Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1[C:8](=[O:19])[N:9]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11][N:10]2[C:17]=1[NH2:18].[NH2:20][C:21]1[C:22]([Cl:29])=[C:23]([OH:28])[C:24]([CH3:27])=[CH:25][CH:26]=1.N.OO>O.C(O)C>[NH2:18][C:17]1[N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][N:9]2[C:8](=[O:19])[C:7]=1[N:6]=[C:26]1[CH:25]=[C:24]([CH3:27])[C:23](=[O:28])[C:22]([Cl:29])=[C:21]1[NH2:20]
Reactant: CN1CCn2c(N)c(N)c(=O)n2CC1
Reactant: Cc1ccc(N)c(Cl)c1O
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: CCO
Solvent: O
Product: CC1=CC(=Nc2c(N)n3n(c2=O)CCN(C)CC3)C(N)=C(Cl)C1=O

Procedure:
0.32 mmol of 8,9-diamino-3-methyl-2,3,4,5-tetrahydro-1H,7H-pyrazolo[1,2-a][1,2,5]triazepin-7-one methanesulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.32 mmol of 3-amino-2-chloro-6-methylphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [Br:1]Br.Br(F)(F)F.[C:7]1([C:13]([F:16])([F:15])[F:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[Br:1][C:9]1[CH:8]=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:12]=[CH:11][CH:10]=1
Reactant: BrBr
Reactant: FC(F)(F)c1ccccc1
Solvent: O
Product: FC(F)(F)c1cccc(Br)c1
Yield: 97.7 %

Procedure:
24 gr of bromine and 14 gr of brominetrifluoride were placed in a 50 ml three necked flask. The mixture was stirred vigorously and swept by the aid of a stream of dry nitrogen into a 250 ml three necked flask equipped with a mechanical stirrer, thermometer and double faced condensor, containing 60 gr of benzotrifluoride. Both mixtures were stirred vigorously and icy water was circulated through the condensor, until all the mixture was swept over to the second flask. When no mixture was left in the first flask the reaction was stopped and treated as described in example 21. 25 gr of benzotrifluoride was recovered under distillation and 33 gr of 3-bromobenzotrifluoride was obtained, 61% yield based on reacted benzotrifluoride.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[N:19]1([CH2:24][CH2:25][CH2:26][NH2:27])[CH:23]=[CH:22][N:21]=[CH:20]1>CN(C)C=O>[CH3:7][N:6]1[C:2]([NH:27][CH2:26][CH2:25][CH2:24][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[C:3]([N+:9]([O-:11])=[O:10])[C:4]([CH3:8])=[N:5]1
Reactant: Cc1nn(C)c(Cl)c1[N+](=O)[O-]
Reactant: NCCCn1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(NCCCn2ccnc2)c1[N+](=O)[O-]
Temperature: 105 °C
Yield: 56.7 %

Procedure:
0.88 g of 5-chloro-1,3-dimethyl-4-nitro-1H-pyrazole (Aldrich), 1 molar equivalent of triethylamine, 1.1 molar equivalents of 3-imidazol-1-ylpropylamine and 5 ml of N,N-dimethylformamide were introduced into a 25 ml three-necked round-bottomed flask equipped with a magnetic stirrer, a thermometer and a condenser. The reaction medium was maintained at a temperature of about 105° C. for 6 hours. The solvent was evaporated off under vacuum. A black liquid was obtained, which was purified by chromatography on silica gel (ethyl acetate/methanol=4/1). 0.75 g of (2,5-dimethyl-4-nitro-2H-pyrazol-3-yl)(3-imidazol-1-yl-propyl)amine was obtained in the form of white crystals in a yield of 56.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:14])[N:3]=1.[NH2:15][NH2:16].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[NH:15]([C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:14])[N:3]=1)[NH2:16]
Reactant: Cc1nc(Cl)cc(-c2ccccc2)n1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1nc(NN)cc(-c2ccccc2)n1
Product: Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 180.4 %

Procedure:
To a solution of 4-chloro-2-methyl-6-phenylpyrimidine (11 g, 0.0537 mol) in dioxane (100 ml) was added anhydrous hydrazine (2 g, 0.0625 mol) followed by potassium carbonate (11 g, 0.080 mol) and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was treated with 2M HCl in dioxane (100 ml) and the solid precipitated was filtered and washed with methanol (100 ml) and dried under suction to afford 10 g (60%) of the titled compound as a solid.
Reaction SMILES: [CH3:1]O.S(=O)(=O)(O)O.[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])[CH:13]=[CH:12]2>CCCCCC>[CH3:1][O:21][C:20](=[O:22])[CH:19]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[CH:15]=1)[CH3:23]
Reactant: CO
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: COC(=O)C(C)c1ccc2cc(O)ccc2c1
Yield: 89.5 %

Procedure:
To a solution of methanol (2100 ml) and sulphuric acid (84 ml) was added 2-(6-Hydroxy-naphthalen-2-yl)-propionic acid (420 grams). The reaction mixture was refluxed for 6 Hours. Methanol (1000 ml) was distilled, and the cooled reaction mass was poured onto ice water to yield crude 2-(6-hydroxy-naphthalen-2-yl)-propionic acid methyl ester which was filtered, dried and recrystallized using a mixture of ethyl acetate:hexane to yield pure product (400 grams, 89.5% yield) as a white fluffy powder with a melting point of 89.5-92° C. The pure product was characterized using 1H NMR spectroscopy in CDCl3 δ 1.60 (d, 3H, CH3), 3.70 (s, 3H, Ester), 3.88 (q, 1H, CH), 5.36 (bs, 1H, OH), 7.08 (m, 2H, Ar), 7.48 (m, 1H, Ar), 7.65 (m, 3H, Ar).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[N:9][S:10][CH:11]=1.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)Cl>[Br:13][CH2:12][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[N:9][S:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1-c1csnn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: BrCc1ccccc1-c1csnn1

Procedure:
A solution of 4-o-tolyl-[1,2,3]thiadiazole (100 mg, 0.57 mmol), N-bromosuccinimide (100 mg, 0.57 mmol) and 2,2′-azobisisobutyronitrile (9.4 mg, 0.057 mmol) in chloroform (10 ml) was heated at reflux temperature for ˜18 h. Additional chloroform was added and the mixture was washed with water, 5% sodium thiosulfate solution and brine. Drying and solvent evaporation gave 4-(2-bromomethyl-phenyl)-[1,2,3]thiadiazole; 1H NMR (CDCl3, 300 MHz) δ 8.87 (s, 1H), 7.67–7.39 (m, 4H), 4.71 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]CC)=[O:36].[OH-].[Na+].C(O)C>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(Cl)cc5)n4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(Nc1cccc(-c2ccc(Cl)cc2)n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 4 h
Yield: 94.4 %

Procedure:
Ethyl 6-chloro-7-(4-(6-(4-chlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (50 mg, 0.089 mmol) was diluted with THF (1 mL) followed by the addition of 1 N aq. NaOH (444 μL, 0.44 mmol) and ethanol (500 μL). After stirring for 4 hours, the reaction was diluted with ethyl acetate and 1N aq. HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 6-chloro-7-(4-(6-(4-chlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (45 mg, 0.084 mmol, 95% yield). MS (ESI, positive) m/z=535.3.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl-].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:23]=[CH:22][C:17]([CH:18]=[N+:19]([CH3:21])[CH3:20])=[CH:16][CH:15]=1.FC(F)(F)C1C=CC(C=O)=CC=1.CNC>>[CH3:20][N:19]([CH3:21])[CH:18]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1])[C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:24])[F:25])=[CH:23][CH:22]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: C[N+](C)=Cc1ccc(C(F)(F)F)cc1
Agent: CNC
Agent: O=Cc1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Product: Cc1[nH]c2ccccc2c1C(c1ccc(C(F)(F)F)cc1)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methyl-1H-indole and (4-trifluoromethyl-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 4-trifluoromethyl-benzaldehyde and dimethylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12](Br)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[C:23]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C:31]1=O)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C1C[O:40]CC1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([C:33]3([OH:40])[CH2:34][CH2:35][N:30]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:31][CH2:32]3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)n1ccc2c(Br)cccc21
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc3c2ccn3C(=O)OC(C)(C)C)CC1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
A solution of 4-bromo-indole-1-carboxylic acid-tert-butyl ester 4-2 (4.9 g, 16.5 mmol) in THF (150 mL) under Argon was cooled to −70° C., and n-BuLi (12.4 mL, 24.8 mmol) was added over 20 min. The reaction mixture was warmed to −5° C. in an ice bath and was stirred at this temperature for 30 min. The mixture was cooled to −70° C. and a solution of N-Boc-piperidone 4-3 (3.3 g, 16.5 mmol) in THF (10 mL) was added over 15 min. The reaction was stirred for 45 min at −70° C. and was then warmed to room temperature. The reaction was quenched with a saturated solution of ammonium chloride (75 mL) and partitioned between water (25 mL) and ethyl acetate (75 mL). The organic layer was washed with water (50 mL) and brine (50 mL), then dried (MgSO4), filtered and concentrated. The remaining brown oil was chromatographed, eluting with ethyl acetate:hexanes (1:9) to afford 1.32 g (19% yield) of 4-(1-tert-butoxycarbonyl-4-hydroxy-piperidin-4-yl)-indole-1-carboxylic acid tert-butyl ester 4-4.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O.C(OCC)C>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[O:14][C@@H:13]([CH2:12][N:30]=[N+:31]=[N-:32])[CH2:22][CH2:21]2
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cccc(-c4ccccc4Cl)c3O2)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@H]1CCc2cccc(-c3ccccc3Cl)c2O1
Yield: 83.4 %

Procedure:
A solution of [(2R)-8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.24 g, 0.56 mmol) and sodium azide (0.15 g, 2.24 mmol) in anhydrous dimethyl sulfoxide (10 mL) was heated to 70° C. under nitrogen for 15 hours. The cooled reaction mixture was then diluted with diethyl ether (50 mL), washed with water (5×25 mL) and saturated brine (25 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford 0.14 g (82%) of {[(2R)-8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}azide as a colorless oil that was used without further purification.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]#[N:10])[C@H:4]([CH2:11][OH:12])[CH2:3]1.C(N(CC)[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C>>[OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[NH:10][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[C@H:4]([CH2:11][OH:12])[CH2:3]1
Reactant: N#CCCN1C[C@@H](O)C[C@H]1CO
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3C[C@@H](O)C[C@H]3CO)cc12

Procedure:
In the same manner as in Example 10b (a) and using (3S,5S)-5-hydroxymethylpyrrolidin-3-ol described in Collect. Czech. Chem. Commun., vol. 61, pp, S234-S237 (1996), 3-[(2S,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile is obtained. In the same manner as in Example 1b (e) and using 3-[(2S,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-{2-[(2S,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]ethyl}-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[F:39][C:27]([F:26])([F:38])[C:28]1[CH:29]=[C:30]([S:34]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=3)=[CH:8][CH:9]=2)(=[O:35])=[O:36])[CH:31]=[CH:32][CH:33]=1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNS(=O)(=O)c3cccc(C(F)(F)F)c3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.5 g (1.4 mmol) of material from Example 50 and 19 mg (0.11 mmol) 3-trifluoromethyl-benzenesulfonyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [CH3:1][N:2]([CH:19]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[CH2:20][CH2:21][C:22](O)=[O:23])[C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:36]1([NH:35][C:22](=[O:23])[CH2:21][CH2:20][CH:19]([N:2]([CH3:1])[C:3](=[O:18])[C:4]2[CH:5]=[C:6]([C:14]([F:16])([F:17])[F:15])[CH:7]=[C:8]([C:10]([F:12])([F:11])[F:13])[CH:9]=2)[CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][CH:27]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)Cc1c[nH]c2ccccc12
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)Nc1ccccc1)Cc1c[nH]c2ccccc12
Reaction time: 16 h

Procedure:
A mixture consisting of 42.9 mg of 4[N'-methyl-N'-(3,5-bis-trifluoromethyl-benzoyl)-amino]-5-(1H-indol-3-yl)-pentanoic acid, 8.9 mg of aniline, 36.65 mg of propanephosphonic acid anhydride, 60 μl of triethylamine and 1.5 ml of methylene chloride is left to stand at room temperature for 16 hours. 0.5 ml of 1N potassium carbonate solution is then added and the mixture is shaken vigorously. After separation of the phases, the organic phase is separated off and concentrated by evaporation. In this way the title compound is obtained in the form of a white foam. Rf value=0.26 (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:18][NH:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NNc1ccccc1
Solvent: C1CCOC1
Product: O=C(NNc1ccccc1)Nc1ccc(Cl)cc1
Yield: 105.5 %

Procedure:
1.1 A solution of 15.35 g of 4-chlorophenyl isocyanate in 50 ml of THF is added to a solution of 9.83 g of phenylhydrazine in 100 ml of THF under a nitrogen atmosphere, and the mixture is refluxed for 2 hours. Conventional work-up gives 25.1 g of N-(4-chlorophenylaminocarbonyl)-N′-phenylhydrazine(“AA”), El 277, m.p. 187-189.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.C(O)(=O)C.[Br:16]Br>O>[NH2:1][C:2]1[C:7]([Br:16])=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Nc1ccc(C(F)(F)F)cn1
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(C(F)(F)F)cc1Br
Temperature: 0 °C
Yield: 78.5 %

Procedure:
In a 100 ml four necked flask equipped with the same equipments as those used in Example 3 were placed 3 g of 2-amino-5-trifluoromethylpyridine and 30 ml of acetic acid to provide a homogeneous solution. 4.4 g of bromine was dropwise added thereto while cooling the flask with ice water at 10° to 20° C., and after completion of the dropwise addition, the mixture was reacted for 1 hour. The reaction product was poured into 200 ml of water, washed with an aqueous solution of sodium thiosulfate and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was evaporated off. The solid thus obtained was washed with n-hexane to obtain 3.5 g of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][CH2:24]C(C2OCCO2)C)[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[O:32]1CCO[CH2:34][CH2:33]1.Cl>O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][CH2:24][C:33](=[O:32])[CH3:34])[C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: C1COCCO1
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCC(C)C1OCCO1
Agent: Cl
Solvent: O
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCC(C)=O

Procedure:
A suspension of 8 g. of 5-chloro-2-[4-(1,3-dioxolan-2-yl)pentyl]-3-phenylisoindole-1-carboxylic acid ethyl ester in a mixture of 40 ml. of dioxane and 10 ml. of water is treated with 2 ml. of concentrated hydrochloric acid and then boiled at reflux for 3 hours. The solution obtained is concentrated to dryness under reduced pressure and the residue partitioned between water and methylene chloride. The organic phase is washed with a 2-N sodium carbonate solution and then with a saturated aqueous sodium chloride solution. After drying over sodium sulfate, the solvent is removed, and there is obtained 5-chloro-2-(4-oxopentyl)-3-phenylisoindole-1-carboxylic acid ethyl ester having a melting point of 93°-94° C. Crystallization from ether/hexane yields colorless crystals; melting point 94°-95° C.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[C:7]([CH3:20])[CH:8]=2)=[CH:26][CH:25]=1)[CH3:23]
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Reactant: CCc1ccc(O)cc1
Product: CCc1ccc(Oc2cccc(Oc3ccc(CCC(=O)O)c(C)c3)c2)cc1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-ethylphenol as in Example 18 to afford 0.020 g (14%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C24H24O4 377.1753, found 377.1747.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[O:5])#[N:2].C=O.N1CCCC[CH2:17]1.O>C(OC(=O)C)CCC>[C:1]([C:3](=[CH2:17])[C:4]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:11])([CH3:13])[CH3:12])=[O:5])#[N:2]
Reactant: C[Si](C)(C)CCCOC(=O)CC#N
Reactant: C1CCNCC1
Agent: C=O
Solvent: CCCCOC(C)=O
Solvent: O
Product: C=C(C#N)C(=O)OCCC[Si](C)(C)C

Procedure:
3-trimethylsilylpropyl 2-cyanoacetate (31.84 g, 0.16 moles) prepared as described in Example 1, was added dropwise over 10 minutes to a stirred solution of paraformaldehyde (4.8 g, 0.16 moles formaldehyde) and piperidine (0.12 g) in n-butylacetate at 70° C. The mixture was heated under reflux in a Dean-Stark apparatus until the quantitative amount of water expected from formaldehyde condensation had been collected (2.8 g). The mixture was allowed to cool and phosphorous pentoxide (0.57 g), p-toluenesulfonic acid (1.09 g) and 1,4-hydroquinone (2.18g) were added. The solvent was removed by distillation under reduced pressure to yield a viscous, orange/yellow coloured liquid. The liquid was fractionated under reduced pressure to give crude monomer (16.80 g b.p. 150°-180° C. at 0.7-10 mbar). Vacuum distillation of the crude material onto a catalytic quantity of methanesulfonic acid and 1,4-hydroquinone (10-4 g) afforded the pure product 3-trimethylsilylpropyl 2-cyanoacrylate as a slightly yellow coloured reactive liquid (12.45 g, 37%).
Reaction SMILES: Cl[Si](C)(C)[CH3:3].[Cl:6][C:7]1[C:8]([C:15]([OH:17])=[O:16])=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=1>CO.ClCCl>[Cl:6][C:7]1[C:8]([C:15]([O:17][CH3:3])=[O:16])=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=1
Reactant: CSc1ncc(Cl)c(C(=O)O)n1
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1nc(SC)ncc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.1 %

Procedure:
16.0 g of chloro(trimethyl)silane are added dropwise to a solution of 6.2 g of 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylic acid 1 in 100 ml of methanol and 100 ml of dichloromethane. The mixture is stirred at ambient temperature for 20 h, and then concentrated under vacuum. The residue is taken up with water and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and concentrated under vacuum so as to obtain 6.3 g of methyl 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxylate 2 in the form of a brown oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Si:11]([O:18][C@H:19]1[CH2:24][CH2:23][NH:22][CH2:21][C@@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C=O)C>[Si:11]([O:18][C@H:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:21][C@@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CNCC[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 98 %

Procedure:
Method 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, tert-butyl (3S,4S)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate and triethylamine in DMF yielding tert-butyl(3S,4S)-4-(tert-butyldimethylsilyloxy)-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (98%). LCMS (m/z): 453.3 (MH+); LC Rt=4.01 min.
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[N:10][C:9]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][N:16]=1.[C:21](Cl)(=[O:23])[CH3:22]>CN(C=O)C.C(OCC)(=O)C>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[N:13]=[C:12]([NH:14][C:21](=[O:23])[CH3:22])[CH:11]=[N:10][C:9]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][N:16]=1
Reactant: CC(=O)Cl
Reactant: Nc1cnc(-c2ccncn2)c(-c2ccco2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cnc(-c2ccncn2)c(-c2ccco2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
Sodium hydride (42 mg, 1.05 mmol) was added to a stirred solution of 6-(2-furyl)-5-pyrimidin-4-ylpyrazin-2-amine (Example 8, 100 mg, 0.42 mmol) in DMF (4 mL) at 0° C. under nitrogen. The solution was allowed to stir for 30 min. at 0° C. Acetyl chloride (60.0 μL, 0.84 mmol) was then added and the reaction mixture was warmed up to room temperature and stirred for 3 days. The reaction was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried (Na2SO4) and evaporated. The residue was purified by silica gel flash chromatography (50% ethyl acetate in hexanes to 75% ethyl acetate in hexanes). Concentration in vacuo of the product-rich fractions provided the titled compound as a pale-yellow solid (8 mg, 7%).