Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]([CH3:26])=[C:17]([CH2:19][CH2:20]OS(C)(=O)=O)[N:18]=2)=[CH:10][CH:9]=1>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[O:15][C:16]([CH3:26])=[C:17]([CH2:19][CH2:20][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:18]=2)=[CH:12][CH:13]=1
Reactant: C1CCNCC1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCCC1
Yield: 74.9 %

Procedure:
Add piperidine (3.04 g, 36.11 mmol) to a solution of Methanesulfonic acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester (See Intermediate 13) (1.3 g, 3.61 mmol) in anhydrous THF (15 mL). Reflux the reaction overnight and cool. Wash organic material with 1N HCl (50 mL) and extract aqueous layer with diethyl ether (2×50 mL). Add 5N NaOH to aqueous layer (pH>10) and extract with dichoromethane (2×50 mL). Dry organics over Na2SO4, filter and concentrate. Purify crude on silica gel, eluting with 5% 2N NH3 in methanol/dichloromethane to give 1-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-piperidine (0.944 g, 75%).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][N:11]([CH3:31])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]([OH:24])[CH2:22][N:23]=2)=[CH:14][CH:13]=1>ClCCCl>[CH3:10][N:11]([CH3:31])[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:19][CH:20]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:21]([O:24][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:22][N:23]=2)=[CH:16][CH:17]=1
Reactant: CN(C)c1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCCl
Product: CN(C)c1ccc(C2=NCC(OC(=O)Nc3ccccc3)C(c3ccccc3)O2)cc1
Yield: 39.2 %

Procedure:
Phenyl isocyanate (0.49 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2-[4-(dimethylamino)phenyl]-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1 g) in 1,2-dichloroethane (12 cc). The solution obtained is heated to reflux for 2 hours and then concentrated to dryness under reduced pressure (2.7 kPa), The residue is purified by chromatography on silica (0.063-0.02 mm; 50 g) contained in a column 2.5 cm in diameter (eluent: cyclohexane/ethyl acetate (7:3 by volume)]collecting 20-cc fractions. Fractions 9 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diethyl ether, (5RS, 6SR)-2-[4-(dimethylamino)phenyl]-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (0.55 g), m.p. 183° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([C:13](O)=[O:14])=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ON1C(=O)C2C=CC=CC=2N=N1.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)=[O:14])=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccn1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C(=O)O)cc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C(=O)Nc2ccccn2)cc1-c1ccccc1

Procedure:
To a solution of the resultant acid from Example 60A (1.0 equivalent) in DMF is added 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (1.5 equivalents) followed by 2-aminopyridine (1.0 equivalent) and 1-(3-dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed by 1N HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[S:7][C:6]=1[C:16]([O:18]C)=[O:17])[CH2:2][CH3:3].C[O-].[Na+].CO.Cl>O>[CH2:1]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[S:7][C:6]=1[C:16]([OH:18])=[O:17])[CH2:2][CH3:3]
Reactant: CCCNc1cc(-c2ccncc2)sc1C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCNc1cc(-c2ccncc2)sc1C(=O)O
Yield: 87.8 %

Procedure:
A mixture of methyl 3-(propylamino)-5-(pyridin-4-yl)thiophene-2-carboxylate (0.573 g, 2.07 mmol), sodium methoxide (0.335 g, 6.21 mmol), methanol (8.0 mL) and water (2.0 mL) was refluxed overnight. The mixture was cooled in an ice-bath and conc. HCl (0.510 mL, 6.21 mmol) was added. The resultant yellow precipitate was collected by filtration and washed with water and methanol to afford the title compound (0.477 g, 88%) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:10]=3[O:9][C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)=[CH:4][CH:3]=1.Br[CH2:36][CH2:37][CH2:38][O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:36][CH2:37][CH2:38][O:39][CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[C:12](=[O:17])[N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:10]=3[O:9][C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)=[CH:33][CH:34]=1
Reactant: C[Si](C)(C)CCOCn1c(=O)[nH]c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)oc21
Reactant: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)oc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 151.6 %

Procedure:
To a solution of 5-(4-chlorobenzyl)-6-(3-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione (25.88 mg, 0.01 mmol) in DMF (3 mL) was added 2-(3-bromopropoxy)tetrahydro-2H-pyran (11.2 mg, 0.05 mmol) and K2CO3 (6.9 mg, 0.05 mmol). The reaction was stirred at 60° C. for 2 h, cooled to RT, then was diluted with EA (12 mL) and water (4 mL). The organic layer was washed with brine (3 mL), dried over Na2SO4, and concentrated to a residue which was purified by chromatography PE/EA (5:1) to give 5-(4-chlorobenzyl)-6-(3-chlorophenyl)-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl) furo[2,3-d]pyrimidine-2,4(1H,3H)-dione (10 mg, 30.7% yield) as an oil. LCMS: (M++Na) 681 and TR=2.289 min.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:12]1[C:18]1[N:19]([CH3:37])[C:20](=[O:36])[C:21]([OH:35])=[C:22]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[O:25])[N:23]=1)=O)C1C=CC=CC=1.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>CO.[Pd]>[F:38][C:39]([F:44])([F:43])[C:40]([O-:42])=[O:41].[F:17][C:14]1([F:16])[CH2:15][NH2+:11][C@H:12]([C:18]2[N:19]([CH3:37])[C:20](=[O:36])[C:21]([OH:35])=[C:22]([C:24]([NH:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)=[O:25])[N:23]=2)[CH2:13]1
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1c([C@@H]2CC(F)(F)CN2C(=O)OCc2ccccc2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Agent: [Pd]
Solvent: CO
Product: Cn1c([C@@H]2CC(F)(F)C[NH2+]2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Product: O=C([O-])C(F)(F)F

Procedure:
A solution of benzyl-(2S)-4,4-difluoro-2-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)pyrrolidine-1-carboxylate in MeOH was treated with Pd/C 10% wt (10% w/w) for 3 hours at room temperature under H2 atmosphere. The mixture was filtrated over a celite pad, concentrated in vacuo and treated with trifluoroacetic acid (10 eq.). The acid in excess was removed in vacuo to obtain title product as a pale yellow solid after trituration with ethyl ether.
Reaction SMILES: [BH4-].[Na+].[Br:3][CH2:4][C:5](=[O:24])[C@@H:6]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1>C(OCC)(=O)C.CCCCCC>[Br:3][CH2:4][C@@H:5]([OH:24])[C@@H:6]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:7][C:8]1[CH:9]=[C:10]([F:15])[CH:11]=[C:12]([F:14])[CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)CBr
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CBr
Reaction time: 0.5 h

Procedure:
Sodium borohydride (1.32 g, 34.9 mmole, 1.1 eq.) is added to tert-Butyl (1S)-3-bromo-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate (III, PREPARATION 1, 12 g, 31.75 mmole) dissolved in absolute alcohol (500 mL) −78°. The reaction mixture is stirred for 30 minutes and monitored by TLC (ethyl acetate/hexane, 20/80; Rf=0.2). The mixture is quenched with water (10 mL) and the solvent removed under reduced pressure with heat (not exceeding 30°) to dryness. The solid is partitioned between dichloromethane and water, washed with saline, dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to give the title compound, TLC (ethyl acetate/hexane, 20/80) Rf=0.2; MS (MH+)=381.2
Reaction SMILES: O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=[N:28][C:29]1([CH2:36][C:37]#[CH:38])[CH2:33][CH2:32][N:31]([CH3:34])[C:30]1=[O:35])(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>C1COCC1>[NH2:28][C:29]1([CH2:36][C:37]#[CH:38])[CH2:33][CH2:32][N:31]([CH3:34])[C:30]1=[O:35]
Reactant: C#CCC1(N=C(c2ccccc2)c2ccccc2)CCN(C)C1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCC1(N)CCN(C)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 107.2 %

Procedure:
Citric acid monohydrate (10.39 g, 49.46 mmol) was added to a solution of 3-(benzhydrylidene-amino)-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (6.26 g, 19.79 mmol) (which may be prepared as described in Description 2) in THF (150 mL) and the reaction was stirred at room temperature for 18 hours. A colourless solid precipitated out. The solvent was evaporated to give a gummy white solid. This was trituated with Et2O and the solid was washed with further Et2O. The solid was suspended in water/MeOH and purified by SCX (70 g Silca), eluting with water/MeOH, MeOH and finally 0.5M NH3 in MeOH. Fractions containing product were evaporated to afford 3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (3.23 g, 21.223 mmol) as a pale yellow oil;
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:12])[C:9]([CH3:11])=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[C:19]1(O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C.O>[CH3:10][C:9](=[CH2:11])[C:8](=[N:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[O:12][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=C(C)C(=O)Nc1ccccc1
Reactant: Oc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)C(=Nc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a suspension of 1.0 g (6.20 mmol) of N-phenylmethacrylamide in 4 ml of toluene was added 1.30 g (6.24 mmol) of phosphorus pentachloride and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 5 ml of DMF and then cooled to 0° C. To a solution of 1.17 g (12.4 mmol) of phenol in 5 ml of DMF was added 546 mg (13.6 mmol) of sodium hydride (60% in oil) under ice cooling and stirred for 5 minutes. The mixture was added portionwise to the above-described DMF solution of the residue under ice cooling and stirred at room temperature for 1 hour. The reaction mixture was poured into water wad extracted with tert-butyl methyl ether (twice). The combined organic layer was washed sequentially with water and saturated NaCl, dried over anhydrous MgSO4, and then concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain 1.28 g of phenyl 2-methyl-N-phenyl-2-propenimidate.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9](Br)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:23]1(OB(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.OO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:17]1([C:2]2[C:3]3[C:8]([C:9]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Reactant: c1ccccc1
Reactant: OB(O)Oc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OO
Solvent: CCO
Product: c1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Yield: 75.5 %

Procedure:
To a mixed solution of 286.6 g (0.85 mol) of 9,10-dibromoanthracene, 29.9 g (0.0255 mol) of Pd(PPh3)4 and 3L of benzene was added 1.5L of 2M Na2CO3aq and 1.2 L of ethanol solution of 228.6 g (1.87 mol) of phenyl boric acid, followed by refluxing for 6 hours. To the reaction solution was added 200 mL of 30% H2O2 to terminate the reaction, and an organic layer was recovered. The organic layer was washed with water and dehydrated by anhydrous magnesium sulfate, followed by filtration and concentration of the filtrate to 750 mL in total. The precipitated crystal was filtered and dried to give 212.0 g of 9,10-diphenylanthracene (Yield 75.5%, HPLC purity 97.6%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([CH3:19])=[CH:4][N:3]=1.[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21].Cl>O1CCOCC1.C(O)(C)C>[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH:33][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=4[C:11]([NH:13][CH3:14])=[O:12])[C:5]([CH3:19])=[CH:4][N:3]=3)[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CCN1CCc2ccc(Nc3ncc(C)c(Nc4ccccc4C(=O)NC)n3)cc2CC1
Yield: 38.7 %

Procedure:
2-(2-Chloro-5-methyl-pyrimidin-4-ylamino)-N-methyl-benzamide (32 mg, 0.12 mmol) and 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (24 mg, 0.13 mmol) were combined with 1 drop of a solution of 4N hydrochloric acid in dioxane and 2 mL isopropanol and subjected to microwave irradiation (CEP) at 170° C. for 150 minutes. The reaction mixture was concentrated and the organics were partitioned between dichloromethane and saturated sodium bicarbonate solution (100 mL each). The dichloromethane extract was separated, dried (sodium sulfate), and concentrated to afford a material which was purified on silica gel (methanol:dichloromethane gradient elution) to afford 20 mg (39%) of a white foam-2-[2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-5-methyl-pyrimidin-4-ylamino]-N-methyl-benzamide. MS: 431.20 (M+H); 1H NMR (d6-dmso): δ 11.20 (s, 1H), δ 8.99 (s, 1H), δ 8.86 (d, J=8 Hz, 1H), δ 8.74 (d, J=4 Hz, 1H), δ 7.97 (s, 1H), δ 7.75 (d, J=8 Hz, 1H), δ 7.49 (s, 1H), δ 7.45 (t, J=8 Hz, 1H), δ 7.38 (d, J=8 Hz, 1H), δ 7.08 (t, J=8 Hz, 1H), δ 6.97 (d, J=8 Hz, 1H), δ 2.82 (d, J=6 Hz, 3H), δ 2.80 (m, 2H), δ 2.70-2.40 (m, 8H), δ 2.10 (s, 3H), δ 1.01 (t, J=8 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O.[CH2:16]([CH:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17].[OH-:24].[K+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:16]([CH:18]([CH2:22][CH3:23])[C:19]([N:9]1[CH2:14][CH2:13][C:12](=[O:24])[CH2:11][CH2:10]1)=[O:20])[CH3:17]
Reactant: [OH-]
Reactant: CCC(CC)C(=O)Cl
Reactant: O=C1CCCCN1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)C(=O)N1CCC(=O)CC1
Temperature: -10 °C
Reaction time: 16 h

Procedure:
Triethylamine (5.8 g, 57.3 mmol) and a catalytic amount of DMAP were added to a solution of piperidone hydrochloride (4.0 g, 26 mmol) in CH2Cl2 (20 ml). After cooling to −10° C., 2-ethylbutyryl chloride (3.9 g, 28.6 mmol) dissolved in CH2Cl2 (10 ml) was slowly added and the mixture was stirred at RT for 16 h. 5M potassium hydroxide solution (25 ml) was added to the suspension, the organic phase was separated off and the aqueous phase was extracted with CH2Cl2 (3×10 ml). After drying of the combined organic phases over Na2SO4, filtration and removal of the solvent, the product 1-(2-ethylbutyryl)piperidin-4-one was obtained in a yield of 4.3 g (84% of theory).
Reaction SMILES: [CH2:1](N1C2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC=CC=4)=S)=CC=3F)C=2C=C1)[C:2]1C=CC=CC=1.[F:38][C:39]1[CH:40]=[C:41]([NH:55][C:56]([NH:58][C:59](=[O:67])[CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[S:57])[CH:42]=[CH:43][C:44]=1[O:45][C:46]1[CH:51]=[CH:50][N:49]=[C:48]2[CH:52]=[CH:53][S:54][C:47]=12.C1(C2(C(N=C=S)=O)CC2)C=CC=CC=1>>[F:38][C:39]1[CH:40]=[C:41]([NH:55][C:56]([NH:58][C:59]([C:60]2([C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)[CH2:2][CH2:1]2)=[O:67])=[S:57])[CH:42]=[CH:43][C:44]=1[O:45][C:46]1[CH:51]=[CH:50][N:49]=[C:48]2[CH:52]=[CH:53][S:54][C:47]=12
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3c2ccn3Cc2ccccc2)c(F)c1
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Agent: O=C(N=C=S)C1(c2ccccc2)CC1
Product: O=C(NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)C1(c2ccccc2)CC1
Yield: 41 %

Procedure:
Starting from the amine 169 (scheme 33), following the procedures described above for the synthesis of compound 170a (example 133) but replacing 2-phenylacetyl isothiocyanate with 1-phenylcyclopropanecarbonyl isothiocyanate, title compound 192d was obtained in 41% yield. Characterization of 192d is provided in table 18.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]#[C:14][CH2:15][O:16][CH3:17])[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH3:2]
Reactant: CCOC(=O)COc1ccccc1C#CCOC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccccc1CCCOC
Reaction time: 2 h

Procedure:
9.54 g (38.4 mmol) of the above prepared [2-(3-methoxy-prop-1-ynyl)-phenoxy]-acetic acid ethyl ester was hydrogenated at RT in 130 ml of AcOEt over 2.39 g of Pd/C (10%) under 1 atm of H2-pressure. After 2 h at ambient temperature, the reaction mixture was filtrated over Celite and carefully rinsed with AcOEt. Evaporation of the solvent left finally 9.39 g of the title compound as colorless oil.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=O)[CH2:3]2.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1.O1CCOCC1.Cl>C(OCC)(=O)C>[ClH:11].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:25]=[CH:24][C:22]([NH:23][CH:4]3[CH:5]4[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]4)[CH2:3]3)=[CH:21][CH:20]=2)=[CH:14][CH:13]=1
Reactant: O=C1CN2CCC1CC2
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Clc1ccc(Oc2ccc(NC3CN4CCC3CC4)cc2)cc1

Procedure:
3-Quinuclidinone hydrochloride (Aldrich, 1.61 g, 10 mmol) was treated with 4-(4-chlorophenyloxy) aniline (Aldrich, 1.10 g, 5.0 mmol) according to the procedure of Example 30A. The free base of the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.10) as a solid (1.52 g, yield, 93%). MS (DCl/NH3) m/z 329 (M+H)+, 331 (M+H)+. The free base (200 mg, 0.61 mmol) was treated with 4M HCl 1,4-dioxane (0.5 mL, 2.0 mmol) in ethyl acetate (5 mL). The hydrochloride salt of the title compound was obtained as a solid (195 mg, yield, 80%). 1H NMR (MeOH-d4, 300 MHz) δ 1.90–2.18 (m, 3H), 2.35–2.45 (m, 2H), 3.24 (ddd, J=12.5, 5.4, 2.3 Hz, 1H) 3.30–3.50 (m, 4H), 3.82 (ddd, J=12.2, 9.8, 2.7 Hz, 1H), 3.95–4.10 (m, 1H), 6.91 (dt, J=9.1, 2.3 Hz, 2H), 6.95–7.02 (m, 4H), 7.30(dt, J=9.2, 2.4 Hz, 1H), 7.26–7.32 (m, 2H) ppm. MS (DCl/NH3) m/z 329 (M+H)+, 331 (M+H)+. Anal Calculated for C19H21ClN2O.2.0HCl.0.5H2O: C, 55.56; H, 5.89; N, 6.82. Found: C, 55.78; H, 5.28; N, 6.62.
Reaction SMILES: [F:1][C:2]1[C:11]([OH:12])=[C:10]([F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH:21]([F:23])[F:22].Cl>CN(C)C=O.O.C(OCC)(=O)C>[F:1][C:2]1[C:11]([O:12][CH:21]([F:23])[F:22])=[C:10]([F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: FC(F)Cl
Reactant: COC(=O)c1ccc(F)c(O)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(F)c(OC(F)F)c1F

Procedure:
In 20 ml of N,N-dimethylformamide was dissolved 1.00 g of methyl 2,4-difluoro-3-hydroxy-benzoate, followed by adding thereto 0.88 g of potassium carbonate and then 12 ml of a 6 M solution of chlorodifluoromethane in N,N-dimethylformamide, and the resulting mixture was stirred in a sealed tube at 120-130° C. for 2.5 hours. The reaction mixture was added to a mixed solvent of 100 ml of ethyl acetate and 200 ml of water and the pH was adjusted to 2 with 6N hydrochloric acid, after which the organic layer was separated. The organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a column chromatography (eluent; n-hexane:ethyl acetate=4:1) to obtain 1.02 g of methyl 2,4-difluoro-3-difluoromethoxybenzoate as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].O>N1C=CC=CC=1>[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([O:1][CH2:2][C@@H:3]([NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:30]
Reactant: COc1cc2ncnc(N[C@H](CO)c3ccccc3)c2cc1OC
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2ncnc(N[C@H](COC(=O)c3cccc(Br)c3)c3ccccc3)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
To a solution of (S)-4-[α-(hydroxymethyl)benzylamino]-6,7-dimethoxyquinazoline (49 mg, 0.15 mmol) in pyridine (2 ml) was added dropwise at 0-5° C. 3-bromobenzoylchloride (33 mg, 0.15 mmol). After 6 h stirring at room temperature the reaction mixture was poured into iced water and extracted with dichloromethane. The organic layer was dried and evaporated to dryness. The residue was purified by flash chromatography on silica gel using as eluant dichloromethane/methanol 95:5 to give pure title compound as a white solid in 71% yield (54 mg).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH:21]1([CH2:26][C:27]([OH:29])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]1.[O:30]1CCCC1>CCCCCC.C1(C)C=CC=CC=1>[OH:30][CH:22]1[CH2:23][CH2:24][CH2:25][CH:21]1[CH2:26][C:27]([OH:29])=[O:28]
Reactant: O=C(O)CC1CCCC1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C(O)CC1CCCC1O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
In an atmosphere of argon, to a solution of LDA (lithium diisopropylamide) prepared with a solution of diisopropylamine (60 ml) in anhydrous tetrahydrofuran (500 ml) and a 1.45M solution of butyl lithium in n-hexane (297 ml), a solution of cyclopentylacetic acid (25 g) in anhydrous toluene (100 ml) was dropped. The solution was stirred for 30 min. at room temperature and for 1 hr at 45° C. With blowing of air dried through phosphorus pentaoxide, the solution was stirred for 16 hrs. After reaction, the supernatant separated by decantation was diluted with water. The diluted solution was washed with diethyl ether, adjusted pH 2 with 6N hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then concentrated under reduced pressure. The residue was purified by recrystallization to give the title compound (17.1 g) having the following physical data: