Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]([O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:2]([Cl:1])[CH:7]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1Cl
Yield: 75.5 %

Procedure:
The product was prepared by the alkylation of 2-chloro-4-nitrophenol (17.35 g) in DMF (150 mL) with ethyl bromoacetate (16.7 g) in the presence of potassium carbonate (13.8 g) to afford 19.6 g (75.6%) of ethyl 4-nitro-2-chlorophenoxyacetate as a white solid, m.p. 73°-74° C.; hydrogenation of the latter (10.0 g, 38.5 mmol) in ethanol (200 mL) on a Parr hydrogenator in the presence of 5% platinum on carbon (sulfided) (200 mg) afforded 8.1 g (92%) of ethyl 4-amino-2-chlorophenoxyacetate, m.p. 59°-62° C., after recrystallization from tert-butylmethylether, and finally, treatment of the latter (7.3 g, 31.8 mmol) in CH2Cl2 (75 mL) at 5° C. with pyridine (3.0 mL, 38.7 mmol) and methanesulfonyl chloride (2.29 mL) to afford N-[4-(ethoxycarbonylmethoxy)-3-chlorophenyl]methanesulfonamide, m.p. 87°-88° C. after recrystallization from tert-butylmethylether.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[NH2:15][C:16](N)=[O:17]>>[CH3:13][O:12][C:11]1[C:10]([CH3:14])=[CH:9][CH:8]=[C:3]2[C:2]=1[N:1]=[C:16]([OH:17])[N:15]=[C:4]2[OH:6]
Reactant: NC(N)=O
Reactant: COC(=O)c1ccc(C)c(OC)c1N
Product: COc1c(C)ccc2c(O)nc(O)nc12
Temperature: 155 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
A mixture of methyl 2-amino-3-methoxy-4-methylbenzoate (139.3 g, 0.714 mol) and urea (214.3 g, 3.57 mol) was heated in an oil bath at 110˜120° C. for 30 minutes. The temperature was then raised to 150-160° C. and the reaction mixture was stirred at this temperature for 8 h. TLC (petroleum ether/ethyl acetate=3:1) indicated the reaction was complete. The mixture was washed with EtOH (1.5 L) and water (1 L×6) and dried in vacuo to give the title compound (123 g, 83.7%) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH3:28])=[N:25][C:24]=2[CH:29]=1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH3:28])=[N:25][C:24]=2[CH:29]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: Cc1nc2cc(N)ccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc2cc(NS(=O)(=O)c3cc(Cl)ccc3Cl)ccc2o1
Reaction time: 0.08 h
Yield: 63 %

Procedure:
To a solution of 2,5-dichlorobenzenesulphonyl chloride (52 mg, 0.21 mmol) in dichloromethane (1.5 mL) was added pyridine (40 μL, 0.5 mmol) and the mixture was stirred under N2 for 5 min, after which time 5-amino-2-methylbenzoxazole (30 mg, 0.20 mmol) was added. The resulting mixture was stirred for 1 h at room temperature, then saturated NaHCO3 solution was added (8 mL) and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale pink solid (45 mg, 63%), single spot at Rf 0.53 (1:1 hexane:ethyl acetate). mp 193.5-193.9° C., HPLC purity 98% (tR 2.27 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.86 (1H, d, J=2.2 Hz), 7.39 (4H, m), 7.12 (1H, dd, J=8.4, 1.8 Hz), 2.58 (3H, s). LCMS: 355.07 (M−). FAB-MS (MH+, C14H10Cl2N2O3S): calcd 356.9867, found 356.9878.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([NH:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[CH:7][N:6]=1)=[O:4].[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:3]([C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][C:13]3[C:14]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[N:15][O:16][C:17]=3[CH3:18])=[CH:7][N:6]=2)=[O:4])[CH2:27][CH2:28]1
Reactant: COC(=O)c1cnc(NCc2c(-c3ccccc3)noc2C)cn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1CNc1cnc(C(=O)NC2CCOCC2)cn1
Yield: 81 %

Procedure:
As described for example 9b, 5-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-pyrazine-2-carboxylic acid methyl ester (650 mg, 2 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (640 mg, 81%) which was obtained as a white solid. MS: m/e=350.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:23])[NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=2)=[CH:4][CH:3]=1.[S:24]1[CH2:30][C:28](=[O:29])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:25]1=[S:26].[Cl-].[NH4+].N>C(O)C>[CH2:20]([O:19][C:17]([C:16](=[C:30]1[S:24][C:25](=[S:26])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:28]1=[O:29])[C:14]1[N:15]=[C:11]([NH:10][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[S:23])[S:12][CH:13]=1)=[O:18])[CH3:21]
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCOC(=O)C(=O)c1csc(NC(=S)Nc2ccc(F)cc2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=S)Nc2ccc(F)cc2)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 550 mg of ethyl 2-(3-p-fluorophenylthioureido)thiazol-4-ylglyoxylate, 29 mg of rhodanine-3-acetic acid, 150 mg of ammonium chloride, 0.15 ml of 28% v/v aqueous ammonia and 10 ml of ethanol. The resulting product was in the form of yellow acicular crystals having the following physical properties.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:7]=1[CH2:8][N:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:10]1=[O:23].CO>C(Cl)Cl>[Cl:28][C:26]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:10]2=[O:23])=[C:6]([F:5])[CH:27]=1
Reactant: COc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=c1ccc(-c2ccc(O)cc2)cn1Cc1ccc(Cl)cc1F
Temperature: -40 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
According to Scheme 14 Step 1: BBr3 (4 eq, 65.6 mmol, 6.56 mL) was added to a solution of 1-(2-fluoro-4-chlorobenzyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (16.4 mmol, 5.64 g) in CH2Cl2 at −50° C. The reaction mixture was stirred 1.5 hour at −40° C., overnight at room temperature then BBr3 (20 mL) was added at −30° C. and the reaction mixture was stirred 4 hours at room temperature. The reaction mixture was cooled down to −40° C. then MeOH (50 mL) was added dropwise and the crude mixture was stirred at room temperature. After evaporation, the crude mixture was purified by silica gel chromatography (300 g SiO2) using CH2Cl2/MeOH 95/5 to afford 1-(4-chloro-2-fluorobenzyl)-5-(4-hydroxyphenyl)pyridin-2(1H)-one (14.9 mmol, 4.80 g, 83%) as an orange solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:11]([CH3:22])=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=1>C(#N)C.C(OCC)(=O)C>[NH2:9][C:10]1[C:11]([CH3:22])=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:1]
Reactant: COC(=O)CCc1cccc(N)c1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CCc1ccc(Cl)c(N)c1C
Reaction time: 0.5 h

Procedure:
At RT, 1.38 g (10.3 mmol) of N-chlorosuccinimide were added to a solution of 2.0 g (10.3 mmol) of methyl 3-(3-amino-2-methylphenyl)propanoate in 10 ml of acetonitrile. The reaction mixture was stirred for 30 min and then diluted with ethyl acetate. The mixture was washed successively with sat. sodium bicarbonate solution and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product gave, after chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1), 279 mg of the target product (11.8% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([N:17]3[C:21]([CH:22]([CH3:24])[CH3:23])=[N:20][N:19]=[N:18]3)[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.[CH3:25][C:26]1[N:27]=[CH:28][C:29]([CH2:32][NH2:33])=[N:30][CH:31]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([N:17]3[C:21]([CH:22]([CH3:23])[CH3:24])=[N:20][N:19]=[N:18]3)[CH:16]=2)[C:11]([NH:33][CH2:32][C:29]2[CH:28]=[N:27][C:26]([CH3:25])=[CH:31][N:30]=2)=[O:13])=[N:6][CH:7]=1
Reactant: CC(C)c1nnnn1-c1cc(C(=O)O)cc(-c2ccc(Cl)cn2)c1
Reactant: Cc1cnc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc(CNC(=O)c2cc(-c3ccc(Cl)cn3)cc(-n3nnnc3C(C)C)c2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
3-(5-Chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid (650 mg, 1.89 mmol), C-(5-methyl-pyrazin-2-yl)-methylamine (233 mg, 1.89 mmol), EDCI (362 mg, 1.89 mmol), HOBt (255 mg, 1.89 mmol) and Et3N (1.32 mL, 9.45 mmol) were added to 10 mL methylene chloride. The reaction mixture was stirred at room temperature for 18 hours, then was partitioned between water and methylene chloride. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (80-100% EtOAc/hexanes) to give 492 mg of 3-(5-chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-benzamide, MS (M+H)=449.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([C:14](O)=[O:15])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[N+:19]([N:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[C-:20]>C1COCC1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[O:15][CH:20]=[N:19][N:21]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: [C-]#[N+]N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)OCCc1sc(-c3nnco3)nc1-2

Procedure:
To a solution of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (22.2 g, 68.1 mmol) in THF (360 mL) was added (isocyanoimino)triphenylphosphorane (20.6 g, 68.1 mmol) portionwise over 1 hour. The resultant mixture was stirred at RT for 18 hours before being concentrated in vacuo and triturated with 1:1 DCM/cyclohexane (200 mL). The title compound was collected by filtration as a yellow solid (14.5 g, 61%). LCMS: RT=4.03 min, M+H+=350/352.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[N+:17]([O-])([OH:19])=[O:18]>>[CH3:1][C:2]1[NH:3][C:4]([N+:17]([O-:19])=[O:18])=[CH:5][N:6]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ncc[nH]1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: Cc1ncc([N+](=O)[O-])[nH]1
Yield: 60 %

Procedure:
Into a glass bottle of 750 ml, provided with a reflux condenser, 50 g of 2-methylimidazole was placed and while constantly stirring and cooling, 10 ml of sulphuric acid of 1.84 density were carefully and gradually introduced in such a way, that the temperature did not exceed 120° (2-methylimidazole is a free base and its transformation into the sulphate of 2-methylimidazole is a highly exothermic reaction). Then there was slowly introduced 20 ml of sulphuric acid and after lowering the temperature to about 50°, 100 ml of nitric acid with a density of 1.50 was poured in, and, if a too violent course of the reaction in the first stage was detected, the reaction could be inhibited by addition of several ml of nitric acid of 1.50 density. Then, after several minutes, as the intensity of the reaction and of the exothermic effect began to diminish sulphuric acid was added up to exhaustion of the entire quantity of 50 ml. After the sulphuric acid was added, the reflux condenser was removed and the temperature raised to 130°-150°. The solution remained for complete cooling and in a known manner, by means of neutralization with ammonia water, 4.5 g of 2-methyl-5-nitroimidazole were isolated corresponding to a yield of about 60% of theoretical.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:17])[CH2:15][CH3:16])=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[CH:9]=1>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]2[C:11]([C:14](=[O:17])[C:15]([CH3:1])=[CH:16][N:18]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:12][CH:13]=1
Reactant: CCC(=O)c1ccc(Cl)cc1Nc1ccccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccccc2Cl)c2cc(Cl)ccc2c1=O
Temperature: -4 °C
Reaction time: 2 h
Yield: 14.9 %

Procedure:
To a 3-necked, 100 mL round-bottom flask was added DMF (26 mL) which was then cooled to −4° C. To the reaction was slowly added oxalyl chloride (2.8 g, 1.93 mL, 22.1 mmol) dropwise. Once the addition was complete, the reaction was warmed to room temperature. To the above mixture was added 1-[4-chloro-2-(2-chloro-phenylamino)-phenyl]-propan-1-one (1.3 g, 4.42 mmol) in DMF (10 mL). The reaction mixture was heated to 130° C. After 2 hr, HPLC showed a 35:65 product to SM ratio. The reaction was heated overnight at 130° C. HPLC the next day showed a 1:1 mixture of product to SM. The reaction mixture was poured over ice. Once the ice melted, the solids were filtered off. The recovery of solids was low so the filtrate was extracted with ethyl acetate. The combined organic layers were washed with water and brine, then dried over magnesium sulfate, filtered, and concentrated. The crude (˜900 mg) was purified by flash chromatography (silica gel, 80 g, 0-40% ethyl acetate in hexanes). The starting material of 1-[4-chloro-2-(2-chloro-phenylamino)-phenyl]-propan-1-one (694 mg 53.4%) was recovered as a yellow oil. The desired product 7-chloro-1-(2-chloro-phenyl)-3-methyl-1H-quinolin-4-one (200 mg, 14.9%) of 7-chloro-1-(2-chloro-phenyl)-3-methyl-1H-quinolin-4-one was obtained as a red solid. 1H NMR (DMSO-d6) δ ppm (d, J=8.7 Hz, 1H) 7.97 (d, J=0.6 Hz, 1H) 7.82 (dd, J=7.8, 1.7 Hz, 1H) 7.76 (dd, J=7.5, 2.0 Hz, 1H) 7.56-7.73 (m, 2H) 7.40 (dd, J=8.6, 1.9 Hz, 1H) 6.63 (d, J=1.8 Hz, 1H) 1.98 (s, 3H). MS calcd. for C16H11Cl2NO [(M+H)+] 305.0, obsd. 304.0.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl-].Cl[CH:13]1N(C)CC[NH+]1C.C(N(CC)CC)C>CO>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: CN1CC[NH+](C)C1Cl
Reactant: Nc1ncccc1C(=O)O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cccnc1N
Yield: 94.8 %

Procedure:
To a mixture of 2-aminonicotinic acid (n) (30.0 g 217 mmol) and 2-chloro1,3-dimethyl imidazolinium chloride (55.2 g 326 mmol) in MeOH (750 ml) was added dropwise triethylamine (91 ml 652 mmol). The resultant mixture was stirred at room temperature for 1 h. The mixture was then evaporated under reduced pressure to afford a residue. The residue was purified by extraction with ethyl acetate (300 ml×2). The combined organic phase was washed with water (200 ml×2) and brine (200 ml). Dried over anhydrous sodium sulfate, filtered and concentrated to give an essentially pure methyl 2-aminonicotinate (31.3 g, yield 94%). This compound was used in next step without further purification.
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([F:27])[CH:26]=1)[N:23]=[CH:22][C:21]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=[O:29])=[C:20]2[OH:39])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2]>C(O)(C(F)(F)F)=O.ClCCl>[P:1]([OH:3])([OH:8])([O:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([F:27])[CH:26]=1)[N:23]=[CH:22][C:21]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=[O:29])=[C:20]2[OH:39])=[O:2]
Reactant: CC(C)(C)OP(=O)(OCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CCCOP(=O)(O)O)cc2c1O
Yield: 84.8 %

Procedure:
A solution of 95 mg of compound of Example 267 (F-2 wherein X=CH2 and Y=F) in 1 mL of 1:1 TFA-dichloromethane is stirred for 30 min, then added dropwise to 50 mL of rapidly stirred 2:1 ether-hexane. The solid is filtered off, washed with hexane, and dried under vacuum to provide 65 mg of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:7][C:8]=2[Cl:12])[N:3]=1.C(=O)(O)[O-:22].[Na+]>>[Cl:12][C:8]1[N:7]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2](=[O:22])[NH:3]2
Reactant: O=C([O-])O
Reactant: COc1ccc(-c2cc3nc(Cl)ccc3c(Cl)n2)cc1
Agent: [Na+]
Product: COc1ccc(-c2cc3[nH]c(=O)ccc3c(Cl)n2)cc1
Yield: 32 %

Procedure:
2,5-Dichloro-7-(4-methoxyphenyl)-[1,6]naphthyridine (Example 26) (700 mg, 2.29 mmol) was stirred in saturated sodium bicarbonate solution (100 mL) for 20 minutes. A white solid precipitated and was isolated by vacuum filtration to afford 5-chloro-7-(4-methoxy-phenyl)-1H-[1,6]naphthyridin-2-one (209 mg, 32%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([OH:16])[CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(N2CCCC(O)C2)cc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: N#Cc1ccc(N2CCCC(=O)C2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a solution of 2-fluoro-4-(3-hydroxypiperidin-1-yl)benzonitrile (1,000 mg, 4.54 mmol) in CH2Cl2 (2 mL) was added Dess-Martin Periodinane (231 mg, 0.545 mmol). The reaction was stirred at rt for 1 h. The reaction was diluted CH2Cl2, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-50% EtOAc/Hex to give the product, 2-fluoro-4-(3-oxopiperidin-1-yl)benzonitrile, (600 mg, 2.75 mmol, 60.6% yield) as a white foam. Anal. Calcd. for C12H11FN2O m/z 218.2, found: 219.1 (M+H)+.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:23][C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:29][C:27]3[S:28][C:24]([CH3:23])=[C:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:26]=3)=[O:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1sc(N)nc1-c1ccccc1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: Cc1sc(NC(=O)c2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2)nc1-c1ccccc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 5-methyl-4-phenylthiazol-2-amine (46 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(5-methyl-4-phenylthiazol-2-yl)benzamide as an off-white solid. Yield: 54 mg (46%). 1H-NMR: 8.19 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.0 Hz, 2H), 7.68 (d, J=7.5 Hz, 2H), 7.61 (d, J=8.5 Hz, 1H) 7.50-7.34 (m, 3H), 7.24-7.08 (m, 3H), 3.84-3.78 (m, 2H), 2.52 (s, 3H), 2.45 (t, J=7.0 Hz, 2H), 1.66-1.57 (m, 2H).
Reaction SMILES: [Cl:1][C:2]([Cl:43])([Cl:42])[C:3]([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:36]([OH:38])=[O:37])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4Br)=[CH:20][CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]2)=[O:8])([CH3:5])[CH3:4].[Cl:44]C(Cl)(Cl)C(OC(N1C2C(C(OCC)=O)=C(C3C=CC(OCCOC4C=CC=C(F)C=4Cl)=CC=3)CC1CN(C(=O)C)C2)=O)(C)C.[OH-].[Na+]>CCO>[Cl:1][C:2]([Cl:43])([Cl:42])[C:3]([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:36]([OH:38])=[O:37])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4[Cl:44])=[CH:20][CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]2)=[O:8])([CH3:5])[CH3:4]
Reactant: CCOC(=O)C1=C(c2ccc(OCCOc3cccc(F)c3Cl)cc2)CC2CN(C(C)=O)CC1N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Reactant: CC(=O)N1CC2CC(c3ccc(OCCOc4cc(F)ccc4Br)cc3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1CC2CC(c3ccc(OCCOc4cc(F)ccc4Cl)cc3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl

Procedure:
As described for compound BN2, but from bicyclononene BM10 (2.82 g, 3.94 mmol), aq. 1M NaOH (30 mL) and EtOH (70 mL). The crude title compound (1.90 g, 74%) was used ftther without purification.
Reaction SMILES: Cl[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH2:12][CH3:13])=[N:7][C:6]=2[N:14]=1.[CH:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:12]([S:11][C:8]1[N:9]=[CH:10][C:5]2[CH:4]=[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:2]([C:26]3[CH:27]=[CH:28][C:23]([CH:21]=[O:22])=[CH:24][CH:25]=3)=[N:14][C:6]=2[N:7]=1)[CH3:13]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCSc1ncc2cc(-c3ccccc3)c(Cl)nc2n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCSc1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Temperature: 150 °C

Procedure:
7-chloro-2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidine (6-3) (0.80 g, 2.66 mmol) was combined with 4-formylphenylboronic acid (1.0 g, 6.64 mmol), cesium carbonate (4.30 g, 13 mmol), and bis(tri-t-butylphosphine)palladium (0.136 g, 0.266 mmol) in dioxane (10 mL) and heated in a microwave reactor at 150° C. for 60 min. The reaction mixture was diluted with water and extracted with CH2Cl2. he combined organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (35% EtOAc in hexane) to give 4-[2-(ethylthio)-6-phenylpyrido[2,3-d]pyrimidine-7-yl]benzaldehyde. LRMS m/z (M+H) Calcd: 372.5, found: 372.5
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:16]3[O:17][CH:18]=[CH:19][C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:16]3[O:17][CH:18]=[CH:19][C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccoc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccoc32)cc1

Procedure:
To a solution of 1 mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]-diazepine in 20 ml of ethyl alcohol is added 0.2 g of 10% Pd/C and 2.5 mmol of hydrazine followed by stirring and heating under reflux for 3 hours. The room temperature reaction mixture is filtered through diatomaceous earth and the filtrate concentrated in vacuo. The residue is dissolved in methylene chloride and passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give the desired product which is purified by flash chromatography on silica gel to give the desired product as a solid.