Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)=[N:34][CH:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[C:19]([C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:6]2[C:5]([Cl:22])=[CH:4][N:3]=[C:2]([NH:29][C:30]3[CH:31]=[CH:32][C:33]([CH:36]4[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]4)=[N:34][CH:35]=3)[N:7]=2)[CH2:18][CH2:17]1)(=[O:20])[NH2:21]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cn2)CC1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1

Procedure:
A suspension of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.150 g, 0.446 mmol), Cs2CO3 (0.436 g, 1.34 mmol) and tert-butyl 4-(5-aminopyridin-2-yl)piperidine-1-carboxylate 19 (247 mg, 0.892 mmol) in 1,4-dioxane (3 mL) was sonicated for 10 minutes. Xantphos (10 mg, 18 μmol) and Pd(II) acetate (2.0 mg, 8.9 μmol) were added and the mixture was irradiated in the microwave at 120° C. for 20 minutes. The mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in cyclohexane) to give the title compound A19 as a yellow oil (79 mg, 31%). LCMS-C: rt 4.92 min; m/z 577.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([O:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)=[CH:8][CH:7]=[CH:6][C:5]=1[OH:20])[CH2:2][CH3:3].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>OP(O)(O)=O.O.CCOCC>[C:14]1([C:12]2[C:8]3[CH:7]=[CH:6][C:5]([OH:20])=[C:4]([CH2:1][CH2:2][CH3:3])[C:9]=3[O:10][CH:11]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCc1c(O)cccc1OCC(=O)c1ccccc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOCC
Solvent: O
Product: CCCc1c(O)ccc2c(-c3ccccc3)coc12
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 2-propyl-3-(2-phenyl-2-oxoethoxy)phenol (9.30 g) in o-phosphoric acid(85%) (93 mL) at room temperature was added over a 45 minutes period phosphorus pentoxide(46.50 g). During this period the reaction mixture was heated several times with a heat gun. After stirring the mixture for 30 minutes the reaction was checked by TLC (to take a little of sample with a capillary and dissolve sample in water and add several drops of ether; elution: 50% methylene chloride in hexane). The reaction mixture was heated again with heat gun if the reaction was not complete. The reaction mixture continued to be stirred for 20 minutes, then was poured into a beaker containing ice. The reaction flask was then rinsed with water and ether, and the washings were added to the beaker. The organic layer was separated, washed with water, dried over MgSO4, and concentrated. Column Chromatography (silica gel 60, 50% methylene chloride in hexane) gave the title compound.
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=[O:21])=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[BH4-].[Na+]>CO>[S:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][OH:21])=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(CO)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.2 %

Procedure:
To a solution of 1-tosyl-1H-indole-3-carbaldehyde (7 g, 23.385 mmol) in MeOH (70 mL), NaBH4 (1.77 g, 46.769 mmol) was added at 0° C. and the mixture was stirred for 10 min. The reaction mixture was allowed to warm to rt and stirring was continued for 18 h. The solvent was removed under reduced pressure at 45° C. and the crude reaction mixture was quenched with saturated aqueous ammonium chloride solution. Ethyl acetate was added and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to yield a solid (6.5 g, 92%). [1H-NMR (CDCl3, 300 MHz) δ 8.02-7.95 (m, 1H), 7.82-7.75 (m, 2H), 7.65-7.53 (m, 2H), 7.40-7.19 (m, 4H)].
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH2:16][CH2:17][CH3:18])=[O:10])C1C=CC=CC=1>CO.[Pd]>[CH2:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])[CH2:17][CH3:18]
Reactant: CCCN1CCCC1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCN1CCC[C@H]1C(=O)O
Reaction time: 12 h

Procedure:
A suspension of 1-n-propyl pyrrolidine-2-carboxylic acid benzyl ester (2.0 g, 8.09 mmol) and 10% Pd on charcoal in methanol (30 mL) was hydrogenated over 12 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated (1 g, 77%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[C:27]([CH3:40])=[C:28]([CH3:39])[C:29]4[O:33][C:32]([CH3:35])([CH3:34])[C:31](=[O:36])[C:30]=4[C:37]=3[CH3:38])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>CCCCCC>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:31]2([OH:36])[C:30]3[C:37]([CH3:38])=[C:26]([N:23]4[CH2:24][CH2:25][N:20]([C:17]5[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=5)[CH2:21][CH2:22]4)[C:27]([CH3:40])=[C:28]([CH3:39])[C:29]=3[O:33][C:32]2([CH3:34])[CH3:35])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Solvent: CCCCCC
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(C(F)(F)F)cc3)C(C)(C)O4)CC2)cc1
Yield: 91 %

Procedure:
Using 1-bromo-4-(trifluoromethyl)benzene and 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine obtained in Reference Example 13, the title compound was synthesized in the same manner as in Example 33. Yield 91%. mp. 181–183° C. (hexane).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]([CH3:17])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[CH:10]=1)[CH3:2].C(N(CC)CC)C.[Se](=O)=[O:27]>N1C=CC=CC=1>[CH3:17][N:7]1[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[CH:10]=[C:6]1[C:5](=[O:27])[C:4]([O:3][CH2:1][CH3:2])=[O:18]
Reactant: O=[Se]=O
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)OCC)n1C
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)c1cc(C)c(C(=O)OCC)n1C
Yield: 52.2 %

Procedure:
Ethyl-1,4 dimethyl-5-ethoxycarbonylpyrrole-2-acetate (26.3 g, 0.104 mol) is mixed with triethylamine (7.2 ml, 0.052 mol), pyridine (165 ml, dried over 4 A sieves) and selenium dioxide (12.9 g, 0.115 mol) under nitrogen. The mixture is stirred mechanically and is heated to 95°-100° for 6.5 hours. The reaction is then allowed to cool and the heterogeneous mixture is filtered through a bed of Celite and washed with ether until no further color comes through. The organic solution is then washed with 2 N HCl (4×200 ml), and the combined acid washes are backwashed with ether (150 ml). The combined ether layers are washed with saturated aqueous sodium bicarbonate (100 ml) and saturated brine (150 ml). The ether solution is dried over sodium sulfate and the solvent is removed to give a brown oil which crystallizes on standing. The product is purified by preparative HPLC (4/1 hexanes/ether) to give 14.5 g of ethyl 1,4-dimethyl-5-ethoxycarbonyl-α -oxopyrrole-2-acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:22])[C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(Cl)(=O)C(Cl)=O.[NH3:34]>C(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[C:17]([C:16]1[CH:20]=[CH:21][C:13]([O:12][C:11]2[C:10]([Cl:22])=[C:9]3[C:4]([CH:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:6][CH2:7][O:8]3)=[CH:3][C:2]=2[Cl:1])=[CH:14][CH:15]=1)(=[O:18])[NH2:34]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)O)cc1)c2Cl
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(N)=O)cc1)c2Cl
Reaction time: 3 h
Yield: 80.2 %

Procedure:
4-(6,8-Dichloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation A; 150 mg, 0.365 mmol) was diluted with DCM (1.5 mL) followed by the addition of oxalyl chloride in DCM (2M) (201 μl, 0.401 mmol) and DMF (1 drop). Ammonia (6.21 mg, 0.365 mmol) was bubbled in for 10 minutes. The reaction was placed under nitrogen and stirred for 3 hours. The reaction was diluted with ethyl acetate and washed with water. The organic layer was concentrated, loaded onto silica gel and eluted with neat ethyl acetate to yield ethyl 7-(4-carbamoylphenoxy)-6,8-dichlorochroman-4-carboxylate (120 mg, 0.293 mmol, 80.2% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[C:12]([NH2:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[C:12]([NH:19][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)c2c1OCCO2
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccc(OCc2ccccc2)c2c1OCCO2
Reaction time: 7 h

Procedure:
To a solution of 30 g of 5-benzyloxy-8-amino-1,4-benzodioxane (XX), code number 760 727, in 250 ml of chloroform, 21.3 ml of triethylamine, then slowly, at 0° C., 15.2 g of ethyl chloroformate were added. The solution was stirred for 7 hours, filtered and the filtrate was washed with a diluted hydrochloric acid solution, with water, with a solution of sodium bicarbonate and with water. The solvent was evaporated and the residue recrystallized in ethylacetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH2:16])[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24].[OH-].[Na+].C(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH:16][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([Cl:19])[CH:21]=3)[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)c3cccc(Cl)c3)ncc2C1
Reaction time: 2 h
Yield: 53.1 %

Procedure:
2-Amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 1202 mg (4.8 mmol) was added at 0° C. to a solution of 3-chlorobenzoic acid chloride 615 μl (4.8 mmol) in pyridine (25 ml) and stirring was performed for 2 h at 0° C. and then overnight at RT under nitrogen as inert gas. After the addition of aqueous 1 M NaOH (40 ml) and stirring for 20 minutes, CH2Cl2 (50 ml) was added and the aqueous phase extracted with CH2Cl2 (3×20 ml). The combined organic phases were dried over Na2SO4. After filtration and removal of the solvent, purification was performed by means of column chromatography and the product 2-(3-chloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 790 mg (2.55 mmol, 53% of theoretical) was obtained.
Reaction SMILES: O=C1O[C@H]([C@H](CO)O)C(O)=C1O.C[C@@H]1[C@@H](O)[C@@H](C)[C@H](C)[O:50][C:48](=[O:49])[CH2:47][C@H:46](O)[CH2:45][C@H:44](O)[CH2:43][CH2:42][C@@H:41](O)[C@H:40]([OH:60])[CH2:39][C@H:38]([OH:61])[CH2:37][C@@:35]2(O)O[C@H:31]([C@H:32](C(O)=O)[C@@H:33]([OH:63])[CH2:34]2)[CH2:30][C@@H:29](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)[CH:28]=CC=CC=CC=CC=CC=CC=C1.C([O-])(O)=O.[Na+].CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C([O-])=O.[K+].C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H](O[C@@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2NC)[C@@]1(O)C=O>C(=O)=O>[CH3:28][CH2:29][CH2:30][CH2:31][CH2:32][C@H:33]([OH:63])/[CH:34]=[CH:35]/[C@@H:37]1[C@@H:41]([CH2:42]/[CH:43]=[CH:44]\[CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])[C:40](=[O:60])[CH2:39][C@H:38]1[OH:61]
Reactant: C[C@@H]1[C@H](O)[C@@H](C)C=CC=CC=CC=CC=CC=CC=C[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: C[C@@H]1[C@H](O)[C@@H](C)/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Reaction time: 3.5 h

Procedure:
Synovial tissue obtained at surgery from patients with rheumatoid arthritis (RA) undergoing joint replacement was cut into pieces of 2 mm or less and incubated at approximately 100 mg/ml in serum-free minimal essential medium (MEM) containing 1 mg/ml bacterial collagenase (Sigma Chemical Co., St. Louis, Mo.) and 10 μg/ml testicular hyaluronidase (Sigma) at 37° C. with rocking. After 3-4 h, the suspension was centrifuged at 150 xg for 10 min. The cells were resuspended (105 cells/ml) in MEM containing 20% fetal calf serum (FCS) and plated in 100-mm diameter Petri dishes (10 ml per dish). The disaggregated cells were cultured overnight at 37° C. in 5% CO2, and the nonadherent cells were aspirated off by vigorous pipetting. Adherent synovial cells were maintained in culture with medium change every four days until they reached confluency, at which time they were subcultured after trypsinization and grown in maintenance medium (Eagle's MEM Supplemented with nonessential amino acids, ascorbic acid, amphotericin B (1 μg/ml), NaHCO3, penicillin (100 U/ml), and streptomycin (100 μ/ml), FCS (9%), and PBS).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[CH3:22][O:23][CH2:24][CH2:25][C:26](=O)[C:27]([OH:29])=[O:28]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:26]([C:27]([OH:29])=[O:28])[CH2:25][CH2:24][O:23][CH3:22])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: COCCC(=O)C(=O)O
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccc2Cl)=NC1
Product: COCCC(=NNC1=Nc2ccc(Br)cc2C(c2ccccc2Cl)=NC1)C(=O)O

Procedure:
In the manner given in Example 9, 7-bromo-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be stirred with 4-methoxy-2-oxobutyric acid at room temperature to give 7-bromo-2-[(1-carboxy-3-methoxypropylidene)-hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:18])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:17])[CH2:15][CH3:16])=[CH:3][C:4](O)=[O:5].[H-].[Na+].C(Cl)(=O)C([Cl:24])=O>C1C=CC=CC=1>[CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:18])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:17])[CH2:15][CH3:16])=[CH:3][C:4]([Cl:24])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC(C)CCCC(C)CC=CC(C)=CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC(C)CCCC(C)CC=CC(C)=CC(=O)Cl
Reaction time: 1 h

Procedure:
One gram of 3,7,11-trimethyltrideca-2,4-dienoic acid in 30 ml. of benzene and one mole of sodium hydride is stirred about two hours and then a slight excess of oxalyl chloride is added at about 0° and stirred for one hour. The product is worked up by removal of solvent in vacuo and extraction with pentane to yield 3,7,11-trimethyltrideca2,4-dienoyl chloride.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:12]I>>[CH3:12][N:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[C:1]1=[O:11]
Reactant: Oc1nccc2cnccc12
Reactant: CI
Product: Cn1ccc2cnccc2c1=O

Procedure:
A method for preparing compounds of Formula (III) is provided in Scheme 6. 2,6-Naphthyridin-1-ol (6-1) is subjected to alkylation with methyl iodide under basic conditions to provide 2-methyl-2,6-naphthyridin-1(2H)-one (6-2). Chlorination of 6-2 with N-chlorosuccinimide provides chloro compound 6-3. Treatment of 6-3 under palladium-catalyzed cross coupling conditions with a suitable halide provides compound 6-4. Selective reduction of the 2,6-naphthyridinone derivative provides the 5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one derivative 6-5.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].I[C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.CNCCNC.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cu]I>[O:7]=[C:2]1[CH2:3][O:4][CH2:5][CH2:6][N:1]1[C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1
Reactant: O=C1COCCN1
Reactant: Nc1ccc(I)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Nc1ccc(N2CCOCC2=O)cc1
Temperature: 110 °C
Yield: 50.3 %

Procedure:
To a blue solution of 3-morpholinone (250 mg, 2.48 mmol), 4-iodoaniline (650 mg, 2.97 mmol), CuI (47 mg, 0.25 mmol) and N,N′-dimethylethylenediamine (0.040 mL, 0.372 mmol) in dioxane (5 mL) in a pressure bottle, K2CO3 (683 mg, 4.95 mmol) was added. The mixture was heated at 110° C. overnight. After being cooled to room temperature, the crude dark solution was loaded to two preparative TLC plates, eluted with EtOAc/MeOH (95/5) to give the desired product as off-white solid (240 mg). MS 193.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]1=[O:18].CS[C:21](=[N:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[NH:22][C:23]#[N:24].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:18]=[C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21]([NH:22][C:23]#[N:24])=[N:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: NCCCCCCn1c(=O)ccc2ccccc21
Reactant: CSC(=Nc1ccncc1)NC#N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: N#CNC(=Nc1ccncc1)NCCCCCCn1c(=O)ccc2ccccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(6-amino-1-hexyl)-1,2-dihydroquinoline-2-one (320 mg), S-methyl-N-cyano-N′-4-pyridyl-isothiourea (210 mg), triethylamine (0.31 ml), 4-(N,N-dimethylamino)-pyridine (7 mg) and pyridine (10 ml) was stirred overnight at 60° C. After cooling to room temperature the pyridine was removed by evaporation twice with toluene in vacuo and the residue was distributed between water and ethyl acetate. The organic phase was dried and evaporated to yield a crude product which was purified by chromatography on silica gel with ethyl acetate/methanol/aqueous ammonia (40:10:1.25) as eluent. The pure fractions were pooled, evaporated, triturated with ethyl acetate and dried in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.CO>C1COCC1>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4](=[O:20])[N:5]([CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]2=[O:19])[C:6]3=[O:11])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccc(Cl)cc4)c3C2=O)C(=O)N1
Yield: 80.9 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.2 g, 4.5 mmol) and 4-chlorobenzoyl chloride (1.1 mL, 8.8 mmol) in THF (40 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with ether (2×10 mL) then methanol (5 mL) to give 4-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-benzamide as a white solid (1.5 g, 81% yield): mp, 261-263° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H, CHH), 2.49-2.65 (m, 2H, CH2), 2.83-2.98 (m, 1H, CHH), 5.18 (dd, J=5.5, 12.8 Hz, 1H, NCH), 7.68-7.72 (m, 3H, Ar), 7.89-8.01 (m, 3H, Ar), 8.52 (d, J=8.2, Hz, 1H, Ar), 10.47 (s, 1H, NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.92; 48.98, 118.48, 119.06, 126.76, 129.10, 129.29, 131.46, 132.13, 136.28, 137.47, 164.08, 166.60, 167.86, 169.67, 172.72; Anal Calcd for C20H14N3O5Cl+0.2H2O: C, 57.83; H, 3.49; N, 10.12; Cl, 8.53; H2O, 0.87. Found: C, 57.88; H, 3.33; N, 9.93; Cl, 8.53; H2O, 0.73.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][C:43]([Cl:49])=[C:44]([Cl:48])[CH:45]=3)[C:40]2=[O:50])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.Cl.[NH2:52][C:53]1[S:54][C:55]([Cl:58])=[CH:56][N:57]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[Cl:58][C:55]1[S:54][C:53]([NH:52][C:36](=[O:38])[CH:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][C:43]([Cl:49])=[C:44]([Cl:48])[CH:45]=3)[C:40]2=[O:50])[CH2:34][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[N:57][CH:56]=1
Reactant: Nc1ncc(Cl)s1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2cc(Cl)c(Cl)cc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Nc1ncc(Cl)s1)C(CC1CCCCC1)N1Cc2cc(Cl)c(Cl)cc2C1=O
Yield: 37 %

Procedure:
This compound was prepared via BOP coupling of (S)-3-cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 4, Step C; 250 mg; 0.70 mmol) and 2-amino-5-chlorothiazole hydrochloride (154 mg; 0.88 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 1, Step B) to provide N-(5-Chloro-thiazol-2-yl)-3-cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide as a beige solid in 37% yield: EI-HRMS m/e calcd for C20H20Cl3N3O2S (M+) 471.0342, found 471.0345.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[OH:13].[Cl:14]N1C(=O)CCC1=O.P(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.CN(C=O)C.O>[Cl:14][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[OH:13])=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: COc1ccc2nccc(O)c2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2ncc(Cl)c(O)c2c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
3-Chloro-6-methoxy-quinolin-4-ol was prepared as described in WO 02\40474 by heating 6-methoxy-quinolin-4-ol with N-chloro-succinimide in acetic acid at 65° C. (96%) and (11 g) in dry DMF (80 mL) cooled in ice, was treated with phosphorus tribromide (15.6 g) and stirred at room temperature for 3.5 h. It was treated with iced-water, basified with sodium carbonate solution, and the solid collected and washed with water and dried in vacuo to afford a yellow solid (13.2 g).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])[N:10]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>CN(C)C=O>[NH2:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[O:30][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])[N:10]=2)[N:7]=1
Reactant: COCC(=O)Nc1cn2nc(I)ccc2n1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Yield: 51.1 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-2-methoxyacetamide (0.60 g, 1.81 mmol), N,N-dimethylformamide (6.0 mL), potassium carbonate (499 mg, 3.61 mmol) and 3-aminophenol (296 mg, 2.71 mmol) as starting materials and in the same manner as in Example 91, the title compound (0.29 g, 51%) was obtained as a dark brown powder.