Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][CH:12]([S-:14])[CH3:13].[Na+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:14][CH:12]([CH3:13])[CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)ccc1F
Reactant: CC(C)[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Sc1ccc(Cl)cc1C#N
Yield: 88.9 %

Procedure:
(Step 1) A mixture of 5-chloro-2-fluorobenzonitrile (6.0 g) and sodium propane-2-thiolate (4.16 g) was stirred in N,N-dimethylformamide (30 ml) at room temperature for 18 hr. The reaction solution was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-chloro-2-[(1-methylethyl)sulfanyl]benzonitrile (7.26 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]=[O:13].[H-].[Na+].[CH3:16]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:16])[CH:7]=[C:6]2[CH:12]=[O:13]
Reactant: CI
Reactant: COc1ccc2[nH]cc(C=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(C=O)cn2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-methoxyindole-3-carboxaldehyde (80 g) in dimethylformamide (1 L) under nitrogen was treated portion-wise with sodium hydride (20.1 g, 60% dispersion in mineral oil) over 15 minutes. After stirring at ambient temperature for 30 minutes the mixture was treated dropwise with methyl iodide (31.3 mL) over 10 minutes and stirring was then continued for a further 2 hours. The reaction mixture was poured cautiously into water then extracted with ethyl acetate. The organic phase was washed with water, then dried over sodium sulfate and then evaporated. The residue was triturated with pentane to give the title compound (76 g) as a pale brown solid, m.p. 133-134° C. 1H NMR [(CD3)2SO]: δ 9.86 (1H, s); 8.20 (1H, s); 7.60 (1H, d, J=2.6 Hz); 7.50 (1H, d, J=8.9 Hz); 6.96 (1H, dd, J=8.9 and 2.6 Hz); 3.86 and 3.80 (6H, s).
Reaction SMILES: [CH3:1][O-:2].[Na+].F[C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:22])[C:10]([C:16]3[N:20]([CH3:21])[N:19]=[N:18][N:17]=3)=[CH:11][N:12]2[CH3:15])=[CH:7][CH:6]=1.CO>O>[CH3:1][O:2][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:22])[C:10]([C:16]3[N:20]([CH3:21])[N:19]=[N:18][N:17]=3)=[CH:11][N:12]2[CH3:15])=[CH:7][CH:6]=1
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(=O)c(-c3nnnn3C)cn(C)c2c1

Procedure:
A mixture of sodium methoxide (0.47 g), 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (2.0 g) and methanol (40 ml) was boiled under reflux for 43 hours. The mixture was cooled and poured into water (100 ml). The solid was collected by filtration, washed with boiling industrial methylated spirit (50 ml) and dried to give the novel compound 7-methoxy-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. 270°-273°.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[S:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[CH:20])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@H:3]1[C:21]([O:23]C(C)(C)C)=[O:22].Cl>ClCCl>[CH3:1][C:2]1([CH3:28])[S:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]#[CH:20])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[C@H:3]1[C:21]([OH:23])=[O:22]
Reactant: C#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Product: C#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)O)cc1
Reaction time: 8 h
Yield: 93.8 %

Procedure:
Through a solution of 0.271 g (0.638 mmol) of tert-butyl (3S)-2,2-dimethyl-4-{[4-(2-propynyloxy)phenyl]sulfonyl}-3-thiomorpholinecarboxylate in 10 mL of dichloromethane was bubbled hydrogen chloride gas for 10 minutes. The reaction was then stoppered and let sit overnight at room temperature. The solvent was evaporated to give 0.221 g of (3S)-2,2-dimethyl-4-{[4-(2-propynyloxy)phenyl]sulfonyl}-3-thiomorpholine carboxylic acid as a white solid. Electrospray Mass Spec 368.2 (M−H)−
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([CH3:19])[CH:12]=2)[C:3]=1[C:4]#[N:5].[NH3:20]>C(O)C.C1COCC1>[NH2:20][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([CH3:19])[CH:12]=2)[C:3]=1[C:4]#[N:5]
Reactant: N
Reactant: COc1cc(C)cc(Sc2cccc(F)c2C#N)c1
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(C)cc(Sc2cccc(N)c2C#N)c1
Temperature: 145 °C

Procedure:
A solution of 0.1 g (0.00037 mol) of 2-fluoro-6-[(3-methyl-5-methoxyphenyl)thio]benzonitrile (Example 23) in 10 mL of absolute ethanol and ca. 2 mL of THF was saturated with ammonia. The resultant solution was sealed in a glass-lined Parr bomb and heated to 145° C. for 48 h. The solvent was removed in vacuo. 20 mL of 1 NaOH was added. This aqueous solution was extracted with 3×20 mL of EtOAc. The EtOAc solution was dried over MgSO4. After solvent removal, the crude product was chromatographed on silica gel (flash; CH2Cl2), resulting in 0.03 g (30%) of 2-amino-6-[(3-methyl-5-methoxyphenyl)thio]benzonitrile as a white solid: mp 108°-110° C.; NMR (Me2SO-d6, 200 MHz) δ 2.32 (s, 3H), 3.78 (s, 3H), 6.28 (br s, 1H), 6.4 (apparent d, 1H), 6.7-6.8 (m, 2H), 6.8-6.9 (narrow m, 2H), 7.28 (apparent d, H). Anal. Calc. for C15H14N2OS: C, 66.64; H, 5.22; N, 10.36; S, 11.36. Found: C, 66.46; H, 5.22; N, 10.25; S, 11.71.
Reaction SMILES: Cl[C:2]1[C:3]2[S:18][C:17]([NH2:19])=[N:16][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=1.[NH2:20][C@H:21]([CH3:31])[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:19][C:17]1[S:18][C:3]2[C:2]([NH:20][C@H:21]([CH3:31])[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:5][C:4]=2[N:16]=1
Reactant: C[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@H](CNC(=O)OC(C)(C)C)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Temperature: 110 °C

Procedure:
The product from example 1 step c) (2.0 g) and the product from example 25 step d) (1.3 g) in a solvent of NMP (10 ml) containing Hunigs base (3 ml) was heated at 110° C. for 10 hours. The mixture was evaporated to dryness and purified (SiO2, (1:1) dichloromethane:ethyl acetate as eluant) to give the subtitle compound (1.9 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)[C:6]([NH:8][NH2:9])=O.Cl.Cl.[CH3:25][O:26][C:27]1[CH:28]=[C:29](/[CH:39]=[CH:40]/[C:41](=[NH:45])OCC)[CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1>C(O)CC>[CH3:25][O:26][C:27]1[CH:28]=[C:29](/[CH:39]=[CH:40]/[C:41]2[N:45]=[C:6]3[CH:5]([CH:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)[CH2:4][CH2:3][CH2:2][N:8]3[N:9]=2)[CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(CCCCl)C(=O)NN)CC1
Reactant: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Agent: Cl
Solvent: CCCO
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCN(C(=O)OC(C)(C)C)CC2)ccc1-n1cnc(C)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
A solution of tert-butyl 4-[4-chloro-1-hydrazinocarbonyl-butan-1-yl]piperidine-1-carboxylate (663 mg) in 1-propanol (4 mL) was added to a solution of ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride obtained in Example 1 (792 mg) and TEA (1.7 mL) in 1-propanol (16 mL), and the reaction solution was stirred at 90° C. overnight. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate, water and a saturated sodium bicarbonate solution were added to the concentration residue, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane-ethyl acetate system) to obtain 361 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[CH2:20]([O:1][C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1)=[O:5])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)c1cccc(C(=O)O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)c1cccc(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 130.3 %

Procedure:
A solution of 2-hydroxy-3-isopropylbenzoic acid (5 g, 27.8 mmol) in acetone (40 ml) was treated with K2CO3 (7.67 g, 55.6 mmol) and benzyl bromide (9.98 g; 58.4 mmol). The reaction was stirred at ambient temperature for 60 hours, then evaporated. The residue was partitioned between ethyl acetate/H2O and the organic phase dried (MgSO4) and evaporated. The residue was purified by chromatography (eluant: ethyl acetate/hexane) to give benzyl 2-benzyloxy-3-isopropylbenzoate (6.52 g, 18.11 mmol, 65%)
Reaction SMILES: [F:1][C:2]1[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1.N1C=CC=CC=1.FC(F)(F)S([O:43][S:44]([C:47]([F:50])([F:49])[F:48])(=[O:46])=[O:45])(=O)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([O:43][S:44]([C:47]([F:48])([F:49])[F:50])(=[O:45])=[O:46])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: COC(=O)c1cn2c3c(c(OS(=O)(=O)c4ccc(C)cc4)c(F)cc3c1=O)CCN2C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cn2c3c(c(OS(=O)(=O)C(F)(F)F)c(F)cc3c1=O)CCN2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.8 g of the compound (169) obtained in Example 46 was added to 10 ml of pyridine, and while cooling on ice, 2.35 ml of trifluoromethanesulfonic anhydride was added to the solution through 20 minutes. The solution was stirred for 24 hours at room temperature. 200 ml of chloroform was added to the solution, and the solution was washed with aqueous 5% citric acid solution. The organic layer was separated and after drying over magnesium sulfate, the solvent was removed by distillation. To the residue, ethanol was added, and the solid matter was filtered off and purified by column chromatography (silica gel, eluent solvent; chloroform:ethyl acetate=1:1). The solid matter was filtered off and washed with isopropyl ether to obtain 1.2 g of the subject compound (170).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH3:9][N:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:9][N:10]1[CH2:15][CH2:14][CH:13]([N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)[CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(n2cc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Nitro-1H-pyrazole (200 mg, 1.77 mmol), 1-methylpiperidin-4-ol (204 mg, 1.77 mmol) and triphenylphosphine (557 mg, 2.12 mmol) were combined in THF (6 mL) and di-tert-butyl azodicarboxylate (529 mg, 2.30 mmol) was added over about 1 minute. The resulting mixture was stirred at room temperature for 4 hours, and concentrated to dryness. The residue was purified by flash chromatography (Analogix, 12 g column, 0 to 7% methanol in CH2Cl2 over 25 minutes) to give 1-methyl-4-(4-nitro-1H-pyrazol-1-yl)piperidine.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH2:9]([N:4]1[CH:3]=[CH:2][CH:6]=[N:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Ic1cn[nH]c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(Cn2cccn2)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-iodopyrazole (400 mg, 2 mmol) in DMF(4 mL) at 0° C. was added sodiumhydride (80 mg, 60% dispersion in mineral oil, 2 mmol) followed by benzyl bromide (342 mg, 2 mmol) and reaction micture was allowed to stir for 2 h. Reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give N-benzylpyrazole in almost quantitative yield. IH NMR 5.29 (s, 2H), 7.18-7.28 (m, 2H), 7.28-7.40 (m, 4H), 7.53 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][C@@H:25]1[CH2:29][O:28][C:27](=[O:30])[NH:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[N:7][C:2]([N:26]4[C@H:25]([CH3:24])[CH2:29][O:28][C:27]4=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)nn3)CC2)c(C)c1
Yield: 50.8 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (28 mg) described in Preparation Example 230 and (R)-4-methyloxazolidin-2-one (10 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (17 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([NH:9][CH3:10])[C:7]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+].[H][H]>[Ni].O>[CH3:10][NH:9][C:8]1[CH:11]=[C:4]([CH:5]=[CH:6][C:7]=1[S:12]([OH:15])(=[O:14])=[O:13])[NH2:1]
Reactant: CNc1cc([N+](=O)[O-])ccc1S(=O)(=O)O
Reactant: [H][H]
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNc1cc(N)ccc1S(=O)(=O)O

Procedure:
23.2 g of 5-nitro-N-methylaniline-2-sulfonic acid were added to 300 g of water. The pH was then adjusted to from 5. 0 to 5.5 with sodium hydroxide solution, 2 g of Raney nickel were added and hydrogenation was carried out under atmospheric pressure at 30° C. After hydrogen uptake had ceased, the catalyst was filtered off, the pH of the filtrate was adjusted to 0.5 to 1.0 with hydrochloric acid, and the precipitated 3-(N-methylamino)aniline-4sulfonic acid was isolated by filtration.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[CH:6][NH:5][CH:4]=1)[CH3:2].[OH:8][C:9]1C=C(NC2C3=CC(C)=CN3N=CN=2)C=CC=1C>>[CH:9]([C:4]1[NH:5][CH:6]=[CH:7][C:3]=1[CH2:1][CH3:2])=[O:8]
Reactant: CCc1cc[nH]c1
Reactant: Cc1cc2c(Nc3ccc(C)c(O)c3)ncnn2c1
Product: CCc1cc[nH]c1C=O

Procedure:
3-Ethylpyrrole was converted to a mixture of Compound A and 2-formyl-41 ethylpyrrole as described in the preparation of Compound A of Example 5. [M+H]+=124.1
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(Cl)(Cl)Cl.[I:15]I>CC(O)=O>[I:15][C:4]1[NH:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]([F:10])([F:9])[F:8]
Reactant: II
Reactant: Cc1nc(C(F)(F)F)c[nH]1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1nc(C(F)(F)F)c(I)[nH]1
Temperature: 60 °C
Reaction time: 3 h
Yield: 107.1 %

Procedure:
To 2-methyl-4-(trifluoromethyl)-1H-imidazole (1 g, 6.7 mmol) was added CHCl3 (4.5 mL) and AcOH (13.5 mL) followed by I2 (1.78 g, 6.99 mmol) and HIO4.2H2O (1.52 g, 6.7 mmol), and the resulting reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was then poured into ice cold 10% aqueous sodium bisulphite solution (100 mL) and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo to obtain 5-iodo-2-methyl-4-(trifluoromethyl)-1H-imidazole (1.98 g) which was used as such in next step without further purification.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.Br[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=1[Cl:22]>>[Cl:22][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:21])[C:15]=1[CH2:14][S:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[N:3]=1
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Reactant: Clc1cncc(Cl)c1CBr
Product: Oc1cc(C(F)(F)F)nc(SCc2c(Cl)cncc2Cl)n1

Procedure:
This example was synthesized from 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol and 4-(bromomethyl)-3,5-dichloropyridine by following general procedure as described in the last step of Example 22. The title compound was obtained as a white solid (660 mg, 37% yield); 1H NMR (400 MHz, DMSO-d6): δ 4.72 (s, 2H), 6.69 (br, 1H), 8.64 (s, 2H); M+356.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C:12]1=[O:20].N1CCCCC1>C(O)C>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][C:12]1=[O:20]
Reactant: Cc1c(Br)cccc1C=O
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(Br)cccc1C=C1C(=O)Nc2ccccc21
Temperature: 82.5 °C
Reaction time: 15.25 h
Yield: 29.9 %

Procedure:
Step 2 A solution of 3-bromo-2-methylbenzaldehyde (200 mg, 1.01 mmol) and indolin-2-one (134 mg, 1.01 mmol) in ethanol (10 mL) was treated with piperidine (0.099 mL, 1.01 mmol) and heated at 80-85° C. After 15.25 h, the solution was cooled to rt and concentrated. The residue was purified by column chromatography (eluting with a gradient from 80:20 to 30:70 hexane-ethyl acetate) to provide 3-(3-bromo-2-methylbenzylidene)indolin-2-one as a bright yellow solid (94.9 mg, 30%). 1H NMR (400 MHz, chloroform-d) δ 7.89 (1H, br. s.), 7.85 (1H, s), 7.64 (1H, d, J=7.9 Hz), 7.47 (1H, d, J=7.7 Hz), 7.20 (1H, td, J=7.7, 1.1 Hz), 7.07-7.16 (2H, m), 6.87 (1H, d, J=7.9 Hz), 6.81 (1H, td, J=7.6, 1.0 Hz), 2.43 (3H, s). Mass spectrum m/z 314, 316 (M+H)+.
Reaction SMILES: [C:1]([OH:10])(=O)[C@H:2]([C@@H:4]([C:6](O)=[O:7])[OH:5])[OH:3].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1(C)C(C)=CC=CC=1>[CH2:11]([N:18]1[C:6](=[O:7])[C@@H:4]([OH:5])[C@H:2]([OH:3])[C:1]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1[C@@H](O)[C@H](O)C(=O)N1Cc1ccccc1
Yield: 84635.8 %

Procedure:
In xylene (500 ml), D-tartaric acid (25.0 g, 0.17 mol) and benzylamine (19.6 g, 0.18 mmol) were heated under reflux for 18 hours by using a Dean-Stark water separator. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent, whereby 1-benzyl-(3S,4S)-dihydroxy-2,5-dioxopyrrolidine (33.7 g, 90%) was obtained as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2([CH2:15]O)[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].C(N(S(F)(F)[F:29])CC)C>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2([CH2:15][F:29])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C1COCC(CO)(c2ccnc(Br)c2)N1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCC(CF)(c2ccnc(Br)c2)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-(2-bromo-pyridin-4-yl)-5-hydroxymethyl-morpholin-3-one (3.25 g, 11.0 mmol), Na2CO3 (3.5 g, 13.06 mmol) in dry THF (15 ml) was added diethylaminosulfur trifluoride (2.25 ml, 17.0 mmol) at 0° C. The reaction mixture was allowed to warm to rt and stirred for 2 h. Solid Na2CO3 (3.5 g) was again added to the reaction mixture and stirred for 4 h at rt. Solids present in the reaction mixture filtered through Buchner funnel. Filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography using 5% methanol in DCM to obtain title compound as a pale yellow solid. Yield=2.1 g (66%). TLC (50% ethyl acetate in hexane) Rf=0.17; LCMS: RtH7=0.201; [M+1]+=289 and 291; HPLC: RtH9=5.171 min. (50%) and 5.063 (21%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)O)cn1
Temperature: 40 °C
Yield: 88 %

Procedure:
A solution of methyl 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridine-5-carboxylate (see reference example 6) (10.2 g, 0.55 mmol) in THF (3 ml) and methanol (5 ml) was treated with 1N aqueous sodium hydroxide solution (2.7 ml) and was heated to 40° C. for 24 hours. The solvents were evaporated at reduced pressure, the residue treated with 1N acetic acid (2.7 ml) and the precipitate filtered, washed with water and air dried to give the title compound (0.17 g, 92%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[CH:14]12[CH2:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][CH:15]2[NH2:21].C(N(CC)CC)C>C(O)(C)C>[CH:14]12[CH2:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][C@@H:15]2[NH:21][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12
Reactant: NC1CC2CCC1C2
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC2CCC1C2
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.064 g, 0.30 mmol) (Example 1, Step 2), bicyclo[2.2.1]heptan-2-amine (from Aldrich, 0.050 g, 0.45 mmol) and triethylamine (0.083 mL, 0.60 mmol) in isopropyl alcohol (1.4 mL) was heated at 90° C. for 2 h. The mixture was concentrated to give the desired product, which was used in the next step without further purification. LCMS calculated for C14H16N3O2S (M+H)+: m/z=290.1. Found: 290.0.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([CH3:23])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[CH:39]1([NH2:43])[CH2:42][CH2:41][CH2:40]1>O1CCCC1>[CH:39]1([NH:43][C:10](=[O:12])[C:9]2[CH:13]=[C:5]([O:4][C:3]3[C:16]([CH3:23])=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:2]=3[CH3:1])[CH:6]=[CH:7][C:8]=2[O:14][CH3:15])[CH2:42][CH2:41][CH2:40]1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)O
Reactant: NC1CCC1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)NC1CCC1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 71.6 %

Procedure:
To a solution of 5-(2,6-Dimethyl-4-nitro-phenoxy)-2-methoxy-benzoic acid (2.0 g, 6.3 mmol) in tetrahydrofuran (60 mL) at 0° C. under nitrogen was added N-methylmorpholine (1.4 mL) and isobutyl chloroformate (1.3 g, 9.5 mmol). The resulting mixture was stirred for 25 minutes at 0° C., and cyclobutyl amine (0.9 g, 13 mmol) was added in a single portion at 0° C. The reaction solution was stirred for another 30 minutes at 0° C. and warmed to room temperature over 1 hour. The solution was then concentrated to a viscous oily solid which was partitioned between water (25 mL) and methylene chloride (25 mL). The organic phase was separated and the aqueous phase was extracted with methylene chloride (10 mL). The combined organic extracts were washed with saturated aqueous NaHCO3, 1N hydrochloric acid and brine, dried over Na2SO4, filtered, and concentrated. To the residue was purified by column chromatography (Et2O/methylene chloride/hexane=1/7/12) to afford the title compound (1.67 grams) as a crude product. 1H NMR (400 MHz, CDCl3) δ8.04 (br s, 1H), 7.98 (s, 2H), 7.54 (d, 1H), 6.90 (d, 1H), 6.86 (dd, 1H), 4.51-4.49 (m, 1H), 3.94 (s, 3H), 2.41-2.38 (m, 2H), 2.17 (s, 6H), 1.95-1.90 (m, 2H), 1.80-1.75 (m, 2H). MS (APCI+) Calc: 370.4, Found: 371.2 (M+1).