Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][C:19]([S:25](Cl)(=[O:27])=[O:26])=[CH:20]3)=[C:11]([O:29][CH3:30])[CH:10]=1>>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][C:19]([S:25]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)(=[O:26])=[O:27])=[CH:20]3)=[C:11]([O:29][CH3:30])[CH:10]=1
Reactant: COc1cc(Cl)ccc1-c1cccc2cc(S(=O)(=O)Cl)ccc12
Reactant: Cc1cc(N)no1
Product: COc1cc(Cl)ccc1-c1cccc2cc(S(=O)(=O)Nc3cc(C)on3)ccc12
Yield: 31862.7 %

Procedure:
This product was prepared as described in Example 43, employing 5-methylisoxazol-3-amine (48.0 mg, 0.49 mmol) and 5-(4-chloro-2-methoxyphenyl)naphthalene-2-sulfonyl chloride (0.498 μl, 0.408 μmol) to provide 5-(4-chloro-2-methoxyphenyl)-N-(5-methylisoxazol-3-yl)naphthalene-2-sulfonamide (55.8 mg, 0.13 mmol) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.27 (s, 3H), 3.67 (s, 3H), 6.19 (s, 1H), 7.12-7.21 (m, 1H), 7.23-7.31 (m, 2H), 7.53-7.64 (m, 2H), 7.69-7.81 (m, 2H), 8.21 (d, J=8.30 Hz, 1H), 8.59 (d, J=1.78 Hz, 1H), 11.55 (br. s., 1H); m/z (ESI, +ve ion) 429.9 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].C[N+]1C=CN([C:26]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]2[CH3:34])=[O:27])C=1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:26]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]3[CH3:34])=[O:27])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: CC1CCCCN1C(=O)n1cc[n+](C)c1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [I-]
Product: CC1CCCCN1C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-3-(2-methyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide. The crude product was purified by flash chromatography using a Quad flash 25 (ethyl acetate/heptane (1:6), (71%, white crystals). HPLC-MS m/z=381.1 (M+1), Rt: 5.2 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:41]=[CH:42][C:43]=4[CH3:44])[C:24]([NH:26][C:27]4([C:30]([NH:32][NH:33]C(OC(C)(C)C)=O)=[O:31])[CH2:29][CH2:28]4)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:26][C:27]5([C:30]([NH:32][NH2:33])=[O:31])[CH2:28][CH2:29]5)[CH:41]=[CH:42][C:43]=4[CH3:44])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C(=O)NNC(=O)OC(C)(C)C)CC4)ccc3C)cc12
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C(=O)NN)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl 2-(1-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzamido)cyclopropanecarbonyl)hydrazinecarboxylate (33.1 mg, 0.055 mmol) in a round-bottom flask at r.t. under N2 was added HCl (1 ml, 4.00 mmol, 4 M in 1,4-dioxane). The mixture was stirred at r.t. for four hours. The mixture was evaporated, and the crude hydrochloride salt used without further purification. LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=501.06, HPLC Rt=1.483 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.N1C=CC=CC=1>C(Cl)Cl>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:1][C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[CH2:6])[CH:3]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: C=Cc1cccc(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=Cc1cccc(NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)c1
Temperature: 25 °C

Procedure:
3-Amino styrene (1.36 g, 11.4 mmol) was added to a solution of 2′,4′-difluorobiphenyl-4-sulphonyl chloride (3.0 g, 10.3 mmol) in DCM (25 mL) at 0° C. Pyridine (6.0 mL, 74 mmol) was then added and the mixture was allowed to stir and warm to room temperature overnight. The reaction was partitioned between further DCM (100 mL) and 2 M HCl (30 mL), stirred and separated. The DCM layer was washed with water (20 mL) and brine (20 mL) and dried over MgSO4. The solvent was evaporated and the title compound obtained as an orange gum (3.46 g) which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[CH3:22][NH:23][CH2:24][C:25](=[O:43])[CH:26]([NH:34][C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[C:35]([NH:34][CH:26]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:25](=[O:43])[CH2:24][N:23]([CH2:2][C:3]([N:5]1[C@H:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4])[CH3:22])(=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CNCC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)C1Cc2ccccc2CN1C(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(CC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1)CC(=O)N1Cc2ccccc2C[C@H]1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of 2-(bromoacetyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, 1,1-dimethylethyl ester (2.12 g., 6 mmole) in dimethylformamide (20 ml.) is added (±)-N-[3-(methylamino)-2-oxo-1-(phenylmethyl)propyl]benzamide (2.0 g., 6 mmole), prepared as set forth in Example 91(b), and diisopropylethylamine (0.77 g., 1.04 ml., 6 mmole). The reaction mixture is stirred overnight, poured into water (50 ml.) and extracted with ethyl acetate (3×50 ml.). The combined ethyl acetate extracts are washed with saturated sodium bicarbonate (twice) and water (twice), dried (Na2SO4), and concentrated into a yellow oily residue (2.9 g.). Flash chromatography (200 g. Merck silica, 2% methanol/chloroform) gives 0.68 g. of (S)-2-[[[3-(benzoylamino)-2-oxo-4-phenylbutyl]methylamino]acetyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, 1,1-dimethylethyl ester as a yellow dried up foam.
Reaction SMILES: C(NC(C)C)(C)C.[Li].C1CCCCC1.[C:15]([O:20][CH2:21][CH3:22])(=[O:19])[CH:16]([CH3:18])[CH3:17].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Br:30]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:17][C:16]([CH3:18])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Br:30])[C:15]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: BrCCCCCCBr
Reactant: CCOC(=O)C(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)CCCCCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of lithium diisopropylamine in cyclohexane (0.15 mol, 100 ml) and tetrahydrofuran (150 ml) was cooled to -60° C. and treated with ethyl isobutyrate (18.59 g, 0.16 mole). The solution was stirred for 1 hour then treated with 1,6-dibromohexane (51.23 g, 0.21 mole), hexamethylphosphoramide (45 g) and was stirred at -70° C. for 1 hour. The solution was then warmed to room temperature and the solvent was removed under reduced pressure. The remaining solution was treated with saturated ammonium chloride solution (400 ml) and extracted with ethylacetate (2×200 ml). The ethyl acetate extracts were combined and washed with dilute hydrochloric acid (100 ml), sodium bicarbonate (100 ml) and then dried over magnesium sulphate. The solvent and unreacted starting material were removed by distillation to give the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:13]([C:19]([O:21]C)=[O:20])#[C:14][C:15]([O:17]C)=[O:16].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+].Cl>O1CCOCC1>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10]/[C:14](=[CH:13]\[C:19]([OH:21])=[O:20])/[C:15]([OH:17])=[O:16])=[CH:8][CH:9]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)C#CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)/C=C(\Oc1ccc(OC(F)(F)F)cc1)C(=O)O
Temperature: 40 °C
Yield: 70 %

Procedure:
A mixture of 4-(trifluoromethoxy)phenol (2.75 g, 12.5 mole) and dimethyl acetylene dicarboxylate (1.69 ml, 13.7 mmole) in dioxane is treated with benzyltrimethylammonium hydroxide (0.15 ml, 40% aqueous) at room temperature under a nitrogen atmosphere, heated to 90°-95° C. (condensation complete by thin layer chromatographic analysis) cooled to 40° C., treated with sodium hydroxide (10 ml, 20% aqueous), heated at 90° C. for 1 hour and cooled to room temperature. The reaction mixture is treated with 10% aqueous HCl to pH 7 and filtered. The filtrate is acidified to about pH 1 with HCl to afford a yellow precipitate. The solid is filtered and dried to give the title product, 2.56 g (70% yield), mp 208°-210° C., identified by 1H, 13C and 19FNMR, mass spectral and elemental analyses.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26]>C(OCC)(=O)C>[ClH:26].[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:25])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2CCN1C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(1-t-butoxycarbonyl-4-piperidinyl)-1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-2-one (4.80 g, 13.9 mmol) in ethyl acetate (300 mL) was saturated with hydrogen chloride gas at 0° C. The reaction was allowed to warm to room temperature and stirred overnight. The solid was filtered and washed with ethyl acetate. The ethyl acetate filtrate was concentrated for a second crop. The title compound was obtained as a solid (2.94 g). MS 246 (M+1). 1H NMR (500 MHz, CD3OD) δ 7.10 (m, 2H), 6.94 (d, J=8 Hz, 1H), 6.91 (t, J=8 Hz, 1H), 4.35 (tt, J=10, 1 Hz, 1H), 3.52 (m, 4H), 3.12 (t, J=12 Hz, 2H), 3.05 (m, 2H), 2.07 (qd, J=12, 4 Hz, 2H), 1.99 (m, 2H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][C:7]=1[Cl:16].C(N(C(C)C)C(C)C)C>ClCCl>[Cl:16][C:7]1[CH:8]=[C:9]([S:12]([NH2:15])(=[O:13])=[O:14])[CH:10]=[CH:11][C:6]=1[N:5]=[C:1]=[O:2]
Reactant: Nc1ccc(S(N)(=O)=O)cc1Cl
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(N=C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a round bottom flask containing a solution of phosgene (1.573 mL) in dichloromethane (5 mL) was added 4-amino-3-chlorobenzenesulfonamide (0.206 g) and N-ethyl-N-isopropylpropan-2-amine (0.521 mL). The resulting clear solution was stirred at room temperature overnight. The mixture was concentrated and further dried under vacuum to provide the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[OH:22]>>[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[O:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Oc1cccc(F)c1F
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCOc1cccc(F)c1F

Procedure:
Quantities: 1-bromohexane (50 g, 0.3 mol), potassium carbonate (83 g, 0.6mol) and compound from Example 37 (39 g, 0.3 mol). The experimental procedure was as described in Example 38.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[CH3:6][CH2:7][CH2:8][CH2:9][SnH:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14]>CC(N=NC(C#N)(C)C)(C#N)C.CCOC(C)=O>[CH2:15]([Sn:10]([CH2:9][CH2:8][CH2:7][CH3:6])([CH2:11][CH2:12][CH2:13][CH3:14])[CH:4]=[CH:3][CH2:2][CH2:1][OH:5])[CH2:16][CH2:17][CH3:18]
Reactant: C#CCCO
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: CCCC[Sn](C=CCCO)(CCCC)CCCC
Temperature: 90 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
A stirred mixture of but-3-yn-1-ol (7.00 g, 99.87 mmol) and AIBN (0.50 g, 2.81 mmol), contained in large round-bottomed flask equipped with a reflux condenser, was degassed with N2 at 25° C. and treated with Bu3SnH (40.4 mL, 150 mmol). The mixture was slowly heated to 90° C. and stirred at 100° C. for 16 hours. The solution was cooled and the crude product was subjected to chromatography on Al2O3 gel with a 1-10% gradient of EtOAc in PE. The mixture of E-isomer and Z-isomer were obtained as colorless oil (15 g, 40.9%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([F:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[CH:44]=2)O1.C(=O)(O)[O-]>CN(C)C=O.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>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([F:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:40]3[CH:41]=[N:42][N:43]([CH2:45][CH2:46][N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)[CH:44]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(F)CCC5)s4)c(Cl)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(CCN4CCOCC4)c3)cc3c(-c4cnc(C5(F)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-fluorocyclobutyl)thiazole (Example 114A) (60 mg, 0.102 mmol) and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine (37.6 mg, 0.122 mmol) in N,N-dimethylformamide (0.765 mL) was added saturated aqueous bicarbonate solution (0.765 mL) followed by bis(triphenylphosphine)palladium dichloride (5.01 mg, 7.14 μmol). The mixture was heated to 70° C. for 4 hours and was then quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. MS ESI(+) m/z 641.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:24])[N:5]=[N:6][C:7]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[S:36](Cl)(=[O:38])=[O:37]>N1C=CC=CC=1>[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][C:27]=1[S:36]([NH:24][C:4]1[N:5]=[N:6][C:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[C:2]([CH3:1])[CH:3]=1)(=[O:38])=[O:37]
Reactant: Cc1cc(N)nnc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2Cl)nnc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Yield: 10.9 %

Procedure:
5-Methyl-6-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridazin-3-ylamine (110 mgs), 2-chloro-4-trifluoromethylbenzenesulfonyl chloride (160 mgs) and pyridine (1 ml) were heated at 50° C. under nitrogen for 72 hours. All volatiles were removed and the residue purified by Preparative HPLC to give 2-chloro-N-{5-methyl-6-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridazin-3-yl}-4-trifluoromethyl-benzenesulfonamide 20 mg. 1H NMR (CDCl3) 8.25 (1H, d) 7.75 (2H, m) 7.7 (1H, s) 7.6 (3H, m) 6.95 (1H, s) 3.0 (4H, m) 2.3 (3H, s) 1.6 (4H, m) 1.45 (2H, m). LCMS Polarity/Scan type: Negative Q1 Scan. M.wt. 605 (—H), 607 (—H). Retention time 7.05 minutes. HPLC:—MS8. Retention time 4.99 minutes.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](NC(=O)C)=[CH:8][CH:7]=1)=[O:5].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C=O)C>[O:21]=[C:19]1[C:18]2[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:26])[N:20]1[CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:18][C:19]([NH2:20])=[O:21])=[CH:10][CH:11]=1)=[O:5]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(=O)Nc1ccc(C(=O)CCCl)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: NC(=O)Cc1ccc(C(=O)CCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Yield: 169.1 %

Procedure:
N-[4-(3-chloro-propionyl)phenyl]acetamide (1.45 g, J. Med. Chem. 8, 1965, 877) and potassium phthalimide (1.31 g) were combined in DMF (5 mL) and heated at 125 C for 30 min, allowed to cool to room temperature diluted with ice water. The suspension was filtered and the filter cake was washed with water and hexanes. The precipitate in a mimimum amount of EtOAc was triturated with hexanes to give 2 g of the title compound. MS (ESI(+)) m/e 337.1 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([CH2:8][NH:9][CH2:10][C:11]#[N:12])=[N:5][C:4]2[CH2:13][CH2:14][O:15][CH2:16][C:3]1=2.[F:17][C:18]1[CH:35]=[CH:34][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1>>[C:11]([CH2:10][N:9]([CH2:8][C:6]1[NH:7][C:2](=[O:1])[C:3]2[CH2:16][O:15][CH2:14][CH2:13][C:4]=2[N:5]=1)[C:31](=[O:32])[CH2:30][N:27]1[CH2:28][CH2:29][CH:24]([C:22](=[O:23])[C:21]2[CH:20]=[CH:19][C:18]([F:17])=[CH:35][CH:34]=2)[CH2:25][CH2:26]1)#[N:12]
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: N#CCNCc1nc2c(c(=O)[nH]1)COCC2
Product: N#CCN(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (5.4 mg) from [(4-oxo-3,5,7,8-tetrahydro-4H-pyrano[4,3-d]pyrimidin-2-ylmethyl)-amino]-acetonitrile and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C24H26FN5O4 467.5. found 468.5 (ESI, M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 12.61 (br. s., 1H) 9.80 (br. s., 1H) 7.96-8.19 (m, 2H) 7.40 (t, J=8.84 Hz, 2H) 4.58 (s, 2H) 4.50 (s, 2H) 4.26-4.46 (m, 4H) 3.80-3.92 (m, 3H) 3.61-3.75 (m, 1H) 3.52 (br. s., 2H) 3.17 (br. s., 1H) 3.09 (br. s., 1H) 2.00 (br. s., 4H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:14]([O-])=O)[C:8]=2[Cl:13])[N:3]=1>[Pt].COCCO.C(O)C>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:14])[C:8]=2[Cl:13])[N:3]=1
Reactant: Nc1nc(N)c2c(Cl)c([N+](=O)[O-])ccc2n1
Agent: [Pt]
Solvent: CCO
Solvent: COCCO
Product: Nc1nc(N)c2c(Cl)c(N)ccc2n1

Procedure:
This compound was prepared in a manner analogous to that of Example 13, using 11.0 grams (0.049 mole) of 2,4-diamino-5-chloro-6-nitroquinazoline and 1.0 gram of 10% platinum on carbon in 70 mL of 2-methoxyethanol and 130 mL of ethanol, yielding 2,4,6-triamino-5-chloroquinazoline.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=2[N:8]=1)[NH2:2].[C:14]([CH2:17][C:18](=O)[CH3:19])(=O)[CH3:15]>C(O)C>[CH3:15][C:14]1[CH:17]=[C:18]([CH3:19])[N:1]([C:3]2[N:4]=[N:5][C:6]3[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=3[N:8]=2)[N:2]=1
Reactant: NNc1nnc2cc(Cl)ccc2n1
Reactant: CC(=O)CC(C)=O
Solvent: CCO
Product: Cc1cc(C)n(-c2nnc3cc(Cl)ccc3n2)n1
Yield: 85.9 %

Procedure:
19.5 g (0.1 mol) of 3-hydrazino-7-chloro-benzo-1,2,4-triazine and 10 g (0.1 mol) of acetylacetone were boiled under reflux in 125 ml of ethanol for 5 hours. The residue after distilling off the solvent was recrystallized from wash benzine. 22.3 g of 3-(3,5-dimethyl-pyrazol-1-yl)-7-chloro-benzo-1,2,4-triazine of melting point 174° C. were obtained, that is to say 86% of theory.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:21])[N:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:25]=1[C:26](O)=[O:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:2][O:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:21])[N:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:26]([C:25]1[C:29]([CH3:33])=[CH:30][CH:31]=[CH:32][C:24]=1[Cl:23])=[O:27]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cccn(C)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cccn(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Reaction time: 15 h
Yield: 88.8 %

Procedure:
To a suspension of 4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride salt (101 mg, 0.313 mmol), 2-chloro-6-methylbenzoic acid (60 mg, 0.35 mmol) and HBTU (133 mg, 0.35 mmol) in DMF (2 mL) was added DIEA (122 μL, 0.88 mmol) at room temperature. The resulting mixture was stirred for 15 h. Then, the mixture was poured into water (25 mL) and the organic compound was extracted into ethyl acetate (2×15 mL). The combined ethyl acetate extracts were washed successively with 0.5 N HCl (25 mL), saturated NaHCO3 solution (25 mL), brine solution (25 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel chromatography using a Biotage (40s) column to afford 122 mg (88% yield) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester as an amorphous white solid. FAB-HRMS m/e calcd for C24H23ClN2O4 (M+H) 439.1425, found 439.1414
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[NH2:16][C@H:17]([CH2:25][CH3:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[CH:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:36]=[C:37]([C:38]([O:40][CH3:41])=[O:39])[C:30]=12)=O>ClCCCl>[C:21]([O:20][C:18](=[O:19])[C@H:17]([NH:16][CH2:27][C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:36]=[C:37]([C:38]([O:40][CH3:41])=[O:39])[C:30]=12)[CH2:25][CH3:26])([CH3:22])([CH3:24])[CH3:23]
Reactant: CC[C@@H](N)C(=O)OC(C)(C)C
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC[C@@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
Sodium triacetoxyborohydride (9.86 mmol) and (R)-tert-butyl 2-aminobutanoate hydrochloride (5.59 mmol) were added to a 100 mL round bottom flask, followed by DCE (20 mL). The reaction mixture was stirred at room temperature for 30 min and cooled to 0° C. A solution of 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (3.29 mmol) in DCE (20 mL) was added. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%) afforded the title compound as a yellow oil (1.4 g, 95%). [M+H] calc'd for C23H33N3O6, 448; found, 448.6.