Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[CH:10]=[C:9]([NH:11][C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=3[Cl:22])=[O:13])[N:8]([C:23]3[CH:31]=[C:30]4[C:26]([CH2:27][CH2:28][CH:29]4[C:32](O)=[O:33])=[CH:25][CH:24]=3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=[N:41]C=2C=1.CCN=C=NCCCN(C)C.N.O1CCOCC1>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>[C:32]([CH:29]1[C:30]2[C:26](=[CH:25][CH:24]=[C:23]([N:8]3[C:9]([NH:11][C:12]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[Cl:22])=[O:13])=[CH:10][C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[N:7]3)[CH:31]=2)[CH2:27][CH2:28]1)(=[O:33])[NH2:41]
Reactant: On1nnc2ccccc21
Reactant: O=C(Nc1cccc(Cl)c1Cl)Nc1cc(C2CCCC2)nn1-c1ccc2c(c1)C(C(=O)O)CC2
Agent: CCN=C=NCCCN(C)C
Agent: N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: NC(=O)C1CCc2ccc(-n3nc(C4CCCC4)cc3NC(=O)Nc3cccc(Cl)c3Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 1:1:1 mix of EtOH:H2O:dioxane (6 mL) was placed ethyl 6-(3-cyclopentyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-2,3-dihydro-1H-indene-1-carboxylate (520 mg, 0.986 mmol) and lithium hydroxide (71 mg, 2.96 mmol). The solution warmed to 40 C and stirred, ON. LC shows complete reaction. The solution cooled to RT and diluted with 5% citric acid (20 mL) and Ethyl acetate (20 mL). The organic phase separated, washed with brine and dried over sodium sulfate. The solvents were evaporated at reduced pressure to give 6-(3-cyclopentyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-2,3-dihydro-1H-indene-1-carboxylic acid as a foam, 474 mg (96%), used as is. In DMF (5 mL) was placed 6-(3-cyclopentyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-2,3-dihydro-1H-indene-1-carboxylic acid (474 mg, 0.949 mmol), HOBt (196 mg, 1.09 mmol) and EDAC (218 mg, 1.42 mmol). The mixture was stirred at RT for 1 hr and then treated with a solution of 0.5N ammonia in dioxane (7.59 mL, 3.80 mmol). The mixture was stirred at RT, ON. LC shows complete reaction. The mixture was diluted with 5% citric acid (20 mL) and Ethyl acetate (20 mL). The organic phase separated, washed with saturated sodium bicarbonate (20 mL), brine (20 mL) and dried over sodium sulfate. The solvents evaporated at reduced pressure to give a foam, dried on high vacuum line at RT for 2 hrs. The foam was then purified by Biotage chromatography (S1-25 column, 65-95% Ethyl acetate/Hex). Fractions 10-19 were combined and evaporated at reduced pressure to give 1-(1-(3-carbamoyl-2,3-dihydro-1H-inden-5-yl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea as a white solid. The solid was dried on the high vacuum line at 65 C in the abderhalden for 3 hrs, 210 mg (44%). 1H NMR (DMSO-d6) 1.59-1.73 (m, 6H), 1.95-1.99 (m, 2H), 2.23-2.33 (m, 2H), 2.88-3.06 (m, 3H), 3.90-4.04 (m, 1H), 6.31 (s, 1H), 6.98 (s, 1H), 7.26-7.42 (m, 5H), 7.63 (br s, 1H), 8.07-8.09 (m, 1H), 8.77 (s, 1H), 9.21 (s, 1H). LC-MS (EI) m/z: 500.0 (M+H+).
Reaction SMILES: [BH4-].[Li+].CO.[Li+].[BH4-].CO.[F:9][C:10]1[C:11]2[O:36][N:35]=[C:34]([C:37](OCC)=[O:38])[C:12]=2[CH:13]=[C:14]2[C:27]=1[N:26]1[CH2:28][C@@H:29]([CH3:33])[O:30][C@@H:31]([CH3:32])[C@@H:25]1[C:16]1([C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18][C:17]1=[O:24])[CH2:15]2>C1COCC1.O>[F:9][C:10]1[C:11]2[O:36][N:35]=[C:34]([CH2:37][OH:38])[C:12]=2[CH:13]=[C:14]2[C:27]=1[N:26]1[CH2:28][C@@H:29]([CH3:33])[O:30][C@@H:31]([CH3:32])[C@@H:25]1[C:16]1([C:17](=[O:24])[NH:18][C:19](=[O:23])[NH:20][C:21]1=[O:22])[CH2:15]2
Reactant: CCOC(=O)c1noc2c(F)c3c(cc12)CC1(C(=O)NC(=O)NC1=O)[C@H]1[C@H](C)O[C@H](C)CN31
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CN2c3c(cc4c(CO)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
Lithium borohydride (0.434 ml, 0.87 mmol) was added to an ice cooled solution of methanol (0.035 ml, 0.87 mmol) in THF (10 ml). The solution was warmed to room temperature and stirred for 1 hour. 1.5 ml of the LiBH4/MeOH solution was added to a solution of (2R,4S,4aS)-rel-ethyl 11-fluoro-2,4-dimethyl-2′,4′,6′-trioxo-2,2′,3′,4,4a,4′,6,6′-octahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-8-carboxylate (Example 134, 30 mg, 0.07 mmol) in 5 ml of THF. The reaction was stirred at room temperature of 1 hour. The reaction was diluted with water and extracted with ethyl acetate 2×. The organic layers were washed twice with brine, dried over MgSO4 and concentrated. The residue was purified by HPLC (Acetonitrile (5 to 50%)/Water with a TFA modifier over 10 minutes). Freeze dried for 48 hours to give the title compound (22 mg, 0.053 mmol, 81%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][C:9]([C:11]2[S:24][C:14]3[C:15]4[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=4[O:17][CH2:18][CH2:19][C:13]=3[CH:12]=2)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:25][Si](C)(C)N[Si](C)(C)C.Cl[Si](CCl)(C)C.COCCOCCOC.[F-].[Cs+]>C(#N)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([N:8]([CH3:25])[C:9]([C:11]2[S:24][C:14]3[C:15]4[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=4[O:17][CH2:18][CH2:19][C:13]=3[CH:12]=2)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncccc1Cl)c1cc2c(s1)-c1ccccc1OCC2
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(Cl)CCl
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ncccc1Cl
Temperature: 25 °C

Procedure:
To a solution of N-(3-chloropyridin-2-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide in acetonitrile (0.702 ml) was added hexamethyldisilazane (0.029 ml, 0.140 mmol) and heated at reflux for 3 hours. Chloro(chloromethyl)dimethylsilane (0.029 ml, 0.224 mmol) was added to the refluxing solution drop-wise and the reaction mixture was refluxed overnight. Next, the reaction mixture was equilibrated to room temperature and concentrated to a solid residue. This solid was taken into diglyme (2 ml, 10 mmol) and treated with cesium fluoride (0.21 g, 1.4 mmol) at reflux for 3 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic was separated from the aqueous in a separatory funnel. The organic was washed with saline, dried (Na2SO4) and concentrated to a solid. This crude material was taken into methanol at 100 mg/ml and purified by RP-HPLC to give 24 mg of 207, 29% of theoretical yield. MS: (ESI+) 371.1
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[NH:16][C:17](=[O:22])C(Cl)(Cl)Cl)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:25](CC)CC)C.C([O-])(=O)C.[NH4+].O>CS(C)=O>[CH:1]1([C:7]2[C:9]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=3)[NH:16][C:17](=[O:22])[N:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1cc(Cl)ccc1NC(=O)C(Cl)(Cl)Cl)C1CCCCC1
Reactant: CCN(CC)CC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1nc(C2CCCCC2)c2cc(Cl)ccc2[nH]1
Reaction time: 24 h
Yield: 100.7 %

Procedure:
To a solution of 7.66 g of 2-trichloroacetamido-5-chlorophenyl cyclohexyl ketone in 150 ml of dimethyl sulfoxide was added 4.0 g of triethylamine and 7.71 g of ammonium acetate. The mixture was left at room temperature for 1 day, and poured into 700 ml of water. The resulting precipitate was collected by filtration, washed with water and dried to obtain 5.29 g of 4-cyclohexyl-6-chloro-2(1H)-quinazolinone, which was recrystallized from chloroform to give colorless needles, m.p. 269.5°-270.5°C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:29][C@@H:30]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([O:33][CH3:34])=[O:32].CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:29][C@@H:30]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([O:33][CH3:34])=[O:32])=[O:15])[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.4 %

Procedure:
To a stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (0.350 g, 1.44 mmol) in DCM (5 ml) EDCI (0.331 g, 1.73 mmol) and HOBt (0.234 g, 1.73 mmol) were added at 0° C. After 10 minutes, (S)-methyl 2-amino-4-methylpentanoate hydrochloride (0.780, 4.32 mmol) and Et3N (1.2 ml, 8.64 mmol) in DCM (5 ml) were added drop wise and the reaction mass was allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, sat. NaHCO3 solution, water, 1N HCl, water and saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude was purified by silica gel column (100-200 mesh, elution 65% EtOAC in hexane) to afford the title compound as a solid. Wt: 0.210 g; Yield: 39.4%; 1H NMR (300 MHz, CDCl3): δ 5.56 (d, 1H), 4.75 (d, 1H, J=9 Hz), 4.70-4.60 (m, 1H), 3.88-3.79 (m, 1H), 3.73 (s, 3H), 2.48-2.25 (m, 2H), 2.14-1.99 (m, 1H), 1.70-1.48 (m, 3H), 1.43 (s, 9H), 1.32 (s, 3H), 0.95-0.91 (m, 9H); Mass: [M+Na]+ 393 (100%); IR (KBr, cm−1): 3344, 2960, 2873, 1743, 1689, 1664, 1531, 1458, 1366, 1271, 1174, 1050, 1028, 873, 827, 744; M.R: 100.5° C.-103.9° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6][CH:5]1[F:15].C([BH3-])#N.[Na+]>C(O)(=O)C>[F:15][CH:5]1[CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:4]1[NH:3][O:2][CH3:1]
Reactant: CON=C1c2ccccc2CCCC1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CONC1c2ccccc2CCCC1F
Temperature: 23 °C
Reaction time: 6 h
Yield: 52 %

Procedure:
To a stirred solution of crude 6-fluoro-6,7,8,9-tetrahydrobenzocylohepten-5-one-O-methyl-oxime E/Z-mixture (1.23 g; 5.95 mmol) prepared as described in example P2a in acetic acid (12 ml) was added portion wise sodium cyanoborohydride 95% (0.75 g; 11.9 mmol) at 15° C. The mixture was stirred for 6 hours at 23° C. Most of acetic acid was removed under reduced pressure. The residue was poured in 2N NaOH (50 ml) and was extracted with ethylacetate (3×30 ml). Combined organics were dried over sodium sulfate and solvent was removed in vacuo. The crude (1.45 g) was subject to flash chromatography (eluant: c-hexane/ethyl acetate 100:0 to 0:100) to afford 0.645 g (52% of theory) of N-(6-fluoro-6,7,8,9-tetrahydro-5-H-benzocyclohepten-5-yl)-O-methyl-hydroxylamine as a yellow oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([C:14]2[N:15]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:16]=[CH:17][CH:18]=2)=[O:13])=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH2:5]([O:4][C:2]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([C:14]2[N:15]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])[CH:16]=[CH:17][CH:18]=2)=[O:13])=[CH:27][CH:28]=1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: C[Si](C)(C)CCOCn1cccc1C(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(C(=O)c2cccn2COCC[Si](C)(C)C)cc1
Reaction time: 1.75 h
Yield: 94.5 %

Procedure:
Ethyl chloroformate (0.21 g, 1.95 mM) was added dropwise to a stirred solution of 2-(4-aminobenzoyl)-1-(2-trimethylsilylethoxymethyl)pyrrole (0.5 g. 1.58 mM) in pyridine (5 ml) at 5° C. After 5 minutes the cooling bath was removed and stirring continued for 1.75 hours. The mixture was treated with MeOH (2 ml) and evaporated and the residue partitioned between EtOAc and aqueous sodium bicarbonate solution. The organic layer was washed with water, aqueous citric acid, dried (MgSO4) and evaporated. to give 2-(4-ethoxycarbonylaminobenzoyl)-1-(2-trimethylsilylethoxymethyl)pyrrole as an oil (0.58 g). MS: 389 (MH+). NMR: 0.0 (9H, s); 0.89 (2H, t); 1.38 (3H, t) 3.57 (2H, t); 4.28 (2H, q); 5.8 (2H, s); 6.34 (1H, m); 6.82 (1H, m); 7.50 (1H, m); 7.7 (2H, d); 7.83 (2H, d); 10.1 (1H, br s).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O>O1CCCC1>[CH2:17]([N:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[CH2:9][OH:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)[C@@H]1CCCCN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@@H]1CCCCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Lithium aluminum hydride was added to an ice-cooled solution of (2S)-1-benzylpiperidine-2-carboxylic acid methyl ester (178 mg) in tetrahydrofuran (2.7 ml) under nitrogen atmosphere. The mixture was stirred for 2 hours below 5° C. The reaction was quenched by a sequential addition of water (0.12 ml), 15% aqueous sodium hydroxide (0.12 ml) and water (0.36 ml) successively, and the whole was stirred at room temperature for 1 hour. The insoluble materials were removed by filtration. The filtrate was dried over sodium sulfate and evaporated under reduced pressure to give (2S)-1-benzyl-2-(hydroxymethyl)piperidine as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C([O-])([O-])=O.[Na+].[Na+].[I:17]I.Cl>O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:17])[C:5]([OH:7])=[O:6]
Reactant: II
Reactant: O=C(O)c1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(I)c(O)c1
Temperature: 25 °C

Procedure:
To a solution of 26 g 3-Hydroxybenzoic acid and 43 g Na2CO3 in 45 mg H2O at 100° C. was added dropwise a solution of 48 g KI and 48 g iodine in 135 ml H2O. After heating for additional 3 h the mixture was cooled to RT and acidified with concentrated HCl. The title compound precipitated as a white solid and was collected by filtration.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[H-].[Na+].[N+:11]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1Cl)([O-:13])=[O:12].Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([C:6]#[N:7])[C:19]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[N+:11]([O-:13])=[O:12])[CH3:2]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)c1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
Ethylcyanoacetate (3.75 g, 38 mmol) in 3 mL DMF was added dropwise at 0° C. to a suspension of sodium hydride (1.5 g, 60% in mineral oil, 38 mmol) in DMF (9 mL). The reaction mixture was stirred at room temperature for 30 minutes then cooled to ° C. and 3-nitro-4-chloropyridine (2.63 g, 19 mmol, 1 eq) in DMF (3 mL) added slowly. 2 M HCl (20 mL) and ethyl acetate (20 mL) were added after 2 hours stirring at room temperature and the organic layer was washed with water and brine, before being dried over sodium sulphate and concentrated to give a red/orange oil. The crude oil was triturated with ethyl acetate and the resultant solid collected by filtration to give the title compound (2.88 g, 48%). 1H NMR (d6-DMSO) δ 13.2 (s, br), 8.70 (1H, s), 7.88 (1H, dd, J=7.1, 1.0), 4.06 (2H, q, J=7.1), 1.18 (3H, t, J=7.1); LC-MS (1) Rt 1.13 min; m/z (ES−) 190, 234.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=3[O:19][CH3:20])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:29]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH:30]([CH3:32])[CH3:31].CN(C)C(=O)C>CN(C)C=O.C(OCC)(=O)C>[CH2:29]([N:33]1[CH2:38][CH2:37][N:36]([C:2]2[N:7]=[C:6]([C:8]3[NH:17][C:16](=[O:18])[C:15]4[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=4[O:19][CH3:20])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:35][CH2:34]1)[CH:30]([CH3:32])[CH3:31]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Reactant: CC(C)CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(CC(C)C)CC4)n3)nc2c1
Temperature: 110 °C
Reaction time: 20 h
Yield: 34.1 %

Procedure:
To a suspension of 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.108 g, 0.36 mmol) in N,N-dimethylformamide (1.5 mL) was added K2CO3 (0.15 g, 1.07 mmol) and 1-isobutyl-piperazine (88.9 μL, 0.54 mmol). The resulting mixture was heated at 110° C. for 6 h. After that time N,N-dimethylacetamide (1.5 mL) was added and heating was continued for 20 h. After that time the reaction mixture was cooled to rt, diluted with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure and the residue was washed with water, and dried under high vacuum. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol) to give 2-(6-(4-isobutylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.052 g, 34%) as a yellow solid: mp 188-189° C.; 1H NMR (400 MHz, CDCl3) δ 10.33 (br s, 1H), 7.83 (d, J=7.42 Hz, 1H), 7.65 (dd, J=8.59, 7.42, 1H), 6.76-6.88 (m, 2H), 6.48 (d, J=2.34 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.64 (t, J=4.88 Hz, 4H), 2.55 (t, J=4.88 Hz, 4H), 2.17 (d, J=7.42 Hz, 2H), 1.75-1.95 (m, 1H), 0.95 (d, J=6.64 Hz, 6H); ESI MS m/z 424 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:22])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][CH:16]=[N:15][C:14]=2[N:13]([CH3:21])[C:11]1=[O:12])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:28]Br>C(O)(=O)C>[C:1]([O:4][C@H:5]([CH3:22])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([Br:28])=[N:15][C:14]=2[N:13]([CH3:21])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]c(Br)nc2n(C)c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a stirring suspension of (R)-1-(5-acetoxyhexyl)-3-methylxanthine (9.3 g, 30.2 mmol) and sodium acetate (4.92 g, 60.0 mmol) in acetic acid (200 ml) at 60° C. was added bromine (5.76 g, 36.0 mmol) dropwise. After stirring at 60° C. for an additional 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was treated with water (100 ml) and stirred at room temperature for 1 hour. After filtration, the solids were washed with water (3×15 ml) and dried under vacuum to provide (R)-1-(5-acetoxyhexyl)-8-bromo-3-methylxanthine (8.8 g, 75% yield) as a beige powder.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][C:35]=1[C:44](=O)[CH3:45]>>[C:38]1([CH2:37][CH:36]=[C:35]([C:44]2[CH:2]=[CH:3][C:4]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:45]=2)[CH3:34])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)c1ccc2ccccc2c1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(=CCc1ccccc1)c1ccc2ccccc2c1
Yield: 53.5 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (2.30 g, 5.14 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 3.2 mL, 5.14 mmol, 1.0 equiv.) and 1-(naphthalen-2-yl)ethanone (1.22 g, 7.20 mmol, 1.4 equiv.), 0.71 g (54%) of the title compound as a yellow oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 995:5).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH2:31][C:32]1[N:33]=[CH:34][S:35][CH:36]=1)[NH:5][C:6](=[O:30])[C@H:7]([CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].O.[NH2:39][NH2:40]>CN(C)C=O>[CH2:12]([O:11][C:9]([NH:8][C@H:7]([C:6]([NH:5][CH:4]([C:3]([NH:39][NH2:40])=[O:2])[CH2:31][C:32]1[N:33]=[CH:34][S:35][CH:36]=1)=[O:30])[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C(Cc1cscn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: NNC(=O)C(Cc1cscn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
2.10 g (4.06 mmole) of this ester were dissolved in 20 ml of dimethylformamide, and then 2.00 g (40.0 mmole) of hydrazine hydrate were added; the mixture was stirred overnight at room temperature. This reaction product was condensed by evaporation under reduced pressure, and then water was added to the residue. The precipitating crystals were collected by filtration, washed with hexane and diethyl ether and dried, to yield 1.90 g (90.5%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[OH:15].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26]>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:15][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26]
Reactant: Cc1ccc(Nc2ccccn2)cc1O
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)=CCOc1cc(Nc2ccccn2)ccc1C
Yield: 48 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-methyl-5-(pyridin-2-ylamino)phenol (67 mg, 0.33 mmol) and Cs2CO3 (113 mg, 0.35 mmol) in acetone (3.3 mL) was treated with 4-bromo-2-methyl-2-butene (0.038 mL, 0.33 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 8/2) in 48% yield (43 mg).
Reaction SMILES: [SH2:1].[CH3:2][O:3][C:4](=[O:15])[C:5]([CH3:14])([N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1)[CH3:6].[BH4-].[Na+]>C(O)(C)C>[CH3:2][O:3][C:4](=[O:15])[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([SH:1])[CH2:9][CH2:8]1)([CH3:14])[CH3:6]
Reactant: S
Reactant: COC(=O)C(C)(C)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)C(C)(C)N1CCC(S)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
H2S gas was bubbled into a solution of 2-methyl-2-(4-oxopiperidin-1-yl)propionic acid methyl ester (1.28 g, 6.42 mmol) in isopropanol (13 mL) for 10 min. The reaction mixture was then sealed, stirred at RT for 18 h and then left standing for 8 days at RT. After this period of time, nitrogen was bubbled into the solution for 10 min, then NaBH4 (364 mg, 9.63 mmol) was added. The reaction mixture was stirred at RT for 10 min and then heated at 80° C. for 2 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was partitioned between diethyl ether and water. The aqueous layer was further extracted with diethyl ether and the combined organic phases were washed with water, followed by brine, then dried over Na2SO4 and concentrated in vacuo. 2-(4-Mercaptopiperidin-1-yl)-2-methylpropionic acid methyl ester (1.497 g, quantitative yield) was obtained as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 3.71 (3H, s), 3.01-2.85 (2H, m), 2.82-2.64 (1H, m), 2.33-2.14 (2H, m), 2.06-1.94 (2H, m), 1.71-1.58 (2H, m), 1.53-1.48 (1H, m), 1.29 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][C:10]([CH3:12])=O>>[CH3:9][C:10]1([CH3:12])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]1
Reactant: Nc1ccccc1S
Reactant: CC(C)=O
Product: CC1(C)Nc2ccccc2S1
Yield: 53 %

Procedure:
Using the method of Example 17a reaction of o-aminothiophenol with acetone yielded 53% of 2,2-dimethylbenzothiazolidine b.p. 120° C./10.2 mm Hg.