Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(C)(C)C(=O)N(Br)C1=O.[CH3:12][O:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([Cl:23])[C:15]=1[CH3:24].C(OCC)(=O)C>ClC1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:12][O:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([Cl:23])[C:15]=1[CH2:24][Br:1]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COc1c([N+](=O)[O-])ccc(Cl)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: COc1c([N+](=O)[O-])ccc(Cl)c1CBr
Reaction time: 1 h
Yield: 181.8 %

Procedure:
A mixture of 5.8 g (20.0 mmol) of 1,3-dibromo-5,5-dimethylhydantoin and 0.5 g of azobisisobutyronitrile was added in portions at 110° C. to a solution of 8.0 g (40.0 mmol) of 2-methoxy-6-chloro-3-nitrotoluene from Example 11aα) in 50 ml of chlorobenzene. After 1 h, a mixture of 3.0 g (10 mmol) of 1,3-dibromo-5,5-dimethylhydantoin and 0.2 g of azobisisobutyronitrile was again added. After a further 1.5 h, the mixture was allowed to cool, and 500 ml of ethyl acetate were added to the reaction solution. The resulting mixture was washed once each with satd Na2SO3 solution, Na2CO3 solution, and NaCl solution, dried (MgSO4), and concentrated. 10.2 g of the title compound resulted in the form of an amorphous powder.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:14][C:15](=[O:22])[CH:16]([OH:21])[CH2:17][CH:18]([CH3:20])[CH3:19])[C:11](=O)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][CH2:9][CH:10]([NH:14][C:15]([CH:16]([O:21][C:29]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:30])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:22])[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)CC(O)C(=O)NC(COCc1ccccc1)C(N)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(OC(=O)N1CCOCC1)C(=O)NC(C#N)COCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-hydroxy-4-methyl-pentanoic acid (2-benzyloxy-1-carbamoyl-ethyl)-amide (0.169 g, 0.55 mmol) in CH2Cl2 (5 mL) was added 4-morpholinecarbonyl chloride (0.082 g, 0.55 mmol), Et3N (0.15 mL, 1.1 mmol) and DMAP (0.034 g, 0.27 mmol). The resulting mixture was allowed to stir overnight (20 h) under argon at room temperature. When the reaction was complete the mixture was diluted with CH2Cl2 (10 mL), then washed with HCl (1.0 N, 10 mL), water and brine, dried over Na2SO4, and concentrated to give the desired product as an off-white oil in 0.20 g 86% yield of the crude product which was chromatographed (SiO2, 5% hexanes in EtOAc) to give desired product in (0.12 g, 52%). (e) Morpholine-4-carboxylic acid 1-[(benzyloxymethyl-cyano-methyl)-carbamoyl]-3-methyl-butyl Ester
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([O:11][CH2:12][CH3:13])[C:7]=1[C:14]#[N:15])=[O:4].S(=O)(=O)(O)[OH:18]>>[CH3:16][N:2]([CH3:1])[C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([O:11][CH2:12][CH3:13])[C:7]=1[C:14](=[O:18])[NH2:15])=[O:4]
Reactant: CCOc1nsc(NC(=O)N(C)C)c1C#N
Reactant: O=S(=O)(O)O
Product: CCOc1nsc(NC(=O)N(C)C)c1C(N)=O

Procedure:
A mixture of 3.8 g of 1,1-dimethyl-3-(4-cyano-3-ethoxy-5-isothiazolyl)urea in 7 ml of concentrated sulfuric acid was treated as described in Example II to give 3.5 g of 1,1-dimethyl-3-(4-carbamoyl-3-ethoxy-5-isothiazolyl)urea, m.p. 172°-172°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])C1C=CC=CC=1.C1CCCCC=1>C(O)C>[OH:8][CH2:9][CH2:10][O:11][CH2:12][P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19]
Reactant: CCOP(=O)(COCCOCc1ccccc1)OCC
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOP(=O)(COCCO)OCC

Procedure:
Paladium on carbon (10%, 100 mg) was added to a solution of diethyl 2-(benzyloxy)ethoxymethylphosphonate prepared in accordance with the process of Example II above (0.9 g,2.8 mmol) and cyclohexene (2.0 ml,20 mmol) in 20 ml ethanol under a nitrogen atmosphere. The resulting slurry was heated to reflux overnight. The catalyst was filtered off and the solution concentrated under vacuum to yield 0.5 g of diethyl 2-hydroxyethoxymethylphosphonate.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: CC1(C)C=CC(=O)CC1
Solvent: CCOC(C)=O
Product: CC1(C)CCC(=O)CC1
Reaction time: 0.75 h

Procedure:
4,4-Dimethylcyclohexanone was prepared by a procedure similar to that described in patent ref: PCT Int. Appl. 2005005456 20, January 2005. 4,4-Dimethylcyclohex-2-enone (3.5 g, 28.18 mmol) was dissolved in ethyl acetate (50 mL). The solution was shaken for 45 minutes under an atmosphere of hydrogen (10 p.s.i.). The completion of the reaction was established by GC-MS then the solution was filtered through a pad of celite and rinsed through with ethyl acetate. The solvent was removed under reduced pressure to give a clear colorless oil which crystallized on standing (3.45 gm, 97%). 1H NMR (400 MHz, CDCl3) δ 2.29 (m, 4H) 1.61 (m, 4H) 1.04 (s, 6H). MS calc 126.5, found 127.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].C1C(=O)N([Br:19])C(=O)C1>FC(F)(F)C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>[Br:19][CH2:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: O=[N+]([O-])c1ccc(F)c(CBr)c1
Temperature: 80 °C
Yield: 50.8 %

Procedure:
A mixture of 1-fluoro-2-methyl-4-nitrobenzene (2.5 g, 16.12 mmol) and NBS (3.16 g, 17.73 mmol) in trifluorotoluene (45 mL) was treated with AIBN (66 mg, 0.403 mmol) and heated at 80° C. overnight. The mixture was cooled to RT, the solids removed via filtration and the filtrate concentrated to dryness. The residue was dissolved in EtOAc, washed with water, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 2-(bromomethyl)-1-fluoro-4-nitrobenzene (1.915 g, 50% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.53-8.52 (m, 1H), 8.28 (ddd, J=9.1, 4.4, 3.0 Hz, 1H), 7.55 (t, J=9.2 Hz, 1H), 4.80 (s, 2H).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.O.[OH-].[Li+].[CH2:53]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C@H:55]([NH2:62])[C@@H:54]1[OH:63].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O1CCCC1.O>[NH:17]1[C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([C:43]([NH:62][C@H:55]3[C:56]4[C:61](=[CH:60][CH:59]=[CH:58][CH:57]=4)[CH2:53][C@H:54]3[OH:63])=[O:44])[CH:47]=[CH:48][CH:49]=2)=[N:20][CH:19]=[N:18]1
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@H]1c2ccccc2C[C@H]1O)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 126.6 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl) (1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.400 g, 0.619 mmol) in a tetrahydrofuran/water mixture (2.50 mL/1.00 mL) was added lithium hydroxide monohydrate (0.0780 g, 1.86 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.00 mL), (1S,2R)-(−)-cis-1-amino-2-indanol (0.277 g, 1.86 mmol), 1-hydroxybenzotriazole hydrate (0.251 g, 1.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.356 g, 1.86 mmol). This mixture was stirred for 18 h at ambient temperature. After the mixture was extracted with ethyl acetate (2×), the combined organic extracts were washed with aqueous saturated sodium bicarbonate, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 40-100% ethyl acetate/hexanes gave the title compound (0.342 g, 72% yield). ES-MS (m/z) 521 [M+1(−Tr)]+.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:7]1[C:30]([F:31])=[CH:29][C:10]([O:11][C:12]2[CH:27]=[CH:26][C:15]([C:16]([N:18]3[CH2:23][C:22](=[O:24])[NH:21][C:20](=[O:25])[CH2:19]3)=[O:17])=[CH:14][C:13]=2[F:28])=[C:9]([O:32]C)[CH:8]=1)[CH3:6].[Cl-].[NH4+]>ClCCl>[CH2:5]([C:7]1[C:30]([F:31])=[CH:29][C:10]([O:11][C:12]2[CH:27]=[CH:26][C:15]([C:16]([N:18]3[CH2:19][C:20](=[O:25])[NH:21][C:22](=[O:24])[CH2:23]3)=[O:17])=[CH:14][C:13]=2[F:28])=[C:9]([OH:32])[CH:8]=1)[CH3:6]
Reactant: CCc1cc(OC)c(Oc2ccc(C(=O)N3CC(=O)NC(=O)C3)cc2F)cc1F
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCc1cc(O)c(Oc2ccc(C(=O)N3CC(=O)NC(=O)C3)cc2F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A commercial solution of boron tribromide (1N in DCM, 0.4 mL, 0.4 mmol) was added to a solution of 4-[4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoyl]piperazine-2,6-dione (which may be prepared in accordance with the experimental described in Example 4, step 5; 60 mg, 0.15 mmol) in dichloromethane (0.5 mL) placed under argon at −30° C. The reaction mixture was stirred at room temperature overnight and then diluted by addition of dichloromethane (10 mL) and a saturated solution of ammonium chloride (10 mL). After separation, the aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (98:2) as eluent. The title product was obtained as a white solid (35 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH2:12][O:13][CH3:14])[C:6]([CH3:15])=[C:5](Br)[C:4]=1[O:17][CH2:18][O:19][CH3:20].C([Li])CCC.CN(C)[CH:28]=[O:29]>CCOCC.CCCCCC>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH2:12][O:13][CH3:14])[C:6]([CH3:15])=[C:5]([CH:28]=[O:29])[C:4]=1[O:17][CH2:18][O:19][CH3:20]
Reactant: COCOc1c(C)c(Br)c(OCOC)c(OC)c1OC
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COCOc1c(C)c(C=O)c(OCOC)c(OC)c1OC
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a cold solution of 2,3-dimethoxy-5-methyl-1,4-bismethoxymethyloxy-6-bromobenzene [oily substance, δ 2.34 (3H), 3.57 (3H), 3.64 (3H), 3.84 (6H), 5.01 (2H), 5.09 (2H)] (9.00 g, 25.6 mmol) in absolute ether (90 ml) was added a solution of 15% n-butyllithium in hexane (17.6 ml). The mixture was stirred for 30 minutes. Dimethylformamide (9.36 g, 128 mmol) was added and the reaction was continued under the same conditions for 30 minutes. Working up in a conventional manner gave 2,3-dimethoxy-5-methyl-1,4-bismethoxymethyloxy-6-formylbenzene [oily substance, δ2.48 (3H), 3.55 (3H), 3.58 (3H), 3.85 (3H), 3.95 (3H), 4.99 (2H), 5.13 (2H)]. Yield 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH3:14][S:15](Cl)(=[O:17])=[O:16].Cl>O>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][S:15]([CH3:14])(=[O:17])=[O:16])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)Oc1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-4-hydroxybenzoic acid (3.45 g, 20 mol) and sodium hydroxide (2.40 g, 60.0 mmol) in 30 ml of water is added, dropwise at 0°, methanesulfonyl chloride (2.57 ml, 3.80 g, 33.0 mmol). After addition is complete, the reaction mixture is stirred at RT for 30 min., after which it is poured into water, acidified with dil. HCl and extracted with ether. The combined organic extracts are washed with brine, dried and evaporated to give 2-chloro-4-methylsulfonyloxybenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][C@H:33]4[CH2:37][CH2:36][O:35][CH2:34]4)=[C:17]([NH:20][C:21]([CH2:23]P(=O)(OCC)OCC)=[O:22])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[Li+].[OH-].[K+].[CH3:42][N:43]([CH2:45][CH:46]=O)[CH3:44].S([O-])(O)=O>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][C@H:33]4[CH2:37][CH2:36][O:35][CH2:34]4)=[C:17]([NH:20][C:21](=[O:22])/[CH:23]=[CH:46]/[CH2:45][N:43]([CH3:44])[CH3:42])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)CC=O
Reactant: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1O[C@H]1CCOC1)OCC
Agent: O=S([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN(C)C/C=C/C(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1O[C@H]1CCOC1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
10 g of diethyl {[4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-ylcarbamoyl]-methyl}-phosphonate and 0.8 g lithium chloride are suspended in 60 ml of ethanol and cooled to −5° C. 11 g of 45% potassium hydroxide solution is added dropwise first of all and then 4.8 g dimethylaminoacetaldehyde-hydrogen sulphite adduct in 48 ml of water is added. The reaction solution is stirred for 1 h and then 60 ml of water are added. The suspension is suction filtered, washed with 40 ml of water and dried in vacuo at 45° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[S:6][CH:7]=1.[C-:15]#[N:16].[K+]>C(#N)C.C1OCCOCCOCCOCCOCCOC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[S:6][CH:7]=[C:3]([CH2:2][C:15]#[N:16])[N:4]=2)=[CH:9][CH:10]=1
Reactant: [C-]#N
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: N#CCc1csc(-c2ccc(Cl)cc2)n1
Yield: 81.4 %

Procedure:
A catalytic amount of 18-crown-6-ether (20 mg) was added to a solution of 4-(chloromethyl)-2-(4-chlorophenyl)thiazole (0.55 g, 2.25 mmol) in acetonitrile (20 mL), followed by potassium cyanide (0.22 g, 3.37 mmol) and the reaction mixture was refluxed for 10 h. The reaction mixture was then quenched with water and the organic product extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 15% EtOAc in petroleum ether) to afford 2-(2-(4-chlorophenyl)thiazol-4-yl)acetonitrile (0.43 g, yield 82%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 7.89-7.86 (d, J=8.6 Hz, 2H), 7.45-7.42 (d, J=8.6 Hz, 2H), 7.32 (m, 1H), 3.96 (s, 2H). MS (ESI) m/z: Calculated for C11H7ClN2S: 234.00. found: 235.0 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([C:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[N:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(OCc3ccccc3)n2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(O)n2)CC1
Reaction time: 8 h
Yield: 60.7 %

Procedure:
Add Pd/C (5 wt/wt %, 0.26 g, 0.12 mmol) to a solution of tert-butyl 4-(6-(benzyloxy)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.6 g; 7.1 mmol) in methanol (20 mL) add Pd/C (5 wt/wt %, 0.26 g, 0.12 mmol) and stir overnight under a hydrogen balloon. Filter and concentrate under vacuum to give the crude product. Purify with normal phase silica gel flash column chromatography, using a gradient of 0-20% MeOH in DCM to give the title product as a white solid (1.2 g, 615). MS (m/z): 223 (M-t-Bu+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:29][CH3:30])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23](C(=O)C)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:8]=1.CC#N.CC1N=C(NC)SC=1C1C=CN=C(NC2C=C(C=CC=2)CNC(=O)C)N=1.[N+]([O-])(O)=O.N(C1C=C(C=CC=1)CNC(=O)C)C(N)=N>Cl>[CH3:1][C:2]1[N:3]=[C:4]([NH:29][CH3:30])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)=[CH:18][CH:19]=2)[N:8]=1
Reactant: CNc1nc(C)c(-c2ccnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)n2)s1
Agent: CC(=O)NCc1cccc(NC(=N)N)c1
Agent: CNc1nc(C)c(-c2ccnc(Nc3cccc(CNC(C)=O)c3)n2)s1
Agent: Cl
Solvent: CC#N
Solvent: O=[N+]([O-])O
Product: CNc1nc(C)c(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)s1

Procedure:
By hydrolysis of 1-(4-{4-[4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone in 2 M aq HCl. Yellow solid. Anal. RP-HPLC: tR=8.8 min (10-70% MeCN, purity >95%). 1H-NMR (DMSO-d6) δ: 2.45 (3, 3H, CH3), 2.83 (t, 4H, J=5.9 Hz, CH2), 2.85 (d, 3H, J=4.9 Hz, CH2), 2.95 (t, 4H, J=4.9 Hz, CH2), 6.81 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 6.85 (d, 2H, J=9.3 Hz, Ph-H), 7.58 (d, 2H, J=8.8 Hz, Ph-H), 7.99 (m, 1H, NH), 8.26 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.14 (brs, 1H). N-{3-[4-(4-Methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino]-benzyl}-acetamide [63]. By condensation of 3-dimethylamino-1-(2-methylamino-4-methyl-thiazol-5-yl)-propenone and N-(3-guanidino-benzyl)-acetamide nitrate. Yellow solid. Mp 253-255° C. Anal. RP-HPLC: tR=11.3 min (10-70% MeCN, purity >95%): 1H NMR (DMSO): δ 1.86 (s, 3H, CH3), 2.46 (s, 3H, CH3), 2.85 (s, 2H, CH2), 3.09 (s, 3H, CH3), 6.82 (d, 1H, J=8.0 Hz, ph-H), 6.88 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.2 (t, 1H, J=8.0 Hz, Ph-H), 7.60 (d, 1H, J=8.0 Hz, Ph-H), 7.73 (s, 1H, Ph-H), and 8.32 (d, 1H, J=5.5 Hz, pyrimidinyl-H). MS (ESI+) m/z 391.55 [M+Na] (C18H20N6OSNa requires 391.46).
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].[O-]S([O-])(=O)=O.[Mg+2].[Si:16]([O:23][CH2:24][CH:25]=O)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(Cl)Cl>[Si:16]([O:23][CH2:24]/[CH:25]=[N:2]/[NH:1][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CC(C)(C)OC(=O)NN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N/N=C/CO[Si](C)(C)C(C)(C)C
Yield: 93.1 %

Procedure:
A mixture of tert-butyl hydrazinecarboxylate (2.5 g, 19 mmol), MgSO4 (11.4 g, 95.0 mmol), and 2-(tert-butyldimethylsilyloxy)acetaldehyde (9.9 g, 57 mmol) in DCM (100 mL) was heated to reflux overnight. The solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:5) to give (E)-tert-butyl 2-(2-(tert-butyldimethylsilyloxy)ethylidene)hydrazinecarboxylate (5.1 g, 94% yield) as colorless oil. LCMS (ESI) m/z: 233.3 [M-56+H+].
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH:17]([OH:18])[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7]1)[CH:2]([CH3:4])[CH3:3].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[CH2:1]([O:5][CH:6]1[C:17](=[O:18])[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC1CCC=CCCC=CCCC1O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)COC1CCC=CCCC=CCCC1=O
Yield: 73.4 %

Procedure:
4.71 g of 12-isobutoxy-4,8-cyclododecadien-1-ol were dissolved in 50 ml of dichloromethane and 8 g of diatomaceous earth were added to this solution, in suspension. After stirring, 8.05 g of PCC were added in small portions, the reaction mixture having been kept under stirring, at room temperature, for 2 h. Afterwards, the chromium salts were precipitated with ethyl ether and the reaction mixture was filtered on SiO2 and concentrated. Distillation in a bulb-to-bulb apparatus gave 3.43 g of 12-isobutoxy-4,8-cyclododecadien-1-one.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:9])=[O:16])=[CH:13][CH:12]=1
Reactant: Cc1cc(C)cc(C)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)c(C)c1
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 61.9 %

Procedure:
A stirred 0° C. solution of mesitylene (7.21 g, 60.0 mmol) and 4-chlorobenzoyl chloride (10.55 g, 60.0 mmol) in carbon disulfide (130 ml) was treated with aluminum chloride (8.83 g, 66.1 mmol) in portions over 10 minutes. The mixture was stirred 75 minutes at 0° C., warmed to ambient temperature over 30 minutes, refluxed 10 hours, kept at ambient temperature 6 hours, cooled to 0° C., and quenched by addition of ice (250 g) and concentrated hydrochloric acid (50 ml). The mixture was extracted twice with diethyl ether and the combined extracts were washed with water (3X), saturated aqueous sodium carbonate, and brine, dried over anhydrous magnesium sulfate, and evaporated to dryness at 30° C. under vacuum. The residue was crystallized from methanol and dried to provide 9.61 g (62%) 4-chlorobenzoylmesitylene, m.p. 65.5°-66.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C(OCC)(=O)C.[ClH:36].[OH-].[Na+]>O>[ClH:36].[NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2cnc3c(N)nc4ccccc4c32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nc2ccccc2c2c1ncn2CCC1CCNCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1.57 g of tert-butyl 4-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-1-piperidinecarboxylate and 40 ml of ethyl acetate solution of hydrogen chloride was stirred at room temperature for 5 hours. The reaction mixture was added with water, adjusted to pH 10 with 10% aqueous sodium hydroxide solution, and extracted with methylene chloride. The extract was dried, and the solvent was evaporated. The resulting residue was washed with ethyl acetate to give 1.01 g of pale brown crystals. The resulting crystals were purified by alumina column chromatography using methylene chloride—methanol (40:1 to 20:1) as eluting solvents, and washed with diisopropyl ether to give colorless crystals. Hydrochloride was prepared in a conventional method. Recrystallization from ethanol gave colorless crystals having the melting point of from 243 to 244° C. (decomposition).
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:31]1(O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH:2]([O:1][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:28][CH:27]=1
Reactant: COc1ccc(C(O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1
Reactant: Oc1ccccc1
Product: COc1ccc(C(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)Oc2ccccc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenol: ESMS m/e: 487.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([OH:14])=[O:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.N1C2C(=CC=CC=2)C(C(O[CH2:27][C:28]23[CH2:35][CH2:34][N:31]([CH2:32][CH2:33]2)[CH2:30][CH2:29]3)=O)=C1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([O:14][CH2:27][C:28]34[CH2:35][CH2:34][N:31]([CH2:32][CH2:33]3)[CH2:30][CH2:29]4)=[O:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C(=O)O)c[nH]c2c1
Reactant: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Product: COc1ccc2c(C(=O)OCC34CCN(CC3)CC4)c[nH]c2c1

Procedure:
Quinuclidin-4-ylmethyl 6-methoxy-1H-indole-3-carboxylate was prepared starting from 6-methoxyindole-3-carboxylic acid (synthesized as described in J. Med. Chem. 51, 1849 (2008)) following the procedure of (Quinuclidin-4-yl)methyl 1H-indole-3-carboxylate. MS (m/e): 314.