Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][C:9]1[CH2:10][S:11][C@@H:12]2[C@H:32]([NH:33][C:34](=[O:41])[CH2:35][C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[C:31](=[O:42])[N:13]2[C:14]=1[C:15]([O:17][CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[C:43](Cl)(=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45]>O1CCCC1>[C:43]([O:7][CH2:8][C:9]1[CH2:10][S:11][C@@H:12]2[C@H:32]([NH:33][C:34](=[O:41])[CH2:35][C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[C:31](=[O:42])[N:13]2[C:14]=1[C:15]([O:17][CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])(=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 16 h
Yield: 74.5 %

Procedure:
A solution of pyridine (2.4 ml.) in dry tetrahydrofuran (5 ml.) was added to a stirred solution of diphenylmethyl 3-hydroxymethyl-7β-(thien-2-yl)acetamido-ceph-3-em-4-carboxylate (3.12 g) and pivaloyl chloride (7.2 g) in dry tetrahydrofuran (150 ml) at 20°. The solution was stirred at 20° for 16 hours, filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with sodium bicarbonate solution, 2 N-hydrochloric acid, sodium bicarbonate solution, water and brine. The dried solution was concentrated under reduced pressure to give a solid residue that was triturated with ether to give the title ester (2.7 g; 75%), [α]D +5.1 (c 1.4, CHCl3), λinflex. (ethanol) 235 (ε14,100), 257 (ε8,300) and 263 nm. (ε8,050), λmax. (CHBr3) 1787 (β-lactam), 1722 (ester), 1680 and 1510 cm.-1 (CONH) τ (CDCl3) values include 8.81 (singlet; C(CH3)3).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10]([O:13][C:14]1[C:15]([CH3:43])=[C:16]2[C:21](=[C:22]([CH3:25])[C:23]=1[CH3:24])[O:20][C:19]([CH2:27][O:28][C:29]1[CH:42]=[CH:41][C:32]([CH2:33][CH:34]3[S:38][C:37](=[O:39])[NH:36][C:35]3=[O:40])=[CH:31][CH:30]=1)([CH3:26])[CH2:18][CH2:17]2)(=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:10]([O:13][C:14]1[C:15]([CH3:43])=[C:16]2[C:21](=[C:22]([CH3:25])[C:23]=1[CH3:24])[O:20][C:19]([CH2:27][O:28][C:29]1[CH:42]=[CH:41][C:32]([CH2:33][CH:34]3[S:38][C:37](=[O:39])[N:36]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:35]3=[O:40])=[CH:31][CH:30]=1)([CH3:26])[CH2:18][CH2:17]2)(=[O:12])[CH3:11]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(CC3SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.87 g of t-butyl bromoacetate was added dropwise, whilst ice-cooling, to a mixture of 1 g of 5-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl ]thiazolidine-2,4-dione [prepared as described in Example 3(b) of copending U.S. Ser. No. 644,996], 0.43 g of anhydrous potassium carbonate, and 8 ml of acetone. The resulting mixture was stirred for 2 hours at room temperature and then allowed to stand for 2 days, also at room temperature. The reaction mixture was then poured into ice-water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (eluent:benzene) to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].CC(N=NC(C#N)(C)C)(C#N)C.Cl[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1.Cl>C1COCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[N:23][C:18]=1[CH2:1][C:2]([CH3:4])=[O:3]
Reactant: CC(C)=O
Reactant: Clc1ncccn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)Cc1ncccn1
Reaction time: 0.25 h
Yield: 41.6 %

Procedure:
In a 100 mL flask, acetone (1.44 mL, 19.6 mmol) was added to KH (30% in oil, 2.89 g, 21.6 mmol) in THF (15 mL) at 0° C. under nitrogen. The reaction mixture was stirred for 0.25 h then additional THF (15 mL) was added. AIBN (74 mg, 0.45 mmol) followed by 2-chloropyrimidine (500 mg, 4.36 mmol) were added cautiously and the reaction mixture kept at 0° C. for 1 h. HCl 3N was added until the pH=6. The two layers were separated and the aqueous phase extracted with dichloromethane. The combined extracts were dried over Na2SO4 then concentrated. The residue was purified on column chromatography (eluent: EtOAc/pentane 20/80 to 80/20) to give the title compound (247 mg, 42%) as a yellow oil (keto/enol form 2:1).
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16][C:17]([OH:19])=O.C(N(CC)CC)C.[NH2:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)Cl>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16][C:17]([NH:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:19]
Reactant: CCOC(=O)c1ccccc1N
Reactant: O=C(O)C=Cc1ccco1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1NC(=O)C=Cc1ccco1
Yield: 30.2 %

Procedure:
Under nitrogen stream, 2-chloro-1-methylpyridinium iodide (1.272 g, 4.34 mmol) was suspended in dry methylene chloride (5 ml). To the suspension a solution of 3-(2-furyl)acrylic acid (500 mg, 3.62 mmol), triethylamine (1.2 ml, 8.69 mmol), and ethyl 2-aminobenzoate (0.53 ml, 3.62 mmol) in dry methylene chloride (5 ml) was added. The mixture was heated under reflux for 40 hours. Then, the reaction mixture was diluted with methylene chloride, and washed with 10% aqueous HCl, saturated aqueous sodium chloride, 1N-aqueous NaOH, and saturated aqueous sodium chloride successively, and dried. Removal of solvent gave a viscous oil, which, on washing with n-hexane gave white solids of the title compound (312 mg, yield: 30.2%), which was recrystallized from methanol. m.p., 85°-86° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH2:49]([CH2:51][NH2:52])[OH:50]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[OH:50][CH2:49][CH2:51][NH:52][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1
Reactant: NCCO
Reactant: NC(=O)c1ccc(Br)c(/C=C/c2ccc(OC(F)(F)F)cc2)c1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: NC(=O)c1ccc(NCCO)c(/C=C/c2ccc(OC(F)(F)F)cc2)c1
Temperature: 65 °C
Reaction time: 3.5 h

Procedure:
The interior of a container containing 4-bromo-3-[(E)-2-(4-trifluoromethoxy-phenyl)-vinyl]-benzamide (50.2 mg) obtained in Example 2-5-1, 2.8 mg of tris(dibenzylideneacetone) dipalladium(0), 10 μL of ethanolamine, and 2.6 mg of 2-(dicyclohexylphosphino)biphenyl was purged with argon. A 1.0M tetrahydrofuran solution (1 mL) of lithium bis(trimethylsilyl)amide was added into the container, and the mixture was stirred for 3.5 hours at 65° C. Then, 2.0 mg of tris(dibenzylideneacetone) dipalladium(0), and 10 μL of ethanolamine were further added, the interior of the container was purged with argon, and the mixture was stirred for 13.5 hours at 65° C. The reaction mixture was cooled to room temperature, and 2 mL of 1N hydrochloric acid was added for neutralization, followed by extracting the aqueous layer with ethyl acetate 4 times. After the respective organic layers were combined, the combined organic layer was filtered through Presep Dehydration Column (produced by Wako Pure Chemical Industries), and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to 11 g silica gel column chromatography to obtain 5.6 mg of 4-(2-hydroxy-ethylamino)-3-[(E)-2-(4-trifluoromethoxy-phenyl)-vinyl]-benzamide with the use of an eluant (dichloromethane and methanol, 15:1).
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=O.[NH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)(O)[O-].[Na+]>CC(O)C>[CH3:15][C:2]1[N:16]=[C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]2[C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1
Reactant: CC(Br)C(=O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1nc2ncccn2c1-c1ccc(C(F)(F)F)cc1
Yield: 21.9 %

Procedure:
Stir a mixture of 2-bromo-1-[4-(trifluoromethyl)phenyl]propan-1-one (500 g, 1.78 mol, 1 equiv), IPA (5 L), 2-aminopyrimidine (205 g, 2.13 mol, 1.2 equiv), and sodium bicarbonate (298.8 g, 3.55 mol, 2 equiv) in a thermally controlled reactor at 80° C. for 18 hours. Cool the suspension, and concentrate in vacuo. Dilute the resulting mixture with DCM (5 L), and the wash with brine (2 L). Re-extract the brine wash with DCM (2.5 L); combine all the organic extracts; dry over MgSO4; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to a red gum. Slurry the resulting red gum in Et2O (1.5 L); filter; and collect the solid. Air dry the solid for 45 min to give the product as a fine off-white solid (108 g, 22% yield). ES/MS (m/z) 278 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](F)[CH:10]=2)[CH:5]=[N:4][CH:3]=1.C(OC(=O)[NH:19][C@H:20]1[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22][CH2:21]1)(C)(C)C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:26][C@@H:23]3[CH2:24][CH2:25][C@H:20]([NH2:19])[CH2:21][CH2:22]3)[CH:10]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Fc1ccc2cncc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Product: N[C@H]1CC[C@@H](Oc2ccc3cncc(Cl)c3c2)CC1

Procedure:
Starting from 4-chloro-6-fluoro-isoquinoline (9) and cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester the title compound was prepared as hydrochloride by the method described for trans-[4-(5-chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (10) followed by deprotection using 4M hydrochloric acid in isopropanol. Rt=0.79 min (Method #1). Detected mass: 277.1/279.1 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[C:14]([O:16][Si](C(C)C)(C(C)C)C(C)C)[CH:13]=[C:12]([CH3:27])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:11]=[C:12]([CH3:27])[CH:13]=[C:14]([OH:16])[CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(O)cc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of Intermediate 54d (300 mg, 0.38 mmol) in THF (4 mL) was added a solution of tetrabutylammonium fluoride in THF (1M, 0.49 mL, 0.49 mmol). Stirred at RT for 0.5 h, then diluted with water and extracted with DCM (5×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the impure product as a solid (210 mg). This was further purified by HPLC (XBridge C18 column, 40-85% MeCN in H2O, 0.1% NH4OH) to give the title compound (73 mg, 30%). LCMS (Method 5): Rt 4.44 min, m/z 635.3 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.57-1.65 (2H, m), 1.68-1.77 (4H, m), 1.81-1.98 (2H, m), 1.99-2.18 (2H, m), 2.27 (3H, s), 3.10-3.18 (4H, m), 4.79-4.88 (1H, m), 5.55 (1H, t, J=4.3 Hz), 6.31 (1H, s), 6.59-6.64 (1H, m), 6.67-6.71 (1H, m), 6.71-6.74 (1H, m), 7.09-7.19 (2H, m), 7.25-7.41 (4H, m), 7.58-7.65 (2H, m), 8.06 (1H, br s), 9.65 (1H, br s).
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O(C1C=CC(P2(=S)SP(=S)(C3C=CC(OC4C=CC=CC=4)=CC=3)S2)=CC=1)C1C=CC=CC=1>C1COCC1.CCOC(C)=O.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH:24]1([C:22]2[N:19]3[C:14]4[CH:13]=[CH:12][N:11]([S:1]([C:4]5[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=5)(=[O:3])=[O:2])[C:15]=4[N:16]=[CH:17][C:18]3=[CH:20][N:21]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)C4CCCCC4)cnc32)cc1
Agent: CC(=O)[O-]
Agent: S=P1(c2ccc(Oc3ccccc3)cc2)SP(=S)(c2ccc(Oc3ccccc3)cc2)S1
Agent: [Hg+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(C4CCCCC4)n23)cc1
Reaction time: 15 h
Yield: 25.9 %

Procedure:
To a solution of N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamide (0.081 g, 0.196 mmol) in THF (1 mL) at rt was added 2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (0.104 g, 0.196 mmol, TCI). After about 15 h at rt, the mixture was concentrated under reduced pressure. The residue was suspended in EtOAc/DCM (1:1) and filtered through a plug of silica gel (5 g) eluting with EtOAc/DCM (1:1, approximately 100 mL). The filtrate was concentrated under reduced pressure to provide a residue. The residue was dissolved in THF (1 mL) and mercury(II) acetate (0.0626 g, 0.196 mmol) was added. After about 30 min at rt, additional mercury(II) acetate (0.0626 g, 0.196 mmol) was added. After about 4 h at rt, the mixture was diluted with EtOAc, filtered, concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 50 to 95% EtOAc in heptane to provide 1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.020 g, 25%): LC/MS (Table 2, Method a) Rt=2.77 min; MS m/z: 395 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([N:10]1[CH2:15][CH2:14][C:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:24]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=[C:29]([CH3:37])[CH:28]=1)=[C:25]=[O:26]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:17]([C:13]1([OH:16])[CH2:14][CH2:15][N:10]([CH:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:2][NH:1][C:25]([NH:24][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[C:29]([CH3:37])[CH:28]=2)=[O:26])[CH2:11][CH2:12]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCC(c1ccccc1)N1CCC(O)(Cc2ccccc2)CC1
Reactant: Cc1cc(N=C=O)c2ccccc2n1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NCC(c2ccccc2)N2CCC(O)(Cc3ccccc3)CC2)c2ccccc2n1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 1-(2-amino-1-phenyl-ethyl)4-benzyl-piperidin-4-ol (54.3 mg, 0.18 mmol) in CH2Cl2 is added a freshly prepared solution of 4-isocyanato-2-methyl-quinoline (33.8 mg, 0.16 mmol) in toluene (2 mL). The mixture is stirred for 15 h at 20° C. Evaporation of the solvent and purification by HPLC provides the title compound.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([C:33]([F:36])([F:35])[F:34])=[N:10][C:11]2[C:16]([C:17]=1Cl)=[CH:15][C:14]([C:19]([C:27]1[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38].C[O-].[Na+].CO>>[CH2:1]([C:8]1[C:9]([C:33]([F:36])([F:35])[F:34])=[N:10][C:11]2[C:16]([C:17]=1[O:38][CH3:37])=[CH:15][C:14]([C:19]([C:27]1[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]
Reactant: Cn1cncc1C(O)(c1ccc2nc(C(F)(F)F)c(Cc3ccccc3)c(Cl)c2c1)c1ccccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1c(Cc2ccccc2)c(C(F)(F)F)nc2ccc(C(O)(c3ccccn3)c3cncn3C)cc12
Temperature: 82 °C

Procedure:
A mixture of (3-benzyl-4-chloro-2-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol•TFA (84 mg, 0.11 mmol, Example 97) and 0.5 M NaOMe in MeOH (0.80 mL, 0.40 mmol) in a sealed tube was heated at 82° C. for 24 hours. The solvent was evaporated, and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.96 (s, 1H), 8.61 (d, J=4.04 Hz, 1H), 8.28 (d, J=2.02 Hz, 1H), 8.20 (d, J=9.09 Hz, 1H), 8.00 (dd, J=2.02, 9.09 Hz, 1H), 7.96 (dd, J=2.02, 8.08 Hz, 1H), 7.80 (d, J=8.08 Hz, 1H), 7.39-7.45 (m, 1H), 7.19-7.26 (m, 2H), 7.12-7.18 (m, 1H), 7.09 (d, J=2.02 Hz, 1H), 7.06 (d, J=7.07 Hz, 2H), 4.36 (s, 2H), 3.78 (s, 3H), 3.63 (s, 3H); MS m/e 505.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]([NH2:16])[C:8]([NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[N:7][C:6]=1[CH3:22])[CH3:2].C(O)(=O)C.[N:28]([O-])=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]2[N:16]=[N:28][N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:8]2=[N:7][C:6]=1[CH3:22])=[O:23])[CH3:2]
Reactant: CCCCNc1c(N)c(NCC(C)C)nc(C)c1C(=O)OCC
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCNc1c(C(=O)OCC)c(C)nc2c1nnn2CC(C)C
Reaction time: 10 h

Procedure:
33 g. of the oil obtained in part d, 5-amino-4-butylamino-6-(2-methylpropyl)amino-2-methylnicotinic acid ethyl ester (about 0.1 mol.), are dissolved in 100 ml. of acetic acid 20 ml. of water. A solution of 0.75 g. of sodium nitrite in 20 ml. of water is added dropwise at about 10° with stirring. Stirring is continued for 10 hours. After this time, the mixture is evaporated. The resulting oil is mixed with 100 ml. of water and extracted three times with 50 ml. portions of ether. The ether phase is dried over sodium sulfate, filtered and evaporated. The residue, 7-butylamino-5-methyl-3-(2-methylpropyl) [1,2,3]triazolo[4,5-b]pyridine-6-carboxylic acid ethyl ester, is recrystallized from benzene, yield 27 g. (81%), m.p. 34°-36°.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9](Cl)=[N:10][OH:11].[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)=[N:10][OH:11]
Reactant: CC(C)(C)CCOc1cccc(C(Cl)=NO)c1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)CCOc1cccc(C(=NO)n2cncn2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To 100 ml of 1,2-dimethoxyethane were added 2.0 g (7.8 mmol) of 3-(3,3-dimethylbutoxy)benzohydroximoyl chloride, 1.9 g (27.5 mmol) of 1,2,4-triazole, and 1.5 g (10.9 mmol) of potassium carbonate. The mixture was stirred for 8 hours at about 50° C. After the resultant mixture was allowed to sit and cool naturally, the solvent in the mixture was removed. The residue was purified by column chromatography, thus obtaining the desired product of 1.2 g (yield: 46% ) .
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[CH2:19][CH2:20][NH:21][C:22]1[C:23]([C:27]([NH2:29])=[O:28])=[N:24][NH:25][CH:26]=1>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[NH:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[CH2:19][CH2:20][NH:21][C:22]1[C:23]([C:27]([NH2:29])=[O:28])=[N:24][NH:25][CH:26]=1
Reactant: NC(=O)c1n[nH]cc1NCCc1cccc(N)c1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1n[nH]cc1NCCc1cccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c1
Temperature: 20 °C
Reaction time: 12 h

Procedure:
A solution of 0.14 ml of 1-fluoro-2-isocyanato-4-trifluoromethylbenzene is added at 20° C. to a solution of 0.25 g of 4-[(3-aminobenzyl)methylamino]-1H-pyrazole-3-carboxamide in 25 ml of anhydrous THF. The reaction medium is stirred for 12 hours at 20° C. and then diluted with 100 ml of ethyl acetate. The organic phase is washed with 50 ml of distilled water, and is then separated out by settling of the phases, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue obtained is chromatographed on a column of silica (15 g of Merck cartridge silica with a particle size of 15 to 45 μm, column diameter 2.2 cm, 5 ml fractions, flow rate of 10 ml/min, eluent 95/5 dichloromethane/methanol—by volume). Fractions 35 to 95 are combined and evaporated to dryness under reduced pressure. 0.02 g of 4-({3-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]benzyl}methylamino)-1H-pyrazole-3-carboxamide is obtained in the form of a solid. ([M+H]+): 451). RT: 3.55 min (Method A).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7]O.[CH2:9]([N:11](CC)[CH2:12]C)C.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:9][N:11]([CH2:7][C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])[CH3:12]
Reactant: CCN(CC)CC
Reactant: Cc1ccsc1CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccsc1CN(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
In 200 ml of methylene chloride were dissolved 20.8 g of 3-methyl-2-thenyl alcohol and 27.1 ml of triethylamine, and 12.9 ml of thionyl chloride was added thereto dropwise at -15° C. to -10° C. over a period of 30 minutes, after which the resulting solution was further subjected to reaction at the same temperature for 30 minutes. The reaction mixture was poured into ice water, and the organic layer was separated and then dried over anhydrous magnesium sulfate. Subsequently, the dried organic layer was added dropwise with ice-cooling to a solution of 95 g of dimethylamine in 550 ml of ethanol, and the resulting mixture was allowed to stand overnight at room temperature. The solvent was removed by distillation under reduced pressure, after which 100 ml of water was added to the residue, and the resulting mixture was adjusted to pH 10 with potassium carbonate, and then extracted with 200 ml of ethyl acetate. The extract was washed with 50 ml of a saturated aqueous sodium chloride solution and dried over anhydrous potassium carbonate, after which the solvent was removed by distillation under reduced pressure, and the oily substance thus obtained was distilled under reduced pressure to obtain 19.0 g (yield 75%) of 2-(dimethylamino)methyl-3-methylthiophene having a boiling point of 85°-86° C./14 mmHg.
Reaction SMILES: ClC([N:6](C)C)=C(C)C.[NH2:9][C:10]1[C:11]([Cl:20])=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:13](O)=[O:14].N>C1COCC1>[NH2:9][C:10]1[C:11]([Cl:20])=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:13]([NH2:6])=[O:14]
Reactant: CC(C)=C(Cl)N(C)C
Reactant: Nc1c(Cl)ccc(C(=O)O)c1Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Cl)c(N)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1-Chloro-2-methyl-propenyl)-dimethyl-amine (16.1 mL, 116 mmol) is added to 3-amino-2,4-dichloro-benzoic acid (20.0 g, 97.1 mmol) in THF (320 mL). After 4 h at rt the mixture is added dropwise to conc. NH3 (320 mL) and stirred at rt overnight. The reaction mixture is concentrated, cooled and filtered. The filtercake is dried to give the sub-title compound.