Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].C1(C)C=CC=CC=1.C1([Li])C=CC=CC=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C@H:24]2[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1)#[N:17].[O:33]1[CH2:37]CC[CH2:34]1>O>[CH3:34][O:33][CH:37]=[CH:31][CH2:30][C@H:27]1[CH2:26][CH2:25][C@H:24]([C:21]2[CH:20]=[CH:19][C:18]([C:16]#[N:17])=[CH:23][CH:22]=2)[CH2:29][CH2:28]1
Reactant: N#Cc1ccc([C@H]2CC[C@H](CC=O)CC2)cc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC=CC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
Commercially available methoxymethyltriphenylphosphornium chloride (15.7 g, 0.0458 mol) was added to tetrahydrofuran (100 ml), followed by dropwise adding a toluene solution (23 ml) of 25% by weight of phenyllithium in argon atmosphere with stirring at -10° C. over 10 minutes, agitating the reaction solution at 0° C. for 30 minutes, dropwise adding a solution of trans-4-(4-cyanophenyl)cyclohexylacetaldehyde (VII) obtained in Example 2(i) (7.3 g, 0.032 mol) in tetrahydrofuran (90 ml) at -10° C. over 10 minutes, agitating the reaction solution at 0° C. for 2 hours, adding toluene (100 ml) and water (200 ml), washing, subjecting the resulting toluene solution to three times washing with water (200 ml) and separating, drying with anhydrous sodium sulfate, separating the drying agent, distilling off toluene, dissolving the resulting residue in ethyl acetate (20 ml) on heating, allowing the solution to stand still at room temperature for one day, filtering off deposited crystals, concentrating the resulting mother liquor, dissolving the concentrate in heptane and purifying according to silica gel chromatography to obtain trans-1-(3-methoxy-2-propenyl)-4-(4-cyanophenyl)cyclohexane (4.4 g, 0.017 mol), adding to the total quantity thereof, tetrahydrofuran (70 ml) and 2N-hydrochloric acid (18 ml), heating the mixture under reflux with stirring for one hour, cooling the reaction solution, adding diethyl ether (50 ml) and water (50 ml) to the solution, subjecting the resulting diethyl ether to three times washing with water (50 ml) and separating, drying with anhydrous sodium sulfate, separating the drying agent and distilling off diethyl ether to obtain trans-4-(4-cyanophenyl)cyclohexylpropylaldehyde (4.2 g, 0.017 mol).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:28]([F:30])[F:29])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.CO.O1CCCC1.[OH-].[Li+]>O>[F:30][CH:28]([F:29])[O:27][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:31])=[O:2])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(F)cc1

Procedure:
A mixture of [4-difluoromethoxy-2-ethyl-8-fluoro-3-(4-fluorobenzyl)quinolin-5-yloxy]acetic acid methyl ester (050 g), methanol (10 mL); tetrahydrofuran (10 mL), water (8 mL) and lithium hydroxide (0.050 g) was stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate and 1.0 M aqueous hydrochloric acid and the aqueous phase was extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. Purification of the residue by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water, followed by washing with diethyl ether gave title compound as a white solid, 0.090 g.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([CH:9]3[CH2:13][CH2:12][CH2:11][N:10]3[C:14]3[N:19]=[C:18](O)[CH:17]=[C:16]([CH2:21][O:22][CH3:23])[N:15]=3)[O:6][N:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:18]1[CH:17]=[C:16]([CH2:21][O:22][CH3:23])[N:15]=[C:14]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:7]2[O:6][N:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:8]=2)[N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1cc(O)nc(N2CCCC2c2cc(C3CC3)no2)n1
Product: COCc1cc(Cl)nc(N2CCCC2c2cc(C3CC3)no2)n1
Yield: 85.7 %

Procedure:
A mixture of 2-[2-(3-cyclopropylisoxazol-5-yl]pyrrolidin-1-yl]-4-hydroxy-6-methoxymethylpyrimidine (Method 18) (563 mg, 1.78 mmol) and phosphoryl chloride (1 ml, 10.7 mmol) was heated at reflux for 45 minutes. The volatiles were removed by evaporation, the residue dissolved in DCM, washed with saturated aqueous sodium hydrogen carbonate solution, dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica gel eluting with DCM/diethyl ether (100:0 and then 80:20) to give the title compound (511 mg, 81%) as a yellow oil.
Reaction SMILES: N1CCOCC1.[N:7]1([CH2:12][C:13]([N:15]2[C@H:19]([C:20](=[O:36])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[CH:24][CH:23]=3)[CH2:18][C@H:17]([NH:37]C(=O)OCC3C4C=CC=CC=4C4C3=CC=CC=4)[CH2:16]2)=[O:14])[CH:11]=[N:10][CH:9]=[N:8]1.CN(C=O)C>O>[N:7]1([CH2:12][C:13]([N:15]2[CH2:16][C@@H:17]([NH2:37])[CH2:18][C@H:19]2[C:20]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[CH:26][CH:27]=2)=[O:36])=[O:14])[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: C1COCCN1
Solvent: O
Product: N[C@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
Step (a) Morpholine (10 mL) was added to a flask charged with the (9H-fluoren-9-yl)methyl (3S,5S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-5-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidin-3-ylcarbamate (0.859 g, 1.33 mmol), prepared as in prepared as in Example 1, and DMF (10 mL). The reaction mixture was stirred at ambient temperature for 30 minutes and then diluted with deionized water (20 mL). The dilution was extracted with ethyl acetate (60 mL) and the extract was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-amino-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (0.465 g, 1.10 mmol), which was carried forward without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]([OH:12])=[CH:5][CH:4]=1.[F:13][C:14]([F:27])([F:26])[C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[NH2:18]>>[F:13][C:14]([F:26])([F:27])[C:15]1[CH:16]=[C:17]([NH:18][C:8](=[O:10])[C:7]2[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[OH:12])[CH:19]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:21]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccc(O)c(C(=O)O)c1
Product: COc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 56.8 %

Procedure:
Using 5-methoxysalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]=[CH:7][C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[BH4-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]=[CH:7][C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC1=NN=C(C=Cc2ccc(F)cc2)c2cc3c(cc2C1)OCO3
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1Cc2cc3c(cc2C(C=Cc2ccc(F)cc2)=NN1)OCO3
Reaction time: 2 h

Procedure:
To a mixture of 2.0 g (6.2 mmoles) of 1-(4-fluorostyryl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine prepared according to Example 86 and 10 ml of glacial acetic acid a solution of 3.0 g (79 mmoles) of sodium borohydride in 10 ml of water is added in small portions, while the temperature of the reaction mixture is kept below 35° C. The mixture is then stirred for further 2 hours and made alkaline by adding some sodium carbonate solution to it. The alkaline solution is extracted three times with 20 ml of ethyl acetate. The ethyl acetate phases are dried, evaporated and the evaporation residue is crystallized from ethanol. The crude product is purified by recrystallization from ethanol. Thus 1.39 g (69%) of substance pure on TLC is obtained. M.p.: 170-174° C.
Reaction SMILES: [CH:1]1([SH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CS([C:13]1[S:14][C:15]([C:30]2[CH:34]=[CH:33][NH:32][N:31]=2)=[C:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[C:18](=[O:29])[C:17]=12)(=O)=O>C1COCC1>[CH:1]1([S:6][C:13]2[S:14][C:15]([C:30]3[CH:34]=[CH:33][NH:32][N:31]=3)=[C:16]3[CH2:21][CH2:20][NH:19][C:18](=[O:29])[C:17]=23)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3cc[nH]n3)sc(S(C)(=O)=O)c2C1=O
Reactant: SC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCCc2c(-c3cc[nH]n3)sc(SC3CCCC3)c21
Temperature: 25 °C

Procedure:
To a solution of cyclopentanethiol (54 μL, 0.50 mmol) in THF (0.5 mL) at 0° C. was added NaH (20.0 mg, 0.50 mmol). The reaction mixture was warmed to rt and tert-butyl 3-(methylsulfonyl)-4-oxo-1-(1H-pyrazol-3-yl)-6,7-dihydrothieno[3,4-c]pyridine-5(4H)-carboxylate (100 mg, 0.25 mmol) was added, After 30 min, the reaction was quenched with aqueous NH4Cl and extracted with CH2Cl2. The combined extracts were dried (Na2SO4) and concentrated. Purification by silica gel chromatography (gradient elution, 0-100% EtOAc /hexanes) afforded the title compound. 1H NMR (400 MHz, ppm, CD3OD) δ 7.73 (d, J=2.3 Hz, 1 H); 6.50 (d, J=2.4 Hz, 1 H); 3.77 (m, 1 H); 3.44 (t, J=6.2 Hz, 2 H); 3.04 (t, J=6.3 Hz, 2 H); 2.32-2.22 (m, 2 H); 1.85-1.77 (m, 2 H); 1.76-1.65 (m, 4 H). HRMS (ES+) m/z 320.0879 [(M+H)+; calcd for C15 H17N3OS2: 320.0886].
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH:8]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1)C=C.[CH2:24]1[CH:33]2C(CCCC2)CC[CH2:25]1>>[CH2:33]([C:6]1[C:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:8][C:9]2[C:14](=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[C:5]=1[OH:4])[CH:24]=[CH2:25]
Reactant: C=CCOc1cc(-c2ccccc2)cc2ccc([N+](=O)[O-])cc12
Reactant: C1CCC2CCCCC2C1
Product: C=CCc1c(-c2ccccc2)cc2ccc([N+](=O)[O-])cc2c1O
Temperature: 180 °C

Procedure:
31 g of 1-Allyloxy-3-phenyl-7-nitro-naphthalene prepared in step (3) were gradually heated to 180° C. in 390 ml of decaline, the solution being stirred and maintained under nitrogen. The temperature of 180° C. was maintained for about 1 hour. After cooling, the crystals formed were washed with petroleum ether, filtered off and dried at 80° C. under reduced pressure.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:25]([F:28])([F:27])[F:26])=[C:18]([C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCN(C2N=NC(C(F)(F)F)=C(C3C=CC(F)=CC=3)C=2)CC1)=O)(C)(C)C>CO>[N:11]1([C:14]2[N:15]=[N:16][C:17]([C:25]([F:27])([F:26])[F:28])=[C:18]([C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[CH:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccsc3)c(C(F)(F)F)nn2)CC1
Agent: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(F)cc3)c(C(F)(F)F)nn2)CC1
Solvent: CO
Product: FC(F)(F)c1nnc(N2CCNCC2)cc1-c1ccsc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To a solution of 4-[5-(3-thienyl)-6-trifluoromethyl-pyridazin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.074 g, 0.18 mmol), prepared by procedures similar to those described for D8, in methanol (5 ml) was added Amberlyst® 15 ion exchange resin, acidic form (4.1 mmol/g) (0.218 g, 0.89 mmol) and the reaction mixture was shaken at room temperature for 18 h. After this period, the mixture was filtered and then a saturated solution of ammonia in methanol was added. The mixture was shaken for 1 h, filtered and the filtrate evaporated in vacuo. The crude product was crystallized from ether/heptane to yield E7 (0.049 g, 87%). C13H13F3N4S requires 314; Found 315 (MH+).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCNCC3)cnc21
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCC(NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
Piperidin-4-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride (0.073 g, 0.158 mmol) was suspended in DCM (1 mL) and pyridine (0.045 mL, 0.55 mmol) was added. Acetic anhydride (0.018 mL, 0.19 mmol) was added and the resulting solution stirred at RT overnight. The solvent was evaporated. The remaining oil was purified by SiO2 chromatography (12 g SiO2, DCM:MeOH 0 to 5% MeOH) to give 0.053 g of 1-(1-acetyl-piperidin-4-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as off-white foam (78% yield).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:7][C:8]1([CH2:21][NH2:22])[C:13]2[NH:14][C:15]3[C:20]([C:12]=2[CH2:11][CH2:10][O:9]1)=[CH:19][CH:18]=[CH:17][CH:16]=3.C(N(CC)CC)C>O1CCCC1>[CH3:7][C:8]1([CH2:21][NH:22][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:13]2[NH:14][C:15]3[C:20]([C:12]=2[CH2:11][CH2:10][O:9]1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: CC1(CN)OCCc2c1[nH]c1ccccc21
Reactant: CCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)NCC1(C)OCCc2c1[nH]c1ccccc21
Yield: 94.4 %

Procedure:
Butanoyl chloride (5.3 g) is added to a stirring mixture at 0° C. of 1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-methanamine (10.0 g, described in Example 3), triethylamine (5 g) and dry tetrahydrofuran (400 ml). The temperature is allowed to rise to room temperature, the reaction mixture is filtered, and the filtrate is evaporated to give the title compound (12.5 g): ir(CHCl3) 3420, 3250, 2855 and 1660 cm-1 ; nmr(CDCl3) δ0.75(t), 1.57(s), 1.62(m), 2.08(t), 2.87(m), 3.91(t), 4.10(t), 6.12(s), 7.0-7.7(m) and 9.86(s)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(C(C)C)C(C)C)C.[CH3:74][N:75]1[CH:79]=[CH:78][N:77]=[C:76]1[SH:80].[ClH:81]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[ClH:81].[ClH:81].[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[N:11][CH:12]=[C:13]([S:80][C:76]2[N:75]([CH3:74])[CH:79]=[CH:78][N:77]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Reactant: Cn1ccnc1S
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(Nc2ncc(Sc3nccn3C)cc2OCc2ccccc2)n1
Yield: 49 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.125 g, 0.332 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.0192 g, 0.0332 mmol), Pd2dba3 (0.0152 g, 0.0166 mmol), N-ethyl-N-isopropylpropan-2-amine (0.116 ml, 0.664 mmol), 1-methyl-1H-imidazole-2-thiol (0.0379 g, 0.332 mmol) were reacted according to Example 42 to provide 3-(benzyloxy)-5-(1-methyl-1H-imidazol-2-ylthio)-N-(4-methylthiazol-2-yl)pyridin-2-amine dihydrochloride (0.0786 g, 49.0% yield) after HCl salt formation. 1H NMR (DMSO-d6) δ 8.16 (d, 1H), 7.81 (d, 1H), 7.78 (s, 1H), 7.73 (d, 1H), 7.53 (d, 2H), 7.41-7.34 (m, 3H), 6.74 (s, 1H), 5.31 (s, 2H), 3.85 (s, 3H), 2.46 (s, 3H). Mass spectrum (apci) m/z=410.0 (M+H-2HCl).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2].C1(P(=[CH:34][C:35]([O:37][CH3:38])=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:34][C:35]([O:37][CH3:38])=[O:36])=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: COc1cc(C=O)ccc1NC(C)=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(NC(C)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.6 %

Procedure:
To a solution of 4-acetamido-3-methoxybenzaldehyde (388 mg) in tetrahydrofuran (10 ml) was added methyl (triphenylphosphoranylidene)acetate (739 mg), and the mixture was stirred for 2 hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=30:1, V/V) to give methyl 4-acetamido-3-methoxycinnamate (113 mg).
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:29])=[CH:30][CH:31]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[O:10][C:9]=2[CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1oc(-c2ccc(F)cc2F)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Product: Cc1oc(-c2ccc(F)cc2F)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 75.7 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-({cyclohexyl[5-(2,4-difluorophenyl)-2-methyl-3-furyl]methyl}amino)benzoic acid (511 mg) as well as ethyl 3-(methylamino)propanoate (197 mg) to give the title compound (464 mg, 76%) as an amorphous compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].I[CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24].C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: FC(F)(F)CCI
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(CCC(F)(F)F)c2cc([N+](=O)[O-])c(N)cc21
Yield: 14.1 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (2 g) is alkylated in a high pressure reaction vessel using 1-iodo-3,3,3-trifluoro-propane (1.8 ml; 15.2 mmol) and K2CO3 (2.1 g; 15.2 mmol) at 60° C. for 14 days After aqueous work-up and purification by RP chromatography the pure material (0.38 g; 1.07 mmol) is de-acetylated in MeOH (80 ml) using DBU (0.3 ml) at reflux. After aqueous work-up 5-amino-3,3-dimethyl-6-nitro-1-(3,3,3-trifluoro-propyl)-1,3-dihydro-indol-2-one (0.34 g) is obtained and used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[C:30]12([NH2:40])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:40][C:30]34[CH2:31][CH:32]5[CH2:38][CH:36]([CH2:35][CH:34]([CH2:33]5)[CH2:39]3)[CH2:37]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NC34CC5CC(CC(C5)C3)C4)n2)cc1
Yield: 8 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 27 mg, 0.078 mmol) in 1.5 mL of ethanol was added 10 L of triethylamine and 1-Adamantanamine (12 mg, 0.078 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (3 mg, 8% yield.) MS/ES+: m/z=465.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](Cl)=[O:10].[Cl:12][C:13]1[CH:27]=[CH:26][C:16]([CH2:17][N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH2:20][NH:19]2)=[CH:15][CH:14]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:19]1[CH2:20][C:21](=[O:25])[NH:22][C:23](=[O:24])[N:18]1[CH2:17][C:16]1[CH:26]=[CH:27][C:13]([Cl:12])=[CH:14][CH:15]=1)=[O:10]
Reactant: O=C(Cl)Cc1ccccc1Cl
Reactant: O=C1CNN(Cc2ccc(Cl)cc2)C(=O)N1
Solvent: c1ccccc1
Product: O=C1CN(C(=O)Cc2ccccc2Cl)N(Cc2ccc(Cl)cc2)C(=O)N1
Yield: 18.3 %

Procedure:
Into a 100 ml round bottomed flask fitted with a reflux condenser sealed with a calcium chloride tube and a magnetic stirrer, were placed 55 g of 2-chlorophenylacetyl chloride and 20 ml of dry benzene. Stirring was commenced and 1 g of 2-(4'-chlorobenzyl)-hexahydro-1,2,4-triazine-3,5-dione was added in one portion and the mixture was stirred and refluxed for 8 hours. The mixture was then cooled and the precipitated crystals were filtered off and recrystallized from isopropanol to yield 0.3 g of 1-(2'-chlorophenylacetyl)-2-(4'-chlorobenzyl)-hexahydro-1,2,4-triazine-3,5-dione; m.p. 224°.
Reaction SMILES: Br[C:2]1[C:3]([CH3:28])=[C:4]([N:8]([CH2:13][C:14]2[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[C:16]([CH3:27])[CH:15]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH2:9]([N:8]([CH2:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[C:16]([CH3:27])[CH:15]=1)[C:4]1[C:3]([CH3:28])=[C:2]([C:33]2[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=2)[CH:7]=[CH:6][CH:5]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Reactant: OB(O)c1ccc(Cl)cc1
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(Cl)cc2)c1C

Procedure:
Prepared from ethyl (4-{[(3-bromo-2-methylphenyl)(butyl)amino]methyl}-2-methylphenoxy)acetate and 4-chlorophenylboronic acid using the procedure described for Example 25 (Method A).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[CH:6]([CH:9]=[CH:10][N:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12](Cl)=[O:13])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:6]([CH:9]=[CH:10][N:11]([C:15]([CH3:17])([CH3:16])[CH3:18])[C:12]([N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)=[O:13])([CH3:8])[CH3:7]
Reactant: CC(C)C=CN(C(=O)Cl)C(C)(C)C
Reactant: c1cn[nH]c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)C=CN(C(=O)n1cccn1)C(C)(C)C
Temperature: 40 °C
Reaction time: 10 h
Yield: 64.4 %

Procedure:
27.2 g (0.2 mole) of pyrazole, 1 g of 4-dimethylaminopyridine and 40.6 g (0.2 mole) of N-(2-isopropylvinyl)-N-tert.-butylcarbamyl chloride are added in succession to a suspension of 42 g of potassium carbonate in 150 ml of dry methylene chloride at 20° C. The mixture is stirred for 10 hours at 40° C., after which the resulting precipitate is filtered off under suction and washed with 200 ml of methylene chloride. The filtrate is washed with three times 80 ml of water, dried over Na2SO4 and evaporated down under reduced pressure, and the oil which remains is evaporated down under reduced pressure. 30.3 g of 1-(N-(2-isopropylvinyl)-N-tert.-butylcarbamyl)-pyrazole are obtained as a colorless liquid of boiling point 104°-105° C./0.3 mbar and nD 1.4828 (Compound No. 3).