Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][NH2:14])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:15](OCC)(OCC)OCC.CS(O)(=O)=O.O1CCCC1>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[O:12][CH:15]=[N:14][N:13]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(OCC)OCC
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cc2nnco2)cc1

Procedure:
A mixture of 2-(4-nitrophenyl)acetohydrazide (2.50 g), triethyl orthoformate (5.69 g), methanesulfonic acid (0.25 g) and tetrahydrofuran (50 mL) was heated under reflux for 1 hr. The reaction mixture was diluted with ethyl acetate. The mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 2-(4-nitrobenzyl)-1,3,4-oxadiazole was obtained as pale-yellow crystals (1.92 g, yield 73%) from a fraction eluted with hexane-ethyl acetate (3:1-1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 104-105° C.
Reaction SMILES: [CH3:1][C:2]1(C)CC(O)CC(C)(C)N1.[CH3:12][N:13]1[C:18]([CH3:20])([CH3:19])[CH2:17][CH:16]([C:21]([O:23][CH3:24])=[O:22])[CH2:15][C:14]1([CH3:26])[CH3:25]>>[CH2:1]=[CH2:2].[CH3:12][N:13]1[C:18]([CH3:20])([CH3:19])[CH2:17][CH:16]([C:21]([O:23][CH:24]=[CH2:1])=[O:22])[CH2:15][C:14]1([CH3:26])[CH3:25]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: COC(=O)C1CC(C)(C)N(C)C(C)(C)C1
Product: C=C
Product: C=COC(=O)C1CC(C)(C)N(C)C(C)(C)C1

Procedure:
The above-named copolymer is prepared by the general procedure of Example 1 by substituting for the 2,2,6,6-tetramethylpiperidin-4-ol an equivalent amount of methyl 1,2,2,6,6-pentamethylpiperidine-4-carboxylate and reacting with an ethylene/vinyl acetate copolymer (75/25).
Reaction SMILES: [CH:1]([O:3][C:4](=[O:19])[O:5][CH2:6][CH:7]1[CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8]1)=[CH2:2].Cl[C:21]([O:23][CH:24]=[CH2:25])=[O:22]>ClCCCl>[CH:24]([O:23][C:21]([N:9]1[CH2:10][CH2:11][CH:7]([CH2:6][O:5][C:4]([O:3][CH:1]=[CH2:2])=[O:19])[CH2:8]1)=[O:22])=[CH2:25]
Reactant: C=COC(=O)Cl
Reactant: C=COC(=O)OCC1CCN(Cc2ccccc2)C1
Solvent: ClCCCl
Product: C=COC(=O)OCC1CCN(C(=O)OC=C)C1
Yield: 82.7 %

Procedure:
A solution of carbonic acid 1-benzyl-pyrrolidin-3-ylmethyl ester vinyl ester (440 mg, 1.68 mmol) and vinyl chloroformate (0.30 mL, 3.5 mmol) in 1,2-dichloroethane (10 mL) was heated to reflux for 6 h then concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (20% EtOAc/hexanes) gave a yellow oil (335 mg, 83%). 1H NMR (CDCl3) δ 1.68-1.85 (m, 1H), 2.03-2.16 (m, 1H), 2.59-2.71 (m, 1H), 3.26 (m, 1H), 3.41-3.52 (m, 1H), 3.55-3.72 (m, 2H), 4.11-4.28 (m, 2H), 4.45 (dd, 1H, J=6.3, 1.5 Hz), 4.61 (m, 1H), 4.78 (dd, 1H, J=14, 1.5 Hz), 4.94 (m, 1H), 7.08 (m, 1H), 7.22 (dd, 1H, J=14, 6.3 Hz).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:12]2[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1>C(O)(=O)C.C(O)C.[Fe]>[C:1]1([CH3:22])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:12]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: Cc1cc(C)c(Nc2nc3cccc([N+](=O)[O-])c3s2)c(C)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C)c(Nc2nc3cccc(N)c3s2)c(C)c1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To a solution of 1.8 g (5.7 mmol) of N2-mesityl-7-nitro-1,3-benzothiazol-2-amine in 7.2 mL of glacial acetic acid and 25 mL of ethanol was added 1.8 g (32 mmol) of iron powder. The resulting solution was heated at reflux for 18 h before being cooled to room temperature. The slurry was filtered and the filtrate was concentrated to a brown solid. The solid was slurried in water, collected by filtration and purified by flash chromatography eluting with a 33% hexanes/ethyl acetate mixture to give 0.9 g (55%) of the title compound as a tan powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([CH:19]5[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21][CH:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:32]([F:35])([F:34])[F:33])[CH:4]=1>CC#N>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C:19]5[CH2:24][NH:23][CH2:22][CH2:21][C:20]=5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:32]([F:35])([F:33])[F:34])[CH:4]=1
Reactant: COc1ccc(-c2cc3c4c(c2)C2CN(C(=O)OC(C)(C)C)CCC2N4CCC3)c(C(F)(F)F)c1
Solvent: CC#N
Product: COc1ccc(-c2cc3c4c(c2)c2c(n4CCC3)CCNC2)c(C(F)(F)F)c1
Yield: 97 %

Procedure:
The title compound (0.60 g, 98%) was prepared by the general method of Example 312, step B from tert-butyl 2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,8,9,10,11-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (0.78 g, 1.6 mmol) as a white foam. 1H NMR (CDCl3, 300 MHz) δ 2.20-2.30 (m, 2H), 2.79 (t, J=5.4 Hz, 2H), 2.90-3.20 (m, 3H), 3.30 (t, J=5.8 Hz, 2H), 3.91 (s, 3H), 3.98 (t, J=5.8 Hz, 2H), 4.12 (s, 2H), 6.84 (s, 1H), 7.07 (dd, J=2.5, 8.4 Hz, 1H), 7.18 (s, 1H), 7.25-7.35 (m, 2H) ppm. MS (ESI): 428 (base, M+CH3CN).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[CH2:7][C@H:8]1[N:15]([S:16]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[N:27]=[CH:26][CH:25]=[CH:24]3)(=[O:18])=[O:17])[CH2:14][C:13]2[CH:29]=[CH:30][CH:31]=[CH:32][C:12]=2[CH2:11][O:10][CH2:9]1)(=[O:3])[CH3:2].O=P(Cl)(Cl)Cl>O>[CH3:2][C:1]1[O:3][C:6]([CH2:7][C@H:8]2[N:15]([S:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)(=[O:18])=[O:17])[CH2:14][C:13]3[CH:29]=[CH:30][CH:31]=[CH:32][C:12]=3[CH2:11][O:10][CH2:9]2)=[N:5][N:4]=1
Reactant: CC(=O)NNC(=O)C[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1nnc(C[C@@H]2COCc3ccccc3CN2S(=O)(=O)c2cccc3cccnc23)o1
Temperature: 110 °C
Reaction time: 3 h
Yield: 42.3 %

Procedure:
A mixture of compound 27a (100 mg, 0.21 mmol) and POCl3 (3 mL) was stirred at 110° C. for 3 h. The mixture was taken up in H2O (10 mL) and extracted with DCM (30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by Prep-TLC to give the pure compound 27 (40 mg, 42% yield). LCMS (m/z): 451.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][S@@](C(C)(C)C)=O)([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.CO>Cl.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([NH2:30])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1
Reactant: CC(C)(C)[S@@](=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Yield: 89.9 %

Procedure:
(R)—N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (234 mg, 0.442 mmol) was stirred in 4N HCl in dioxane (1.5 mL) and MeOH (1.5 mL) at room temperature under Ar for 10 min. The reaction mixture was concentrated, and then purified by flash chromatography (silica gel, hexanes/EtOAc) to give (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (169 mg, 90%). LC-MS (ESI) 409.16 (M-NH3+H), retention time=3.26 minutes (0-100% MeOH in H2O with 0.1% TFA in 4-min run); Analytical HPLC: 2.52 minutes (0-100% CH3CN in H2O with 0.1% TFA in 4-min run); 1H NMR (400 MHz, CD3OD) δ ppm 7.29-7.50 (m, 2H), 6.87-7.22 (m, 8H), 6.77 (d, J=6.15 Hz, 2H), 6.04-6.48 (m, 1H), 3.57 (s, 2H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1.O.[NH2:33][NH2:34]>CN(C=O)C>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[O:27][CH3:28])[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:34][N:33]=1
Reactant: COc1ccc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc1OC
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1OC
Yield: 80.3 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(3,4-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (200 mg, 0.48 mmol, prepared in Synthetic Example 22) in DMF (5 ml) was added hydrazine monohydrate (80%, 100 μl, 2.50 mmol, 5.2 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(3,4-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (159 mg, 80%).
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[C:46](N1C=CN=C1)(N1C=CN=C1)=[S:47]>O1CCCC1>[SH:47][C:46]1[NH:45][C:44]2[CH:43]=[CH:42][CH:41]=[C:3]([C:4]([NH:6][C:7]3[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])=[O:12])=[CH:9][C:8]=3[O:39][CH3:40])=[O:5])[C:2]=2[N:1]=1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(S)nc12
Reaction time: 24 h
Yield: 81.7 %

Procedure:
To a solution of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (110 mg) in anhydrous tetrahydrofuran (2 ml) was added 1,1′-thiocarbonyldiimidazole (48 mg) under nitrogen at ambient temperature and stirred at same temperature for 1 day. After being concentrated in vacuo, the residue was diluted with a mixture of chloroform and saturated sodium bicarbonate aqueous solution and the organic layer was separated. The organic layer was washed with water and brine and the solution was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by preparative thin-layer chromatography (ethyl acetate-methanol=1:1) to give 4-(2-mercapto-1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (96 mg) as a powder.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:15][CH2:16][C:17]([NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=O>CCOCC>[Cl-:15].[Cl:15][CH2:16][C:17]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[CH2:21][CH2:20][NH+:19]=1
Reactant: COc1cccc(CCNC(=O)CCl)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOCC
Product: COc1ccc2c(c1)CC[NH+]=C2CCl
Product: [Cl-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Two equiv. of P2O5 (12.9 g) was boiled in xylenes (180 mL) as a 0.25 M solution. The crude product from Step 1 above was also first boiled in xylenes (45 mL) to make a 0.5 M solution, and it was then added dropwise via an addition funnel to the P2O5 solution. The mixture was stirred and heated at reflux for 1 h. The reaction was then cooled to RT and the xylenes decanted off at this point. The flask was then placed in an ice bath and stirred while ice, water, EtOAc, and finally 4 M NaOH were added carefully until the pH>12. Reaction was kept <25° C. until pH=12 was reached. The reaction was then extracted with EtOAc (3×). The combined organic extracts were dried over MgSO4 and concentrated to give a dark solution. This was cooled in an ice bath while 400 mL of cold Et2O was added followed by 100 mL of cold HC1/Et2O. A precipitate formed and was filtered away, washing with Et2O. The solid was immediately placed on high vac for 2 h to give the target product as a colored foamy solid. This crude product was directly used in the next step without further purification.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9](=[O:12])([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[C:16]1([CH2:15][O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:12][CH2:9][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1O
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(COc2ccccc2OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
To a solution of 1,2-dihydroxybenzene (60 g, 0.54 mol) in 240 mL acetone, potassium carbonate (220 g, 1.59 mol) was added. After heating to reflux, benzylbromide (256.6 g, 1.5 mol) was added dropwise. The mixture was heated to reflux overnight, cooled, and poured onto 1 liter ice-water. The resulting precipitate (title compound) was filtered off with suction, washed with water, and dried in vacuo.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OCC3C=CC=CC=3)=O)=[N:9][C:10]=2Br)[CH:5]=[CH:6][N:7]=1.[CH3:27][O:28][C:29]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[CH:40][C:30]=1[C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)=[O:32]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][C:10]=2[C:42]2[CH:41]=[CH:40][C:30]([C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[O:32])=[C:29]([O:28][CH3:27])[CH:43]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(Br)c12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C(=O)Nc1ccccn1
Product: COc1cc(-c2nc([C@@H]3CCCN3)n3ccnc(N)c23)ccc1C(=O)Nc1ccccn1
Yield: 56.6 %

Procedure:
This intermediate was prepared, in an analogous manner as described for intermediate 2, from (S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Intermediate 1e) and 2-methoxy-N-(pyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (intermediate 18) to afford the title compound (175 mg, 56.6%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[CH:7]=1.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C(C)(C)C)=O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C[N:36]1CCCC1=O>C(OCC)C.[Cu]Cl>[CH:11]([C:8]1[N:6]2[CH:7]=[C:2]([O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH2:36])=[O:24])=[CH:17][CH:16]=3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1nnc2ccc(I)cn12
Reactant: CN1CCCC1=O
Reactant: CC(C)(C)OC(=O)Cc1ccc(O)cc1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Product: CC(C)c1nnc2ccc(Oc3ccc(CC(N)=O)cc3)cn12
Temperature: 25 °C
Yield: 8 %

Procedure:
A solution of Example 23 step a (430 mg, 1.5 mmol), tert-butyl 2-(4-hydroxyphenyl)acetate (WO2008/024746, 621 mg, 3 mmol), cesium carbonate (978 mg, 3 mmol), copper (I) chloride (74 mg, 0.75 mmol) and 2,2,6,6-tetramethylheptanedione (28 mg, 0.15 mmol) in N-methylpyrrolidinone (2 mL) was heated at 115° C. for 1 h. The reaction mixture was left to cool to RT, diluted with diethyl ether and washed with water. The aqueous layer was extracted with EtOAc and DCM and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The resulting oil was purified on a SCX-2 cartridge eluting with EtOAc, MeOH then 1N ammonia in MeOH. The ammonia fractions were concentrated in vacuo and purified twice by FCC (DCM/MeOH containing NH3 10/0 to 9/1 then EtOAc) to provide the title compound as an orange gum (44 mg, 8%). LCMS (Method 8): Rt 4.30 min, m/z 368 [MH+].
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].C1(C=C(O)C=C(O)C=1)O.[CH2:14]([O:16][C:17](=[O:23])[CH:18](I)[CH:19]([CH3:21])[CH3:20])[CH3:15]>CN(C)C=O>[CH2:14]([O:16][C:17](=[O:23])[CH:18]([N+:1]([O-:3])=[O:2])[CH:19]([CH3:21])[CH3:20])[CH3:15]
Reactant: O=N[O-]
Reactant: CCOC(=O)C(I)C(C)C
Agent: Oc1cc(O)cc(O)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(C)C)[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To an ice cooled solution of 5.31 g sodium nitrite and 8 g dried phloroglucinol in 70 ml dimethyl formamide is added a solution of 11.3 g 2-iodo-3-methyl-butyric acid ethyl ester in 30 ml dimethyl formamide. The solution is allowed to warm up to room temperature and is stirred over night. The solvent is removed at reduced pressure. The residue is dissolved in ethyl acetate and washed with water. The organic layer is dried and the solvent is removed. The title compound is obtained as an oil. MS: m/z (M+)=176.1
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=4)[CH:17]=3)[S:12][C:11]([CH3:33])([CH3:32])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CCO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][C:21]4[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=4)[CH:17]=3)[S:12][C:11]([CH3:32])([CH3:33])[CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)S3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccc(C2=CC(C)(C)Sc3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of ethyl 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoate (940.0 mg, 2.08 mmol) in 10.0 mL THF and 5.0 mL EtOH was added NaOH (416.0 mg, 10.4 mmol, 5.2 mL of a 2M aqueous solution). The resulting solution was stirred overnight at room temperature. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 786.0 mg (89%) of 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoic acid as a colorless solid. 1H NMR (300 MHz, d6-acetone) δ: 8.01 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.5 Hz), 7.42 (2H, m), 7.29 (2H, m), 7.22 (3H, m), 5.94 (1H, s), 2.69 (2H, q, J=7.7 Hz), 1.47 (6H, s), 1.25 (3H, t, J=7.7 Hz). This compound, the final desired product, was termed AGN 194310.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:24])=[N:17][C:18]([N:21]([CH3:23])[CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]([OH:28])[CH2:26][CH3:27])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P)CCC.[F:52][C:53]([F:57])([F:56])[CH2:54]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[N:17][C:16]=4[CH3:24])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]([O:28][CH2:54][C:53]([F:57])([F:56])[F:52])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(N(C)C)nc1C
Reactant: OCC(F)(F)F
Agent: CCCCP
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCC(OCC(F)(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(N(C)C)nc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.9 %

Procedure:
A mixture of 1-{9-chloro-1-[6-(dimethylamino)-2-methylpyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}propan-1-ol (71.1 mg, 0.178 mmol), 1,1′-(azodicarbonyl)dipiperidine (89.7 mg, 0.355 mmol) and n-butylphosphine (71.8 mg, 0.355 mmol) in tetrahydrofuran (2.0 mL) was stirred at room temperature for 15 min. 2,2,2-Trifluoroethanol (178 mg, 1.78 mmol) was added to the mixture, and the mixture was stirred at 60° C. for 7 hr. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with a 35-80% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (30.8 mg, 0.0639 mmol, 36%)
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:29]([NH:31][CH2:32][CH2:33][S:34][C:35](=[O:37])[CH3:36])=[O:30])[CH2:8][S:9]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(N[C@H](C(NCCSC(=O)C)=O)CS)(=O)C.C(Cl)Cl.CCOCC>C(Cl)(Cl)Cl>[C:1]([NH:6][C@H:7]([C:29]([NH:31][CH2:32][CH2:33][S:34][C:35](=[O:37])[CH3:36])=[O:30])[CH2:8][SH:9])(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(=O)SCCNC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)C(C)C
Agent: CC(=O)N[C@@H](CS)C(=O)NCCSC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC(=O)SCCNC(=O)[C@H](CS)NC(=O)C(C)C
Yield: 70 %

Procedure:
This compound is obtained by the S-detritylation of 14 (2.56 mmol). The protocol used is the same as that described in example 1 for the synthesis of I-152. After the various treatments, a gum is collected, which gum is purified by flash chromatography on a silica gel column (eluent: CH2Cl2/ether 30%). I-203 is isolated in the form of white solid with a yield of 70%. Rf CH2Cl2/ether, 5/5): 0.44. M.p.=117-120° C. [α]D20=−36.5° (c 1.04, CHCl3).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:16]([NH:19][C:20](=[O:22])[CH3:21])([CH3:18])[CH3:17])[N:15]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>O1CCCC1.C(O)C>[C:20]([NH:19][C:16]([C:14]1[N:15]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:23])=[O:3])=[CH:10][CH:9]=2)[S:12][CH:13]=1)([CH3:18])[CH3:17])(=[O:22])[CH3:21]
Reactant: CCOC(=O)c1ccc(-c2nc(C(C)(C)NC(C)=O)cs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)NC(C)(C)c1csc(-c2ccc(C(=O)O)cc2)n1
Yield: 89.3 %

Procedure:
4-[4-(1-Acetylamino-1-methyl-ethyl)-thiazol-2-yl]-benzoic acid ethyl ester (0.13 g, 0.39 mmol) is dissolved in 2 mL tetrahydrofuran and 2 mL ethanol. 2N sodium hydroxide (1.17 mmol, 0.587 mL) is added and the mixture is heated to reflux for 1 hour. The reaction is concentrated to dryness and the resulting residue is dissolved in 95:5 dichloromethane/isopropanol layered with 0.1N HCl. The organics are separated and dried over sodium sulfate, filtered, and concentrated to give 0.106 g of the pure titled compound. MS (m/e) 303.2 (M−H)−
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][NH:25][CH2:26][CH3:27])([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15].C(N(C(C)C)CC)(C)C.[F:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:39]=1[C:40](Cl)=[O:41]>ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][N:25]([C:40]([C:39]1[C:38]([F:37])=[CH:46][CH:45]=[CH:44][C:43]=1[F:47])=[O:41])[CH2:26][CH3:27])([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CCNCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F)C(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of 5-amino-N-{2-[(ethylamino)methyl]-3,3,3-trifluoro-2-hydroxypropyl}-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (0.277 g, 0.712 mmol) in dry dichloromethane (ca. 11 ml), diisopropylethylamine (0.245 ml, 1.42 mmol) was added and then cooled in a freezer to −10 to −15° C. before a similarly cooled solution of 2,6-difluorobenzoyl chloride (0.123 g, 0.712 mmol) in dichloromethane (2 ml) was added with stirring. The mixture was stirred for 1 minute and then allowed to stand in the fridge for approx. 2 hours and then allowed to warm to room temperature. The next day the mixture was evaporated under reduced pressure and purified on a column of silica. Elution with 2% ethanol in chloroform gave, upon evaporation under reduced pressure, a clear glass (0.421 g) which, upon scraping, gave the title compound (0.356 g) as a white solid.