Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:13](=O)[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.CN.[C:19]([BH3-])#[N:20].[Na+]>>[CH3:19][NH:20][CH:13]1[CH:12]2[CH2:15][CH2:16][N:9]([CH2:10][CH2:11]2)[CH:8]1[CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C2CCN(CC2)C1Cc1cccnc1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Product: CNC1C2CCN(CC2)C1Cc1cccnc1

Procedure:
Another illustration of derivatization of saturated ketone intermediates is the reductive amination to give amines. Thus, 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one reacts with ammonium formate, zinc chloride and sodium cyanoborohydride to give 3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane as predominantly the cis diastereomer. Likewise, reaction of 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one with methylamine and sodium cyanoborohydride provides 3-(methylamino)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane. These amine derivatives can be used as a template for library formation by reacting them with a variety of acylating agents (e.g., acid chlorides, acid anhydrides, active esters, and carboxylic acids in the presence of coupling reagents) and isocyanates to produce 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanes with amide and urea substituents in the 3-position of the 1-azabicyclo[2.2.2]octane, both of which classes are compounds of the present invention. Commercially unavailable isocyanates can be prepared in situ from corresponding amines and triphosgene in the presence of triethylamine. Such derivatives can be produced as single enantiomers, using the single enantiomers of 3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane and 3-(methylamino)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane as starting materials. For instance, the (2R,3R)- and (2S,3 S)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanes can be produced by resolution of the cis 3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane, for example, using diastereomeric amides. Thus, when the cis amine is reacted with a chiral acid such as (S)—N-(tert-butoxycarbonyl)proline using a suitable coupling agent such as diphenylchlorophosphate, a pair of diastereomeric amides, separable by reverse phase chromatography, is produced. The separated proline amides can then be deprotected, for example, by treatment with trifluoroacetic acid (to remove the tert-butoxycarbonyl protecting group) and then the proline can be cleaved from the desired amine, for example, using Edman degradation conditions (i.e., phenylisothiocyanate, followed by trifluoroacetic acid).
Reaction SMILES: [OH:1][CH:2]([CH:22]=[CH2:23])[CH:3]([NH:9][C:10]([C:12]1[C:13]([C:18]([F:21])([F:20])[F:19])=[N:14][N:15]([CH3:17])[CH:16]=1)=[O:11])[C:4]([O:6]CC)=O.[CH3:24][NH2:25]>CO>[OH:1][CH:2]([CH:22]=[CH2:23])[CH:3]([NH:9][C:10]([C:12]1[C:13]([C:18]([F:19])([F:20])[F:21])=[N:14][N:15]([CH3:17])[CH:16]=1)=[O:11])[C:4](=[O:6])[NH:25][CH3:24]
Reactant: CN
Reactant: C=CC(O)C(NC(=O)c1cn(C)nc1C(F)(F)F)C(=O)OCC
Solvent: CO
Product: C=CC(O)C(NC(=O)c1cn(C)nc1C(F)(F)F)C(=O)NC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.65 g (4.92 mmol) of ethyl 3-hydroxy-2-[(1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]pent-4-enoate were dissolved in methanol. At 0° C., methylamine gas was introduced for 1 h. After 16 h of stirring at RT, the solvent was removed and the residue was recrystallized from acetone. The precipitate gave 0.65 g of erythro title compound as a colorless powder, the filtrate contained 0.75 g of isomer mixture. Accordingly, the total yield was 1.40 g (89% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH:13]=[C:12]([C:15]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=3[O:25][CH3:26])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+].B(F)(F)F.C1C[O:36]CC1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C:15]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=3[O:25][CH3:26])[CH:13]([OH:36])[CH2:14]2)=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: COc1ccc(N2CC=C(c3c(OC)cc(OC)cc3OC)CC2)cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(N2CCC(c3c(OC)cc(OC)cc3OC)C(O)C2)cc1
Temperature: 52.5 °C
Reaction time: 1 h

Procedure:
Compound of example 118 (15 g, 42 mmol) was subjected to hydroboration using NaBH4 (2.7 g, 71.4 mmol) and BF3-etherate (12.6 g, 88.8 mmol) in THF (50 mL). Excess diborane was destroyed by the addition of water. Conc. HCl (15 mL) was added and the reaction mixture was stirred at 50-55° C. for 1 h. It was cooled to room temperature The resulting mixture was made basic (pH 12-14) using an aqueous 50% NaOH solution. 30% H2O2 (9 mL) was added and the reaction mixture was stirred at 50-55° C. for 1 h. The reaction mixture was processed as described in example 2 to obtain the title compound.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][N:12]=[C:13]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=1.[H-].[Na+].I[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C.[Cl-].[Na+].O>[CH:29]1([O:1][N:2]=[CH:3][C:4]2[N:9]=[C:8]([CH2:10][O:11][N:12]=[C:13]([C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: IC1CCCCC1
Reactant: Cn1nnnc1C(=NOCc1cccc(C=NO)n1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnnc1C(=NOCc1cccc(C=NOC2CCCCC2)n1)c1ccccc1
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
To a stirred solution of N-({6-[(hydroxyimino)methyl]pyridin-2-yl}methoxy)-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.2 g, 0.593 mmol, 1 eq.) in 2.5 ml of dry DMF, was added NaH (0.024 g, 0.623 mmol, 1.05 eq.) in one portion. After 10 mins, 1-iodocyclohexane (0.130 g, 0.623 mmol, 1.05 eq.) was added rapid dropwise. Stirring was continued for 20 hrs and warmed at 45° C. for 4 hrs. “brine” was added and the reaction was extracted with EtOAc (2×75 ml). The combined organic layers were washed with water (2×), dried over MgSO4 and evaporated. The residue was purified by chromatography on silica gel to give N-[(6-{[(cyclohexyloxy)imino]methyl}pyridin-2-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.107 g, 41% yield) as a colourless viscous oil.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:19][CH:20]1[CH2:25][NH:24][CH2:23][CH2:22][NH:21]1>>[CH3:19][CH:20]1[NH:21][CH2:22][CH2:23][N:24]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:25]1
Reactant: CC1CNCCN1
Reactant: Clc1ccc(OCCOc2nccnc2Cl)cc1
Product: CC1CN(c2nccnc2OCCOc2ccc(Cl)cc2)CCN1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine*(150 mg, 0.53 mmol) and 2-methylpiperazine (256 mg, 2.56 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 143 mg (77%) of the title product. HRMS m/z calcd for C17H21CIN4O2(M)+348.1353, found 348.1370. Anal. (C17H21CIN4O2)C, H, N.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[N+:10]([O-])([OH:12])=[O:11]>OS(O)(=O)=O>[N+:10]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH2:3][NH:2][CH2:1]2)([O-:12])=[O:11]
Reactant: c1ccc2c(c1)CNC2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2c(c1)CNC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 51 %

Procedure:
To the suspension of isoindoline (2 g, 16.8 mmol) in 98% H2SO4 (10 mL) was added dropwise the mixture of concentrated nitric acid (2 mL) and 98% sulfuric acid (2 mL) at 0° C. The mixture was stirred at 0° C. for 45 minutes. The resulting yellow solution was then poured into ice water. The white solid precipitate was collected by filtration. The solid was washed with water (20 mL×2) and dried in vacuum to afford 231a as a white solid (700 mg, 51%). MS: [M+H]+ 165.
Reaction SMILES: [CH3:1][N:2]([N:4]=[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])=[C:7]([F:32])[CH2:6]1)[CH3:3].N1CC[CH2:34]1.CC(O)=O>>[N:2]1([N:4]=[C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[CH:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[O:16])=[C:7]([F:32])[CH2:6]2)[CH2:1][CH2:34][CH2:3]1
Reactant: CN(C)N=C1C=CC(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2)=C(F)C1
Reactant: C1CNC1
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Cl)cc1)NC(C(=O)NC1=C(F)CC(=NN2CCC2)C=C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
To the thioimidate solution in MeOH (4 mL, 0.284 mmol) from EXAMPLE 33, a pre-mixed azetidine (0.096 mL, 1.43 mmol) and HOAc (0.122 mL, 2.14 mmol) were added. The mixture was then stirred at room temperature overnight. After being concentrated in vacuo, the residue was purified by HPLC to give a white powder (24 mg). MS 480.1 and 482.1 (M+H, Cl pattern).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>CN1C(=O)CCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:2]2[N:11]=[C:10]([O:12][CH3:13])[C:9]3[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=3)[N:3]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1cc2nc(Cl)nc(OC)c2cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COc1cc2nc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc(OC)c2cc1OC
Yield: 15 %

Procedure:
A mixture of 2-chloro-4,6,7-trimethoxy-quinazoline (0.8 g, 3.14 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.26 g, 6.28 mmol, 2.0 equiv; commercially available) in anhydrous NMP (8 mL) and triethylamine (2 mL) was heated by microwave irradiation to 170° C. for 1 h. The organic phase was concentrated under reduced pressure and the residue extracted with dichloromethane (3×50 mL) from a sat. solution of sodium bicarbonate (100 mL). The combined organic phases were dried over MgSO4 and the product purified by column chromatography on silica eluting with a gradient of toluene/ethyl acetate (4:1→2:1) providing 0.2 g (15%) of the title compound. MS (ISP): 419.4 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH2:9][N:8]3[CH:7]=1)=[O:5].[OH-].[NH4+:20]>O1CCCC1>[C:6]1([C:4](=[O:5])[C:3]([NH2:20])=[O:2])[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH2:9][N:8]3[CH:7]=1.[C:6]1([CH2:4][C:3]([NH2:20])=[O:2])[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH2:9][N:8]3[CH:7]=1
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Product: NC(=O)Cc1cn2c3c(cccc13)CCC2
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of (5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester (0.50 g, 2.06 mmol) in 10 mL of tetrahydrofuran at 0° C. was added concentrated ammonium hydroxide (2 mL). The bath was removed and the mixture stirred 3 hours. After diluting with 20 mL of water, the suspension was filtered, washed with 10 mL of water followed by 10 mL of diethyl ether, and dried under reduced pressure to provide 0.403 g (86%) of the desired compound as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:9]=2)=[CH:4][CH:3]=1.[Cl:25]CCl.C(N(CC)CC)C.CS(Cl)(=O)=O>O>[Cl:25][CH2:14][C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[N:11][C:12]=1[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CCl
Reaction time: 5 h
Yield: 88 %

Procedure:
N-[4-(4-fluorophenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (50.0 g), dichloromethane (250.0 mL), and triethylamine (47.3 mL) were added to a reactor and then the reaction mixture was cooled to 0˜5° C. Methanesulfonyl chloride (13.2 mL) was slowly added to the reaction mixture, which was then stirred at 20˜25° C. for 5 hours. Water (100.0 mL) was added to the reaction mixture. The separated organic layer was sequentially washed with 0.5N hydrochloric acid solution (100.0 mL) and then water (100.0 mL). The organic layer was concentrated under reduced pressure to remove the solvent. n-Hexane (150.0 mL) was added to the resulting residue under stirring. The resulting suspension was filtered under reduced pressure. The resulting white solid was dried to obtain N-[5-chloromethyl-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (45.5 g, yield 88%).
Reaction SMILES: [NH:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:10][N:11]=[C:12]2[Cl:15])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>C(O)CCC>[ClH:15].[NH:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:10][N:11]=[C:12]2[NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:24]([Cl:23])[CH:25]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccc2c(Cc3ccncc3)nnc(Cl)c2c1
Reactant: Nc1cccc(Cl)c1
Solvent: CCCCO
Product: CC(=O)Nc1ccc2c(Cc3ccncc3)nnc(Nc3cccc(Cl)c3)c2c1
Product: Cl

Procedure:
By analogy with Example 25, 300 mg (0.96 mmol) 7-acetamino-1-chloro-4-(4-pyridylmethyl)-phthalazine is reacted in 3.9 ml 1-butanol with 302 μl (2.88 mmol) 3-chloroaniline. Suspension of the raw product in 1 ml boiling ethanol and filtration lead to the title compound: HPLC: tRet(Grad5-40)=11.3; FAB MS (M+H)+=404.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.CCN(CC)CC.[CH:23]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[CH:23]1([C:28]([CH:11]2[CH2:12][NH:13][CH2:14][CH2:15][N:10]2[C:7]2[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=2)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N2CCNCC2C(=O)C2CCCC2)cc1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
4-Methylphenyl piperazine dihydrochloride (4.20 g, 16.9 mmol) and NEt3 (7.0 mL, 50.2 mmol) were dissolved in DCM (125 mL) at 0° C. Cyclopentanecarbonyl chloride (2.0 mL, 16.5 mmol) was added and the reaction mixture was allowed to warm to room temperature over 16 hours. The reaction mixture was washed with 1M aq Na2CO3 solution (3×100 mL), dried (MgSO4) and concentrated in vacuo to give cyclopentanecarbonyl 4-(methyl)phenyl piperazine (4.42 g, 98%) as a pale brown oil which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2([C:11]#N)[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CC[O:16]CC>CCCCCC>[C:1]1([C:7]2([CH:11]=[O:16])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOCC
Reactant: N#CC1(c2ccccc2)CCC1
Agent: Cl
Solvent: CCCCCC
Product: O=CC1(c2ccccc2)CCC1
Temperature: 40 °C

Procedure:
A 1M solution of diisobutylaliminohydride in hexane (200 ml) was added under nitrogen to a solution of 1-phenyl-1-cyclobutane carbonitrile (31.4 g) in ether (100 ml) at a temperature below -30° C. The temperature was maintained below 0° C. for thirty minutes and 5N hydrochloric acid (200 ml) at a temperature of -10° C. added. The reaction mixture was washed with petroleum ether (b.p. 60°-80° C.) and then warmed to 40° C. The reaction mixture was extracted with petroleum ether (b.p. 60°-80° C.) and the extract dried and evaporated to yield 1-phenyl-1-cyclobutane-carbaldehyde as an oil.
Reaction SMILES: [Si](OCCC1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)(C(C)(C)C)(C)C.BrC[C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][C:38]=1[Cl:45].CO.N(CC)CC>CC#N>[Cl:45][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:37]=1)[C:41]#[N:42]
Reactant: N#Cc1ccc(CBr)c(Cl)c1
Agent: CC(C)(C)[Si](C)(C)OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CO
Solvent: CC#N
Solvent: CCNCC
Product: N#Cc1cccc(Cl)c1
Temperature: 80 °C

Procedure:
4-[2-(tert-Butyldimethylsilanyloxy)ethyl]-1-trityl-1H-imidazole (3.98 g, 8.5 mmol) and 4-bromomethyl-3-chlorobenzonitrile (2.93 g, 12.7 mmol) are dissolved in MeCN (40 mL) and heated at 80° C. for 5 h. After cooling to room temperature MeOH (40 mL) and Et2NH (7 mL) are then added and the solution is warmed 70° C. for 1 h. The solution is evaporated to dryness and the residue purified via flash column chromatography (acetone/CH2Cl2 1:3→MeOH/CH2Cl2 5:95) to give 4-{5-[2-tert-butyl-dimethylsilanyloxy)ethyl]-imidazol-1-ylmethyl}-3-chlorobenzonitrile as an oil. MS (ESI) m/z 376.3, 378.3 (M+H).
Reaction SMILES: N1C2C(=C(C[NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([CH:24]5[CH2:28][CH2:27]CO5)[NH:21][N:20]=4)[CH:15]=[CH:14][N:13]=3)C=CC=2)C=C1.ClC1N=C(NC2C=C([C@@H]3C[C@H]3C3C=CC=CC=3[F:51])NN=2)C=CN=1>>[CH:24]1([C:22]2[NH:21][N:20]=[C:19]([NH:18][C:16]3[C:15]([F:51])=[CH:14][N:13]=[C:12]([NH2:11])[N:17]=3)[CH:23]=2)[CH2:28][CH2:27]1
Reactant: Fc1ccccc1[C@@H]1C[C@H]1c1cc(Nc2ccnc(Cl)n2)n[nH]1
Reactant: c1cc(CNc2nccc(Nc3cc(C4CCCO4)[nH]n3)n2)c2cc[nH]c2c1
Product: Nc1ncc(F)c(Nc2cc(C3CC3)[nH]n2)n1

Procedure:
N2-((1H-indol-4-yl)methyl)-N4-(5-(tetrahydrofuran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (I-119) and N2-(1H-indol-4-yl)methyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoropyrimidine-2,4-diamine (I-120) were prepared analogously except 2-chloro-N-(5-(trans-2-(2-fluorophenyl)cyclopropyl)-1H-pyrazol-3-yl)pyrimidin-4-amine was replaced with 83 and 55, respectively
Reaction SMILES: [ClH:1].[N:2]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:18]=[C:19]([NH:26][C@@H:27]4[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]=[N:21][C:22]=3[C:23]([NH2:25])=[O:24])=[CH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:33][N:34]([CH3:41])[CH2:35]/[CH:36]=[CH:37]/[C:38](O)=[O:39].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[CH3:33][N:34]([CH3:41])[CH2:35]/[CH:36]=[CH:37]/[C:38]([N:29]1[CH2:30][CH2:31][CH2:32][C@@H:27]([NH:26][C:19]2[N:20]=[N:21][C:22]([C:23]([NH2:25])=[O:24])=[C:17]([NH:16][C:13]3[CH:14]=[CH:15][C:10]([C:8]([N:2]4[CH2:3][CH2:4][O:5][CH2:6][CH2:7]4)=[O:9])=[CH:11][CH:12]=3)[N:18]=2)[CH2:28]1)=[O:39].[ClH:1]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: NC(=O)c1nnc(N[C@@H]2CCCNC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C/C=C/C(=O)N1CCC[C@@H](Nc2nnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(piperidin-3-ylamino)-1,2,4-triazine-6-carboxamide HCl salt (47 mg, 0.10 mmol) in NMP (4 mL) was added (E)-4-(dimethylamino)but-2-enoic acid (50 mg, 0.30 mmol), DIEA (180 μL, 1.0 mmol) and then PyBOP (104 mg, 0.20 mmol). The mixture was stirred at RT for 2 h, quenched with TFA (0.2 mL), diluted with 2 mL water, and subjected to reverse phase preparative HPLC to isolate the title compound (80) as an HCl salt (32 mg). MS found for C26H35N9O4 as (M+H)+ 538.2, (M−H)− 536.3. UV: λ=246 nm.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C@@H:10]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:25]([C@H:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:12][C:2](=[O:3])[NH:9]1)[CH:26]([CH3:28])[CH3:27]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H]1NC(=O)OC1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.5 %

Procedure:
Trichloromethyl chloroformate (13.0 g, 65.8 mmol) was added to a mixture of (S)-2-amino-1,1-diphenyl-4-methylpentan-1-ol 16 (12.4 g of 65%, 29.9 mmol) and triethylamine (12.7 g, 125.5 mmol) in CH2Cl2 at 0° C. The reaction mixture was stirred for 15 h, allowing to warm to room temperature. The mixture was then washed with HCl (3×200 ml) and water (2×200 ml), and dried over MgSO4. Concentration gave a crude product, which was washed with diethyl ether to afford the title compound 17 (7.9 g, 90%) as a white solid. m.p. 212–214° C. [α]D25=−286.1° (c, 4.32 in CHCl3). δH 0.85 (3H, d, J=6.6 Hz, CH3), 0.91 (3H, d, J=6.6 Hz, CH3), 0.96–1.08 (2H, m, CH2), 1.53–1.73 (1H, m, CH—Me2), 4.57 (1H, dd, J=10.5 and 3.60 Hz, CH—NH), 7.05 (1H, s, NH), 7.16–7.50 (10H, m, Ar—H). δC 20.8, 23.7, 24.9, 41.8, 58.8, 89.1, 125.9, 126.3, 127.6, 127.8, 128.1, 128.3, 139.3, 142.5 (Ar), 158.8 (C═O). νmax (cm−1): 3261, 3160 (N—H), 2955, 2869 (methyl and methylene C—H), 1752, 17235 (C═O), 1495, 1447 (Ar C═C), 1251 (C—O). m/e 313 (MNH4+, 12%), 296 (MH+, 15%), 237 (100%).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][CH:19]=1)=[CH2:17]>CCCCCC>[CH:1]([NH:4][CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH:16]=[CH2:17])=[CH:19][CH:20]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: C=Cc1ccc(C=C)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C=Cc1ccc(CCNC(C)C)cc1
Reaction time: 0.17 h
Yield: 48.7 %

Procedure:
In a 300 ml four necked flask equipped with a thermometer, a reflux condenser, an inlet for nitrogen and a stirrer were charged 1860 ml of dry n-hexane and 148 g of iso-propylamine. While stirring the mixture, 119 ml of a 15% n-butyllithium n-hexane solution were added dropwise thereto. During the addition, the temperature was maintained at 5° C. to 7° C. The color of the solution was changed from colorless to pale yellow. After 10 minutes, 325 g of p-divinylbenzene having a purity of 96% were added to the mixture, whereby the color of the reaction mixture was changed to brown. Then, the inner temperature was elevated to 45° C., at which the reaction was continued for 6 hours. After the reaction, the reaction was terminated with ethanol and the solvent was evaporated. The residue was poured into 2 l of n-hexane and the insoluble are filtered off, followed by evaporation and distillation, whereby there were obtained 230 g of the product having a boiling point of 62° C.-64° C./0.08 mmHg.