Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>ClCCl>[F:32][C:33]1[CH:34]=[CH:35][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:17]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[O:19])[CH2:41][CH2:40]2)=[CH:37][CH:38]=1
Reactant: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 71.2 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-methyl-3-(3-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(4-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (566 mg, 1.31 mmol, 71%) was obtained.
Reaction SMILES: [OH-].[Na+].[OH:3][NH:4][C:5](N)=[O:6].Br[CH:9]([CH:14](Br)[CH2:15][CH:16]([NH:21][C:22]1[C:27]([F:28])=[CH:26][N:25]=[C:24]([C:29]2[C:37]3[C:32](=[N:33][CH:34]=[C:35]([F:38])[CH:36]=3)[NH:31][CH:30]=2)[N:23]=1)[C:17]([CH3:20])([CH3:19])[CH3:18])C(OC)=O.CC(O)=O>O.CO>[F:28][C:27]1[C:22]([NH:21][CH:16]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:15][C:14]2[O:3][N:4]=[C:5]([OH:6])[CH:9]=2)=[N:23][C:24]([C:29]2[C:37]3[C:32](=[N:33][CH:34]=[C:35]([F:38])[CH:36]=3)[NH:31][CH:30]=2)=[N:25][CH:26]=1
Reactant: COC(=O)C(Br)C(Br)CC(Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C(C)(C)C
Reactant: NC(=O)NO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)C(Cc1cc(O)no1)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F

Procedure:
To a solution of NaOH (0.015 g) dissolved in water (0.410 mL) was added hydroxyurea (0.008 g, 0.100 mmol). The resulting mixture was stirred for 30 minutes before the dropwise addition of methyl 2,3-dibromo-5-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-6,6-dimethylheptanoate, 85a, (0.064 g, 0.110 mmol) in MeOH (0.150 mL). The solution was stirred for 6 hours before the addition of AcOH (0.031 mL). The residue was purified by reverse phase preparative HPLC to afford the desired product: 1H NMR (300 MHz, MeOD) δ 8.57 (dd, J=9.7, 2.8 Hz, 1H), 8.16 (d, J=5.5 Hz, 2H), 8.00 (d, J=4.1 Hz, 1H), 5.68 (s, 1H), 3.03 (ddd, J=27.4, 15.4, 12.3 Hz, 2H), 1.10 (d, J=3.3 Hz, 11H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.15 minutes (M+H) 416.04.
Reaction SMILES: C(C([N:7]([C:14]1[CH:19]=[CH:18][C:17](CC#N)=[C:16]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:15]=1)C(C(C)(C)C)=O)=O)(C)(C)C.C(C(NC1C=CC(CC#N)=C(OCC(F)(F)F)C=1)=O)(C)(C)C.[ClH:51].[C:52]([OH:55])(=[O:54])[CH3:53]>>[ClH:51].[NH2:7][C:14]1[CH:19]=[CH:18][C:17]([CH2:53][C:52]([OH:55])=[O:54])=[C:16]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])[CH:15]=1
Reactant: CC(C)(C)C(=O)N(C(=O)C(C)(C)C)c1ccc(CC#N)c(OCC(F)(F)F)c1
Reactant: CC(=O)O
Agent: CC(C)(C)C(=O)Nc1ccc(CC#N)c(OCC(F)(F)F)c1
Agent: Cl
Product: Nc1ccc(CC(=O)O)c(OCC(F)(F)F)c1

Procedure:
A ~3:1 mixture of 4-(N,N-di-(tert-butylcarbonyl)-amino)-2-(2,2,2-trifluoroethoxy)phenylacetonitrile and 4-(tert-butylcarbonylamino)-2-(2,2,2-trifluoroethoxy)phenylacetonitrile (1.1 g) from Step 5 above was refluxed in a 1:1 mixture of acetic acid and concentrated aqueous HCl for 3 h. The solvents were removed under reduced pressure. The residue was dissolved in water and the solvent was evaporated under reduced pressure to remove residual acetic acid. 4-Amino-2-(2,2,2-trifluoroethoxy)phenylacetic acid hydrochloride was obtained as a colorless gum (HPLC retention time=4.2 min (method A)).
Reaction SMILES: [F:1][C:2]1([F:26])[O:25][C:5]2=[CH:6][C:7]3[NH:11][C:10]([S:12][CH2:13][C:14]4[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][N:15]=4)=[N:9][C:8]=3[CH:24]=[C:4]2[O:3]1.Cl[O-].[Na+].S([O-])([O-])(=[O:32])=S.[Na+].[Na+]>O1CCOCC1.[OH-].[Na+]>[F:26][C:2]1([F:1])[O:25][C:5]2=[CH:6][C:7]3[NH:11][C:10]([S:12]([CH2:13][C:14]4[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][N:15]=4)=[O:32])=[N:9][C:8]=3[CH:24]=[C:4]2[O:3]1
Reactant: O=S([O-])([O-])=S
Reactant: COc1cnc(CSc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)cc1OC
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cnc(CS(=O)c2nc3cc4c(cc3[nH]2)OC(F)(F)O4)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.76 g of 2,2-difluoro-6-[(4,5-dimethoxy-2-pyridyl)methylthio]-5H-[1,3]-dioxolo[4,5-f]benzimidazole are dissolved in 10 ml of dioxane and 2 ml of 1N sodium hydroxide solution. An equimolar amount of a titrated aqueous sodium hypochlorite solution, to which 1 mole per liter of sodium hydroxide solution has been added, is first added dropwise, while cooling with ice, and after one hour a further equivalent and after 3 hours half the equimolar amount of sodium hypochlorite are added, to achieve complete reaction. After a reaction time of 4 hours, 5 ml of 5% strength sodium thiosulfate solution and another 25 ml of dioxane are added and the upper dioxane phase is separated off, washed once with 5 ml of sodium thiosulfate solution and concentrated on a rotary evaporator. The oily residue is dissolved in 20 ml of water and 10 ml of ethyl acetate and the solution is brought to pH 7 with about 100 ml of a buffer solution of pH 6.8. The solid which has precipitated out is filtered off with suction over a suction filter, washed with water, extracted by stirring at 0° C. with acetone and dried. 0.7 g (87% of theory) of the title compound is obtained in the form of colorless crystals; decomp. at 211°-213° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C@@H:10]2[C:18](=[O:19])[N:17]3[C@H:12]([CH2:13][CH2:14][C@@H:15]([NH:20][C:21]4[C:22]5[CH:29]=[CH:28][N:27](S(C6C=CC(C)=CC=6)(=O)=O)[C:23]=5[N:24]=[CH:25][N:26]=4)[CH2:16]3)[CH2:11]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[N:24]1[C:23]2[NH:27][CH:28]=[CH:29][C:22]=2[C:21]([NH:20][C@@H:15]2[CH2:14][CH2:13][C@H:12]3[N:17]([C:18](=[O:19])[C@@H:10]([NH:9][C:4]4[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:11]3)[CH2:16]2)=[N:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@@H]4CC[C@@H]5C[C@H](Nc6cc(F)cc(Cl)c6)C(=O)N5C4)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1[C@@H](Nc2cc(F)cc(Cl)c2)C[C@H]2CC[C@@H](Nc3ncnc4[nH]ccc34)CN12
Temperature: 70 °C
Yield: 50.5 %

Procedure:
A solution of (2S,6R,8aR)-2-(3-chloro-5-fluorophenylamino)-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)hexahydroindolizin-3(5H)-one (19 mg) 127.6 in MeOH (0.5 mL) & H2O (2 mL) was treated with of K2CO3 (5 mg, 0.033 mmol) and heated at 70° C. for 24 hours. The white suspension was cooled and diluted with H2O. The precipitate was collected on a Whatman 0.45 um nylon membrane filter and concentrated in vacuo to afford of (2S,6R,8aR)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-(3-chloro-5-fluorophenylamino)hexahydroindolizin-3(5H)-one 127.7 (7 mg) as a white solid that exists as 3:1 mixture of diasteromers. LCMS (ESI) m/z: 415.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:15]=[C:14]([C:16]4[S:17][C:18]5[C:24]([C:25]6[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=6)=[C:23]([C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35]C)=[O:34])[C:22]([CH3:42])=[CH:21][C:19]=5[N:20]=4)[CH:13]=[CH:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:15]=[C:14]([C:16]4[S:17][C:18]5[C:24]([C:25]6[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=6)=[C:23]([C@H:32]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[C:33]([OH:35])=[O:34])[C:22]([CH3:42])=[CH:21][C:19]=5[N:20]=4)[CH:13]=[CH:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5[nH]ncc5c4)c3)sc2c1-c1ccc(Cl)cc1
Solvent: CO
Solvent: O
Product: Cc1cc2nc(-c3ccnc(-c4ccc5[nH]ncc5c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
The solution of crude (S)-methyl 2-(2-(2-(1H-indazol-5-yl)pyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate from the previous reaction was treated directly with LiOH monohydrate (60 mg, 1.42 mmol), H2O (500 μL), and MeOH (500 μL). The reaction was heated to 50° C. for 15 h. The reaction failed to reach completion (LCMS analysis). The reaction was then heated to 100° C. for 30 min and reached completion. The system was cooled to 23° C. and filtered (0.45 micron Teflon® filter). The filtrate was purified directly on a C-18 Gemini column using a Gilson liquid handler (Eluent H2O/CH3CN gradient with both mobile phase components spiked 0.1% v/v with TFA). The title compound was obtained as a mono-trifluoroacetic acid salt. LCMS-ESI+: calc'd for C32H27ClN4O3S: 583.2 and 585.2 (M+H+); Found: 583.3 and 585.3 (M+H+). 1H NMR (400 MHz, CD3OD) δ: 8.78 (d, J=5.5 Hz, 1H), 8.58 (s, 1H), 8.51 (s, 1H), 8.22 (s, 1H), 8.11 (dd, J=8.6, 1.2 Hz, 1H), 8.04 (dd, J=5.4, 1.2 Hz, 1H), 7.99 (s, 1H), 7.74-7.70 (m, 2H), 7.65-7.60 (m, 3H), 5.23 (s, 1H), 2.65 (s, 3H), 0.99 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:52]=[CH:51][C:6]([CH2:7][N:8]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:32]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)([CH3:35])[C:33]#N)[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.C[Mg]Br>C1COCC1>[F:29][C:27]1[CH:28]=[C:23]([NH:22][C:21]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:7][C:6]4[CH:51]=[CH:52][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:42][C:43]4[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=4)[N:10]=3)=[CH:17][C:18]([C:32]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)([CH3:33])[CH3:35])=[CH:19][N:20]=2)[CH:24]=[N:25][C:26]=1[O:30][CH3:31]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C#N)N4CCOCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)N4CCOCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A solution of 2-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-2-morpholinopropanenitrile (0.500 g, 0.708 mmol) in THF (2 mL) at 0° C. was treated with methylmagnesium bromide (3.0 M in diethyl ether; 1.181 mL, 3.54 mmol). The cooling bath was removed after 10 min, and the reaction was allowed to warm to ambient temperature. After 2 h total, the reaction was cooled to 0° C. and quenched with EtOAc (1 mL) followed by ice and sat'd aq. NH4Cl. The reaction was partitioned between satd NH4Cl and DCM. The aqueous layer was extracted with DCM (3×) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography using 10-80% EtOAc/hexane. The product-containing fractions were concentrated to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-morpholinopropan-2-yl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.363 g, 0.522 mmol, 73.7% yield) as a yellow solid. m/z (ESI, +ve ion) 695 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.86 (s, 1H); 8.96 (d, J=2.5 Hz, 1H); 8.47 (d, J=2.5 Hz, 1H); 8.13 (dd, J=12.5, 2.2Hz, 1H); 7.91-8.01 (m, 1H); 7.17-7.26 (m, 4H); 6.75-6.96 (m, 4H); 4.89 (s, 2H); 4.84 (s, 2H); 4.02 (s, 3H); 3.82 (s, 3H); 3.79 (s, 3H); 3.55-3.65 (m, 4H); 2.59 (s, 3H); 2.42-2.51 (m, 4H); 1.35 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH:12](O)[CH2:13][CH:14](O)[C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[CH:5]=1.[H][H]>C(O)C.Cl.[Pd]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(OC)c(C(O)CC(O)c2cccc(C)c2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(OC)c(CCCc2cccc(C)c2)c1
Yield: 63.2 %

Procedure:
The compound of step 1 (140 mg, 0.424 mmol) was dissolved in ethanol (10 ml) and 12 N hydrochloric acid (0.2 ml), palladium on charcoal (10%) was added, and the mixture was hydrogenated at a hydrogen pressure of 6 bar at room temperature overnight. After filtration and evaporation, the residue was purified by silica gel chromatography (HEP/EA gradient) to give 80 mg of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(C(C)C)CC)(C)C.[CH3:63][N:64]1[C:68]([CH3:69])=[CH:67][C:66]([C:70](Cl)=[O:71])=[N:65]1>ClCCl>[CH3:63][N:64]1[C:68]([CH3:69])=[CH:67][C:66]([C:70]([N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[O:71])=[N:65]1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: Cc1cc(C(=O)Cl)nn1C
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5)ncnc43)CC2)nn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.5 %

Procedure:
A mixture of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27; 63 mg, 0.13 mmol), TSTU (O—(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate; 78 mg, 0.26 mmol), and diisopropylethylamine (0.14 mL, 0.8 mmol) in dichloromethane (4 mL) was shaken at room temperature for 3 h. 1,5-Dimethyl-1H-pyrazole-3-carbonyl chloride (available from Maybridge, Tintagel, Cornwall, UK; 23 mg, 0.16 mmol) was added and the mixture was shaken at room temperature overnight. The solution was diluted with dichloromethane (˜6 mL) and washed with water (2×5 mL), 1 M aqueous hydrochloric acid (5 mL), water (5 mL), saturated aqueous sodium bicarbonate (5 mL) and brine (5 mL). The organic layer was evaporated and the crude product was purified by HPLC to give (1,5-dimethyl-1H-pyrazol-3-yl)-{4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-methanone (28 mg, 43%) as a white solid. Mass spectrum (ES) MH+=496.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[OH-].[Na+].Cl[CH:15]([F:17])[F:16]>O1CCOCC1.O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH:15]([F:17])[F:16]
Reactant: FC(F)Cl
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(OC(F)F)c(Br)c1
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
2-Bromo-4-nitrophenol (10.9 g) was dissolved in dioxane (60 ml), a solution of sodium hydroxide (18.4 g) in water (50 ml) was added thereto, and the resulting mixture was heated up to 60° C. while stirring vigorously. Chlorodifluoromethane gas was introduced therein, whereby the generation of heat was initiated. The reaction was continued for about 40 minutes. The reaction mixture was cooled to room temperature, poured onto ice-water and extracted with ether. The extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-bromo-4-difluoromethoxynitrobenzene (8.7 g) as a pale yellow oil. nD20.5 1.5500.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:17][CH3:18])=[C:11]([NH:13][C:14]([NH2:16])=[S:15])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.BrBr>C(Cl)(Cl)Cl.ClCCl>[CH:1]1([C:7]2[C:12]3[S:15][C:14]([NH2:16])=[N:13][C:11]=3[C:10]([O:17][CH3:18])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(C2CCCCC2)cc1NC(N)=S
Agent: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C2CCCCC2)c2sc(N)nc12
Yield: 68.4 %

Procedure:
To a solution of 0.9 g (0.0034 Mol) (5-cyclohexyl-2-methoxy-phenyl)-thiourea in 18 ml chloroform were added 0.2 ml (0.0041 Mol) bromine, dissolved in 4.5 ml chloroform and heated to reflux for 16 h. The reaction mixture was diluted with dichloromethane, extracted with sat. aqueous potassium carbonate and brine, dried over sodium sulfate and evaporated to dryness in vacuo. The residue was crystallized from ethyl acetate/diethyl ether to yield 0.61 g (68%) of 7-cyclohexyl-4-methoxy-benzothiazol-2-ylamine as an off-white solid; F.p.: 199-200° C.
Reaction SMILES: Cl.Cl.[CH3:3][C@@H:4]([N:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])[CH2:5][N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7]1.ClC1C=CC=C(C(OO)=[O:40])C=1.Cl>>[CH3:3][C@@H:4]([N:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])[CH2:5][N:6]1[CH2:7][CH:8]=[C:9]([C:12]2[S:13](=[O:40])[CH:14]=[CH:15][CH:16]=2)[CH2:10][CH2:11]1
Reactant: C[C@H](CN1CC=C(c2cccs2)CC1)N(C(=O)C1CCCCC1)c1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Product: C[C@H](CN1CC=C(C2=CC=CS2=O)CC1)N(C(=O)C1CCCCC1)c1ccccn1
Yield: 45.7 %

Procedure:
The title compound was prepared from cyclohexanecarboxylic acid (R)-[1-methyl-2-(4-thiophen-2-yl-3,6-dihydro-2H-pyrid-1-yl)-ethyl]-(pyrid-2-yl)-amide dihydrochloride (1.5 g, 3.6 mmol) and meta-chloroperbenzoic acid (0.632 g, 3.6 mmol) to yield 0.7 g of the title compound as the 1.8 hydrochloride, m.p. 109°-11° C.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7].[C:10](O)(=[O:14])/[CH:11]=[CH:12]/[CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:7][CH:6]([O:8][C:10](=[O:14])[CH:11]=[CH:12][CH3:13])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:9])[CH3:1]
Reactant: CC(C)=CCCC(C)O
Reactant: C/C=C/C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=CC(=O)OC(C)CCC=C(C)C
Temperature: 121.5 °C

Procedure:
6-Methyl-hept-5-en-2-ol (256 g, commercially available at IFF), crotonic acid (193 g), PTSA (2.5 g), and toluene (250 mL) were charged into a 2-L reaction flask fitted with a mechanical stirrer, a thermocouple, a Dean-Stark trap, and a condenser. The reaction mixture was heated to reflux at about 110-133° C. Water was removed azeotropically. The reaction was aged at reflux for about 6 hours until no more water evolved. The reaction mixture was cooled to under 60° C. and quenched with water (300 mL). The aqueous and organic layers were split. The organic layer was subsequently washed with sodium carbonate (2%, 300 mL) and further fractional distilled to provide but-2-enoic acid 1,5-dimethyl-hex-4-enyl ester (204 g) with a boiling point of 98° C. at 4 mmHg.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][C:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=2)=[O:28])=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:37]>O1CCOCC1>[ClH:36].[ClH:37].[NH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][C:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=2)=[O:28])=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Trans-3-[4-(t-butoxycarbonylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (10.70 g) obtained in Example 203 is dissolved in dioxane (150 ml), and thereto is added 4N hydrogen chloride in dioxane (150 ml). The mixture is stirred at room temperature for 12 hours, and concentrated under reduced pressure. The residue is crushed in diethyl ether, and collected by filtration to give the title compound (9.80 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=O)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:37]=[CH:36][CH:35]=[C:32]([C:33]#[N:34])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: Cc1cccc(-c2ccc(NC(=O)OC(C)(C)C)c(N)c2)c1
Product: Cc1cccc(-c2ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c3cccc(C#N)c3)c2)c1

Procedure:
Prepared from (3-amino-3′-methyl-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G20) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a viscous orange oil (290 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:23](=[O:24])[CH2:22][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)Nc1nc2cccc(-c3ccoc3)n2n1
Yield: 33 %

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 41 mg; 0.20 mmol; 1.0 eq.) and phenylacetyl chloride (38 μl; 0.41 mmol; 2.0 eq). Purification of the compound by flash chromatography on silica (EtOAc/c-Hex, 50:50) gave the title compound as a white powder (21 mg, 29%). 1H NMR (DMSO-d6) δ 8.98 (brs, 1H), 8.61 (brs, 1H), 7.55 (m, 3H), 7.37 (m, 5H), 7.22 (m, 1H), 6.91 (s, 1H), 3.96 (brs, 2H), 1.99 (brs, 3H, water). HPLC, Rt: 3.27 min. (purity 94.5%). LC/MS, M+(ESI): 319.3, M−(ESI): 317.3.