Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[CH:27]=3)[CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.[CH3:40][CH2:41][OH:42].CCOCC>CCOCC>[ClH:1].[C:41]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[CH:14][C:15]([C@@H:18]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[CH:27]=3)[CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)(=[O:42])[CH3:40]
Reactant: CCO
Reactant: COc1ccc([C@@H](Cc2ccncc2)c2ccc(Oc3ccc(N)cc3)cc2)cc1OC1CCCC1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc([C@@H](Cc2ccncc2)c2ccc(Oc3ccc(NC(C)=O)cc3)cc2)cc1OC1CCCC1

Procedure:
Treatment of the free base (303.6 mg) in EtOH-Et2O (30 ml; 1:2) with 1.0M HCl in Et2O (0.62 ml) as described for the compound of Example 7 followed by the recrystallisation (THF-Et2O) afforded the title compound as an off-white amorphous solid (highly hygroscopic). δH (CD3OD) 1.50-1.90 (8H, br m), 2.11 (3H, s), 3.67 (2H, d, J 8.3 Hz), 3.76 (3H, s), 4.40 (1H, t, J 8.3 Hz), 4.73 (1H, br m), 6.79 (1H, s), 6.83 (1H, s), 6.84 (1H, s), 6.85-6.95 (4H, m), 7.28 (2H, d, (fine split), J 8.5 Hz), 7.50 (2H, dd, J 6.9, 2.3 Hz), 7.80 (2H, d, J 6.4 Hz), and 8.60 (2H, d, J 5.9 Hz).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.C[N:12]1CCOCC1.C(OC(Cl)=O)C(C)C>COCCOC>[SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:12])=[O:7])=[CH:4][CH:3]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)c1ccc(S)cc1
Agent: CC(C)COC(=O)Cl
Solvent: COCCOC
Product: NC(=O)c1ccc(S)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-mercaptobenzoic acid (1.00 g, 6.49 mmol) and N-methylmorpholine (0.78 ml, 7.14 mmol) in ethyleneglycol dimethylether (20 ml) was added iso-butylchloroformate (0.92 ml, 7.14 mmol). The reaction was stirred at ambient temperature overnight and filtered to a clear pale yellow solution which was treated with excess ammonia as a solution in dioxane (0.5M, ˜15 ml). This solution was stirred for two hours at room temperature, and concentrated in vacuo to a white solid. The solid was dissolved in a mixture of H2O (10 ml) and CHCl3 (30 ml), the aqueous was basified using 2N NaOH(aq) and the organic layer separated and dried (MgSO4) before being concentrated in vacuo to a white solid (679 mg). The solid was treated with a solution of sodium methoxide in methanol (10 ml) and when TLC showed no more starting material, the reaction was acidified using 2N HCl(aq) to pH=4, then concentrated in vacuo. The residue was treated with water and extracted with CHCl3, then concentrated in vacuo to give the title compound as an off white solid (376 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[NH:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:4](=O)[CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][NH2:18].S(=O)(=O)(O)O>CO.[Pd]>[CH3:1][C:2]1([CH3:11])[CH2:3][CH:4]([NH:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][NH2:18])[CH2:6][C:7]([CH3:10])([CH3:9])[NH:8]1
Reactant: NCCNCCN
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC1(C)CC(NCCNCCN)CC(C)(C)N1

Procedure:
A mixture of 155 g of triacetone amine, 113 g of diethylene triamine, and 2.5 g of conc. sulfuric acid in 2.5 liters of methanol is hydrogenated in the presence of 7 g of 5% palladium on carbon in the manner described in Example 1. In addition to yielding 1,7-bis(2,2,6,6-tetramethyl-4-piperidyl)-1,4,7-triazaheptane, distillation of the hydrogenation mixture yields at 115°-118° C./0.09 mm Hg 1-(2,2,6,6-tetramethyl-4-piperidyl)-1,4,7-triazaheptane as main product.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[CH:11][C:10]=1[O:22]COCC[Si](C)(C)C)=[O:8])=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]([CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[CH:11][C:10]=1[OH:22])=[O:8])=[O:4]
Reactant: COC(=O)CNC(=O)c1ccc(OCc2ccsc2)cc1OCOCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)c1ccc(OCc2ccsc2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A mixture of 1-[N-(methoxycarbonylmethyl)carbamoyl]-2-[2-(trimethylsilyl)ethoxy]methoxy-4-(3-thienylmethoxy)benzene (3.3 g), tetrabutylammonium fluoride (20 mL of a 1 M solution in tetrahydrofuran) and tetrahydrofuran (30 mL) is stirred at ambient temperature for one hour and at reflux for 45 minutes, then it is cooled to ambient temperature and concentrated in vacuo. The resulting residue is partitioned between ethyl acetate (100 mL) and saturated brine (100 mL), and the organic layer is washed with brine (2×50 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. Flash chromatography of the residual oil on silica gel, eluting with a mixture of methanol and dichloromethane (2:98 v/v) gives 2-[N-(methoxycarbonylmethyl)carbamoyl]-5-(3-thienylmethoxy)phenol (2.3 g), in the form of a white solid.
Reaction SMILES: Br[CH2:2][C:3](=[N:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])[O:4][CH2:5][CH3:6].[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O>[N:23]([CH2:2][C:3](=[N:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])[O:4][CH2:5][CH3:6])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(CBr)=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CN=[N+]=[N-])=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 80 °C

Procedure:
to a solution of 3.8 parts of 2-(2-bromo-1-ethoxyethylideneamino)-5-chlorobenzophenone produced in Step (1) in 30 parts by volume of dimethylformamide is added 0.72 part of sodium azide. The mixture is heated at 80° C. for 10 minutes, and is poured into 60 parts by volume of ice water. The resulting oily precipitate is extracted with ethyl acetate. Ethyl acetate layer is washed with water and dried over anhydrous sodium sulfate. After evaporation of the solvent, 2-(2-azido-1-ethoxyethylideneamino)-5-chlorobenzophenone is obtained quantitatively as an oily substance. The product shows an absorption band at 2100 cm-1 due to N3 in an infrared absorption spectrum.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.[Pd]>[C:1]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=4)[CH2:17][CH2:18]3)=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N2CCN(Cc3ncc(-c4ccccc4)o3)CC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(N2CCN(Cc3ncc(-c4ccccc4)o3)CC2)cc1

Procedure:
A solution of 1-(5-phenyloxazol-2-ylmethyl)-4-(4-nitrophenyl)-piperazine (7.28 g; 0.02 mole) in glacial acetic acid (50 ml) was hydrogenated over 5% Palladium-on-charcoal catalyst (100 mg) at atmospheric pressure and room temperature, until the uptake of hydrogen was complete. The solvent was evaporated off under vacuum and the residue treated with aqueous sodium bicarbonate solution, yielding a white crystalline solid. Weight after drying = 6.54 g (98%), m.p. 130° C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:20][C:21]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>>[F:20][C:21]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Nc1cccc(F)c1F
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(F)c1F
Yield: 21.1 %

Procedure:
The product is prepared according to the procedure described in Example 9, using 300 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 and 840 mg of 2,3-difluoroaniline in place of the 2-fluoroaniline. 83 mg of N-(2,3-difluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[N:11][C:12]([NH:15][NH2:16])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:17][CH2:18][C:19](OC)(OC)OC>Cl.CCOCC>[Cl:17][CH2:18][C:19]1[N:11]2[N:10]=[C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:14]=[CH:13][C:12]2=[N:15][N:16]=1
Reactant: COC(CCl)(OC)OC
Reactant: NNc1ccc(Nc2cccc(Cl)c2)nn1
Agent: Cl
Solvent: CCOCC
Product: ClCc1nnc2ccc(Nc3cccc(Cl)c3)nn12
Reaction time: 0.17 h
Yield: 80 %

Procedure:
(Step 3-i) N-(3-chlorophenyl)-6-hydrazinylpyridazin-3-amine (4.0 g, 17 mmol)) was taken up in HCl/Et2O (20 mL) and stirred for 10 min. The reaction mixture was concentrated, taken up in DMF (20 mL), and 2-chloro-1,1,1-trimethoxyethane (5.2 g, 34 mmol) was added. After stirring for 3 hours, a precipitate began to form. After one hour additional stirring, the reaction mixture was filtered to give the product, 3-(chloromethyl)-N-(3-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine, as a white solid. (4 g, 13.6 mmol, 80% yield): 1H-NMR (500 MHz, DMSO-d6) 10.40 (s, 1H), 8.19 (d, J=9.8 Hz, 1H), 8.13 (t, J=1.8 Hz, 1H), 7.68 (dd, J=1.7, 8.2 Hz, 1H), 7.40 (t, J=8.1 Hz, 1H), 7.28 (d, J=9.9 Hz, 1H), 7.11-7.09 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[N-:22]=[N+:23]=[N-:24].[Na+]>C(Cl)Cl.CC(C)=O.O>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([N:22]=[N+:23]=[N-:24])=[O:10])=[N:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cnc(C(=O)O)cn1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cnc(C(=O)N=[N+]=[N-])cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
A mixture of 5-methylpyrazine-2-carboxylic acid (2.76 g, 20 mmol) and oxalyl chloride (1.83 mL, 2.66 g, 21 mmol) in methylene chloride (40 mL) was treated with N,N-dimethylformamide (0.5 mL), and the mixture was stirred at 25° C. for 1 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give an oily solid. The solid was dissolved in acetone (120 mL) at 0° C. and then sodium azide (1.03g, 20 mmol) in water (50 mL) was added dropwise. After the addition was complete, stirring was continued at 0° C. for 30 min. The mixture was then poured into ice cold water (100 mL) and extracted with methylene chloride (3×100 mL). The combined organic extracts were washed with water (1×100 mL), a mixture of a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution (1:1, 1×100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo to give 5-methyl-pyrazine-2-carbonyl azide (1.46 g, 45%) as a tan solid. The 5-methyl-pyrazine-2-carbonyl azide (500 mg, 3.07 mmol) was combined with benzyl alcohol (0.63 mL, 663 mg, 6.14 mmol) at 25° C. The mixture was then slowly heated on an oil bath to 90° C., upon which gas was violently evolved. The oil bath temperature was maintained until gas evolution ceased. The oil bath temperature was raised to 120° C. and stirring was continued for 10 min at that temperature. The mixture was cooled and triturated with diethyl ether/hexanes (1:4) to give (5-methylpyrazin-2-yl)-carbamic acid phenyl ester (438 mg, 58%) as a yellow solid. The (5-methylpyrazin-2-yl)-carbamic acid phenyl ester (500 mg, 2.2 mmol) and 10% palladium on carbon (212 mg) were mixed in ethanol (30 mL). The reaction vessel was flushed with hydrogen, and the mixture was stirred at 25° C. for 1 h under hydrogen (1 atm). The excess hydrogen was evacuated from the reaction vessel, and the mixture was filtered through a pad of celite. Concentration of the filtrate in vacuo gave 2-amino-5-methylpyrazine (183 mg, 76%) as a tan solid which was used without further purification.
Reaction SMILES: BrC1C([C:20]2[S:21][C:22]([Cl:30])=[C:23]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH:24]=2)=NC(NCCN2C(C)(C)C(=O)NC2=O)=NC=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:40][CH2:41]CCBr>C(#N)C>[Cl:30][C:22]1[S:21][CH:20]=[CH:24][C:23]=1[CH2:25][CH2:26][N:27]1[CH2:28][CH2:41][CH2:40][CH2:29]1
Reactant: BrCCCCBr
Reactant: CN(C)CCc1cc(-c2nc(NCCN3C(=O)NC(=O)C3(C)C)ncc2Br)sc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Clc1sccc1CCN1CCCC1
Yield: 13.8 %

Procedure:
A solution of 2-(2-chlorothiophen-3-yl)ethanamine hydrochloride (3.00 g, 15.1 mmol, prepared as described in Example 329) in acetonitrile (30 mL) was treated with anhydrous potassium carbonate (7.50 g, 54.3 mmol), sodium iodide (5.45 g, 36.4) and 1,4-dibromo-butane (2.2 mL, 18 mmol). The resulting suspension was heated to reflux for 18 h, then cooled, filtered and concentrated to a dark brown oil. Purification by flash chromatography eluting with 1-5% (0.5 M ammonia in MeOH)/dichloromethane afforded the product as a colorless oil (0.45 g, 2.09 mmol, 14% yield). MS (M+H)+ 216.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][C:3]=1[O:11][C:12]1[C:17]([F:18])=[C:16]([N:19]([CH3:30])[C:20]2([C:25]([O:27]CC)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:15]([F:31])=[C:14]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]3[N:40]([CH3:44])[CH2:41][CH2:42][N:43]=3)[CH:34]=2)[N:13]=1>Cl.C(#N)C.FC(F)(F)C(O)=O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][C:3]=1[O:11][C:12]1[C:17]([F:18])=[C:16]([N:19]([CH3:30])[C:20]2([C:25]([OH:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:15]([F:31])=[C:14]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]3[N:40]([CH3:44])[CH2:41][CH2:42][N:43]=3)[CH:34]=2)[N:13]=1
Reactant: CCOC(=O)C1(N(C)c2c(F)c(Oc3cccc(C4=NCCN4C)c3)nc(Oc3cc(C(=N)N)ccc3O)c2F)CCCC1
Agent: Cl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN=C1c1cccc(Oc2nc(Oc3cc(C(=N)N)ccc3O)c(F)c(N(C)C3(C(=O)O)CCCC3)c2F)c1
Temperature: 25 °C

Procedure:
A solution of 4-hydroxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzamidine, trifluoroacet acid salt (0.80 g, 1.2 mmol) in 25 mL of 6 N aqueous HCl was stirred at 60° C. for 1 hour. It was then cooled to ambient temperature, diluted with acetonitrile and trifluoroacetic acid and purified by HPLC on a C18 Dynamax column with 20-80% acetonitrile in water gradient with 0.1% trifluoroacetic acid to afford 4-hydroxy-3-[(4-(N-methyl-N-(1-carboxycyclopent-1-yl)amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzamidine, trifluoroacet acid salt as a white solid: NMR (DMSO-d6)/TFA) 10.2 (br s, 1), 9.0 (br s , 2), 8.8 (br s, 2), 7.3-7.6, (m, 6), 7.0 (d, 2), 4.1 (m, 2), 3.9 (m, 2), 3.2 (s, 3), 3.0 (s, 3), 2.9 (s, 3), 2.1 (m, 4), 1.6-1.8 n(m, 4) ppm.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([NH2:6])([CH3:5])[CH3:4].Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:11].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]([F:8])([F:7])[C:3]([NH:6][C:10](=[O:11])[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)([CH3:5])[CH3:4]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(N)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Temperature: -15 °C
Reaction time: 2 h
Yield: 26.1 %

Procedure:
To a solution of 0.35 g (2.75 mmol) of 1,1,1-trifluoro-2-methylpropan-2-ylamine (CAS 812-18-0) in 20 ml of dichloromethane, cooled to −15° C., is added dropwise 1.00 g (4.96 mmol) of 4-nitrophenyl chloroformate (CAS 7693-46-1) dissolved in 15 ml of dichloromethane, while maintaining the temperature at −15° C. 0.48 ml (2.75 mmol) of diisopropylethylamine in 10 ml of dichloromethane is then added, still at −15° C. Stirring is continued at −15° C. for 2 hours, and the temperature of the mixture is then allowed to return to 0° C. over 1 hour. 20 ml of saturated aqueous sodium hydrogen carbonate solution are then added. The organic phase is separated out by settling and dried over sodium sulfate, and the solvent is partially evaporated off under reduced pressure to a volume of about 8 ml. This solution is chromatographed on a column of 40 g of silica gel, eluting with a mixture of 20% cyclohexane in dichloromethane, to give 0.21 g of 4-nitrophenyl 1,1,1-trifluoro-2-methylpropan-2-ylcarbamate in the form of a white solid.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11](C=O)[S:12][CH:13]=1.[OH-].[K+].Cl>N1C=CC=CC=1.N1CCCCC1.O>[Br:8][C:9]1[CH:10]=[C:11](/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4])[S:12][CH:13]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(Br)cs1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)/C=C/c1cc(Br)cs1
Temperature: 100 °C

Procedure:
Malonic acid (16.2 g) was added to a solution of 4-bromothiophen-2-aldehyde (25.1 g) in pyridine (100 cm3) and piperidine (3.2 cm3) and the resulting mixture was heated at 100° C. for 6.5 hours, allowed to cool to room temperature overnight and was then evaporated down to give a beige semi-solid. The semi-solid was treated with aqueous potassium hydroxide solution and the resulting mixture was diluted with water (50 cm3), acidified with concentrated hydrochloric acid (90 cm3) and then cooled to yield a precipitate which was filtered off, washed with ether/40-60 petrol and was then sucked dry (26.1 g) m.p. 167°-169° C. (aqueous methanol) Analysis; Calculated; C, 36.05; H, 2.15; Found; C, 36.30; H, 2.03.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.CS(O[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])(=O)=O>>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1
Reactant: COc1ccccc1COS(C)(=O)=O
Reactant: O=Cc1c[nH]c2ccccc12
Product: COc1ccccc1Cn1cc(C=O)c2ccccc21

Procedure:
The same procedures used in Example 1 were repeated except for using 870 mg of indole-3-carbaldehyde and 2-methoxybenzyl methanesulfonate in place of the benzyl bromide used in Example 1 to give 926 mg of 1-(2-methoxybenzyl)indole-3-carbaldehyde as pale yellow crystals. The yield thereof was found to be 58%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH2:10][C:11]2([CH2:22][CH3:23])[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH2:9])[CH:5]=[CH:6][CH:7]=1.O.O.O.C([O-])(=[O:29])C.[Na+].C(OO)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([O:29][CH2:9]2)[CH2:10][C:11]2([CH2:22][CH3:23])[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: C=C(CC1(CC)C(=O)c2ccccc2C1=O)c1cccc(Cl)c1
Agent: CC(=O)OO
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC1(CC2(c3cccc(Cl)c3)CO2)C(=O)c2ccccc2C1=O
Yield: 149.1 %

Procedure:
To the mixture of 1.62 g of 2-[2-(3-chlorophenyl) propen 3-yl]-2-ethylindan-1,3-dione, 0.34 g of sodium acetate trihydrate and 10 ml of chloroform was added-2.85 g of 40% peracetic acid. After refluxing for 3 hours, excess peroxide was decomposed with 10% sodium thiosulfate aqueous solution, and the organic layer was washed with water, neutralized with a saturated sodium bicarbonate aqueous solution, washed with water and with a saturated saline solution, and dried over anhydrous magnesium sulfate. After the solvent was evaporated, the residue was separated and purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=4/1) to obtain 1.27 g of the compound No. 53 shown in Table 2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[CH3:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][O:16][CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(COCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(COCCC2CCNCC2)cc1
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-[2-(4-methylbenzyloxy)ethyl]piperidine (470 mg, 1.41 mmol) in MeOH (0.5 mL) was added 2N anhydrous HCl/ether (2 mL, 4.0 mmol). The reaction mixture was stirred overnight. After evaporation, the residue was dissolved in deionized water. EtOAc was used to wash the aqueous layer before the pH was altered to approx. 9-10. The aqueous layer was extracted three times with CH2Cl2 and dried over Na2SO4. After evaporation, 4-[2-(4-methylbenzyloxy)ethyl]piperidine (269 mg, 82%) was obtained as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.20 (d, 2H, J=7.6 Hz), 7.13 (d, 2H, J=8.0 Hz), 4.44 (s, 2H), 3.47 (t, 2H, 6.0 Hz), 3.02 (d, 2H, J=12.0 Hz), 2.53 (m, 3H), 2.33 (s, 3H), 1.64 (d, 2H, J=12.4 Hz), 1.51 (m, 3H), 1.06 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:36]1[C:44]2[C:39](=[C:40](B3OC(C)(C)C(C)(C)O3)[C:41]([F:45])=[CH:42][CH:43]=2)[CH:38]=[CH:37]1)(C(C)(C)C)(C)C>>[F:45][C:41]1[C:40]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:16][CH:15]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:39]2[C:44](=[CH:43][CH:42]=1)[NH:36][CH:37]=[CH:38]2
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)ccc2n1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Product: Fc1ccc2[nH]ccc2c1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)ccc2n1

Procedure:
4-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)morpholine (119 mg) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 46 mg of 126 following reverse phase HPLC purification. MS (Q1) 504.2 (M)+
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:36][CH2:35][C:26]3[N:27]=[C:28]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[O:29][C:25]=3[CH3:24])=[CH:11][CH:12]=2)[C:4]([OH:3])=[O:23])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(4-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the procedure of Example 63. 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, 1H, J=3.52 Hz, J=1.17 Hz), 7.36 (dd, 1H, J=5.08 Hz, J=1.17 Hz), 7.18 (d, 2H, J=8.60 Hz), 7.06 (dd, 1H, J=5.08 Hz, J=3.91 Hz), 6.93-6.85 (m, 4H), 6.82 (d, 2H, J=8.60 Hz), 4.18 (t, 2H, J=6.65 Hz), 3.21 (d, 1H, J=13.69 Hz), 3.13 (d, 1H, J=13.69 Hz), 2.96 (t, 2H, J=6.65 Hz), 2.35 (s, 3H), 1.36 (s, 3H); HRMS (ES+) m/z exact mass calcd for C26H25NO5FS 482.1437, found 482.1451.