Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][N:22]=1.COC1C=C([N+]([O-])=O)C=C[N+]=1[O-].C(Cl)(Cl)Cl>CO.C1COCC1.O.[Ni].CCOC(C)=O>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([NH:27][C:2]2[C:3]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=4)[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:24]=[CH:23][N:22]=1
Reactant: COc1cc(N)ccn1
Reactant: OCc1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Agent: [Ni]
Agent: COc1cc([N+](=O)[O-])cc[n+]1[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(Nc2ncnc3[nH]c(-c4ccc(CO)cc4)cc23)ccn1
Temperature: 70 °C

Procedure:
To 4.16 g (16 mMol) of [4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-methanol (see Step 108.3) and 1.99 g (16 mMol) of 2-methoxy-pyridin-4-ylamine [see Rec. Trav. Chim. (1955) 74, 1160; prepared from 2-methoxy-4-nitro-pyridine-1-oxide by hydrogenation in the presence of Raney-Nickel in methanol/THF] in 90 ml degassed DMF under N2-atmosphere, 996 mg of R(+)-BINAP [R(+)-2,2′-bis-(diphenylphosphino)-1,1′-binaphthalin); 1.6 mMol], 414 mg Pd2(dba)3.CHCl3 [tris(dibenzylideneacetone)dipalladium (0) chloroform complex; 0.40 mMol] and 3.08 g (32 mMol) of sodium-tert-butylate are subsequently added. The red solution is stirred at 70° C. over night and then poured into a mixture of 0.5 l of EtOAc and 1 l buffer (7.8 g of NaH2PO4.2H2O, 5 g of Na2HPO4.2H2O in 1 l H2O). After stirring for 1 h, the title compound is filtered off and washed with water and EtOAc; HPLC (conditions see Examples 67-78) tR=8.2 min; MS-ES+=348.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][S:16]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NS(C)(=O)=O)CC1
Reaction time: 2 h

Procedure:
tert-Butyl 4-aminopiperidine-1-carboxylate (0.10 g, 0.50 mol) was combined with methanesulfonyl chloride (0.043 mL, 0.56 mol) and triethylamine (0.21 mL, 1.5 mmol) in methylene chloride (2 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give tert-butyl 4-[(methylsulfonyl)amino]piperidine-1-carboxylate, LCMS [M+Na]+: m/z=301.0. The later was treated with 4.57 M hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) at room temperature for 1 hour. The mixture was concentrated to give the desired HCl salt, which was used directly in the next step. LCMS calculated for C6H15N2O2S (M+H)+: m/z=179.1; Found: 179.1.
Reaction SMILES: [CH3:1]C(C)C(=O)C(P(=O)([O-])[O-])=[N+]=[N-].[CH:13]([CH2:15][CH2:16][C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:20]=2[CH:21]=1)=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH2:16]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:20]=2[CH:21]=1)[CH2:15][C:13]#[CH:1]
Reactant: COC(=O)c1ccc2oc(CCC=O)cc2c1
Reactant: CC(C)C(=O)C(=[N+]=[N-])P(=O)([O-])[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CCCc1cc2cc(C(=O)OC)ccc2o1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
See Callant, P. D. H. L.; Vandewalle, M. An efficient preparation and the intramoleucalur cyclopropanation of a-diazo-b-ketophosphonates and a-diazophoshonoacetates. Snyth. Commun. 1984, 14, 155-161. A solution of dimethyl-1-diazo-2-oxopropylphosphonate (8.9 g, 46.4 mmol) in dry methanol (50 mL) was added to a stirring mixture of 97 (8.5 g, 36.6 mmol) and K2CO3 (10.2 g, 74 mmol) in 500 mL of dry methanol. The mixture was stirred at room temperature until complete conversion was attained according to HPLC (2 hours) and concentrated. The residue was diluted with diethyl ether (500 mL), washed with water (2×100 mL) and dried over CaCl2. The solvent was removed following by recrystallization (EtOAc/hexanes, 9/1) to give white crystals (7.66 g, 92%): mp 57-58° C. 1H NMR (DMSO-d6) δ8.23 (d, J=1.6 Hz, 1H), 7.88 (dd, J=8.8, 1.6 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 6.82 (s, 1H), 3.86 (s, 3H), 3.00 (t, J=7.1 Hz, 2H), 2.84 (t, J=2.8 Hz, 1H), 2.63 (td, J=7.1, 2.8 Hz, 2H). HPLC (method B) tR 6.73 min (100.00 area %). Anal. (C14H12O3.0.2H2O) C, H.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]C)=[O:14])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[OH-].[Na+]>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cn(Cc2ccccc2)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cn(Cc2ccccc2)nn1

Procedure:
Methyl 1-benzyl-1H-[1,2,3]triazol-4-carboxylate (217 mg) was dissolved in 4 ml of methanol and hydrolyzed with 2 ml of 2N sodium hydroxide solution. After acidification with 4 ml of 2N hydrochloric acid, the resulting precipitate was filtered off, taken up in 5 ml of ethyl acetate and purified by preparative HPLC. This resulted in the product with the molecular weight of 203.2 (C10H9N3O2); MS (ESI): 204 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[C:10]2[N:20]([CH2:23][CH3:24])[N:21]=[CH:22][C:9]1=2)=[O:7].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:23]([N:20]1[C:10]2[C:11](=[O:19])[NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[C:9]=2[CH:22]=[N:21]1)[CH3:24]
Reactant: CN1CCNCC1
Reactant: CCn1ncc2c1C(=O)Nc1ccccc1N2C(=O)CCCCCl
Product: CCn1ncc2c1C(=O)Nc1ccccc1N2C(=O)CCCCN1CCN(C)CC1

Procedure:
4-(5-chlorovaleryl)-1-ethyl-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, respectively, with a corresponding amount of N-methylpiperazine.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](C1C=CC([C:20]2[C:28]([CH2:29][C@H:30]3[C@@H:35]([OH:36])[C:34]4[CH:37]=[C:38]([O:41][CH2:42][C:43]5[S:44][C:45]6[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:46]=6[N:47]=5)[CH:39]=[CH:40][C:33]=4[O:32][CH2:31]3)=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([O-])=[O:23])=CC=1)([O-])=O.[H-].[Na+]>>[F:52][C:49]1[CH:50]=[CH:51][C:45]2[S:44][C:43]([CH2:42][O:41][C:38]3[CH:39]=[CH:40][C:33]4[O:32][CH2:31][C@@H:30]([CH2:29][C:28]5[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=5)[C:22]([NH:10][S:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:9])=[O:8])=[O:23])[C@@H:35]([OH:36])[C:34]=4[CH:37]=3)=[N:47][C:46]=2[CH:48]=1
Reactant: O=C([O-])c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1-c1ccc([N+](=O)[O-])cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=C(NS(=O)(=O)c1ccccc1)c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1

Procedure:
Synthesis was carried out as in example 1, but using 4.4 grams benzene sulfonamide instead of methane sulfonamide, and using 2.4 grams optically pure (-) cis-4-nitrophenyl-3-[[6-[(5-fluoro-2-benzothiazolyl)methoxy]-3,4-dihydro-4-hydroxy-2H-1-benzopyran-3-yl]methyl]benzoate and 628 milligrams sodium hydride. There was obtained 1.02 grams of product, m.p. 161°-162° C. αD =-30° ; c =0.005 in tetrahydrofuran.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[C:15]([CH:21]=[O:22])=[C:16]([O:19]C)[CH:17]=[CH:18][C:12]=3[N:11]=2)=[CH:6][CH:5]=1.B(Br)(Br)Br>ClCCl>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:14][C:13]3[C:15]([CH:21]=[O:22])=[C:16]([OH:19])[CH:17]=[CH:18][C:12]=3[N:11]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2nc3ccc(OC)c(C=O)c3[nH]2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc3ccc(O)c(C=O)c3[nH]2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.1 %

Procedure:
To a solution of 4-(7-Formyl-6-methoxy-1H-benzoimidazol-2-yl)-benzoic acid methyl ester (650 mg, 2.1 mmol) in abs. dichloromethane (30 mL) at −78° C., boron tribromide (1.20 mL, 3.20 g, 12.60 mmol) was added dropwise and the mixture was stirred for 1 h, then overnight at room temperature. The yellow suspension was cooled to −78° C. and quenched with methanol (30 mL) followed by evaporation. The residue was partitioned between saturated sodium bicarbonate (30 mL) and chloroform (30 mL). The organic phase was dried (Na2SO4) and evaporated. The title compound (360 mg, 1.22 mmol, 58%) was isolated as a light green solid.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[O:12]1CCBN1.CSC.B>C([C@]1(N)C=CC=CC1[C@H](O)C)(C)(C)C.C1COCC1>[CH2:1]1[CH:11]([OH:12])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1
Reactant: B1CCON1
Reactant: O=C1CCCc2ccccc21
Agent: B
Agent: C[C@@H](O)C1C=CC=C[C@@]1(N)C(C)(C)C
Solvent: C1CCOC1
Solvent: CSC
Product: OC1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(1R, 2S)-2-tert-butyl-2-aminophenylethanol (1.0 g, 5.2 mmol), toluene (16 mL), and trimethylboroxine (0.50 mL) were combined at ambient temperature and stirred for 16 hr. Water, toluene and excess boroxine were distilled off until about 8 mL volume remained. The reaction was chased with toluene (3×10 mL), and the remainder of toluene removed under vacuum to afford to oxazaborolidine as a pale yellow oil (1.10 g, 98%). To a solution of α-tetralone (2.92 g, 19.7 mmol), THF (80 mL), and the oxazaborolidine derived from (1R, 2S)-2-tert-butyl-2-aminophenylethanol (228 mg, 1.2 mmol) under a nitrogen atmosphere was added borane methylsulfide complex (2M in THF, 7.0 mL, 14 mmol) over 75 min. After the addition was complete, the contents were stirred for an additional 15 min, cooled to 0° C., and quenched with methanol (27 mL). After stirring the quenched reaction for 18 hrs the solvents were removed under vacuum, the residual oil was dissolved in methylene chloride (50 mL), washed with pH 4 phosphate buffer (50 mL), water (50 mL), treated with magnesium sulfate, and the solvent was removed under vacuum to give the (R) tetralol as a colorless oil 3.1 g (90% ee).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:24]1[N:29]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](=[O:37])[C:27]2=[CH:38][CH:39]=[C:40]([Cl:41])[N:26]2[N:25]=1)[CH2:22][CH3:23])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(C)(C)C.Cl>O1CCOCC1>[ClH:41].[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:24]1[N:29]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](=[O:37])[C:27]2=[CH:38][CH:39]=[C:40]([Cl:41])[N:26]2[N:25]=1)[CH2:22][CH3:23])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1
Reactant: CCC(c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1)N(CCCN)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 182.3 %

Procedure:
A mixture of {3-[[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester (0.42 g, 0.71 mmol) and 4 N HCl in dioxane (4.5 mL, 18 mmol) in dioxane (5 mL) stirred at rt for 6.5 h. After concentration the mixture was diluted with water, washed with Et2O (50 mL) and lyophilized to obtain the title compound (0.342 g, 91%): 13C NMR (DMSO-d6) δ 153.0, 128.6, 128.3, 126.9, 125.8, 125.5, 117.6, 115.3, 110.0, 108.3, 53.8, 44.2, 41.2, 36.2, 28.3, 23.4, 20.6, 10.1; MS (ESI+) 492.16, 493.22 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][CH3:8])=[O:6].C(O)(=O)C.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C.[O-2].[Mn+4].[O-2]>[CH:15]([N:14]1[C:12](=[O:13])[C:11]2[C:2](=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=2)[N:1]=[C:22]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:17])[CH3:16]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)NC(C)C)c(N)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1ccc2c(=O)n(C(C)C)c(-c3ccccc3)nc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-amino-4-[(isopropylamino)carbonyl]benzoate (15 mg, 0.07 mmol) in ethanol (1.5 mL) was added acetic acid (32 μL, 0.56 mmol) and benzaldehyde (19.4 μL, 0.19 mmol). The reaction mixture was heated to 110° C. and stirred overnight. The mixture was then concentrated to dryness and taken up in chloroform (1 mL). To this solution was added manganese (IV) oxide (28 mg, 0.32 mmol) and the reaction mixture was heated to 110° C. and stirred for 2 d. The reaction mixture was then filtered through Celite, rinsed with chloroform and concentrated to dryness to afford methyl 3-isopropyl-4-oxo-2-phenyl-3,4-dihydroquinazoline-7-carboxylate. LC-MS: (FA) ES+ 323.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])=[C:11]([F:20])[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:16]([C:12]1[C:11]([F:20])=[CH:10][C:9]([O:8][CH2:7][C:6]([OH:21])=[O:5])=[CH:14][C:13]=1[F:15])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)COc1cc(F)c(C(C)(C)C)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1c(F)cc(OCC(=O)O)cc1F
Yield: 77.3 %

Procedure:
To a suspension of sodium hydride (75 mg, 1.9 mmol) in THF (5 ml) was added 4-tert-butyl-3,5-difluorophenol (290 mg, 1.6 mmol) at 0° C., followed by stirring for 30 minutes. Then, tert-butyl bromoacetate (370 mg, 1.9 mmol) was added and the mixture was refluxed at 90° C. for 1 hour. The reaction was quenched with saturated ammonium chloride aqueous solution and the product was extracted with EtOAc, washed with brine, dried over magnesium sulfate. Then, filtration, evaporation, and purification through silica gel column chromatography eluting with hexane/EtOAc (20:1 to 4:1) gave the tert-butyl(4-tert-butyl-3,5-difluorophenoxy)acetate (403 mg, 86%). The DCM (2.0 ml) solution of tert-butyl(4-tert-butyl-3,5-difluorophenoxy)acetate (400 mg, 1.34 mmol) and TFA (2.0 ml), was stirred for 1 hour at room temperature. Evaporation gave the residue which was triturated with Hexane to furnish the title compound as a white solid (253 mg, 77%). 1H NMR (300 MHz, CDCl3): δ 1.42 (9H, t, J=2.2 Hz), 4.63 (2H, s), 6.39 (2H, d, J=12.1 Hz). MS (ESI) m/z 243 (M−H)−.
Reaction SMILES: [CH2:1]([C:4]1([C:17](Cl)=[O:18])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:2]=[CH2:3].Cl.[F:21][C:22]([F:26])([F:25])[CH2:23][NH2:24]>>[F:21][C:22]([F:26])([F:25])[CH2:23][NH:24][C:17]([C:4]1([CH2:1][CH:2]=[CH2:3])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:18]
Reactant: NCC(F)(F)F
Reactant: C=CCC1(C(=O)Cl)c2ccccc2-c2ccccc21
Agent: Cl
Product: C=CCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-allyl-9H-fluorene-9-carboxylic acid chloride and 2,2,2-trifluoroethylamine-hydrochloride.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][C:11](=O)[CH3:12]>>[Br:1][C:2]1[N:7]2[CH:10]=[C:11]([CH3:12])[N:8]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)n1
Reactant: CC(=O)CCl
Product: Cc1cn2c(Br)cccc2n1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
A mixture of 6-bromopyridin-2-ylamine (1.0 g, 5 6 mmol) and 1-chloropropan-2-one (0.5 mL, 6.3 mmol) in IMS (4 mL) was stirred at reflux for 36 hours, then cooled to room temperature and loaded onto an Isolute® SCX-2 cartridge (20 g). The cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. After the solvents were removed, the residue was purified by flash chromatography (Si—PPC, MeOH:Et2O, gradient 0:100 to 10:100) to give 5-Bromo-2-methylimidazo[1,2-a]pyridine as a yellow oil (547 mg, 45%). LCMS (Method H): RT=0.31 min and 2.04 min, [M+H]+ 211(79Br) and 213(81Br)
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=[O:3].[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:15]1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=3)=[O:3])[CH2:23][CH2:22]2)[CH2:15]1
Reactant: CN1CCCC(CN2CCNCC2)C1
Reactant: O=C(Cl)Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCCC(CN2CCN(C(=O)Oc3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 18 h
Yield: 60.6 %

Procedure:
3,4-Dichlorophenyl chloroformate (282 mg) in dichloromethane (10 ml) was added to a solution of 1-[(1-methylpiperidin-3-yl)methyl]piperazine (246 mg) in dichloromethane (2 ml) at room temperature. N,N-Diisopropylethylamine (0.44 ml) was added and the mixture stirred for 18 hours. Saturated aqueous sodium bicarbonate solution (5 ml) was added and the dichloromethane layer separated then concentrated in vacuo onto silica gel (0.5 g). The resulting powder was subjected to chromatography on silica gel (20 g) using a gradient of 100% dichloromethane through to 20% methanolic ammonia in dichloromethane to give the title compound (292 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1COc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a solution of 2-chloro-4-nitrophenol (3.5 g) and 2-(bromomethyl)benzonitrile (4.0 g) in N,N-dimethylformamide (50 mL) was added potassium carbonate (3.7 g), and the mixture was stirred at room temperature for 30 min. After the completion of the reaction, water (50 mL) was added, and the mixture was stirred for 10 min. The resultant pale-yellow solid was collected by filtration. The residue was washed with diisopropyl ether, and dried to give the title compound (5.04 g) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][N:23]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:30][C:31]1[C:32](F)=[N:33][CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1>>[Cl:30][C:31]1[C:32]([N:20]2[CH2:19][CH2:18][O:17][C:16]3[CH:21]=[C:12]([S:9]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=4)[C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]2=3)=[N:33][CH:34]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:36]=1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
4-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide was synthesized from N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide and 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine (Aldrich) in a manner similar to that described for EXAMPLE 94, Step 3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:36])[NH:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]([C:25]([O:27]C)=[O:26])[CH2:16][CH:15]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:13])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>O.CO>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:36])[NH:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:17]([C:25]([OH:27])=[O:26])[CH2:16][CH:15]2[C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C)c2)C1c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)O)C2c2ccccc2)c1
Yield: 45 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 1.6 g of 2-tert-butyl 4-methyl (2RS,4RS,5SR)-1-{2-[3-(3-methylphenyl)ureido]acetyl}-5-phenylpyrrolidine-2,4-dicarboxylate and 0.18 g of potassium hydroxide in 20 cm3 of distilled water and 60 cm3 of methanol. After treatment, there is obtained 0.7 g of 2-tert-butyl hydrogen (2RS,4SR,5SR)-1-{2-[3-(3-methylphenyl)ureido]acetyl}-5-phenylpyrrolidine-2,4-dicarboxylate, melting at 160° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[O:27]1[CH2:32][CH2:31][CH:30]([CH2:33]O)[CH2:29][CH2:28]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9](=[O:10])[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:33][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Reactant: OCC1CCOCC1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OCC2CCOCC2)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and tetrahydro-2H-pyran-4-ylmethanol in analogy to Example 9c): MS (ISP): 494.2 and 496.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2(O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:25](N(CC)CC)[CH3:26].S(Cl)(Cl)=O.C([Mg]Br)C>C1COCC1.C(Cl)Cl>[CH2:25]([C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[NH:8][C:7](=[O:12])[N:6]1[CH2:13][C:14]([F:17])([F:16])[F:15])[CH3:26]
Reactant: O=C1Nc2ccc(F)cc2C(O)(c2ccccc2)N1CC(F)(F)F
Reactant: CCN(CC)CC
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCC1(c2ccccc2)c2cc(F)ccc2NC(=O)N1CC(F)(F)F
Reaction time: 0.42 h

Procedure:
To a −15° C. solution of 6-fluoro-4-hydroxy-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (3.00 g, 8.82 mmol) in THF (40 mL) was added triethylamine (6.14 mL, 44.08 mmol). The reaction was stirred for a couple of minutes and then thionyl chloride (0.68 mL, 9.26 mmol) was added dropwise. After 25 min, 1M ethylmagnesium bromide in THF (27.33 mL, 27.33 mmol) was added over 10 min. After an additional 30 min at −15° C., the reaction was quenched with saturated ammonium chloride solution (60 mL) and extracted with CH2Cl2 (120 mL×2). The combined organics were washed with brine (60 mL), dried over dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (0-70% EtOAc/hexanes) followed by chiral reverse phase chromatography (ChiralPak AD packing, 10-60% iPrOH/hexanes with DEA modifier) yielded a yellow residue that was taken up in a minimal amount of CH2Cl2, diluted with hexanes, and then concentrated in vacuo to give (−)-4-ethyl-6-fluoro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. 1H NMR (CDCl3, 400 MHz) 8.26 (s, NH); 7.38 (m, 5H, ArH); 6.85 (m, 1H, ArH); 6.70 (m, 1H, ArH); 6.25 (m, 1H, ArH); 3.92 (m, 1H, CH2); 3.48 (m, 1H, CH2); 2.35 (m, 2H, CH2); 0.91 (t, J=6.87 Hz, 3H, CH3); MS (Electrospray): m/z 353.1292 (M+H); [α]D=−41.8° (c0.11, MeOH). For the (+)-enantiomer, [α]D=+41.1° (c0.12, MeOH).