Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:21])[CH2:6][CH2:7][O:8][CH2:9][CH:10]([NH2:20])[CH2:11][O:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:3].[C:22]([NH:32][CH2:33][CH2:34][C:35](O)=[O:36])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(N=C=NCCCN(C)C)C.CCN(CC)CC>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH:10]([NH:20][C:35](=[O:36])[CH2:34][CH2:33][NH:32][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:9][O:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:21])[CH3:19]
Reactant: CCOC(=O)CCOCC(N)COCCC(=O)OCC
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCOCC(COCCC(=O)OCC)NC(=O)CCNC(=O)OCc1ccccc1
Yield: 91.5 %

Procedure:
The compound 29 was prepared using General Procedure B with the ester hydrochloride salt (28) (1.53 g, 5.26 mmol), N-Cbz-β-alanine (1.41 g, 6.31 mmol), 1-hydrobenzotriazole (HOBt) (0.99 g, 7.36 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (1.41 g, 7.36 mmol) and Et3N (1.02 mL, 7.36 mmol) in CH2Cl2 (30 mL). Purification by flash column chromatography (on silica gel, EtOAc:n-hexane=3:1) afforded 2.39 g (92%) of the desired product (29) as a colorless liquid. 1H NMR (CDCl3): δ 7.33 (m, 5H, ArH), 6.33 (d, J=8.0 Hz, 1H, NH), 5.57 (s, 1H, NM, 5.08 (s, 2H, OCH2Ar), 4.18 (m, 1H, CH), 4.13 (q, J=7.2 Hz, 4H, CH2O), 3.70 (m, 4H, CH2O), 3.56 (m, 2H, CH2O), 3.48 (d, J=6.0, 12.0 Hz, 2H, CH2NHCO), 3.40 (m, 2H, CH2O), 2.53 (m, 4H, CH2CO), 2.42 (t, J=6.0 Hz, 2H, CH2CO), 1.25 (t, J=7.2 Hz, 6H, CH3).
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[CH2:3][C:4](=O)[C:5](=[C:11]([CH3:13])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7].O.[NH2:18][NH2:19]>C(O)(=O)C>[CH3:12][C:11]1([CH3:13])[NH:19][N:18]=[C:4]([CH2:3][C:2]([OH:1])([CH3:16])[CH3:15])[CH:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: NN
Reactant: CCOC(=O)C(C(=O)CC(C)(C)O)=C(C)C
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1C(CC(C)(C)O)=NNC1(C)C
Temperature: 180 °C
Yield: 98 %

Procedure:
500 mg of the product of Step B were added to 3 ml of acetic acid and 121 mg of hydrazine hydrate and the temperature rose spontaneously to 40° C. The acetic acid was distilled by heating the mixture up to 180° C. during which the majority of the acetic acid was removed. The mixture was cooled and water was added thereto. The mixture was extracted with chloroform and the organic phase was dried over magnesium sulfate and evaporated to dryness to obtain 520 mg of ethyl 4,5-dihydro-5,5-dimethyl-3-(2-hydroxy-2-methylpropyl)-[1H]-pyrazole-4-carboxylate in the form of a liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH:2]=1.[H][H]>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:2]1
Reactant: [H][H]
Reactant: NC(=O)c1cccc2nc(-c3ccc(-c4cccnc4)cc3)oc12
Agent: O=[Pt]=O
Solvent: O
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(C4CCCNC4)cc3)oc12
Yield: 9.8 %

Procedure:
2-(4-(Pyridin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide (100 mg, 0.35 mmol) and platinum (IV) oxide monohydrate (55 mg) in methanol (20 mL) was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by pre-HPLC. 11 mg of 2-(4-(piperidin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 11%. 1H-NMR (400 MHz, DMSO-d6) δ 1.45 (s, 3H), 1.74-1.77 (m, 2H), 1.89-1.96 (m, 2H), 2.87-2.90 (m, 1H), 3.06-3.09 (m, 2H), 7.85-7.90 (brs, 2H), 7.94-7.96 (d, J=8.0 Hz, 2H), 8.26-8.28 (d, J=8.2 Hz, 2H); LC-MS (ESI) m/z: 316 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]3[C:24]4[CH2:32][CH2:31][C:30]5[C:26](=[CH:27][N:28]([CH:33]6[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]6)[N:29]=5)[C:25]=4[S:46][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:19]=[CH:20][N:21]=[C:22]3[S:46][C:25]4[C:26]5[C:30]([CH2:31][CH2:32][C:24]=4[C:23]=23)=[N:29][N:28]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:27]=5)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc3c(n2)CCc2c-3sc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCc3nn(C4CCNCC4)cc3-5)cc2Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of tert-butyl 4-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl]piperidine-1-carboxylate 1.2 g (1.8 mmol, 1 eq) in DCM (40 mL) was added trifluoroacetic acid (4.2 mL, 30 eq). The reaction mixture was stirred at rt for 3 h. The Volatile material was evaporated and the residue was diluted with EtOAc. Sat. Na2CO3 was added until pH about 7. The layers were separated and the aqueous layer was extracted with EtOAc (3 times) and the combined organic layers were concentrated to give a brown solid (1 g, quantitative). 1H-NMR (DMSO-d6) δ 8.41 (s, 1H), 8.33 (s, 1H), 8.01 (s, 1H), 7.74 (d, 1H), 7.47 (m, 2H), 7.30 (m, 2H), 7.20 (m, 2H), 5.24 (s, 2H), 4.25 (m, 1H), 3.40 (t, 2H), 3.18 (m, 2H), 2.93 (t, 2H), 2.76 (t, 2H), 2.05 (m, 2H), 1.91 (m, 2H). LCMS RT=2.83 min; [M+H]+=561.2.
Reaction SMILES: CO.C1C[O:6][CH2:5]C1.[H-].[Na+].[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:18])[C:16]=1Br>O>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:18])[C:16]=1[O:6][CH3:5]
Reactant: C1CCOC1
Reactant: Brc1cncc(Br)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(Br)cncc1Br
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a solution of MeOH (0.115 mL, 2.85 mmol) and THF (0.5 mL) at 0° C. was added sodium hydride (60% dispersion, 114 mg, 2.85 mmol). After stirring for 15 min, Intermediate 31B (600 mg, 1.900 mmol) was added, and the resulting mixture was stirred at room temperature for 19 hours, diluted with water (3 mL) and extracted with EtOAc (2×10 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield Intermediate 31 (0.480 g, 1.798 mmol, 95% yield) as a beige color solid. MS (ES): m/z=267.9 [M+H]+. 1H NMR (400 MHz, MeOD) δ ppm 8.68 (2 H, s), 3.99 (3 H, s). Intermediate 31 was used in the synthesis of Example 185.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=3[Cl:19])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(F)cc1Cl
Product: CC(=O)c1csc(Cn2ccc(NC(=O)/C=C/c3ccc(F)cc3Cl)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-4-fluoro-phenyl)-acrylic acid. LC-MS-conditions 05: tR=0.83 min; [M+H]+=404.9.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[S:7]([Cl:10])(=[O:9])=[O:8].C(Cl)[Cl:13]>S(Cl)(Cl)(=O)=O.O.[S]Cl.[Cl-].[Cl-].[Cl-].[Al+3]>[Cl:1][C:2]1[S:3][C:4]([Cl:11])=[C:5]([Cl:13])[C:6]=1[S:7]([Cl:10])(=[O:8])=[O:9]
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Reactant: ClCCl
Agent: [Al+3]
Agent: [Cl-]
Agent: [S]Cl
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: O=S(=O)(Cl)c1c(Cl)sc(Cl)c1Cl

Procedure:
A mixture of 63 g (0.25 mol) 2,5-dichlorothien-3-yl-sulfonyl chloride, 0.5 g sulfur monochloride and 25 g sulfuryl chloride was heated under reflux. To the refluxing reaction was then added dropwise 0.5 g aluminum trichloride in 25 g sulfuryl chloride. The reaction mixture was then heated under reflux for 3 hours, cooled diluted with 400 ml cold water and cooled, with methylene chloride. The methylene chloride extracts were washed with water, saturated aqueous sodium bicarbonate, dried over magnesium sulfate and stripped to give 62 g of 2,4,5-trichlorothien-3-ylsulfonyl chloride, which crystallized from hexane as a solid, m.p. 55° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25]([OH:27])=O)[CH:22]=[CH:21][C:19]=2[N:20]=1.[NH4+].[Cl-].C[N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25]([NH2:31])=[O:27])[CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(N)=O)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
To a mixture of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid (containing 1 equivalent of DMA, 145 mg, 0.33 mmol), NH4Cl (160 mg, 3.0 mmol) and HATU (141 mg, 0.37 mmol) in DMF (2 mL) was added DIEA (0.52 mL, 388 mg, 3.0 mmol). The reaction mixture was stirred at room temperature for 3 h and heated at 60° C. for 15 h, and then evaporated under reduced pressure. The residue was purified by chromatography (333:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (29 mg, 24%). 1H NMR (DMSO-d6) δ 3.94 (s, 3H), 7.11-7.17 (2H), 7.36 (br s, 1H), 7.64 (d, J=9 Hz, 1H), 7.67 (d, J=9 Hz, 1H), 7.83-7.88 (2H), 8.05 (br s, 1H), 8.19-8.21 (2H), 8.30 (s, 1H). ESI-MS m/z 361.3 (MH+).
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:10].[CH2:11]([O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)[CH2:12][CH2:13][CH3:14]>>[CH2:11]([O:15][C:16]1[CH:21]=[C:20]([C:2]2[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[F:10])[CH:19]=[CH:18][CH:17]=1)[CH2:12][CH2:13][CH3:14]
Reactant: Nc1cc(F)c(Br)c(F)c1
Reactant: CCCCOc1cccc(B(O)O)c1
Product: CCCCOc1cccc(-c2c(F)cc(N)cc2F)c1
Yield: 62 %

Procedure:
The title compound (172 mg) was prepared from 4-bromo-3,5-difluoroaniline (200 mg, 1 mmol) and 3-butoxyphenyl boronic acid (242 mg, 1.2 mmol) as a colourless liquid.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[CH2:9][C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=1.[C:26](O)(=[O:29])[CH2:27][OH:28].Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>C(Cl)Cl>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[O:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][N:6]3[C:27](=[O:28])[CH2:26][OH:29])=[CH:25][CH:24]=1
Reactant: c1ccc2sc(Oc3ccc(CN4C[C@@H]5C[C@H]4CN5)cc3)nc2c1
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CO)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.3 %

Procedure:
To a stirred suspension of (S,S)-2-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole hydrochloride (1.6 g, 3.9 mmol), glycolic acid (600 mg, 7.8 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 g, 7.8 mmol) in CH2Cl2 (15 mL) was added Et3N (2.7 mL, 19.5 mmol). The resulting solution was then stirred at rt for 16 h. The resulting white suspension was partitioned between CH2Cl2 (600 mL) and satd. aq. NaHCO3 (100 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 5% CH3OH in CH2Cl2) afforded the title compound as a white solid (853 mg, 55%). MS (ESI): mass calcd. for C21H21N3O3S, 395.13; m/z found, 396.2 [M+H]+. 1H NMR (500 MHz, CDCl3, mixture of rotamers): 7.73 (d, J=8.5 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.41 (m, 2H), 7.38 (m, 1H), 7.32 (br m, 2H), 7.28 (m, 1H), 4.83 (br m, 0.5H), 4.21 (br d, J=14.5 Hz, 0.5H), 4.10-3.99 (br m, 2H), 3.80 (br d, J=11.7 Hz, 0.5H), 3.76 (d, J=13.8 Hz, 2H), 3.61 (br s, 1H), 3.50 (br s, 0.5H), 3.48-3.45 (m, 0.5H), 3.42 (br s, 0.5H), 3.39-3.35 (m, 0.5H), 3.23 (dd, J=9.2, 2.3 Hz, 0.5H), 3.01 (dd, J=9.7, 2.1 Hz, 0.5H), 2.90 (dd, J=9.8, 2.2 Hz, 0.5H), 2.81-2.77 (m, 0.5H), 2.58 (dd, J=9.7, 1.2 Hz, 0.5H), 2.07-2.01 (m, 0.5H), 2.00-1.96 (m, 0.5H), 1.80 (d, J=9.8 Hz, 0.5H), 1.70 (d, J=10.0 Hz, 0.5H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f36) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[N:5]=1)=[N+:2]=[N-:3].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.C([O-])(O)=O.[Na+]>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N:1]2[CH:16]=[C:15]([Si:12]([CH3:14])([CH3:13])[CH3:11])[N:3]=[N:2]2)[N:5]=1
Reactant: [N-]=[N+]=Nc1cccc(Cl)n1
Reactant: C#C[Si](C)(C)C
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: C[Si](C)(C)c1cn(-c2cccc(Cl)n2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Azido-6-chloropyridine (500 mg, 3.24 mmol) and trimethylsilylacetylene (545 μL, 3.88 mmol) were combined in t-BuOH (5.0 mL) and water (3.0 mL) CuSO4.5H2O (40 mg, 0.16 mmol) in water (1.0 mL) was added, followed by sodium ascorbate (128 mg, 0.65 mmol) in water (1.0 mL). The reaction was stirred at room temperature overnight, diluted with saturated NaHCO3, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated to a crude residue that was purified by flash chromatography (0-40% EtOAc/hexanes) to afford the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]OCC(F)(F)CCC1C=CC=CC=1>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:4][CH2:3][C:2]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)([F:11])[F:1]
Reactant: OCC(F)(F)c1ccccc1
Reactant: FC(F)(CCc1ccccc1)COCCCCCCBr
Product: FC(F)(COCCCCCCBr)c1ccccc1
Yield: 78 %

Procedure:
Obtained from Intermediate 6 (6.88 g, 43.5 mmol) by the procedure described in Intermediate 3. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (10:1) as eluent gave the title compound (10.9 g, 78%) as oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][C:16]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([CH3:28])[C:18](=[O:29])[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16]3[N:21]=[C:20]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:19]([CH3:28])[C:18](=[O:29])[CH:17]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1c(-c2ccccc2)nc(CCl)cc1=O
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1c(-c2ccccc2)nc(CN2CCN(c3ccc(O)cc3)CC2)cc1=O
Yield: 65.6 %

Procedure:
According to the same procedure as described in Example 20, starting from 3.39 g (19 mmol) of 1-(4-hydroxyphenyl)piperazine and 4.20 g (17.9 mmol) of 6-chloromethyl-3,4dihydro-3-methyl-2-phenylpyrimidin-4-one, using 1.24 g (9 mmol) of K2CO3, 4.42 g (=65.6% yield) of 4-(4-hydroxyphenyl)-1-(3,4-dihydro-3-methyl-2-phenylpyrimidin-4-on-6-ylmethyl)piperazine were obtained; melting point 206°-207° C., analysis: C22H24N4O2 (MW 376.46) calc. C 70.19 H6.43 , N 14.88; found C 69.2, H 6.4, N 14.5%. For workup of the reaction mixture, the DMF had been evaporated off in vacuo, the residue had been taken up in water/CH2Cl2 and neutralized, and the CH2Cl2 extract residue had been crystallized from CH3OH.
Reaction SMILES: C([O:5][C:6](=[O:37])[C:7]([CH3:36])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:36][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:28][CH2:29]3)=[CH:22][CH:23]=2)[N:14]=1)([CH3:8])[C:6]([OH:37])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(N3CCN(c4ccccc4)CC3)cc2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCOc2ccc(N3CCN(c4ccccc4)CC3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.2 %

Procedure:
2-Methyl-2-[(4-{2-[4-(4-phenylpiperazin-1-yl)phenoxy]ethyl}-1,3-thiazol-2-yl)thio]propionic acid tert-butyl ester (490 mg) obtained in Example 148-1 was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (330 mg) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5].C(N(CC)CC)C.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>CN(C=O)C>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]([NH:1][CH2:2][CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5])=[O:37]
Reactant: O=C=Nc1ccccc1F
Reactant: CCNC(=O)Nc1nc2ccc(C(=O)CCN)cc2s1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(C(=O)CCNC(=O)Nc3ccccc3F)cc2s1
Yield: 26 %

Procedure:
Similar to the synthesis of Example 249, a mixture of 1-(6-(3-aminopropanoyl)-2-benzothiazolyl)-3-ethylurea, triethylamine and 2-fluorophenyl isocyanate in DMF was reacted to give the desired compound 0.022 g (26%). LC/MS 430.01 (M+1); LC retention time 2.89 min.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][CH2:7][C:8]([OH:10])=O.[CH3:11][NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16](=[O:30])[C:17]1[C:22]([I:23])=[C:21]([NH2:24])[C:20]([I:25])=[C:19]([C:26]([OH:28])=[O:27])[C:18]=1[I:29].CNC(=O)[C@H](CC1C=CC=CC=1)NC(=O)C1C(I)=C(N)C(I)=C(C(O)=O)C=1I>CC(N(C)C)=O>[CH3:11][NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16](=[O:30])[C:17]1[C:22]([I:23])=[C:21]([NH:24][C:8](=[O:10])[CH2:7][O:6][CH3:5])[C:20]([I:25])=[C:19]([C:26]([OH:28])=[O:27])[C:18]=1[I:29]
Reactant: CNC(=O)CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: COCC(=O)O
Agent: CNC(=O)[C@H](Cc1ccccc1)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CNC(=O)CNC(=O)c1c(I)c(NC(=O)COC)c(I)c(C(=O)O)c1I
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At maximally 10° C., 29.0 ml. of thionyl chloride is added dropwise under agitation to 28.2 ml. of methoxyacetic acid in 100 ml. of dimethylacetamide within 40 minutes. After, at 0° C., the reaction mixture has been agitated for another 2 hours, 63.0 g. (0.1 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine methylamide (IV a), m.p. 252°-253° C. (decomposition), in 100 ml. of dimethylacetamide is added dropwise under agitation to the reaction mixture at maximally 8° C. during the course of one hour. Then, the solution is agitated overnight. After the addition of 5 ml. of water, the mixture is concentrated under vacuum, the residue is stirred with 700 ml. of water, the precipitate is vacuum-filtered, carefully washed with water, and, while still moist, reprecipitated from dilute ammonia with concentrated hydrochloric acid. After allowing the mixture to stand for some time, the acid is vacuum-filtered, washed well with water, stirred with fresh water, and, after another filtering step, dried under vacuum at 70° C.
Reaction SMILES: CC(OC(C)=O)=O.[CH3:8][S:9][C:10]1[NH:15][C:14](=[O:16])[CH:13]=[CH:12][N:11]=1.C1C(=O)N([Cl:24])C(=O)C1>CC(O)=O>[Cl:24][C:13]1[C:14](=[O:16])[NH:15][C:10]([S:9][CH3:8])=[N:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSc1nccc(=O)[nH]1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CSc1ncc(Cl)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 24 h
Yield: 48.5 %

Procedure:
To a mixture of HOAc (500 mL) and Ac2O (10 mL) was added compound 2-(methylthio)pyrimidin-4(3H)-one (40 g, 0.28 mol). The resulting mixture was heated at 80° C. for 30 min to remove any moisture. Then NCS (49 g, 0.37 mol) was added at 50˜60° C. The resulting mixture was stirred at 50˜60° C. for 24 h. The mixture was then cooled to room temperature and was poured into ice-water (500 mL). The solid formed was collected and was treated with MeOH (100 mL) at reflux. Then the solid was filtered and dried on vacuum to give title compound (24 g, 48%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[N:5][C:6]([NH2:12])=[N:7][C:8]=1[S:9]([CH3:11])=O)[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]CS.C1CCN2C(=NCCC2)CC1>COCCOC>[CH2:1]([C:3]1[C:4]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[N:5][C:6]([NH2:12])=[N:7][C:8]=1[S:9][CH2:11][CH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1)[CH3:2]
Reactant: CCc1c(-c2ccco2)nc(N)nc1S(C)=O
Reactant: SCCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CCc1c(SCCc2ccccn2)nc(N)nc1-c1ccco1
Temperature: 90 °C
Yield: 19.1 %

Procedure:
To a stirred suspension of 100 mg (0.40 mmol) 5-ethyl-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-ylamine in 5 ml DME in a pressure tube were added 230 mg (1.65 mmol) 2-pyridylethyl mercaptan and 0.18 ml (1.19 mmol) DBU and the mixture heated at 90° C. for 16 hours. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/1 then ethyl acetate) followed by trituration in ether afforded 25 mg (19%) 5-ethyl-4-furan-2-yl-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidin-2-ylamine as a beige crystalline solid. ES-MS m/e (%): 327 (M+H+, 100).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[N:14][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[N:14]2[CH:15]=[C:10]([F:9])[CH:11]=[CH:12][C:13]2=[N:16][N:17]=1
Reactant: O=C(NNc1ccc(F)cn1)c1ccccc1Cl
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1ccc2nnc(-c3ccccc3Cl)n2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.6 %

Procedure:
Hexachloroethane (3.47 g, 14.68 mmol) was added portionwise at RT to a stirred mixture of Intermediate 31a (1.95 g, 7.34 mmol), triphenylphosphine (3.85 g, 14.68 mmol), and triethylamine (4.12 mL, 29.36 mmol) in anhydrous THF (60 mL). The reaction mixture was stirred at RT for 3.5 h. The resulting suspension was filtered, washing the solid with Et2O. The filtrate was concentrated in vacuo and the resultant residue purified by FCC using SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 2M NH3 in MeOH to give the title compound (1.81 g, quantitative) as a fawn coloured solid. LCMS (Method 3): Rt 2.96 min, m/z 248 [MH+].