Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:25][CH3:26])[N:13]=[C:12]([NH2:27])[N:11]=2)=[C:6]([F:28])[CH:5]=1.Cl>C1COCC1>[NH2:27][C:12]1[N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[CH:5][C:6]=2[F:28])[C:15]([C:16]#[C:17][C:18]2[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[C:14]([CH2:25][CH3:26])[N:13]=1
Reactant: CCc1nc(N)nc(-c2ccc(C(=O)OC)cc2F)c1C#Cc1ccc(N)nc1
Agent: Cl
Solvent: C1CCOC1
Product: CCc1nc(N)nc(-c2ccc(C(=O)O)cc2F)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 200 mg (0.54 mmol) 4-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-3-fluoro-benzoic acid methyl ester using 0.81 mL (0.81 mmol) 1 N NaOH in 4 mL THF. After completion of the reaction, the reaction mixture is combined with the mother liquid from the proceeding Suzuki coupling. The pH is adjusted to 4-5 (using 1 N HCl) upon which the product precipitates from the reaction mixture and is isolated by filtration. Yield: 240 mg (58% over two steps).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[Br:11]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[C:10]=1[Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc2scnc2c1
Solvent: CC#N
Product: Nc1ccc2scnc2c1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
A stirred solution of 3 g of 5-aminobenzothiazole in 100 ml of acetonitrile at room temperature was treated with 3.5 g of N-bromosuccinimide and the resulting solution was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue purified by silica gel chromatography (eluent cyclohexane/ethyl acetate 7:3) to afford 3.9 g of 5-amino-4-bromobenzothiazole as a pink solid. MS (ES+) 229/231 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8][CH:7]=1)=[O:5])[CH3:2]>CC(O)=O.[Rh]>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:15]2[C@@H:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cncc2ccccc12
Agent: [Rh]
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1CNC[C@@H]2CCCC[C@@H]21

Procedure:
Isoquinoline4-carboxylic acid ethyl ester (85.7 g, 0.426 mol) is dissolved in HOAc (1000 ml) and hydrogenated at 150 bar and 60° for 2 h in the presence of 5% Rh/C (86 g). The mixture is filtered and the filtrate evaporated. The residue is dissolved in MTBE (500 ml) and washed with 2N KHCO3 (400 ml) and brine (100 ml). The combined water phases are exhaustively extracted with DCM (3×150 ml), the extracts dried over Na2SO4 and evaporated to yield the crude acetate salt of the desired product. Recrystallization from DCM/Et2O yields the pure acetate salt. This salt is dissolved in water (200 ml) and cooled to 0°. Cold 2N NaOH (150 ml) is slowly added and the mixture extracted with DCM (1×250 ml, 2×150 ml, 1×100 ml). The extracts are dried (Na2SO4) and evaporated. The residue is crystallised from 300 ml hexanes at −20° to yield the pure product as a white crystal powder, m.p. 44°-52°. TLC (silicagel, EtOAc/MeOH/NH4OH 85:15:1): rf 0.25. Two further portions can be crystallised from the mother liquor with somewhat lower melting points (42°-52° and 38°-51°).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=2[N:7]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].C(OC(C)C)(C)C>CN(C=O)C.O>[N+:12]([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([CH2:2][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:7][C:6]=2[CH:8]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc2oc(CCl)nc2c1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2oc(CN3CCCC3)nc2c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A reaction mixture of 3 g (14.11 mmol) of 2-chloromethyl-5-nitrobenzoxazole, 1.5 mL (17.97 mmol) of pyrrolidine, and 3.9 g (28.22 mmol) of potassium carbonate in 30 mL of DMF is stirred for 4 hours at 50° C. Then the reaction mixture is diluted with water and covered with diisopropyl ether, The precipitated yellow solid is suction filtered, washed again, and dried in the circulating air dryer at 60° C. Yield: 1.8 g (52% of theory); C12H13N3O3 (M=247.25); calc.: molecular ion peak (M+H)+: 248; found: molecular ion peak (M+H)+: 248; Rf value: 0.4 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:11][C:12]([N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16][CH2:15]3)=[O:13])=[N:7][C:6]=2[CH:24]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].N1C=CC=CC=1>C(Cl)Cl>[N:14]1([C:12](=[O:13])[CH2:11][S:10][C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:24][C:6]=3[N:7]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: Nc1ccc2sc(SCC(=O)N3CCCc4ccccc43)nc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2sc(SCC(=O)N3CCCc4ccccc43)nc2c1
Reaction time: 8 h
Yield: 60 %

Procedure:
To a 0° C. solution of compound 50 (160 g, 0.45 mmol) in dry CH2Cl2 (5 mL) was added methanesulfonyl chloride (70 μL, 0.90 mmol)) followed by dropwise addition of pyridine (100 μL, 1.40 mmol). The reaction was stirred overnight under N2. The reaction mixture was diluted with CH2Cl2 (40 mL), washed with 1N HCl (10 mL), water (2×10 mL), and saturated NaCl (2×10 mL). Dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the product was purified by column chromatography (EtOAc/hexanes 1:1) to afford 54 as a pale yellow solid (117 mg, 60%); MS m/z: 434 (M+H)+. Anal. Calcd. For, C19H19N3O3S2: C, 52.63; H, 4.42; N, 9.69; S, 22.19. Found: C, 52.69; H, 4.49; N, 9.54; S, 22.11.
Reaction SMILES: [C:1]1([C:7]2[C:15](N)=[C:11]3[CH2:12][CH2:13][O:14][C:10]3=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.N([O-])=O.[Na+].[I-:22].[K+]>O.[Cl-].[Na+].O.CCOCC>[I:22][C:15]1[C:11]2[CH2:12][CH2:13][O:14][C:10]=2[CH:9]=[CH:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1c(-c2ccccc2)ccc2c1CCO2
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: Ic1c(-c2ccccc2)ccc2c1CCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
A mechanically stirred solution of 2,3-dihydro-5-phenyl-4-benzofuranamine (1.88 g, 8.90 mmol), ice (~5 g), and concentrated hydrochloric acid (3.9 mL) at 5° C. was treated slowly with a solution of sodium nitrite (0.675 g, 9.78 mmol) in H2O (4 mL). The resulting suspension was stirred 15 min and filtered through a plug of glass wool into a solution of potassium iodide (5.00 g, 30.1 mmol) in H2O. The suspension was allowed to stand for 12 h, treated with Et2O (200 mL) and brine (200 mL), the layers separated, and the aqueous layer further extracted with fresh Et2O (2×300 mL). The combined organic portions were, filtered, washed with 1 N HCl (2×300 mL), brine (200 mL), dried (K2CO3), filtered, and concentrated in vacuo to afford 1.63 g (57%) of the product as a clear oil: 1H NMR (300 MHz, CDCl3) δ 3.23 (t, J=8 Hz, 2H), 4.63 (t, J=8 Hz, 2H), 6.75 (d, J=8 Hz, 1H), 7.02 (d, J=8 Hz, 1H), 7.29-7.42 (m, 5H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.C[N:14](C=O)C>>[F:3][C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][N:10]([NH2:14])[C:7]2=[N:8][CH:9]=1
Reactant: Fc1cnc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Nn1ccc2cc(F)cnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A suspension of NaH (4.4 g, 110 mmol, 60% in mineral oil) in DMF (37 mL) at 0° C. is treated with 5-fluoro-1H-pyrrolo[2,3-b]pyridine (1.0 g, 7.4 mmol) and stirred at 0° C. for 1 h. The mixture is treated with HOSA (4.2 g, 37 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, filtered through a pad of Celite, and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 30%-70% EtOAc in heptane to afford 5-fluoro-pyrrolo[2,3-b]pyridin-1-ylamine (980 mg, 88%). MS: 152 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 7.60 (m, 1H), 7.42 (m, 1H), 6.36 (s, 1H), 5.01 (s, NH2, 2H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].[CH3:34][C:35](=O)[CH3:36]>CO.[Pd]>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][N:20]([CH:35]([CH3:36])[CH3:34])[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CNC3)n(C)c2n1
Reactant: CC(C)=O
Agent: [Pd]
Solvent: CO
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(C(C)C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxyazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (553 mg, 1.23 mmol) and propan-2-one (1.0 mL) in MeOH (20 mL) was added 10% Pd/C (30 mg) as a slurry in MeOH (0.5 mL) and the resulting mixture stirred under an atmosphere of H2 for 1.5 h at r.t. The reaction mixture was filtered through Celite®, washing with MeOH, and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, 2M NH3/MeOH:EtOAc, 0-12%) then (C18, MeOH:H2O, 5-25%). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM and MeOH and the product eluted with 2M NH3/MeOH. The resulting colourless foam was recrystallised from iPrOAc and pentane affording 739 as colourless crystals (166 mg, 28%). LCMS (method I): RT 2.48 min, [M+H]+ 491.3. 1H NMR (CDCl3, 400 MHz): δ 8.03-8.02 (1 H, m), 7.64-7.63 (1 H, m), 7.29-7.28 (2 H, m), 4.40 (4 H, s), 4.05 (2 H, d, J=8.89 Hz), 3.86 (4 H, s), 3.81 (3 H, s), 3.57-3.55 (2 H, m), 3.31-3.30 (2 H, m), 3.10 (3 H, s), 2.54-2.53 (1 H, m), 1.40 (3 H, t, J=7.50 Hz), 1.02 (6 H, d, J=6.24 Hz)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([N:32]2[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]2)[N:27]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:38]([CH:35]3[CH2:34][CH2:33][N:32]([C:28]4[N:27]=[C:26]([CH3:25])[CH:31]=[CH:30][N:29]=4)[CH2:37][CH2:36]3)=[O:39])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: Cc1ccnc(N2CCC(C(=O)O)CC2)n1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Product: Cc1ccnc(N2CCC(C(=O)N3C[C@@H](N(C)C(=O)Oc4ccc(F)cc4)[C@H](c4ccc(Cl)cc4)C3)CC2)n1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound {(3S,4R)-4-(4-chloro-phenyl)-1-[1-(4-methyl-pyrimidin-2-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-(4-methyl-pyrimidin-2-yl)-piperidine-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a yellow foam. MS m/e: 552.4 [M]+.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]([CH3:19])[CH2:5][CH2:6][O:7][C:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[N:10]([CH3:18])[N:9]=1.Cl>CCO>[CH3:3][N:4]([CH3:19])[CH2:5][CH2:6][O:7][C:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]([CH3:18])[N:9]=1
Reactant: CCOC(=O)c1cc(OCCN(C)C)nn1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCOc1cc(C(=O)O)n(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
KOH (2.09 g, 37.4 mmol) was dissolved into EtOH (30 mL) and to this solution was added ethyl 3-(2-(dimethylamino)ethoxy)-1-methyl-1H-pyrazole-5-carboxylate (4.5 g, 18.7 mmol) and the mixture stirred at rt overnight. To the reaction mixture was added concentrated HCl (3.1 mL) with stirring and the resulting suspension was filtered and the cake was washed with EtOH (two×20 mL). The filtrate was concentrated to give the title compound (3.3 g, 83% yield) as a brown gum.
Reaction SMILES: S(Br)([Br:3])=O.[C:5]1([NH:11][C:12]2[N:17]=[C:16]([CH2:18]O)[CH:15]=[C:14]([CH:20]3[CH2:22][CH2:21]3)[N:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(OCC)C.O>[C:5]1([NH:11][C:12]2[N:17]=[C:16]([CH2:18][Br:3])[CH:15]=[C:14]([CH:20]3[CH2:22][CH2:21]3)[N:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCc1cc(C2CC2)nc(Nc2ccccc2)n1
Reactant: O=S(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: BrCc1cc(C2CC2)nc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
15.6 g (75 mmol) of thionyl bromide in 50 ml of diethyl ether are added dropwise within a period of half an hour, with stirring, to 12 g (50 mmol) of 2-phenylamino-4-hydroxymethyl-6-cyclopropylpyrimidine and 0.4 g (50 mmol) of pyridine in 350 ml of diethyl ether. After stirring for 2 hours at room temperature, a further 0.4 g (50 mmol) of pyridine are added and the mixture is heated under reflux for 5 hours. After cooling to room temperature, 200 ml of water are added and the pH is adjusted to 7 by the dropwise addition of 140 ml of saturated sodium hydrogen carbonate solution. The diethyl ether phase is separated off and then washed twice with 100 ml of water each time, dried over sodium sulfate and filtered, and the solvent is evaporated. The brown oil which remains is purified by column chromatography over silica gel (toluene/chloroform/diethyl ether/petroleum ether (b.p. 50°-70° C.): 5/3/1/1). After the eluant mixture has been evaporated off, the yellow oil is diluted with diethyl ether/petroleum ether (b.p. 50°-70° C.) and crystallised at reduced temperature. The yellow crystalline powder melts at 77.5°-79.5° C. Yield: 9.7 g (32 mmol; 64% of the theoretical yield).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([OH:12])[C:9]([NH2:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.[C:13]([C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][C:30]=1[C:31]([F:34])([F:33])[F:32])[O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)#[N:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CCO.COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:13]([C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][C:30]=1[C:31]([F:32])([F:33])[F:34])[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:7]=[C:6]([CH:8]([OH:12])[C:9]([NH2:11])=[O:10])[CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)#[N:14]
Reactant: N#Cc1cc(Oc2ccc(B(O)O)cc2)ccc1C(F)(F)F
Reactant: NC(=O)C(O)c1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: N#Cc1cc(Oc2ccc(-c3cccc(C(O)C(N)=O)n3)cc2)ccc1C(F)(F)F
Temperature: 90 °C

Procedure:
A mixture of 3-cyano-4-trifluoromethyl-1-fluorobenzene (70, g, 0.37, mol, Oakwood), 4-hydroxyphenylboronic acid (50, g, 0.36, mol, Boron Molecular), K2CO3, (70, g) and DMF/water (400, mL/40, mL) was heated to 100° C. for 3, h. After cooling to RT, the mixture was diluted with water (1, L) and extracted with EtOAc (1.5, L). The organic layer was washed with water (0.5, L) and brine, concentrated and purified by chromatographed over silica gel with 4% MeOH in chloroform to give (4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid as pink solid (50, g, 45%). 1H NMR (400, MHz, CD3OD) 7.70-7.70, (3H, m), 7.35, (1H, d, J=2.4, Hz), 7.24, (1H, dd, J=2.2, & 8.8, Hz), 7.00, (2H, d, J=7.7, Hz). [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17, mg, 0.022 mmol, Aldrich) was added to a mixture of 2-(6-bromopyridin-2-yl)-2-hydroxyacetamide (50, mg, 0.22, mmol), (4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid (100, mg, 0.32, mmol) and cesium carbonate (140, mg, 0.43 mmol) in EtOH/DME/water (2, mL/2, mL/1, mL) at room temperature. The reaction mixture was flushed with argon, then, shaken at 90° C. for 3, h. After cooling to RT, the reaction was quenched with water (2, mL), and extracted with EtOAc (10 mL). The organic layer was separated, concentrated and purified by reverse-phase prep HPLC (C18, 0-100% 0.1% TFA in water/0.1% TFA in ACN) to give 2-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2-hydroxyacetamide (Cpd. No. 6) as off-white solid (45, mg, 50%). LC/MS: m/z=414.1, [M+H]+, ; 1H NMR (400, MHz, DMSO-d6) 8.15, (2H, d, J=8.4, Hz), 7.93 (1H, d, J=9.2, Hz), 7.82-7.86, (3H, m), 7.37-7.45, (3H, m), 7.26, (2H, d, J=9.2, Hz), 4.95, (1H, s).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:10]2[CH2:11][C:6]3([C:13]([NH2:15])=[O:14])[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.CCN(C(C)C)C(C)C.[CH3:25][CH:26]1[CH2:31][N:30]([C:32]2[C:37]([Cl:38])=[CH:36][C:35]([Cl:39])=[CH:34][C:33]=2[Cl:40])[S:29](=[O:42])(=[O:41])[N:28]([CH2:43][C:44](O)=[O:45])[CH2:27]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O.O>[CH3:25][CH:26]1[CH2:31][N:30]([C:32]2[C:37]([Cl:38])=[CH:36][C:35]([Cl:39])=[CH:34][C:33]=2[Cl:40])[S:29](=[O:42])(=[O:41])[N:28]([CH2:43][C:44]([NH:2][CH:3]2[CH:10]3[CH2:11][C:6]4([C:13]([NH2:15])=[O:14])[CH2:7][CH:8]([CH2:12][CH:4]2[CH2:5]4)[CH2:9]3)=[O:45])[CH2:27]1
Reactant: CC1CN(CC(=O)O)S(=O)(=O)N(c2c(Cl)cc(Cl)cc2Cl)C1
Reactant: NC(=O)C12CC3CC(C1)C(N)C(C3)C2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC1CN(CC(=O)NC2C3CC4CC2CC(C(N)=O)(C4)C3)S(=O)(=O)N(c2c(Cl)cc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.6 %

Procedure:
To 4-aminoadamantan-1-carboxamide hydrochloride (900 mg, 3.9 mmol) in DMSO (40 mL) and i-prOH (50 mL), were added DIPEA (2.5 g, 19.5 mmol), 2-(4-methyl-1,1-dioxido-6-(2,4,6-trichlorophenyl)-1,2,6-thiadiazinan-2-yl)acetic acid (1.8 g, 4.7 mmol), EDC (894 mg, 4.7 mmol) and HOBT (632 mg, 4.7 mmol), and then agitated for 5 hr at room temperature. After the addition of water, the resultant extracted with EtOAc, dried (Na2SO4), filtered and concentrated under reduced pressure, followed by column chromatography (MeOH/DCM 5%), finally giving the title compound (solid, 980 mg, y=64%) E-form. 1H NMR (300 MHz, DMSO-d6) δ 7.41 (d, J=2.4 Hz, 1H), 7.39 (d, J=2.4 Hz, 1H), 5.58 (s, 1H), 5.35 (s, 1H), 4.35 (d, J=17 Hz, 1H), 4.08-4.00 (m, 2H), 3.91-3.85 (m, 1H), 3.73 (d, J=17 Hz, 1H), 3.30-3.17 (m, 2H), 2.70-2.54 (m, 1H), 2.17-1.54 (m, 13H); LC/MS MH+ 563
Reaction SMILES: [Cl:1][C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][C:3]=1[CH:9]=O.[CH2:11]([O:13][C:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15])[CH3:12]>C1C=CC=CC=1>[Cl:1][C:2]1[CH2:6][C:5]([CH3:7])([CH3:8])[CH2:4][C:3]=1/[CH:9]=[CH:16]/[C:14]([O:13][CH2:11][CH3:12])=[O:15]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)CC(Cl)=C(C=O)C1
Solvent: c1ccccc1
Product: CCOC(=O)/C=C/C1=C(Cl)CC(C)(C)C1
Reaction time: 14 h
Yield: 36.4 %

Procedure:
The following two procedures were adapted from Organic Preparations and Procedures Int., 29 (4), 471-498. A 500-mL single neck round bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 2-chloro-4,4-dimethylcyclopent-1-enecarbaldehyde (38 g, 240 mmol) in benzene (240 mL). See FIG. 3. To the solution was added ethoxycarbonylmethylene triphenylphosphorane (84 g, 240 mmol). The mixture was stirred for 14 h. After that time, the solvent was evaporated and the residue was triturated with hexanes (2 L) to extract the product away from the PPh3 by-products. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography using a 100% hexane-1:1 hexane/ethyl acetate gradient to afford a 37% yield (20 g) of 103a.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=CC=1CC(OC)=O)(=[O:4])=[O:3].C([N:20]=[C:21]=[O:22])CCC.C(=O)([O-])[O-].[K+].[K+].Cl>C(C(C)=O)C>[CH2:5]([S:2]([NH:1][C:21]([NH2:20])=[O:22])(=[O:3])=[O:4])[CH2:10][CH2:9][CH3:8]
Reactant: COC(=O)Cc1ccccc1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCS(=O)(=O)NC(N)=O
Temperature: 0 °C
Yield: 135 %

Procedure:
A mixture of 22.9 g methyl o-aminosulfonylbenzeneacetate, 13.5 g n-butyl isocyanate, 15.2 g potassium carbonate and 250 ml methyl ethyl ketone was stirred and refluxed for three hours. The reaction mixture was cooled, poured into 1250 g of ice-water, and acidified to pH 1.5 with concentrated HCl. The product was filtered, washed and dried. The crude product was recrystallized from 1-chlorobutane to yield 24.3 g of purified N-(n-butyl)sulfonylurea derivative of methyl o-isocyanatosulfonylbenzeneacetate, m.p. 164°-166° (dec.).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[C:17]12([C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>C(O)CCC>[C:17]12([C:27]([N:29]3[CH2:34][CH2:33][N:32]([C:2]4[N:11]=[C:10]([NH2:12])[C:9]5[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=5)[N:3]=4)[CH2:31][CH2:30]3)=[O:28])[CH2:18][CH:19]3[CH2:20][CH:21]([CH2:22][CH:23]([CH2:25]3)[CH2:24]1)[CH2:26]2
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(N1CCNCC1)C12CC3CC(CC(C3)C1)C2
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(C(=O)C45CC6CC(CC(C6)C4)C5)CC3)nc(N)c2cc1OC

Procedure:
A mixture of 2-chloro-4-amino-6,7-dimethoxyquinazoline (2.4 g), 1-(1-adamantanecarbonyl)piperazine (2.5 g) and n-butanol (60 ml) was refluxed for 10 hours. After cooling, the solvent was evaporated under reduced pressure, and water was added to the residue. After treating with aqueous ammonia, the precipitated crystals were collected to give crude 2-{4-(1-adamantanecarbonyl)-1-piperazinyl}-4-amino-6,7-dimethoxyquinazoline, m.p. 237°-240° C. Recrystallization from methanol gave pure 2-{4-(1-adamantanecarbonyl)-1-piperazinyl}-4-amino-6,7-dimethoxyquinazoline, m.p. 242°-243° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]([C:15]1[C:20]([Br:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[C:30][CH2:31][NH:32]C(OC(C)(C)C)=O)=[CH:25][CH:24]=2)[N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[NH:8]([C:15]1[C:20]([Br:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][CH2:31][NH2:32])=[CH:27][CH:28]=2)[N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC#Cc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Reaction time: 3 h
Yield: 105.7 %

Procedure:
Trifluoroacetic acid (0.25 ml) was added to a solution of 4-anilino-5-bromo-2-{4-[3-(t-butoxycarbonylamino)-1-propynyl]anilino}pyrimidine (Method 25; 30 mg, 0.06 mmol) in DCM (1 ml). The solution was left to stand for 3 hours and volatile material was removed by evaporation. The residue was triturated with diethyl ether to give the product as a trifluoroacetate salt (25 mg, 81%). NMR: 4.0 (m, 2H), 7.2 (m, 2H), 7.4 (m, 2H), 7.5–7.7 (m, 4H), 7.8 (m, 1H), 8.2 (br s, 2H), 8.7 (s, 1H), 9.6 (s, 1H); MS (MH+): 394.3, 396.3.