Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.C(=O)(O)[O-].[Na+].[O:13]=[C:14]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[NH:17][CH2:16][C@H:15]1[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CN(C)C=O>[O:13]=[C:14]1[NH:20][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:17]([CH:18]2[CH2:24][CH2:23][CH2:22][CH:21]=[CH:19]2)[CH2:16][C@H:15]1[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNc2ccccc2NC1=O
Reactant: BrC1C=CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C2C=CCCC2)c2ccccc2NC1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
3-Bromocyclohexene (7.06 g) and sodium bicarbonate (3.68 g) were added to a solution of (R)-(+)-2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (6.08 g) in anhydrous N,N-dimethylformamide (50 ml), and the mixture was stirred at 50° C. for one hour. The reaction mixture was allowed to cool, ice-water was added, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure,the residue was purified by silica gel column chromatography(ethyl acetate:n-hexane=1:3), to thereby obtain 7.84 g of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[CH2:17](Br)[CH:18]=[CH2:19]>>[CH2:19]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=2)[CH2:13][CH2:12]1)[CH:18]=[CH2:17]
Reactant: Cc1ccc(N2CCNCC2)cc1[N+](=O)[O-]
Reactant: C=CCBr
Product: C=CCN1CCN(c2ccc(C)c([N+](=O)[O-])c2)CC1

Procedure:
Beginning with 1-(4-methyl-3-nitro-phenyl)-piperazine and allylbromide, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 261 (M+, 60), 96 (70), 69 (bp), 68 (48), 56 (73).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[Cl-].[Cl-].[Al+3].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][C:23]([N:25]2[CH2:30][C@H:29]([CH3:31])[N:28]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:27][C@H:26]2[CH3:40])=[O:24])=[C:14]([C:16](=[O:20])[CH2:17][C:18]#[N:19])[CH:15]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.CS(C)=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][C:23]([N:25]2[CH2:30][C@H:29]([CH3:31])[N:28]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[CH2:27][C@H:26]2[CH3:40])=[O:24])=[C:14]([C:16](=[O:20])[CH2:17][C:18]2[NH:19][N:3]=[N:2][N:1]=2)[CH:15]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)CC#N
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)Cc1nnn[nH]1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a mixture of sodium azide (0.061 g, 0.95 mmol) and aluminum trichloride (0.042 g, 0.31 mmol) was added 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-3-oxo-propionitrile (0.035 g, 0.076 mmol) in tetrahydrofuran (2 mL). The reaction was warmed to 70° C. and stirred for 18 hours. To this was added saturated aqueous sodium bicarbonate (0.5 mL) and dimethylsulfoxide (0.5 mL) and the solution was stirred for 1 hour at ambient temperature. The solids were removed by filtration and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase HPLC to give the title compound which was converted to its hydrochloride salt (0.020 g, LRMS: 501.2).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[N:5][CH:4]=1)=[O:2].ON1C2N=CC=CC=2N=N1.[NH2:23][C@@H:24]([CH3:45])[C:25]([NH:27][C@@H:28]([CH3:44])[C:29]([NH:31][C@@H:32]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)[C:33]([NH2:35])=[O:34])=[O:30])=[O:26].CN1CCOCC1.C(Cl)CCl>CN(C=O)C.CO>[NH2:35][C:33](=[O:34])[C@@H:32]([NH:31][C:29](=[O:30])[C@@H:28]([NH:27][C:25](=[O:26])[C@@H:24]([NH:23][C:10](=[O:12])[CH2:9][NH:8][C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1)[CH3:45])[CH3:44])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1
Reactant: O=Cc1cnc(NCC(=O)O)s1
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CO
Product: C[C@H](NC(=O)CNc1ncc(C=O)s1)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 51.8 %

Procedure:
To a mixture of material from Example 3 (62 mg, 0.207 mmol), 1-hydroxy-7-azabenzotriazole (7.2 mg, 0.126 mmol), and (S)-2-amino-N-((S)-1-((S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-ylamino)-1-oxopropan-2-yl)propanamide (53.8 mg, 0.167 mmol) in anhydrous DMF (2.0 mL) is added sequentially N-methylmorpholine (125 μL, 1.137 mmol) and EDC (51.8 mg, 0.270 mmol). The resulting solution is stirred at room temperature for 6 h, diluted with MeOH (8 mL) and purified by preparative HPLC (Condition A) using a PHENOMENEX® Luna Axia 30×100 mm S10 column from 10% Solvent B to 80% Solvent B over 11 min, ret. T=4.19-5.20 min. The fractions containing the desired product were evaporated to dryness to give 42.4 mg (34%) of the title compound as a yellow solid as a TFA salt. LC/MS (Condition A): ret. T=1.81 min, (M+H)+ 491.15.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:10]2[C:11]([CH:14]([CH3:16])[CH3:15])=[N:12][CH:13]=[C:9]2[CH:8]=[C:7]([Cl:17])[N:6]=1>>[Cl:17][C:7]1[N:6]=[C:5]([O:2][CH3:1])[N:10]2[C:11]([CH:14]([CH3:16])[CH3:15])=[N:12][CH:13]=[C:9]2[CH:8]=1
Reactant: C[O-]
Reactant: CC(C)c1ncc2cc(Cl)nc(Cl)n12
Agent: [Na+]
Product: COc1nc(Cl)cc2cnc(C(C)C)n12

Procedure:
Using the method of Example 48, sodium methoxide was reacted with 5,7-dichloro-3-isopropylimidazo[1,5-c]pyrimidine (from Example 37) to provide 7-chloro-3-isopropyl-5-methoxyimidazo[1,5-c]pyrimidine. This free base was a white solid which was converted into its white solid dihydrogen sulfate salt, m.p. 155° C. (dec.). Analysis: Calculated for C10H12ClN3O.H2SO4 : %C, 37.1; %H, 4.4; %N, 13.0; Found; %C, 36.7; %H, 4.2; %N, 12.9.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:16][CH:3]([CH3:4])[CH2:2][C:1]([O:6][CH2:7][CH3:8])=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: C/C=C/C(=O)OCC
Product: CCOC(=O)CC(C)NCc1ccccc1
Yield: 68.9 %

Procedure:
A solution of ethyl crotonate (5.0 ml, 40 mmol) and benzyl amine (4.8 ml, 44 mmol) was heated to 100° C. for 18 hs. The reaction was allowed to cool and the product was distilled at 90° C. at 200 mtorr pressure to give the ethyl 3-(benzylamino)butanoate (6.1 g, 69%) as a clear oil, MS (M+H)+=222.
Reaction SMILES: C1C=CC=CC=1.[C:7]1([CH:13]2[NH:17][C:16]([CH3:19])([CH3:18])[CH2:15][O:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(N(CC)CC)C>[C:7]1([CH:13]2[N:17]([C:22](=[O:23])[CH2:21][Cl:20])[C:16]([CH3:19])([CH3:18])[CH2:15][O:14]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)CCl
Reactant: CC1(C)COC(c2ccccc2)N1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC1(C)COC(c2ccccc2)N1C(=O)CCl
Reaction time: 0.5 h

Procedure:
Twenty-one and three tenths ml. of a benzene solution containing 5.3 g. of 2-phenyl-4,4-dimethyl oxazolidine was mixed with 50 ml. of benzene and 3.4 g. of chloroacetyl chloride. To this solution was added 3.1 g. of triethylamine, dropwise with stirring in an ice bath. The mixture was stirred for about 30 minutes after addition was complete and then washed with water, separated and dried over magnesium sulfate and the solvent stripped. There was obtained a yield of 6.5 g. of an oil, the title compound, ND30 = 1.5364.
Reaction SMILES: Br.Br[CH:3]([C:5]1[O:6][C:7](=[O:27])[C:8]2[C:13]([C:14]=1[C:15]1[S:16][C:17]([CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:18][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:4].C(OC([N:35](C(OC(C)(C)C)=O)[C:36]1[N:44]=[CH:43][N:42]=[C:41]2[C:37]=1[NH:38][CH:39]=[N:40]2)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:35][C:36]1[N:44]=[CH:43][N:42]=[C:41]2[C:37]=1[N:38]=[CH:39][N:40]2[CH:3]([C:5]1[O:6][C:7](=[O:27])[C:8]2[C:13]([C:14]=1[C:15]1[S:16][C:17]([CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:18][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:4]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncnc2nc[nH]c12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCOCC2)s1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(c1oc(=O)c2ccccc2c1-c1ccc(CN2CCOCC2)s1)n1cnc2c(N)ncnc21
Yield: 45.3 %

Procedure:
3-(1-Bromoethyl)-4-(5-(morpholinomethyl)thiophen-2-yl)-1H-isochromen-1-one hydrobromide (intermediate C16, 52 mg, 0.113 mmol), N6,N6-bis(tert-Butoxycarbonyl)-adenine (74.1 mg, 0.221 mmol), K2CO3 (30.5 mg, 0.221 mmol) were reacted in DMF (0.5 ml) at 80° C. The crude was purified via reverse phase chromatography with a Biotage C18 30 g SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) and recovered material was then treated with HCl 37% before evaporation to give a crude that was further purified via reverse phase chromatography with a Biotage C18 12 g SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give the title compound (25 mg, 69%).
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]2[NH:8][C:9](=[C:11]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=3)[C:12]([NH2:14])=[O:13])[S:10][C:6]=2[CH:5]=1)(O)=[O:2].C(N(CC)CC)C.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.[N:54]1([CH2:60][CH2:61][CH2:62][NH2:63])[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.[ClH:64]>C(#N)C.O1CCOCC1>[ClH:64].[N:54]1([CH2:60][CH2:61][CH2:62][NH:63][C:1]([C:4]2[CH:26]=[CH:25][C:7]3[NH:8][C:9](=[C:11]([C:15]4[N:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][N:16]=4)[C:12]([NH2:14])=[O:13])[S:10][C:6]=3[CH:5]=2)=[O:2])[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1
Reactant: NC(=O)C(=C1Nc2ccc(C(=O)O)cc2S1)c1nccc(C(F)(F)F)n1
Reactant: NCCCN1CCOCC1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: NC(=O)C(=C1Nc2ccc(C(=O)NCCCN3CCOCC3)cc2S1)c1nccc(C(F)(F)F)n1
Temperature: 25 °C
Yield: 73 %

Procedure:
To a room temperature solution of 2-[6-carboxybenzothiazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetamide (350 mg, 0.92 mmol) in acetonitrile (5 mL) was added triethylamine (250 μL, 1.79 mmol, 2 eq.), DEPBT (299 mg, 1.0 mmol, 1.1 eq.), and 3-(4-morpholinyl)-propan-1-amine (134 μL, 0.92 mmol, 1.0 eq.), and the mixture was stirred at room temperature until a yellow-brown precipitate formed. The precipitate was collected by filtration, washed with acetonitrile, and dried under vacuum to give a yellow solid. About 2 mL of 4.0 M hydrogen chloride in dioxane was added, and the mixture was stirred for 15 min and then concentrated under reduced pressure to give 2-(6-{[3-(morpholin-4-yl)propyl]aminocarbonyl}-benzothiazol-2(3H)-ylidene)-2-(4-trifluoromethyl-pyrimidin-2-yl)acetamide hydrochloride (340 mg, 73% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[NH:17][C:16]2=[O:29])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[H-].[Na+].S(OC)(O[CH3:36])(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:27])([F:28])[C:23]([F:25])([F:26])[F:24])[N:17]=[C:16]2[O:29][CH3:36])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9.51 g of isopropyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-4-pentafluoroethyl -1(2H)-pyrimidinyl ]-4-fluorobenzoate are added at room temperature while stirring to a suspension of 0.93 g of a 55% sodium hydride dispersion in 25 ml of dimethylformamide and the mixture is stirred at room temperature for 30 minutes. The mixture is subsequently treated with 4.04 g of dimethyl sulphate and stirred at 50° C. for 4 hours. The reaction mixture is cooled and poured into 500 ml of water, and the aqueous solution is extracted twice with 100 ml of ethyl acetate each time. The organic phase is washed twice with 100 ml of water each time, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is separated by chromotography on a silica el column using n-hexane/diethyl ether (2:1) as the eluent. The product is recrystallized from n-hexane. There is obtained isopropyl 2-chloro-4-fluoro-5-[2-methoxy-6-oxo-4-pentafluoroethyl -1(6H)-pyrimidinyl]-benzoate, m.p. 82°-84° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[N:13][N:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([O:40][CH:41]([CH3:43])[CH3:42])[C:26]([F:39])=[C:27]([CH:38]=1)/[CH:28]=[N:29]/[C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1)[CH3:21]>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([N:29]([CH2:28][C:27]2[CH:38]=[C:23]([O:22][CH2:20][CH3:21])[CH:24]=[C:25]([O:40][CH:41]([CH3:43])[CH3:42])[C:26]=2[F:39])[C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)=[N:13][N:12]=[N:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCn2cnnn2)cc1
Reactant: CCOc1cc(/C=N/c2ccc(C#N)cc2)c(F)c(OC(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(CN(c2ccc(C#N)cc2)c2nnnn2COCc2ccccc2)c(F)c(OC(C)C)c1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 24.3 %

Procedure:
To a solution of Intermediate 12.1 (50.0 mg, 0.263 mmol) in 2 mL THF at −78° C. was added 1.6 M solution of BuLi in THF (181 μL, 0.289 mmol). The mixture was stirred at −78° C. for 2 min, then a solution of Intermediate 7.3 (86 mg, 0.263 mmol) in 0.6 mL THF was added dropwise. The mixture was stirred at −78° C. for 30 min, was allowed to warm to rt over 1 h, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (25 to 30% EtOAc/hexanes, stepwise gradient) to afford 33 mg of Intermediate 12.2 as yellow residue.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>>[OH:8][C:9]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2ccccn2)cc1O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1ccc(-c2ccccn2)cc1O
Yield: 74.4 %

Procedure:
A trifluoroacetic acid (5 mL) solution of the obtained tert-butyl 2-(2-hydroxy-4-(pyridin-2-yl)benzamido)-4-phenylbenzoate (0.11 g) was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the obtained residue. After adjusting the pH to 6.0 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected by filtration. Water (4 mL), methanol (4 mL), and dioxane (4 mL) were added to the obtained solid substance, and carbon dioxide gas was introduced thereinto at room temperature. The solvent was evaporated under reduced pressure, and water was added to the obtained residue. The solid substance was collected by filtration to obtain 0.072 g of 2-(2-hydroxy-4-(pyridin-2-yl)benzamido)-4-phenylbenzoic acid as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:15][C:16]([OH:20])([C:18]#[CH:19])[CH3:17].C(OCC)(=O)C>COCCOC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][C:16]([OH:20])([C:18]#[C:19][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:17]
Reactant: Brc1cccnc1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1cccnc1
Temperature: 0 °C
Yield: 40 %

Procedure:
3-Bromopyridine (3.0 mL, 31 mmol), triethylamine (22 mL, 160 mmol), CuI (1.2 g, 6.2 mmol), and PdCl2(PPh3)2 (1.1 g, 1.5 mmol) were combined in DME (92 mL) and cooled to 0° C. 2-Methyl-3-butyne-2-ol (9.0 mL, 93 mmol) was then added and the reaction was allowed to slowly warm to ambient temperature. The mixture was then heated to 55-60° C. for 16 h. The mixture was filtered through Celite.™., and the pad was washed thoroughly with ethyl acetate. The combined filtrates were washed with brine (3.times.100 mL), dried over MgSO4, and filtered. The solution was concentrated in vacuo, and the residue was purified by column chromatography eluting with 90:10 hexane:ethyl acetate then ethyl acetate to afford 2-methyl-4-(3-pyridinyl-)-3-butyn-2-ol (2.0 g, 40% yield) as a brown oil 1H NMR (CDCl3, 300 MHz) Δ8.76 (br s, 1H), 8.52 (br s, 1H), 7.74-7.70 (m, 1H), 4.08 (br s, 1H), 1.63 (s, 3H). MS (EI ionization) 161 (M+).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[CH:7][C:5]=2[N:6]=1.[F:24][C:25]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28].[F-].[K+]>CN(C=O)C.O>[C:27]([C:26]1[CH:30]=[CH:31][C:32]([C:2]2[O:3][C:4]3[CH:10]=[CH:9][C:8]([CH:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)=[CH:7][C:5]=3[N:6]=2)=[CH:33][C:25]=1[F:24])(=[O:28])[NH2:29]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3oc(Br)nc3c2)CC1
Reactant: CC1(C)OB(c2ccc(C(N)=O)c(F)c2)OC1(C)C
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3oc(-c4ccc(C(N)=O)c(F)c4)nc3c2)CC1
Temperature: 90 °C
Yield: 6.8 %

Procedure:
Intermediate 52 (40 mg, 0.1 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (30 mg, 0.12 mmol) and KF (18 mg, 0.3 mmol) were dissolved in a mixture of DMF (1 ml) and water (0.4 ml). This mixture was purged with N2 for 30 mins. Pd(dppf)Cl2.CH2Cl2 was added to the above mixture and again purged with N2 for 30 mins. This reaction mixture was heated to 90° C. for 12 h. Work up (EtOAc and H2O) followed by purification on combiflash using a gradient mixture of EtOAc and Petether (55:45) as eluent afforded the titled compound (3 mg) as an Off-White solid. MS (m/z): 439.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:5]=1[Br:12].[Al+3].[Cl-].[Cl-].[Cl-].CCS>ClCCl>[Br:12][C:5]1[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:13]
Reactant: COC(=O)c1cc(OC)ccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: COC(=O)c1cc(O)ccc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cold solution (ice water bath) of the methyl-2-bromo-5-methoxybenzoate (2.00 g, 8.16 mmol) in dichloromethane (15 mL) was added AlCl3(5.44 g, 40.8 mmol) under argon, and the reaction temperature was maintained below 10° C. using an ice-water bath. The light brown suspension was stirred for 10 min, then EtSH (3.02 mL, 40.8 mmol) was added dropwise at such a rate that the reaction temperature was maintained below 5° C. After 2.5 h of stirring below 10° C., the reaction mixture was slowly poured into ice water with agitation. The organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to afford a light yellow oil which was used in the next step without further purification.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][N:4]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1>>[N:6]1[CH:7]=[CH:8][C:3]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccncn1
Agent: Cl
Product: CCOC(=O)C1CCN(c2ccncn2)CC1
Yield: 46 %

Procedure:
Using an analogous procedure to that described in Example 32, 4-chloropyrimidine hydrochloride was reacted with ethyl piperidine-4-carboxylate to give ethyl 1-(4-pyrimidinyl)piperidine-4-carboxylate in 46% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:24][C:25]([CH3:29])([CH3:28])[CH2:26][NH2:27]>>[OH:24][C:25]([CH3:29])([CH3:28])[CH2:26][NH:27][C:20]([C:17]1[NH:18][N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:23])[CH:16]=1)=[O:22]
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)[nH]n1
Reactant: CC(C)(O)CN
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NCC(C)(C)O)[nH]n1
Yield: 26 %

Procedure:
As described for example 132, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2H-pyrazole-3-carboxylic acid was converted, using 2-hydroxy-2-methyl-propylamine instead of morpholine, to the title compound (9.1 mg, 26%) which was obtained as a brown solid. MS: m/e=385.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]=CN(C)C)[C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[C:17]([CH2:19][C:20]([NH2:22])=[O:21])#[N:18].C[O-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:19]([C:17]#[N:18])[C:20](=[O:21])[NH:22][C:9]=2[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)C(C=CN(C)C)c1ccc(F)cc1
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(F)cc1
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A mixture of 1-(4-fluorophenyl)-2-(dimethylamino)ethenyl-2-propanone (59.6 grams), cyanoacetamide (26.7 grams) and sodium methoxide (34.3 grams) in 830 ml of dimethylformamide is heated under reflux for two hours and then the reaction mixture is concentrated on a rotary evaporator. The residual solid is suspended in water (2 liters) and is stirred overnight. The aqueous mixture is acidified with 12 N HCl, diluted with water to a volume of 4 liters, and stirred for two hours. The solid product is collected, washed with water (500 ml) and then with ethanol to give 55.4 grams of 1,2-dihydro-5-(4-fluorophenyl)-6-methyl-2-oxo-3-pyridinecarbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][NH:7][CH2:8][CH3:9])=[CH:4][CH:3]=1.[CH2:12]([O:14][C@H:15]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:16][C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]([OH:25])=O)=[CH:19][CH:18]=1)[CH3:13].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][CH3:9])[C:23](=[O:25])[CH2:22][O:21][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][C@H:15]([O:14][CH2:12][CH3:13])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:27][CH:26]=2)=[CH:10][CH:11]=1
Reactant: CCNCc1ccc(Cl)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccc(Cl)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of N-(4-chlorobenzyl)-N-ethylamine (0.150 g, 0.88 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.270 g, 0.91 mmol) in methylene chloride (10 mL) were added N,N-diisopropylethylamine (0.34 mL, 1.9 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.320 g, 1.00 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (40 mL) and the organic phase was washed with 5% HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 50 g/150 mL) with methylene chloride/ethyl acetate 10:1 as the eluent yielded 0.24 g (61%) of a colourless oil.