Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:26])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.[Cl:27][C:28]1[C:29]([CH3:41])=[N:30][N:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:34]=2I)[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[Cl:27][C:28]1[C:29]([CH3:41])=[N:30][N:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:34]=2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH2:26])[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16]3)[CH:32]=1
Reactant: Cc1cccc(-n2cc(Cl)c(C)n2)c1I
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(-n2cc(Cl)c(C)n2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 140 °C

Procedure:
A glass microwave reaction vessel was charged with 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.150 g, 0.422 mmol, prepared as in Example 2, Step 1-2) and 4-chloro-1-(2-iodo-3-methylphenyl)-3-methyl-1H-pyrazole (0.281 g, 0.845 mmol) in dioxane (3 mL) and 2 M aqueous sodium carbonate (1.0 mL, 2.0 mmol). The vessel was capped with a septum and the solution was degassed by bubbling nitrogen gas through the solution for 10 min. Next, Pd (PPh3)4 (0.049 g, 0.042 mmol) was added and the vessel was sealed. The reaction mixture was stirred and heated in a microwave reactor at 140° C. for 15 min. The reaction was poured into water and the mixture was extracted with EtOAc. The combined organic extracts were washed with water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by reverse-phase preparative HPLC with 0.1% TFA in CH3CN/H2O, gradient 5-70% over 20 min to provide 6-(2-(4-chloro-3-methyl-1H-pyrazol-1-yl)-6-methylphenyl)-3-morpholinoquinolin-2-amine as a white solid. The purified compound was portioned between DCM and saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with saturated sodium chloride and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give 6-(2-(4-chloro-3-methyl-1H-pyrazol-1-yl)-6-methylphenyl)-3-morpholinoquinolin-2-amine as a white solid. MS (ESI, pos. ion) m/z: 434 (M+1).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[NH2:8][OH:9].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[CH3:19]>CO>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15](=[N:8][OH:9])[NH2:16])=[CH:13][C:12]=1[CH3:19]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: NO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Cc1cc(C(N)=NO)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.8 %

Procedure:
Methanol (20 ml) at 5° C. was treated portionwise over 5 min. with stirring with potassium t-butoxide (1.68 g, 0.015 mole), then after a further 5 mins the solution was treated with hydroxylamine hydrochloride (1.11 g, 0.016 mole). The resulting mixture was allowed to warm to room temperature, stirred for 1 h, then treated with a solution of 4-bromo-3-methylbenzonitrile (2.0 g, 0.010 mole) in methanol (10 ml) and heated under reflux for 3 h. The mixture was allowed to cool, then filtered through kieselguhr and the filtrate concentrated in vacuo to afford the title compound as a white solid (2.56 g, 100%).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3].[CH3:31][N:32]([CH3:37])[C:33](=[O:36])[CH2:34]Cl>C(Cl)Cl.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[C:17]4[CH:20]=[CH:21][C:22]([CH:24]5[CH2:29][CH2:28][N:27]([CH2:34][C:33]([N:32]([CH3:37])[CH3:31])=[O:36])[CH2:26][CH2:25]5)=[CH:23][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3]
Reactant: CN(C)C(=O)CCl
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(CC(=O)N(C)C)CC4)cc2OCC3)n(C(C)C)n1
Yield: 37.5 %

Procedure:
A suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (310 mg, 0.72 mmol) in DCM (6 mL) and TEA (0.3 mL, 2.16 mmol) was sonicated and stirred before adding N,N-dimethyl-2-chloroacetamide (98 mg, 0.8 mmol) and TBAI (28 mg, 0.072 mmol) and the reaction mixture stirred for 72 h at RT before being concentrated in vacuo. The resultant residue was partitioned between water and DCM and the aqueous extracted five times with DCM, the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) then triturated in diethyl ether to give 329 as a white solid (129 mg, 38%). LCMS: RT=2.71 min, [M+H]+=478. 1H NMR 400 MHz (CDCl3) δ: 8.44 (1H, d, J=8.30 Hz), 7.61 (1H, s), 7.04 (1H, d, J=8.43 Hz), 6.91 (1H, s), 5.91 (1H, t, J=6.63 Hz), 4.45 (4H, d, J=14.92 Hz), 3.39 (2H, m), 3.11 (2H, m), 3.10 (3H, s), 2.99 (1H, m), 2.98 (3H, s), 2.54 (2H, m), 2.41 (3H, s), 1.90 (4H, s), 1.57 (6H, d, J=6.65 Hz)
Reaction SMILES: C(OC(=O)[NH:5][CH2:6][CH:7]1[C:10]2=[CH:11][C:12]3[O:16][CH2:15][O:14][C:13]=3[CH:17]=[C:9]2[CH2:8]1)C.O.[OH-].[Na+]>O1CCCC1>[O:14]1[C:13]2[CH:17]=[C:9]3[CH2:8][CH:7]([CH2:6][NH2:5])[C:10]3=[CH:11][C:12]=2[O:16][CH2:15]1
Reactant: CCOC(=O)NCC1Cc2cc3c(cc21)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCC1Cc2cc3c(cc21)OCO3
Reaction time: 2 h
Yield: 45.1 %

Procedure:
7.5 g (30 mmoles) of the product of Step 1 are dissolved in 15 mL of anhydrous tetrahydrofuran. The solution is poured dropwise into a suspension comprising 1.48 g (1.3 equivalents) of AlLiH4 suspended in 38 mL of anhydrous tetrahydrofuran. Stirring is carried out at 25° C. for 2 hours. The mixture is hydrolysed in the cold state using 2.7 mL of water, 2.7 mL of NaOH (20%) and then 2.7 mL of water. Filtration and evaporation of the filtrate to dryness are carried out. There are obtained 2.4 g of a residue which is purified by column chromatography over silica (eluant: CH2Cl2/ethanol/NH4OH: 95/5/0.5. The expected product is obtained in the form of a brown oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[C:19]([NH:22][C:23]1[S:24][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:26][N:27]=1)(=[O:21])[CH3:20]>>[C:19]([NH:22][C:23]1[S:24][C:25]([S:28]([NH:1][CH2:2][C:3]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])([OH:10])[CH2:4][N:5]2[CH:9]=[N:8][CH:7]=[N:6]2)(=[O:29])=[O:30])=[CH:26][N:27]=1)(=[O:21])[CH3:20]
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CC(=O)Nc1ncc(S(=O)(=O)Cl)s1
Product: CC(=O)Nc1ncc(S(=O)(=O)NCC(O)(Cn2cncn2)c2ccc(Cl)cc2Cl)s1

Procedure:
Following the procedure described in the preceeding examples but using 3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 2-acetamido-5-thiazolesulfonylchloride, the title compound was obtained in a similar yield: mp 96°-112° C.; 1H NMR (80 MHz, MeOH-d4)δ(TMS) 8.27 (s, 1H, CH=N), 7.74 (s, 1H, CH=N), 7.55 (d, J=8.5 Hz, 1H, arom), 7.3-7.1 (m, 2H, arom), 4.80 (AB system, Δv=0.35, J=14.5 Hz, 2H, CH2 -Tr), 3.74 (AB system, Δv=0.36, J=13.8Hz, 2H, CH2NH), 2.37 (s, 1H, Me), 2.22 (s, 1H, Me). Anal calcd. for C17H18Cl2N6O4S2 : C 40.40%; H 3.59%; N 16.63%. Found: C 40.69%; H 4.06%; N 16.70 %.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.O1CC[CH2:12][CH2:11]1>>[CH2:11]([C:6]1([OH:9])[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)[CH3:12]
Reactant: O=C1CCC(CO)CC1
Reactant: C1CCOC1
Product: CCC1(O)CCC(CO)CC1
Temperature: 25 °C

Procedure:
4-(Hydroxymethyl)cyclohexanone (1.22 g) in tetrahydrofuran (20 mL) was treated with 1-Methylmagnesium bromide in tetrahydrofuran (28.6 mL) at 0° C. The reaction was warmed to room temperature over 4 hours and quenched with methanol (2 mL) and water (2 mL). The resulting mixture was concentrated and the residue was suspended in ethyl acetate. The precipitates were filtered off and the filtrate was concentrated and purified by flash chromatography, eluted with 0-100% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[H-].[Na+].[CH3:22][O:23][CH2:24]Cl>CN(C=O)C>[Br:1][C:2]1[N:6]([CH2:22][O:23][CH3:24])[C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCn1c(Br)c(C2CCCCC2)c2sc(C(=O)OC)cc21
Temperature: 25 °C
Yield: 66 %

Procedure:
Methyl 5-bromo-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (prepared as in Example 7, Step 1) was dissolved in DMF and sodium hydride (1.4 eq.) was added. The mixture was stirred at RT until evolution of gas had ceased, then chloromethyl methyl ether (excess) was added and stirring was continued. After 5 h all volatiles were evaporated i. vac. and the residual material was filtered through silica gel (PE:Et2O, 12:1). The product was obtained as a colourless solid (66%). 1H-NMR (400 MHz, CDCl3, 300 K, δ): 7.73 (s, 1H), 5.41 (s, 2H), 3.90 (s, 3H), 3.32 (s, 3H), 2.73-2.67 (m, 1H), 1.90-1.76 (m, 5H), 1.65-1.58 (m, 2H), 1.47-1.29 (m, 3H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]1([CH2:26][C:27]([NH:29][CH3:30])=[O:28])[CH2:23][S:22](=[O:25])(=[O:24])[CH2:21]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:19][C:20]3([CH2:26][C:27]([NH:29][CH3:30])=[O:28])[CH2:23][S:22](=[O:25])(=[O:24])[CH2:21]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CNC(=O)CC1(N)CS(=O)(=O)C1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: CNC(=O)CC1(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)CS(=O)(=O)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example 48c) and 2-(3-amino-1,1-dioxo-thietan-3-yl)-N-methyl-acetamide (example 282a) as starting materials and isolated (56 mg, 76%); MS (ESI, m/z): 436.3 (M+H+).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1.O>CS(C)=O>[CH:18]1([O:6][C:5]2[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=2[O:8][CH3:9])[CH:2]=[O:1])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc(C=O)cc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To the solution of 15.22 g (100 mmoles) of isovanilline in 125 ml of dimethylsulphoxide, 27 g of powdered anhydrous potassium carbonate are added. The suspension is stirred at 60° C. for 30 minutes and then 12.9 ml (120 mmoles) of cyclopentyl bromide are added at 60° C. during 60 minutes. Then the suspension is stirred at the same temperature 8 hours, cooled to 25° C. and poured into 500 ml of water. The aqueous emulsion is extracted four times with 100 ml of ether. The collected ethereal phases are washed twice with 20 ml of 1 N sodium hydroxide solution, dried over anhydrous magnesium sulphate and evaporated. To the oily residue 100 ml of benzene are added and the evaporation is repeated. The remained oil is fractionally distilled in vacuo to give 20.65 g (94%) of title compound, b.p. 136°-138° C./0.01 Hgmm.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=2)=[CH:12][N:11]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=2)=[CH:12][N:11]=1
Reactant: CCCCCCBr
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(O)c(F)c3F)nc2)cn1
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCCCCCC)c(F)c3F)nc2)cn1
Yield: 73 %

Procedure:
The etherification of 2.4 mmol of 2-(2,3-difluoro-4-hydroxyphenyl)-5-(6-octyloxypyridin-3-yl)pyrimidine using 2.7 mmol of 1-bromohexane is carried out analogously to the procedure indicated in Example 3. Corresponding purification gives 0.88 g (73%) of colorless crystals, X 81.5 S3 75.5 SC 165.6 SA 174 I.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[F:5][C:6]1[CH:15]=[C:14]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH3:21])[C:13]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:12][C:7]=1[C:8](OC)=[O:9]>>[NH2:3][C:2]([NH2:4])=[N:1][C:8](=[O:9])[C:7]1[CH:12]=[C:13]([S:22]([CH3:25])(=[O:24])=[O:23])[C:14]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH3:21])=[CH:15][C:6]=1[F:5]
Reactant: N=C(N)N
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(-n2ccnc2C)cc1F
Product: Cc1nccn1-c1cc(F)c(C(=O)N=C(N)N)cc1S(C)(=O)=O

Procedure:
In analogy to Example 1, by reaction of guanidine with methyl 2-fluoro-4-(2-methyl-1-imidazolyl) -5-methylsulfonylbenzoate [obtainable by reacting 2-fluoro-4-chloro-5-methylsulfonylbenzoic acid with 2-methylimidazole followed by esterification] , N-diaminomethylene-2-fluoro-4- (2-methyl-1-imidazolyl) -5-methylsulfonylbenzamide is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[Cl:12][CH2:13][C:14](O)=O>Cl>[Cl:12][CH2:13][C:14]1[NH:11][C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: O=C(O)CCl
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: Cl
Product: O=C(O)c1ccc2[nH]c(CCl)nc2c1
Yield: 76.4 %

Procedure:
3,4-Diaminobenzoic acid (6.09 g, 40 mmol) and chloroacetic acid (4.35 g, 46 mmol) were refluxed in 5 N HCl (30 ml) for 5 h. The reaction mixture was cooled, the gray precipitate obtained was separated by filtration and subsequently washed with acetone (100 ml) and ether (100 ml) to obtain 6.44 g of product 4 (76%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].C([Li])CCC.[Cl:16][CH:17]([C:21]1[O:26][C:25](=[O:27])[C:24]2[CH:28]=[CH:29][CH:30]=[C:31]([C:32]([F:35])([F:34])[F:33])[C:23]=2[N:22]=1)[CH:18]([CH3:20])[CH3:19]>CCCCCC>[Cl:16][CH:17]([CH:18]([CH3:20])[CH3:19])[C:21]([NH:22][C:23]1[C:31]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](=[O:27])[CH2:2][C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:3])=[O:26]
Reactant: CC(=O)Nc1ccccn1
Reactant: CC(C)C(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(C)C(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2ccccn2)cccc1C(F)(F)F
Yield: 71.6 %

Procedure:
Using the procedure of Step A of Example 13, 10.16 g of 2-acetylaminopyridine, 106 ml of a hexane solution of n-butyllithium (1,4M) and 11.4 g of 2-(1-chloro-2-methylpropyl)-8-trifluoromethyl-4H-3,1-benzoxazin-4-one of Step A of example 3 were reacted to obtain 11.8 g of 2-[(2-chloro-3-methyl-1-oxobutyl)-amino]-β-oxo-N-(2-pyridinyl)-3-trifluoromethyl-benzene propanamide melting at 136°-138° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:47])[C:8]2[CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[C:11]([S:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:5][C:4]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:30][CH2:31][CH2:32][CH3:33])[N:3]1CC1C=CC(OC)=CC=1>C(O)(C(F)(F)F)=O>[O:47]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[C:11]([S:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:5][C:4]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:30][CH2:31][CH2:32][CH3:33])[NH:3]1
Reactant: CCCCC1(CCCC)CN(c2ccccc2)c2cc(SC)c(OCC(=O)OC(C)(C)C)cc2S(=O)(=O)N1Cc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCC1(CCCC)CN(c2ccccc2)c2cc(SC)c(OCC(=O)O)cc2S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.6 %

Procedure:
1,1-Dioxo-2-(4-methoxybenzyl)-3,3-dibutyl-5-phenyl-7-methylthio-8-(t-butoxycarbonylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Method 25; 6.902 g, 10.11 mmol) was dissolved in a mixture of TFA (50 ml) and Et3Si (8 ml) and the solution was stirred for 90 min at RT. The solvent was removed under reduced pressure and the residue was dissolved in t-BuOMe (100 ml). The organic phase was washed with water (20 ml) and then extracted three times with diluted NaOH (2×50 ml 0.5M). The combined aqueous extracts were acidified with diluted HCl (70 ml, 1M) (pH 1–2) and were then extracted twice with t-BuOMe (2×50 ml). The ether layer was washed with brine, dried over MgSO4 and concentrated. 4.694 g (92%) of the desire product as brown oil were obtained. NMR (400 MHz, CD3OD): 0.70–0.85 (m, 6H), 1.00–1.25 (m, 6H), 1.25–1.50 (m, 4H), 1.55–1.70 (m 2H), 2.10 (s, 3H), 3.90 (brs, 2H), 4.55 (s, 2H), 6.60 (s, 1H), 6.95–7.35 (m, 6H).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]([F:22])([F:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:7]1=[O:23])C.[OH-].[Li+].Cl>CO.CCOCC>[F:22][C:14]([F:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH2:13][NH:12][C:8]1[C:7](=[O:23])[N:6]([CH2:5][C:4]([OH:24])=[O:3])[CH:11]=[CH:10][N:9]=1
Reactant: CCOC(=O)Cn1ccnc(NCC(F)(F)c2ccccn2)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: O=C(O)Cn1ccnc(NCC(F)(F)c2ccccn2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.84 g (8.41 mmol) [3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2oxo-2H-pyrazin-1-yl]-acetic acid ethyl ester (preparation described in example 17, step K) in 10.0 mL methanol was added 8.83 mL (8.83 mmol) 1.0N lithium hydroxide (aq) and the light yellow solution stirred 1 h at room temperature. The reaction pH was adjusted to 7.0 with a dropwise addition of 1.0N HCl in ether to give a precipitate. The solid was removed by filtration, washed well with water and dried under high vacuum for 24 h to give 3-[2,2-Difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-1-yl]acetic acid as a white solid: 1H NMR (DMSO-d6, 400 MHz): δ 13.13 (br s, 1H), 8.70 (d, 1H, J=4.7 Hz), 7.98 (t, 1H, J=7.8 Hz), 7.70 (d, 1H, J=7.9 Hz), 7.60–7.55 (m, 1H), 7.16 (t, 1H, J=6.7 Hz), 6.84 (d, 1H, J=4.7 Hz), 6.73 (d, 1H, J=4.6 Hz), 4.57 (s, 2H), 4.24 (dt, 2H, J=6.6 and 15.2 Hz); MS (Electrospray): M+H=311.0.
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][N:30]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:25][CH:24]=2)[N:13]=1.[H][H]>CN(C=O)C.[OH-].[OH-].[Pd+2].CCOC(C)=O>[NH2:1][C:2](=[O:42])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][N:30]3[C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:27][CH:28]=2)[N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3CC(N)=O)n2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.5 %

Procedure:
tert-Butyl 2-(4-((4-((2-(2-amino-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I40) (0.120 g, 0.207 mmol) was dissolved in dry DMF (5 mL) under an atmosphere of nitrogen. 20% Pearlman's catalyst (0.060 g) in EtOAc (5 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with a balloon and stirred at room temperature for 20 hours at room temperature. The catalyst was removed by filtration through Celite, which was washed with EtOAc (5×10 mL). The solvent was removed in vacuo to give a pale yellow gum which was purified by silica gel chromatography (Biotage, Isolera 12 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I41) (0.090 g, 74% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.20 (s, 1H), 8.67 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.43 (s, 1H), 7.26-7.21 (m, 1H), 7.20-7.09 (m, 5H), 6.89 (s, 1H), 5.31-5.19 (m, 1H), 3.92 (d, J=13.2 Hz, 1H), 3.49 (s, 2H), 3.16-2.98 (m, 4H), 2.71 (t, J=11.8 Hz, 1H), 2.29 (d, J=13.2 Hz, 1H), 1.75 (t, J=11.0 Hz, 1H), 1.58-1.50 (m, 2H), 1.46-1.23 (m, 11H). LCMS Method C: rt 6.59 min; m/z 584.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31]3[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=3)[CH:26]=[C:27]([CH3:29])[CH:28]=2)=[CH:19][N:18]=1>CS(C)=O>[CH3:7][C:2]([NH:1][C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31]3[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=3)[CH:26]=[C:27]([CH3:29])[CH:28]=2)=[CH:19][N:18]=1)([CH2:5][OH:6])[CH2:3][OH:4]
Reactant: CC(N)(CO)CO
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(Cl)nc2)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(NC(C)(CO)CO)nc2)c1
Temperature: 130 °C

Procedure:
2-Amino-2-methyl-1,3-propanediol (28.7 mg, 0.273 mmol), potassium phosphate, tribasic (58 mg, 0.273 mmol), and N-[3-(2-chloropyrimidin-5-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine (50 mg, 0.137 mmol) were dissolved in DMSO (300 μL). The mixture was heated to 130° C. for 48 hours, and then allowed to cool to room temperature. The mixture was diluted with DMSO (0.7 mL), filtered, and purified by reverse phase preparative HPLC (0:100 to 95:5 acetonitrile:water+0.1% formic acid) to afford 2-methyl-2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propane-1,3-diol. MS ESI calcd for C20H22F3N6O2 [M+H]+ 332. found 332. 1H NMR (600 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.80 (d, J=5.2 Hz, 1H), 8.52 (d, J=23.4 Hz, 2H), 7.82 (s, 1H), 7.43 (s, 1H), 7.23 (d, J=5.1 Hz, 1H), 7.08 (s, 1H), 6.36 (s, 1H), 3.60-3.50 (m, 4H), 2.30 (s, 3H), 1.25 (d, J=12.1 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[F:10][C:11]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:12]=1[C:13](=[S:16])[NH:14][NH2:15]>CCO.C(Cl)Cl>[F:10][C:11]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:12]=1[C:13]1[S:16][C:1]([CH3:2])([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:15][N:14]=1
Reactant: CC(=O)c1ccccc1
Reactant: NNC(=S)c1cc(F)ccc1F
Solvent: CCO
Solvent: ClCCl
Product: CC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a solution of acetophenone (0.600 g, 5.00 mmol) in 20 mL of a 3:1 EtOH/DCM mixture was added 2,5-difluorobenzothiohydrazide (0.941 g, 5.00 mmol). The reaction was allowed to stir overnight at room temperature. The reaction was then heated to 45° C., for 14 hours. The reaction mixture was then concentrated in vacuo, and the residue was loaded directly to Biotage (45), followed by flash column chromatography (20% ethyl acetate/hexanes), yielding 5-(2,5-the desired product (1.021 g, 70% yield) as a yellow semi-solid.