Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(C[C@H](C2C([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=CN=C(NCCOC)N=2)NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C=C(F)C=1.Br[C:50]1[C:51]([C@@H:61]([NH:71][C:72](=[O:90])[CH2:73][N:74]2[C:82]3[C:81]([F:84])([F:83])[CH2:80][CH2:79][C:78]([F:86])([F:85])[C:77]=3[C:76]([CH:87]([F:89])[F:88])=[N:75]2)[CH2:62][C:63]2[CH:68]=[C:67]([F:69])[CH:66]=[C:65]([F:70])[CH:64]=2)=[N:52][C:53]([NH:56][CH2:57][CH2:58][O:59][CH3:60])=[N:54][CH:55]=1>>[F:89][CH:87]([F:88])[C:76]1[C:77]2[C:78]([F:86])([F:85])[CH2:79][CH2:80][C:81]([F:84])([F:83])[C:82]=2[N:74]([CH2:73][C:72]([NH:71][C@H:61]([C:51]2[C:50]([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=[CH:55][N:54]=[C:53]([NH:56][CH2:57][CH2:58][O:59][CH3:60])[N:52]=2)[CH2:62][C:63]2[CH:64]=[C:65]([F:70])[CH:66]=[C:67]([F:69])[CH:68]=2)=[O:90])[N:75]=1
Reactant: COCCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Reactant: COCCNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Product: COCCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1

Procedure:
The title compound (12E) was prepared according to the method presented for the synthesis of compound 11J of Example 11 utilizing 12D. 1H NMR (400 MHz, CD3OD) δ 8.80 (d, J=8.0 Hz, 1H), 8.05 (s, 1H), 7.47-7.29 (m, 2H), 7.21 (dd, J=10.7, 8.6 Hz, 1H), 6.97-6.61 (m, 2H), 6.44 (d, J=6.1 Hz, 2H), 5.22 (dd, J=14.9, 7.7 Hz, 1H), 5.05 (s, 2H), 3.89-3.51 (m, 4H), 3.41 (s, 3H), 3.02 (ddd, J=20.2, 13.2, 7.5 Hz, 2H), 2.66-2.28 (m, 4H). MS (m/z) 730.24 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:21])/[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:11]([CH2:22][CH3:23])[C:10]([CH3:24])=[C:9]2[C:5]=1[C:6](=[O:25])[O:7][CH2:8]2)([OH:3])=[O:2].[C:26]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:21])/[CH2:16][CH2:17][C:18]([O:20][CH3:26])=[O:19])=[C:11]([CH2:22][CH3:23])[C:10]([CH3:24])=[C:9]2[C:5]=1[C:6](=[O:25])[O:7][CH2:8]2)([OH:3])=[O:2]
Reactant: CCc1c(C)c2c(c(C(=O)O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCc1c(C)c2c(c(C(=O)O)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2

Procedure:
A solution of 3.88 g of (E)-6-(4-carboxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid and 0.2 g of p-toluenesulfonic acid in methanol (60 ml) is stirred at room temperature for 8 hours. The solvent is evaporated under reduced pressure. The residue is dissolved in ethyl acetate, and this solution washed twice with water, once with brine, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure to give methyl (E)-6-(4-carboxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[H-].[Na+].[F:13][C:14]([F:44])([F:43])[C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][N:22]2[C:31](OC2C=CC([N+]([O-])=O)=CC=2)=[O:32])=[CH:17][CH:16]=1.O>C1COCC1.CO>[C:7]([C:6]1[CH:9]=[C:2]([NH:1][C:31]([N:22]2[CH2:23][CH2:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:21]2[C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:43])([F:13])[F:44])=[CH:16][CH:17]=2)=[O:32])[CH:3]=[CH:4][C:5]=1[F:10])#[N:8]
Reactant: N#Cc1cc(N)ccc1F
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: N#Cc1cc(NC(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-amino-2-fluorobenzonitrile (62 mg, 452 μmol) and sodium hydride, 60% dispersion in mineral oil (26 mg, 678 μmol) in THF (1.0 mL) was stirred at RT for 15 min. Then, (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 226 μmol, example 88) was added and the mixture was stirred at RT for overnight. Then, a solution of H2O and MeOH (1:1, 0.2 mL) was added and the solvents were removed. The residue was then dissolved in a solution of DMSO and MeOH (1:1, 1 mL). The solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was dissolved in MeOH (1 mL). The solution was then washed through PL-HCO3 MP resin (polymerlabs, 200 mg/6 mL tube) and the resin was washed with MeOH (2×0.5 mL). The combined washings were then concentrated and dried under vacuum to give the title compound as an orange solid. MS (ESI, positive ion) m/z: 440 (M+H).
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([O:7][C:8]([C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[CH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:3][CH:2]=1.[K+].[Br-]>P(Cl)(Cl)Cl>[Br:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]2[O:18][C:10]([C:11]3[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=3)=[CH:9][C:8]=2[O:7][C:4]2[CH:3]=[CH:2][C:1]([CH3:28])=[CH:6][CH:5]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(OC(=CC(=O)c2ccc(Br)cc2)C(=O)c2ccc(Br)cc2)cc1
Agent: [Br-]
Agent: [K+]
Solvent: ClP(Cl)Cl
Product: Cc1ccc(Oc2cc(-c3ccc(Br)cc3)oc2-c2ccc(Br)cc2)cc1

Procedure:
A solution of 5.0 g (0.01 mole) 1-(4-tolyloxy)-1,2-bis-(4-bromobenzoyl)ethylene in 10 ml phosphorus trichloride was heated under reflux for 3-4 hr (TLC followed). The excess PCl3 was removed by distillation and the residue was triturated with ice/water (exothermic reaction). The solution was extracted with dichloromethane (75 ml) and the dichloromethane layer was washed with saturated sodium bicarbonate solution, water, and dried (Na2SO4). The solvent was removed under reduced pressure. The residual solid was chromatographed over silica gel using ether:hexane (2:8 to 1:1) as eluant. An off white crystalline solid was obtained, 2.78 g (56%), mp 92°-3° C. IR (KBr) 2923, 2851, 1560, 1506, 1467, 1390, 1209, 1072, 1066, 945, 825, 707, 486. 1H NMR (CDCl3 /35° C.) 7.69 (d, 2H, J=8.8), 7.46-7.43 (m, 6H), 7.12 (d, 2H, J=8.3), 7.0 (d, 2H, J=8.3), 6.47 (s, 1H), 2.31 (s, 3H). 13C NMR (CDCl3 /135° C.) 150.8, 150.1, 142.8, 139.3, 133.0, 131.9, 131.7, 130.3, 129.1, 128.6, 125.1, 125.0, 121.8, 120.5, 117.1, 102.7, 20.6. MS m/e 484 (M+).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1.[F:21][C:22]1[C:30]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33])=[CH:29][CH:28]=[C:27]([F:38])[C:23]=1[C:24](O)=[O:25].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:21][C:22]1[C:30]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:33])=[O:34])=[CH:29][CH:28]=[C:27]([F:38])[C:23]=1[C:24]([NH:11][C:8]1[CH:9]=[C:10]2[C:2]([I:1])=[CH:3][N:4]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1)=[O:25]
Reactant: Nc1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
3-Iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine (0.506 g, 1.27 mmol), 2,6-difluoro-3-(propylsulfonamido)benzoic acid (0.389 g, 1.39 mmol), EDCI (0.267 g, 1.39 mmol) and HOBt (0.188 g, 1.39 mmol) were dissolved in DMF (10 mL) and stirred at room temperature overnight. The organic portion was washed with water (3×), brine, dried over Na2SO4 and concentrated. The resulting residue was purified by column chromatography (1:1:1 hexane/Et2O/DCM) giving 2,6-difluoro-N-(3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.738 g, 88.2%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([CH:10]=[CH:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)=[O:4].[NH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][NH:19][C:12](=[O:14])[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:18])[F:17])=[CH:16][CH:15]=2)[CH:22]=1
Reactant: O=C(O)C=Cc1ccc(NC(=O)C(F)(F)F)cc1
Reactant: NCc1cccnc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(C=Cc1ccc(NC(=O)C(F)(F)F)cc1)NCc1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
A solution of 4-(trifluoroacetylamino)cinnamic acid (1.30 g) and 3-(aminomethyl)pyridine (540 mg) in 20 ml dimethylformamide was mixed with 0.9 ml diethyl cyanophosphate and subsequently with 0.8 ml triethylamine on ice, and then stirred at room temperature for 4 hours. The solid precipitated from water was then filtered, washed with water, and dried by heating under reduced pressure to give N-(3-pyridylmethyl)-4-[(trifluoroacetyl)amino]cinnamamide (1.61 g, 92%).
Reaction SMILES: [C@@:1]12(O)[CH2:9][C@@H:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH2:3][C:2]2([OH:11])[CH3:10].CS(C)=[O:15].N1C=CC=CC=1>C(N(CC)CC)C>[OH:11][C:2]1([CH3:10])[C:3](=[O:15])[CH2:4][CH:5]2[CH2:9][CH:1]1[C:6]2([CH3:8])[CH3:7]
Reactant: CS(C)=O
Reactant: CC1(O)CC[C@H]2C[C@]1(O)C2(C)C
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1(O)C(=O)CC2CC1C2(C)C

Procedure:
A process for producing 2-hydroxy-3-pinanone, comprising the steps of reacting α-pinene with catalytic potassium osmate in solution of pyridine, N-methylmorpholine-N-oxide and aqueous acetone to produce cis-pinanediol; and thereafter oxidizing said cis-pinanediol with DMSO activated by pyridine.SO3 and triethylamine in an appropriate solvent to produce 2-hydroxy-3-pinanone.
Reaction SMILES: S([C:5]1C=C[C:8](C)=[CH:7][CH:6]=1)([O-])(=O)=O.[F:12][C:13]1[CH:27]=[CH:26][C:16]2[C:17]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:18][O:19][C:15]=2[CH:14]=1.C(=O)([O-])[O-:29].[K+].[K+]>C(#N)C>[F:12][C:13]1[CH:27]=[CH:26][C:16]2[C:17]([CH:20]3[CH2:21][CH2:22][N:23]([CH2:5][CH2:6][C@H:7]([OH:29])[CH3:8])[CH2:24][CH2:25]3)=[N:18][O:19][C:15]=2[CH:14]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](O)CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 60 %

Procedure:
(R)-Hydroxyburyl rosylate was prepared in a manner described by Ferreira et al., Tetrahedron, 46, pp. 6311-6318, (1990). To a solution of the tosylate (8.4 g, 34.2 mmol) in acetonitrile (120 ml) was added 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (7.5 g, 34.2 mmol) followed by milled potassium carbonate (7.1 g, 51.3 mmol) at room temperature under nitrogen. The reaction mixture was warmed to reflux for 2 hours and allowed to cool to room temperature. The solids were removed via filtration through a pad of Celite and were washed with EtOAc. The combined filtrates were concentrated to give the crude product. Purification via flash column chromatography (silica gel, 10% MeOH/EtOAc) afforded 6.0 g (60%) of the desired product as an oil which solidified on standing, m.p.: 82°-84° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)CCC>>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2ccco2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 5 from (R)-3′-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-(tri-n-butylstannyl)furan. The title compound (52 mg) was obtained as a pale solid, m/z 347 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[O:11]=O>[Pt].C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10])[CH:8]=[O:11]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: O=O
Agent: [Pt]
Solvent: CC(=O)O
Product: Cc1cc(C=O)cc(C)c1O
Temperature: 75 °C
Reaction time: 4.5 h
Yield: 75 %

Procedure:
Into a 300-ml stainless steel Parr bomb is placed 25 g of 2,4,6-trimethylphenol, 2.0 g of 5 percent platinum on carbon and 75 ml of acetic acid. The bomb is pressurized to 250 psig with O2 and heated to 75° C. The bomb is held at this temperature for 4.5 hours. The material is filtered through celite and the acetic acid is removed by rotary evaporation. A 75 percent yield of 3,5-dimethyl-4-hydroxybenzaldehyde is obtained. This material is further purified using a toluene slurry wash (m.p. 111° C.-113° C.). The principle by-product is 2,6-dimethyl p-benzoquinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])([C:13]([O:15][CH3:16])=[O:14])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:23].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])([C:13]([O:15][CH3:16])=[O:14])[C:5]2[C:10]([C:11](=[O:23])[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)C1(CCC(C)C)C(OC)=CCc2ccccc21
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(CCC(C)C)C(OC)=CC(=O)c2ccccc21
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A mixture of Example 178A (0.3 g, 1.0 mmol) and pyridinium dichromate (0.98 g, 2.6 mmol) in chloroform (20 mL) was heated at reflux with a Dean-Stark trap for 18 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo. Column chromatography on silica (5%-15% ethyl acetate/hexane) afforded product as a white solid (0.18 g, 58%). 1H NMR (300 MHz, CDCl3) 8 ppm 0.40 (m, 1 H), 0.72 (m, 7 H), 1.37 (m, 1 H), 2.36 (m, 2 H), 3.61 (s, 3 H), 3.83 (s, 3 H), 5.96 (s, 1 H), 7.42 (m, 2 H), 7.56 (m, 1 H), 8.19 (d, J=7.72 Hz, 1 H); MS m/z 303.1 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[C:11]=1[C:12]#[N:13]>>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)[C:11]=1[C:12]#[N:13]
Reactant: OB(O)c1ccoc1
Reactant: N#Cc1c(N)cccc1Br
Product: N#Cc1c(N)cccc1-c1ccoc1
Yield: 74 %

Procedure:
Prepared as in Example 129c from furan-3-ylboronic acid and 2-amino-6-bromobenzonitrile in 74% yield as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 4.51 (br s, 2H), 6.66 (dd, J=1.2, 8.4 Hz, 1H), 6.78 (dd, J=1.2, 2.0 Hz, 1H), 6.82 (dd, J=1.2, 8.0 Hz, 1H), 7.31 (t, J=8.0 Hz, 1H), 7.50 (t, J=1.6 Hz, 1H), 7.95 (dd, J=1.2, 1.6 Hz, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:3]1.Cl.[CH3:23][C:24]1([NH2:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11]([NH:30][C:24]3([CH3:23])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:10]=2)[CH2:3]1
Reactant: CS(=O)(=O)c1ncc(C(N)=O)c(N[C@@H]2CCC[C@H](O)C2)n1
Reactant: CC1(N)CCOCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(Nc2ncc(C(N)=O)c(N[C@@H]3CCC[C@H](O)C3)n2)CCOCC1
Temperature: 180 °C
Yield: 10.7 %

Procedure:
4-((1R,3S)-3-Hydroxycyclohexylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (0.740 g, 2.354 mmol; synthesis described herein), 4-methyltetrahydro-2H-pyran-4-amine hydrochloride (0.892 g, 5.88 mmol), DIEA (1.645 mL, 9.42 mmol) and NMP (20 mL) were combined and heated for 1 h at 180° C. in a microwave. The solvent was concentrated under reduced pressure and the residue was purified by column chromatography (0-10% methanol in DCM) to afford 4-((1R,3S)-3-hydroxycyclohexylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)pyrimidine-5-carboxamide (88 mg, 0.252 mmol, 10.70% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.96 (br. s., 1H), 8.35 (s, 1H), 6.76 (br. s., 1H), 4.65 (d, J=4.69 Hz, 1H), 3.56 (dd, J=3.32, 6.83 Hz, 4H), 3.40-3.47 (m, 1H), 2.20-2.29 (m, 2H), 2.10 (d, J=10.93 Hz, 1H), 1.76-1.89 (m, 2H), 1.66-1.73 (m, 1H), 1.50-1.59 (m, 2H), 1.39 (s, 3H), 1.16-1.26 (m, 1H), 1.03-1.12 (m, 3H). MS (ESI) m/z 350.4 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.F[C:14]1[N:43]=[CH:42][CH:41]=[CH:40][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[C:31]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([NH:38][CH3:39])[N:33]=3)=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][CH:20]=1)=[O:17].Cl>C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCOC(C)=O.O.O>[CH3:39][NH:38][C:34]1[N:33]=[C:32]([C:31]2[C:26]([O:25][C:22]3[CH:23]=[CH:24][C:19]([NH:18][C:16](=[O:17])[C:15]4[CH:40]=[CH:41][CH:42]=[N:43][C:14]=4[NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:20][CH:21]=3)=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:37]=[CH:36][N:35]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccnc3F)cc2)n1
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccnc3Nc3ccccc3)cc2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a brown solution of aniline (0.18 ml, 1.9 mmol) in lithium bis(trimethylsilyl)amide, 1.0 m solution in tetrahydrofuran (1.9 ml, 1.9 mmol) was added 2-fluoro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)nicotinamide (0.200 g, 0.48 mmol). The mixture was sealed and heated to 70° C. After 2 h, the reaction was cooled to ambient temperature. Water was added, and the pH was adjusted with 6N HCl until slightly acidic. Add to EtOAc/water. Wash the mixture 1× with brine. The organic layer was dried over anhyd. sodium sulfate, filtered, and concentrated to give a brown solid. This material was purified by silica gel chromatography using 90/10 dichloromethane/methanol as eluent to give a yellow solid. Further purification was performed by trituration with dichloromethane and methanol to give N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-2-(phenylamino)nicotinamide as a yellow solid. MS m/z=490 [M+1]+. Calc'd for C28H23N7O2: 489.53.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH:7]1[C:17]2[CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]([CH:22]([NH2:40])[CH2:23][O:24][CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.[NH3:41]>CO>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:1]([CH2:2][NH:40][CH:22]([CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:17]=2[CH2:16][CH2:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]1=2)[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:27]=1)(=[O:6])[NH2:41]
Reactant: N
Reactant: NC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1c2ccccc2CCc2ccccc21
Agent: O=C(O)C(=O)O
Solvent: CO
Product: NC(=O)CNC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1c2ccccc2CCc2ccccc21
Reaction time: 48 h

Procedure:
A solution of the product of Example 6 in 5ml methanol saturated with ammonia was sealed in a reaction vessel and left at 0° C. for 48h. Solvent was removed in vacuo, and the residue dissolved in ethanol. Oxalic acid and water were added to give the title compound. mp 120°-122° C. 1H NMR (360MHz, DMSO-d6) 2.8-3.0 (2H, m), 3.3-3.7 (6H, m), 4.2-4.6 (4H, m), 7.00-7.4 (8H, m), 7.9 (1H, s), 7.95 (2H, s).,
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20](OB(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1.C(O)C.O>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]3)=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(OB(O)O)cc1
Reactant: CCOC(=O)c1cc2ccc(Br)cc2[nH]1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2ccc(-c3ccc(C)cc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A mixture of ethyl 6-bromo-1H-indole-2-carboxylate (2.5 g) and 4-methylphenylboric acid (1.39 g), potassium carbonate (2.58 g) and toluene/ethanol/water (90/9/9 ml) was stirred at room temperature for one hour. Into the reaction mixture was added tetrakis(triphenylphosphine)palladium (0.32 g), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to purification using column chromatography (ethyl acetate/hexane 1:5→1:2→1:1) and to recrystallization (ethyl acetate/hexane) to obtain ethyl 6-(4-methylphenyl)-1H-indole-2-carboxylate (1.92 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=4[Cl:25])[CH2:13][C@H:12]3[CH3:26])=[N:10][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:1][C:2]2[C:7]3[NH:8][C:9]([N:11]4[CH2:16][CH2:15][N:14]([C:17]5[C:18]([Cl:25])=[CH:19][C:20]([CH2:23][OH:24])=[CH:21][N:22]=5)[CH2:13][C@H:12]4[CH3:26])=[N:10][C:6]=3[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(N)c2[nH]1
Reactant: O=C(O)c1ccc(Cl)cc1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(NC(=O)c3ccc(Cl)cc3)c2[nH]1

Procedure:
{6-[(3R)-4-(7-Amino-5-trifluoromethyl-1H-benzoimidazol-2-yl)-3-methyl-piperazin-1-yl]-5-chloro-pyridin-3-yl}-methanol (221 mg, 0.5 mmol, Example 175b) and 4-chloro-benzoic acid (86 mg, 0.55 mmol, Aldrich) reacted under the conditions of Example 65 to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 579 (M+1).
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Al+3].Cl[C:6]1([OH:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]1[OH:12].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(=S)=S>[Cl:1][C:10]1[CH:11]=[C:6]([OH:13])[C:7]([OH:12])=[CH:8][C:9]=1[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:21]
Reactant: [Cl-]
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1C=CC=CC1(O)Cl
Agent: [Al+3]
Solvent: S=C=S
Product: O=C(c1ccccc1)c1cc(O)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 300 ml of carbon disulphide, 80 g (0.60 mol) of powdered aluminium trichloride and 28.9 g (0.20 mol) of 2-chloro-1,2-benzenediol is stirred for 15 minutes at room temperature and then for 1 hour at 40°. 30.9 g (0.220 mol) of benzoyl chloride are then added over a period of 10 minutes and the whole is stirred for a further 15 minutes at 40° and heated in order slowly to distil off the carbon disulphide. The dry residue is then heated to 140° (bath temperature) in the course of 1 hour and maintained at this temperature for 31/2 hours. The brown solid mass is cooled, 300 ml of 3 N hydrochloric acid and 200 ml of ethyl acetate are added and the mixture is stirred until completely dissolved. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulphate, treated with carbon and concentrated by evaporation. The dark-brown residue is dissolved in 100 ml of 1,2-dichloroethane, 105 ml of n-hexane are added and the whole is triturated until crystallisation takes place. The crystals are filtered with suction and recrystallized from dichloroethane/hexane. The (2-chloro-4,5-dihydroxyphenyl)phenylmethanone, obtained in the form of white crystals (melting point 130°-135°), can be further reacted directly.