Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:5]2=[CH:4][CH:3]=1.C[Si]([C:43]#[CH:44])(C)C.C(N(CC)CC)C.[OH-].[Na+]>CO.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:43]#[CH:44])[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OC2CCOCC2)N1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: C#Cc1ccc(OC2CCOCC2)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1

Procedure:
In a manner similar to the method described in Example 2, racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-Iodo-2-(tetrahydro-pyran-4-yloxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (1.3 g, 1.97 mmol) was reacted with trimethylsilyl acetylene (0.4 g, 3.94 mmol), CuI (0.75 g, 3.94 mmol), triethylamine (0.4 mL, 3.94 mmol) and dichlorobis(triphenylphosphine) palladium(0) (0.28 g, 0.39 mmol), then treated with aqueous NaOH solution in methanol to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-(tetrahydro-pyran-4-yloxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off white solid (Yield 0.62 g, 56%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([Br:13])=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[H-].C([Al+]CC(C)C)C(C)C.O>C1COCC1>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([Br:13])=[C:4]2[C:3]=1[C:8](=[O:9])[NH:7][CH:5]2[OH:6]
Reactant: Nc1ccc(Br)c2c1C(=O)NC2=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Br)c2c1C(=O)NC2O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.1 %

Procedure:
3-Amino-6-bromophthalimide (3.10 g, 12.9 mmol) was dissolved in THF (240 mL), and the solution was added with diisobutylaluminiumhydride (0.94 mol/L, 68.6 mL, 64.5 mmol) by drops at −78° C. for 25 minutes, then the reaction mixture was warmed to room temperature, followed by stirring for 1.5 hours. Then, the reaction mixture was ice-cooled, added with water and filtered using Celite. The filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by slurry using chloroform to obtain 7-amino-4-bromo-3-hydroxyisoindolinone (2.26 g, yield 72%).
Reaction SMILES: [CH3:1][N:2]([C:20]1[C:21]2[CH:28]=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1)[C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([OH:19])[CH2:14]2)(=[O:12])=[O:11])[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[P:38](OCl)([O:43][CH2:44][CH3:45])([O:40][CH2:41][CH3:42])=[O:39].CO>ClCCl>[P:38]([O:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][N:13]([S:10]([CH2:9][C@H:6]2[CH2:5][CH2:4][C@H:3]([N:2]([CH3:1])[C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:8][CH2:7]2)(=[O:12])=[O:11])[CH2:14]1)([O:43][CH2:44][CH3:45])([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CN(c1ncnc2[nH]ccc12)[C@H]1CC[C@H](CS(=O)(=O)N2CCC[C@@H](O)C2)CC1
Reactant: CCOP(=O)(OCl)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CCOP(=O)(OCC)O[C@@H]1CCCN(S(=O)(=O)C[C@H]2CC[C@H](N(C)c3ncnc4[nH]ccc34)CC2)C1
Reaction time: 8 h

Procedure:
(3R)-1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-methyl)sulfonyl]piperidin-3-ol (100 mg, 0.24 mmol) was suspended in dichloromethane (5 mL). Diisopropylethylamine (0.05 mL, 0.3 mmol) was added followed by diethyl chloro phosphate (0.036 mL, 0.24 mmol). The reaction mixture was stirred under nitrogen overnight. Methanol (1 mL) was added to the flask and the reaction mixture was concentrated in vacuo and the resulting residue was purified by preparative reverse phase HPLC. (100 mg, 75%) 1H NMR (400 MHz, DMSO-d6) ppm 1.19 (t, J=6.95 Hz, 6H) 1.23-1.29 (m, 3H) 1.40-1.49 (m, 1H) 1.64-1.76 (m, 5H) 1.80 (d, J=12.81 Hz, 1H) 1.87 (d, J=3.66 Hz, 1H) 2.02 (d, J=10.98 Hz, 2H) 2.58 (dd, J=10.98, 8.42 Hz, 1H) 2.73-2.81 (m, 1H) 2.88-2.99 (m, 2H) 3.15 (s, 3H) 3.44-3.55 (m, 2H) 4.05-4.12 (m, 2H) 4.14-4.21 (m, 2H) 5.00 (d, J=4.03 Hz, 1H) 6.79 (br. s., 1H) 7.27 (dd, J=3.66, 2.20 Hz, 1H) 8.23 (s, 1H). LCMS m/z 544.8 (M+H calcd for C23H38N5O6PS requires 543.2). LCMS (C-18 column, gradient elution 5 minute chromatograph, 95:5 to 5:95 water/acetonitrile, retention time 1.81 min).
Reaction SMILES: [OH:1][CH:2]([CH2:5][OH:6])[CH2:3][SH:4].[H-].[Na+].CN(C)C=[N:12][S:13]([C:16]1[S:17][C:18](Br)=[CH:19][CH:20]=1)(=[O:15])=[O:14]>CN(C=O)C.O>[OH:1][CH:2]([CH2:5][OH:6])[CH2:3][S:4][C:18]1[S:17][C:16]([S:13]([NH2:12])(=[O:15])=[O:14])=[CH:20][CH:19]=1
Reactant: CN(C)C=NS(=O)(=O)c1ccc(Br)s1
Reactant: OCC(O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NS(=O)(=O)c1ccc(SCC(O)CO)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2,3-dihydroxypropanethiol (8.11 g, 0.075 mol) in DMF (10 ml) was added dropwise to a stirred mixture of NaH (3.45 g, 50% oil, 0.075 mol) and DMF (40 ml) under nitrogen. When gas evolution was complete, a solution of N,N-dimethyl-N'-(5-bromothiophene-2-sulfonyl)formamidine (14.85 g, 0.05 mol) in DMF (50 ml) was added rapidly and the resulting mixture was heated on the steam bath for one hour. After an additional 16 hours at ambient temperature, the reaction mixture was diluted with water (500 ml) and extracted with ethyl acetate (250 ml). Sodium hydroxide (100 g) was added to the aqueous layer and this solution warmed on the steam bath for two hours. After cooling to ambient temperature, the mixture was filtered and the clear filtrate was acidified with concentrated HCl. The solution was extracted with ethyl acetate (3×300 ml), the extracts were washed with saturated NaCl and dried (Na2SO4) Filtration and evaporation of the solvent left the product as a light amber oil, 13.3 g.
Reaction SMILES: [OH:1][C:2]1[O:6]N[C:4](=[O:7])[C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22].[CH3:23]O.C[Si]([CH:29]=[N+:30]=[N-])(C)C>C1(C)C=CC=CC=1.O>[CH3:23][O:6][C:2]1[O:1][N:30]([CH3:29])[C:4](=[O:7])[C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]
Reactant: CO
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1ccccc1OCc1ccccc1-c1c(O)o[nH]c1=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1on(C)c(=O)c1-c1ccccc1COc1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
5-Hydroxy-4-[2-[(2-methylphenoxy)methyl]phenyl]-3(2H)-isoxazolone (31.3 g) was dissolved in 330 mL of 10:1 toluene:methanol and cooled in an ice-water bath. Trimethylsilyl-diazomethane (~2M in hexane) (55 mL) was added dropwise. Gas evolution was observed. The yellow solution was stirred at 25° C. for 2 h. The solution was diluted with 100 mL of water and extracted with ethyl acetate (4×100 mL). The combined organic extracts were dried (Mg SO4), filtered and concentrated under reduced pressure to yield an oil, which was purified by flash chromatography (silica gel; 1:1 hexane:ethyl acetate as eluant). The second eluting component was collected to yield 4.35 g (13%) of the title compound of Step E as a white solid, mp 90°-92° C. 1H NMR (CDCl3) δ7.61(d,1H), 7.35(m,3H), 7.12(m,2H), 6.84(m,2H), 5.12(s,2H), 3.96(s,3H), 3.41(s,3H), 2.24(s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:42])[CH:4]=[C:5]([C:8]([N:10]([CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[NH:11][S:12]([NH:15][C:16]([N:18]2[CH2:21][C@H:20]([NH:22]C(OCC3C=CC=CC=3)=O)[C:19]2=[O:33])=[O:17])(=[O:14])=[O:13])=[O:9])[NH:6][CH:7]=1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].C1(SC)C=CC=CC=1>>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[NH2:22][C@H:20]1[CH2:21][N:18]([C:16]([NH:15][S:12]([NH:11][N:10]([CH2:34][C:35]([OH:37])=[O:36])[C:8]([C:5]2[NH:6][CH:7]=[C:2]([OH:1])[C:3](=[O:42])[CH:4]=2)=[O:9])(=[O:13])=[O:14])=[O:17])[C:19]1=[O:33]
Reactant: CC(C)(C)OC(=O)CN(NS(=O)(=O)NC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C1=O)C(=O)c1cc(=O)c(O)c[nH]1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CN(C(=O)NS(=O)(=O)NN(CC(=O)O)C(=O)c2cc(=O)c(O)c[nH]2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 2.39 g (3.9 mmol) of (3S)-[1-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]-2-[[[[2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinyl]carbonyl]amino]sulfonyl]hydrazino]acetic acid, 1,1-dimethylethyl ester was added to a mixture of 7.0 ml of trifluoroacetic acid and 1.66 ml of thioanisole. After stirring overnight at room temperature, the solution was evaporated in vacuo. The residue was successively washed (stirred) with ethyl acetate, ethyl acetate/petroleum ether (1:1), petroleum ether and dichloromethane and then dried in vacuo. This crude salt was used in the next step without any further purification. Yield: 2.15 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[CH:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][C:22]1[C:26](B(O)O)=[C:25]([CH3:30])[O:24][N:23]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:21][C:22]1[C:26]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[CH:5]3[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:25]([CH3:30])[O:24][N:23]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CN1C(=O)N(C)C(c2ccccc2)c2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)N(C)C(=O)N2C
Temperature: 100 °C

Procedure:
A solution of 6-Bromo-1,3-dimethyl-4-phenyl-3,4-dihydro-1H-quinazolin-2-one (100 mg, 0.3 mmol) in dioxane (3 mL) is added NaCO3 (50 mg, 0.45 mmol) and 3,5-dimethylisoxazole-4-boronic acid (56 mg, 0.39 mmol) and Pd(dppf)Cl2 then the mixture is refluxed at 100° C. overnight. The reaction is concentrated and is purified by chromatography on silica gel to give product.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7](Cl)=[N:6][C:5]=2[CH:4]=1.[OH:19][C:20]1[NH:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C([O-])([O-])=O.[K+].[K+].C[N:36]([CH:38]=O)C>>[NH:36]1[C:38]2[C:10](=[C:5]([C:7]3[N:8]=[C:9]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:10]4[S:11][C:3]([CH2:2][N:21]5[C:22]6[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=6[NH:24][C:20]5=[O:19])=[CH:4][C:5]=4[N:6]=3)[CH:4]=[CH:3][CH:2]=2)[CH:9]=[N:8]1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: Oc1nc2ccccc2[nH]1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1[nH]c2ccccc2n1Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 from Example 9 (90 mg, 0.3 mmol) in DMF (3 mL) was added 2-hydroxybenzimidazole (35 mg, 0.3 mmol) and K2CO3 (50 mg, 0.4 mmol). The resulting solution stirred at room temperature overnight then was concentrated in vacuo. The residue was diluted with water and filtered. The crude product was utilized in a Suzuki coupling using General Procedure A with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide 326 after reverse phase HPLC purification (3 mg). MS (Q1) 484 (M)+
Reaction SMILES: [OH:1][CH:2]([C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][O:8][CH2:7][O:6][CH2:5]1)[CH3:3].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>N1C=CC=CC=1>[S:21]([O:1][CH:2]([C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][O:8][CH2:7][O:6][CH2:5]1)[CH3:3])([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C1(C(C)O)COCOC1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C1(C(C)OS(=O)(=O)c2ccc(C)cc2)COCOC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
To a mixture of ethyl 5-(1-hydroxyethyl)-1,3-dioxane-5-carboxylate (16.8 g, 83 mmol) in dry pyridine (40 mL) at 0° C. was added 4-toluenesulfonyl chloride (19.1 g, 99 mmol). The mixture was stirred at rt for 16 h. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (2×400 mL). The organic layer was washed with brine (3×). After concentrated in vacuo, the crude product was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate 25:1 to 5:1 to provide the title compound (22.7 g, 76%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.26 (m, 3H), 1.34 (d, J=6.8 Hz, 3H), 2.45 (s, 3H), 3.80 (d, J=11.6 Hz, 1H), 3.87 (d, J=11.6 Hz, 1H), 4.02 (d, J=11.6 Hz, 1H), 4.08 (d, J=12.0 Hz, 1H), 4.20-4.17 (m, 2H), 5.03-4.98 (m, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.8 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[C:4]#N.[OH-:15].[Na+].[OH2:17]>>[F:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[C:4]([OH:17])=[O:15]
Reactant: N#Cc1cc(C(F)(F)F)cc(F)c1F
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Product: O=C(O)c1cc(C(F)(F)F)cc(F)c1F
Temperature: 97 °C
Reaction time: 2 h

Procedure:
2,3-Difluoro-5-(trifluoromethyl)benzonitrile (60.03 g, 0.29 moles) is added to a solution of 17.5 g (0.43 moles) of sodium hydroxide in 158 ml of water. The mixture is heated to 97° C. during 1 hour and then heating is continued for an additional 2 hours. The mixture is acidified and the solid acid filtered off and air dried to yield 2,3-difluoro-5-(trifluoromethyl)benzoic acid, m.p. 94°-96° C.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][Cl:11])[N:6]=1)[C:2]([CH3:4])=O.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.[NH2:21]/[C:22](/[CH3:28])=[CH:23]\[C:24]([O:26][CH3:27])=[O:25]>C(O)(C)C>[CH3:4][C:2]1[NH:21][C:22]([CH3:28])=[C:23]([C:24]([O:26][CH3:27])=[O:25])[CH:16]([C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=2)[C:1]=1[C:5]1[O:9][N:8]=[C:7]([CH2:10][Cl:11])[N:6]=1
Reactant: O=Cc1cccc(F)c1
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)Cc1nc(CCl)no1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(c2nc(CCl)no2)C1c1cccc(F)c1
Yield: 72.1 %

Procedure:
A stirred solution of 500 mg of 5-acetonyl-3-chloromethyl-1,2,4-oxadiazole, 390 mg of 3-fluorobenzaldehyde and 362 mg of methyl 3-aminocrotonate in 20 ml of isopropyl alcohol was heated under reflux for 5 hours. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel using chloroform as eluent to give 780 mg of methyl 1,4-dihydro-2,6-dimethyl-3-(3-chloromethyl-1,2,4-oxadiazol-5-yl)-4-(3-fluorophenyl)pyridine-5-carboxylate. Recrystallization from ethyl acetate-isopropyl ether afforded pale yellow crystals, m,p, 186° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[N:6]=[C:5]2[CH3:11]
Reactant: ClCCN1CCCC1
Reactant: Cc1n[nH]c2ccc(Br)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nn(CCN2CCCC2)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.9 %

Procedure:
A solution of 5-bromo-3-methyl-1H-indazole (4.23 g, 20.0 mmol) in DMSO (150 mL) was treated with Cs2CO3 (19.55 g, 60.00 mmol) and 1-(2-chloroethyl)pyrrolidine hydrochloride (5.27 g, 31.0 mmol). After stirring for 16 hours at room temperature, the mixture was diluted with water (300 mL) and extracted with EtOAc (3×200 mL). The combined organics were washed with water (200 mL) and brine (200 mL), dried over Na2SO4, filtered and concentrated to dryness. Purification by flash column chromatography (silica gel, MeOH/EtOAc/hexanes, 1.4:5) gave the title compound (0.67 g, 11%) as an orange oil. 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J=1.5 Hz, 1H), 7.42 (dd, J=9.0, 1.5 Hz, 1H), 7.26 (d, J=9.0, 1H, overlapping with solvent peak), 4.43 (t, J=7.5 Hz, 2H), 2.96 (t, J=7.5 Hz, 2H), 2.58-2.55 (m, 4H), 2.53 (s, 3H), 1.79-1.74 (m, 4H).
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[NH2:15][C:16]([NH2:18])=[O:17]>C(O)C>[C:7]1([C:6]2[N:18]=[C:16]([OH:17])[N:15]=[C:4]([OH:14])[CH:5]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: NC(N)=O
Solvent: CCO
Product: Oc1cc(-c2ccccc2)nc(O)n1
Temperature: 30 °C

Procedure:
A mixture of 3-oxo-3-phenylpropionic acid ethyl ester (20 g, 104.05 mmol) and urea (6.24 g, 104.05 mmol) was reacted in a microwave irradiation for 3 minutes. The mixture was cooled to temperature in the range of 20-40° C. and diluted with ethyl alcohol (100 mL). The solid precipitated was filtered, washed with hexane (2×20 mL) to afford the desired compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[C:10]([C:19](OCC)=[O:20])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([NH:38][NH2:39])(=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[C:10]([C:19]([NH:39][NH:38][C:25](=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:20])[C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ccccc2n(Cc2ccccc2)c1=O
Reactant: CCCCCCCCCCCC(=O)NN
Product: CCCCCCCCCCCC(=O)NNC(=O)c1c(O)c2ccccc2n(Cc2ccccc2)c1=O

Procedure:
Reagents: Comp 32 (0.12 mmols, 0.04 g); dodecanoyl hydrazine (0.15 mmols, 0.033 g). Yield: 0.045 g (75%), white solid, m.p.=150° C.-151° C.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Ca+2].Br[CH2:17][C:18](Br)=[O:19].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CC#N>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[CH:35]1[CH2:40][CH2:39][N:38]([CH2:17][C:18]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)=[O:19])[CH2:37][CH2:36]1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: O=C(Br)CBr
Reactant: CC(C)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC#N
Product: COc1cc2ncnc(C3CCN(CC(=O)Nc4ccc(C(C)C)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.04 h
Yield: 56.8 %

Procedure:
A mixture of 4-isopropylaniline (17.7 mg, 131 μmol), CaCO3 (33.1 mg, 331 μmol) (10 micron powder), and CH3CN (240 μL) was stirred in an ice bath for 2-3 min before adding bromoacetyl bromide (10.3 μL, 119 μmol) dropwise over 10-15 s with stirring at 0° C. After an additional 2-3 min stirring at 0° C., the ice bath was removed and the slurry was stirred at rt for 30 min. Then 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (35.1 mg, 129 μmol), as prepared in Example 1d, was added in one portion and the mixture was stirred at 100° C. for 40 min. The reaction was then allowed to cool to rt, quenched with 2 M K2CO3 (2 mL), and extracted with DCM (2×2 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. Flash chromatography of the residue (1:1 hex/acetone) provided the title compound (30.3 mg, 57%). 1H-NMR (300 MHz, CDCl3) δ 9.11 (s, 2H), 7.51 (m, 2H), 7.33 (s, 1H), 7.25 (s, 1H), 7.19 (m, 2H), 4.05 (s, 6H), 3.41 (tt, 1H), 3.21 (s, 2H), 3.18-3.10 (m, 2H), 2.88 (heptet, 1H), 2.51 (td, 2H), 2.24 (qd, 2H), 2.02-1.92 (m, 2H), 1.22 (d, 6H). LC/MS (ESI): calcd mass 448.3, found 449.3 (MH)+.
Reaction SMILES: CC1N=[CH:4][C:5]([C:8]([NH:10][C@@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])[C:12]([OH:14])=[O:13])=[O:9])=[N:6]C=1.[CH3:22][N:23]1[C:27](C)=[CH:26]C(C(O)=O)=N1>>[CH3:22][N:23]1[C:27]([CH3:26])=[CH:4][C:5]([C:8]([NH:10][C@@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])[C:12]([OH:14])=[O:13])=[O:9])=[N:6]1
Reactant: C=CCCCCC[C@H](NC(=O)c1cnc(C)cn1)C(=O)O
Reactant: Cc1cc(C(=O)O)nn1C
Product: C=CCCCCC[C@H](NC(=O)c1cc(C)n(C)n1)C(=O)O

Procedure:
Example 50 can be prepared according to the procedure described for the preparation of Example 49, replacing 5-methylpyrazine-2-carboxylic acid from Example 49a with -(1,5-dimethyl-1H-pyrazole-3-carboxylic acid in Example 50a to produce (S)-2-(1,5-dimethyl-1H-pyrazole-3-carboxamido)non-8-enoic acid. All subsequent steps should proceed in a similar fashion to Example 49 to produce Example 50.
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[C:8]([Cl:11])[CH:9]=2)[C:4](=[O:13])[O:3]1.[O:14]1CCOCC1>Cl>[Cl:11][C:8]1[C:7]([Cl:12])=[CH:6][C:5]([C:4]([OH:3])=[O:13])=[C:10]([CH:2]=[O:14])[CH:9]=1
Reactant: O=C1OC(Br)c2cc(Cl)c(Cl)cc21
Reactant: C1COCCO1
Agent: Cl
Product: O=Cc1cc(Cl)c(Cl)cc1C(=O)O
Yield: 73 %

Procedure:
A suspension of 3-bromo-5,6-dichloro-3H-isobenzofuran-1-one (2.0 g) in 5% aqueous HCl (10 mL) and 80% aqueous dioxane (25 mL) was heated to reflux for 2 hours. The solvent was removed and the resulting residue re-dissolved in ethyl acetate, dried (magnesium sulfate) and concentrated. The resultant yellow solid was recrystallized from DCM/hexane to give the sub-title compound as a white solid (1.13 g, 73%). 1H NMR (400 MHz, CDCl3) δ 6.66 (0.84H, s), 7.95 (0.16H, s), 8.05 (0.84H), 8.12 (0.16H, s), 8.14 (0.84H, s), 8.41 (0.84H,), 10.41 (0.16H, s), 11.07 (0.16H, brd s) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].Cl.[CH3:13][NH:14][O:15][CH2:16][C:17]([OH:19])=[O:18].[CH2:20](N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:20])[C:3]=1[NH:9][C:10]([N:14]([CH3:13])[O:15][CH2:16][C:17]([OH:19])=[O:18])=[S:11]
Reactant: Cc1cccc(Cl)c1N=C=S
Reactant: CCN(CC)CC
Reactant: CNOCC(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCc1cccc(Cl)c1NC(=S)N(C)OCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
A mixture of 2-chloro-6-methylphenyl-isothiocyanate (18.3 g), N-methyl aminooxy acetic acid hydrochloride (15.5 g), triethylamine (30 g) and chloroform (300 mL) was heated at reflux for one hour, stirred at ambient temperature for one hour, then evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with 2N HCl (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness affording (28 g) of [[[[(2-Chloro-6-ethylphenyl)amino]thioxomethyl]methylamino]oxy]acetic acid as a semi solid. 1H-NMR (DMSO-d6; 300 Mhz) δ12.8 (br s, 1H), 10.04 (s, 1H), 7.38-7.20 (m, 3H), 4.61 (s, 2H), 3.58 (s, 3H), and 2.20 ppm (s, 3H). The acid (26.8 g) was dissolved in benzene (300 mL). Phosphorus pentachloride (18 g) was added in portions. The mixture was heated at reflux for one half hour then evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with sodium bicarbonate saturated solution (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. Crystallization from ethanol afforded the title compound (10.5 g) as a solid, m.p. 176-178° C. Mass spectrum (ESl, [M+H]+) m/z 271/273. 1H-NMR (CDCl3; 400 MHz) δ7.37 (d, 1H), 7.29 (t, 1H), 7.22 (d, 1H), 4.86 (ABq, 2H), 3.76 (s, 3H), and 2.21 ppm (s, 3H).