Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[O:34][C@H:33]([CH2:35][O:36][S:37]([C:40]2[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[C@@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3].C12BC(CCC1)CCC2.[OH-:56].[Na+].OO>O1CCCC1.O>[CH2:8]([O:7][C@@H:6]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:33]([CH2:35][O:36][S:37]([C:40]2[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[O:34][C@@H:5]1[O:4][CH2:1][CH2:2][CH2:3][OH:56])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [OH-]
Reactant: C=CCO[C@H]1O[C@H](COS(=O)(=O)c2ccc(C)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@H](OCCCO)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Reaction time: 10 h

Procedure:
To a solution of the compound (5) (29.0 g, 45.0 mmol) in anhydrous tetrahydrofuran (THF, 150 ml), added was a solution of 0.5 M 9-borabicyclo[3,3,1]nonane (9-BBN) in tetrahydrofuran (180 ml, 90.0 mmol) at 0° C. in an argon atmosphere. After a lapse of 1 hour, the reaction liquid was returned to room temperature, and continuously stirred for 10 hours. The reaction liquid was cooled again to 0° C., to which water (20 ml) was added firstly, and then 3 M sodium hydroxide solution (70 ml) and 35% hydrogen peroxide solution (70 ml) were added sequentially. After a lapse of 1 hour, the reaction liquid was returned to room temperature, and stirred for 12 hours. After the sufficient progress of the reaction was confirmed, the solution was extracted with ethyl acetate (3×100 ml), the organic layers were combined and washed with saturated saline (2×100 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified with silica gel chromatography (hexane-ethyl acetate, 3:2→1:1→2:3) to obtain the title compound (6) in the form of a colorless oily substance {28.2 g (42.5 mmol), 94.4%}.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[C:4]#[CH:5].Br[CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14]>C1COCC1.O>[CH3:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:6][CH2:3][C:4]#[CH:5]
Reactant: C#CCO
Reactant: COCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCOCCOCCOC
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 3 %

Procedure:
To a stirred suspension of sodium hydride (3.12 g, 78.0 mmol) in THF (100 mL) cooled to 5° C. in an ice-bath was added a solution of propargyl alcohol (4.60 g, 78.0 mmol) in THF (20 mL) drop-wise. The mixture was stirred at 5° C. for 30 min and was then allowed to warm to RT and treated dropwise with 1-bromo-2-(2-methoxyethoxy)ethane (7.00 mL, 52.0 mmol). The reaction mixture was stirred at RT for 16 hr and was then, diluted with water (100 mL) and extracted with diethyl ether (2×100 mL). The combined organic extracts were dried, filtered and evaporated in vacuo. The residue was purified by flash column chromatography, eluting with 30% EtOAc in heptane, to afford the title compound (9) (250 mg, 9%) as a colourless oil: 1H NMR (500 MHz, MeOD) δ: 4.18 (2H, d), 3.66-3.69 (2H, m), 3.60-3.66 (4H, m), 3.52-3.56 (2H, m), 3.36 (3H, s), 2.84 (1H, t).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[N:7]=1.[C:13](O)(=[O:16])[CH:14]=[CH2:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:12][C:8]1[N:7]=[C:6]([NH:5][CH2:4][CH2:3][NH:2][C:13](=[O:16])[CH:14]=[CH2:15])[CH:11]=[CH:10][CH:9]=1
Reactant: NCCNc1cccc(N)n1
Reactant: C=CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)NCCNc1cccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
A mixture of 105c (1.88 g, 10 mmol), acrylic acid (720 mg, 10 mmol), HATU (3.80 g, 10 mmol) and DIPEA (6.97 mL, 40 mmol) in DCM (50 mL) was stirred at rt for 16 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (EA/MeOH=4/1) to give N-(2-(6-aminopyridin-2-ylamino)ethyl)acrylamide 105d (1.07 g, 52%) as pale-yellow oil.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH3:37])[C:22]([C:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][C:25]=3[CH2:33][CH2:34][CH2:35][CH3:36])=[O:23])=[CH:16][CH:15]=2)[CH:9]=[CH:10][C:11]=1[O:12]C.C(=O)=O.CC(C)=O.O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][N:21]([CH3:37])[C:22]([C:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][C:25]=3[CH2:33][CH2:34][CH2:35][CH3:36])=[O:23])=[CH:18][CH:19]=2)[CH:9]=[CH:10][C:11]=1[OH:12]
Reactant: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc(-c2ccc(OC)c(Br)c2)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc(-c2ccc(O)c(Br)c2)cc1
Reaction time: 1.5 h
Yield: 100.8 %

Procedure:
Boron tribromide (31.8 mL of a 1 M solution in methylene chloride; 31.8 mmol) was added under nitrogen dropwise over 30 minutes to a solution of N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-2-butyl-N-methyl-1-benzofuran-3-carboxamide (5.37 g, 10.6 mmol), prepared in the previous step, in 150 mL of methylene chloride at dry ice-acetone temperature. After the addition the dry ice-acetone bath was replaced with an ice bath and the stirring continued for 1.5 h. At ice bath temperature-water was added dropwise. The aqueous layer was separated and extracted two times with methylene chloride. The extracts were combined, dried (MgSO4) and the solvent removed under reduced pressure to give N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-2-butyl-N-methyl-1-benzofuran-3-carboxamide (5.26 g, 100%) as a light brown foam, MS (ESI) m/z 492 [M+H]+. Elemental Analysis for C27H26BrNO3. Calc'd: C, 65.86; H, 5.32; N, 2.84. Found: C, 64.98; H, 5.15; N, 2.63.
Reaction SMILES: [OH-].[Li+].[CH3:3][CH:4]([CH3:46])[CH2:5][CH2:6][N:7]([CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[N:15]([CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:14]=2[CH:40]=1)=[O:9]>O1CCCC1.O.C(OCC)C>[CH3:44][CH:43]([CH3:45])[CH2:42][CH2:41][N:7]([CH2:6][CH2:5][CH:4]([CH3:46])[CH3:3])[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[N:15]([CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[C:14]=2[CH:40]=1)=[O:9]
Reactant: COC(=O)c1ccc(Nc2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCCNC(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc2nc(Nc3ccc(C(=O)O)cc3)n(CCCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Yield: 79 %

Procedure:
Lithium hydroxide (141 mg, 5 eq) is added to methyl 4-[(6-{[bis(3-methylbutyl)amino]carbonyl}-1-{3-[(tert-butoxycarbonyl)amino]propyl}-1H-benzimidazol-2-yl)amino]benzoate prepared according to reaction diagram A, Example A1, (405 mg, 1 eq) in a mixture of tetrahydrofuran (4 ml) and water (3 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. Dichloromethane (50 ml) and water (20′ ml) are added to the residue. The mixture is acidified by the addition of acetic acid to pH 5. After decantation and extractions, the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The solid obtained is taken up in ethyl ether in order to produce the expected compound (309 mg; 79%).
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][C:8]3([NH2:11])[CH2:10][CH:4]([CH2:5]2)[CH2:3][CH:2]1[CH2:9]3.C(OC([NH:19][C:20](=[N:23]C(OC(C)(C)C)=O)SC)=O)(C)(C)C.O>CN(C=O)C.Cl[Hg]Cl>[C:8]12([NH:11][C:20]([NH2:23])=[NH:19])[CH2:10][CH:4]3[CH2:5][CH:6]([CH2:1][CH:2]([CH2:3]3)[CH2:9]1)[CH2:7]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl[Hg]Cl
Solvent: CN(C)C=O
Solvent: O
Product: N=C(N)NC12CC3CC(CC(C3)C1)C2

Procedure:
Amantadine (0.30 g, 2 mmol), HgCl2 (0.54 g, 2 mmol), and 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (0.58 g, 2 mmol) were stirred in DMF (10 mL) under a N2 atmosphere for 24 h. H2O was added to the reaction mixture, and the white precipitate was removed by filtration. The precipitate was washed with CH2Cl2 twice, and the combined filtrate was extracted with CH2Cl2, washed with brine and dried over MgSO4, concentrated in vacuo, and purified by flash chromatography. The Boc protecting group was removed by 50% TFA/CH2Cl2 for 2 h at RT. Excess TFA was removed by passing N2 through the solution to give a yellow solid which was subsequently purified by flash chromatography (0.41 g, 74% over two steps). 1H-NMR (360 MHz, CD3OD) δ 2.13 (br s, 3H), 1.97 (br s, 6H), 1.76 (br s, 6H); 13C-NMR (90 MHz, CD3OD) δ 160.35, 53.83, 42.45, 36.86, 31.03; ESI-MS: Calculated for C11H19N3 (M+H)+ 194.2. Found: 194.7.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][S:6](=[O:9])(=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.ClC1C=C(C=CC=1)C(OO)=[O:18]>C(Cl)Cl>[CH3:1][C:2]1([CH3:12])[CH2:7][S:6](=[O:9])(=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH+:3]1[O-:18]
Reactant: CC1(C)CS(=O)(=O)CC(C)(C)N1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)CS(=O)(=O)CC(C)(C)[NH+]1[O-]
Temperature: 25 °C

Procedure:
5.7 g (0.03 mole) of 2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide is dissolved in 100 ml of methylene chloride. To this solution there is then added dropwise at 20° C in ca. 90 minutes a solution of 11.2 g of m-chloroperoxybenzoic acid in 100 ml of methylene chloride. The reaction is slightly exothermic. Stirring is subsequently maintained for 15 hours at room temperature, and the precipitated m-chlorobenzoic acid filtered off. The reddish coloured methylene chloride solution is extracted twice with 50 ml of 2N sodium hydroxide solution each time, and then with 50 ml of 2N hydrochloric acid, and subsequently dried over sodium sulphate. After the solvent has been distilled off, the residue is crystallised from ethanol to obtain 2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-1,4,4-trioxide (8) of the formula ##STR19## M.P. 163° C.
Reaction SMILES: C(=O)(OC1N=CC=CN=1)N.[Cl:11][C:12]([Cl:17])([Cl:16])[C:13]([NH2:15])=[NH:14].[C:18]([O-])(=O)[CH2:19][C:20](C)=[O:21]>>[OH:21][C:20]1[CH:19]=[CH:18][N:15]=[C:13]([C:12]([Cl:17])([Cl:16])[Cl:11])[N:14]=1
Reactant: N=C(N)C(Cl)(Cl)Cl
Reactant: CC(=O)CC(=O)[O-]
Agent: NC(=O)Oc1ncccn1
Product: Oc1ccnc(C(Cl)(Cl)Cl)n1

Procedure:
The pyrimidinyl carbamate compounds of the present invention may be prepared by reacting trichloroacetamidine with the corresponding acetoacetate to form the corresponding 4-hydroxy-2-trichloromethylpyrimidine, which is then reacted with a selected carbamoyl chloride. These general reactions are illustrated below in equations (A) and (B). In equation (A), trichloroacetamidine is reacted with methylacetoacetate to form 4-hydroxy-6-methyl-2-trichloromethylpyrimidine. In equation (B), the 4-hydroxy-6-methyl-2-trichloromethylpyrimidine is reacted with dimethylcarbamoyl chloride to form 6-methyl-2-trichloromethyl-4-pyrimidinyl dimethylcarbamate. ##STR3##
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH:29]=[C:28]2[C:23]([CH:24]=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:27]2)=[N:22]1)C.[S:34]([O-:38])([O-])(=[O:36])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:34]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH:29]=[C:28]2[C:23]([CH:24]=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:27]2)=[N:22]1)(=[O:38])=[O:36])[CH3:11]
Reactant: CCSc1ccccc1-n1cc2ccc(C(F)(F)F)cc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ccccc1-n1cc2ccc(C(F)(F)F)cc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
607 mg of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 407 mg of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-2H-indazole and 5 ml of chloroform under ice cooling, and the mixture was stirred at room temperature for 4 hours. A 10% aqueous sodium thiosulfate solution was poured to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure to obtain 452 mg of 2-(2-ethylsulfonylphenyl)-6-trifluoromethyl-2H-indazole (hereinafter, referred to as Compound of Present Invention 2)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:19]2[C:14]([CH:15]=[N:16][C:17](S(C)=O)=[N:18]2)=[CH:13][CH:12]=1.Cl.[OH-:24].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:19]2[C:14]([CH:15]=[N:16][C:17]([OH:24])=[N:18]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2ccc3cnc(S(C)=O)nn23)c(OC)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc(-c2ccc3cnc(O)nn23)c(OC)c1
Temperature: 80 °C

Procedure:
7-(2,4-Dimethoxy-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (605 mg) was suspended in 5M NaOH (20 ml) and heated to 80° C. for 3 hours. Cooled to room temperature and acidified with concentrated HCl. Extracted with dichloromethane. Dried over magnesium sulfate. Concentrated to afford 7-(2,4-dimethoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol as a brown solid (245 mg) that was used without further purification.
Reaction SMILES: Br[C:2]1[C:11]2[O:10]C[N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][C:6]=2[CH:5]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1.[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25](B(O)O)[CH:26]=1>>[ClH:20].[ClH:20].[C:16]([C:4]1[CH:3]=[C:2]([C:25]2[CH:24]=[N:23][CH:22]=[C:21]([Cl:20])[CH:26]=2)[C:11]([OH:10])=[C:6]([CH2:7][NH:8][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:5]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: OB(O)c1cncc(Cl)c1
Reactant: CC(C)(C)c1cc(Br)c2c(c1)CN(C(C)(C)C)CO2
Product: CC(C)(C)NCc1cc(C(C)(C)C)cc(-c2cncc(Cl)c2)c1O
Product: Cl

Procedure:
The title compound was prepared as a white solid using the procedure described in Example 1 from 8-bromo-3,6-di-tert-butyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (Intermediate 1) and 3-chloropyridine-5-boronic acid [purchased from Frontier Scientific].
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+]>O1CCOCC1.O>[OH:1][CH:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: C=CCCCCCCCCC(O)CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=CCCCCCCCCC(O)CC(=O)O
Reaction time: 1 h
Yield: 90 %

Procedure:
Purification by distillation (Kugelrohr, 135° C./0.2 torr) gave ethyl 3-hydroxy-12-tridecenoate as a colorless oil (12.3 g, 80% yield). To this ester (10.8 g, 42.2 mmol) in dioxane (50 ml) at room temperature was added 1M NaOH (50 ml). After one hour, the resulting slurry was diluted with water and washed twice with hexane. The aqueous layer was acidified with 10% citric acid, and the resulting solid collected by filtration and dried in vacuo to give 3-hydroxy-12-tridecenoic acid as a white solid, mp 62°-64° C. (8.65 g, 90% yield). To a solution of this hydroxy-acid (8.60 g, 37.6 mmol) in DMF (27 ml) at room temperature were added t-butyl-dimethylsilyl chloride (10.8 g) and imidazole (9.7 g). The reaction was stirred for 24 hours, poured into ice water (250 ml), and extracted three times with hexane. The extracts were combined, dried (Na ), filtered, and evaporated to give the bis-silyl derivative as a light yellow oil (14.5 g, 84% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[C:3]=1[OH:11].C(N=C=N)C.[OH:17]N1C2C=CC=CC=2N=N1.CN(C1C=CC=CN=1)C.CO[C:38]1[CH:43]=[C:42]([CH2:44][NH:45]CCCNCCCCNCCCN)C=C[C:39]=1[OH:59].O=C1CCNC1C(O)=O>C(Cl)Cl>[Br:10][C:4]1[C:3]([OH:11])=[C:2]([NH:1][C:39]([CH:38]2[CH2:43][CH2:42][C:44](=[O:17])[NH:45]2)=[O:59])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: COc1cc(N)c(O)c(Br)c1
Reactant: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Reactant: On1nnc2ccccc21
Agent: CCN=C=N
Agent: CN(C)c1ccccn1
Agent: O=C(O)C1NCCC1=O
Solvent: ClCCl
Product: COc1cc(Br)c(O)c(NC(=O)C2CCC(=O)N2)c1
Reaction time: 3 h
Yield: 102.3 %

Procedure:
2-Amino-6-bromo-4-methoxy-phenol (0.40 g), 1,3-dimethylaminopropyl)-3-ethylcarbodiimide (1.06 g), 1-hydroxybenzotriazole (0.50 g), dimethylaminopyridine (0.22 g) and DL-5-oxo-pyrrolidine-2-carboxylic acid (0.25 g) were reacted together in methylene chloride (7.3 mL). After 3 h, the reaction was diluted with methylene chloride (10 mL) and washed successively with 1N HCl (10 mL), sat. aq. NaHCO3 (10 mL), sat. aq. NaCl (10 mL). The organic layer was dried over sodium sulfate, filtered through celite and concentrated. Chromatography on silica gel (eluant: 0 to 20% methanol:methylene chloride) afforded 5-oxo-pyrrolidine-2-carboxylic acid (3-bromo-2-hydroxy-5-methoxy-phenyl)-amide (0.18 g). MS: 370.2 (100%), 372.2 (90%) (MH+); HPLC tR: 1.51 min. 5-Oxo-pyrrolidine-2-carboxylic acid (3-bromo-2-hydroxy-5-methoxy-phenyl)-amide was cyclized according to synthetic method R to obtain the title compound (0.09 g) after purification on silica gel (eluant: 0 to 30% methanol:methylene chloride). MS: 352.2 (100%), 354.2 (95%) (MH++CH3CN), 311.2 (20%), 313.2 (20%) (MH+).; HPLC tR: 1.84 min.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17].[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[O:12]=[C:7]1[C:6]2[NH:13][CH:14]=[CH:15][C:5]=2[C:4]2[CH:3]=[C:2]([CH:21]=[CH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:11]=[CH:10][C:9]=2[NH:8]1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17]
Reactant: C=Cc1ccccc1
Reactant: O=c1[nH]c2ccc(Br)cc2c2cc[nH]c12
Agent: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(C=Cc3ccccc3)cc2c2cc[nH]c12
Yield: 13.2 %

Procedure:
This compound is prepared according to synthesis 68, from 70 mg (0.21 mmol) of 8-bromo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 71) and 26 μL (0.23 mmol) of styrene. After filtration and trituration in diethyl ether, 10 mg (14%) of 4-oxo-8-styryl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a light brown solid.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH3:16])[C:6](=[O:15])[C:7]([CH3:14])=[C:8]([Cl:13])[C:9]=1[C:10](O)=[O:11])(=O)[CH3:2].O.[NH2:18][NH2:19].Cl>C1COCC1.C(OCC)(=O)C>[Cl:13][C:8]1[C:9]2[C:10](=[O:11])[NH:19][N:18]=[C:1]([CH3:2])[C:4]=2[N:5]([CH3:16])[C:6](=[O:15])[C:7]=1[CH3:14]
Reactant: NN
Reactant: CC(=O)c1c(C(=O)O)c(Cl)c(C)c(=O)n1C
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(Cl)c2c(=O)[nH]nc(C)c2n(C)c1=O
Reaction time: 16 h

Procedure:
To a solution of 2-acetyl-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (1 equivalent) and hydrazine monohydrate (3.30 equivalents) in THF is added 1 N HCl (0.80 equivalents). After 16 hours, the reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and concentrated under reduced pressure. The desired product purified by trituration or flash column chromatography to afford the desired product as necessary.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([NH2:17])=[O:16])[CH3:2].[CH3:18][C:19](=O)[CH2:20][CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:4]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[S:6][C:5]=2[C:15](=[O:16])[NH:17][C:19]1([CH2:20][CH3:21])[CH3:18])[CH3:2]
Reactant: CCC(C)=O
Reactant: CCNc1cc(-c2ccncc2)sc1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCN1c2cc(-c3ccncc3)sc2C(=O)NC1(C)CC
Temperature: 120 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A mixture of 3-(ethylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.100 g, 0.400 mmol), 2-butanone (2.5 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 1 h at 120° C. in a sealed tube. Then, this mixture was stirred for 3 h at 150° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was purified by column chromatography (Combiflash, 40 g silica gel, dichloromethane to ethyl acetate) to afford the title compound (0.0547 g, 45%) as a yellow solid:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:19][CH:18]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Ic1ccc(OC2CCCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc(OC2CCCCO2)cc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
A mixture of 4-benzyloxy-1H-pyridin-2-one (7.04 g, 35.0 mmols), 2-[(4-iodophenyl)oxy]tetrahydropyran (13.6 g, 44.8 mmols), cuprous iodide (2.1 g, 11.2 mmols), potassium carbonate (10.3 g, 73.5 mmols) and N,N-dimethylformamide (200 mL) was stirred overnight at 150° C. The reaction liquid was cooled to room temperature, into which water (1.2 L) was poured, and the formed insoluble matter was recovered by filtration. Chloroform (300 mL) was added to the insoluble matter, followed by another filtration. The filtered organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, ethyl acetate was added to the resulting residue. The precipitate was recovered by filtration and dried to provide the title compound (7.6 g, 58%).