Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:28]([NH:30][C:31](=[N:39][CH2:40][CH2:41][S:42][CH2:43][C:44]1[N:45]=[C:46]([NH:49][C:50]([NH2:52])=[NH:51])[S:47][CH:48]=1)OC1C=CC=CC=1)#[N:29]>>[C:28]([NH:30][C:31]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:26]=[CH:27][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:25])=[N:39][CH2:40][CH2:41][S:42][CH2:43][C:44]1[N:45]=[C:46]([NH:49][C:50]([NH2:52])=[NH:51])[S:47][CH:48]=1)#[N:29]
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Reactant: CN(CCCCCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Product: CN(CCCCCCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.57 g (1.53 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,7-heptanediamine and the equimolar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=654 ([M+H]+, 2), 91 (100); IR (KBr): 2163 cm-1 (C≡N). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt in an ethanol/ether solvent mixture; m.p. 118° C. (ethanol/ether).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.COC1C=CC(C[S:16][C@@H:17]2[CH2:21][N:20]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[C@H:19]([C:35]([N:37]3[CH2:42][CH2:41][CH:40]([N:43]4[CH:47]=[CH:46][N:45]=[CH:44]4)[CH2:39][CH2:38]3)=[O:36])[CH2:18]2)=CC=1.C(=O)([O-])O.[Na+]>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OCC)(=O)C>[SH:16][C@@H:17]1[CH2:21][N:20]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=2)=[O:23])[C@H:19]([C:35]([N:37]2[CH2:38][CH2:39][CH:40]([N:43]3[CH:47]=[CH:46][N:45]=[CH:44]3)[CH2:41][CH2:42]2)=[O:36])[CH2:18]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCC(n4ccnc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Product: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCC(n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
350 μl of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a solution of 1.44 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[4-(imidazol-1-yl)piperidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (i) above] in a mixture of 1.5 ml of anisole and 7.5 ml of trifluoroacetic acid, and the resulting mixture was stirred at room temperature for 1 hour and then at 35° C. for a further 30 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was washed four times with diethyl ether to give a colorless powder. The whole of this powder was suspended in ethyl acetate and the suspension was made alkaline by the addition of an aqueous solution of sodium hydrogencarbonate. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, to give 1.15 g of the title compound, as a colorless powder.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]3[O:11][CH2:12][CH2:13][CH2:14][C:6]=3[C:5]=2[C:4]([CH:15]=O)=[CH:3]1.C([O-])(=O)C.[NH4+].O.[N+:23]([CH2:26][CH3:27])([O-:25])=[O:24]>>[N+:23]([C:26]([CH3:27])=[CH:15][C:4]1[C:5]2[C:6]3[CH2:14][CH2:13][CH2:12][O:11][C:7]=3[CH:8]=[CH:9][C:10]=2[N:2]([CH3:1])[CH:3]=1)([O-:25])=[O:24]
Reactant: CC[N+](=O)[O-]
Reactant: Cn1cc(C=O)c2c3c(ccc21)OCCC3
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: CC(=Cc1cn(C)c2ccc3c(c12)CCCO3)[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
A mixture of 3-methyl-3,7,8,9-tetrahydro-pyrano[3,2-e]indole-1-carboxaldehyde (1.02 g, 4.74 mmol) and ammonium acetate (0.30 g, 3.90 mmol) in 12 ml of nitroethane was heated at 100° C. for 3 h, stirred at room temperature for 18 h, mixed with water (50 ml) and extracted with EtOAc (3×50 ml). The combined extracts were dried (MgSO4), filtered and evaporated to dryness. Crystallization of the residue from a mixture of dichloromethane and hexane gave an orange solid (1.10 g, 85%): mp 200-202° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[CH3:21][N:22]=[C:23]=[O:24]>O1CCCC1CO>[CH3:21][NH:22][C:23]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:24]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: CN=C=O
Agent: Cl
Solvent: OCC1CCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)NC)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.1 %

Procedure:
To a solution of diethyl 2-aminomalonate hydrochloride (4.2 g) and triethylamine (2.12 g) in tetrahydrofuran-methanol is added dropwise methyl isocyanate (1.25 g) at 0° to 5° C., and the mixture is stirred at room temperature for 5 hours. The reaction mixture is concentrated under reduced pressure, and to the residue is added chloroform. The organic layer is separated, washed, dried and then concentrated. The residue is recrystallized from chloroform-isopropyl ether to give diethyl 2-[(methylcarbamoyl)amino]malonate (4.2 g), m.p. 139° C.
Reaction SMILES: O1CCOCC1.Cl.[CH:8]1(/[CH:13]=[C:14](/[C:23]2[N:28]=[C:27]([O:29]C)[C:26]([CH:31]3[CH2:33][CH2:32]3)=[CH:25][CH:24]=2)\[C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1>O>[CH:8]1(/[CH:13]=[C:14](/[C:23]2[NH:28][C:27](=[O:29])[C:26]([CH:31]3[CH2:33][CH2:32]3)=[CH:25][CH:24]=2)\[C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COc1nc(/C(=C/C2CCCC2)c2ccc(SC)cc2)ccc1C1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccc(/C(=C\C2CCCC2)c2ccc(C3CC3)c(=O)[nH]2)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
A 4 M hydrogen chloride-1,4-dioxane solution (4.5 mL) was added to a suspension of 6-{(E)-2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}-3-cyclopropyl-2-methoxypyridine (150 mg) in water (1.5 mL), and the mixture was stirred at 90° C. for 1.5 hours. The reaction solution was cooled to room temperature and extracted with chloroform twice. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in a hexane-ethyl acetate solution with heating, and then recrystallization by cooling to room temperature gave the title compound as a colorless powder (111 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[C:28](=[O:30])=[O:29]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:28]([OH:30])=[O:29]
Reactant: O=C=O
Reactant: Clc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12 %

Procedure:
A solution of 3-chloropyridine (1.00 mL, 10.5 mmol) in THF at −78° C. was treated dropwise with a solution of lithium diisopropylamide in THF [freshly prepared by addition of butyllithium (7.21 mL, 11.5 mmol) to diisopropylamine (11.5 mmol)]. After 0.25 h, the mixture was treated with carbon dioxide (g) and slowly warmed to ambient temperature. The mixture was concentrated, partitioned between EtOAc and water, and the aqueous layer was washed with EtOAc (2×). The pH of the aqueous layer was adjusted (˜3) by addition of 1 N HCl and then washed with EtOAc (3×). The combined extracts were dried with magnesium sulfate and concentrated. The residue was recrystallized from EtOAC yielding 200 mg (12%) of 3-chloroisonicotinic acid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=[CH:7][C:8]=1Br.[Mg].II.[C:17](=[O:19])=[O:18].Cl>O1CCCC1>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=[CH:7][C:8]=1[C:17]([OH:19])=[O:18]
Reactant: O=C=O
Reactant: COc1ccc(Br)c(C(F)(F)F)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(C(F)(F)F)c1
Reaction time: 2 h
Yield: 39.5 %

Procedure:
Dry tetrahydrofuran (10 ml) was added to 3-trifluoromethyl-4-bromo-1-methoxybenzene (compound III) (4.4 g) and metallic magnesium (0.41 g) and thereto was further added a catalytic amount of iodine, followed by refluxing for 1.5 hours with stirring. After the temperature was returned to room temperature, to the mixture was slowly added dropwise a solution prepared by adding dry ice (30 g) to dry tetrahydrofuran (10 ml) at -40° C. or lower. The temperature was returned to room temperature and then the reaction was allowed to proceed for further 2 hours. Then, the reaction mixture was added to 1N hydrochloric acid (50 ml) to stop the reaction and repeatedly extracted with ethyl acetate. The ethyl acetate layer was sufficiently washed with water and dried by adding anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and then, the resulting solid was recrystallized from methylene chloride to obtain 2-trifluoromethyl-4-methoxybenzoic acid (compound IV, 1.5 g).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1I.Cl>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.[Cu]I.C(NCC)C>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:5]#[C:4][CH2:3][CH2:2][C:1]([OH:7])=[O:6]
Reactant: C#CCCC(=O)O
Reactant: Brc1ccccc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCNCC
Product: O=C(O)CCC#Cc1ccccc1Br
Reaction time: 2 h

Procedure:
To 10 ml of diethylamine was added with stirring 0.5 g (5.1 mmol) of 4-pentynoic acid, 1.4 g (5 mmol) of 1-bromo-2-iodobenzene, and 60 mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium(0) The slurry was degassed with argon and 0.19 g (1.0 mmol) of CuI was added. The reaction mixture was stirred for 2 hr. at room temperature and then poured into approximately 100 ml of a 10% HCl solution. The resulting precipitate was filtered, washed with water and dried. The solid was taken up in hot CHCl3 and filtered to remove insoluble salts. After evaporation of the solvent, the resulting orange solid was recrystallized from a a chloroform-hexane mixture to produce a tan solid, m.p. 87°-91° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:14][CH:13]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: ClCCCCCCCc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1ccc(CCCCCCCCl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
1.07 g of 7-chloroheptylbenzene and 0.89 g of 4-chlorobenzoyl chloride were dissolved in 10 ml of nitrobenzene and treated with 0.82 g of aluminium chloride under argon and while cooling with ice. The mixture was then stirred at room temperature for 18 hours, taken up in 100 ml of ice-cold 2N hydrochloric acid solution and extracted three times with 50 ml of ether each time. The organic phases were washed with 50 ml of a 10 percent sodium bicarbonate solution and 50 ml of a saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The nitrobenzene was removed by distillation at 80°-100° C. and 20 Pa. By distillation at 240°-250° C. and about 13.4 Pa there were obtained 1.32 g (74%) of 4-chloro-4'-(7-chloroheptyl)benzophenone as a light yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([NH:25][CH3:26])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][C:10]=2[O:23][CH3:24])=[N:6][CH:7]=1.[CH:27]1([B-](F)(F)F)[CH2:30][CH2:29][CH2:28]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].C12(P(C34CC5CC(CC(C5)C3)C4)CCCC)CC3CC(CC(C3)C1)C2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:27]1([C:2]2[C:3]([NH:25][CH3:26])=[N:4][C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])=[CH:11][C:10]=3[O:23][CH3:24])=[N:6][CH:7]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)cc2OC)ncc1Br
Reactant: F[B-](F)(F)C1CCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: Cc1ccccc1
Product: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)cc2OC)ncc1C1CCC1
Temperature: 11 °C
Yield: 8.5 %

Procedure:
To a microwave tube was added (4-(5-bromo-4-(methylamino)pyrimidin-2-ylamino)-3-methoxyphenyl)(morpholino)methanone (100 mg, 0.24 mmol), potassium cyclobutyltrifluoroborate (177 mg, 1.1 mmol), cesium carbonate (0.23 g, 0.71 mmol), toluene (2.9 mL) and water (0.3 mL). The mixture was degassed by nitrogen bubbling for 15 mintues. di-(1-admantyl)-n-butylphosphine (19 mg, 0.053 mmol) and palladium acetate (2.6 mg, 0.026 mmol) was then added. The reaction was sealed and heated at 11° C. for 2 hours. The reaction mixture was filtered and concentrated. The crude product was purified by RP-HPLC to give the desire product (8.1 mg, 8.6%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].[CH2:11]([CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14]Br)[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:11]([CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14][N:4]([CH2:1][CH2:2][CH3:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:12]
Reactant: CCCCC(CC)CBr
Reactant: CCCNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CC)CN(CCC)c1ccccc1
Temperature: 125 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A mixture of N-propylaniline (24 parts), 2-ethylhexyl bromide (58 parts), anhydrous potassium carbonate (42 parts) and dry N,N-dimethylformamide (50 parts) was stirred at 125° C. for 16 hours. The cooled reaction mixture was poured into water (250 parts), the organic phase separated and washed with water (2×200 parts) and dried at 90° C. and 15 mmHg to yield N-(2-ethylhexyl)-N-propylaniline (49 parts, 89%). Acetic anhydride was added to this to make a total of 69.5 parts.
Reaction SMILES: BrBr.[CH2:3]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[S-:17][C:18]#[N:19].[NH4+]>C(O)(=O)C>[NH2:19][C:18]1[S:17][C:15]2[CH:16]=[C:10]([CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:11]=[CH:12][C:13]=2[N:14]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Cc3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
11.2 ml of bromine were added dropWise to a solution of 39.7 g of 4-benzylaniline and 33 g of ammonium thiocyanate in 400 ml of acetic acid at a temperature of from 12 to 18° C. After completion of the addition, the mixture was stirred at room temperature for 2 hours and then the solvent was distilled off. The residue was mixed with 600 ml of ethyl acetate and 300 ml of water and the mixture was neutralized by the addition of potassium carbonate powder The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residual solid was recrystallized from ethyl acetate to give 37.6 g of the title compound melting at 173-175° C.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl.N1C=CC=CC=1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:16]([C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: Nc1ccccc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a solution of o-phenylenediamine (4 mmol) in DCM (20 mL) and pyridine (4 mL) at 0° C., 4-chlorobenzenesulfonyl chloride (4.4 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with water (2×20 mL) and 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give 960 mg of N-(2-aminophenyl)-4-chlorobenzenesulfonamide. LC: Tr 0.92 min, MS: 284.0 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10]O.Cl.[Na+].[I-].O>C(#N)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:10])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(F)cc1
Temperature: 30 °C
Yield: 77.4 %

Procedure:
To a solution of 4-fluoro benzaldehyde (8 g, 64 mmol) in acetonitrile (100 mL) was added NH2OH.HCl (5.78 g, 83 mmol) and NaI (4.8 g, 32 mmol) with stirring. The mixture was then stirred for 7 hours at refluxing temperature, cooled at the temperature in the range of 20-40° C., poured into water (200 mL) and extracted with EtOAc (2×250 mL). The organic layers were collected, combined, washed with brine solution, dried over anhydrous Na2SO4 and concentrated under vacuum to give the 4-fluoro-benzonitrile (6.0 g, 76% yield).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[F:24][C:25]1[CH:26]=[C:27]([Mg]Br)[CH:28]=[C:29]([F:31])[CH:30]=1>>[F:24][C:25]1[CH:26]=[C:27]([C:4]([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH2:14][CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][C@H:17]4[CH3:21])=[CH:11][C:10]=3[CH:22]=2)=[O:5])[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Product: C[C@@H]1CCCN1CCc1cc2cc(C(=O)c3cc(F)cc(F)c3)ccc2o1

Procedure:
The product from Example 71E and 3,5-difluorophenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.45 (d, 3H), 1.75 (m, 1H), 2.13 (m, 2H), 2.35 (m, 1H), 3.30 (m, 4H), 3.56 (m, 1H), 3.82 (m, 2H), 6.88 (s, 1H), 7.38 (dd, 2H), 7.30 (m, 3H), 7.63 (dd, 1H), 7.80 (dd, 1H), 8.05 (d, 1H); MS (ESI) m/z 370 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[CH2:19]([NH:26][CH:27]=[CH:28][C:29](=[O:31])[CH3:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:29]([C:28]1[CH:15]([CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:16]=[CH:17][N:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=1)(=[O:31])[CH3:30]
Reactant: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O
Reactant: CC(=O)C=CNCc1ccccc1
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3ccccc3)C=C1C(C)=O)C2=O

Procedure:
The title compound 52 is prepared according to the procedure reported in step D of Example 8 with aldehyde 54 (100 mg, 0.41 mmol) and enamine 30 (70 mg, 0.4 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum 4/EtOAc=4:1) afford the title compound 52 as a yellow oil. (Yield 55.0 mg, 35%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Si:13]([O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]2[CH:36]=[C:35]([C:37]3[S:41][CH:40]=[N:39][CH:38]=3)[CH:34]=[C:33]([CH3:42])[CH:32]=2)[N:25]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[CH3:43][C:44]1([CH3:51])[O:49][CH2:48][C:47](=[O:50])[CH2:46][O:45]1>O1CCCC1>[Si:13]([O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]2[CH:36]=[C:35]([C:37]3[S:41][C:40]([C:47]4([OH:50])[CH2:48][O:49][C:44]([CH3:51])([CH3:43])[O:45][CH2:46]4)=[N:39][CH:38]=3)[CH:34]=[C:33]([CH3:42])[CH:32]=2)[N:25]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: Cc1cc(Nc2nccc(OCCO[Si](C)(C)C(C)(C)C)n2)cc(-c2cncs2)c1
Reactant: CC1(C)OCC(=O)CO1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(OCCO[Si](C)(C)C(C)(C)C)n2)cc(-c2cnc(C3(O)COC(C)(C)OC3)s2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
To diisopropyl amine (185 μL, 1.29 mmol) in tetrahydrofuran (2.2 mL) at 0° C. was added n-butyllithium (2.2 M in hexanes, 589 μL, 1.29 mmol). The mixture was stirred for 15 minutes, then cooled to −78° C. 4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine (191 mg, 0.43 mmol), dissolved in tetrahydrofuran (1 mL), was added dropwise over 5 minutes. The mixture was stirred for 30 minutes at −78° C., then 2,2-dimethyl-1,3-dioxan-5-one (57 μL, 0.47 mmol) was added dropwise. The reaction was stirred for 2 h, and then quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (3×), and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography on silica gel (Biotage 25 G, eluting with 0:100 to 100:0 ethyl acetate:hexanes) gave 5-[5-(3-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]-2,2-dimethyl-1,3-dioxan-5-ol (185 mg, 0.32 mmol, 75% yield) as a pale yellow solid. MS ESI: [M+H]+ m/z 573.3.
Reaction SMILES: C(N)C1C=CC=CC=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1.[F:29][C:30]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:31]=1[CH2:32][Cl:33].Cl>O1CCOCC1>[ClH:33].[F:29][C:30]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:31]=1[CH2:32][N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1
Reactant: Fc1ccc(CCl)c(F)c1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: NCc1ccccc1
Product: Nc1nc(N)c2c(OCC3CCN(Cc4ccc(F)cc4F)CC3)cccc2n1
Temperature: 25 °C
Yield: 78 %

Procedure:
The benzylamine was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (75 mg; 0.27 mmol) and 2,4-difluorobenzyl chloride (69 mg; 0.35 mmol) via Method BB. Solids were suspended in 2 mL dioxane and 0.5 mL 4M HCl in dioxane was added and after 2 hours stirring at room temperature solids were collected by filtration to yield 92 mg. (78% yield). 1HNMR (400 MHz, DMSO-d6) δ 12.8 (s, 1H), 11.2 (s, 1H), 8.84 (s, 1H), 8.23 (s, 1H), 7.88 (q, J=8.8, 6.4 Hz, 1H), 7.7 (m, 2H), 7.4 (m, 1H), 7.23 (m, 1H), 7.02 (m, 2H), 4.28 (d, J=4.4 Hz, 2H), 4.17 (d, J=6.4 Hz, 2H), 3.4 (br d, J=11.6 Hz, 2H), 2.95 (m, 2H), 2.23 (m, 1H), 1.81 (d, J=13.2 Hz, 2H), 1.73 (m, 2H). MS m/z (ESI) 400 (M+H)+.