Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:26]3[C:25]4[CH:24]=[C:23]([C:27]5[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=5)[CH:22]=[CH:21][C:20]=4[N:19]=[CH:18][C:17]=3[N:16]([CH3:33])[C:15]2=[O:34])=[CH:10][CH:9]=1)(C)(C)C.Cl.N1C=CC=CC=1.[S:44](Cl)([CH3:47])(=[O:46])=[O:45]>O1CCOCC1.C(Cl)Cl>[CH3:6][N:7]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:26]3[C:25]4[CH:24]=[C:23]([C:27]5[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=5)[CH:22]=[CH:21][C:20]=4[N:19]=[CH:18][C:17]=3[N:16]([CH3:33])[C:15]2=[O:34])=[CH:10][CH:9]=1)[S:44]([CH3:47])(=[O:46])=[O:45]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-n2c(=O)n(C)c3cnc4ccc(-c5cccnc5)cc4c32)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(c1ccc(-n2c(=O)n(C)c3cnc4ccc(-c5cccnc5)cc4c32)cc1)S(C)(=O)=O
Reaction time: 17.5 h

Procedure:
62 mg (0.128 mmol) of methyl-[4-(3-methyl-2-oxo-8-pyridin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-carbamic acid tert-butyl ester (Example 50a) is treated with 2.5 ml of 1 M HCl in dioxane at it for 1 h, and then the solution is evaporated to dryness. The residue is taken in 2 ml of CH2Cl2 together with 414 μl (5.13 mmol) of pyridine and 66 mg (0.579 mmol) of mesylchloride (Fluka, Buchs, Switzerland). The solution is stirred at it for 17.5 h, then 15 mg (0.129 mmol) of mesylchloride are added and the reaction mixture is stirred at rt for 5.5 h. The reaction is quenched with sat. aqueous NaHCO3 and extracted with CH2Cl2 (2×). The organic layers are washed with brine, dried over Na2SO4, filtered and evaporated. The residue is purified by preparative HPLC to give the title compound as a yellowish solid. ES-MS: 460 (M+H)+; analytical HPLC: tret=2.25 min (Grad 1).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([N:6]([CH2:8][CH2:9][C:10]#[N:11])[CH3:7])=[O:5].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([Cl:24])=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:10]([CH2:9][CH2:8][N:6]([CH3:7])[C:4](=[O:5])[C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[NH:1][C:19]1[C:20]([Cl:24])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)#[N:11]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CN(CCC#N)C(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCC#N)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 80 °C
Reaction time: 96 h
Yield: 50.6 %

Procedure:
2-Amino-N-(2-cyano-ethyl)-N-methyl-benzamide (5.73 g, 28.2 mmol) in N,N-Dimethylformamide (50 mL) was treated with 2,4,5-Trichloro-pyrimidine (4.00 mL, 34.9 mmol) and Potassium carbonate (5.8 g, 42 mmol). The mixture was heated at 80° C. for 4 h, then cooled to room temperature and stirred for 4 days. The reaction was diluted with 200 mL water, extracted with DCM (200 mL, then 2×50 mL). The combined organics were washed 1×100 mL brine, dried over sodium sulfate and conc. in vacuo to give an oil, which was chromatographed (ISCO 330 g silica gel, 0-80% EtOAc:Hex). The product eluted with ˜60% EtOAc to afford N-(2-Cyano-ethyl)-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide as an oil (5.0 g, 50%). 1H-NMR (CDCl3): 9.36 (s, 1H), 8.34 (d, 1H, J=8.4 Hz), 8.22 (s, 1H), 7.53 (m, 1H), 7.38 (m, 1H), 7.21 (m, 1H), 3.81 (m, 2H), 3.22 (s, 3H), 2.80 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[N:10]([C:11]=1[C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([O:19]S(C3C=CC(C)=CC=3)(=O)=O)=[CH:15][CH:14]=1)[CH:9]=[CH:8][CH:7]=[CH:6]2)[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[CH2:1]([C:3]1[CH:4]=[C:5]2[N:10]([C:11]=1[C:12](=[O:30])[C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)[CH:9]=[CH:8][CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1cc2ccccn2c1C(=O)c1ccc(OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1cc2ccccn2c1C(=O)c1ccc(O)cc1

Procedure:
In a 20-liter flask, a suspension of 1050 g (2.5 mols) of 2-ethyl-3-(4-tosyloxy-benzoyl)-indolizine in a solution of 420 g (10.5 mols) of sodium hydroxide dissolved in 8 l of ethanol and 4 l of water was refluxed for 6 hours. At the end of the reaction, the mixture was cooled, diluted with 2.5 l of water, neutralized with hydrochloric acid and the desired product was allowed to crystallize while being stirred. The product was then suction-filtered and dried under vacuum in a drying-oven maintained at 70° C.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)#[N:2].[O:16]([CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.O>[O:16]([CH2:23][CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][N:29]([CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:3]2([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:1]#[N:2])[CH2:30][CH2:31]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(OCCCN2CCNCC2)cc1
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: N#CC1(c2ccccc2)CCCCC1N1CCN(CCCOc2ccccc2)CC1
Temperature: 25 °C
Yield: 50 %

Procedure:
5.0 g (0.025 mol) of 4-cyano-4-phenylcyclohexanone and 5.5 g (0.025 mol) of 3-phenoxypropylpiperazine were dissolved with 3.0 g of acetic acid in 70 ml of ethanol and then, while stirring at room temperature, a solution of 1.7 g (0.027 mol) of sodium cyanoborohydride was slowly added dropwise. The mixture was stirred overnight and then diluted with water and extracted with dichloromethane. The organic phase was subsequently washed with dilute acid (pH 4), dilute sodium hydroxide solution and water and finally dried and evaporated. The residue was converted into the hydrochloride with isopropanolic hydrochloric acid, and the product was recrystallized from isopropanol/water. Yield: 50%, C26H33N3O×2 HCl dihydrochloride, melting point >250° C.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.O>CN(C)C=O.C(OCC)(=O)C>[N:1]1([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCC2)nc1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 97 %

Procedure:
4.7 g (80.76 mmol) of azetidine are added dropwise to a suspension, stirred at 20° C., of 27.9 g (0.201 mol) of potassium carbonate and of 11 g (67.3 mmol) of 2-chloro-5-nitropyridine in 100 ml of dimethylformamide. The mixture is stirred for 5 minutes at 20° C. and then for 6 hours at 70° C. After this period of time, the suspension is poured into a mixture of 300 ml of water and 300 ml of ethyl acetate. The aqueous phase is separated and then extracted with 200 ml of ethyl acetate. The organic phases are combined, washed three times with 250 ml of water and then dried over sodium sulphate and concentrated under reduced pressure. 11.7 g of the expected product are thus obtained in the form of a solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[C:18]=S.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:30][NH2:31]>C1COCC1.O.C(O)(=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]1[C:7]2[CH2:8][C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6]=2[NH:31][N:30]=1
Reactant: NN
Reactant: S=C=Nc1ccccc1Cl
Reactant: O=C1CCc2sccc21
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccccc1Nc1n[nH]c2c1Cc1sccc1-2
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-Chloro-2-isothiocyanato-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (2-Chloro-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine as brown solid in 30% yield.
Reaction SMILES: [C:1]([C:5]1N=C(N2CC[C@H](O)C2)C2[C:9](=[N:11][N:12]([CH2:14]C3C(C)=NON=3)N=2)[N:10]=1)(C)(C)C.[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([O:45]C(=O)C(F)(F)F)[CH2:41]2)[C:34]2[N:39]=[N:38][NH:37][C:35]=2[N:36]=1)([CH3:30])([CH3:29])[CH3:28].Cl.ClCC1N(C)N=CN=1>>[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41]2)[C:34]2[C:35](=[N:37][N:38]([CH2:1][C:5]3[N:12]([CH3:14])[N:11]=[CH:9][N:10]=3)[N:39]=2)[N:36]=1)([CH3:28])([CH3:29])[CH3:30]
Reactant: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Agent: Cl
Agent: Cn1ncnc1CCl
Product: Cn1ncnc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 5-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride and isolated as light yellow gum. MS (m/e): 358.2 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]([CH2:18][C:19]1[C:24](Cl)=[N:23][C:22]([N:26]([CH3:31])[CH:27]([CH3:30])[CH2:28][CH3:29])=[CH:21][N:20]=1)[CH2:15][CH2:16][OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CN(C=O)C>[CH2:7]([N:14]1[CH2:18][C:19]2[N:20]=[CH:21][C:22]([N:26]([CH3:31])[CH:27]([CH3:30])[CH2:28][CH3:29])=[N:23][C:24]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCC(C)N(C)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)N(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 2.5 h
Yield: 77.3 %

Procedure:
To a solution of potassium tert-butoxide (0.77 g) in DMF (5 mL) was added dropwise a solution of 2-[benzyl({3-chloro-5-[methyl(1-methylpropyl)amino]pyrazin-2-yl}methyl)amino]ethanol (2.07 g) in DMF (5 mL) at 0° C., and the mixture was stirred for 2.5 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 20→80% ethyl acetate/hexane) to give the title compound (1.44 g, 77%) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[S:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]([NH:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[S:15][C:16]([Cl:19])=[CH:17][CH:18]=4)[CH:11]=[C:10]([C:20]([F:23])([F:21])[F:22])[N:9]=3)[CH:3]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)s2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-[4-(5-Chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidine (example B.3) (0.42 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.334 g, 1.3 mmol) according to the general procedure III. Obtained as an off-white solid (0.22 g), which was subsequently deprotected.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([S:12][CH2:13][CH3:14])[N:3]=1.Cl.[Cl:16][C:17]1[C:21]([Cl:22])=[C:20]([CH3:23])[NH:19][C:18]=1[C:24]([NH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:25]>>[Cl:16][C:17]1[C:21]([Cl:22])=[C:20]([CH3:23])[NH:19][C:18]=1[C:24]([NH:26][CH:27]1[CH2:32][CH2:31][N:30]([C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([S:12][CH2:13][CH3:14])[N:3]=2)[CH2:29][CH2:28]1)=[O:25]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: CCSc1cc(C(=O)OC)nc(Cl)n1
Agent: Cl
Product: CCSc1cc(C(=O)OC)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
The title compound was synthesized by a method analogous to Example 9 by coupling methyl 2-chloro-6-(ethylthio)pyrimidine-4-carboxylate (Intermediate 96) with 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1).
Reaction SMILES: [C:1]1([S:7]([C:10]#[N:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH3:18])[CH:17]=CC=[CH:14][CH:13]=1>C(O)CCC>[C:1]1([S:7]([C:10]2[CH:14]=[CH:13][C:12]([CH3:18])=[CH:17][N:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1
Reactant: N#CS(=O)(=O)c1ccccc1
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)c2ccccc2)nc1
Temperature: 110 °C
Yield: 88 %

Procedure:
First, 8.40 g (100 mmol) tiglic aldehyde (trans-2-methyl-2-butenal) and 8.35 g (50.0 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and the mixture was heated under reflux for 3 hours while agitating at an internal temperature of 110° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 10.5 g of 2-benzenesulfonyl-5-methylpyridine with the following properties as colorless crystals (purity of 99%, yield of 88% based on benzenesulfonyl cyanide).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13](=O)[NH:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:34]4[N:35]=[C:36]([CH:39]5[CH2:45][C:42]6([CH2:44][CH2:43]6)[CH2:41][N:40]5[C:46](=[O:56])[CH:47]([NH:51][C:52]([O:54][CH3:55])=[O:53])[CH:48]([CH3:50])[CH3:49])[NH:37][CH:38]=4)[CH:30]=3)[CH:25]=2)=[CH:20][CH:19]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:62]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]1[NH:62][C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:34]5[N:35]=[C:36]([CH:39]6[CH2:45][C:42]7([CH2:43][CH2:44]7)[CH2:41][N:40]6[C:46](=[O:56])[CH:47]([NH:51][C:52]([O:54][CH3:55])=[O:53])[CH:48]([CH3:50])[CH3:49])[NH:37][CH:38]=5)[CH:30]=4)[CH:25]=3)=[CH:22][CH:23]=2)=[CH:15][N:14]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1nc(-c2ccc3cc(-c4ccc(C(=O)CNC(=O)C5SCCN5C(=O)OC(C)(C)C)cc4)ccc3c2)c[nH]1)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1nc(-c2ccc3cc(-c4ccc(-c5cnc(C6SCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 0.75 h
Yield: 44.3 %

Procedure:
2-{2-[4-(6-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-1H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-2-oxo-ethylcarbamoyl}-thiazolidine-3-carboxylic acid tert-butyl ester (350 mg, 0.44 mmol) was dissolved in m-xylenes (3.0 mL) and heated at 135° C. Solid ammonium acetate (400 mg, 9.07 mmol) was added and the reaction was stirred at 135° C. After 45 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude reaction product was partitioned between chloroform and water. The organic layer was collected and dried over sodium sulfate. Filtration and evaporation of solvents gave the crude product. The crude material was purified via silica gel chromatography (eluent: EtOAc/hexanes) to yield the product (151.3 mg, 0.195 mmol).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8](=[O:24])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([CH2:22]O)=[N:11][CH:10]=1.ClCCl.[H-].[Na+].[CH3:40][C:41]1[NH:42][CH:43]=[CH:44][N:45]=1>CN(C)C=O>[F:1][C:2]([F:33])([F:34])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8](=[O:24])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([CH2:22][N:42]2[CH:43]=[CH:44][N:45]=[C:41]2[CH3:40])=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(CO)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1cc(Cn2ccnc2C)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of 100 mg (0.207 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-hydroxymethyl-N-methyl-4-o-tolyl-nicotinamide (Example 7) in 1 ml dichloromethane 0.03 ml (0.4 mmol) thionyl chloride were added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The solvent was evaporated and the light yellow residue was dried in high vacuo. The residue was dissolved in 1 ml dry N,N-dimethylformamide and added to a suspension of 2-methylimidazole sodium salt that had previously been prepared by addition of 54 mg (1.2 mmol) sodium hydride (55% dispersion in mineral oil) to a solution of 52 mg (0.62 mmol) 2-methylimidazole in 3 ml dry N,N-dimethylformamide under argon at room temperature. After stirring for 3 h the reaction was quenched by addition of excess water, followed by extraction with three portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 52 mg (46%) of the title compound as an orange solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH2:16])=[N:6][CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:9]=2)[CH2:3][CH2:2]1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[C:26](O)=[O:27])=[CH:20][CH:19]=1>>[CH:1]1([C:4]2[NH:9][C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:7][N:6]3[C:26](=[O:27])[C:25]([CH2:24][C:21]4[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=4)=[N:16][C:5]=23)[CH2:3][CH2:2]1
Reactant: Nc1ncc(-c2ccccc2)nc1C1CC1
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Product: O=c1c(Cc2ccc(O)cc2)nc2c(C3CC3)[nH]c(-c3ccccc3)cn1-2

Procedure:
Synthesized using method A with 3-cyclopropyl-5-phenylpyrazin-2-amine and 3-(4-hydroxyphenyl)-2-oxopropanoic acid as starting materials. Exact mass calculated for C22H18N3O2− m/z− 356.14, found m/z− 356.
Reaction SMILES: Cl.NCCC[CH:6]=[C:7]([CH3:11])[C:8]([NH2:10])=[O:9].C(O[C:16](=O)[CH3:17])(=O)C.[CH2:19](N(CC)CC)C.C([NH-])(=O)C>CO>[CH3:19][CH2:16][CH2:17][NH:10][C:8](=[O:9])[C:7]([CH3:11])=[CH2:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=CCCCN)C(N)=O
Reactant: CCN(CC)CC
Agent: CC([NH-])=O
Agent: Cl
Solvent: CO
Product: C=C(C)C(=O)NCCC
Yield: 92 %

Procedure:
0.8 g of 3-aminopropyl methacrylamide hydrochloride was dissolved in a methanol solvent and 0.9 g of acetic anhydride and 0.9 g of triethylamine (TEA) were added thereto. The resultant mixture was stirred under ice-cooling for 4 hours. After the completion of the reaction, the solvent was distilled off with an evaporator and the precipitate was filtered off. The filtrate was recovered and introduced into a silica column. Thus, the eluate fraction containing the target product was taken up and subjected to recrystallization to thereby purify the target acetylamide, N-3-propyl methacrylamide (yield: 92%).
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1.[CH3:19][NH:20]/[C:21](/[C:28]([F:31])([F:30])[F:29])=[CH:22]\[C:23](OCC)=[O:24].C(NC(C)C)(C)C>C1COCC1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23](=[O:24])[CH:22]=[C:21]([C:28]([F:31])([F:30])[F:29])[N:20]([CH3:19])[C:16]2=[O:17])=[CH:11][CH:10]=1
Reactant: CCOC(=O)/C=C(\NC)C(F)(F)F
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: CN1C(=O)C(c2ccc(Cl)cc2)C(=O)C=C1C(F)(F)F
Temperature: -62.5 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
To 200 ml of toluene, 6.7 g (35 mmol) of 4-chlorophenylacetyl chloride and 14.0 g (71 mmol) of ethyl 3-methylamino-4,4,4-trifluorocrotonate were added, followed by stirring for 8 hours under heating and refluxing. After completion of the reaction, the reaction solution was washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Toluene was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography. This crotonic acid ester was dissolved in 20 ml of THF and dropwise added to a LDA-THF solution [prepared from 54 ml (86 mmol) of a 1.6N-n-butyllithium-hexane solution, 11.3 g (112 mmol) of diisopropylamine and 200 ml of THF] under cooling to −65 to −60° C., followed by stirring at room temperature for 2 hours. After completion of the reaction, excess THF was distilled off, and a 10% citric acid aqueous solution was added thereto. Precipitated crude crystals were washed with ethyl acetate to obtain 3.6 g (yield: 34%) of the desired product. 1H-NMR (300 MHz, DMSO-d6) δ value: 3.39(3H,s), 5.82(1H,s), 7.14(2H,d), 7.40(2H,d)ppm.
Reaction SMILES: O1CCCC1.[O:6]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:29]=1[C:30](Cl)=[O:31]>O>[O:6]([C:13]1[CH:14]=[CH:15][C:16]([NH:17][C:30](=[O:31])[C:29]2[CH:33]=[C:34]([N+:37]([O-:39])=[O:38])[CH:35]=[CH:36][C:28]=2[Cl:27])=[CH:18][CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
Into 5 mL of a tetrahydrofuran solution comprising 420 mg of 4-phenoxyaniline and 250 mg of triethylamine, 5 mL of a tetrahydrofuran solution comprising 500 mg of 2-chloro-5-nitrobenzoylchloride was dropwise added under cooling with ice. After stirring for about 30 minutes, water was added thereto, and precipitated crystals were collected by filtration. The collected crystals were washed with water and then dried to obtain 730 mg of N-(4-phenoxyphenyl)-2-chloro-5-nitrobenzamide (Compound No. 27) having a melting point of 128° C.
Reaction SMILES: O.[CH3:2][CH:3]([OH:10])[CH2:4][NH:5][CH2:6][CH:7]([OH:9])[CH3:8].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[C:12]1([CH:11]2[N:5]([CH2:6][CH:7]([OH:9])[CH3:8])[CH2:4][CH:3]([CH3:2])[O:10]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: CC(O)CNCC(C)O
Solvent: c1ccccc1
Solvent: O
Product: CC(O)CN1CC(C)OC1c1ccccc1
Yield: 96.8 %

Procedure:
A reaction vessel equipped with a thermometer, a dropping funnel, a stirrer and a condenser having a water separator was charged with 133 g of diisopropanolamine and 100 g of benzene, to which 107 g of benzaldehyde was added dropwise at room temperature for one hour. The content was heated to reflux and, after removing water produced during reacting, reacted for another 5 hours. Benzene was removed under a reduced pressure and then distilled at 125° to 127° C./1 mmHg to obtain 214 g of 2-phenyl-3-(2-hydroxypropyl)-5-methyloxazolidine.