Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:15]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=Cc1cccnc1
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN(Cc2cccnc2)C2CCCC(N3CCCC3)C21
Temperature: 25 °C
Reaction time: 21 h

Procedure:
2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (120 mg, 0.30 mmol) was dissolved in absolute CH2Cl2 (10 ml), and nicotinaldehyde (65 mg, 0.61 mmol), NaBH(OAc)3 (128 mg, 0.61 mmol) and glacial acetic acid (36 mg, 0.61 mmol) were added. The mixture was stirred at room temperature. After 21 hours, the same amounts of nicotinaldehyde, NaBH(OAc)3 and glacial acetic acid were again added and the mixture was stirred for 3.5 hours. The mixture was then filtered and the organic phase was extracted by shaking three times with HCl (1 N). The aqueous phase was brought to pH 8 with NaOH (2 N) and extracted by shaking three times with CH2Cl2. The organic phases were dried over Na2SO4 and evaporated in vacuo. The residue was purified by preparative HPLC (as described under Example 14 in MeOH/H2O/Et2NH 80:20:0.1). MeOH was evaporated off from the product fraction, the aqueous phase was extracted by shaking three times with CH2Cl2 and the combined organic phases were dried over Na2SO4 and evaporated. A yellowish resin was isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]1[N:12]=[N:13][C:14]([O:17]C)=[CH:15][CH:16]=1)(=[O:10])=[O:9].Cl.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]1[CH:16]=[CH:15][C:14](=[O:17])[NH:13][N:12]=1)(=[O:9])=[O:10]
Reactant: COc1ccc(S(=O)(=O)c2ccccc2F)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1ccc(S(=O)(=O)c2ccccc2F)n[nH]1
Yield: 42.2 %

Procedure:
A mixture of 3-(2-fluoro-benzenesulfonyl)-6-methoxy-pyridazine (200 mg) and concentrated hydrochloric acid (2 mL) was prepared and refluxed for one hour. The reaction mixture was cooled and diluted with water (20 mL). Sufficient 40% aqueous sodium hydroxide was then added to adjust the pH of the mixture to 3 and the mixture was extracted with ethyl acetate (2×20 mL). The ethyl acetate extract portions were collected and combined, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to obtain the title compound as a white solid (45%, 80 mg), mp, 173-176° C.; NMR, 7.06 (d, 1H), 7.23 (m, 1H), 7.3 (m, 1H), 7.89 (d, 1H), 8.02 (m, 2H) and 11.66 (s, 1H).
Reaction SMILES: [C:1]1([S:15]([OH:18])(=[O:17])=[O:16])[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([OH:14])(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:19]([CH:21]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:22][N:23]1[CH2:28][C:27]([N+:30]([O-:32])=[O:31])([CH3:29])[CH2:26][N:25]([CH2:33][CH:34]([CH2:39][CH3:40])[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:24]1)[CH3:20]>>[CH2:39]([CH:34]([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:33][N:25]1[CH2:26][C:27]([N+:30]([O-:32])=[O:31])([CH3:29])[CH2:28][N:23]([CH2:22][CH:21]([CH2:19][CH3:20])[CH2:41][CH2:42][CH2:43][CH3:44])[CH2:24]1)[CH3:40].[C:1]1([S:15]([O-:18])(=[O:17])=[O:16])[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([O-:14])(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Agent: CCCCC(CC)CN1CN(CC(CC)CCCC)CC(C)([N+](=O)[O-])C1
Product: O=S(=O)([O-])c1cccc2c(S(=O)(=O)[O-])cccc12

Procedure:
adding naphthalene-1,5-disulphonic acid to said 1,3-bis-(β-ethylhexyl)-5-nitro-5-methyl-hexahydropyrimidine in said solution, whereby a reaction mixture is formed and 1,3-bis-(β-ethylhexyl)-5-nitro-5-methyl-hexahydropyrimidine-naphthalene-1,5-disulphonate is produced as a reaction product;
Reaction SMILES: O[C:2]([C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=1)=[CH:3][C:4](=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[CH2:24]([NH:31][NH2:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]1[C:2]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[CH:3][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NNCc1ccccc1
Reactant: CCOC(=O)C(=O)C=C(O)c1cc(OC)c(OC)c(OC)c1
Agent: Cl
Product: CCOC(=O)c1cc(-c2cc(OC)c(OC)c(OC)c2)n(Cc2ccccc2)n1

Procedure:
Ethyl 4-hydroxy-2-oxo-4-(3,4,5-trimethoxyphenyl)-3-butenoate (3.12 g) and benzylhydrazine hydrochloride (1.59 g) were treated in the same manner as in Preparation Example 26 to obtain the title compound.
Reaction SMILES: [OH-].[Na+].[I-:3].[Na+].[OH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].Cl[O-].[K+]>CO>[OH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[I:3])[C:9]([OH:11])=[O:10]
Reactant: [I-]
Reactant: O=C(O)c1cccc(O)c1
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Product: O=C(O)c1ccc(I)c(O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
21.0 g (0.52 mol, 1.05 eq) of sodium hydroxide and then 78.7 g (0.52 mol, 1.05 eq) of sodium iodide are added to a solution of 69.1 g (0.5 mol, 1 eq) of 3-hydroxybenzoic acid in 700 ml of methanol. The reaction mixture is cooled to 0° C. and potassium hypochlorite solution (0.52 mol, 1.05 eq) is then added dropwise. The reaction medium is stirred at 0-5° C. for 2 hours and then at room temperature overnight. The methanol is evaporated off and the reaction medium is then acidified with concentrated hydrochloric acid solution. The precipitated product is filtered off, washed with water and dried. 121 g of 3-hydroxy-4-iodobenzoic acid are obtained in the form of an off-white solid. Yield=92%
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]1>CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]1
Reactant: COCOc1ccc(C2CCC(=O)C2)c(OCOC)c1
Solvent: CO
Product: O=C1CCC(c2ccc(O)cc2O)C1
Yield: 69.3 %

Procedure:
(±)-3-[2,4-Bis(methoxymethoxy)phenyl]cyclopentanone (8 mg) was heated at 50° C. in MeOH (3 ml) containing acidic ion exchange resin (0.1 g) for 3 hr. The reaction mixture was filtered and the resin washed with ethyl acetate (20 ml). The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (SiO2, ethyl acetate) to furnish the title compound as a white solid (3.8 mg, 70%). δH (d4-MeOH) 2.52-2.13 (1H, m), 2.26-2.48 (4H, overlapping m), 2.53-2.60 (1H, m), 3.55-3.61 (1H, m), 6.29 (1H, dd), 6.33 (1H, d), 6.96 (1H, d); m/z (ES−) 251 ((M+60)−1)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.[NH:28]1[CH2:31][CH2:30][C@@H:29]1[C:32]([OH:34])=[O:33]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:5][N:28]1[CH2:31][CH2:30][C@@H:29]1[C:32]([OH:34])=[O:33]
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: O=C(O)[C@H]1CCN1
Product: O=C(O)[C@H]1CCN1Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (106.1 mg, 0.283 mmol) and (R)-azetidine-2-carboxylic acid (86 mg, 0.850 mmol) according to Reference R and the general procedure for reductive amination gave (R)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)azetidine-2-carboxylic acid as a brown solid. MS (ESI) m/z: Calculated: 459.1; Observed: 460.1 (M++1).
Reaction SMILES: [C:1](O)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(OC(Cl)=O)C.C(N(CC)CC)C.[NH2:20][C:21]1[CH:29]=[C:25]([C:26]([OH:28])=[O:27])[C:24]([OH:30])=[CH:23][CH:22]=1.Cl>C(#N)C>[C:26]([C:25]1[CH:29]=[C:21]([NH:20][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH:22]=[CH:23][C:24]=1[OH:30])([OH:28])=[O:27]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: C=C(C)C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(C)C(=O)Nc1ccc(O)c(C(=O)O)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
Into a 1 liter flask were added 600 ml of acetonitrile, 95.2 g (1.1 mol) of methacrylic acid and 120.1 g (1.1 mol) of chloroformic acid ethyl ester. To this mixture 111.8 g (1.1 mol) of triethylamine was added over a period of 1 hour in a cold bath. Stirring was continued for 1 hour at room temperature and 141.2 g (1 mol) of 5-aminosalicylic acid was added. The mixture was heated for 2 hours at 60° C. The mixture was poured into 5 liter of 1% HCl solution. The deposit was filtered, washed and dried to produce 164.7 g of N-(3-carboxy-4-hydroxyphenyl)methacrylamide.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([NH:14][C:15]([CH3:19])([CH3:18])[CH2:16]O)=[O:13])=[C:10]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].S(Cl)([Cl:26])=O>ClCCl>[Cl:1][C:2]1[C:11]([C:12]([NH:14][C:15]([CH3:19])([CH3:18])[CH2:16][Cl:26])=[O:13])=[C:10]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)NC(C)(C)CO)c1Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)NC(C)(C)CCl)c1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
A mixture of 6.9 g (20 mmol) of methyl 2-chloro-3-(1-hydroxy-2,2-dimethyleth-2-ylaminocarbonyl)-4-methylsulfonylbenzoate and 5 ml of thionyl chloride was stirred at room temperature for 6 hours. The solution was diluted with 50 ml of dichloromethane and subsequently concentrated. The residue was dissolved in 20 ml of dichloromethane. Addition of cyclohexane resulted in the formation of a crystalline precipitate which was filtered off with suction and dried. 6.4 g (88% of theory) of methyl 2-chloro-3-(1-chloro-2,2-dimethyleth-2-ylaminocarbonyl)-4-methylsulfonylbenzoate were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.S(OC)(O[CH3:13])(=O)=O.Cl>[OH-].[Na+]>[OH:8][C:6]1[CH:5]=[CH:4][N:3]([CH3:13])[C:2](=[O:1])[CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: Oc1ccnc(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1ccc(O)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
2,4-Dihydroxypyridine (3.0 g) was dissolved in 2N aqueous sodium hydroxide solution (30 ml) and dimethyl sulphate (3.7 g) was added dropwise over 90 minutes. The mixture was stirred at room temperature overnight, acidified with concentrated hydrochloric acid, the solvent removed under reduced pressure, the residue stirred in 5% methanol/dichloromethane and filtered. The filtrate was evaporated and the crude product was chromatographed on silica using 7:93 methanol: dichloromethane as the eluent to yield 1,2-dihydro-4-hydroxy-1-methyl-2-oxopyridine (0.77 g) as a yellow solid. m.p. 165-169° C. Found: C,57.28; H,5.47; N,10.89. C6H7NO2 requires C,57.59; H,5.64; N,11.19%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)=[CH:14][CH:13]=2)[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.[NH:23]1[CH:27]=[CH:26]N=C1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:22]=[N:21][NH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:9][N:10]2[CH:26]=[CH:27][N:23]=[CH:11]2)=[CH:6][CH:7]=1
Reactant: CNCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Reactant: c1c[nH]cn1
Product: Clc1ccc(C(Cn2ccnc2)c2ccc(-c3cn[nH]c3)cc2)cc1

Procedure:
By following the procedures described in Examples 42A through to 42C but substituting methylamine for imidazole, the title compound was obtained. LC/MS: (PS-B3) Rt 2.73 [M+H]+ 349. 1H NMR (d6-DMSO) δ 4.60 (1H, t), 4.95 (2H, d), 7.32 (2H, d), 7.42 (4H, s), 7.53-7.60 (3H, m), 7.70 (1H, s), 8.05 (2H, s), 9.0 (1H, s).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([F:15])=[C:13]2[C:8]([CH2:9][C:10]([CH3:29])([CH3:28])[CH:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[NH:12]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[F:15][C:14]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:17]=1)[C:10]([CH3:28])([CH3:29])[CH2:9]2
Reactant: COC(=O)c1ccc2c(c1F)NC(c1cccc(N3CCOCC3)c1)C(C)(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2ccc(C(=O)O)c(F)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a stirred mixture solution of 8-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (400 mg, 1.0 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 8-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid (345 mg, 90%) as a light yellow solid: LC/MS m/e calcd for C22H25FN2O3 (M+H)+: 385.45, observed: 385.1.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2C(OC(C)(C)C)=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH:14]1[CH2:15][CH2:16][CH2:17][C@@H:13]1[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CNC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@H]1CCCN1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a solution of 1,1-dimethylethyl (2R)-2-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (D108, 2.07 g, 6.1 mmol) in 16 ml of dichloromethane, cooled to 0° C., were added 4 ml of TFA. The reaction mixture was allowed to warm-up to r.t. and then it was stirred at this temperature for 30 mins. The title compound (1.06 g, y=88%) was isolated after purification by SCX.
Reaction SMILES: [CH2:1]([N:8]([C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C@@H:9]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.CO.Cl>C1COCC1>[CH2:1]([N:8]([C@H:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:19])[C@@H:9]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[C@@H](CC(=O)O)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCC[C@@H](CCO)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
The product from step (iii) (12 g) was dissolved in THF (120 mL) and borane-tetrahydrofuran complex (1M in THF, 132.3 ml) added dropwise. The reaction mixture was stirred at rt overnight then MeOH was added followed by 2M HCl (20 mL). The mixture was evaporated and the residue taken up in MeOH and purified via SCX resin and the residue was further purified via column chromatography eluting with 10-20% EtOAc in isohexane to give the subtitle compound 6 g.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7]([CH:9]1[CH2:12][CH2:11][CH2:10]1)=O.C(=O)([O-])O.[Na+]>C(O)C>[CH:9]1([C:7]2[N:1]=[C:2]([NH2:4])[S:3][CH:6]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: O=C(CBr)C1CCC1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(C2CCC2)cs1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Thiourea (2.3 g, 30.0 mmol) was dissolved in ethanol (100 ml), added with 2-bromo-1-cyclobutyl-1-ethanone synthesized in the same manner as in Example 1, (E), and then heated to 100° C. The reaction solution was stirred for 1 hour, then returned to room temperature, neutralized with saturated sodium hydrogencarbonate and extracted with chloroform. The collected organic layer was washed with saturated brine, dried over magnesium sulfate and then concentrated under reduced pressure. The title compound was obtained as the residue without purification as a brown oily substance (5.4 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12](=[O:16])[O:13][C@@H:14]([CH3:15])[C@@H:7]1[CH2:6][CH2:5]2.Br[CH2:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:15][C@H:14]1[C@@H:7]2[CH2:6][CH2:5][C:4]3[C:9]([N:8]2[C:12](=[O:16])[O:13]1)=[CH:10][CH:11]=[C:2]([O:1][CH2:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:3]=3
Reactant: FC(F)(F)CCCBr
Reactant: C[C@@H]1OC(=O)N2c3ccc(O)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1OC(=O)N2c3ccc(OCCCC(F)(F)F)cc3CC[C@@H]12
Temperature: 90 °C
Yield: 75.9 %

Procedure:
To a solution of 0.70 g (3.2 mmol) of cis-(±)-7-hydroxy-3-methyl-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one in 15 ml of dimethylformamide are added 0.90 g (4.8 mmol) of 1-bromo-4,4,4-trifluorobutane and 0.90 g (6.4 mmol) of potassium carbonate. The mixture is heated at 90° C. for 4 hours and then diluted with ethyl acetate and washed with water. The organic phase is then dried over sodium sulphate and concentrated under reduced pressure, and the residue is chromatographed on a column of silica, with cyclohexane containing 20% of ethyl acetate. After trituration in diisopropyl ether, 0.80 g of product is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[O:5][C@H:6]([C:8]1[CH:26]=[CH:25][C:11]([C:12]([NH:14][CH2:15][C:16]2[C:17]([OH:24])=[N:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])=[O:13])=[CH:10][CH:9]=1)[CH3:7].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:44][C:41]1[N:42]=[CH:43][C:38]([C:2]2[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=2)[O:5][C@H:6]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][CH2:15][C:16]3[C:17]([OH:24])=[N:18][C:19]([CH3:23])=[CH:20][C:21]=3[CH3:22])=[O:13])=[CH:10][CH:9]=2)[CH3:7])=[CH:39][N:40]=1
Reactant: Cc1cc(C)c(CNC(=O)c2ccc([C@H](C)Oc3cccc(Br)c3)cc2)c(O)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2ccc([C@H](C)Oc3cccc(-c4cnc(N)nc4)c3)cc2)c(O)n1
Temperature: 90 °C
Reaction time: 12 h
Yield: 58.1 %

Procedure:
To a solution of (S)-4-(1-(3-bromophenoxy)ethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (0.20 g, 0.44 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.13 g, 0.59 mmol), tetrakis(triphenylphosphine) palladium(0) (0.05 g, 0.04 mmol) in 1,4-dioxane (10 mL) and water (1.0 mL) was added sodium carbonate (0.14 g, 1.0 mmol). The reaction mixture was stirred at 90° C. for 12 hours. After the reaction, the reaction mixture was poured to the water (100 mL) and the product was extracted by dichloromethane (100 mL), concentrated and purified by column chromatography (silica gel:dichloromethane:methanol=12:1 with 1% ammonia aqueous solution) to give pure product (S)-4-(1-(3-(2-aminopyrimidin-5-yl)phenoxy)ethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (0.12 g, 60%) as a white solid. LR MS (M+H+): calcd for: 469.21. found 469.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:18])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27]>>[CH3:18][C:7]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[O:8][CH2:9][C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][C:2]([C:23]3[CH:24]=[CH:25][C:26]([F:27])=[C:21]([Cl:20])[CH:22]=3)=[CH:19][C:6]1=2
Reactant: CC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: CC1(c2cccs2)OCC(=O)Nc2ccc(-c3ccc(F)c(Cl)c3)cc21

Procedure:
Prepared from 7-bromo-5-methyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chloro-4-fluorobenzeneboronic acid generally according to the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.13 (s, 1H), 7.86 (dd, J=6.8, 2.0 Hz, 1H), 7.64 (m, 2H), 7.55 (m, 2H), 7.48 (t, J=8.8 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 6.99 (dd, J=4.9, 3.4 Hz, 1H), 6.91 (dd, J=3.4, 1.0 Hz, 1H), 4.16 (d, J=16.1 Hz, 1H), 4.06 (d, J=16.1 Hz, 1H), 2.08 (s, 3H); MS (ES) m/z 388 (M+H)+; Anal. Calc. For C20H15ClFNO2S: C, 61.93; H, 3.90; N, 3.61. Found: C, 61.88; H, 3.99; N, 3.35.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[C:6]2[C:29](=[CH:30][CH:31]=1)[C:10]1=[N:11][O:12][C:13]([C:14]3C(C(F)(F)F)=C(C4C=CC=CC=4)ON=3)=[C:9]1[CH2:8][CH2:7]2.[CH2:32]([O:34][C:35]1[CH:36]=[C:37](C2ON=C3C4C(CCC=23)=CC(C=C)=CC=4)C=[CH:39][C:40]=1[O:41][CH2:42][CH3:43])[CH3:33]>>[CH2:42]([O:41][C:40]1[CH:39]=[C:14]([C:13]2[O:12][N:11]=[C:10]3[C:29]4[C:6]([CH2:7][CH2:8][C:9]=23)=[CH:5][C:4]([CH:2]2[CH2:3][O:1]2)=[CH:31][CH:30]=4)[CH:37]=[CH:36][C:35]=1[O:34][CH2:32][CH3:33])[CH3:43]
Reactant: FC(F)(F)c1c(-c2onc3c2CCc2cc(C4CO4)ccc2-3)noc1-c1ccccc1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OCC)c(OCC)c1
Product: CCOc1ccc(-c2onc3c2CCc2cc(C4CO4)ccc2-3)cc1OCC

Procedure:
This compound was prepared according to the procedure described for Preparation 13A, employing 70 mgs of 3-(3,4-diethoxyphenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (80A). Yield: 80 mgs (25%); LC/MS M+1=378.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[O:20])[NH:15]3)[CH:8]=[CH:9][CH:10]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=O)[NH:33][C:32]=2[CH3:39])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1>N1CCCC1.C(O)C>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34](/[CH:37]=[C:13]3\[C:14](=[O:20])[NH:15][C:16]4[C:12]\3=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][CH2:2][OH:1])[CH:6]=3)[CH:19]=[CH:18][CH:17]=4)[NH:33][C:32]=2[CH3:39])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1Cc2c(cccc2-c2cccc(OCCO)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Solvent: C1CCNC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3cccc(-c4cccc(OCCO)c4)c32)c(C)c1C(=O)NCCN1CCCC1
Yield: 15991.9 %

Procedure:
4-[3-(2-Hydroxy-ethoxy)-phenyl]-1,3-dihydro-indol-2-one (0.25 mg) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (0.25 mmol) and pyrrolidine (2 drops) in ethanol (2 mL) at rt for overnight to give 76.4 mg (60%) of the titled compound as a yellow solid.