Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2([CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[C:3]1=[O:24].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2([CH2:5][CH2:6][NH:7][CH2:8]2)[C:3]1=[O:24]
Reactant: CN1CC(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)C2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC(c2ccccc2)C2(CCNC2)C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of tert-butyl 7-methyl-6-oxo-9-phenyl-2,7-diazaspiro[4.4]nonane-2-carboxylate (diastereomer 1, step 1) (488.3 mg, 1.48 mmol) in DCM (10 mL) was treated with TFA (2.3 mL, 29.6 mmol). The reaction mixture was stirred at room temperature for 5 hours and concentrated in vacuo. The residue was dissolved in EtOAc and washed with a saturated sodium bicarbonate solution. The organic portion was dried (MgSO4), filtered and concentrated in vacuo to afford the title compound which was used in the next step without further purification;
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:18])[N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.[C:19](=[O:22])([O-])[O-].[K+].[K+].C=O.[C:27]([O-])(O)=[O:28].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:19][OH:22])([CH2:27][OH:28])[C:7](=[O:18])[N:8]2[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)Cc2ccc(Br)cc21
Reactant: O=C([O-])[O-]
Reactant: O=C([O-])O
Agent: C=O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(=O)C(CO)(CO)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 6-bromo-2-oxoindoline-1-carboxylate (5.20 g, 16.7 mmol) in THF (100 mL) was added potassium carbonate (6.91 g, 50.0 mmol) followed by paraformaldehyde (12.00 g, 400 mmol). The resulting suspension was stirred at rt for 90 min. The suspension was cooled and poured into saturated aqueous NaHCO3 and extracted with DCM. Organic extracts were purified by column chromatography (eluting with a gradient of 0-10% MeOH in DCM) to give tert-butyl 6-bromo-3,3-bis(hydroxymethyl)-2-oxoindoline-1-carboxylate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.90 (1H, s), 7.41 (2H, br. s.), 4.97 (2H, t, J=5.18 Hz), 3.63-3.76 (4H, m), 1.57 (s, 9H).
Reaction SMILES: [Cl:1]C1C(OC)=C(COC)N=CN=1.O[C:14]1[C:19]([S:20][CH3:21])=[C:18]([CH2:22][S:23][CH3:24])[N:17]=[CH:16][N:15]=1>>[Cl:1][C:14]1[C:19]([S:20][CH3:21])=[C:18]([CH2:22][S:23][CH3:24])[N:17]=[CH:16][N:15]=1
Reactant: COCc1ncnc(Cl)c1OC
Reactant: CSCc1ncnc(O)c1SC
Product: CSCc1ncnc(Cl)c1SC

Procedure:
The preparation was analogous to the synthesis of the starting compound 4-chloro-5-methoxy-6-methoxymethylpyrimidine, using 42 g of 4-hydroxy-5-methylthio-6-methylthiomethylpyrimidine
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37]C(C)(C)C)=O)[CH2:30][CH2:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:42](O)(C(F)(F)F)=O.C(N(CC)CC)C.C(OC(=O)C)(=O)C.[ClH:63]>C(Cl)Cl>[ClH:63].[ClH:63].[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:34][CH2:33][CH2:32][N:31]([C:35](=[O:37])[CH3:42])[CH2:30][CH2:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CCCN(C(=O)OC(C)(C)C)CC2)ns1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3cccnc3C)n2)CC1
Yield: 95.2 %

Procedure:
tert-Butyl 4-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)azepane-1-carboxylate (70.4 mg, 0.119 mmol) was dissolved in CH2Cl2 (2 mL) and TFA (2 mL) was added. After 10 minutes the reaction was concentrated and placed on high vacuum pump to remove excess TFA. The residue was dissolved in CH2Cl2 (2 mL) and triethylamine (82.3 μL, 0.591 mmol) and acetic anhydride (16.7 μL, 0.177 mmol) were added. After 10 minutes the reaction was partitioned between saturated aqueous NaHCO3 and EtOAc, dried over sodium sulfate, filtered and concentrated. The residue was purified over silica gel (10% methanol in EtOAc) to afford 1-(4-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)azepan-1-yl)ethanone dihydrochloride (68.2 mg, 0.112 mmol, 95.2% yield) as a solid after HCl salt formation. Mass spectrum (apci) m/z=534.2 (M+H-2HCl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18](OC)=[CH:17][CH:16]=1.ClC1C=CC(O)=CC=1[N+]([O-])=O>>[CH2:14]([O:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: COc1ccc(CCl)cc1
Agent: O=[N+]([O-])c1cc(O)ccc1Cl
Product: O=[N+]([O-])c1cc(OCc2ccccc2)c(Cl)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 10C substituting benzyl bromide and the product from Example 73C for 1-chloromethyl-4-methoxy-benzene and 4-chloro-3-nitro-phenol (0.72 g, 79%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:29])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)C.S(=O)(=O)(O)O>CO>[CH3:1][O:3][C:4](=[O:30])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:29])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[S:9][CH:10]=1
Reactant: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)n1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)n1
Yield: 53.3 %

Procedure:
A solution of {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (prepared as in Example 23, 160 mg, 0.37 mmol) in methanol (10 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was heated under reflux for 68 h. The reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 hexanes/ethyl acetate) afforded {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid methyl ester (82.3 mg, 53.3%) as a pale yellow oil: FAB-HRMS m/e calcd for C20H23N3O5S (M+H)+ 418.1436, found 418.1424.
Reaction SMILES: [CH:1](OC)=[O:2].[CH3:5][O:6][C:7]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]2[C:8]=1[C:9](=[O:31])[NH:10][C:11]([C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=1)=[N:12]2>>[CH3:5][O:6][C:7]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]2[C:8]=1[C:9](=[O:31])[NH:10][C:11]([C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH2:26][CH2:27][N:28]([CH:1]=[O:2])[CH2:29][CH2:30]3)=[CH:21][CH:20]=1)=[N:12]2
Reactant: COC=O
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C=O)CC4)cc3)nc2c1
Yield: 99 %

Procedure:
A mixture of methyl formate (75 mL) and 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.300 g, 0.82 mmol) was heated at reflux for 48 hours. The mixture was concentrated, and purified by silica gel chromatography, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH, to afford the title compound (0.320 g, 99%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 11.79 (br s, 1H), 8.10-8.19 (m, 3H), 7.06 (d, J=9.1 Hz, 2H), 6.69 (d, J=2.3 Hz, 1H), 6.48 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.46-3.59 (m, 4H), 3.32-3.38 (m, 4H). APCI MS m/z 393 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[CH3:12].C[Sn](C)(C)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[CH3:12][CH:7]1[C:8]2[C:3](=[C:2]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][NH:6]1
Reactant: CC1NCCc2c(Br)cccc21
Reactant: C[Sn](C)(C)c1ccccn1
Product: CC1NCCc2c(-c3ccccn3)cccc21

Procedure:
In close analogy to the procedure described above, 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with 2-trimethylstannyl-pyridine to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:4][NH:5][CH:6]=1.[CH2:11]=[O:12]>C(N(CC)CC)C.CC(C)=O>[Br:1][C:2]1[C:3]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:4][N:5]([CH2:11][OH:12])[CH:6]=1
Reactant: CC(C)(C)c1n[nH]cc1Br
Reactant: C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nn(CO)cc1Br
Temperature: 130 °C
Reaction time: 7 h
Yield: 105.2 %

Procedure:
The mixture of 3.14 g of 4-bromo-3-t-butyl-1H-pyrazole, 0.93 g of paraformaldehyde and 0.11 g of triethylamine was stirred at 130° C. for 7 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. Hexane was added to the residue obtained by concentration of the filtrate under reduced pressure, as a result, a crystal was formed. The crystal was collected to obtain 3.79 g of 4-bromo-3-t-butyl-1H-pyrazole-1-ylmethanol.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[CH3:32][C:33]([CH3:35])=O.CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:33]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)([CH3:35])[CH3:32]
Reactant: CC(C)=O
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)N1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cc2nccn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture of 100 mg (0.24 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo [1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 5 mL chloroform was treated with 0.2 mL (2.4 mmol) acetone, 45 mg (0.72 mmol) NaBH3(CN) and 1 mL methanol consequently. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a yellow solid. MS (ES+):454 (M+H)+.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([C:27]2[N:28]=[CH:29][NH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O.C(N(CC)CC)C>[C:21]1([C:27]2[N:28]=[CH:29][N:30]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:31]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: c1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7.6 mmol of triphenylmethyl chloride in 150 ml of dimethylformamide are added, under an argon atmosphere, to a solution of 6.9 mnmol of 4-phenyl-1H-imidazole in 50 ml of dimethylformamide and 10 ml of triethylamine. The solution is stirred for 4 hours at ambient temperature. After the addition of water, the precipitate obtained is triturated in ethyl ether, filtered and then dried, enabling the product obtained to be isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH2:19])[CH:15]=[N:16][CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:20][C:21]([F:28])([F:27])[CH2:22][S:23](Cl)(=[O:25])=[O:24]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH:19][S:23]([CH2:22][C:21]([F:28])([F:27])[F:20])(=[O:25])=[O:24])[CH:15]=[N:16][CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1c(-c2cncc(CN)c2)cc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)CC(F)(F)F
Product: Cn1c(-c2cncc(CNS(=O)(=O)CC(F)(F)F)c2)cc2ccc(Cl)cc21

Procedure:
C-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine (Example 205a) and 2,2,2-trifluoro-ethanesulfonyl chloride are processed according to the method described in Example 186f to give 2,2,2-trifluoro-ethanesulfonic acid [5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide. 1H NMR (400 MHz, MeOD) δ ppm 3.75 (d, J=0.6 Hz, 3H), 4.16-4.28 (m, 2H), 4.44 (s, 2H), 6.67 (s, 1H), 7.07 (ddd, J=8.4, 1.8, 0.8 Hz, 1H), 7.50 (s, 1H), 7.55 (d, J=8.3 Hz, 1H), 8.04 (d, J=0.6 Hz, 1H), 8.58 (d, J=1.4 Hz, 1 H), 8.68 (d, J=1.6 Hz, 1H). HRMS (ESI) m/z 418.06107 [(M+H)+ Calcd for C17H16N3O2F3SCl: 418.06039].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[CH:2].C(N(CC)CC)C.Cl[C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][N:24]=[C:23]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)[N:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:25]2[C:26]([C:27]([F:29])([F:28])[F:30])=[CH:21][N:22]=[C:23]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([N:38]4[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]4)=[CH:36][CH:37]=3)[N:24]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1cccc(C(=O)OC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C#Cc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Temperature: 120 °C
Yield: 57.3 %

Procedure:
To a nitrogen de-gassed solution of methyl 3-ethynylbenzoate (I31) (0.105 g, 0.655 mmol) in dry DMF (6 mL) were added triethylamine (0.308 mL, 2.18 mmol) followed by tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I3) (0.250 g, 0.546 mmol), triphenylphosphine (0.021 g, 0.082 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.038 g, 0.055 mmol) and Cu(I)I (0.016 g, 0.082 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes, concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I32) (0.182 g, 57% yield) as an orange solid; 1H NMR (400 MHz, d6-DMSO) δ 10.28 (br s, 1H), 8.78 (s, 1H), 8.16-8.03 (m, 2H), 7.90 (d, J=7.8 Hz, 1H), 7.69 (t, J=7.9 Hz, 1H), 7.55 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 3.90 (s, 3H), 3.50-3.41 (m, 4H), 3.11-2.99 (m, 4H), 1.42 (s, 9H). LCMS Method C: rt 6.82 min; m/z 582.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl.[F:11][C:12]1([F:16])[CH2:15][NH:14][CH2:13]1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[Cl:9][C:4]1[CH:5]=[C:6]([I:8])[CH:7]=[C:2]([N:14]2[CH2:15][C:12]([F:16])([F:11])[CH2:13]2)[N:3]=1
Reactant: FC1(F)CNC1
Reactant: Clc1cc(I)cc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC1(F)CN(c2cc(I)cc(Cl)n2)C1
Temperature: 90 °C
Yield: 49.7 %

Procedure:
To a suspension of 2,6-dichloro-4-iodopyridine (1 g, 3.65 mmol) and 3,3-difluoroazetidine hydrochloric acid salt (0.497 g, 3.83 mmol) in 25 mL tetrahydrofuran was added diisopropylethylamine (0.797 ml, 4.56 mmol). The reaction mixture was heated at 90° C. for 16 hours. Further addition of another equivalent of amine and base was performed, and the suspension was heated at 100° C. for several hours, and then cooled, diluted with ethyl acetate, washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel using flash chromatography (5% to 20% ethyl acetate/hexane) to afford 0.6 g of the title compound. MS (DCI+) m/z 331.0 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8](O[K])[CH3:9].I[CH2:13][CH2:14][CH2:15][CH2:16]I>C(O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[S:1][CH2:13][CH2:14][CH2:15][CH2:16][S:1][C:2]1[N:7]=[CH:9][CH:8]=[CH:4][N:3]=1
Reactant: CCO[K]
Reactant: ICCCCI
Reactant: Sc1ncccn1
Solvent: CCO
Product: c1cnc(SCCCCSc2ncccn2)nc1
Yield: 86 %

Procedure:
20 mmole of 2-mercaptopyrimidine was dissolved in 20 ml of ethanol with stirring. 20 mole of EtOK (24 weight % in ethanol) was added to the solution, stirred for 5 minutes. Then, about 10 mmole of 1,4-diiodobutane was added, and stirred overnight. The white precipitate was removed by filtration, the solvent in the filtrate was removed in vacuum. The obtained solid was dissolved in CH2Cl2, and separated with a Si gel column (solvents: 1 ethylacetate/1 hexane in volume). Yield: 86%. 1H NMR (CDCl3) of PyrC4: δ(ppm) 8.50 (4H, d, JH-H=4.77), 6.94 (2H, t, JH-H=4.77), 3.20 (4H, t, JH-H=6.93), and 1.91 (4H, t, JH-H=6.93).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[CH:18](=O)[CH3:19].[BH4-].[Na+]>O>[NH:1]([CH2:18][CH3:19])[C@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:5]=1
Reactant: CC(C)(C)c1cc(C[C@H](N)C(N)=O)ccc1O
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCN[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O
Yield: 72.3 %

Procedure:
A mixture of Tyr(3-tBu)-NH2 (1.6 g, 6.8 mmol) and acetaldehyde (7.6 ml, 0.14 mol) was stirred under cooling with ice for 10 min. The reaction mixture was concentrated under reduced pressure under cooling with ice; the thus obtained residue was mixed with methanol (34 ml) and then under cooling with ice with sodium borohydride (0.28 g, 7.4 mmol) and stirred at the same temperature for 15 min. The resultant was mixed with water and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (CHCl3:MeOH=20:1), giving N-Et-Tyr(3-tBu)-NH2 (T7) (1.3 g, 73%).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][S:8][C:9]1[N:14]=[C:13]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][N:10]=1.[OH2:26]>CO>[CH3:7][S:8]([C:9]1[N:14]=[C:13]([C:15]2[N:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][N:10]=1)(=[O:1])=[O:26]
Reactant: O
Reactant: O=S([O-])OO
Reactant: CSc1nccc(-c2ccnn2-c2ccccc2)n1
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)c1nccc(-c2ccnn2-c2ccccc2)n1
Reaction time: 20 h

Procedure:
A solution of oxone (521 mg, 0.850 mmol, 1.30 equiv) in water (10 mL) was added to a solution of 2-(methylthio)-4-(1-phenyl-1H-pyrazol-5-yl)pyrimidine (1-5, 175 mg, 0.652 mmol, 1 equiv) in methanol (20 mL) at 23° C., and the resulting mixture was stirred for 20 hours. The reaction mixture was partitioned between brine and ethyl acetate (3×75 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 2-(methylsulfonyl)-4-(1-phenyl-1H-pyrazol-5-yl)pyrimidine (1-7) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH:11]([CH3:15])[C:12]([OH:14])=O)=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH:23]=1>>[C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH:11]([CH3:15])[C:12]([NH:32][CH2:31][CH2:30][CH2:29][CH2:28][C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)=[O:14])=[C:6]([CH2:18][CH2:19][CH3:20])[C:5]=1[OH:21])(=[O:3])[CH3:2]
Reactant: NCCCCc1cccnc1
Reactant: CCCc1c(OCCC(C)C(=O)O)ccc(C(C)=O)c1O
Product: CCCc1c(OCCC(C)C(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
4-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-methyl butanoic acid was allowed to react with 3-pyridine butanamine according to procedure A and the product was purified by HPLC to give 4-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-methyl-N-[4-(3-pyridinyl)butyl]butanamide, the title compound as an oil in 89% yield.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[C:24](I)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:29]1[CH2:33][CH2:32][O:31][CH:30]1[C:34]1[O:38][C:37]([Sn](CCCC)(CCCC)CCCC)=[CH:36][CH:35]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[C:24]([C:37]4[O:38][C:34]([CH:30]5[O:31][CH2:32][CH2:33][O:29]5)=[CH:35][CH:36]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1-c1ccc(C2OCCO2)o1
Temperature: 100 °C
Reaction time: 4 h
Yield: 59.4 %

Procedure:
Synthesized according to Procedure B from a solution of (4-benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride (508 mg, 1 mmole), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (645 mg, 1.5 mmole), diisopropylethyl amine (650 mg, 5 mmole), and dichlorobis(triphenylphosphine) palladium (140 mg, 0.2 mmole) in 6 ml of DMF under nitrogen was stirred at 100° C. (oil bath temperature) for 4 hours. The cooled reaction mixture was extracted with water (100 ml) and ethyl acetate (100 ml). The organic phase was washed with brine (100 ml). The aqueous layers were combined and washed with additional ethyl acetate (100 ml). The organic layers were combined, dried with MgSO4, filtered and concentrated to a residue. The residue was chromatographed on silica gel with a methanol-chloroform mixture. Fractions were collected, combined, and concentrated. The resultant solid was suspended in dichloromethane (10 ml) and diethyl ether was added facilitate precipitation. The solid was filtered and dried under vacuum at room temperature to yield a yellowish solid 287 mg (59%). 1H NMR (400 MHz, DMSO-d6) δ: 10.1(s, 1H), 8.85(d, 1H), 8.45(s, 1H), 7.6(m, 3H), 7.44(d, 2H), 7.38(m, 2H), 7.31 (m, 1H), 7.03(m, 2H), 6.94(m, 1H), 6.74(d, 1H), 6.01 (s, 1H), 5.1(s, 2H), 4.10(m, 2H), 3.96(m, 2H). ESI-MS m/z 482(M−1).
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:11]1[C:16]([Br:17])=[CH:15][N:14]=[CH:13][C:12]=1Br)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:20]#[N:21].O>CN(C=O)C>[CH2:1]([O:8][CH:9]([C:11]1[C:12]([C:20]#[N:21])=[CH:13][N:14]=[CH:15][C:16]=1[Br:17])[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[Cu]C#N
Reactant: CC(OCc1ccccc1)c1c(Br)cncc1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(OCc1ccccc1)c1c(Br)cncc1C#N
Temperature: 150 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
To a solution of 4-(1-benzyloxy-ethyl)-3,5-dibromo-pyridine (400 mg, 1.1 mmol) in DMF (5 mL) is added copper cyanide (116 mg, 1.3 mmol). The mixture is heated and stirred at 150° C. for 3 h, then stirred at room temperature for 16 h. H2O is added and the mixture is extracted with EtOAc. The organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography provides 225 mg of 4-(1-benzyloxy-ethyl)-5-bromo-nicotinonitrile.