Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:39]([O:43][C:44]([N:46]1[CH2:50][CH:49]([C:51]#[N:52])[CH2:48][CH:47]1[C:53]1[NH:54][C:55]([C:58]2[CH:67]=[CH:66][C:65]3[C:60](=[CH:61][CH:62]=[C:63](Br)[CH:64]=3)[CH:59]=2)=[CH:56][N:57]=1)=[O:45])([CH3:42])([CH3:41])[CH3:40].C([O-])([O-])=O.[K+].[K+]>COCCOC.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:39]([O:43][C:44]([N:46]1[CH2:50][CH:49]([C:51]#[N:52])[CH2:48][CH:47]1[C:53]1[NH:54][C:55]([C:58]2[CH:67]=[CH:66][C:65]3[C:60](=[CH:61][CH:62]=[C:63]([C:26]4[CH:25]=[CH:24][C:23]([C:20]5[NH:19][C:18]([CH:17]6[CH2:16][C:13]7([CH2:14][CH2:15]7)[CH2:12][N:11]6[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=5)=[CH:28][CH:27]=4)[CH:64]=3)[CH:59]=2)=[CH:56][N:57]=1)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CC(C#N)CC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC(C#N)CN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Temperature: 25 °C
Yield: 51 %

Procedure:
[2-Methyl-1-(6-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl ester (997 mg, 1.91 mmol), 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester, Pd(PPh3)4 (184 mg, 0.159 mmol), and K2CO3 (2 M in H2O, 1.9 mL, 3.8 mmol) were combined in 1,2-dimethoxyethane (16 mL). The reaction mixture was degassed with bubbling N2 for 10 minutes then heated to reflux for 3.5 h. After heating, the reaction mixture was cooled to RT, diluted with EtOAc and washed with H2O and brine. The organic phase was dried over MgSO4, then filtered and concentrated. The resulting residue was purified with silica column chromatography 0% to 100% (10% MeOH/DCM)/EtOAc to afford the title compound (641 mg, 51%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH:17]1([C:23](O)=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([C:23]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)C1CCCCC1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(C2CCCCC2)o1
Yield: 82 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using cyclohexanecarboxylic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 233 mg, 82%) which was obtained as a white solid. MS: m/e 362.3 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:17]=2)=[CH:11][C:10]=1[C:25]#[N:26])C1C=CC=CC=1>CO.C1COCC1.[C].[Pd]>[C:25]([C:10]1[CH:11]=[C:12]([C:16]2[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:17]=2)[CH:13]=[C:14]([F:15])[C:9]=1[OH:8])#[N:26]
Reactant: COC(=O)c1ccc(-c2cc(F)c(OCc3ccccc3)c(C#N)c2)s1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(F)c(O)c(C#N)c2)s1

Procedure:
Methyl 5-[4-(benzyloxy)-3-cyano-5-fluorophenyl]thiophene-2-carboxylate was stirred at room temperature in methanol-THF (1:1) under a hydrogen atmosphere at normal pressure in the presence of palladium-carbon to obtain methyl 5-(3-cyano-5-fluoro-4-hydroxyphenyl)thiophene-2-carboxylate. FN: 276.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:3]=1[C:4]#[N:5].[C:16]([O:19][CH2:20][C:21](Cl)=[O:22])(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([O:19][CH2:20][C:21]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[C:3]=1[C:4]#[N:5])=[O:22])(=[O:18])[CH3:17]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N#Cc1c(N)cccc1N1CCOCC1
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1cccc(N2CCOCC2)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-morpholinobenzonitrile (5.6 g) in pyridine (15 ml) is added dropwise acetoxyacetyl chloride (3.3 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, pyridine is distilled off under reduced pressure and thereto is added water, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is recrystallized from ethanol-toluene-water to give the title compound (4.7 g) having the following physical properties.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.O=S(Cl)Cl.[CH3:15]O>>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:15])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](O)CC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of (trans)-4-hydroxycyclohexanecarboxylic acid (4.32 g, 30 mmol) in MeOH (20 mL) was added SOCl2 (7.08 g, 60 mmol, 2.0 eq) dropwise at rt. Then the mixture was stirred at 70° C. for 18 h, and the solvent was removed in vacuo to give the title compound as a colorless oil (4.74 g, yield: 100%). 1H NMR (400 MHz, DMSO-d6) δ: 4.33 (br, 1H), 3.68-3.60 (m, 1H), 3.57 (s, 3H), 2.37-2.31 (m, 1H), 1.82-1.74 (m, 2H), 1.53-1.45 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:31])[CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][N:11]=[CH:10]2)[CH3:2].FC(F)(F)S(O[CH2:39][CH:40]([F:42])[F:41])(=O)=O>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]([CH2:39][CH:40]([F:42])[F:41])[N:11]=[CH:10]2)[CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:31])[CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[CH3:2]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc2cn[nH]c2cc1C
Product: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc2cnn(CC(F)F)c2cc1C
Yield: 70.9 %

Procedure:
Using the compound (1.92 g, 4.37 mmol) of Example 244, step B and 2,2-difluoroethyl trifluoromethanesulfonate (1.49 g, 6.96 mmol), and according to the method of Example 241, step C, the title compound (1.56 g, yield 71%) was obtained as a colorless amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:19][CH2:20][NH:21][C:22]2[C:31]3[C:26](=[C:27]([F:33])[CH:28]=[CH:29][C:30]=3[F:32])[N:25]=[CH:24][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=1.[CH:34]([Sn](CCCC)(CCCC)CCCC)=[CH2:35].C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[F:32][C:30]1[CH:29]=[CH:28][C:27]([F:33])=[C:26]2[C:31]=1[C:22]([NH:21][CH2:20][CH2:19][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=3)=[C:2]([CH:34]=[CH2:35])[CH:3]=1)=[N:23][CH:24]=[N:25]2
Reactant: Fc1ccc(F)c2c(NCCc3ccc(Oc4cc(C(F)(F)F)ccn4)c(Br)c3)ncnc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: C=Cc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1Oc1cc(C(F)(F)F)ccn1
Reaction time: 20 h
Yield: 46.7 %

Procedure:
{2-[3-Bromo-4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-(5,8-difluoroquinazolin-4-yl)-amine (890 mg, 1.7 mmol), vinyl tri-n-butyltin (591 mg, 544 μL, 1.9 mmol), 1,4-bis(diphenylphosphino)butane (145 mg, 0.3 mmol), 2,6-di-tert-butyl-4-methylphenol (75 mg, 0.3 mmol) and Pd(OAc)2 (49 mg, 0.22 mmol) were added to a Carousel reactor tube containing toluene (5 mL) and fitted with a magnetic stir bar and a dry nitrogen gas line. The reaction mixture was heated to reflux. After 20 h, more Pd(OAc)2 (49 mg, 0.22 mmol) was added, and heating was continued. After another 20 h, the reaction was cooled. The reaction mixture was washed sequentially with water and brine, then dried (Na2SO4), filtered through a silica gel and Celite plug, and concentrated in vacuo. The residue was partitioned between acetonitrile (30 mL) and pentane (5×20 mL). The acetonitrile fraction then was purified by normal phase chromatography (silica gel with ethyl acetate/cyclohexane eluent) and reverse phase chromatography (C-18 solid phase with acetonitrile/water eluent, 0.5% H3PO4) to provide (5,8-difluoroquinazolin-4-yl)-{2-[4-(4-trifluoromethylpyridin-2-yloxy)-3-vinylphenyl]-ethyl}-amine as a white powder (375 mg), M.P. 86°. 1H NMR (CDCl3): δ 8.7 (s, 1H), 8.31 (d, 1H), 7.54 (d, 1H), 7.35 (m, 1H), 7.24 (m, 1H), 7.18 (m, 1H), 7.14 (s, 1H), 7.06 (d, 1H), 6.78 (bm, 2H), 5.76 (d, 1H), 5.26 (d, 1H), 3.97 (m, 2H), 3.07 (t, 2H). MS: m/z 472.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:4]=1.F[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[C:5]([C:10]([F:11])([F:12])[F:13])[CH:4]=1
Reactant: COc1ccc(O)c(C(F)(F)F)c1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Oc2ccc(C#N)cc2)c(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A solution of 4 g (20.82 mmol) of 4-methoxy-2-trifluoromethyl-phenol and 2.52 g (20.82 mmol) of 4-fluorobenzonitrile in 60 mL DMSO was combined with 5.75 g (41.64 mmol) of potassium carbonate and stirred for 3 h at 120° C. The reaction mixture was diluted with water, and extracted three times with dichloromethane. The organic phase was washed twice with water, dried on sodium sulphate and evaporated down. The residue was purified by chromatography (reversed phase).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:26]=[C:27]([CH3:38])[C:28]([O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:30]=[N:29][C:28]([O:31][CH:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[C:27]([CH3:38])[CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(Br)cnc1OC1CCOCC1
Product: Cc1cc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)c(Cl)c2)cnc1OC1CCOCC1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 5-bromo-3-methyl-2-(tetrahydro-pyran-4-yloxy)-pyridine (Intermediate 24) in analogy to Example 1a): MS (ISN): 493.1 and 495.2 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:13][C:14](=[O:15])[C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:33])[C:29]([F:32])([F:30])[F:31])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:8]=[C:9]([F:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(F)c[nH]1
Reactant: O=C(CBr)c1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(F)cn1CC(=O)c1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1
Temperature: 25 °C

Procedure:
4-Fluoro-1H-pyrrole-2-carboxylic acid ethyl ester (1.07 g; 6.83 mmol) and 1-{4-[4-(2-bromo-acetyl)-phenyl]-piperidin-1-yl}-2,2,2-trifluoro-ethanone (2.00 g; 5.26 mmol) are dissolved in acetone (20 ml). To this clear brown solution potassium carbonate (1.45 g; 10.51 mmol) is added and the reaction mixture is stirred at ambient temperature over night. The reaction mixture is diluted with acetone, filtered off by suction and washed with acetone. The filtrate is evaporated to dryness. The crude product is purified by flashchromatography to afford 4-fluoro-1-(2-oxo-2-{4-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl]-phenyl}-ethyl)-1H-pyrrole-2-carboxylic acid ethyl ester as off-white solid; HPLC/MS 2.67 min (A), [M+H] 455.
Reaction SMILES: C(O[CH2:5][C@@H:6]([O:23]S(C)(=O)=O)[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.C1COCC1.C([O-])([O-])=O.[K+].[K+]>CO>[O:23]1[CH2:5][C@H:6]1[C@@H:7]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)OC[C@@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
To a suitable reactor was added 5 (2 g, 4.98 mmol), THF (20 mL), MeOH (20 mL), and K2CO3 (1.5 g, 10.96 mmol) at 20-30° C. under N2. The mixture was stirred at 20-30° C. for 15 hr. The mixture was filtered, and the filtrate was concentrated at 40-50° C. under reduced pressure to yield a pale yellow oil. After being purified by flash column chromatography, 6 was obtained as a white solid in 90% yield.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:11]1[C:15]([CH2:16][CH3:17])=[CH:14][CH:13]=[C:12]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1)[CH2:9][CH3:10].[O-:26][C:27]#[N:28].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CO>[CH2:8]([N:11]1[C:15]([CH2:16][CH3:17])=[CH:14][CH:13]=[C:12]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:27]([NH2:28])=[O:26])[CH:20]=1)[CH2:9][CH3:10]
Reactant: N#C[O-]
Reactant: CCCn1c(CC)ccc1Cc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCn1c(CC)ccc1Cc1cccc(NC(N)=O)c1
Yield: 74.5 %

Procedure:
A solution of 3.5 ml (39 mmol) of trifluoroacetic acid in 200 ml of methylene chloride was added dropwise, over a 2 hour period and under nitrogen atmosphere, to a stirred suspension of 4.8 g (19 mmol) of 1-propyl-2-(3'-aminobenzyl)-5-ethylpyrrole and 2.58 g (39 mmol) of sodium cyanate in 400 ml of anhydrous methylene chloride and 90 ml of methanol. The reaction mixture was stirred at room temperature for 18 additional hours, 2 g (18 mmol) of sodium carbonate were added and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on 300 g of silica gel, using hexane-acetone (1:1) as eluant, obtaining 4.04 g (72%) of the title compound, 1-propyl-2-(3'-ureidobenzyl)-5-ethylpyrrole, which was recrystallized from ether-hexane. M.P. 116°-118° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].CS([C:11]1[N:16]=[C:15]([CH3:17])[C:14]([C:18]([O:20][CH2:21][CH2:22][C:23]([CH3:27])=[C:24]([F:26])[F:25])=[O:19])=[CH:13][N:12]=1)(=O)=O.C(N(CC)CC)C>O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:11]1[N:16]=[C:15]([CH3:17])[C:14]([C:18]([O:20][CH2:21][CH2:22][C:23]([CH3:27])=[C:24]([F:26])[F:25])=[O:19])=[CH:13][N:12]=1
Reactant: OCCCCCl
Reactant: CC(CCOC(=O)c1cnc(S(C)(=O)=O)nc1C)=C(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: CC(CCOC(=O)c1cnc(OCCCCCl)nc1C)=C(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 27.7 %

Procedure:
To 1.02 g (9.4 mmol) of 4-chlorobutanol was dissolved 1.00 g (3.1 mmol) of 4,4-difluoro-3-methyl-3-butenyl 2-methanesulfonyl-4-methylpyrimidine-5-carboxylate, followed by the addition of 0.38 g (3.8 mmol) of triethylamine under ice-cooling and stirring at room temperature for 14 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 0.30 g (yield: 27%) of 4,4-difluoro-3-methyl-3-butenyl 2-(4-chlorobutoxy)-4-methylpyrimidine-5-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].O[C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)[C@@H](C)O
Reactant: Cc1ccc(O)c(Cl)c1
Product: COC(=O)[C@H](C)Oc1ccc(C)cc1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the 2-chloro-4-methylphenol instead of the m-cresol and the (R)-methyl 2-hydroxypropanoate instead of the (S)-methyl 2-hydroxypropanoate.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([CH2:7][C:8](O)=[O:9])#[N:6].C(N=C=NC(C)C)(C)C.O>O1CCCC1.CC#N>[CH:1]1([NH:4][C:8](=[O:9])[CH2:7][C:5]#[N:6])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: N#CCC(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: N#CCC(=O)NC1CC1
Temperature: 20 °C
Reaction time: 20 h
Yield: 84.1 %

Procedure:
Cyclopropylamine (5.0 grams, 88 mmole) was combined with 7.5 grams (g) (88 mmol) of cyanoacetic acid in 50 milliliters (ml) tetrahydrofuran (THF) and 50 ml CH3CN. Diisopropylcarbodiimide (20 g, 97 mmol) dissolved in 10 ml THF was added dropwise. The reaction mixture exothermed and a white precipitate formed. The mixture was stirred at 20° C. for 20 hours, 5 ml water was added and the reaction mixture was stirred another 5 minutes. The precipitate was filtered off and the filtrate evaporated giving a white solid which was then recrystallized to yield 9.2 g (74 mmol) of N-(cyclopropyl)-2-cyanoacetamide, a white solid (m.p. 104°-106° C.) (84% yield).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])=[CH:7][C:6]=1[Cl:27].[NH:28]1[CH2:32][CH:31]=[CH:30][CH2:29]1>CCN(C(C)C)C(C)C>[Cl:27][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:28]1[CH2:32][CH:31]=[CH:30][CH2:29]1
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCBr)c(Cl)c1
Reactant: C1=CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCN2CC=CC2)c(Cl)c1

Procedure:
A solution of 0.145 g (0.300 mmol) of N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and 30.6 μL (0.400 mmol) 2,5-dihydro-1H-pyrrole in 2 mL Hünig base was stirred for 3h at 80° C. and then evaporated down i. vac. Column chromatography (Alox, neutral, act. II-III, gradient dichloromethane/MeOH 20:0→19:1) yielded the product.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:15]1([N:21]=[C:22]=[S:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:22]([NH:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[S:23])=[CH:13][CH:14]=1
Reactant: Clc1ccc(CNC2CCCC2)cc1
Reactant: S=C=Nc1ccccc1
Product: S=C(Nc1ccccc1)N(Cc1ccc(Cl)cc1)C1CCCC1
Yield: 92.8 %

Procedure:
Analogously to Example 1, 21 grams (0.1 mole) of N-4-chlorobenzyl-N-cyclopentylamine were reacted with 13.5 grams (0.1 mole) of phenylisothiocyanate. 32 grams of N-4-chlorobenzyl-N-cyclopentyl-N'-phenylthiourea were obtained. Yield: 92%, Melting point: 129°-132° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][C:16]([N:19]([CH3:30])[CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)=[CH:17][CH:18]=2)=[C:9]([O:31][CH3:32])[CH:8]=1)(=O)=O.[NH:35]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>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].O.O1CCOCC1>[CH3:32][O:31][C:9]1[CH:8]=[C:7]([C:38]2[CH:39]=[N:35][NH:36][CH:37]=2)[CH:12]=[CH:11][C:10]=1[C:13]1[N:14]=[N:15][C:16]([N:19]([CH3:30])[CH:20]2[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23][C:24]([CH3:26])([CH3:27])[CH2:25]2)=[CH:17][CH:18]=1
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Reactant: OB(O)c1cn[nH]c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2cn[nH]c2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 100 °C

Procedure:
To a microwave vial was added 3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl trifluoromethanesulfonate (60 mg, 0.12 mmol), 1H-pyrazole-4-boronic acid (25.5 mg, 0.13 mmol), potassium phosphate (76 mg, 0.36 mmol), Pd2(dba)3 (6 mg, 5.9 umol), and SPhos (5 mg, 0.012 mmol), followed by addition of 1,4-dioxane (1 mL)/H2O (0.2 mL). The vial was purged with N2 for 10 minutes and the reaction mixture was heated at 100° C. in the microwave for one hour. The reaction mixture was concentrated in vacuo, and the crude product was adjusted to pH 3 using 1 M aqueous HCl, then loaded on an SCX column. The crude product was washed with methanol then eluted with 2 N ammonia in methanol. The product fractions were collected and dried to afford 6-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (MS: 421.4 [M+H+].).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:4][CH2:3]1.[CH:23](=O)[CH2:24][CH2:25][CH2:26][CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][C:2]1([CH3:22])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:17]2)=[CH:4][CH2:3]1
Reactant: CCCCC=O
Reactant: COc1ccc(C2=CCC(C)(C)CC2)c(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCN1CCN(c2cc(OC)ccc2C2=CCC(C)(C)CC2)CC1
Reaction time: 3 h
Yield: 102.4 %

Procedure:
To a solution of 1-[2-(4,4-dimethylcyclohex-1-enyl)-5-methoxyphenyl]piperazine (90 mg, 0.29 mmol) prepared in Example (1e) in tetrahydrofuran (10 mL) were added valeraldehyde (31 mg, 0.36 mmol), sodium triacetoxyborohydride (95 mg, 0.59 mmol) and acetic acid (35 mg, 0.59 mmol) in that order, and the mixture was stirred for 3 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off and then the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 110 mg of 1-[2-(4,4-dimethylcyclohex-1-enyl)-5-methoxyphenyl]-4-pentylpiperazine as a light yellow oil.