Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.[F:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]#[N:20])[CH:15]=[CH:16][CH:17]=1.C[O-].[Na+]>CCO>[CH3:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:18](\[C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[CH:13]=2)/[C:19]#[N:20])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: N#CCc1cccc(F)c1
Reactant: Cc1ccc(C=O)cc1C
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(/C=C(/C#N)c2cccc(F)c2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a solution of 3,4-dimethylbenzaldehyde (CAS 68844-97-3) (4.0 g, 29.6 mmol) and 3-fluoro-benzeneacetonitrile (CAS 501-00-8) (4.35 g, 29.6 mmol) in absolute EtOH, 30 mL, was added NaOMe (0.1 equiv), then the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and filtered. The precipitate was washed with cold EtOH and gave (2E)-3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)acrylonitrile as a white solid (6.20 g, 78%). NaBH4 (1.8 g, 47 mmol) was added slowly to a solution of (2E)-3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)acrylonitrile (6.17 g, 23.5 mmol) in EtOH (100 mL) under argon. The mixture was stirred at 70° C. for 16 h. The solution was cooled to room temperature and quenched with water. The reaction mixture was diluted with 100 mL water and acidified with 6M HCl (aq.). After extraction with ether (3×100 mL), the combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated and gave 3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)propanenitrile as a white solid (6 g, 96%). DIBAL-H (1.0 M in toluene, 14 mL, 14 mmol) was added dropwise to a solution of 3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)propanenitrile (2.93 g, 11.72 mmol) in Toluene (40 mL) at −78° C. under argon. The mixture was stirred at −78° C. to −20° C. for 3 h and then quenched by slow addition of saturated NH4Cl solution (2 mL) followed by Celite (2 g) at −20° C. The mixture was diluted with Et2O (50 mL), warmed slowly to room temperature, and stirred till all aluminum precipitated. The solid was filtered and washed with ether (3×50 mL), the combined organic layers were dried over MgSO4, filtered, concentrated and gave Intermediate 5 (2.34 g, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH2:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[SH:21]>C(O)C>[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][CH2:13][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:10]([OH:12])=[O:11]
Reactant: C=C(C(=O)O)c1ccc(OC)cc1
Reactant: Nc1ccccc1S
Solvent: CCO
Product: COc1ccc(C(CSc2ccccc2N)C(=O)O)cc1

Procedure:
A solution of 125 ml of ethanol, 8.9 g of 4-methoxy-α-methylene benzeneacetic acid and 5.35 ml of 2-amino thiophenol was refluxed for 7 hours. The ethanol was evaporated off and the residue was crystallized from 500 ml of isopropyl ether to obtain 11 g of the desired product melting at 118° C. and used as is for the following step.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[CH:24][C:3]=1[O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[C:6]1=[O:23].[ClH:32]>C(Cl)Cl.O1CCOCC1>[ClH:32].[F:1][C:2]1[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[CH:24][C:3]=1[O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[C:6]1=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc(S(C)(=O)=O)cc3F)C2=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(O[C@H]2CCN(C3CCNCC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109 %

Procedure:
(S)-tert-Butyl 4-(3-(2-fluoro-4-(methylsulfonyl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.6 g, 3.5 mmol) was dissolved in CH2Cl2 (20 mL) and 4N HCl in dioxane (˜15 mL) was added and stirred at ambient temperature overnight. The reaction was concentrated to afford (S)-3-(2-fluoro-4-(methylsulfonyl)phenoxy)-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (1.5 g, 3.8 mmol, 109% yield) as a white solid. Mass spectrum (apci) m/z=357.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH2:16][CH2:15][CH2:14][N:12]3[CH:13]=2)=[CH:5][CH:4]=1.C([Li])CCC.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]3[CH2:16][CH2:15][CH2:14][N:12]3[C:13]=2[Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:7][CH:8]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COc1ccc(-c2cn3c(n2)CCC3)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(-c2ccc(OC)cc2)nc2n1CCC2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
To an ice cold (0° C.) solution of [16.8 g, 0.078 mol] 2-(4-methoxyphenyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole in 200 ml of dry tetrahydrofuran under argon was added dropwise over 20 minutes 35 mL [0.0858 mol] of a 2.5M solution of n-butyl lithium in hexane. Once the addition was complete, the deep-red solution was stirred in the cold for five minutes and then a solution of the tributyltin chloride [26.4 g, 0.0975 mol] in 50 ml of dry tetrahydrofuran was added over 20 min. The reaction mixture was stirred at ice-bath temperatures for 1.5 hours and then saturated ammonium chloride was added. The layers were shaken together and separated and the organic extract was washed an additional time with saturated ammonium chloride and then dried with anhydrous potassium carbonate. The solvent was removed in vacuo to give 50 g of a crude oil, which was taken up twice in cold hexane, filtering off the unreacted 2-(4-methoxyphenyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole each time. The product was purified on a column of silica, eluting with 1:1 ethyl acetate/hexane in the presence of 1% diethylamine, to give 19.2 g (49% of a yellow oil.
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][O:65][C:66]2[CH:73]=[CH:72][C:69]([CH:70]=[O:71])=[CH:68][CH:67]=2)[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:74][O:75][C:76]1[CH:81]=[CH:80][C:79]([Mg]Br)=[CH:78][CH:77]=1>C1COCC1>[CH3:74][O:75][C:76]1[CH:81]=[CH:80][C:79]([CH:70]([C:69]2[CH:68]=[CH:67][C:66]([O:65][CH2:64][CH:22]3[CH2:21][CH:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23]3)=[CH:73][CH:72]=2)[OH:71])=[CH:78][CH:77]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C=O)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C(O)c3ccc(OC)cc3)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
4-(3,4,5-Tris-octadecyloxy-cyclohexylmethoxy)-benzaldehyde (130 mg, 127 μmol) was dissolved in dehydrated THF (2 mL), 4-methoxy-phenyl-magnesiumbromide (350 μmol) was added, and the mixture was stirred at 40° C. for 1.5 hours. After evaporation of the solvent, 1N hydrochloric acid (5 mL) was added to the residue to allow crystallization. The crystals were filtered, and thoroughly washed with hydrochloric acid, water and methanol in this order to give (4-methoxy-phenyl)-[4-(3,4,5-tris-octadecyloxy-cyclohexylmethoxy)-phenyl]-methanol (110 mg, 97.2 μmol, 96%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]([O:16]C)=O)=[N:4][C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:6][C:7]=1[OH:8].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.Cl>CN(C=O)C>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:14]([C:3]2[C:2]([OH:1])=[C:7]([OH:8])[N:6]=[C:5]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)[N:4]=2)=[O:16])=[CH:21][CH:20]=1
Reactant: COC(=O)c1nc(-c2cccs2)nc(O)c1O
Reactant: NCc1ccc(F)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)cc1)c1nc(-c2cccs2)nc(O)c1O
Reaction time: 8 h

Procedure:
Methyl 5,6-dihydroxy-2-thien-2-ylpyrimidine-4-carboxylate (A-2) was dissolved in DMF and 2.0 eq. of 4-fluorobenzylamine were added to the stirred solution. Reaction mixture was left overnight at 90° C. After cooling to room temperature 1 N HCl was added and a solid precipitated from the mixture. This solid was collected by filtration, washed with ethyl ether and dried under vacuum to afford the compound (A-3).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:31][CH2:32][CH2:33][OH:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]([CH2:32][CH2:33][OH:34])[C:21](=[O:23])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cn1
Reactant: OCCNCc1ccccc1
Product: COc1ccc(N(CC(=O)N(CCO)Cc2ccccc2)S(=O)(=O)c2ccccc2C)cn1

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-acetic acid with 2-benzylamino-ethanol
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([N+:9]([O-:11])=[O:10])[O:8][C:4]=2[CH:3]=1.[H-].[Na+].Cl.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][Cl:27]>C(COC)OC>[ClH:27].[CH3:23][N:24]([CH2:25][CH2:26][O:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([N+:9]([O-:11])=[O:10])[O:8][C:4]=2[CH:3]=1)[CH3:28]
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1oc2cc(O)ccc2c1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CN(C)CCOc1ccc2c(-c3ccccc3)c([N+](=O)[O-])oc2c1

Procedure:
To a solution of 2 g. (0.008 mole) of 6-hydroxy-2-nitro-3-phenylbenzofuran (described in U.S. Pat. No. 3,927,037, Example 2) in 25 ml. of glyme is added a solution of 0.016 mole of sodium hydride in 20 ml. of glyme. To this solution is added 1.2 g. (0.008 mole) of N,N-dimethyl-N-(2-chloroethyl)amine hydrochloride. The mixture is heated to its reflux temperature and maintained at reflux for 6 hours. The reaction mixture is extracted thrice with diethyl ether, the ether is washed with water and saturated sodium chloride solution and then dried. The ether extracts are treated while stirring with hydrogen chloride gas. A yellow residue is separated and washed with diethyl ether, then recrystallized from isopropanol to provide N,N-dimethyl-2-(2-nitro-3-phenyl-6-benzofuranyloxy)ethylamine hydrochloride, m.p. 231°-235° C. (dec.), having the structure
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:9]=[C:8]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)(Cl)Cl>[Cl:23][CH2:24][C:25]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[CH:9]=[C:8]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[N:7]=[C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:11]=2)[CH2:13][CH2:14]1)=[O:26]
Reactant: c1c(N2CCCC2)nc(N2CCCC2)nc1N1CCNCC1
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Product: O=C(CCl)N1CCN(c2cc(N3CCCC3)nc(N3CCCC3)n2)CC1
Yield: 97 %

Procedure:
The starting 1-(2-chloroacetyl)-4-[2,6-di(1-pyrrolidinyl)-4-pyrimidinyl]piperazine was prepared as follows: 1-[2,6-di(1-pyrrolidinyl)-4-pyrimidinyl]piperazine (1.65 g, 5.4 mmol) was dissolved in anhydrous chloroform (30 ml), the solution was cooled to 0°-5° C. and 2-chloroacetyl chloride (0.50 ml, 0.79 g, 7.0 mmol) in anhydrous chloroform (5 ml) was added dropwise under stirring. The mixture was stirred for one hour, concentrated and the residue was dissolved in 100 ml of water. The aqueous solution was made alkaline with conc. NH4OH and stirred for one hour. During this period the separated oil solidified. The solids were collected, washed with icecold water until neutral and dried. In this manner 2.0 g of the desired chloroacetyl compound was obtained, yield: 97.0% mp. 153°-156° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Br:17])[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>CN(C)C=O.O>[Br:17][C:4]1[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=[C:2]([C:30]2[CH:29]=[N:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=2)[CH:3]=1
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(Br)c2s1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cncc(OC)c3)cc(Br)c2s1
Temperature: 100 °C
Yield: 15.2 %

Procedure:
A stirred mixture of 1-(5,7-dibromo-benzothiazol-2-yl-3-ethyl urea (300 mg, 0.79 mmol), sodium carbonate (167 mg, 1.58 mmol), (1,1′-bis(diphenylphosphino)ferrocene)dichloro-palladium(II) (45 mg, 0.05 mmol), 3-methoxy-5-pyridineboronic acid pinacol ester (186 mg, 0.79 mmol) in dimethyl formamide (8 ml) and water (2 ml), was purged with nitrogen for 5 min and heated at 100° C. for 1 h. The reaction mixture was concentrated in vacuo then partitioned between ethyl acetate and water. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0 to 5% methanol in ethyl acetate to give 1-[7-Bromo-5-(5-methoxy-pyridin-3-yl)-benzothiazol-2-yl]-3-ethyl-urea 1 as a white solid (49 mg, 15%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(CCN(C)C)C.[Li]C(CC)C.C1CCCCC1.[CH3:30][Si:31](Cl)([CH3:33])[CH3:32].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:31]([CH3:33])([CH3:32])[CH3:30])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1Cl
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cccc(Cl)c1C(=O)O
Temperature: -100 °C
Yield: 63 %

Procedure:
2-Chlorobenzoic acid (3.91 g, 25 mmol), THF (60 mL), and TMEDA (8.6 mL, 57 mmol) were stirred under nitrogen and cooled to -100° C. 1.3M s-BuLi in cyclohexane (0.055 mol, 42.3 mL) was added dropwise keeping the temperature below -80° C. After the addition was complete TMSCl (2.7 g, 25 mmol) was added dropwise and the resulting mixture was allowed to stir and slowly warm to -30 C. 25% citric acid (100 mL) was added and the mixture was extracted with two 50 mL portions of ether, which were then combined and washed three times with water, dried (MgSO4) and concentrated. The crude product was purified by HPLC, eluting with 2:3 ethyl acetate/hexanes. The product was recovered as a white solid in 63% yield. m.p. 129°-131° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.C(S)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[CH2:10]([S:8][C:7]1[C:2]([Cl:1])=[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[N:4]=[C:5]([NH2:11])[N:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Reactant: SCc1ccccc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(SCc2ccccc2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, benzyl mercaptan and DBU in dioxane. ES-MS m/e (%): 320 (M{37Cl}+H+, 45), 318 (M{35Cl}+H+, 100).
Reaction SMILES: OO.[NH2:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:11])[C:9]=1[Cl:10].C(=O)([O-])[O-].[Na+].[Na+].[ClH:18]>O>[NH2:3][C:4]1[C:5]([Cl:18])=[N:6][CH:7]=[C:8]([Cl:11])[C:9]=1[Cl:10]
Reactant: Cl
Reactant: Nc1cncc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1c(Cl)ncc(Cl)c1Cl
Temperature: 25 °C

Procedure:
Thirty percent aqueous hydrogen peroxide (3.0 g, 26 mmole) was added dropwise with stirring at 15° C. to a solution of 8.0 g (49 mmol) of 3-amino-4,5-dichloropyridine in 450 mL of 37 percent aqueous hydrochloric acid. After 30 min another 2.6 g (23 mmol) of 30 percent aqueous hydrogen peroxide was added and the solution was allowed to slowly warm to room temperature. The resulting mixture was diluted with water, neutralized with sodium carbonate, and extracted with ether. The ethereal extract was dried over magnesium sulfate and filtered. The filtrate was concentrated by evaporation under reduced pressure to obtain a viscous oil. This oil was partially purified by column chromatography to obtain 2.5 g (26 percent of theory) of the title compound, a white solid melting at 88°-90° C., and 5.3 g of a mixture of the title compound and 3-amino-2,4,5,6-tetrachloropyridine.
Reaction SMILES: [CH:1]1([N:6]([C:11](=[O:16])[CH:12]([CH3:15])[CH2:13][SH:14])[CH2:7][C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C(SSC2N=CC=CC=2)N=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH:1]1([N:6]2[C:11](=[O:16])[CH:12]([CH3:15])[CH2:13][S:14][C:8](=[O:9])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CS)C(=O)N(CC(=O)O)C1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: Cc1ccccc1
Product: CC1CSC(=O)CN(C2CCCC2)C1=O
Temperature: 25 °C

Procedure:
A solution of N-cyclopentyl-N-(3-mercapto-2-methylpropanoyl)glycine (2.0 g., 8.1 mmol) in 125 ml of toluene was freed of air by bubbling nitrogen through it. To this solution was then added 2,2'-dipyridyldisulfide (2.7 g., 12.2 mmol) and triphenylphosphine (3.2 g., 12.2 mmol) and the resulting solution was stirred under nitrogen for 5 hours. This solution was then diluted to 250 ml with toluene and added at a rate of 20-25 ml/hr to 2 l of reluxing toluene under nitrogen. The resulting mixture was stirred at reflux for 48 hours and then cooled to room temperature. The solution was washed successively with 0.1 N hydrochloric acid, saturated sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, and then filtered and concentrated under vacuum. The resulting solid material was dissolved in 25% ethyl acetate/hexane, filtered to remove the triphenyl phosphine oxide which crystallized, and purified by medium pressure liquid chromatography, eluting with 25% ethyl acetate/hexane, to give 0.8 g. of a pale yellow solid. This solid was recrystallized from 10% ethyl acetate/hexane to give 0.5 g (27%) of 4-cyclopentyl-6,7-dihydro-6-methyl-1,4-thiazapen-2,5-(3H,4H)-dione as a white crystalline solid, mp. 77°-79°.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C[Li].Cl.[C:15](=O)([O-])O.[Na+]>O1CCCC1.ClCCl>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH3:15]
Reactant: O=C([O-])O
Reactant: Cc1cccc(C(=O)O)c1Cl
Agent: Cl
Agent: [Li]C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1cccc(C)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-3-methylbenzoic acid (1.71 g, 10.0 mmol) in anhydrous tetrahydrofuran (10 ml), at 0° C. and under nitrogen, was added methyllithium (1.6M in diethyl ether, 13.1 ml, 21.0 mmol), via syringe. The reaction mixture was stirred at 0° C. for 30 min and then allowed to warm to room temperature over 1 h. To the reaction mixture was added cold hydrochloric acid (1M, 100 ml) and dichloromethane (110 ml). The mixture was adjusted to pH 7 by addition of saturated aqueous sodium hydrogen carbonate solution and the two layers were separated. The aqueous layer was extracted with further dichloromethane and the combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (1.19 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]2[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]=12.[CH:25]12[O:33][CH:29]([CH2:30][NH:31][CH2:32]1)[CH2:28][N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26]2.C(N(CC)CC)C>C(O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]3[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]3=[C:2]([N:31]3[CH2:32][CH:25]4[O:33][CH:29]([CH2:28][N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26]4)[CH2:30]3)[N:7]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CN(c3nc(-c4ccc([N+](=O)[O-])cc4)nc4c3cnn4CC(F)(F)F)CC(C1)O2
Temperature: 150 °C
Yield: 70.2 %

Procedure:
To a Smith process vial containing a suspension of 4-chloro-6-(4-nitro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidine (0.50 g, 1.4 mmol) and tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (0.34 g, 1.5 mmol) in ethanol (10 mL) was added triethylamine (0.55 mL, 4.2 mmol). The mixture was heated in the microwave reactor for 12 minutes at 150° C. The precipitate was collected by Buchner filtration, washed with methanol, and dried under house vacuum to provide tert-butyl 7-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate as a pale yellow solid (0.54 g, 70%). MS (ES+): 550.2 (M+H)+
Reaction SMILES: I[C:2]1([CH2:17][C:18]([OH:20])=[O:19])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:4]2[O:3]1.C1CCCCC=1.[N+:27]([O-:32])([N+]([O-])=O)=[O:28]>C(Cl)(Cl)Cl>[N+:27]([C:2]1([CH2:17][C:18]([OH:20])=[O:19])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:4]2[O:3]1)([O-:32])=[O:28]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(O)CC1(I)OC2=CC=CC2=CC1c1ccccc1
Solvent: C1=CCCCC1
Solvent: ClC(Cl)Cl
Product: O=C(O)CC1([N+](=O)[O-])OC2=CC=CC2=CC1c1ccccc1
Reaction time: 20 h

Procedure:
To a solution of 2.2 g. (5.8 mmoles) of 2-iodo-3-phenyl-7-benzofuranacetic acid, 1 g. (5.8 mmoles) of cyclohexene and 175 ml. of chloroform is added 0.9 g. (10 mmoles) of dinitrogen tetroxide in 15 ml. of chloroform. The mixture is stirred for 20 hours, washed with water and made basic with sodium hydroxide. The chloroform layer is acidified with hydrochloric acid, washed with water twice and dried, then evaporated to provide 2-nitro-3-phenyl-7-benzofuranacetic acid, identical to the sample prepared in Example 2.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:33])[C@H:18]([NH:25]C(=O)OC(C)(C)C)[CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[NH2:25][C@H:18]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[CH:10][C:4]=23)[CH2:12][CH2:13]1)=[O:33]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)C1CCCCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
(R)-tert-Butyl 2-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-1-cyclohexyl-2-oxoethylcarbamate (0.010 g, 0.019 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added. The reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give (R)-2-amino-1-(4-(5-bromo-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)-2-cyclohexylethanone (0.005 g, 62% yield) as the dihydrochloride salt. MS ESI (+) m/z 421 detected.