Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1.Cl.ClC1C=CN=CC=1>O1CCOCC1>[Cl:10][C:6]1[C:3]([C:4]#[N:5])=[C:2]([N:1]2[CH:13]=[CH:17][CH:16]=[CH:15]2)[CH:9]=[CH:8][CH:7]=1
Reactant: COC1CCC(OC)O1
Reactant: N#Cc1c(N)cccc1Cl
Agent: Cl
Agent: Clc1ccncc1
Solvent: C1COCCO1
Product: N#Cc1c(Cl)cccc1-n1cccc1
Yield: 87.8 %

Procedure:
A solution of 2-amino-6-chloro-benzonitrile (30 g), 2,5-dimethoxytetrahydrofuran (30 g) and 4-chloropyridine hydrochloride (17 g) in dioxane was heated to 70° C. for 2.5 h. The solvent was evaporated in vacuo. Dichloromethane was then added to the residue and the spent 4-chloropyridine hydrochloride filtered off. The dichloromethane was evaporated in vacuo to give 1-(3′chloro-2′-cyanophenyl)pyrrole (35 g)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[C:8]#[CH:9].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21].[K+].[Br-]>CS(C)=O.O.C(N(CC)CC)C>[CH2:7]([NH:10][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21])[C:8]#[CH:9]
Reactant: C#CCN
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: C#CCNc1ccc([N+](=O)[O-])cc1C
Temperature: 50 °C

Procedure:
To a suspension of potassium carbonate (20.0 g) in DMSO (7 ml) was added triethylamine (3 ml) and 2-propyn-1-amine (7.10 g, 1.29×10-1 mole). 2-Fluoro-5-nitrotoluene (20.00 g, 1.29×10-1 mole) was added with stirring and the reaction mixture was heated at 50° C. for three days. The mixture was cooled, poured into excess water, and extracted with methylene chloride. The methylene chloride solution was dried over sodium sulfate, filtered and evaporated. The residue was chromotographed on a silica column, eluting with benzene, and recrystallized from benzene to afford yellow crystals; m.p. 121°-123° C. Yield: 15.02 g (61%). I.R. (KBr): 3344 (NH), 3226 (CH), 1580 and 1282 cm-1 (Ar-NO2).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[C:6](C)[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([CH3:15])([CH3:14])[CH:3]1[CH3:16].S(OOS([O-])(=O)=O)([O-])(=O)=[O:19].[K+].[K+].C(Cl)Cl.[C:33](#N)[CH3:34]>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH:6]([C:7]1[C:33]([CH3:34])=[C:5]2[C:10](=[CH:9][C:8]=1[O:11][CH3:12])[C:2]([CH3:17])([CH3:1])[CH:3]([CH3:16])[C:4]2([CH3:15])[CH3:14])=[O:19]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: CC#N
Reactant: COc1cc(C)c2c(c1)C(C)(C)C(C)C2(C)C
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(c(C)c1C=O)C(C)(C)C(C)C2(C)C
Temperature: 25 °C

Procedure:
The 1,1,2,3,3,4-hexamethyl-6-methoxyindane (10.8 g) is then heated with copper(II) sulfate pentahydrate (18.04 g) and potassium peroxydisulfate (60.55 g) in acetonitrile and water (1:1, 500 ml) at reflux for about 15 to 20 minutes, following procedures similar to those described in Hauser et al., Synthesis, pp. 723-724 (1987). The mixture is then cooled to room temperature and methylene chloride (150 ml) is added. The layers are separated and the aqueous phase is further extracted with additional methylene chloride (2×70 ml). The combined organic solutions are dried with anhydrous sodium sulfate, filtered, and evaporated at reduced pressure to yield 5-formyl-1,1,2,3,3,4-hexamethyl-6-methoxyindane.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[F:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[F:10][C:11]1[C:16]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Cc1nc(N)cc(Cl)n1
Reactant: OB(O)c1cccnc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nc(N)cc(-c2cccnc2F)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
A mixture of 6-chloro-2-methyl-4-pyrimidinamine (SynChem, Inc., Des Plaines, Ill.) (0.500 g, 3.48 mmol), 2-fluoropyridin-3-ylboronic acid (0.589 g, 4.18 mmol), PdCl2(dppf) complex with dichloromethane (0.199 g, 0.244 mmol) and 2 M Na2CO3 (aq., 5.22 mL, 10.45 mmol) in dioxane (17 mL) was stirred at 110° C. overnight. After cooling to RT, water was added and the mixture was filtered through Celite® (diatomaceous earth). The mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 0% to 5% MeOH in CH2Cl2, to provide 6-(2-fluoro-3-pyridinyl)-2-methyl-4-pyrimidinamine (0.173 g, 0.85 mmol, 24% yield) as an off-white solid. m/z (ESI, +ve) 205.1 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 8.52-8.62 (m, 1H); 8.27-8.34 (m, 1H); 7.44-7.61 (m, 2H); 7.00 (br. s., 1H); 6.75-6.83 (m, 1H); 2.39 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1(N)[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[CH2:3]1.[CH3:13][N:14]([CH3:21])[C:15]([NH:17][CH2:18][C:19]#[CH:20])=[O:16].C([NH:25]C(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[NH2:25][C:3]1[C:4]2[O:8][CH2:7][O:6][C:5]=2[C:9]([C:20]#[C:19][CH2:18][NH:17][C:15](=[O:16])[N:14]([CH3:21])[CH3:13])=[CH:10][C:2]=1[Cl:1]
Reactant: C#CCNC(=O)N(C)C
Reactant: CC(C)NC(C)C
Reactant: NC1(Cl)C=C(I)C2=C(C1)OCO2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)NCC#Cc1cc(Cl)c(N)c2c1OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
5-Chloro-7-iodo-1,3-benzodioxol-5-amine (682 mg, 2.29 mmol) and N,N-dimethyl-N′-prop-2-yn-1-ylurea (289 mg, 2.29 mmol) in ethyl acetate (10 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, then treated with bis(triphenylphosphine) palladium(II) dichloride (161 mg, 10 mol %) followed by copper(I) iodide (43 mg, 10 mol %) and diisopropylamine (463 mg, 4.03 mmol). The reaction was allowed to warm to room temperature and stirred 3 hr. then filtered through Celite. The filtrate was purified by column chromatography on silica using ethyl acetate as eluent to give N′-[3-(7-amino-6-chloro-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]-N,N-dimethylurea (463 mg, 68%) as an off-white solid; NMR Spectrum:(DMSOd6) 2.79 (s, 6H), 4.01 (d, 2H), 5.50 (s, 2H), 6.05 (s, 2H), 6.78 (t, 1H), 6.79 (s, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.I[CH3:18].O>CN(C=O)C>[CH3:18][O:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
A 57% oil dispersion containing 0.6 g (0.025 mole) NaH was added in one portion to a solution of 4.7 g (0.023 mole) 1-hydroxy-4-(1,1-dimethylethoxycarbonyl)piperazine in 100 ml DMF under a dry N2 atmosphere. The mixture was stirred for 2 hours at room temperature and then 6.5 g (0.046 mole) iodomethane was added over 1 minute. After stirring for an additional 15 minutes, the mixture was poured into 100 ml H2O, stirred briefly, and extracted thoroughly with low boiling (35°-65° C.) petroleum ether. The extracts were dried (MgSO4), filtered and evaporated in vacuo to give 1.8 g of an oil. The oil was dissolved in ethyl ether, washed with dilute aqueous HCl, dried (MgSO4), filtered, and evaporated in vacuo to yield 1.3 g yellow oil. Short path distillation (Kugelrohr) returned 0.8 g colorless distillate, b.p.* 55°-65° C./0.15 mm. Calc. for C10H 20 N2O3 (216.28): C, 55.53; H, 9.32; N, 12.95; O, 22.19. Found: C, 55.61; H, 9.13; N, 12.96; O, 22.33.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[CH3:11].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>C(Cl)Cl>[CH3:11][C:5]1[CH:6]=[C:7]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)[CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1ccc(F)cc1C
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCN(C)CC2)cc1C
Temperature: 110 °C
Yield: 37.8 %

Procedure:
In a cylindrical quartz tube were placed 4-fluoro-2-methyl-benzoic acid methyl ester (1.2 g, 7.14 mmol), N-methylpiperazine (0.95 ml, 8.5 mmol), K2CO3 (990 mg, 7.14 mmol) and DMSO (4 ml). The reaction was heated for 20 hours at 110° C. until HPLC revealed the disappearance of the starting-material. DCM (15 ml) was added and the solution was washed twice with water and the organic phase was dried over anhydrous Na2SO4. The crude was purified by flash chromatography (DCM/MeOH 95:5) affording the desired compound (670 mg, 38%).
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]1([C:31]2[C:32]([O:41][CH:42]3[CH2:47][CH2:46][C:45]4([CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)[CH2:44][CH2:43]3)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([OH:38])=O)[CH2:30][CH2:29]1.CS(N)(=O)=O.[N:58]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60][CH2:59]1>>[N:58]1([S:62]([NH:65][C:36](=[O:38])[C:35]2[CH:39]=[C:31]([CH:28]3[CH2:30][CH2:29]3)[C:32]([O:41][CH:42]3[CH2:47][CH2:46][C:45]4([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]4)[CH2:44][CH2:43]3)=[CH:33][C:34]=2[F:40])(=[O:64])=[O:63])[CH2:61][CH2:60][CH2:59]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(C2CC2)c(OC2CCC3(CCCCC3)CC2)cc1F
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OC2CCC3(CCCCC3)CC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-2-fluoro-4-(spiro[5.5]undecan-3-yloxy)benzoic acid and making variations as required to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a white solid (0.045 g, 44%): 1H NMR (300 MHz, DMSO-d6) δ11.57 (s, 1H), 7.13 (d, J=8.5 Hz, 1H), 7.00 (d, J=13.3 Hz, 1H), 4.62-4.54 (m, 1H), 4.04 (t, J=7.8 Hz, 4H), 2.74-2.55 (m, 2H), 2.29-1.97 (m, 2H), 1.84-1.73 (m, 2H), 1.69-1.51 (m, 4H), 1.38-1.23 (m, 11H), 0.90-0.86 (m, 2H), 0.70-0.65 (m, 2H); MS (ES+) m/z 465.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C@@H:6]([OH:9])[C:7]#[N:8])=[CH:4][CH:3]=1.CO>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:6]([OH:9])[CH2:7][NH2:8])=[CH:10][CH:11]=1
Reactant: N#C[C@H](O)c1ccc(Cl)cc1
Solvent: CO
Solvent: C1CCOC1
Product: Cl
Product: NC[C@H](O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
1.9 g of (R)-(+)-4-chloromandelonitrile (11 mmol) were dissolved in 18 ml THF and cooled down to 0° C. under nitrogen. 58 ml of a 1M borane-THF complex solution in THF were then added dropwise over 30 min, keeping the temperature between 0-2° C. After addition the reaction mixture was stirred at rt for additional 45 min and then refluxed for 16 h. The reaction mixture is then cooled down to 0° C. and treated between 2 and 5° C. with 13 ml methanol over a period of 35 min. After 1 h refluxing the reaction mixture is concentrated, the residue dissolved in DCM and the amine extracted twice with 1N aqueous HCl. The combined aqueous phases are then treated with concentrated NaOH to adjust the pH to 12, and then extracted twice with DCM. The combined organic phases were then washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo leading to a colorless solid which was dissolved in 100 ml diethylether, treated with 4 ml 2.6N HCl in diethylether, stirred at rt for additional 1 h, filtered and dried under high vacuo, leading to 1.24 g white solid (54%). MS (ISP) 172.1 (M+H)+.
Reaction SMILES: [CH:1]([O:4]C(N=NC(OC(C)C)=O)=O)(C)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:34][C:35]1[CH:45]=[C:44]([CH2:46]O)[CH:43]=[CH:42][C:36]=1[O:37][CH2:38][C:39]([NH2:41])=[O:40].[S:48]1C=CC=C1CC(O)=O>C1COCC1>[C:1]([S:48][CH2:46][C:44]1[CH:43]=[CH:42][C:36]([O:37][CH2:38][C:39]([NH2:41])=[O:40])=[C:35]([Cl:34])[CH:45]=1)(=[O:4])[CH3:2]
Reactant: NC(=O)COc1ccc(CO)cc1Cl
Reactant: O=C(O)Cc1cccs1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SCc1ccc(OCC(N)=O)c(Cl)c1
Reaction time: 8 h

Procedure:
Diisopropylazocarboxylate (5.5 ml) was added to a stirred solution of triphenylphosphine (7.31 g) in THF at 0° C. Upon completion of addition a colourless precipitate deposited. To this suspension was added a mixture of the product from example 15 step b) (3.0 g) and thiolacetic acid (2.00 ml) in THF (30 ml) at 0° C. The mixture was allowed to attain room temp overnight, evaporated to dryness and the residue purified (SiO2, 10% ethyl acetate: 90% ether as eluant) to give the subtitle compound (3.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[C:4](Cl)[C:3]=1Cl.[C-:21]#[N:22].[Na+].[Cl-].[NH4+].C[N:27]([CH3:30])C=O>>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[C:4]([C:21]#[N:22])[C:3]=1[C:30]#[N:27]
Reactant: Nc1c(Cl)c(Cl)c(N)c2c1C(=O)c1ccccc1C2=O
Reactant: [C-]#N
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: N#Cc1c(N)c2c(c(N)c1C#N)C(=O)c1ccccc1C2=O
Temperature: 120 °C

Procedure:
31 parts of 1,4-diamino-2,3-dichloroanthraquinone is introduced into 280 parts by volume of dimethylformamide and the whole is heated to 120° C. At this temperature 30 parts of sodium cyanide is introduced in about five minutes, the supply of heat being decreased because the temperature is maintained by the heat of reaction. After a short time the exothermic reaction ceases and the whole is heated at 125° to 130° C. for about another 35 minutes. After this period the whole of the starting material has reacted. The whole is cooled to 110° C., 11 parts of ammonium chloride is added and the solvent is substantially distilled off at subatmospheric pressure; 200 to 210 parts by volume of dimethylformamide is recovered. The residue in the still is stirred vigorously while 300 parts of water is slowly added; the reaction product is thus precipitated. The whole is stirred for about another hour until the product has become easily filterable, and suction filtered while hot, and the filter cake is washed with hot water until the water running away has become colorless. The product is rinsed with methanol and dried. 26 parts of 1,4-diaminoanthraquinone-2,3-dinitrile is obtained. The product has the same properties as those obtained according to Examples 1 and 2.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][S:5][CH3:6].[O-2].[Zn+2:11].[ClH:12]>>[NH2:1][C@H:2]([C:7]([Cl:12])=[O:9])[CH2:3][CH2:4][S:5][CH3:6].[Zn:11]
Reactant: CSCC[C@H](N)C(=O)O
Reactant: [Zn+2]
Reactant: Cl
Agent: [O-2]
Product: CSCC[C@H](N)C(=O)Cl
Product: [Zn]
Temperature: 90 °C

Procedure:
Methionine (74.6g, 0.5 mol) was dissolved in a 165 ml of 6.08 N hydrochloric acid and zinc oxide (40.65g) was added. The mixture was heated at 90° C. for 1 hour to provide zinc methionine chloride solution. The product contained 19.9% zinc and 44.0% methionine. The presence of zinc methionine chloride was confirmed by quantitative and instrumental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24](O)=[O:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OC(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH2:24][OH:25])=[C:5]2[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Solvent: CC(C)OC(C)C
Product: CS(=O)(=O)c1ccc(Cn2c(CO)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1

Procedure:
In the same manner as in Example 310, the title compound was synthesized using 6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid. Crystals (diisopropyl ether).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:16])([F:15])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][C:12]([NH2:14])=[O:13])[N:6]=1.[N:17]([C:20]1[CH:33]=[CH:32][C:23]([O:24][CH2:25][CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)=[CH:22][CH:21]=1)=[C:18]=[S:19].O>C1COCC1>[N:27]1([CH2:26][CH2:25][O:24][C:23]2[CH:32]=[CH:33][C:20]([NH:17][C:18](=[S:19])[CH:11]([C:7]3[N:6]=[C:5]([C:4]([F:3])([F:15])[F:16])[CH:10]=[CH:9][N:8]=3)[C:12]([NH2:14])=[O:13])=[CH:21][CH:22]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: NC(=O)Cc1nccc(C(F)(F)F)n1
Reactant: S=C=Nc1ccc(OCCn2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)C(C(=S)Nc1ccc(OCCn2ccnc2)cc1)c1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
Sodium hydride (0.531 g of a 60 wt % dispersion in oil, 13.3 mmol) was added in portions to a stirred solution of 2-(4-trifluoromethylpyrimidin-2-yl)acetamide (0.911 g; 4.43 mmol) in THF (20 mL) over 10 min. A solution of 1-[2-(4-isothiocyanatophenoxy)ethyl]-1H-imidazole (1.21 g; 4.92 mmol) in THF (10 mL) was then added over 15 min. The mixture was stirred at room temperature for a further 1 hr, and then water (1 mL) was added and the mixture was concentrated under reduced pressure. Water (75 mL) was added to the residue, the pH adjusted to 7 with 2N hydrochloric acid, and the mixture was extracted three times with EA. The combined EA extracts were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 3-{-4-[2-(1H-imidazol-1-yl)ethoxy]phenylamino}-3-thioxo-2-(4-trifluoromethylpyrimidin-2-yl)propanamide (1.47 g) as an orange semi-solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:18][C:19]1[CH:20]=[C:21]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=[C:23]([Cl:26])[C:24]=1[OH:25].O>CC(C)=O>[C:28]([NH:27][C:21]1[CH:22]=[C:23]([Cl:26])[C:24]([O:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:19]([Cl:18])[CH:20]=1)(=[O:30])[CH3:29]
Reactant: CCOC(=O)CCCCCBr
Reactant: CC(=O)Nc1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CCCCCOc1c(Cl)cc(NC(C)=O)cc1Cl

Procedure:
13.3 ml (74.9mmol) of ethyl 6-bromohexanoate and 52.1 g (160 mmol) of cesium carbonate were added to a solution of 15.0 g (68.1 mmol) of N-(3,5-dichloro-4-hydroxyphenyl)acetamide in 300 ml of acetone. The suspension was boiled under reflux for 8 hours, and then 600 ml of water were added. The mixture was extracted twice with 400 ml of dichloromethane and with 400 ml of MTB ether each time. The combined organic phases were washed with water and concentrated in a rotary evaporator. The product was employed in the next step without purification. Crude yield was 30 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][C:3]=1[CH3:21].[C:22]([C:24]1[CH:25]=[C:26]([C:30](O)=[O:31])[CH:27]=[N:28][CH:29]=1)#[N:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:30](=[O:31])[C:26]3[CH:25]=[C:24]([C:22]#[N:23])[CH:29]=[N:28][CH:27]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:4][C:3]=1[CH3:21]
Reactant: Cc1cc(-c2cc(N)cnc2OCC(F)(F)F)ccc1Cl
Reactant: N#Cc1cncc(C(=O)O)c1
Product: Cc1cc(-c2cc(NC(=O)c3cncc(C#N)c3)cnc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-3-methyl-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example 57 a) and 5-cyano-3-pyridinecarboxylic acid, (CAN 887579-62-6) as starting materials; LC-MS (UV peak area/ESI) 98.7%, 445.0693 (M−H)−.
Reaction SMILES: S[C:2]1[N:3]=[C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=[C:5]2[N:6]=1.C(=O)(O)[O-].[Na+]>[N+]([O-])(O)=O>[N:3]1[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][C:5]2=[N:6][CH:2]=1
Reactant: Sc1nc2cccccc-2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: c1ccc2ncnc-2cc1

Procedure:
With reference to Journal of the American Chemical Society, vol. 76, pages 3352 and 3353 (1954) 23 g of 2-mercaptocycloheptimidazole as synthesized in Synthetic example 1(b) was added to 210 ml of 10% nitric acid, and stirred with heating to the inner temperature of 80° to 90° C. for one hour. The reaction solution was neutralized with sodium bicarbonate and extracted with chloroform (250 ml×2). The chloroform layer was dried over anhydrous sodium sulfate and concentrated to 50 ml under reduced pressure, and then 200 ml of hexane was added. Deposited crystals were collected by filtration and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[C:11]([NH:18][CH2:19][CH2:20]Br)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:20][CH2:19][NH:18][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=c1ccc(Br)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1cc(Br)ccc1=O
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of 5-bromo-2(1h)-pyridone (550 mg, 3161 μmol) in DMF (5 mL) under nitrogen was added NaH (60% dispersion in mineral oil; 152 mg, 6322 μmol). After for 10 min, 2-(boc-amino) ethyl bromide (779 mg, 3477 μmol) was added. The mixture was stirred for 18 h at 23° C. The mixture was partitioned between CH2Cl2 and 5% NaHCO3. The aqueous was extracted with CH2Cl2 (10 mL) twice. The combined organics were dried over MgSO then concentrated to a solid from toluene under reduced pressure. The residue was purified on silica (40 g) eluting with 0-30% of 5% MeOH/CH2Cl2 to give the product as a white solid. MS (ESI pos. ion) m/z (MH+): 317/319. Calc'd exact mass for C12H17BrN2O3: 316. 1H NMR (400 MHz, Chloroform-d) δ ppm 1.44 (s, 9H) 3.45 (q, J=6.02 Hz, 2H) 4.03-4.09 (m, 2H) 4.92 (br. s., 1H) 6.48 (d, J=10.04 Hz, 1H) 7.34-7.39 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ ppm 26.08, 37.26, 47.20, 95.56, 119.79, 135.87, 140.53
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22](O)=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1.C(N(C(C)C)C(C)C)C.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.F[P-](F)(F)(F)(F)F.C(C(=NO[C+](N(C)C)N1CCOCC1)C(OCC)=O)#N>CN(C=O)C.O>[F:34][C:3]([F:2])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1
Reactant: C1COCCN1
Reactant: O=C(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: CCOC(=O)C(C#N)=NO[C+](N(C)C)N1CCOCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCC(=O)N2CCOCC2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-2-oxo-2,5-dihydro-1,3-thiazol-4-yl]glycine hydrochloride (500 mg), N-ethyl-N-(1-methylethyl)propan-2-amine (0.49 mL) and morpholine (0.25 mL) in DMF (5 mL) was added (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (403 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and the solid was recrystallized from diisopropyl ether/heptane to give the title compound (160 mg).