Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1.[CH:21]1([Mg]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrCCCCCCCCCCCCOC1CCCCO1
Reactant: Br[Mg]C1CCCCC1
Product: C(CCCCCCC1CCCCC1)CCCCCOC1CCCCO1

Procedure:
57.8 g (165 millimole) of 2-[(12-bromododecyl}oxy]tetrahydro-2H-pyran and 39.6 g (247 millimole) of cyclohexyl magnesium bromide were reacted by following a procedure similar to that of Working Example 16, to give crude 2-[(12-cyclohexyldodecyl)oxy]tetrahydro-2H-pyran. This crude product was dissolved in 450 ml of methanol, to which 4.5 g of Amberlist® H-15 was added, and the resulting mixture was stirred at 45° C. for 2 hours. The resin was filtrated off, and the filtrate was concentrated to dryness under reduced pressure. The residue wa subjected to column chromatography on silica gel (1 kg), and eluted with hexane-ethyl acetate (6:1), to give the above-captioned compound as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]N)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:19]1(=[O:35])[N:23]([CH2:24][CH2:25][CH2:26][C:27](=O)[CH3:28])[C:22](=[O:30])[C:21]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:20]12.Cl.CCCCCC>C(O)C>[CH3:28][C:27]1[NH:15][C:12]2[C:13]([C:26]=1[CH2:25][CH2:24][N:23]1[C:22](=[O:30])[C:21]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:20]3[C:19]1=[O:35])=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]1[CH:17]=[CH:18][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:10][CH:11]=2
Reactant: CC(=O)CCCN1C(=O)c2ccccc2C1=O
Reactant: NNc1ccc(NC(=O)c2ccc(F)cc2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Product: Cc1[nH]c2ccc(NC(=O)c3ccc(F)cc3)cc2c1CCN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 6 h
Yield: 6.6 %

Procedure:
To a solution of 5.33 gm (21.7 mMol) 4-(4-fluorobenzoyl)aminophenylhydrazine and 5.03 gm (21.8 mMol) 5-phthalimidyl-2-pentanone in 100 mL ethanol were added 2 mL concentrated hydrochloric acid and the reaction mixture was heated at 80° C. for 14 hours. To the reaction mixture were then added an additional 3 mL concentrated hydrochloric acid and heating continued for an additional 6 hours. The reaction mixture was then cooled to 0° C. and 100 mL hexane were slowly added. The solid which formed was filtered and washed with hexane and provided, after drying, 6.67 gm of the desired compound. The mother liquor was concentrated under reduced pressure and then subjected to silica gel chromatography, eluting with 1:1 hexane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide an additional 0.63 gm of product. Overall yield was 7.3 gm (76%).
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[Cl:15][C:16]1[CH:27]=[C:26]([F:28])[C:25]([N:29]=[C:30]=[O:31])=[CH:24][C:17]=1[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]>CCCCCC.CN(C)C=O>[Cl:15][C:16]1[CH:27]=[C:26]([F:28])[C:25]([NH:29][C:30]([NH:1][C:2]([C:9]([F:10])([F:11])[F:12])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:31])=[CH:24][C:17]=1[C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F)C(F)(F)F
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.55 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 50 ml of n-hexane is added dropwise while stirring at 0°-3° C. during 15 minutes to 0.85 g of a 55% sodium hydride dispersion in 50 ml of dimethylformamide and the mixture is stirred for 30 minutes. A solution of 5.0 g of isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate in 100 ml of n-hexane is subsequently added dropwise during 5 minutes while stirring and cooling at -15° C. The temperature of the reaction mixture rises to 10° C. and the mixture is thereafter stirred at room temperature for one hour. The intermediate isopropyl 2-chloro-4-fluoro-5-[3-(2-ethoxycarbonyl -1-trifluoromethyl-vinyl)ureido]-benzoate which thereby separates is not isolated.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[C:26]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:26]([C:30]1[CH:31]=[CH:32][C:33]([NH:34][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([O:15][C:12]3[CH:13]=[CH:14][C:9]4[N:10]([CH:25]=[C:7]([NH:6][C:4]([CH:1]5[CH2:3][CH2:2]5)=[O:5])[N:8]=4)[N:11]=3)[CH:17]=2)=[CH:35][CH:36]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(NC(=O)c2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)cc1
Yield: 49.7 %

Procedure:
Using 3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoic acid (100 mg, 0.30 mmol), 4-tert-butylaniline (57 mg, 0.36 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (68 mg, 0.36 mmol), 4-(dimethylamino)pyridine (43 mg, 0.36 mmol) and pyridine (5.0 mL) as starting materials and in the same manner as in Example 318, the title compound (70 mg, 50%) was obtained as a white powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([CH:8]=O)=[CH:6][CH:7]=1.[F:10][C:11]([F:25])([F:24])[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][C:22]#[N:23])(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[CH3:1][S:2][C:3]1[S:4][C:5](/[CH:8]=[C:21](/[S:18]([C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:25])([F:10])[F:24])=[CH:17][CH:16]=2)(=[O:20])=[O:19])\[C:22]#[N:23])=[CH:6][CH:7]=1
Reactant: N#CCS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CSc1ccc(C=O)s1
Product: CSc1ccc(/C=C(\C#N)S(=O)(=O)c2ccc(C(F)(F)F)cc2)s1

Procedure:
Reaction of 2-methylmercaptothiophen-5-carboxaldehyde and 4-trifluoromethylphenylsulfonylacetonitrile as in Example 1 gave (E)-3-(2-methylmercaptothien-5-yl)-2-[4-(trifluoromethyl)phenylsulfonyl]acrylonitrile
Reaction SMILES: C(N)C=C.[CH3:5][O:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[C:15]1[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH:20]=1.C([Li])CCC.[C:27]1(=[O:32])[O:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[CH3:5][O:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[C:15]1([C:30](=[O:31])[CH2:29][CH2:28][CH2:27][OH:32])[CH:16]=[CH:17][N:18]([CH3:21])[CH2:19][CH2:20]1
Reactant: COc1cccc(C2=CCN(C)CC2)c1OC
Reactant: O=C1CCCO1
Agent: [Li]CCCC
Solvent: C=CCN
Solvent: C1CCOC1
Product: COc1cccc(C2(C(=O)CCCO)C=CN(C)CC2)c1OC
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
A solution of 9.32 g (0.04 mol) of the allylamine, Compound IV, in 75 mL of dry tetrahydrofuran was cooled to -10° and treated with 40 mL of 1.65 M solution (0.066 mol) of n-butyl lithium. The resulting red solution was stirred at -10° for 15 min and transferred under nitrogen to a solution of 18.4 g (0.21 mol) of γ-butyrolactone in 40 mL of dry tetrahydrofuran at -76° over a period of 5 min. After the addition was complete the reaction mixture was stirred at -70° for 15 min and then quenched with 100 mL of 20% sodium hydroxide solution and stirred at room temperature for 1 hour. At the end of this period the reaction mixture was diluted with 200 mL of dichloromethane and the organic layer was separated. The aqueous layer was extracted with an additional 200 mL portion of dichloromethane. The organic layers were washed with brine, dried (K2CO3) and concentrated under reduced pressure to afford 12.6 g of product (98.8% yield) which contained Compound V and was used for the next step without further purification. A sample prepared in another experiment was purified by HPLC to afford a pure sample of Compound V; NMR (90 MHz, CDCl3): 2.63 (s, 3), 3.45 (br., 3), 3.73 (s, 3), 3.88 (s, 3), 4.3 (d, j=8 Hz, 1), 6.15 (d, J=8 Hz, 1), 6.7-7.2 (br., 3); IR (film): 3440, 2940, 1700, 1630 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[F:19][C:20]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:21]=1[CH2:22]P(=O)(OC)OC.C1OCCOCCOCCOCCOC1.[H-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]1[CH:18]=[CH:17][C:14](/[CH:15]=[CH:22]/[C:21]2[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:20]=2[F:19])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: COP(=O)(Cc1ccc(F)cc1F)OC
Reactant: O=Cc1ccc(S(=O)(=O)c2ccccc2Br)cc1
Agent: C1COCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)cc1)c1ccccc1Br
Temperature: 0 °C
Yield: 61.9 %

Procedure:
4-[(2-bromophenyl)sulfonyl]benzaldehyde (Step 4, 3.4 g, 10 46 mmol), dimethyl (2,4-difluorobenzyl)phosphonate (2.36 g, 11.51 mmol) and 15-crown-5 (0.23 mL, 1.15 mmol) were dissolved in tetrahydrofuran (21 mL) under nitrogen and cooled to 0° C. Sodium hydride (276 mg) was added and the reaction allowed to warm slowly to room temperature. Saturated sodium carbonate solution and ethyl acetate were added. The organic layer was washed with brine, dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 35% ethyl acetate/isohexane, to give 1-((E)-2-{4-[(2-bromophenyl)sulfonyl]phenyl}vinyl)-2,4-difluorobenzene as a white solid (3.1 g, 69%). δH (400 MHz, d6 DMSO): 8.33 (1H, dd, J=1.7, 7.9 Hz), 7.89-7.81 (6H, m), 7.72 (1H, td, J=1.2, 7.6 Hz), 7.62 (1H, td, J=1.8, 7.6 Hz), 7.45-7.35 (2H, m), 7.33-7.29 (1H, m), 7.16 (1H, td, J=2.5, 8.3 Hz).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([N:9]3[CH2:13][CH2:12][C@@H:11]([N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25](=[O:28])[NH:24][CH:23]=1.CN[C@@H]1CCCC[C@H]1NC>N1C=CC=CC=1.CCOCC.[Cu].[Cu]I>[N:14]1([C@@H:11]2[CH2:12][CH2:13][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([N:24]5[C:25](=[O:28])[CH:26]=[CH:27][N:22]=[CH:23]5)[CH:21]=[CH:20][C:5]=4[N:6]=3)[CH2:10]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=c1ccnc[nH]1
Reactant: Brc1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Agent: [Cu]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=c1ccncn1-c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1

Procedure:
A solution of (R)-6-bromo-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole (Example 14, 80 mg, 0.218 mmol), pyrimidin-4(3H)-one (31.5 mg, 0.328 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (31.1 mg, 0.218 mmol), copper (27.8 mg, 0.437 mmol) and copper(I) iodide (8.32 mg, 0.044 mmol) in pyridine (3 ml) was heated in a microwave reactor to 200° C. for 30 minutes. The mixture was diluted with ether (20 mL) and washed with water, a small amount of aqueous NH4OH and brine. The organic layer was separated and dried with MgSO4 and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel column eluting with 3% (9:1 methanol:concentrated NH4OH) in dichloromethane to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.43-1.52 (m, 2H), 1.58-1.69 (m, 4H), 1.94-2.11 (m, 1H), 2.25-2.37 (m, 1H), 2.39-2.58 (m, 4H), 2.96-3.09 (m, 1H), 3.40-3.63 (m, 2H), 3.72-3.92 (m, 2H), 6.56 (d, J=6.74 Hz, 1H), 7.22 (dd, J=8.72, 2.38 Hz, 1H), 7.62 (d, J=2.38 Hz, 1H), 7.65 (d, J=8.33 Hz, 1H), 7.94 (d, J=6.74 Hz, 1H), 8.20 (s, 1H); MS (DCI/NH3) m/z 382 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.C([O:16][C:17]1[N:22]=[CH:21][C:20]([C:23](=[S:25])[NH2:24])=[CH:19][CH:18]=1)(C)(C)C>>[CH3:11][C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:3]1[N:24]=[C:23]([C:20]2[CH:19]=[CH:18][C:17](=[O:16])[NH:22][CH:21]=2)[S:25][CH:2]=1
Reactant: CC(C)(C)Oc1ccc(C(N)=S)cn1
Reactant: Cc1ccncc1C(=O)CBr
Product: Cc1ccncc1-c1csc(-c2ccc(=O)[nH]c2)n1
Yield: 56.1 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-methylpyridin-3-yl)ethanone hydrobromate (188 mg) and 6-tert-butoxy-3-pyridinecarbothioamide (167 mg), the title compound (120 mg) was obtained as colorless powder crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](OCC)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=CC1CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of ethyl 1-benzylpiperidine-4-carboxylate (9.2 g, 0.037 mol) in 400 ml of toluene was added 1.5M diisobutylaluminum hydride in toluene (28 ml, 0. 042 mol) at -78° C. The mixture was stirred at -78° C. for 1 hr and quenched with 150 ml of MeOH and the dry ice bath was removed. After stirring for 2 hr at r.t., the mixture was filtered through diatomaceous earth (Celite (trademark)) and washed with methanol. The filtrate was concentrated to dryness to give 6.91 g (92%) of 1-benzylpiperidine-4-carboxaldehyde which can be used directly or purified by vacuum distillation, bp 93°-97° C./1 mmHg. HNMR (CDCl3)δ 1.6-1.8 (m, 2H), 1.8-1.9 (m, 2H), 2.05-2.17 (m, 2H), 2.17-2.3 (m, 1H), 2.75-2.9 (m, 2H), 3.5 (s, 2H), 7.2-7.4 (m, 5H), 9.6 (s, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:12]([O:14][C:15]1[C:16](=O)[C:17](=[O:22])[C:18]=1[O:19]CC)[CH3:13]>C(O)C>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][C:16]2[C:17](=[O:22])[C:18](=[O:19])[C:15]=2[O:14][CH2:12][CH3:13])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2cccc3cccnc23)c(=O)c1=O
Yield: 70.4 %

Procedure:
To a solution of 8-aminoquinoline (1.00 g, 6.94 mmol) in ethanol (20 mL) was added 3,4-diethoxy-3-cyclobutene-1,2-dione (1.03 mL, 6.94 mmol) and the resulting mixture was heated to reflux for 24 hours. The mixture was cooled, diluted with ethanol, and filtered. The crude product was triturated with chloroform/hexanes, then purified by chromatography (EtOAc/hexane) to give 1.31 g (70%) of product: 1H NMR (DMSO-d6) δ9.75 (br m, 1H), 8.86 (dd, 1H), 8.26 (br m, 1H), 8.20 (dd, 1H), 7.57 (m, 2H), 7.53 (dd, 1H), 4.95 (q, 2H), 1.59 (t, 3H).
Reaction SMILES: [N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=O.Cl.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][NH:26][CH3:27])[CH3:22].ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([N:26]([CH3:27])[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:28])=[O:5]
Reactant: O=C(O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CN(C)C(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Reaction time: 12 h
Yield: 80.1 %

Procedure:
To a stirring solution of Cbz-D-hPro-OH (6.0 g, 22.8 mmol), sarcosine ethyl ester hydrochloride (4.38 g, 28.5 mmol), 1-hydroxybenzotriazole (3.08 g, 22.8 mmol), and N,N-diisopropylethylamine (11.9 mL, 68.4 mmol) in dichloromethane (200 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.46 g, 28.5 mmol). After stirring for 12 hours, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed twice with 1N citric acid (200 mL), twice with saturated aqueous NaHCO3, and twice with a saturated aqueous sodium chloride solution. The organic phase was then dried with MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with a step gradient of hexanes through 50% ethyl acetate/hexanes. Fractions containing product (based on TLC) were combined and concentrated to give 6.62 g (80%) of a colorless oil.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1([CH3:29])[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:8][CH:9]=2)[O:4]1.[H][H]>C(O)C.[Pd]>[ClH:1].[CH3:2][C:3]1([CH3:29])[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:23][CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])=[CH:8][CH:9]=2)[O:4]1
Reactant: [H][H]
Reactant: CN(C)CCOc1ccc2c(c1)OC(C)(C)C=C2c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2c1cccc(C(F)(F)F)c1
Yield: 74.2 %

Procedure:
To a solution of 2,2-dimethyl-7-dimethylaminoethyloxy-4-(3-trifluoromethylphenyl)-2H-chromene hydrochloride (4.96 g) in ethanol (75 ml) was added 10% palladium on charcoal. The mixture was hydrogenated under hydrogen (1 atmosphere pressure) at ambient temperature (about 18° C.) until no further hydrogen was taken up. The mixture was filtered and the solvent removed from the resulting filtrate under reduced pressure to yield the title compound (3.7 g), m.p,. 188°-190° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][N:5]1C(OC(C)(C)C)=O.[Cl:18][C:19]1[CH:20]=[C:21](O)[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:24]=1[Cl:25])[O:9][C@@H:7]1[CH2:6][NH:5][C@H:4]([C:3]([O:2][CH3:1])=[O:17])[CH2:8]1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: Oc1ccc(Cl)c(Cl)c1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc(Cl)c(Cl)c2)CN1

Procedure:
The compound was prepared by analogy with Example 217(ii) from N-Boc-cis-4-hydroxy-L-proline methylester and 3,4-dichlorophenol.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:10]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])=[C:9]([F:17])[CH:8]=[C:7]([Cl:18])[C:5]=2[N:6]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[Cl-].[NH4+].[Cl-].[Na+]>O1CCCC1>[N:19]1([C:2]2[S:3][C:4]3[C:10]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])=[C:9]([F:17])[CH:8]=[C:7]([Cl:18])[C:5]=3[N:6]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNCC1
Reactant: CCOC(=O)Nc1c(F)cc(Cl)c2nc(Cl)sc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1c(F)cc(Cl)c2nc(N3CCCCC3)sc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
Under a nitrogen atmosphere a solution of 3.0 grams (9.7 mmole) of ethyl N-(2,4-dichloro-6-fluorobenzothiazol-7-yl)carbamate in 75 mL of tetrahydrofuran was stirred, and 1.7 grams (20 mmole) of piperidine was added. Upon completion of the addition the reaction mixture was stirred for 1.5 hours at ambient temperature. The reaction mixture was then poured into a mixture of 75 mL of aqueous 10% ammonium chloride and 75 mL of an aqueous saturated sodium chloride solution. The resulting mixture was extracted with three 75 mL portions of ethyl acetate. The combined extracts were washed with two 50 mL portions of an aqueous saturated sodium chloride solution. The organic layer was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, yielding a brown solid, which was purified by column chromatography on silica gel. Elution was accomplished with 2:1 heptane:ethyl acetate. The product-containing fractions were combined and concentrated, yielding 2.6 grams of ethyl N-[2-(1-piperidinyl)-4-chloro-6-fluorobenzothiazol-7-yl]carbamate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CC(O)=O.O>CCO>[N:26]1([CH2:32][CH2:33][NH:34][C:3]([C:5]2[N:6]=[C:7]([C:24]#[N:25])[C:8]3[C:9](=[O:23])[N:10]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:11]=[CH:12][C:13]=3[C:14]=2[OH:15])=[O:4])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: N#Cc1nc(C(=O)NCCN2CCOCC2)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Yield: 55.4 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.075 mmol) and 2-morpholin-4-yl-ethylamine (0.034 mL, 0.26 mmol) in EtOH (2 mL) was refluxed for 16 h. After the mixture was cooled to r.t., AcOH (0.1 mL) and water (5 mL) were added. The resulting mixture was extracted with EtOAc, and the organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (0-10% MeOH/CH2Cl2) to give 18 mg of the title compound. MS: (+) m/z 434.34 (M+1).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[CH2:8][CH:7]([C:9]2[NH:14][C:13]3=[CH:15][CH:16]=[N:17][C:12]3=[CH:11][N:10]=2)[CH2:6][CH:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:4]1.[Br:24]Br>CC(O)=O.O>[ClH:1].[Br:24][C:15]1[CH:16]=[N:17][C:12]2[C:13]=1[NH:14][C:9]([CH:7]1[CH2:6][CH:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:4][CH:3]([CH3:2])[CH2:8]1)=[N:10][CH:11]=2
Reactant: BrBr
Reactant: CC1CC(c2ncc3nccc-3[nH]2)CC(c2ccccc2)N1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC1CC(c2ncc3ncc(Br)c-3[nH]2)CC(c2ccccc2)N1
Temperature: 45 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To an oven-dried, 50-mL, round-bottomed flask was added 2-methyl-6-phenyl-4-(piperidinyl)pyrrolo[3,2-d]pyrimidine (Example 35)) (500 mg, 1.71 mmol) which was dissolved in glacial AcOH (15 mL). To this solution was added Br2 (Aldrich Chemical Company) (90.0 mL, 1.8 mmol) dropwise over 2 min. The resulting dark mixture was diluted with H2O (10 mL) and the mixture was warmed to 45° C. and stirred for 2 h. The reaction was allowed to cool to room temperature and the crude material was extracted with EtOAc (50 mL) and washed with saturated NaHCO3 (3×50 mL). The organic layer was washed with brine (50 mL), dried over MgSO4, filtered and evaporated in vacuo to give an oily residue. The residue was purified by silica gel chromatography with 50% EtOAc/hexanes as eluant to give 500 mg (79.4% yield) of a yellow solid. Mp: 239-240 ° C. 1H NMR (DMSO-d6; 400 MHz): d 1.74 (s, 6), 2.63 (s, 3), 3.83 (s, 4), 7.44 (t, 1, J=2.4), 7.5 (t, 2, J=7.0), 7.80 (d, 2, J=7.1). MS m/z: 373.0 (M+1); 369.0, 371.0 (M−1).