Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][C:5]=1[O:12][CH3:13].[C:15](N1C=CN=C1)([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:15]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[O:16])=[CH:6][C:5]=1[O:12][CH3:13]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(CN)cc1OC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNC(=O)n2ccnc2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
To a mixture of 4-aminomethyl-2-methoxy-benzoic acid methyl ester (149 mg, 0.763 mmol) in N,N-dimethyl formamide (4.0 mL) was added 1,1′-carbonyldiimidazole (Aldrich, 127 mg, 0.762 mmol). After it was stirred at rt for 16 hrs under an argon atmosphere, the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give 4-{[(imidazole-1-carbonyl)-amino]-methyl}-2-methoxy-benzoic acid methyl ester (224.3 mg, 101% crude) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[N:38][C:5]2[N:6](S(C3C=CC=CC=3)(=O)=O)[C:7]3[C:12]([C:4]=2[CH:3]=1)=[CH:11][C:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:15][CH:14]=1)=[CH:9][CH:8]=3>CO>[Cl:1][C:2]1[CH:39]=[N:38][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[CH:11][C:10]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)=[CH:17][CH:18]=1)=[CH:9][CH:8]=3
Reactant: CN1CCN(CCOc2ccc(-c3ccc4c(c3)c3cc(Cl)cnc3n4S(=O)(=O)c3ccccc3)cc2)CC1
Solvent: CO
Product: CN1CCN(CCOc2ccc(-c3ccc4[nH]c5ncc(Cl)cc5c4c3)cc2)CC1
Reaction time: 2 h
Yield: 83.3 %

Procedure:
3-chloro-6-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indole (203 mg, 0.36 mmol) is added to a solution of Na (83 mg, 3.6 mmol, 10 equiv.) in anhydrous MeOH (3.6 ml). The reaction is carried out at 65° C. for 2 hours, the mixture is then hydrolysed with ethanol and H2O and extracted with ethyl acetate (3×20 ml). The organic layers are dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue (orange solid) is purified over flash chromatography (eluted with THF/MeOH 9:1) to give the product R347 as a white solid (124 mg, 0.30 mmol) in 83% yield. 1H NMR (300 MHz, (CD3)2C0) δ 12.01 (br s, 1H), 8.74 (d, 1H, J=2.3 Hz), 8.49 (d, 1H, J=1.7 Hz), 8.42 (d, 1H, J=2.5 Hz), 7.76 (dd, 1H, J=1.8, 8.5 Hz), 7.66 (d, 2H, J=8.9 Hz), 7.55 (d, 1H, J=8.5 Hz), 7.06 (d, 2H, J=8.9 Hz), 4.13 (t, 2H, J=5.8 Hz), 2.72 (t, 2H, J=5.8 Hz), 2.38 (br s, 8H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][CH2:5]2.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[O:6][CH2:5]2
Reactant: Cc1c(Br)ccc2c1COC2=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: Cc1c(Br)ccc2c1COC2O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-4-methylisobenzofuran-1(3H)-one (3.45 g, 15.19 mmol) in toluene (100 mL) at −78° C. was added DIBAL-H (21.27 mL, 21.27 mmol) dropwise. After stirring at −78° C. for 2 h, the reaction was quenched by methanol at −78° C., then warmed to rt, then 20 mL of saturated sodium sulfate was added and the mixture was vigorously stirred at rt for 30 min. Next, the mixture was filtered and washed with ethyl acetate. The filtrate was washed with saturated sodium bicarbonate, dried over sodium sulfate, then concentrated to give the title compound. LC/MS: (M−17)+: 210.92; 212.91.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:37]([CH3:39])[CH3:38])[C:6]2[O:10][C:9]([C:11]3[CH:35]=[CH:34][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[CH:29][N:28]=[C:27]([C:31]([CH3:33])=[CH2:32])[N:26]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:36]=1)#[N:2]>CO.O1CCCC1.[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([CH:37]([CH3:39])[CH3:38])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[CH:29][N:28]=[C:27]([CH:31]([CH3:32])[CH3:33])[N:26]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:34][CH:35]=3)=[N:8][C:7]=2[CH:36]=1)#[N:2]
Reactant: C=C(C)c1nccc(N2CCC(CNC(=O)c3ccc(-c4nc5cc(C#N)cc(C(C)C)c5o4)cc3)CC2)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1nccc(N2CCC(CNC(=O)c3ccc(-c4nc5cc(C#N)cc(C(C)C)c5o4)cc3)CC2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 1115.7 %

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[1-(2-isopropenylpyrimidin-4-yl)piperidin-4-yl]methyl}benzamide (10 mg) in 1.33 ml of methanol and 0.66 ml of tetrahydrofuran was added 3 mg of 10% palladium on carbon. This mixture was evacuated and flushed with a hydrogen-filled balloon ten times. The reaction mixture was stirred at 50° C. for 1 h, and then at room temperature for 15 h. The mixture was then filtered through a plug of Celite, eluting with methanol. After concentration of the eluent in vacuo, the residue was further purified by filtration through a plug of silica gel, eluting with ethyl acetate. Concentration of the residue in vacuo provided the title compound (112 mg, 93%). Mass spectrum (ESI) 523.4 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.34 (d, J=8.3 Hz, 2H), 8.16 (d, J=6.2 Hz, 1H), 7.95 (d, J=8.0 Hz, 3H), 7.52 (s, 1H), 6.32 (m, 3H), 4.52 (d, J=9.1 Hz, 2H), 3.46 (m, 3H), 2.97 (sept, J=6.9 Hz, 1H), 2.91 (t, J=11.3 Hz, 2H), 2.00 (s, 1H), 1.88 (d, J=12.1 Hz, 2H), 1.46 (d, J=6.8, 6H), 1.33 (m, 2H), 1.28 (d, J=6.9, 6H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[N:27]=[CH:26][N:25](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:24]=4)[CH:21]=3)[N:16](C3CCCCO3)[N:15]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:24]1[C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[C:10]2[CH:9]=[C:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:13]=[CH:12][CH:11]=2)=[N:27][CH:26]=[N:25]1
Reactant: CC(C)(C)NC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55 %

Procedure:
To a stirred solution of N-(tert-butyl)(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide (0.334 g, 0.486 mmol) was added 4.0 M hydrochloric acid in dioxane (10.0 mL) and the mixture was stirred at ambient temperature for 20 h. The mixture was cooled and poured into saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate phase was pipetted off. The crystals were filtered. Purification by preparative HPLC (30-80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0964 g, 55% yield). 1H NMR (CD3OD) δ 8.77 (m, 1H), 8.37 (m, 1H), 8.35 (br s, 1H), 8.16 (d, 1H), 8.11 (d, 1H), 7.82 (d, 1H), 7.69 (d, 1H), 7.64 (t, 1H), 1.51 (s, 9H). ES-MS (m/z) 361 [M+1]+
Reaction SMILES: [C:1]1([S:7]([NH:10][N:11]2[C:15](=[O:16])[CH2:14][S:13][C:12]2=[S:17])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.CC([O-])=O.[Na+]>CO>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[C:14]2[S:13][C:12](=[S:17])[N:11]([NH:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:15]2=[O:16])=[CH:21][CH:20]=1
Reactant: O=C1CSC(=S)N1NS(=O)(=O)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1C(=Cc2ccc(F)cc2)SC(=S)N1NS(=O)(=O)c1ccccc1
Reaction time: 5 h
Yield: 9.8 %

Procedure:
3-(Benzenesulfonylamino)-4-oxo-2-thionothiazolidine 624 mg (2.17 mmol, 1.0 equiv) was combined with 349 μL 4-fluorobenzaldehyde (3.26 mmol, 1.5 equiv) and 18 mg NaOAc (0.217 mmol, 0.1 equiv) in 8 mL MeOH. The solution was allowed to stir for 5 h, at which time the resulting yellow solid was removed via filtration. The solid was washed (4×MeOH) and dried under vacuum to give the product as a yellow solid 83.5 mg (0.212 mmol, 10%). 1H NMR (DMSO, 400 MHz) δ 7.90-9.86 (m, 3 H), 7.77-7.70 (m, 3 H), 7.61 (t, J=8.8 Hz, 2 H), 7.42 (t, J=8.8 Hz, 2 H).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].Br[C:29]1[N:30]=[C:31]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH3:46])[CH2:41][CH2:40]2)[C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:45]([N:42]1[CH2:41][CH2:40][N:39]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:38]=[C:29]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][C:2]([C:3]([O:5][CH3:6])=[O:4])([CH3:1])[CH3:27])=[CH:13][CH:12]=3)[N:30]=2)[CH2:44][CH2:43]1)[CH3:46]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CC(C)(C)C(=O)OC)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(CC(C)(C)C(=O)OC)cc3)cc3ccccc23)CC1
Yield: 95 %

Procedure:
Methyl 2,2-dimethyl-3-(4-tributylstannylphenyl)propionate (2.81 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.18 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.17 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (toluene/acetone system), to give 1-(4-ethylpiperazin-1-yl)-3-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]isoquinoline (1.51 g) as a brown viscous oil.
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH:17]2[CH2:20][N:19]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH2:18]2)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1>CO.[Pd]>[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[N:19]1[CH2:20][CH:17]([O:16][C:3]2[CH:2]=[CH:7][N:6]=[C:5]([N:8]3[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]3)[N:4]=2)[CH2:18]1
Reactant: OCC1CCN(c2ncc(Br)c(OC3CN(c4ccc5ccccc5n4)C3)n2)CC1
Agent: [Pd]
Solvent: CO
Product: OCC1CCN(c2nccc(OC3CN(c4ccc5ccccc5n4)C3)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
A mixture of (1-(5-bromo-4-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrimidin-2-yl)piperidin-4-yl)methanol (see PREPARATION P7.1; 115 mg, 0.25 mmol) and wet Pd—C (50%, 50 mg) in MeOH (10 mL) was stirred under H2 (15 psi) at room temperature for 1.5 hours then the reaction mixture was filtered through CELITE® and washed with MeOH. The filtrate was concentrated in vacuo to give (1-(4-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrimidin-2-yl)piperidin-4-yl)methanol (93 mg, 0.24 mmol, yield 96%). ESI-MS (M+1): 392 calc. for C22H25N5O2 391.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=[O:24])[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:3]=12.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1.C(O)=O.Cl>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:22][CH2:21][N:20]([C:23]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=4)=[O:24])[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:39]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:41])([F:42])[F:30])[CH:33]=4)=[O:40])=[CH:13][CH:12]=3)[C:3]=12
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2nc(-c3ccc(N)cc3)c3c(N)ncnc32)C1
Agent: Cl
Solvent: O=CO
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc1)nn2[C@H]1CCN(C(=O)Nc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (S)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.080 g, 0.17 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)phenyl isocyanate (0.026 mL, 0.19 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 6 hours. After, formic acid (5 mL) and concentrated HCl (0.5 mL) were added dropwise directly to the reaction mixture. Three major species were observed by LC-MS corresponding to AD71a, AD71b, and AD71c. The reaction mixture was left stirring for 12 hours and then was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD71a (ESI-MS m/z [M+H]+ found 483.5, calculated 483.2), AD71b (ESI-MS m/z [M+H]+ found 483.5, calculated 483.2), and AD71c (ESI-MS m/z [M+H]+ found 670.5, calculated 670.2).
Reaction SMILES: [CH3:1][C:2](=[CH2:30])[C:3]([N:5]1[C@@:9]2([CH2:13][CH2:12][N:11]([C@@H:14]([C:19]([O:21]CC3C=CC=CC=3)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]2=[O:29])[CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].O>CO>[CH3:30][C:2](=[CH2:1])[C:3]([N:5]1[C@@:9]2([CH2:13][CH2:12][N:11]([C@@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]2=[O:29])[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: C=C(C)C(=O)N1CCC[C@]12CCN([C@H](CC(C)C)C(=O)OCc1ccccc1)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C(C)C(=O)N1CCC[C@]12CCN([C@H](CC(C)C)C(=O)O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of 15 (65 mg, 0.16 mmol) in methanol (2.5 ml) were added aq. NaOH (1.6 ml, 1N) and H2O (1.6 ml) and the mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated at reduced pressure, and the residue was partitioned between H2O (20 ml) and DCM (20 ml). The aqueous phase was acidified to pH=2 with aq HCl (10 ml, 0.1 N) and extracted with DCM (3×20 ml). The combined organic phases were washed with brine (25 ml), dried (Na2SO4) and concentrated at reduced pressure to afford 18 (44 mg, 85%) as a white solid. HPLC [Column Novapack C18 (Waters), 3.9×150 mm, Φ=1 ml/min, λ=214 nm, eluent: ACN/0.05% TFA, (25/75)] Rt=6.38 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]#[CH:18])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:20]1[S:24][C:23]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]#[C:18][C:20]4[S:24][C:23]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:22][CH:21]=4)=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C#Cc1cnn2ccc(-c3ccc(Cl)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3ccc(-c4ccc(Cl)cc4)nc23)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.6) (37 mg, 0.17 mmol) and 5-bromo-thiophene-2-sulfonamide (35 mg, 0.17 mmol) according to general procedure II. Obtained as a yellow solid (45 mg, 74%). MS (ISP) 415.0 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1Cl.[NH2:11][CH2:12][CH2:13][OH:14].C(N(C(C)C)CC)(C)C>CC(O)C>[NH2:1][C:2]1[C:7]([NH:11][CH2:12][CH2:13][OH:14])=[N:6][C:5]([CH3:9])=[N:4][C:3]=1[Cl:10]
Reactant: NCCO
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)c(N)c(NCCO)n1
Temperature: 150 °C
Reaction time: 27 h
Yield: 61.5 %

Procedure:
Charge a 1 L auto-clave with 5-amino-4,6-dichloro-2-methylpyrimidine (50.0 g, 0.281 mol), 2-amino ethanol (18.8 g, 0.309 mol), diisopropylethylamine (54.5 g, 0.421 mol), and IPA (500 mL). Heat the mixture to 145-155° C., with stirring for 24 to 30 h. Cool the reaction to 25-30° C. Concentrate the reaction mixture, removing the solvent under vacuum below 50° C. Charge DCM (500 mL) into the mixture and stir at 10-25° C. for 2 h. Filter the mixture and dry the cake in the oven at 45-50° C. to give the product as a pale yellow solid (35.0 g). 1H NMR (dmso-d6): δ 6.76 (s, 1H); 4.79 (s, 3H); 3.53-3.37 (m, 4H); 2.09 (s, 3H).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[N:3][C:2]=1[CH2:10][OH:11]>CO>[N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[N:3][C:2]=1[CH:10]=[O:11]
Reactant: OCc1nc2ncccn2n1
Solvent: CO
Product: O=Cc1nc2ncccn2n1

Procedure:
The title compound was prepared analogously to step 8 of example A(1) where [1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethanol was substituted in place of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-methanol.
Reaction SMILES: [Na].N.[C:3]1([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:22](Br)[CH3:23]>O.CCOCC>[C:3]1([C:9]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH3:23])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(C(c2ccccc2)c2ccncc2)cc1
Reactant: CCBr
Agent: N
Agent: [Na]
Solvent: CCOCC
Solvent: O
Product: CCC(c1ccccc1)(c1ccccc1)c1ccncc1
Reaction time: 0.33 h

Procedure:
Dissolve 2.5 g. of sodium in 500 ml. of liquid ammonia in the presence of a catalytic amount of ferric nitrate. Add dropwise to the resulting suspension over a 20 minute interval a solution containing 24.5 g. of 4-diphenylmethyl pyridine in 600 ml. of ether. Stir the resulting dark red mixture for an additional 20 minutes, then add 13 g. of ethyl bromide dropwise. Add an additional 500 ml. of ammonia, stir overnight, then add 300 ml. of ether followed by 150 ml. of water. Separate the solvent layers. Wash the ether layer with water until neutral, dry and remove the solvent under reduced pressure to a residue. Distill the residue at 192°-200° C./1.6 to 2 mm. and obtain thereby 14.7 g. of the title compound as an orange colored oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:20][CH3:21])[C:12]1[N:17]=[C:16](Cl)[N:15]=[C:14]([CH3:19])[N:13]=1.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C(OCC)(=O)C.C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:20][CH3:21])[C:12]1[N:17]=[C:16]([C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][C:27]=2[Cl:29])[N:15]=[C:14]([CH3:19])[N:13]=1
Reactant: CCN(c1nc(C)nc(Cl)n1)c1ccc(C(C)C)cc1Br
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN(c1nc(C)nc(-c2ccc(Cl)cc2Cl)n1)c1ccc(C(C)C)cc1Br

Procedure:
Part C: A mixture of N-(2-bromo-4-isopropylphenyl)-N-ethyl-4-chloro-6-methyl-1,3,5-triazine-2-amine (370 mg), 2,4-dichlorophenylboronic acid (210 mg) tetrakis(triphenylphoshine)palladium(0) (50 mg), 1M aqueous sodium carbonate (2 mL), ethanol (0.75 mL) and benzene (6 mL) was refluxed for 10 hr.The cooled mixture was diluted with ethyl acetate and the aqueous layer was removed. The organic layer was washed with water and brine, dried, and concentrated in vacuo The crude reaction product was chromatographed on silica gel using ethyl acetate/hexanes (1:9) as eluent. The title compound was obtained as a pure colorless viscous oil (210 mg) that crystallized on standing and trituration with petroleum ether to colorless crystals (82 mg). Elemental Analysis: Calcd. for C21H21N4Cl2Br: C, 52.52: H, 4.417; N, 11.67. Found: C, 52.79; H, 4.34; N, 11.40.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[Br:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[OH:31]>C(OCCO)C>[Br:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])=[CH:26][C:25]=1[OH:31]
Reactant: Nc1ccc(Br)c(O)c1
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cccc2c(Nc3ccc(Br)c(O)c3)c(C#N)cnc12
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 250.0 mg (1.1 mmol) of 4-chloro-8-methoxy -3-quinolinecarbonitrile, 131.7 mg (1.1 mmol) of pyridine hydrochloride and 286.7 mg (1.3 mmol) of 4-bromo-3-hydroxy-aniline in 10 mL of 2-ethoxyethanol was heated at 100° C. for 1.5 hr. The work up gave 374.1 mg (88.6%) of the product as a pink solid, m.p. 146° C. (dec.), mass spectrum (electrospray, m/e): M+H 369.9.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH2:9]1.[H-].[Na+].[Cl:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1.Cl>CN(C)C=O.C(O)C>[ClH:18].[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][N:11]3[C:12](=[O:14])[CH2:13][N:8]([CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:9][C:10]3=[O:15])[CH2:23][CH2:24]2)=[O:36])=[CH:34][CH:33]=1
Reactant: O=C1CN(Cc2ccccn2)CC(=O)N1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCCl)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(c1ccc(F)cc1)C1CCN(CCCN2C(=O)CN(Cc3ccccn3)CC2=O)CC1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.86 g of 4-(2-pyridylmethyl)piperazine 2,6-dione in 30 ml of dimethylformamide is added at 20° C. to a suspension of 0.36 g of sodium hydride. The mixture is brought to 60° C. for 30 minutes and 2.7 g of 1-(3-chloropropyl)-4-(4-fluorobenzoyl)piperidine, dissolved in 30 ml of dimethylformamide, are then added, again at 20° C. The mixture is kept stirring at 20° C. for approximately 15 hours and the reaction is completed by bringing to 70° C. for 2 hours. After concentration, the residue is taken up in water and the product is extracted with benzene. The oil obtained is purified by chromatography under pressure on 280 g of b 230-400 mesh silica, eluting with a mixture of dichloromethane and methanol (93.5:6.5 V/V). The base obtained is converted to the hydrochloride in ethanol. The precipitate obtained is then filtered off.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])C=O)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(/[CH:32]=[C:33]2/[C:34]([NH:36][C:37]([S:39]/2)=[NH:38])=[O:35])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:3][C:1]([C:5]1[CH:6]=[C:7]([CH:32]=[C:33]2[S:39][C:37](=[NH:38])[NH:36][C:34]2=[O:35])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:2])[CH3:4]
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=C2SC(=N)NC2=O)cc(C(C)(C)C)c1O
Temperature: 0 °C
Yield: 70.7 %

Procedure:
A mixture of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (9.4 g, 0.04 mole), pseudothiohydantoin (4.7 g, 0.0405 mole), sodium acetate (8.3 g, 0.1 mole), and glacial acetic acid (200 mL) is stirred and heated at reflux for 21 hours. The cooled mixture is added to ice-water and the precipitated solid is filtered and washed with water. The solid residue is dissolved in ether and washed successively with water, aqueous sodium bicarbonate solution, and water. The extract is dried and the solvent is removed to give 9.4 g of a residue. The crude product is recrystallized from methanol-ethyl acetate to give 3.8 g (38%) of 5-[[3,5-Bis(1,1-dimethylethyl)-4hydroxyphenyl]methylene]-2-imino-4-thiazolidinone, (Z)-, mp 277°-279° C.