Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[O:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[C@@H:10]2[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)[CH:6]=[CH:7][CH:8]=1.C[S-].[Li+].Cl>CN(C)P(N(C)C)(N(C)C)=O.O>[OH:2][C:3]1[CH:4]=[C:5]([C@@:9]23[O:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[C@@H:10]2[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([C@]23CCN(C)C[C@H]2c2ccccc2O3)c1
Agent: C[S-]
Agent: Cl
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CN1CC[C@]2(c3cccc(O)c3)Oc3ccccc3[C@@H]2C1
Yield: 94.8 %

Procedure:
A mixture of 3.50 g of cis-1,2,3,4,4a,9b-hexahydro-4a-(3-methyoxyphenyl)-2-methyl-benzofuro[3,2-c]pyridine and 3.62 g of lithium thiomethoxide in 30 ml of dry hexamethylphosphoramide was treated at 140° under a drying tube for 41/2 hours. The cooled reaction mixture was diluted with 350 ml of water and the pH adjusted to 7 by slow addition of 2N HCl with stirring. The mixture was extracted with ether (2×300), and the combined extracts were washed with water (3×300 ml), dried over anhydrous Na2SO4, and evaporated in vacuo to provide 3.16 g (94.8%) a solid foam. This material was boiled and triturated with a small amount of ether. After cooling to 0°, the resulting soild was filtered off, washed with cold ether, and dried to afford 2.58 g (77.4%) of crystalline solid, m.p. s 157, 158°-160°.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[Cl-:13].[CH2:1]([N+:8]1[CH:12]=[CH:11][N:10]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCCCCCCl
Reactant: c1ccc(Cn2ccnc2)cc1
Product: CCCCCCCCCCCCCCCCn1cc[n+](Cc2ccccc2)c1
Product: [Cl-]
Reaction time: 72 h

Procedure:
103 g of 1-benzylimidazole (Aldrich) and 170 g of 1-chlorohexadecane were added into a 2000 ml three-neck round-bottom flask. A refluxing/cooling condenser was set on the left neck. A thermometer was set on the right neck. A rubber stopper was set on the middle neck. Nitrogen gas was breathed into the liquid phase through the needle from the middle neck. The reactants were mixed with vigorous stirring using a magnetic stirrer. Temperature was kept between 70° C. and 80° C. After heating up, 1-benzyl imidazole dissolved into 1-chlorohexadecane. The solution in the flask turned into red brown solution. The reaction was continued for three days. Then, the product was cooled down. The white product came out of the solution. The product was washed with ethyl acetate five times. After that, it was dried in vacuum for seven hours at about 50° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>C(OCC)C.N1C=CC=CC=1>[C:21]([NH:25][C:14]([C:9]1[C:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:16])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(O)c1ccccc1Cc1ccccc1
Reactant: CC(C)(C)N
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)NC(=O)c1ccccc1Cc1ccccc1

Procedure:
To a mixture of 49.8 g. (0.235 mole) α-phenyl-o-toluic acid, 300 ml. ether and 10 ml. pyridine, add dropwise with stirring 25 ml. (0.35 mole) of thionyl chloride. The resulting mixture is stirred 21 hours at room temperature then filtered and the solvent removed in vacuo. The resulting acid chloride is dissolved in 150 ml. ether and added dropwise to 35.7 g (0.48 mole) of tert.butylamine in 500 ml. of ethyl ether, and the mixture cooled to 0° C. After addition is complete the resulting mixture is stirred 1 hour at room temperature, the layers separated, the ether washed with 100 ml. of water, 100 ml. of 2 N sodium hydroxide and then with water again, dried over magnesium sulfate, filtered and evaporated to give N-tert.butyl-α-phenyl-o-toluamide; m.p. 91°-92° C.
Reaction SMILES: [C:1]([CH:4]([O:29][CH2:30][CH3:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)(=O)[NH2:2].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1>[C:1]([CH:4]([O:29][CH2:30][CH3:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)#[N:2]
Reactant: CCOC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(N)=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(C#N)Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.9 %

Procedure:
1-Carbamoyl-2-[4-(2-{4-tert-butyloxycarbonylaminophenyl}ethoxy)phenyl]-1-ethoxyethane(0.63 g, 1.47 mmole) was dissolved in dioxane (20 ml) and pyridine (0.35 g, 4.41 mmole) was added. The mixture was placed in a ultrasonic bath for 5 minutes, then trifluoroacetic acid anhydride (0.37 g, 1.76 mmole) was added. After stirring at room temperature for 16 hours it was checked using HPLC that all the starting material was consumed. Sodium carbonate solution was added and extracted three times with dichloromethane. The organic phase was dried with magnesium sulfate and evaporated. Purification of the crude product with preparative HPLC (Kromasil C8, 7 μm, 50×250 mm) using acetronitrile (70-80%) in ammonium acetate buffer (pH 7) as mobil phase gave 0.47 g (75% yield) of the desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>ClCCl.[O-2].[Mn+2]>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OCc1ccc2[nH]ccc2c1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 40.1 %

Procedure:
A mixture of (1H-indol-5-yl)-methanol (3.8 g, 25.8 mmol) and manganese oxide (5 g, 57.5 mmol) in dichloromethane (50 mL) was stirred at room temperature for 60 hours. After the usual work-up and chromatography, 1.5 g (40%) of 1H-indole-5-carbaldehyde was obtained.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1([CH:22]([F:24])[F:23])[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[O:4]1.C(=O)(O)[O-:27].[Na+].C(C1C(CO)=C(SC2C=CC=C(CCCC)C=2CO)C=CC=1)CCC.ClC1C=CC=C(C(OO)=O)C=1>ClCCl.O.ClCCCl>[F:25][CH:2]([F:1])[C:3]1([CH:22]([F:24])[F:23])[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-:27])[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[O:4]1
Reactant: O=C([O-])O
Reactant: O=[N+]([O-])c1ccc2c(c1)N(c1ccccn1)CC(C(F)F)(C(F)F)O2
Agent: CCCCc1cccc(Sc2cccc(CCCC)c2CO)c1CO
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc2c(c1)N(c1cccc[n+]1[O-])CC(C(F)F)(C(F)F)O2
Reaction time: 8 h
Yield: 34.4 %

Procedure:
2- (2,2-bis(difluoromethyl)-6-nitro-3,4-dihydro-2H-1,4-benzoxazine-4-yl)pyridine (1.32 g) 50% m-chloroperbenzoic acid (2.56 g), sodium bicarbonate (1.26 g), 1,2-dichloroethane (12 mL), water (12 mL), and butylhydroxymethylphenylsulfide (0.1 g) were stirred at reflux under nitrogen for 2 hours. Additional m-chloroperbenzoic acid (1.28 g), and Sodium bicarbonate (0.063 g) were added and reflux was continued overnight. The reaction mixture was cooled, diluted with dichloromethane and washed with sodium bicarbonate solution. The organic layer was separated, washed (water), dried and concentrated. Chromatography, eluting with dichloromethane followed by ethyl acetate, gave the title compound as a yellow amorphous solid (0.475 g); mp 138°-140 ° C.; NMR: 4.12 (s,2), 6.61 (t,2), 7.12 (s,1), 7.33 (d,1), 7.49 (m,2) 7.62 (d,1), 7.79 (d,1), 8.42 (d,1); MS: m/z=374(M+1). Analysis for C15H11 F4N3O4 : Calculated: C, 48.27; H, 2.97; N, 11.26; Found: C, 48.30; H, 2.97; N, 11.25.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([NH:11][NH2:12])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH3:13][CH2:14][O:15][C:16]([CH:18]([C:22]([CH3:24])=O)[C:19]([CH3:21])=O)=[O:17]>CC(O)=O.O>[CH2:14]([O:15][C:16]([C:18]1[C:19]([CH3:21])=[N:12][N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)[C:22]=1[CH3:24])=[O:17])[CH3:13]
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nn(-c2cccc([N+](=O)[O-])c2)c1C
Reaction time: 20 h

Procedure:
Following the procedure described in Helvetica Chimica Acta (1952), 35, 478-85, 5.00 g (26.37 mmmol) of 3-nitrophenylhydrazine hydrochloride suspended in 46 ml of 55% aqueous AcOH were dissolved by careful heating and treated (without further heating) with 4.13 ml (26.37 mmol) of ethyl diacetoacetate. The reaction was immediately cooled and kept 20 h at 0° C. The precipitate was diluted with 28 ml of water and after 6 h filtered and washed with 2×5 ml of water to give after drying under reduced pressure 4.66 g (61%) of the title compound as a light yellow solid. MS: 289.9 (MH+).
Reaction SMILES: C([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[S:10])=[CH:7][CH:6]=1)(=O)C.C(O)C.S(=O)(=O)(O)O>O>[NH2:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[S:10])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(C(=S)N2CCCCC2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(=S)N2CCCCC2)cc1
Temperature: 40 °C

Procedure:
1-(4-Acetamidothiobenzoyl)piperidine (131.2 g, 0.5 mole), ethanol (500 ml), water (1 l) and concentrated sulphuric acid (125 ml) were mixed together and refluxed for 16 hours with stirring; nearly all the solid dissolved during the first hour. The reaction mixture was cooled to about 40°C and filtered quickly to remove any insoluble material. The filtrate was then made alkaline with 6N sodium hydroxide solution using external ice-cooling. The yellow crystalline solid was filtered off, washed with water and dried in vacuo at a temperature of under 50°C. Recrystallisation of the crude product (91 g; m.p. 162°-164°) by dissolving in 6 volumes of warm chloroform (about 546 ml) followed by adding 5 volumes of petroleum ether (b.p. 40°-60°) (about 455 ml) yielded yellow crystals (85 g; 77.3%), m.p. 164°-165°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([Br:14])[C:8]=3[S:7][C:6]=2[CH:15]=1.[C:16]1([N:22]2[C:34]3[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1(P([Pd-4](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)C=CC=CC=1>[Br:14][C:13]1[C:8]2[S:7][C:6]3[CH:15]=[C:2]([C:31]4[CH:32]=[CH:33][C:34]5[N:22]([C:16]6[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=6)[C:23]6[C:28]([C:29]=5[CH:30]=4)=[CH:27][CH:26]=[CH:25][CH:24]=6)[CH:3]=[CH:4][C:5]=3[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reactant: Brc1ccc2c(c1)sc1c(Br)cccc12
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc2c1sc1cc(-c3ccc4c(c3)c3ccccc3n4-c3ccccc3)ccc12

Procedure:
2.47 g (8.1 mmol) of tetrakistriphenylphosphinopalladium(0) are added to a vigorously stirred suspension of 6.8 g (20 mmol) of 3,6-dibromodibenzothiophene, 15 g (40 mmol) of 9-phenyl-9H-carbazole-3-boronic acid and 63.9 g (127 mmol) of Na2CO3 in 500 ml of DMF, and the mixture is subsequently heated under reflux for 16 h. After cooling, the precipitated solid is filtered off with suction, washed three times with 50 ml of toluene, three times with 50 ml of ethanol:water (1:1, v:v) and three times with 100 ml of ethanol and recrystallised three times from DMF (about 15 ml/g). Yield 17.4 g (33 mmol), 86.0%, purity 99.9% (HPLC).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][N:6]([CH2:17][C:18]([O:20]CC)=[O:19])[C:7]1[CH:12]=[C:11]([C:13]([NH2:15])=[S:14])[CH:10]=[CH:9][C:8]=1[CH3:16])C.Cl[CH2:25][C:26](=O)[CH3:27]>C(O)C.CN(C)C=O>[CH3:16][C:8]1[CH:9]=[CH:10][C:11]([C:13]2[S:14][CH:25]=[C:26]([CH3:27])[N:15]=2)=[CH:12][C:7]=1[N:6]([CH2:5][C:4]([OH:3])=[O:23])[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CC(=O)CCl
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(C(N)=S)ccc1C
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1csc(-c2ccc(C)c(N(CC(=O)O)CC(=O)O)c2)n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
The compound (0.70 g, 2.1 mmol) obtained in step A was dissolved in a ethanol (14 ml)-N,N-dimethylformamide (4 ml) mixed solvent. Then, chloroacetone (0.18 ml, 2.3 mmol) was added, and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the obtained oil was diluted with dichloromethane, washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give a crude oil of the title compound containing N,N-dimethylformamide. Using this oil and according to the method of Reference Example 62, step B, the title compound (0.56 g, yield 83%) was obtained as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.C(OC([NH:32][CH:33]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:34](O)=[O:35])=O)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>N1C=CC=CC=1.C(OCC)(=O)C>[NH2:32][CH:33]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:34]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: NC(C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F)c1ccccc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 54.2 %

Procedure:
N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.58 mmol) produced in Example 16(vi) was dissolved in pyridine (3.0 mL), [(tert-butoxycarbonyl)amino](phenyl)acetic acid (290 mg, 1.2 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (440 mg, 1.2 mmol) were added, and the mixture was stirred at 60° C. for 7 hr. [(tert-Butoxycarbonyl)amino](phenyl)acetic acid (145 mg, 0.58 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (220 mg, 0.58 mmol) were added to the reaction mixture, and the mixture was further stirred at 60° C. for 1 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed successively with 5% aqueous ammonium chloride solution (10 ml), saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (4 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate (20 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), and the obtained oil residue was crystallized from ethyl acetate/heptane to give the title compound (150 mg, 53%) as a pale-yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([NH:20][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:5].[Cl:1][C:2]1[CH:10]=[C:9]([NH:20][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([NH:20][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:5]
Reactant: NC1CCCC1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl
Solvent: ClCCl
Product: O=C(NC1CCCC1)c1cc([N+](=O)[O-])c(F)cc1Cl
Product: O=C(NC1CCCC1)c1cc([N+](=O)[O-])c(NC2CCCC2)cc1Cl
Reaction time: 12 h
Yield: 14 %
Yield: 28 %

Procedure:
2-Chloro-4-fluoro-5-nitrobenzoyl chloride (1.5 g, 6.30 mmol) was added to a mixture of cyclopentylamine (430 L, 12.6 mmol), TEA (1.76 mL, 12.6 mmol) and DCM (30 mL) at −20° C. After 12 h at rt, the mixture was diluted with DCM and washed with NH4OH (aq sat). The organic layer was washed with H2O and brine, dried over Na2SO4, concentrated and purified by HPLC to afford 510 mg (28%) of 2-chloro-N-cyclopentyl-4-fluoro-5-nitrobenzamide and 300 mg (14%) of 2-chloro-N-cyclopentyl-4-cyclopentylamino-5-nitrobenzamide.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[N:14]1([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:18]=[CH:17][N:16]=[CH:15]1>>[F:1][C:2]1[CH:13]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:11][C:10](=[O:12])[N:23]([CH2:22][CH2:21][CH2:20][CH2:19][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[C:7]2=[O:9]
Reactant: NCCCCn1ccnc1
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Product: O=c1[nH]c2ccc(F)cc2c(=O)n1CCCCn1ccnc1

Procedure:
When 5-fluoroisatoic anhydride and 1H-imidazole 1-butanamine are reacted by the procedure of example 24, this compound is obtained.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[N:5][C:6]([S:22][CH3:23])=[N:7][C:8]=1[CH2:9][CH2:10][CH:11](C(OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:2].[Sn](Cl)(Cl)(Cl)Cl.O.CCOC(C)=O>C(Cl)Cl>[NH2:2][C:1]1[C:3]2[C:4]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)=[N:5][C:6]([S:22][CH3:23])=[N:7][C:8]=2[CH2:9][CH2:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(CCc1nc(SC)nc(-c2cccc(OC)c2)c1C#N)C(=O)OCC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1=C(N)c2c(nc(SC)nc2-c2cccc(OC)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Cyano-4-(3-methoxyphenyl)-2-methylthio-6-(1,1-bis(ethoxycarbonyl)prop-3-yl)pyrimidine (example 25b, 81 mg) was dissolved in dry CH2Cl2 (1 ml). A 1M solution of tin(IV) chloride in CH2Cl2 (1 ml) was added dropwise and the mixture was stirred at room temperature for 1 h. H2O (10 ml) and EtOAc (10 ml) were then added to the reaction mixture. The organic layer was washed with H2O (10 ml) and sat. aq. NaCl (10 ml), dried (MgSO4) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel with hept/EtOAc=1/0 to 3/2 (v/v) as eluent.
Reaction SMILES: [ClH:1].OS(O)(=O)=O.[Na+].[Cl-].[CH3:9][C:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH2:11]>>[CH3:11][C:10]([Cl:1])([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9]
Reactant: Cl
Reactant: C=C(C)CC(C)(C)C
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)(C)CC(C)(C)Cl

Procedure:
Dry gaseous HCl, generated by the reaction of H2SO4 and NaCl, was passed through a 30% solution of 2,4,4-trimethyl-1-pentene in dry and distilled CH2Cl2 at 0° C. for 24 hours. The solvent and excess gaseous HCl were removed and the product was purified by distillation from CaH2 under vacuum to avoid decomposition. TMPCl, when stored in a freezer (-20° C.) under N2, was found to be stable at least for a year. Structure was confirmed by 1H NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:9])=[O:8])=[CH:5][CH:4]=1.[N:12]1[CH:17]=CC=[CH:14][CH:13]=1.C(OCC)(=[O:20])C>>[ClH:9].[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:20][CH2:14][CH2:13][NH:12][CH3:17])=[O:8])=[CH:5][CH:4]=1
Reactant: CCOC(C)=O
Reactant: c1ccncc1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: CNCCOC(=O)c1ccc(OC)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl (methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL) were added 4-methoxybenzoyl chloride (1.88 g) and pyridine (0.97 mL). After stirring at room temperature for 14 hrs., 4-methoxybenzoyl chloride (0.70 g) and pyridine (0.97 mL) were added and the mixture was stirred at room temperature for 1 hr. Ethyl acetate (80 mL) was added to the reaction mixture, and the mixture was washed with water (20 mL), a saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in ethyl acetate (10 mL), and a 4N hydrogen chloride—ethyl acetate solution (10 mL) was added. After stirring at room temperature for 1 hr., diethyl ether (20 mL) was added, and the precipitated solid was collected by filtration. The solid was washed twice with ethyl acetate (15 mL) and dried under reduced pressure at 60° C. to give the title compound (1.99 g) as a white solid.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N:13]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(-n2cccn2)cc1
Temperature: 130 °C
Reaction time: 16 h
Yield: 68.2 %

Procedure:
To a solution of ethyl 4-fluorobenzoate (105 g) in DMSO (250 mL) were added pyrazole (34.0 g) and potassium carbonate (138 g), and the mixture was heated with stirring at 130° C. for 16 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (73.7 g).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[O:13]=[C:14]1[NH:18][CH2:17][CH:16]([C:19](O)=[O:20])[CH2:15]1>C(OCC)(=O)C>[F:1][C:2]1[C:7]([O:8][C:19]([CH:16]2[CH2:15][C:14](=[O:13])[NH:18][CH2:17]2)=[O:20])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: O=C1CC(C(=O)O)CN1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCOC(C)=O
Product: O=C1CC(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)CN1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCI (1.5 mmol) in 8 mL ethyl acetate was added pentafluorophenol (3 mmol) at 0° C. After 10 minutes, 5-oxo-pyrrolidine-3-carboxylic acid VI (1 mmol) was added at 0° C. and the reaction mixture was stirred for 1 hour at room temperature. After evaporation of the solvent, the crude product was purified by chromatography on silica gel (ethyl acetate:hexane=1:2) to yield the corresponding 5-oxo-pyrrolidine-3-carboxylic acid pentafluorophenyl ester VII as a colourless oil.