Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9]C(=O)[C:7]2=[O:12].[OH-:14].[Na+].OO.Cl>O>[NH2:9][C:10]1[C:2]([Br:1])=[C:3]([F:13])[CH:4]=[CH:5][C:6]=1[C:7]([OH:12])=[O:14]
Reactant: [OH-]
Reactant: O=C1Nc2c(ccc(F)c2Br)C1=O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1c(C(=O)O)ccc(F)c1Br
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
A 2 L 3-neck flask with a temperature probe adapter was fixed with a mechanical stirrer, addition funnel, and temperature probe. The flask was charged with 7-bromo-6-fluoroindoline-2,3-dione (719b; 11.53 g, 47.3 mmol) and 1 N NaOH (104 mL, 104 mmol) at RT; 30% hydrogen peroxide (10.62 mL, 104 mmol) was added via addition funnel over 15 min when the temperature of the brown solution raised to 45° C. The reaction mixture was stirred for 1.5 h when mostly product was observed via LCMS. The slurry was acidified to pH 7 with 2 N HCl when a solid was still present; the reaction mixture was diluted with water (100 mL) to effect stirring when it began to bubble. The slurry was then acidified to pH 1.8 with 2 N HCl (no exotherm was observed). After stirring at RT for 30 min, the slurry was filtered, washed with water, and dried in a vacuum oven to give 2-amino-3-bromo-4-fluorobenzoic acid (9.90 g, 42.3 mmol, 90% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.59 (t, J=8.61 Hz, 1H) 7.08 (br. s., 2H) 7.86 (dd, J=8.90, 6.75 Hz, 1H) 13.04 (br. s., 1H). 19F NMR (377 MHz, DMSO-d6) δ ppm −97.39 (s, 1F). MS (ESI, pos. ion) m/z: 233.9/235.9 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][C:14](=[O:17])[C:15]=2[CH3:16])=[CH:6][CH:5]=1.[CH2:30](I)[CH2:31][CH3:32]>CS(C)=O>[CH3:16][C:15]1[C:14](=[O:17])[CH:13]=[C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:30][CH2:31][CH3:32])=[CH:9][CH:8]=1
Reactant: CCCI
Reactant: Cc1c(-c2ccc(O)cc2)n(-c2ccccc2)c(-c2ccccc2)cc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCOc1ccc(-c2c(C)c(=O)cc(-c3ccccc3)n2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.3 %

Procedure:
To 50 ml of a suspension of 0.36 g (0.018 mole) of sodium hydride in DMSO, 1.7 g (0.0048 mole) of 2-(4-hydroxyphenyl)-3-methyl-1,6-diphenyl-4(1H)-pyridinone was added, followed by further dropwise addition of 1.0 g (0.0058 mole) of propyl iodide. The reaction mixture was then stirred at room temperature for 6 hours. The reaction mixture was thereafter poured into ice water, followed by extraction with chloroform. After washing the organic layer with water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off, followed by recrystallization from a 2:1 mixed solvent of acetone and hexane to obtain 1.6 g of 3-methyl-1,6-diphenyl-2-(4-propoxyphenyl)-4(1H)-pyridinone having a melting point of 165°-168° C.
Reaction SMILES: [CH3:1][C:2]1O[C:4]([CH3:15])=[CH:5][C:6](=[O:14])[C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[NH3:16]>>[CH3:1][C:2]1[NH:16][C:4]([CH3:15])=[CH:5][C:6](=[O:14])[C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: Cc1cc(=O)c(-c2ccncc2)c(C)o1
Reactant: N
Product: Cc1cc(=O)c(-c2ccncc2)c(C)[nH]1

Procedure:
A solution of compound C (8.4 g) in saturated ethanolic ammonia (700 ml) was heated at 120° C. in an autoclave for 67 hours. The solvent was removed by evaporation and the residue recrystallised from ethyl acetate/methanol to give 1,4-dihydro-2,6-dimethyl-4-oxo-3-(4-pyridyl)pyridine (B) (5.1 g) as a brown solid; NMR (d6 -DMSO): 2.1(s,3H), 2.2(s,3H), 6.0(s,1H), 7.2(d,2H), 8.5(broad s,2H), 11.2(broad s,1H); mass spectrum (chemical ionisation, ammonia): 201 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:22])([CH3:21])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)=[O:10].[H][H]>CO.[Ni]>[NH2:18][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]([CH3:21])([CH3:22])[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:2]=2[CH3:1])[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Nc2cccc([N+](=O)[O-])c2)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Nc2cccc(N)c2)c1

Procedure:
5-(2,5-Dimethylphenoxy)-2,2-dimethyl-N-(3-nitrophenyl)pentanamide (Example 1i), 22.39 g (0.0604 mol), is dissolved in 400 ml of methanol, 1.5 g of Raney nickel is added and the mixture is exposed to hydrogen gas until the required amount of hydrogen is absorbed. The methanol solution is filtered and concentrated in vacuo and the residue solidifes to afford 19.8 g of N-(3-aminophenyl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide after recrystallization from isopropyl ether; mp 93°-94° C.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][C:4]1[S:5][CH:6]=[CH:7][N:8]=1.[O:10]1[C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1>CCOCC>[CH3:1][N:2]([CH2:3][C:4]1[S:5][C:6]([C:17]2([OH:20])[CH2:18][CH2:19][C:14]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:15][CH2:16]2)=[CH:7][N:8]=1)[CH3:9]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CN(C)Cc1nccs1
Solvent: CCOCC
Product: CN(C)Cc1ncc(C2(O)CCC3(CC2)OCCO3)s1

Procedure:
The title compound was prepared as a white solid from dimethyl-thiazol-2-ylmethyl-amine, as prepared in the previous step, and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 33.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]3[N:18]=[C:19]([NH:22][CH2:23][CH3:24])[N:20]=[CH:21][C:10]=3[C:9]2=[O:25])[CH:7]=1.C([Sn](CCCC)(CCCC)[C:31]1[O:32][CH:33]=[CH:34][CH:35]=1)CCC.[F-].[NH4+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:23]([NH:22][C:19]1[N:20]=[CH:21][C:10]2[C:9](=[O:25])[N:8]([C:6]3[CH:7]=[C:2]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[CH:3]=[N:4][CH:5]=3)[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]=2[N:18]=1)[CH3:24]
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cncc(Br)c1)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cncc(-c3ccco3)c1)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
Compound 21 (68.0 mg, 0.169 mmol) obtained in Example 21 was dissolved in toluene (4 mL), and the mixture was stirred overnight under reflux after adding tri-n-butyl(2-furyl)tin (106 mg, 0.338 mmol) and bis(triphenylphosphine)palladium dichloride (12.0 mg, 0.0169 mmol). The mixture was cooled to room temperature, vigorously stirred after adding a saturated aqueous ammonium fluoride solution, and filtered through sellite. The filtrate was collected and diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was purified by preparative TLC to give the title compound (Compound 36) (40.9 mg, 62%).
Reaction SMILES: Cl.[F:2][C:3]([F:23])([F:22])[C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]([O:13][CH:14]1[CH2:17][NH:16][CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N-:24]=[C:25]=[O:26]>>[F:23][C:3]([F:2])([F:22])[C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]([O:13][CH:14]1[CH2:17][N:16]([C:25]([NH:24][CH:4]([CH2:5][CH3:6])[CH3:3])=[O:26])[CH2:15]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccccc1
Reactant: [N-]=C=O
Agent: Cl
Product: CCC(C)NC(=O)N1CC(OC(c2ccccc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared 3-[2-(trifluoromethyl)benzhydryloxy]azetidine hydrochloride (133) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12]1[O:17][CH2:18][O:19][C:11]=1[CH:10]=2)=[O:5])C.[OH-].[K+]>C(O)C>[OH:16][C:15]1[C:14]2[C:9](=[CH:10][C:11]3[O:19][CH2:18][O:17][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1O)OCO3
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc2cc3c(cc2c1O)OCO3
Reaction time: 20 h

Procedure:
4-Hydroxy-6,7-methylenedioxy-3-quinolinecarboxylic acid ethyl ester (45.0 g, 0.172 mol) was added to a solution of KOH (16.8 g, 0.258 mol) in ethanol (500 mL) and the mixture was heated to reflux with stirring for 20 hours. The reaction flask was then cooled and ethanol was evaporated under reduced pressure. Then 800 mL of water were added with stirring to fully dissolve the potassium salt, and the solution was filtered to remove any impurities. Concentrated HCl was added to bring the mixture to pH 1, and the free acid was filtered off and dried under vacuum, to give 33.9 g as a beige solid, in 84%; mp >300° C. (lit.221 mp >290° C.); 1H NMR (DMSO-d6) δ 6.27 (s, 2H), 7.30 (s, 1H), 7.55 (s, 1H), 8.72 (s, 1H); 13C NMR (DMSO-d6) δ 98.5, 101.8, 103.8, 107.9, 120.8, 137.9, 143.5, 148.1, 153.7, 167.4, 177.4.
Reaction SMILES: [NH2:1][C@H:2]1[C:5](=[O:6])[NH:4][C@@H:3]1[CH2:7][C:8]([O:14][CH3:15])=[CH:9][C:10]([O:12][CH3:13])=[O:11].[CH:16](OC(=O)C)=[O:17]>>[CH:16]([NH:1][C@H:2]1[C:5](=[O:6])[NH:4][C@@H:3]1[CH2:7][C:8]([O:14][CH3:15])=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[O:17]
Reactant: CC(=O)OC=O
Reactant: COC(=O)C=C(C[C@H]1NC(=O)[C@@H]1N)OC
Product: COC(=O)C=C(C[C@H]1NC(=O)[C@@H]1NC=O)OC

Procedure:
A solution of methyl 4-[(2R,3R)-3-amino-4-oxoazetidin-2-yl]-3-methoxybut-2-enoate [(E,Z)-isomeric mixture] (145 mg) in acetic formic anhydride (1 ml) was stirred at 5° C. for one hour. The resultant solution was evaporated in vacuo, and the residue was chromatographed on silica gel (2.5 g) eluting with 3 to 5% methanol in dichloromethane to give methyl 4-[(2R,3R)-3-formamido-4-oxoazetidin-2-yl]-3-methoxybut-2-enoate [(E,Z)-isomeric mixture] (133 mg) as an amorphous solid.
Reaction SMILES: [S:1](=[C:4]1[CH2:9][C:8](=[O:10])[CH:7]=[CH:6][O:5]1)(=[O:3])=[O:2].[BH4-].[Na+]>CO>[S:1](=[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][O:5]1)(=[O:3])=[O:2]
Reactant: O=C1C=COC(=S(=O)=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=S(=O)=c1cc(O)cco1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of sulfonylpyran-4-one (1.2 g, 8.1 mmol) in MeOH (20 mL) was cooled to 0° C. under Argon and treated with NaBH4 (331 mg, 9.0 mmol). The reaction was stirred over 16 h and allowed to warm to ambient temperature. The solvent was removed under reduced pressure and the crude oil was chromatographed on a silica gel column packed in 50:50 EtOAc:hexanes and eluted with same. The appropriate fractions were combined and the solvent was removed under reduced pressure to give the sulfonylpyran-4-ol.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:35])=[C:8]([N:10]2[CH2:33][CH2:32][C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[N:16]=[CH:17][C:12]=3[C:11]2=[O:34])[CH:9]=1)=[C:2]=S.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[OH:43].CCN=C=NCCCN(C)C.Cl>C1COCC1>[O:43]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:2]1[NH:1][C:4]1[CH:5]=[CH:6][C:7]([CH3:35])=[C:8]([N:10]2[CH2:33][CH2:32][C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[N:16]=[CH:17][C:12]=3[C:11]2=[O:34])[CH:9]=1
Reactant: Nc1ccccc1O
Reactant: Cc1ccc(N=C=S)cc1N1CCc2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(Nc2nc3ccccc3o2)cc1N1CCc2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2C1=O
Reaction time: 12 h
Yield: 115.6 %

Procedure:
To a clear solution of 6-(5-Amino-2-methyl-phenyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one (75 mg, 0.169 mmol) in the DCM (5 ml) was added Di(2-pyridyl)thionocarbonate (47 mg, 0.203 mmol) all at once, and the reaction mixture was allowed to stirred for 3 hours at room temperature. After 3 hours, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was given a brine wash, dried over sodium sulphate and concentrated to dryness to get sticky mass which was given a hexane wash to get 70.3 mg of 6-(5-Isothiocyanato-2-methyl-phenyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one [53] [Yield: 85.6%] as light brown coloured. To a solution of 6-(5-Isothiocyanato-2-methyl-phenyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one (50.0 mg, 0.089 mmol), and 2-Amino-phenol (9.73 mg, 0.089 mmol) in THF (5 ml) was added EDC.HCl (25.6 mg, 0.133 mmol), and the reaction mixture was refluxed for 12 hour under nitrogen atmosphere. After 12 hrs, the reaction mass was concentrated to dryness to get crude compound. The crude obtained was subjected to preparative HPLC. The desired compound i.e., 6-[5-(Benzooxazol-2-ylamino)-2-methyl-phenyl]-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one was obtained as brown solid [54] [Yield: 57.7 mg, 63.2%]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[CH:5]([C:8]([CH3:16])([CH3:15])[O:9][SiH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=C.N#N.CSC.C[OH:26]>ClCCl>[CH3:1][O:2][C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[CH:5]([C:8]([CH3:16])([CH3:15])[O:9][SiH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[O:26]
Reactant: C=CC(C(C)(C)O[SiH2]C(C)(C)C)C(C)(C)C(=O)OC
Reactant: CO
Agent: N#N
Solvent: CSC
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(C=O)C(C)(C)O[SiH2]C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of Example 2C (3.5 g, 12.2 mmol)in dichloromethane (25 mL) and methanol (2.5 mL) was cooled to −78° C. and O3 was bubbled for twenty-five minutes. The reaction was purged with N2 and DMS (5.29 g, 85.4 mmol) was added. The reaction was stirred at room temperature for three hours. The solvent was evaporated in vacuo and the product purified by flash column chromatography (hexanes:ethyl acetate) 100:0 to 50:50) to provide the title compound as an oil.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=3)=[N:14][N:15]=2)=[O:10])=[CH:3][CH:2]=1.C1(CCCCCCC(C2OC(C3N=C([C:54]([O:56][CH3:57])=[O:55])C=CC=3)=NN=2)=O)C=CC=CC=1>CO.C(Cl)Cl>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([C:11]2[O:12][C:13]([C:16]3[N:17]=[C:18]([C:54]([O:56][CH3:57])=[O:55])[CH:19]=[CH:20][CH:21]=3)=[N:14][N:15]=2)=[O:10])=[CH:3][CH:2]=1
Reactant: O=C(CCc1ccc(-c2ccccc2)cc1)c1nnc(-c2cccc(Br)n2)o1
Reactant: COC(=O)c1cccc(-c2nnc(C(=O)CCCCCCc3ccccc3)o2)n1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2nnc(C(=O)CCc3ccc(-c4ccccc4)cc3)o2)n1
Yield: 48 %

Procedure:
The title compound was prepared from 30 (70 mg, 0.16 mmol) by using a procedure similar to that detailed for 8f. Flash chromatography (SiO2, 2.5×15 cm, 0-1% MeOH—CH2Cl2) afforded the title compound (32 mg, 48%) as a white solid: 1H NMR (CDCl3, 600 MHz) δ 8.47 (d, 1H, J=7.8 Hz), 8.34 (d, 1H, J=7.8 Hz), 8.10 (t, 1H, J=7.8 Hz), 7.57 (d, 2H, J=7.2 Hz), 7.53 (d, 2H, J=8.1 Hz), 7.43 (t, 2H, J=7.7 Hz), 7.33 (m, 3H), 4.06 (s, 3H), 3.61 (t, 2H, J=7.5 Hz), 3.19 (t, 2H, J=7.5 Hz); 13C NMR (CDCl3, 150 MHz) δ 186.1, 164.9, 164.6, 161.5, 149.3, 142.9, 141.0, 139.7, 138.9, 138.8, 129.0, 128.9, 127.9, 127.5, 127.3, 127.2, 127.1, 53.4, 41.8, 29.1; HRMS-ESI-TOF m/z 414.1451 ([M+H]+, C24H19N3O4 requires 414.1448).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]2[C:10]([C:11](=[O:30])[C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[NH:33]1[CH:37]=[N:36][CH:35]=[N:34]1>N1C=CC=CC=1.[Cu]>[CH3:32][O:31][C:5]1[CH:4]=[N:3][C:2]([N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:30])[C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)=[O:13])[C:6]=12
Reactant: c1nc[nH]n1
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Agent: [Cu]
Solvent: c1ccncc1
Product: COc1cnc(-n2cncn2)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Temperature: 145 °C

Procedure:
A mixture of 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione (80 mg, 0.163 mmol), 1H-1,2,4-triazole (45.0 mg, 0.651 mmol) and copper (20.69 mg, 0.326 mmol) in pyridine (1 mL) was heated at 145° C. for 10 hours, LCMS indicated the formation of desired product. The reaction mixture was filtered and the clear solution purified by prep. HPLC to give 1-(4-methoxy-7-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione as pale yellow solid (28 mg, 35%). LCMS: m/e 480.11 (M+H)+, 1.52 min (method 9). 1H NMR (500 MHz, MeOD) δ ppm 2.81-3.10 (m, 2H) 3.70-4.04 (m, 5H) 4.76-5.10 (m, 2H) 7.37-7.72 (m, 3H) 7.80-7.93 (m, 1H) 8.00-8.22 (m, 2H) 8.30-8.42 (m, 2H) 8.55-8.75 (m, 1H) 8.83-8.99 (m, 1H) 9.39 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8](O)[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([Cl:28])(=O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([Cl:28])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: O[C@@H](CN1CCOCC1)c1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cl[C@@H](CN1CCOCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
To a stirred 0° C. solution of (1R)-1-(4-Bromophenyl)-2-(4-morpholinyl)ethanol (48.5 g, 0.17 mol) in 200 mL CH2Cl2 was added 52 mL of triethylamine (0.37 mol, 2.2 equiv). Following the addition of triethylamine, 15.8 mL of methanesulfonyl chloride (0.2 mol, 1.2 equiv) was added to the reaction mixture through an addition funnel. After the addition, the reaction mixture was stirred at room temperature overnight. HPLC analysis indicated a 5:1 ratio of starting material to product and an additional 6.58 mL of methanesulfonyl chloride (0.085 mols) and 11.8 mL of triethylamine (0.085 mol) were added. After stirring overnight at ambient temperature, the reaction was heated to 40° C. and stirred for 48 h. The reaction mixture was concentrated, and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude brown oil was purified by silica gel chromatography (800 g silica gel 60, 230-400 mesh, 20-50% EtOAc/CH2Cl2 as eluent). Concentration of the pure fractions yielded the title compound as a yellow oil (34.5 g, 67%). MS (ES) m/e 304, 306 [M+H]+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1.[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25]([SH:27])=[N:26][C:22]=2[CH:21]=1.[OH-].[Na+]>C(O)C>[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25]([S:27][CH2:3][C:4]3[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]4[O:14][CH:15]=[CH:16][CH:17]=4)[CH:7]=[CH:6][N:5]=3)=[N:26][C:22]=2[CH:21]=1
Reactant: Cc1c(SCc2ccco2)ccnc1CCl
Reactant: COc1ccc2[nH]c(S)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2[nH]c(SCc3nccc(SCc4ccco4)c3C)nc2c1
Yield: 81 %

Procedure:
2-Chloromethyl-4-(2-furylmethylthio)-3-methylpyridine hydrochloride, 5-methoxy-2-mercapto-1H-benzimidazole and sodium hydroxide are reacted in ethanol at 60° C. for 4 h. This gives the title compound as a colorless solid. Yield: 81%, m.p. 106-108° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1.CN([CH:22]=[O:23])C.Cl>CCCCCC.C1COCC1>[CH:22]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)=[O:23]
Reactant: CN(C)C=O
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2cc(C=O)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-BuLi in hexane (1.59M, 125 ml) was added dropwise to a solution of 2-bromo-6-methoxynaphthalene (42.27 g) in THF (600 ml) at −78° C. and was stirred at −78+ C. for 30 minutes. To the mixture was added DMF (28 ml), and the whole was allowed to warm to room temperature. The reaction mixture was acidified with HCl and extracted with ethyl acetate. The extract was dried and concentrated to give the titled compound (32.31 g) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:18][C:17](=[O:19])[CH2:16][CH2:15][C@@H:14]([O:20]C(OCC)=O)[CH2:13][O:12][C:11](=[O:26])[C:10]2[C:27]([CH3:41])=[C:28]([O:39][CH3:40])[CH:29]=[C:30]([O:31][Si](C(C)(C)C)(C)C)[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:4]>C[O-].[Na+].CO.Cl>[CH3:1][O:2][C:3]([C@H:5]1[NH:18][C:17](=[O:19])[CH2:16][CH2:15][C@@H:14]([OH:20])[CH2:13][O:12][C:11](=[O:26])[C:10]2[C:27]([CH3:41])=[C:28]([O:39][CH3:40])[CH:29]=[C:30]([OH:31])[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:4]
Reactant: CCOC(=O)O[C@@H]1CCC(=O)N[C@H](C(=O)OC)CSCc2c(O[Si](C)(C)C(C)(C)C)cc(OC)c(C)c2C(=O)OC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)OC[C@H](O)CCC(=O)N1
Yield: 35.9 %

Procedure:
A solution of 20 mg of (4R,9R)-16-(tert-butyl-dimethylsilanyloxy)-9-ethoxycarbonyloxy-14-methoxy-13-methyl-6,12-dioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecine-4-carboxylic acid methyl ester was subjected in an analogous manner to the procedure described in Example 1. The crude product was dissolved in 0.5 ml of a 0.6M solution of sodium methoxide in methanol. The solution was stirred at 0° C. for 7 min whereupon 2 ml of IN hydrochloric acid were added. The mixture was extracted with ethyl acetate and the organic layer was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from ethyl acetate/hexane to afford 5 mg of (4R,9R)-9,16-dihydroxy-14-methoxy-13-methyl-6,12-dioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecine-4-carboxylic acid methyl ester as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH:13](O)[CH2:12]1.O=S(Cl)[Cl:32].N1C=CC=CC=1>O1CCOCC1>[Cl:32][CH:13]1[CH2:12][CH:11]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[O:9][CH3:10])[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:14]1=[O:28]
Reactant: COc1cccc(OC)c1C1CC(O)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1cccc(OC)c1C1CC(Cl)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 80 °C

Procedure:
A solution of rac-(3S*,5S*)-5-(2,6-dimethoxyphenyl)-3-hydroxy-1-(4-(trifluoromethoxy)-benzyl)pyrrolidin-2-one (200 mg; 0.48 mmol) in dioxane (1 ml) was treated at rt successively with SOCl2 (69 mg; 0.58 mmol) and pyridine (46 mg; 0.58 mmol). The resulting mixture was then heated to 80° C. for 3 h. After cooling to rt, the mixture was concentrated under reduced pressure before water and AcOEt were added. The separated organic layer was washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=50/1) afforded rac-(3R*,5S*)-3-chloro-5-(2,6-dimethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one as a pale yellow solid. LC-MS (conditions A): tR=0.95 min.; [M+H]+: 430.20 g/mol.