Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH3:18].Cl>CN(C)C=O>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1])[CH3:18]
Reactant: CCI
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C=O)cc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3,4-Dihydroxybenzaldehyde (101.6 g) and potassium carbonate (101.7 g) were suspended in N,N-dimethylformamide (500 mL). To the mixture was added dropwise ethyl iodide (58.8 mL) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added dropwise 2 mol/L hydrochloric acid (500 mL), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/1) to give the title compound (74.3 g).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[SiH:15]([C:30]2[C:31]4[C:36]([CH:37]=[C:38]5[C:43]=2[CH:42]=[CH:41][CH:40]=[CH:39]5)=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:16]2[C:17]4[C:22]([CH:23]=[C:24]5[C:29]=2[CH:28]=[CH:27][CH:26]=[CH:25]5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:45].[K+]>O1CCCC1>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[Si:15]([C:16]2[C:29]4[C:24]([CH:23]=[C:22]5[C:17]=2[CH:18]=[CH:19][CH:20]=[CH:21]5)=[CH:25][CH:26]=[CH:27][CH:28]=4)([C:30]2[C:31]4[C:36]([CH:37]=[C:38]5[C:43]=2[CH:42]=[CH:41][CH:40]=[CH:39]5)=[CH:35][CH:34]=[CH:33][CH:32]=4)[OH:45])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: c1ccc2c([SiH](c3c4ccccc4cc4ccccc34)c3c4ccccc4cc4ccccc34)c3ccccc3cc2c1
Agent: [K+]
Solvent: C1CCOC1
Product: O[Si](c1c2ccccc2cc2ccccc12)(c1c2ccccc2cc2ccccc12)c1c2ccccc2cc2ccccc12
Reaction time: 15 h

Procedure:
The oxidation of the tris(9-anthracenyl)silane is carried out analogously to Example 1.1 with 5 molar equivalents of potassium permanganate in boiling tetrahydrofuran. The reaction is interrupted after 15 h and, after filtration over silica gel to separate off pyrolusite from the solution, the silanol formed is obtained as a yellowish solid by concentration of the reaction mixture, yield: 10.75 g with a purity of 85% (GC-MS). Further purification is carried out by crystallization from boiling ethanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:14])=[C:9]([CH:12]=[O:13])[C:10]=1[CH3:11])=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][C:23]1[CH:27]=[C:26]([C:28]2[S:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[O:25][N:24]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23]2[CH:27]=[C:26]([C:28]3[S:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[O:25][N:24]=2)[C:8]([CH3:14])=[C:9]([CH:12]=[O:13])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C)c(C=O)c1C
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)c(C=O)c(C)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To 4-formyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.60 g) in DMF (26 mL) was added Cs2CO3 (6.51 g). The mixture was stirred for 30 min at RT, then 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole (3.71 g) was added. Stirring was continued for 2 h at RT. Water was added and the phases were separated. The aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried (MgSO4) and was concentrated under reduced pressure to give crude 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-4-formyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (4.20 g), which was directly used in the next step without further purification.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH2:19][O:20][CH3:21])=[CH:11][C:10]=2[O:22][CH2:23][O:24][CH3:25])=[N:7][NH:6][C:5]1=[S:26])([CH3:3])[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].CI>C(O)C>[CH:1]([N:4]1[C:5]([S:26][CH3:27])=[N:6][N:7]=[C:8]1[C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH2:19][O:20][CH3:21])=[CH:11][C:10]=1[O:22][CH2:23][O:24][CH3:25])([CH3:2])[CH3:3]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=S)n1C(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CI
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(SC)n1C(C)C
Temperature: 80 °C
Yield: 94.9 %

Procedure:
4-isopropyl-5-(5-isopropyl-2,4-bis-methoxymethoxy-phenyl)-2,4-dihydro-[1,2,4]triazol-3-thione (F63-03, 1.96 g, 5.14 mmol) and potassium carbonate (710.4 mg, 5.14 mmol) were weighed and placed in a reaction vessel, and ethanol (30 mL) was added and then methyl iodide (0.32 mL, 5.14 mmol) was added. After heating at 80° C. for 1 hour while stirring, the mixture was returned to room temperature, and the solvent was distilled off under reduced pressure. After adding water, the reaction system was extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution. After drying the extract over anhydrous sodium, sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure to obtain yellow syrup. After purification by silica gel column chromatography (chloroform, methanol), 4-isopropyl-3-(5-isopropyl-2,4-bis-methoxy methoxyphenyl)-5-methylsulfanyl-4H-[1,2,4]triazole (F63-04, pale yellow syrup, 1.93 g, 95%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][C@H:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]([NH2:40])=[O:39]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][CH:33]3[CH2:37][CH2:36][CH2:35][CH:34]3[C:38]([NH2:40])=[O:39])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NC(=O)[C@@H]1CCC[C@@H]1N
Product: Cc1cc(F)ccc1-c1nc(NC2CCCC2C(N)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
Following the general procedure outlined in Example 225, the product of Example 48 (150 mg, 0.34 mmol) and cis-2-amino-1-cyclopentanecarboxamide (139 mg, 1.02 mmol) were reacted to give the crude material. Purification by flash chromatography eluting with EtOAc/hexane/triethylamine (50/50/2, v/v/v), followed by recrystallization from dichloromethane and hexane, afforded the desired product, 87 mg (52%). LC-MS: 494.0 (MH+, m/z), 2.00 (Rt, min).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:40]2[S:41][C:42]([Sn](CCCC)(CCCC)CCCC)=[CH:43][C:39]=2[C:38]([CH3:57])=[N:37]1>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:42]3[S:41][C:40]4[N:36]([CH3:35])[N:37]=[C:38]([CH3:57])[C:39]=4[CH:43]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(C)nn(C)c2s1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nn(C)c2sc(-c3nc(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)cc12
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.399 mmol), 1,3-dimethyl-5-(tributylstannyl)-1H-thieno[2,3-c]pyrazole (352 mg, 0.798 mmol) and tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.200 mmol) in toluene (3 mL) was heated to 120° C. in a Biotage Initiator microwave for 30 minutes. The mixture was concentrated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was subsequently dissolved in DCM (5 mL) and TFA (5 mL). The resulting solution was stirred at room temperature for 20 minutes, concentrated, and purified by preparatory HPLC, eluting with a gradient of 10-30% ACN (0.035% TFA) and water (0.05% TFA). The collected fractions were combined and dried to give a TFA salt of the title compound as a white solid (85 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79-1.81 (m, 1H), 2.13-2.14 (m, 1H), 2.53 (s, 3H), 3.61-3.63 (m, 1H), 3.85-3.87 (m, 2H), 3.87 (s, 3H), 4.01-4.07 (m, 2H), 4.33-4.35 (m, 1H), 4.44 (d, J=7.80 Hz, 2H), 7.33-47.34 (m, 1H), 8.01-8.02 (m, 2H), 8.53 (s, 1H), 9.16 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C19H21FN6O2S, 417. found, 417.
Reaction SMILES: [C:1]([N:11]([CH3:19])[C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:20][C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1.C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([N:11]([CH3:19])[C@H:12]([C:16]([NH:20][C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:31])[CH3:32])[CH:24]=1)=[O:18])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)(C)c1cc(C[C@H](N)C(N)=O)ccc1O
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 131.9 %

Procedure:
To a solution of 400 mg (1.52 mmol) of Z-N-Me-Val-OH, 300 mg (1.27 mmol) of Tyr(3-tBu)-NH2 and 230 mg (1.52 mmol) of HOBT in 7 ml of DMF, 0.24 ml (1.52 mmol) of DIC was added dropwise under cooling with ice and the mixture was stirred at room temperature for 15 hours and a half. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of methylene chloride, methanol and aqueous ammonia at a ratio of 100:3:1) to give 810 mg of Z-N-Me-Val-Tyr(3-tBu)-NH2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:12]2[N:13]=[CH:14][N:15]=[C:16](O)[C:11]=2[CH:10]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:16]1[C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[NH:18][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccccc1-c1cc2c(O)ncnc2[nH]1
Product: COc1ccccc1-c1cc2c(Cl)ncnc2[nH]1
Temperature: 0 °C

Procedure:
Under argon, 6.2 g (25.7 mmol) of 6-(2-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol and 62 ml of phosphorus oxychloride are heated at 125° C. for 1.5 hours. The reaction mixture is poured into ice-water and extracted three times with ethyl acetate. The organic phases are washed with water, NaHCO3 solution and brine, dried with MgSO4 and concentrated by evaporation. Filtering through a silica gel column with ethyl acetate yields the title compound; TLC-Rf =0.8 (hexane/ethyl acetate [1:1]).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][CH2:7][C:8]([CH3:21])([CH3:20])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-])=O)([O-])=O.[H][H]>CN(C=O)C.[Ni]>[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH2:9][C:8]([CH3:21])([CH3:20])[CH2:7][O:6][C:5]1[CH:22]=[CH:23][CH:24]=[CH:25][C:4]=1[NH2:1]
Reactant: CC(C)(COc1ccccc1[N+](=O)[O-])COc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CN(C)C=O
Product: CC(C)(COc1ccccc1N)COc1ccccc1N

Procedure:
343 g 1,3-bis-(2-nitrophenoxy)-2,2-dimethyl-propane were hydrogenated at 60° C./50 bar in 1800 ml DMF in the presence of 53 g Raney nickel. After the uptake of hydrogen had stopped, the catalyst was filtered off and the solvent was removed in vacuo.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][CH:3]=1.[ClH:16].[N:17](OCCC(C)C)=[O:18]>O1CCCC1>[ClH:16].[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[N:17]=[O:18]
Reactant: CC(C)c1ccc(-n2nccc2N)cc1
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)c1ccc(-n2ncc(N=O)c2N)cc1
Temperature: 2.5 °C

Procedure:
14.9 g (74 mmol) of 5-amino-1-(4-isopropylphenyl)pyrazole [sic] from Step 2.1 was dissolved in 130 mL of tetrahydrofuran. 42.2 g of 32% hydrochloric acid was added, and the reaction mixture was cooled to 0 to 5° C. Then, 9.5 g (81 mmol) of isopentyl nitrite was added dropwise with agitation so that the temperature did not exceed 5° C. Gradually, a yellowish precipitate formed which after an additional 1.5-hour agitation period in an ice bath was removed by suction filtration and washed with a small amount of tetrahydrofuran. Drying gave 12.3 g (46.1 mmol, 62% of the theoretical) of 5-amino-1-(4-isopropylphenyl)4-nitroso-1H-pyrazole hydrochloride.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[CH:34]=[C:35]([OH:40])[CH:36]=[CH:37][C:38]=1[F:39].C(OC([N:48]1[CH2:53][CH2:52][CH:51](O)[CH2:50][CH2:49]1)=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1>[Cl:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][C:38]=1[F:39])[O:40][CH:51]1[CH2:52][CH2:53][NH:48][CH2:49][CH2:50]1
Reactant: Oc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Fc1ccc(OC2CCNCC2)cc1Cl
Reaction time: 8 h
Yield: 105.2 %

Procedure:
DEAD (0.43 ml) was added to a solution of triphenylphosphine (0.72 g), 3-chloro-4-fluorophenol (0.403 g) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.5 g) in THF at RT. The resulting mixture was stirred overnight, HCl in dioxan (2 ml of 4M) was added and the mixture stirred at RT overnight. The mixture was then evaporated to dryness and triethylamine (5 ml) was added. The mixture was evaporated and the residue was dissolved in methanol (10 ml), placed onto a SCX cartridge (Varian, 10 g, SCX cartridge available from International Sorbent Technology Isolute® Flash SCX-2) and eluted: first with methanol then with 10% NH3 in methanol. The basic fractions were combined and evaporated to give the product as an oil (0.6 g).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]#[CH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH2:14](Br)[C:15]#[CH:16]>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[N:8]([CH2:16][C:15]#[CH:14])[CH2:9][C:10]#[CH:11])([CH3:5])([CH3:6])[CH3:7]
Reactant: C#CCBr
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN(CC#C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-Boc-propargylamine (2.63 g, 16.9 mmol) and DMF (35 mL) was prepared under argon and cooled to 0° C. for 20 min. Sodium hydride (60%, 0.714 g, 17.9 mmol) was added and the reaction stirred at 0° C. for 30 min. Propargyl bromide (80% in toluene, 2.7 mL, 24.2 mmol) in DMF (5 mL) was added slowly and the reaction stirred at 0° C. for 15 min then warmed to room temperature and stirred for additional 17 hr. The reaction mixture was quenched with water and extracted two times with EtOAc. The combined organic layers were washed with water (3×) and brine, dried over Na2SO4, filtered, and concentrated. The crude product was carried to the next reaction without purification. ESI-MS m/z 194 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([OH:18])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[C:15]([C:24]([O:26][CH3:27])=[O:25])=[N:14]1.[H-].[Na+].S(OC)(O[CH3:34])(=O)=O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([O:18][CH3:34])=[C:16]([S:19][C:20]([F:21])([F:22])[F:23])[C:15]([C:24]([O:26][CH3:27])=[O:25])=[N:14]1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(O)c1SC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(OC)c1SC(F)(F)F
Yield: 62.3 %

Procedure:
A suspension of 5.8 g (0.013 mole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methoxycarbonyl-4-trifluoromethylsulfenyl-5-hydroxypyrazole and 0.37 g (0.015 mole) sodium hydride in 150 ml of dioxane was heated to reflux for 0.5 hr. during which time the color changed from brown to orange with evolution of gas. To the cooled mixture was added 1.94 g (0.015 mole) of dimethyl sulfate diluted in 10 ml of dioxane. The mixture was heated again to reflux for 1 hr. It was then cooled, the solids were filtered off and the filtrate was concentrated. The brown oil was taken up in dichloromethane and washed with water. The organic layer was dried and concentrated to afford 3.8 g (62.4 percent yield) of a brown oil. Purification by column chromatography using silica gel gave a solid, m.p. 97°-98° C.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[N:17]3)[CH2:10][CH2:9]2)[S:6][CH:7]=1)=O.[CH3:27][NH:28][CH:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:30][NH2:31].C(=O)([O-])[O-].[K+].[K+].II>C(O)(C)(C)C>[CH3:27][N:28]1[CH:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:30][N:31]=[C:1]1[C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[N:17]3)[CH2:10][CH2:9]2)[S:6][CH:7]=1
Reactant: CNC(CN)c1ccccc1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=O)cs2)CC1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C3=NCC(c4ccccc4)N3C)cs2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-formyl-2-thiazolyl)-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e. the product of Example 2, Step B) (0.8 g, 2.07 mmol) in tert-butanol (5 mL) was added N1-methyl-1-phenyl-1,2-ethanediamine (43.57 mg, 0.29 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes, and then potassium carbonate (107.8 mg, 0.78 mmol) and iodine (43.57 mg, 0.33 mmol) were added. The reaction mixture was stirred at 70° C. for 3 h and then quenched by addition of saturated aqueous sodium sulfite solution until the iodine color almost disappeared. The reaction mixture was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative thin-layer chromatography on silica gel using a mixture of 94% ethyl acetate, 5% methanol and 1% triethylamine as eluant to give 64 mg of the title product, a compound of the present invention, as an oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]12[CH2:14][CH2:13][CH:12]=[C:11]1[CH2:10][N:9]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:8]2)=[O:6]>CO>[CH2:18]([O:17][C:15]([N:9]1[CH2:10][C:11]2[C:7]([C:5]([OH:6])=[O:4])([CH2:14][CH2:13][CH:12]=2)[CH2:8]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C12CCC=C1CN(C(=O)OCc1ccccc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(OCc1ccccc1)N1CC2=CCCC2(C(=O)O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 1N sodium hydroxide solution (1.86 mL) was added to a solution of {3-benzyloxycarbonyl-3-azabicyclo[3.3.0]oct-5-en-1-yl}carboxylic acid methyl ester (187 mg, 0.620 mmol) in methanol (6.20 mL) in a nitrogen atmosphere, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and then washed with diethyl ether (50 mL×2). The aqueous layer was made acidic with 1N hydrochloric acid under ice-cooling, followed by extraction with ethyl acetate (100 mL×1, 80 mL×1). The organic layer was washed with water (80 mL) and brine (80 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 186 mg (quantitative) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[NH2:9].[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH:19]=O.C(OC)(C)(C)C>[Pd].C(O)C>[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][NH:9][C:8]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])[CH:7]=1
Reactant: COc1ccc(N)cc1OCCN(C)C
Reactant: COC(C=O)OC
Agent: [Pd]
Solvent: CCO
Solvent: COC(C)(C)C
Product: COc1ccc(NCC(OC)OC)cc1OCCN(C)C
Reaction time: 16 h
Yield: 67 %

Procedure:
A solution of 3-(2-dimethylaminoethoxy)-4-methoxyaniline (D11, 5.7 g, 0.027 mole) ethanol (120 ml) was treated with a solution of 2,2-dimethoxyacetaldehyde in methyl tert-butyl ether (9.5 g of approx. 40% solution, 0.036 mole) and kept at room temperature for 16 hours. The solution was then hydrogenated over 10% Pd-C (0.6 g) at atmospheric pressure and temperature for 7 hours. The catalyst was removed by filtration through kieselguhr and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate (100 ml), washed twice with water (2×60 ml), then dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5% methanol/chloroform to afford the title compound as a red oil (5.4 g, 67%).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:22]([O:23][CH3:24])=[C:21]([F:25])[C:20]([I:26])=[C:19]([CH3:27])[C:15]=1[C:16]([OH:18])=[O:17]>O1CCCC1>[F:25][C:21]1[C:20]([I:26])=[C:19]([CH3:27])[C:15]2[C:16](=[O:18])[O:17][C:2](=[O:4])[NH:13][C:14]=2[C:22]=1[O:23][CH3:24]
Reactant: COc1c(N)c(C(=O)O)c(C)c(I)c1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COc1c(F)c(I)c(C)c2c(=O)oc(=O)[nH]c12
Temperature: 40 °C
Reaction time: 16 h

Procedure:
Under nitrogen atmosphere, triphosgene (1.5 g, 5.04 mmol) was added to a tetrahydrofuran (200 ml) solution of 2-amino-4-fluoro-5-iodo-3-methoxy-6-methylbenzoic acid (I-30) (4.1 g, 12.6 mmol), followed by stirring at 40° C. for 16 hours.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:8]([F:37])=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:35][CH3:36])=[C:21]([O:24][CH:25]4[CH2:34][CH2:33][C:28]5(OCC[O:29]5)[CH2:27][CH2:26]4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1.[OH-].[Na+]>O1CCCC1>[Cl:6][C:7]1[C:8]([F:37])=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:35][CH3:36])=[C:21]([O:24][CH:25]4[CH2:34][CH2:33][C:28](=[O:29])[CH2:27][CH2:26]4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCC2(CC1)OCCO2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
25 ml 4M sulphuric acid are added to 9.0 g 4-[(3-chloro-2-fluoro-phenyl)amino]-6-(1,4-dioxa-spiro[4.5]decan-8-yl-oxy)-7-methoxy-quinazoline in 110 ml of tetrahydrofuran and the mixture is stirred for 18 hours at ambient temperature. The mixture is made alkaline with 4M sodium hydroxide solution and extracted several times with ethyl acetate. The combined organic phases are dried, evaporated down and stirred with diethyl ether. The solid is suction filtered and dried.