Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH:19](=O)[CH2:20][CH3:21].O>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:13]([CH2:19][CH2:20][CH3:21])[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1
Reactant: CCC=O
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCCCC1
Solvent: O
Solvent: ClCCCl
Product: CCCN1CCCCC(C(=O)OC)=Cc2cc(Br)ccc21
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of methyl 9-bromo-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (2.0 g) in 1,2-dichloroethane (20 ml) were added propion aldehyde (1.87 g) and triacetoxy sodium borohydride (4.11 g) and the mixture was stirred overnight. Water was added and the mixture was extracted with ethyl acetate, after which it was washed with aqueous saturated sodium bicarbonate solution and saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give methyl 9-bromo-1-propyl-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (2.15 g) as a yellow oily material.
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([OH:14])=[C:6]([N+:15]([O-])=O)[CH:5]=1>C1(C)C=CC=CC=1.[Fe]>[NH2:15][C:6]1[CH:5]=[C:4]([Cl:3])[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=1[OH:14]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)cc(N)c1O
Yield: 59.4 %

Procedure:
To 100 ml of an aqueous 0.78N ammonium chloride solution (with heating at 85° C.) is added 33.4 g of powdery iron with stirring followed by addition of a solution of 49.1 g of methyl 5-chloro-3-nitrosalicylate in 500 ml of toluene over 30 minutes. The reaction temperature rises to 95° C. The resultant solution is stirred at 80°-90° C. for an hour, and filtered with suction through hot celite. The mother liquor is poured into 1 l of ice-cold water, and the toluene layer is separated, washed with water and dried over magnesium sulfate. The solvent is distilled off and the residue is recrystallized from ethanol to give 25.4 g of methyl 3-amino -5-chlorosalicylate, melting at 65°-67° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10].CN(C1C=CC=CN=1)C.[C:30]([NH:40][C@H:41]([C:45](O)=[O:46])[CH:42]([CH3:44])[CH3:43])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>ClCCl>[C:30]([NH:40][C@H:41]([C:45]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)=[O:10])=[O:46])[CH:42]([CH3:44])[CH3:43])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]
Reactant: COc1ccc(COC(=O)Cc2ccccc2O)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COc1ccc(COC(=O)Cc2ccccc2OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Yield: 93.5 %

Procedure:
4-Methoxybenzyl 2-hydroxyphenylacetate 3 g, 11 mmol), N,N-dicyclohexyl-carbodiimide (2.7 g, 13.2 mmol), dimethylaminopyridine (0.134 g, 1.1 mmol) and CBz-L-valine (3.3 g, 13.2 mmol) were dissolved in dichloromethane (50 ml). After the weekend the solid was filtered off, the solvent removed under reduced pressure and the crude product purified by chromatography (ethyl acetate, hexane, 1:2) to give the title compound (5.2 g, 93%).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:18]1([CH2:17][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(CN3CCCC3)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c(cc1CN1CCCC1)CNC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.90 g 5-pyrrolidin-1-ylmethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (raw material; 4.96 mmol) in 5 ml dichloromethane was added 3.82 ml trifluoroacetic acid (49.6 mmol) and the reaction mixture was stirred at room temperature overnight. The trifluoroacetic acid and dichloromethane were evaporated under reduced pressure, water was added to the residue, the acidic aqueous phase extracted two times with ethyl acetate, the aqueous phase was basified with diluted NaOH and then subsequently extracted three times with dichloromethane. The dichloromethane phase was washed once with brine, dried over Na2SO4, filtered, and the solvent was removed under vacuum. The title compound was used without further purification in the next step. LCMS: m/z 203.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH2:18][CH2:19][CH3:20])[C:9]=2[CH3:21])=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:18][CH2:19][CH3:20])[C:9]([CH3:21])=[C:8]2[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:28])[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(C)c(-c2ccc(Cl)cc2)c2cc(O)ccc21
Product: CCCn1c(C)c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 3-(4-chloro-phenyl)-2-methyl-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][OH:21])=[NH:19])=[CH:16][CH:15]=1)[C:6]([C:24](=[O:27])[CH2:25][CH3:26])=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1CCN2C(=NCCC2)CC1.C1C[O:48][CH2:47]C1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]3[NH:19][C:47](=[O:48])[O:21][N:20]=3)=[CH:16][CH:15]=1)[C:6]([C:24](=[O:27])[CH2:25][CH3:26])=[C:5]2[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C1CCOC1
Reactant: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=N)NO)cc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 15 h
Yield: 48 %

Procedure:
To a suspension of 4-(6-bromo-1-oxo-4-phenyl-3-propionyl-1H-isoquinolin-2-ylmethyl)-N-hydroxybenzamidine (230 mg) in THF (10 ml) was added 1,1′-carbodiimidazole (89 mg) and then 1,8-diazabicyclo[5.4.0]-7-undecene (0.08 ml) was added and the mixture was stirred at 40° C. for 15 hrs. The residue was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was washed with brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1-+1/4) to give the title compound (102 mg, 48%).
Reaction SMILES: C1(CCO)CC1.[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[OH:17])[CH2:14]2.FC1C=C(F)C(F)=CC=1C(NS(C)(=O)=O)=O.[Cl:34][C:35]1[C:36](F)=[CH:37][C:38]([F:48])=[C:39]([CH:47]=1)[C:40]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[O:41]>>[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[O:17][C:36]1[C:35]([Cl:34])=[CH:47][C:39]([C:40]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[O:41])=[C:38]([F:48])[CH:37]=1)[CH2:14]2
Reactant: OC1C2CC3CC(C2)CC1C3
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Agent: OCCC1CC1
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(OC2C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 1 and making variations as required to replace 2-cyclopropylethanol with adamantan-2-ol and 2,4,5-trifluoro-N-(methylsulfonyl)benzamide with 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide, the title compound was obtained as a colorless solid (0.055 g, 4%): 1H NMR (300 MHz, DMSO-d6) δ 12.07 (s, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.33 (d, J=12.6 Hz, 1H), 4.82 (br s, 1H), 3.34 (s, 3H), 2.08-2.03 (m, 4H), 1.84 (br s, 6H), 1.71 (br s, 2H), 1.55-1.51 (m, 2H); MS (ES−) m/z 400.1, 402.1 (M−1).
Reaction SMILES: [CH2:1]([N:4]([CH3:24])[C:5](=[O:23])[C:6]1[C:18]([I:19])=[C:17]([NH2:20])[C:16]([I:21])=[C:8]([C:9]([N:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])=[O:10])[C:7]=1[I:22])[CH:2]=[CH2:3].[C:25](Cl)(Cl)=[O:26].C1(C)C=CC=CC=1>O1CCOCC1>[CH2:1]([N:4]([CH3:24])[C:5](=[O:23])[C:6]1[C:18]([I:19])=[C:17]([N:20]=[C:25]=[O:26])[C:16]([I:21])=[C:8]([C:9]([N:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])=[O:10])[C:7]=1[I:22])[CH:2]=[CH2:3]
Reactant: O=C(Cl)Cl
Reactant: C=CCN(C)C(=O)c1c(I)c(N)c(I)c(C(=O)N(C)CC=C)c1I
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: C=CCN(C)C(=O)c1c(I)c(N=C=O)c(I)c(C(=O)N(C)CC=C)c1I
Temperature: 60 °C

Procedure:
To a solution of N,N′-diallyl-5-amino-2,4,6-triiodo-N,N′-dimethyl-isophthalamide (5 g, 7.5 mmol) in 1,4-dioxane (10 mL) was added ˜11 equivalents of 20% phosgene solution in toluene (35 mL, 70 mmol) at ambient temperature, the solution was heated at 60° C. for 15 hours. The reaction was allowed to cool to ambient temperature and then concentrated at reduced pressure to yield an off white, semi-crystalline solid. Dioxane (50 mL×2) was added and removed slowly at reduced pressure to give an off white, semi-crystalline solid which was placed on a vacuum line to remove any residual solvent. The material was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][C:3]1=[O:22]>C(O)C.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:4][C:3]1=[O:22]
Reactant: Cn1ccc(-c2ccncc2NC(=O)OC(C)(C)C)cc1=O
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(c2ccncc2NC(=O)OC(C)(C)C)CC1=O
Yield: 60.9 %

Procedure:
A 0.05 M solution of tert-butyl N-[4-(1-methyl-2-oxo-4-pyridyl)-3-pyridyl]carbamate (120 mg, 0.3982 mmol) in Ethanol (8 mL) was passed through a Pd/C CatCart in the H-cube at a flow rate of 0.5 mL/min at 50 C and 50 bar. The procedure was repeated 3 more time. The product solution was concentrated in vacuo to afford tert-butyl (4-(1-methyl-2-oxopiperidin-4-yl)pyridin-3-yl)carbamate as a colourless oil (74 mg, 61%). MS (ES+) 306.1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].N1C=CC=CC=1>ClCCl>[C:9]([O:8][C:6]([N:13]1[CH2:18][CH2:17][N:16]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH2:14]1)=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.3 mL of methanesulfonyl chloride was slowly added to a solution of 2 g of 1-Boc-piperazine and 1.3 mL of pyridine in 6 mL of dichloromethane at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h while being monitored by TLC. Upon completion, the mixture was diluted with dichloromethane, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatograph (20-100% ethyl acetate/hexane) to afford tert-butyl-4-(methylsulfonyl)piperazine-1-carboxylate. 930 mg of tert-butyl-4-(methylsulfonyl)piperazine-1-carboxylate was treated with 4N HCl in dioxane for 2 h. The reaction mixture was evaporated to give the HCl salt of 1-(methylsulfonyl)piperazine. Procedure F was performed using 50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide, 69 mg of 1-(methylsulfonyl)piperazine and DIEPA (1 eq) in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(4-(methylsulfonyl)piperazin-1-yl)nicotinamide. MS (Q1) 486.3 (M)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:24]([O:26][CH3:27])=[O:25])=[N:11][N:12]2[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16]NC(=O)[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].IC.Cl.[CH3:33][N:34]([CH:36]=[O:37])[CH3:35]>>[CH2:1]([O:8][C:9]1[C:10]([C:24]([O:26][CH3:27])=[O:25])=[N:11][N:12]2[C:17]([CH3:16])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:33][N:34]([CH3:35])[C:36](=[O:37])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CNC(=O)c2c(OCc3ccccc3)c(C(=O)OC)nn21
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CCOC(=O)C1(C)CN(C)C(=O)c2c(OCc3ccccc3)c(C(=O)OC)nn21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-benzyloxy-7-ethoxycarbonyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (500 mg, 1.34 mmol) in anhydrous DMF at 0° C. were added sodium hydride (35 mg, 1.47 mmol, 95% dispersion in oil) and iodomethane (100 μL, 1.61 mmol). The reaction was stirred for 1 hour and allowed to warm to room temperature. The mixture was quenched with aqueous 3N HCl (447 μL, 1.34 mmol) and partitioned between EtOAc and H2O. The aqueous layer was extracted several times with EtOAc, and the combined organic extracts were dried over Na2SO4 and concentrated to a yellow residue. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product as a clear oil. 1H NMR (400 MHz, d6-DMSO) δ 7.49-7.47 (m, 2H), 7.43-7.31 (m, 3H), 5.20 (dd, J=11.2, 39.6 Hz, 2H), 4.19-4.11 (m, 2H), 3.98 (q, J=13.6 Hz, 2H), 3.80 (s, 3H), 2.99 (s, 3H), 1.81 (s, 3H), 1.13 (t, J=7.2 Hz, 3H); ES MS (M+H)=402.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][N:27]([CH3:29])[CH3:28])([OH:19])[C:9]2[C:10]([C:15](NC)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:26][N:27]([CH3:29])[CH3:28])[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:15](=[O:16])[O:19]2)=[CH:6][CH:7]=1
Reactant: CNC(=O)c1ccccc1C(O)(c1ccc(Cl)cc1)c1ccccc1CN(C)C
Solvent: Clc1ccccc1Cl
Product: CN(C)Cc1ccccc1C1(c2ccc(Cl)cc2)OC(=O)c2ccccc21

Procedure:
A mixture of 40.8 g. (0.1 mole of α-(4-chlorophenyl)-α-(2-dimethylaminomethyl phenyl)-α-hydroxy-N-metyl-o-toluamide and 200 ml. o-dichlorobenzene is refluxed for 20 hours, cooled and the solvent is removed in vacuo. The residue is triturated with ether and the resulting solid is recrystallized from ether-methylene chloride (1:1) to give 3-(4-chlorophenyl)-3-(2-dimethylaminomethyl phenyl) phthalide; m.p. 138.5° - 140°C.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[S:35](Cl)(=[O:37])=[O:36]>>[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][N:19]([S:35]([C:31]4[S:30][CH:34]=[CH:33][CH:32]=4)(=[O:37])=[O:36])[CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Reactant: O=S(=O)(Cl)c1cccs1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccs1)N1CCc2ccc(OCCCN3CCCCC3)cc2C1

Procedure:
7-(3-Piperidin-1-yl-propoxy)-2-(thiophene-2-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline is prepared from 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (175 mg, 0.5 mmol), NEt3 (0.25 mL, 1.8 mmol), and thiophene-2-sulfonyl chloride (114 mg, 0.63 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the product (160 mg, 76% yld). MS(ES+)421.1(M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:21][C:22](NC2C=CC(OC3C=CN=CC=3)=CC=2)=[O:23])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F:38][C:39]1[CH:44]=[C:43]([O:45][C:46]2[CH:51]=[CH:50][N:49]=[C:48]([CH3:52])[CH:47]=2)[CH:42]=[CH:41][C:40]=1[NH2:53]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:21][C:22]([NH:53][C:40]2[CH:41]=[CH:42][C:43]([O:45][C:46]3[CH:51]=[CH:50][N:49]=[C:48]([CH3:52])[CH:47]=3)=[CH:44][C:39]=2[F:38])=[O:23])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Oc2ccc(N)c(F)c2)ccn1
Reactant: COCCOc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Product: COCCOc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(C)c3)cc2F)cc1

Procedure:
The title compound was prepared in the same manner as described for 1-{5-tert-butyl-2-[4-(2-methoxyethoxy)phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-4-yloxy)-phenyl]-urea, replacing 4-(pyridin-4-yloxy)phenylamine with 2-fluoro-4-(2-methyl-pyridin-4-yloxy)phenyl-amine. 1H-NMR (DMSO-d6) δ 8.96 (s, 1H), 8.74 (s, 1H), 8.29 (d, J=6.0 Hz, 1H), 8.14 (t, J=9.3 Hz, 1H), 7.38 (d, J=9.0 Hz, 2H), 7.18 (d, J=9.0 Hz, 1H), 7.08 (dd, J=11.7, 2.4 Hz, 2H), 6.95 (d, J=7.5 Hz, 1H), 6.76 (d, J=2.4 Hz, 1H), 6.73 to 6.70 (m, 1H), 6.34 (s, 1H), 4.16 to 4.12 (m, 2H), 3.68 to 3.65 (m, 2H), 3.30 (s, 3H), 2.38 (s, 3H), 1.24 (s, 9H); MS LC-MS [M+H]+=534, RT=2.39 min.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[C:4](=[O:7])[NH:5][N:6]=1.[H-].[Na+].S(OC)(O[CH3:23])(=O)=O>CS(C)=O>[CH3:23][N:5]1[C:4](=[O:7])[N:3]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[C:2]([CH3:1])=[N:6]1
Reactant: COS(=O)(=O)OC
Reactant: Cc1n[nH]c(=O)n1-c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1nn(C)c(=O)n1-c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h

Procedure:
To a stirred solution of 13.5 parts of 2,4-dihydro-5-methyl-4-(4-nitrophenyl)-3H-1,2,4-triazol-3-one in 100 parts of dimethyl sulfoxide are added 2 parts of sodium hydride dispersion 78% and the whole is stirred till foaming has ceased. Then there are added dropwise 8.1 parts of dimethyl sulfate. Upon completion, stirring is continued for 3 hours at room temperature. The reaction mixture is poured onto water and the product is extracted three times with trichloromethane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product is filtered off and recrystallized from 4-methyl-2-pentanone, yielding 6.3 parts of 2,4-dihydro-2,5-dimethyl-4-(4-nitrophenyl)-3H-1,2,4-triazol-3-one; mp. 153.2° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:33][CH2:34][CH2:35][OH:36])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[C:27]([CH:32]=4)[C:28](OC)=[O:29])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:37][NH:38][CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:33][CH2:34][CH2:35][OH:36])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[C:27]([CH:32]=4)[C:28]([N:38]([CH3:39])[CH3:37])=[O:29])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cncc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)c1
Reactant: CNC
Product: C[C@@H](c1ccc(-c2cncc(C(=O)N(C)C)c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared methyl 5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate following a procedure analogous to that described in Example 444 Step 3 using dimethylamine in place of ammonia. LC-MS Method 2 tR=1.086 min, m/z=506.3; 1H NMR (CDCl3) 0.87 (m, 1H), 1.21-1.37 (m, 4H), 1.64 (m, 1H), 1.98 (m, 2H), 2.22 (m, 1H), 2.35 (m, 1H), 2.54 (m, 1H), 2.65 (m, 1H), 3.05 (m, 3H), 3.15 (m, 4H), 3.45 (m, 2H), 5.63 (m, 1H), 7.03-7.18 (m, 4H), 7.34 (m, 2H), 7.49 (m, 2H), 8.06 (m, 1H), 8.58 (m, 1H), 8.81 (m, 1H).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[N:25]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([C:35]2[S:36][C:37](Br)=[CH:38][CH:39]=2)(=[O:34])=[O:33])=[CH:27][CH:26]=1>>[N:25]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([C:35]2[S:36][C:37]([C:13]#[C:12][C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]5[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=5)=[N:6][C:7]=34)=[CH:38][CH:39]=2)(=[O:33])=[O:34])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Nc1ccncc1)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(Nc1ccncc1)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid pyridin-4-ylamide (example B.57) (160 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (140 mg, 49%). MS (ISN) 574.1 [(M−H)−]; mp 215° C.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][C:30]([OH:39])([CH3:38])[CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:38][C:30]([OH:39])([CH3:29])[CH2:31][CH:32]1[CH2:33][CH2:34][N:35]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:36][CH2:37]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC(C)(O)CC1CCNCC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(CC(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure E of amine alkylation, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 2-methyl-1-(piperidin-4-yl)propan-2-ol were reacted to give 266. LCMS: M+H+=519.4
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[C:22]([NH2:26])[CH:23]=[N:24][CH:25]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:26][C:22]1[CH:21]=[C:20]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)[CH:25]=[N:24][CH:23]=1
Reactant: Nc1cncc(Br)c1
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Temperature: 95 °C
Yield: 43.5 %

Procedure:
(General Suzuki reaction procedure 1) A mixture of 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.32 g, 5 mmol), 5-Bromo-pyridin-3-ylamine (865 mg, 5 mmol), s-PHOS (103 mg, 0.25 mmol), potassium phosphate (2.12 g, 10 mmol) and Pd2(dba)3 (41.2 mg, 0.1 mmol) in toluene (20 mL) was heated to 95° C. overnight (18 h). After filtration and concentration, the residue was dissolved into CH2Cl2 and mixed with celite. After concentration, the residue was loaded to column (MeOH—CH2Cl2, v/v, 1%-3.5%) and resulted in a light brown solid (500 mg). 1HNMR (400 MHz, CDCl3): δ 4.82 (brs, 2H), 7.11 (t, J=2 Hz, 1H), 7.55 (dd, J=2 Hz, 8 Hz, 1H), 7.69 (d, J=2 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 8.16 (d, J=2 Hz, 1H), 8.22 (d, J=2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10](Br)=[CH:9][CH:8]=[N:7][C:6]=1[Cl:12])[CH3:2].[CH3:14][O-:15].[Na+]>CO.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([O:15][CH3:14])=[CH:9][CH:8]=[N:7][C:6]=1[Cl:12])[CH3:2]
Reactant: C[O-]
Reactant: CCOC(=O)c1c(Br)ccnc1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1c(OC)ccnc1Cl
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of 4-bromo-2-chloronicotinic acid ethyl ester (5.06 mmol) in 15 mL MeOH was added 1.0 mL of a solution of NaOMe (30% in MeOH). The reaction mixture was stirred at 40° C. for 4 h, cooled to RT, diluted with EtOAc and then quenched with sat. aq. NH4Cl solution. The organic layers was dried over MgSO4 and concentrated in vacuo to give the desired compound as brown oil;