Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClCCl.[Br:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Cl[C:17]([CH3:25])([CH2:19][CH2:20][C:21](Cl)([CH3:23])[CH3:22])[CH3:18]>O>[Br:8][C:9]1[CH:10]=[C:11]([OH:15])[C:12]2[C:17]([CH3:25])([CH3:18])[CH2:19][CH2:20][C:21]([CH3:23])([CH3:22])[C:13]=2[CH:14]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Oc1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(C)(C)c2c(O)cc(Br)cc21
Temperature: 25 °C

Procedure:
13.40 g (100.0 mmol) of aluminium chloride and 100 ml of dichloromethane are introduced into a three-necked flask under an argon atmosphere. A solution composed of 34.60 g (199.0 mmol) of 3-bromophenol, 89.00 g (486.0 mmol) of 2,5-dichloro-2,5-dimethylhexane and 300 ml of dichloromethane is added dropwise. The reaction mixture is stirred for sixteen hours at room temperature. The reaction mixture is poured into water and extracted with dichloromethane, the extract is washed with water and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture composed of 80% heptane and 20% dichloromethane. After evaporating the solvents, 30.00 g (53%) of the expected compound are collected in the form of white crystals with a melting point of 93° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:18](=[O:19])[CH2:17][CH2:16][C:15]3=[O:20])=[CH:10][C:9]=2[F:21])=[C:5]([O:24][CH3:25])[CH:4]=1)[CH3:2].CO.[BH4-].[Na+]>C(#N)C>[CH2:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][OH:19])=[CH:10][C:9]=2[F:21])=[C:5]([O:24][CH3:25])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2ccc(N3C(=O)CCC3=O)cc2F)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CCc1ccc(Oc2ccc(NC(=O)CCCO)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]pyrrolidine-2,5-dione (169.8 mg, 0.49 mmol) was added methanol (2 mL). The reaction mixture was stirred for 1 h 30 at room temperature under argon. Acetonitrile (2 mL) and NaBH4 (190.7 mg, 4.9 mmol) were added to the reaction. The reaction mixture was stirred at 50° C. for 17 h. Then it was concentrated, dissolved in dichloromethane, washed with a saturated solution of NH4Cl and extracted with dichloromethane. Combined organic phases were dried over Na2SO4, concentrated in vacuo, to give the title product as a white solid used without further purification (169.5 mg; 100%).
Reaction SMILES: CC1C(C)=C(C)[SiH](C)[SiH-](C)(C)C=1.[Na+].[CH3:14][C:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].[CH2:24]([CH:26]1[CH:52]=[C:51]([CH3:53])[CH2:50][CH:49]([CH3:54])[CH2:48][CH:47]([O:55][CH3:56])[CH:46]2[O:57][C:42]([OH:61])([CH:43]([CH3:60])[CH2:44][CH:45]2[O:58][CH3:59])[C:41](=[O:62])[C:40](=[O:63])[N:39]2[CH:34]([CH2:35][CH2:36][CH2:37][CH2:38]2)[C:33](=[O:64])[O:32][CH:31]([C:65]([CH3:76])=[CH:66][CH:67]2[CH2:72][CH2:71][C:70](=[O:73])[CH:69]([O:74][CH3:75])[CH2:68]2)[CH:30]([CH3:77])[CH:29]([O:78][Si:79]([C:82]([CH3:85])([CH3:84])[CH3:83])([CH3:81])[CH3:80])[CH2:28][C:27]1=[O:86])[CH3:25]>O1CCCC1>[CH2:24]([CH:26]1[CH:52]=[C:51]([CH3:53])[CH2:50][CH:49]([CH3:54])[CH2:48][CH:47]([O:55][CH3:56])[CH:46]2[O:57][C:42]([OH:61])([CH:43]([CH3:60])[CH2:44][CH:45]2[O:58][CH3:59])[C:41](=[O:62])[C:40](=[O:63])[N:39]2[CH:34]([CH2:35][CH2:36][CH2:37][CH2:38]2)[C:33](=[O:64])[O:32][CH:31]([C:65]([CH3:76])=[CH:66][CH:67]2[CH2:72][CH2:71][C:70]([OH:73])([CH2:14][C:15](=[O:16])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:69]([O:74][CH3:75])[CH2:68]2)[CH:30]([CH3:77])[CH:29]([O:78][Si:79]([C:82]([CH3:83])([CH3:84])[CH3:85])([CH3:81])[CH3:80])[CH2:28][C:27]1=[O:86])[CH3:25]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reactant: CC(=O)Cc1ccccc1
Agent: CC1=C[SiH-](C)(C)[SiH](C)C(C)=C1C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)(CC(=O)Cc4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 45.5 %

Procedure:
A solution of 20 mL of a 1.0M solution of sodium hexamethyldisilamide in tetrahydrofuran was cooled to -78° C. in an ice bath under nitrogen. Then a solution of 3.0 g (20 mmole) of benzyl methyl ketone in 10 mL of dry THF was cooled to -78° C. and added dropwise by canula to the first solution. After 5 min., a pre-cooled (-78° C.) solution of 4.5 g (5 mmole) of 17-ethyl-1-hydroxy-12-[2'-(4"-oxo-3"-methoxycyclohexyl)-1'-methylvinyl]-14-t-butyldimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (Example 9) in 10 mL of dry tetrahydrofuran was added dropwise over 5 minutes and the solution was stirred at -78° C. under nitrogen. After 1 h, the reaction was quenched by addition of 2 mL of glacial acetic acid in 10 mL of dry tetrahydrofuran. Ether was added and the mixture was partitioned between ether and water and the aqueous layer was washed with ether. The two ether extracts were sequentially washed with saturated KHCO3 solution and brine, then the combined extract was dried over MgSO4, filtered and concentrated. The oily residue was purified by HPLC (silica gel, Waters RCM) using 1:3:6 acetonitrile: methyl-tert-butylether:hexanes to afford 2.36 g (46%) of the title compound as a colorless foam; NMR (CDCl3) shows distinct AB pattern at 2.6 ppm; MS (FAB) 1044 (M+Li).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH2:23])=[N:19][C:18]=3[C:17]([O:24][CH3:25])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.C(N(CC)CC)C.[N:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:45]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[O:46])=[N:19][C:18]=3[C:17]([O:24][CH3:25])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)N1CCOCC1
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(N)nc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)N3CCOCC3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a suspension of 0.15 g (0.42 mMol) 4-(2-amino-4-methoxy-benzothiazol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 5 ml dioxane 44 mg (1.0 mMol) NaH (dispersion in mineral oil 60%) were added and stirred for 1 h at room temperature. Then 0.174 ml (1.24 mMol) triethyl amine and 0.114 ml (1.0 mMol) morpholine-4-carbonyl chloride were added and stirred for 16 h at room temperature. After addition of 10 ml water the mixture was extracted three times with 15 ml ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate) to yield 0.135 g (69%) 4-{4-methoxy-2-[(morpholine-4-carbonyl)-amino]-benzothiazol-7-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a colorless foam. ES-MS m/e (%): 475 ([M+H]+, 100).
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[C:11](=[O:20])[N:12]([CH2:14][C:15]([O:17]CC)=[O:16])[N:13]=[C:6]2[C:5]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[S:37]([OH:40])(=[O:39])=[O:38])=[O:30])=[CH:24][CH:23]=1)[CH2:2][CH3:3].Cl>O.[OH-].[Na+]>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[C:11](=[O:20])[N:12]([CH2:14][C:15]([OH:17])=[O:16])[N:13]=[C:6]2[C:5]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[S:37]([OH:40])(=[O:38])=[O:39])=[O:30])=[CH:24][CH:23]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(C)n2c(=O)n(CC(=O)OCC)nc2c1Cc1ccc(NC(=O)c2ccccc2S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCc1nc(C)n2c(=O)n(CC(=O)O)nc2c1Cc1ccc(NC(=O)c2ccccc2S(=O)(=O)O)cc1
Temperature: 60 °C
Yield: 84.2 %

Procedure:
2.5 g of 2- {[4 - {[7 -n-propyl-5-methyl- 3-oxo-2-(ethoxycarbonylmethyl)-2,3-dihydro-1,2,4-triazolo[4,3-c]-pyrimidin- 8-Yl]methyl}phenyl]aminocarbonyl}benzenesulphonic acid, prepared in Example 34, are dissolved in 30 ml of water containing 1 g of sodium hydroxide. The mixture is heated to 60° C. for 2 hours, cooled and acidified with hydrochloric acid to give 2 g of 2-{[4-{[7-n-propyl-5-methyl-3-oxo-2-(carboxymethyl)-2,3-dihydro-1,2,4-triazolo[4,3-c]pyrimidin-8-yl]methyl}phenyl]-aminocarbonyl}benzenesulphonic acid in the form of crystals of melting point 296°-300° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]3[C:15]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:17][C:9]2=3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:38]1[CH2:39][CH2:40][N:35]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:13](=[O:14])[CH:12]=[CH:11][C:10]4[C:15]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:17][C:9]3=4)=[CH:4][CH:3]=2)[CH2:36][CH2:37]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(Br)cc2)c1-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(N3CCOCC3)cc2)c1-c1ccccc1
Yield: 39.5 %

Procedure:
To a mixture of the compound of Example 57 (100 mg, 0.22 mmol), caesium carbonate (101 mg, 0.31 mmol), Pd(OAc)2 (5 mg, 0.022 mmol, 10 mol %) and 2,2′-bis(diphenylphosphino)-1-1′-binaphthyl (BINAP) (21 mg, 0.033 mmol, 15 mol %) in toluene (2 mL) and under nitrogen was added morpholine (0.024 mL, 0.27 mmol). The reaction mixture was heated to 100° for 18 h. Solvent was removed in vacuo and the crude product purified by chromatography on silica (0–20% THF in DCM) to give the title compound as a white solid (40 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>C(Cl)Cl.O1CCOCC1>[ClH:22].[NH:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)SCc1ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1ccc2c(c1)CSC21CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
150 mg (0.49 mmole) of 1′-t-butoxycarbonylspiro[benzo[c]thiophene-1(3H),4′-piperidine] [prepared as described in step (b) above] were dissolved in 3 ml of anhydrous methylene chloride, and 1 ml of a 4 N solution of hydrogen chloride in dioxane was added. The mixture was then stirred at room temperature for 1 hour. At the end of this time, the crystals which deposited were collected by filtration, to give 108 mg (yield 91%) of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[C:20]3([CH2:21][CH2:22][CH2:23][CH2:24]3)[CH2:19][NH:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CN(C(=O)OC(C)(C)C)CC34CCCC4)n2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(Nc2ncc(Cl)c(NC3CNCC34CCCC4)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a solution of tert-butyl 4-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (650 mg, 1.45 mmol) in DCM (20 mL) was added CF3COOH (5 mL) and the reaction mixture was stirred at rt for 2 hours. The reaction mixture was concentrated in vacuo and adjusted to pH=8-9 with a saturated Na2CO3 solution, then the mixture was diluted with H2O (20 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL), then dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1 to 5/1) to give the product as a white solid (490 mg, 97%).
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][C@@H:5]([C:18]([OH:20])=O)[CH2:4][CH2:3]1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH3:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([C:18]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:20])[CH2:6][N:7]1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: Nc1ccccc1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1C(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@@H]1CC[C@H](C(=O)Nc2ccccc2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of (3S,6R)-6-methyl-1-{[(phenylmethyl)oxy]carbonyl}-3-piperidinecarboxylic acid (17 g, 61.3 mmol) in DMF (400 mL) was added aniline (8.56 g, 92 mmol), Hunig's base (32.1 mL, 184 mmol), HOBt (14.08 g, 92 mmol) and EDC (17.63 g, 92 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature, then diluted with H2O (˜100 mL), and extracted with EtOAc (3×250 mL). The combined organic layers were washed with 1N HCl (100 mL), H2O (3×100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the crude title compound (21 g). LC-MS (ES) m/z=353 [M+H]+.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=[C:14]1[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:18]([C:17]3[S:13][C:14]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][CH:16]=3)=[O:19])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc(-c2cccs2)s1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(-c2cccs2)s1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 2,2′-bithiophene-5-carboxylic acid (Acros) according to methods A and C; yield 105 mg, 0.27 mmol (76%): 1H NMR (300 MHz, methanol-d4) δ 1.97 (d, J=14 Hz, 2H), 2.20 (s, 1H), 2.32 (d, J=14 Hz, 2H), 2.47 (s, 2H), 3.56 (s, 2H), 3.66 (s, 4H), 4.37 (s, 1H), 7.08 (dd, J=5, 4 Hz, 1H), 7.24 (d, J=4 Hz, 1H), 7.35 (dd, J=4, 1 Hz, 1H), 7.43 (dd, J=5, 1 Hz, 1H), 7.78 (d, J=4 Hz, 1H); MS (DCI/NH3) m/z 345 (M+H)+; Anal. C18H20N2OS2.HCl: C, H, N.
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.Br[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14]>C(N(CC)CC)C>[C:15]1([CH:13]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cccc2cccnc12
Reactant: CC(Br)c1ccccc1
Solvent: CCN(CC)CC
Product: CC(Nc1cccc2cccnc12)c1ccccc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A mixture of 1.44 g (10.0 mmol) of 8-aminoquinoline, 1.01 g (10.0 mmol) of triethylamine and 1.85 g (10.0 mmol) of 1-bromo-1-phenylethane (1) was stirred for 2 hr at 120° C. One more portion of 1.01 g of triethylamine as well as 1.85 g of 1-bromo-1-phenylethane was added. The resulting mixture was stirred for additional 2 hr at 120° C. One more portion of triethylamine and 1-bromo-1-phenylethane was added, and the reaction mixture was stirred for 2 hr at 120° C. Finally, the product was isolated using flash chromatography on silica gel 60 (40-63 um, eluent: hexanes-ethyl acetate=20:1, vol.) to give 2.26 g (91%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][OH:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[CH2:13]O.[ClH:15]>C1(C)C=CC=CC=1>[Cl:15][CH2:13][C:3]1[C:2]([F:1])=[C:7]([F:8])[C:6]([CH2:9][OH:10])=[C:5]([F:11])[C:4]=1[F:12]
Reactant: OCc1c(F)c(F)c(CO)c(F)c1F
Reactant: Cl
Solvent: Cc1ccccc1
Product: OCc1c(F)c(F)c(CCl)c(F)c1F
Temperature: 90 °C

Procedure:
2,3,5,6-Tetrafluoro-1,4-benzene dimethanol (1 g; 4.8 m.mol) was added to hydrochloric acid 36°Tw (10 ml; 115 m.mol) at 20° C., followed by toluene (10 ml). The mixture was then stirred and warmed to 90° C. and maintained at this temperature for 7 hours to complete the reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([O:17][CH2:18][CH3:19])=[CH:10][C:9]=2Br)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:67][N:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([O:17][CH2:18][CH3:19])=[CH:10][C:9]=2[N:71]1[CH2:72][CH2:73][N:68]([CH3:67])[CH2:69][CH2:70]1)=[O:5])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cc(=O)c2cc(OCC)cc(Br)c2o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(=O)c2cc(OCC)cc(N3CCN(C)CC3)c2o1
Temperature: 80 °C
Yield: 94.3 %

Procedure:
Into a 100 mL, 3 neck round bottom flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet is added 350 mg (1.03 mmol, 1.0 equiv.) of 8-Bromo-6-ethoxy-4oxo-4H-chromene-2-carboxylic acid ethyl ester (Reference Example 23b), 18.9 mg (0.02 mmol, 0.02 equiv.) of tris dibenzylidineacetone dipalladium, 77 mg (0.123 mmol, 0.12 equiv.) of racemic 2,2′-bis(diphenylphosphino)-1,1′-binapthyl and 1 g of 4 A molecular sieves and 60 mL of dry toluene. To the stirred suspension is then added 113 mg, 1255 μL, (1.13 mmol, 1.1 equiv.) of 1-methylpiperazine, followed by 470 mg (1.44 mmol, 1.4 equiv.) of cesium carbonate. The mixture is then heated to 80° C. for 3 days. At the end of this time completion was monitored by LC/MS analysis of an aliquot. When the reaction was determined to be complete it was cooled to room temperature then filtered through a plug of diatomaceous earth, with toluene washing to remove solid by products. Purification by flash chromatography, using a gradient of 5 to 40% methanol in methylene chloride as eluent, yielded 350 mg (75%) of the desired product as a yellow solid. Mass Spec.: calc. for [C19H24N2O5+H]+ Theor. m/z=361; Obs.=361
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29](O)=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH:43]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH3:44])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O=P(Cl)(Cl)Cl.C(O)CO.C(=O)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([C:29]([N:42]([CH2:41][CH2:40][O:39][Si:32]([C:35]([CH3:36])([CH3:38])[CH3:37])([CH3:34])[CH3:33])[CH:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH3:44])=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(NCCO[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: O=C=O
Solvent: OCCO
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(c1ccccc1)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
To a solution of 5-(benzyloxy)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylic acid (28-02) (170 mg, 387 μmol, Eq: 1.00) and 2-(tert-butyldimethylsilyloxy)-N-(1-phenylethyl)ethanamine (34) (108 mg, 387 μmol, Eq: 1.00) in pyridine (2.00 ml) was added POCl3 (178 mg, 108 μl, 1.16 mmol, Eq: 3.00) at −10° C. (ethylene glycol-dry-ice bath), then the reaction mixture was stirred at 0° C. for 2 hr. The reaction mixture was quenched with ice cooled-water (0.5 ml), concentrated, and chromatographed (silica gel, gradient 5 to 30% ethyl acetate-hexane) to obtain 5-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-(1-phenylethyl)pyrimidine-4-carboxamide (35) (220 mg, 314 μmol, 81.1% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[CH:8]([C:15]([C:17]([O:19]CC)=[O:18])=O)[CH2:7][CH2:6][CH2:5]2>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:5][CH2:6][CH2:7][C:8]3=[C:15]([C:17]([OH:19])=[O:18])[NH:12][C:10]([CH:11]=1)=[C:9]23
Reactant: CCOC(=O)C(=O)C1CCCc2cc(Cl)cc([N+](=O)[O-])c21
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1[nH]c2cc(Cl)cc3c2c1CCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a mixture of aqueous 20% TiCl3 (145 g, 0.188 mol), water (150 mL), and acetone (150 mL) was added dropwise a solution of 6-chloro-1-ethoxalyl-8-nitrotetralin (8.39 g, 0.027 mol) in acetone (150 mL) at 0° C. The mixture was stirred for 1 h at room temperature, diluted with water, and extracted with ethyl acetate (400 mL×2). The combined organic layers were washed successively with water and brine, dried over magnesium sulfate, and concentrated. The residue was dissolved in a mixture of THF (60 mL) and MeOH (60 mL) and 1N NaOH (60 mL) was added. The mixture was stirred for 2 h at room temperature, washed with diethyl ether (600 mL), acidified to pH 3 by using aqueous 5% KHSO4 and extracted with ethyl acetate (400 mL×2). The combined organic layers were washed successively with water and brine, dried over magnesium sulfate, and concentrated to give 2.07 g of the title compound: 1H NMR (CDCl3) δ8.57 (bs, 1H), 7.18 (s, 1H), 6.86 (s, 1H), 3.14 (t, 2H, J=6.1 Hz), 2.91 (t, 2H, J=6.1 Hz), 2.10 (m, 2H).
Reaction SMILES: C(O)(=O)C.[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1/[CH:10]=[C:11]1\[CH2:12][NH:13][CH2:14][CH2:15][CH:16]\1[OH:17].Br[CH:19]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21].C(N(CC)CC)C.O>CN(C)C=O>[CH:22]1([C:20](=[O:21])[CH:19]([N:13]2[CH2:14][CH2:15][CH:16]([OH:17])/[C:11](=[CH:10]/[C:6]3[O:5][CH:9]=[CH:8][CH:7]=3)/[CH2:12]2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH2:24][CH2:23]1
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Reactant: OC1CCNC/C1=C\c1ccco1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(C1CC1)C(c1ccccc1F)N1CCC(O)/C(=C/c2ccco2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a solution of (E)-3-[(furan-2-yl)methylidene]piperidin-4-ol hydrogen acetate (2.81 g) and 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone (2.71 g) in N,N-dimethylformamide (60 ml) was added triethylamine (1.22 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:7 to 1:1) as the eluent to afford the title compound (2.30 g, yield: 74%) as a pale yellow amorphous solid.