 mg, 88%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([N:12]([CH3:22])[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CCO.O.[Fe]>[CH2:1]([O:8][CH2:9][C:10]([N:12]([CH3:22])[C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)COCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN(C(=O)COCc1ccccc1)c1ccc(N)cc1
Temperature: 25 °C
Yield: 53 %

Procedure:
To a suspension of above 2-benzoxy-N-methyl-N-(4-nitrophenyl)acetamide in EtOH (8 mL) and H2O (4 mL) was added ammonium formate (1.3 g, 20 mmol) and Fe (0.47 g, 8.4 mmol). After heating at reflux for 2 h, the reaction was cooled to room temperature, iron was filtered off, and the filtrate was diluted with EtOAc and water, EtOAc layer was separated and the aqueous layer was further extracted with EtOAc, organic layers were combined, dried over Na2SO4, and was concentrated under vacuo to provide 2-benzoxy-N-methyl-N-(4-aminophenyl)acetamide (0.4 g, 53%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[C:10]3[C:14]([O:18][CH2:19][CH2:20][CH2:21]Cl)=[CH:15][CH:16]=[CH:17][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][N:24]1[C:29]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:28][C:27](=[O:36])[N:26]([CH3:37])[C:25]1=[O:38].C(N(CC)CC)C>CN(C)C=O.[Br-].C([N+](CC)(CC)CC)C>[CH3:23][N:24]1[C:29]([N:30]2[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][O:18][C:14]3[C:10]4[C:11](=[O:13])[CH2:12][CH:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[O:8][C:9]=4[CH:17]=[CH:16][CH:15]=3)[CH2:32][CH2:31]2)=[CH:28][C:27](=[O:36])[N:26]([CH3:37])[C:25]1=[O:38]
Reactant: O=C1CC(c2ccccc2)Oc2cccc(OCCCCl)c21
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(N2CCN(CCCOc3cccc4c3C(=O)CC(c3ccccc3)O4)CC2)cc(=O)n(C)c1=O

Procedure:
In 10 ml of N,N-dimethylformamide, reaction was carried out at 100° C. for 8 hours among 2.5 g of the previously obtained 2-phenyl-5-(3-chloropropoxy)-4-oxo-2,3-dihydro-4H-1-benzopyran (Compound 20), 1.2 g of 1,3-dimethyl-6-(piperazine-1-yl)-2,4(1H,3H)-pyrimidinedione (Compound 3), 1.0 g of tetraethylammonium bromide and 2.0 ml of triethylamine. The resultant reaction solution was concentrated under reduced pressure, and the residue was then dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate, and then purified through a silica gel column chromatograph (chloroform:methanol=40:1 in volume ratio), thereby obtaining 0.80 g of 1,3-dimethyl-6-(4-[3-(2-phenyl-4-oxo-2,3-dihydro-4H-1-benzopyran-5-yl)oxypropyl]piperazine-1-yl)-2,4(1H,3H)-pyrimidinedione (the non-oxalate of Compound 21).
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][N:8]([CH3:30])[CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(NCC)C.[Li].[CH2:37]([O:39][C:40]([C:42]1[NH:43][C:44]2[C:49]([C:50]=1[CH:51]=O)=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[CH3:38]>C1COCC1>[CH2:37]([O:39][C:40]([C:42]1[NH:43][C:44]2[C:49]([C:50]=1[CH:51]=[CH:10][CH2:9][N:8]([CH3:30])[CH3:7])=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[CH3:38]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C=O
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCNCC
Product: CCOC(=O)c1[nH]c2ccccc2c1C=CCN(C)C
Reaction time: 0.5 h

Procedure:
Butyllithium (1.1 equiv.) was added to a suspension of (2-dimethylaminoethyl)triphenylphosphonium bromide in THF (0.2 M) at 0° C. After stirring for 30 minutes, lithium diethylamine (1.1 equiv.) was added dropwise followed by the cold suspension of 3-formyl-1H-indole-2-carboxylic acid ethyl ester (3.96 g, 18.2 mmol) in THF. The resulting orange suspension was stirred for 18 hours. The reaction was then quenched with saturated ammonium chloride and extracted with 10% MeOH in DCM. The organic layer was washed with saturated sodium bicarbonate, dried and concentrated to give 3-(3-dimethylaminopropenyl)-1H-indole-2-carboxylic acid ethyl ester as a brownish-red waxy solid.
Reaction SMILES: [C:1]1(=[O:14])[N:9]2[CH:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[CH2:3][NH:2]1.[H-].[Na+].Cl[CH2:18][C:19]1[N:20]=[CH:21][N:22]([C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]=1[CH3:24].O>CN(C)C=O>[CH3:24][C:23]1[N:22]([C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:21]=[N:20][C:19]=1[CH2:18][N:2]1[CH2:3][CH:4]2[CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]2[C:1]1=[O:14]
Reactant: O=C1NCC2COc3ccccc3N12
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN2CC3COc4ccccc4N3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2,3,3a,4-tetrahydro-1H-imidazo [5,1-c][1,4]benzoxazin-1-one (0.89 g; 0.0047 moles) in 20 ml of anhydrous dimethylformamide kept under nitrogen atmosphere, 50% NaH (0.22 g; 0.0047 moles) is added. The solution is stirred for 1 hour at 60° C.; then, at room temperature, 4-chloromethyl-5-methyl-1-triphenylmethyl-1H-imidazole (1.75 g; 0.0047 moles) is added. The mixture is stirred for 6 hours at 70° C., then cooled, poured into water and extracted with methylene chloride.
Reaction SMILES: [CH3:1][C:2]1[C:9]2[CH2:8][O:7][C:6](=[O:10])[C:5]=2[S:4][CH:3]=1.[Br:11]Br>C(Cl)(Cl)Cl.ClCCl>[Br:11][C:3]1[S:4][C:5]2[C:6](=[O:10])[O:7][CH2:8][C:9]=2[C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1csc2c1COC2=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1c(Br)sc2c1COC2=O

Procedure:
In a 50 mL round bottom flask was added 3-methylthieno[2,3-c]furan-6-(4H)-one (130 mg, 0.843 mmol, 1.0 eq) and chloroform (5 mL). To above solution was added bromine (86 μL, 1.08 mmol, 2.0 eq) in chloroform. The reaction was heat to reflux for 3 hr, cooled down, diluted with dichloromethane, washed with water, diluted sodium thiosulfate. The organic phase was dried over MgSO4, filtered and concentrated. The desired product was obtained after purification by flash column chromatography. LC-MS (IE, m/z): 235.2 [M+1]+; 1H NMR (500 MHz, CDCl3, δ in ppm): 5.16 (2H, s), 2.19 (3H, s);
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].C(N(CC)CC)C.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23]>C(O)C>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23]
Reactant: CNCc1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(CC(=O)c1ccc(F)cc1)Cc1ccccc1[N+](=O)[O-]

Procedure:
135.8 g (0.67 mol) of methyl-(2-nitrobenzyl)-amine and 187.5 ml (1.339 mols) of triethylamine are dissolved in 1.87 liters of ethanol at room temperature, with stirring, and 148 g (0.682 mol) of 2-bromo-1-(4-fluorophenyl)ethanone are then added in portions. The reaction mixture is stirred for 3 hours. The solvent is then stripped off on a rotary evaporator and the residue is dissolved in 1.3 liters of toluene. The toluene phase is washed several times with H2O and dried over Na2SO4, and HCl/diethyl ether is added. The glutinous precipitate is separated from the toluene by decanting and crystallized with acetone. The colorless precipitate is filtered off with suction and dried.
Reaction SMILES: C(O)C(C)C.[OH-].[NH3+:7][NH2:8].[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[C:19]([CH2:27][CH3:28])[C:18]=1[CH3:29])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(O)C>[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([NH:7][NH2:8])=[O:22])=[C:19]([CH2:27][CH3:28])[C:18]=1[CH3:29])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCc1c(C(=O)OC)ccc(OCc2ccccc2)c1C
Reactant: N[NH3+]
Agent: [OH-]
Solvent: CC(C)CO
Solvent: CC(C)O
Product: CCc1c(C(=O)NN)ccc(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 ml of 2-propanol and 10 ml of isobutanol (2-methylpropan-1-ol) and also 20.0 ml of hydrazinium hydroxide are added to 17.5 g of methyl 4-benzyloxy-2-ethyl-3-methylbenzoate (C1). The reaction mixture is subsequently heated under reflux for 18 h overnight. After cooling, a further 30 ml of 2-propanol are added to the solution, which is subsequently stirred at room temperature for 30 min. The precipitate is filtered off with suction, and the filter cake is rinsed a number of times with a little 2-propanol. The product is subsequently recrystallised from 2-propanol, and the precipitate obtained is dried overnight in vacuo, giving 12.3 g of the title compound as a colourless, amorphous solid having a melting point of 179° C.; MS: 284.2 (M+); TLC: Rf=0.27 (ethyl acetate/ethanol 97:3 parts by volume).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:18]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])=[CH:17][C:13]=1[C:14](O)=[O:15])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:47][CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][N:53]=[CH:52][CH:51]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:18]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])=[CH:17][C:13]=1[C:14]([NH:47][CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][N:53]=[CH:52][CH:51]=1)=[O:15])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(OC/C=C(\C)CCC=C(C)C)c(C(=O)O)c1
Reactant: NCCc1ccncc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)=CCC/C(C)=C/COc1ccc(OC/C=C(\C)CCC=C(C)C)c(C(=O)NCCc2ccncc2)c1
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
2,5-digeranyloxybenzoic acid(2.40 g) was dissolved in chloroform(40 ml) and triethylamine(1.58 ml), and then diphenylphosphinic chloride(1.08 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 4-(2-aminoethyl)pyridine(0.69 g) added thereto, was stirred for 1 hour at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 1.90 g of the aimed compound.