Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].[NH2:16]Cl>CN(C=O)C.CCOCC>[N:1]1([NH2:16])[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: NCl
Reactant: c1cc2cc[nH]c2cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nn1ccc2ccncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
A solution of pyrrolo[2,3-c]pyridine (8.47 mmol) and potassium tert-butoxide (16.9 mmol) in DMF (38 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2Cl in ether (84.6 mL) is added drop-wise at rt, and the reaction mixture is stirring at rt for 2 h., quenched with 5% Na2S2O3 aqueous solution (10 mL), and extracted with ether. The organic layer is separated, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-10% MeOH in DCM to afford pyrrolo [2,3-c]pyridin-1-ylamine (226 mg, 11%) as a solid. MS: 134 (M+H); 1H NMR (300 MHz, CDCl3): δ 4.96 (br, 2N—H), 6.43 (d, H), 7.29 (m, H), 7.50 (d, H), 8.29 (d, H), 8.89 (s, H).
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)OCC1.I[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl>CN(C=O)C>[F:24][C:23]([F:26])([F:25])[C:20]1[CH:21]=[CH:22][C:17]([N:10]2[CH2:11][CH2:12][C:8]3([CH2:7][CH2:6][C:5](=[O:1])[CH2:15][CH2:14]3)[C:9]2=[O:13])=[CH:18][CH:19]=1
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: CNCCNC
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: O=C1CCC2(CC1)CCN(c1ccc(C(F)(F)F)cc1)C2=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
1,4-Dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (60 mg, obtained in example 121, step 3) was dissolved in DMF (5 mL) at r.t. Then, 4-iodobenzotrifluoride (155 mg, [CAS Reg. No. 455-13-0]), N,N′-dimethylethylenediamine (sym) (50 mg), Cuprous iodide (81 mg) and K3PO4 (181 mg) were added to the reaction mixture. The mixture was heated at 70° C. for 16 hours and at reflux for 2 hours. The reaction mixture was cooled, poured into ice/water and HCl (2M, 50 mL) was added to the mixture. Stirring was continued for 1 hour at room temperature. The mixture was then extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless solid (51 mg, 58%). MS (m/e): 312.3 [MH+].
Reaction SMILES: B(O)O.Br[C:5]1[CH:6]=[C:7]2[C:11](=[N:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2.CC1(C)C(C)(C)OB([C:22]2[CH:23]=[C:24]3C=CN[C:25]3=[N:26][CH:27]=2)O1.N1C2C(=CC=CC=2)C=N1>>[N:26]1[CH:27]=[CH:22][CH:23]=[C:24]([C:5]2[CH:6]=[C:7]3[CH:8]=[CH:9][NH:10][C:11]3=[N:12][CH:13]=2)[CH:25]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: OBO
Agent: c1ccc2[nH]ncc2c1
Product: c1cncc(-c2cnc3[nH]ccc3c2)c1

Procedure:
Additional compounds were prepared following the protocol of Scheme 32, either by substituting pyridine-3-boronic acid with an appropriate boronic acid or by substituting the 5-bromo-7-azaindole with 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine and reacting with a suitable aryl or heteroaryl halide (i.e. coupling with the boronic acid ester on the azaindole, and the halide on the group to be coupled to the 5-position of the azaindole). The following compounds were prepared by this procedure:
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[NH:3]1.C(N(CC)CC)C.[CH3:16][C:17]1([CH3:29])[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([N:26]=[C:27]=[O:28])[C:20]=2[CH2:19][CH2:18]1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:6](=[O:7])[CH:5]([C:27]([NH:26][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH2:19][CH2:18][C:17]3([CH3:29])[CH3:16])=[O:28])[C:4]([CH3:8])=[N:3]1
Reactant: Cc1cc(=O)n(C)[nH]1
Reactant: CC1(C)CCc2c(N=C=O)cccc21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1=NN(C)C(=O)C1C(=O)Nc1cccc2c1CCC2(C)C
Temperature: 25 °C
Yield: 60.5 %

Procedure:
1.12 g (10 mmol) of 1,3-dimethylpyrazoline-5-one was suspended in 10 ml of toluene containing 1.11 g of triethylamine. To the suspension was added dropwise a solution of 1.87 g of 1,1-dimethylindane-4-yl isocyanate in 2 ml of toluene with stirring at room temperature, followed by further stirring at room temperature for 12 hours. Thereafter, the reaction mixture was extracted with water three times. The aqueous layers were made acidic with concentrated hydrochloric acid and cooled with ice. The precipitate produced was filtered and air-dried to obtain 1.81 g of 1,3-dimethyl-5-oxo-N-(1,1-dimethylindane-4-yl)4,5-dihydropyrazole-4-carboxamide (mp 141.4° C.). Then, thus obtained 1,3-dimethyl-5-oxo-N-(1,1-dimethylindane-4-yl)-4,5-dihydropyrazole-4-carboxamide was added to a mixture of 5 ml of phosphorus oxychloride and 907 mg of N,N-diethylaniline. The resultant mixture was stirred under reflux with heating for 1.5 hour. The obtained reaction mixture was poured into ice water and extracted with chloroform three times. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure and the residue was recrystallized with ethanol to obtain 0.96 g of 5-chloro-1,3-dimethyl-N-(1,1-dimethylindane-4-yl)pyrazole-4-carboxamide (mp 175.2° C.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:33][C:34]1[S:35][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:37][N:38]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18](=[O:20])[NH:33][C:34]3[S:35][C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[N:37][N:38]=3)=[CH:21][CH:22]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: Nc1nnc(-c2ccccc2)s1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4nnc(-c5ccccc5)s4)cc3)c(C#N)cc21
Reaction time: 0.25 h
Yield: 57.9 %

Procedure:
4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (20 mg, 0.057 mmol) was diluted with DCM (1 ml) followed by the addition of oxalyl chloride in DCM (2M) (31 μl, 0.062 mmol) and DMF (1 drop). After stirring for 15 minutes, 2-amino-5-phenyl-[1,3,4]-thiadiazole (10 mg, 0.057 mmol) and DIEA (25 μl, 0.14 mmol) were added. After stirring for 12 hours, the reaction was loaded directly onto a biotage 25 column and eluted with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield methyl 6-cyano-7-(4-(5-phenyl-1,3,4-thiadiazol-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (17 mg, 0.033 mmol, 59% yield).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:21])([F:20])[C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=1)[NH:10][C:11](=[O:16])[CH2:12][C:13]([CH3:15])=[O:14].[Br:22]Br.II>O>[Br:22][CH2:15][C:13](=[O:14])[CH2:12][C:11]([NH:10][C:9]1[CH:17]=[CH:18][CH:19]=[C:7]([C:6]([F:20])([F:21])[F:5])[CH:8]=1)=[O:16]
Reactant: CC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: BrBr
Agent: II
Solvent: CC(=O)O
Solvent: O
Product: O=C(CBr)CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
A one-liter reaction flask equipped with a mechanical stirrer, air-cooled condenser, thermometer and dropping funnel was charged with 290 ml of acetic acid and 167.3 g (0.68 mole) of 3'-trifluoromethylacetoacetanilide. Only a portion of the latter dissolved. The dropping funnel contained 108.8 g (0.68 mole) of bromine, a crystal of iodine and 65 ml of acetic acid. The pot mixture was stirred as the bromine solution was added dropwise while maintaining the reaction temperature at 20°-25°. The reaction solids appeared to dissolve and reprecipitate as the bromine addition was continued. When about 65% of the bromine solution had been added, a clear reaction solution was obtained. All material remained in solution when the remaining quantity of bromine solution was added. The reaction solution was allowed to stir overnight at ambient temperature. On the following morning, the solidified mass was added to 2.8 liters of cold water and stirred. The white solid was collected on a vacuum filter and the filter cake was washed with an additional one liter of water. After drying, there was obtained 210 g (95%) of 4-bromo-3'-trifluoromethylacetoacetanilide, m.p. 66°-8°. N.M.R. (CDCl3) ##STR3##
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.FC(F)(F)C(O)=O.[CH2:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35](=[O:48])[C@@H:36]([NH2:47])[CH2:37][CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:31][CH2:30]1)=[O:28])[CH2:23][CH2:24][CH3:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:22]([O:26][C:27]([N:29]1[CH2:30][CH2:31][N:32]([C:35](=[O:48])[C@@H:36]([NH:47][C:12]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:14])[CH2:37][CH2:38][O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:33][CH2:34]1)=[O:28])[CH2:23][CH2:24][CH3:25]
Reactant: O=C(O)c1cc(O)c2ccccc2n1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCOCc2ccccc2)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(O)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1 g of 4-Hydroxy-quinoline-2-carboxylic acid and 2.6 g of 4-((S)-2-Amino-4-benzyloxy-butyryl)-piperazine-1-carboxylic acid butyl ester trifluoroacetate in 12 ml of DMF, 0.8 g of HOBT, 1.0 g of EDC and 1.2 g of NEM was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was precipitated from a mixture of n-heptane and ethyl acetate. The precipitated product was collected by filtration and dried under reduced pressure. The isolated product was pure enough for the next reaction step. Yield: 900 mg.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[F:16][C:17]1[CH:18]=[C:19]([CH2:27][NH2:28])[CH:20]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:28]([CH2:27][C:19]2[CH:20]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:22]=[C:17]([F:16])[CH:18]=2)[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CS(=O)(=O)c1cc(F)cc(CN)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)cc(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Yield: 40.9 %

Procedure:
(Step 4) A mixture of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (2.04 g), 1-[3-fluoro-5-(methylsulfonyl)phenyl]methanamine hydrochloride obtained in Step 3 (2.5 g) and potassium carbonate (3.6 g) was stirred in ethanol (50 ml) at 85° C. for 20 hr. The reaction mixture was treated with 1N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (3 ml) was added. The mixture was crystallized from methanol-ethyl acetate, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (0.7 g).
Reaction SMILES: Cl.Cl.[CH3:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][NH:19][CH2:18][CH2:17]2.[CH3:24][C:25]([CH3:27])=O.[BH3-]C#N.[Na+]>CO.O>[CH:25]([N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([O:13][CH2:12][CH2:11][CH2:10][N:5]3[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]3[CH3:3])[CH:15]=2)[CH2:20]1)([CH3:27])[CH3:24]
Reactant: CC1CCCCN1CCCOc1ccc2c(c1)CCNC2
Reactant: CC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)N1CCc2cc(OCCCN3CCCCC3C)ccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a flask equipped with a stir bar is placed 6-[3-(2-Methyl-piperidin-1-yl)-propoxy]-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (300 mg, 0.83 mmol), acetone (excess), NaCNBH3 (155 mg, 2.5 mmol) in MeOH (8 mL) and the mixture stirred at room temperature for 2 h. The reaction mixture is diluted with water, and extracted with CH2Cl2. The organic phase is dried over Na2SO4 and concentrated. M+1 331, LCMS >98% @ 230 nm and ELSD.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.N(CCO)CCO.O.CS(C)=O.[Pd](Cl)Cl>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Agent: [F-]
Solvent: OCCNCCO
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 81.3 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 15.8 g of potassium fluoride in 50 ml of p-xylene, 40 ml of diethanolamine and 10 ml of water were heated to 120° C. At 80° C., a mixture of 38.66 mg of palladium(II) chloride and 1.1 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 17.1 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: S(=O)(=O)(O)O.COCCOC[O:12][C:13]1[CH:33]=[CH:32][C:16]([C:17]([NH:19][CH2:20][C@H:21]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:15][CH:14]=1>O1CCCC1.CO>[OH:12][C:13]1[CH:33]=[CH:32][C:16]([C:17]([NH:19][CH2:20][C@H:21]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:15][CH:14]=1
Reactant: COCCOCOc1ccc(C(=O)NC[C@@H](C(=O)OC)N2CCCCC2)cc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@H](CNC(=O)c1ccc(O)cc1)N1CCCCC1
Temperature: 35 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
1.5 ml of 98% sulphuric acid are added to a solution of 9.6 g (24.3 mmol) of methyl (S)-3-[4-(2-methoxyethoxymethoxy)benzoylamino]-2-piperidin-1-yl-propanoate in 50 ml of tetrahydrofuran and 50 ml of methanol. The reaction medium is then stirred at 35° C. for 18 h. The solvents are concentrated under vacuum to 80% then the residue is taken up in ethyl acetate and hydrolysed. The pH is brought to 8 with a saturated aqueous solution of sodium hydrogen carbonate. The product is extracted with ethyl acetate. The organic phase is washed with water then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under vacuum. 6.9 g (93%) of methyl (S)-3-(4-hydroxybenzoylamino)-2-piperidin-1-ylpropanoate are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:12][CH2:11][CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:4]2[CH2:3]1)=O.[C:13]([C:17]1[CH:18]=[C:19]([CH2:28][CH2:29][C:30]([NH:32][NH2:33])=[O:31])[CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])([CH3:16])([CH3:15])[CH3:14].C1(C)C(C)=CC=CC=1>O>[C:24]([C:21]1[CH:20]=[C:19]([CH2:28][CH2:29][C:30]([NH:32][N:33]2[C:9](=[O:10])[CH:4]3[CH2:3][CH:2]([CH3:1])[CH2:12][CH2:11][CH:5]3[C:6]2=[O:8])=[O:31])[CH:18]=[C:17]([C:13]([CH3:14])([CH3:15])[CH3:16])[C:22]=1[OH:23])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC1CCC2C(=O)OC(=O)C2C1
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Solvent: O
Solvent: Cc1ccccc1C
Product: CC1CCC2C(=O)N(NC(=O)CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C(=O)C2C1
Yield: 100.5 %

Procedure:
A mixture of 4-methylhexahydrophthalic anhydride (32.8 g, 200 mmol), 3-(3,5-di-t-butyl-4-hydroxyphenyl)propanoic acid hydrazide (58.4 g, 220 mmol) and 650 ml of xylene was refluxed for 90 minutes under a nitrogen atmosphere with the azeotropic removal of water. The solvent was removed on a rotary evaporator to afford approximately 89 g of a white solid having a melting range of 87°-92° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH2:14][CH2:15][CH2:16][CH2:17]O)[C:12]3[C:19]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][CH:21]=[C:22]([Cl:23])[C:11]=3[N:10]=2)=[C:4]([O:29][C:30]([F:33])([F:32])[F:31])[CH:3]=1.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(N(CC)CC)C.C(=O)([O-])O.[Na+].CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3=[N:10][C:11]4[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([CH:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[C:12]=4[N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]2)=[C:4]([O:29][C:30]([F:33])([F:31])[F:32])[CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Br)cc3OC(F)(F)F)n(CCCCO)c12
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(Br)cc1OC(F)(F)F
Temperature: 0 °C
Reaction time: 4 h
Yield: 48.8 %

Procedure:
To a solution of 4-[2-{[4-bromo-2-(trifluoromethoxy)phenyl]amino}-4-chloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butan-1-ol (Reference Example 62; 1.63 g, 2.97 mmol) in tetrahydrofuran (40 mL) and triethylamine (2.0 mL) was added methanesulfonyl chloride (0.69 mL, 11.9 mmol) at 0° C. The mixture was stirred at 0° C. for 4 hr, diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. A mixture of the resulting mesylate, potassium carbonate (2.04 g, 14.8 mmol) in N,N-dimethylformamide (15 mL) was stirred at 70° C. for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with n-hexane to give the title compound as a colorless powder (770 mg, 1.45 mmol, 49%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH2:17]([NH:19][C:20]([O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])=[O:21])[CH3:18]>>[CH2:17]([NH:19][C:20]([O:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)[CH:27]=[CH:28][CH:29]=1)=[O:21])[CH3:18]
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: CCNC(=O)Oc1cccc(N)c1
Product: CCNC(=O)Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3-[(N-ethylamino)carbonyloxy]aniline were reacted to provide N2-[3-[(N-ethylamino)carbonyloxy]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.92 (d, 1H, J=3.0 Hz), 7.67-7.55 (m, 2H), 7.24 (t, 1H, J=7.5 Hz), 7.16 (t, 1H, J=7.5 Hz), 7.07-6.98 (m, 2H), 6.84-6.79 (m, 2H), 6.67 (m, 2H), 6.60 (d, 1H, J=7.5 Hz), 5.22-5.14 (m, 1H), 3.36-3.27 (m, 2H), 2.95 (s, 1H), 2.88 (s, 1H), 1.20 (t, 3H, J=7.5 Hz); 19F NMR (282 MHz, CDCl3): −47012; LCMS: purity: 99%; MS (m/e): 384(MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCOCC.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]>[CH2:9]([NH:16][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1cncc(Br)c1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Brc1cncc(NCc2ccccc2)c1
Temperature: 80 °C

Procedure:
3,5-Dibromopyridine (20.0 g, 84.4 mmol) and benzylamine (9.23 mL, 84.4 mmol) were dissolved in toluene (100 mL). Pd2(dba)3 (1.55 g, 1.69 mmol), BINAP (2.10 g, 3.38 mmol) and sodium tert-butoxide (12.2 g, 127 mmol) were added to the reaction mixture. The reaction was heated to 80° C. for 16 h, then allowed to cool to ambient temperature, diluted with ether (400 mL) and washed with brine (3×100 mL). The organic layer was dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (25% EtOAc in hexanes) to afford the title compound as a slightly yellow solid (14.75 g, 66%). MS (DCI/NH3) m/z 263 (M+H)+.
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(OCC)(=O)C.O>[CH2:26]([O:25][C:23](=[O:24])[NH:13][C:12]1[CH:14]=[CH:15][C:9]([CH2:1][C:2]2[CH:3]=[CH:4][C:5]([NH2:6])=[CH:7][CH:8]=2)=[CH:10][CH:11]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(Cc2ccc(N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(Cc2ccc(NC(=O)OCc3ccccc3)cc2)cc1

Procedure:
A mixture of 4,4′-methylenedianiline (19.8 g), potassium carbonate (20 g) in ethyl acetate (300 mL) and water (200 mL) was stirred in an ice bath. Benzyl chloroformate (15 mL) was slowly added to the mixture. The resulting mixture was stirred for 1 hour, then the organic layer was separated, and the aqueous layer extracted with additional ethyl acetate. The combined organic extracts were washed with water and brine, dried (Na2SO4), and the solvent removed in vacuo. The crude mixture was isolated by column chromatography on silica gel, eluting with 30% ethyl acetate/hexanes, to give 4-(4-aminobenzyl)phenyl-carbamic acid benzyl ester as solid.
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.CO[C:17](=[O:27])[CH2:18][NH:19][C:20]([C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1)=[O:21]>CO>[C:20]1(=[O:21])[NH:19][CH2:18][C:17](=[O:27])[N:23]2[CH2:24][CH2:25][CH2:26][C@@H:22]12
Reactant: COC(=O)CNC(=O)[C@@H]1CCCN1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C1NCC(=O)N2CCC[C@@H]12
Temperature: 25 °C
Yield: 34.4 %

Procedure:
Triethylamine (75 ml, 540 mmol) was added to a solution of the crude trifluoroacetic acid salt of [((S)-pyrrolidine-2-carbonyl)amino]acetic acid methyl ester (15.4 g), which was isolated in the previous step, in methanol (300 ml). The reaction mixture was heated to reflux for 16 hours. It was cooled to room temperature. The solvent was removed in vacuo. The residue was suspended in 2-propanol (150 ml). The precipitation was isolated and dried in vacuo to give 4.38 g of (S)-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione.