Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:49][C:50]1[CH:51]=[CH:52][C:53]([C:56](O)=[O:57])=[N:54][CH:55]=1>CN(C=O)C.C(OCC)(=O)C>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:56]([C:53]3[CH:52]=[CH:51][C:50]([Cl:49])=[CH:55][N:54]=3)=[O:57])=[CH:7][CH:6]=2)[CH2:9]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)C1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3ccc(Cl)cn3)cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.2 %

Procedure:
To a stirred suspension of (RS)-tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate (200 mg, CAS 908334-28-1) in DMF (10 ml) were added sequentially N-methylmorpholine (0.22 ml), TBTU (490 mg) and 5-chloro-2-pyridine carboxylic acid (180 mg) and the mixture was stirred at room temperature for 90 min. The mixture was then diluted with ethyl acetate and washed sequentially with 1 M aq. hydrochloric acid and with saturated brine. The phases were separated and the organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (RS)-3-{4-[(5-chloro-pyridine-2-carbonyl)-amino]-phenyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (310 mg, quant.) as a white solid. MS (ISP): 421.3 ([M+NH4]+), 419.2 ([M+NH4]+).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][O:20][CH3:21])[O:16][C:15]2=[O:22])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl.N([O-])=O.[Na+].[I-:28].[K+]>O>[CH:8]1([C:7]2[CH:6]=[CH:5][C:4]([N:14]3[CH2:18][CH:17]([CH2:19][O:20][CH3:21])[O:16][C:15]3=[O:22])=[CH:3][C:2]=2[I:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: [I-]
Reactant: COCC1CN(c2ccc(C3CCCCC3)c(N)c2)C(=O)O1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: COCC1CN(c2ccc(C3CCCCC3)c(I)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
180 mg (0.6 mmol) of (RS)-3-(3-amino-4-cyclohexyl-phenyl)-5-methoxymethyl-oxazolidin-2-one (from the mother liquor of the foregoing reaction) were suspended in a mixture of 0.32 ml of water, 0.32 g of 37 percent hydrochloric acid and 0.64 g of ice and treated with a solution of 41.4 mg (0.6 mmol) of sodium nitrite in 0.3 ml of water at 0°-5°. After stirring at this temperature for 30 minutes a solution of 0.1 g (0.6 mmol) of potassium iodide in 0.3 ml of water was added. The mixture was stirred at room temperature overnight, extracted with ethyl acetate and chromatographed over silica gel with ethyl acetate/hexane 3:1 to give 100 mg of oil. MS: m/e (% basic peak): 415 (M+, 100), 372 (5), 346 (9), 289 (9), 245 (12), 143 (15), 71 (22).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C:15]([NH:14][N:5]2[C:6](=[O:13])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([CH2:2][NH:1][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:4]2)=[O:24])=[CH:22][CH:21]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Product: CC(C)(C)C(=O)NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product from Example 42 and pivaloyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.45 (d, J=7.8 Hz, 1H), 8.23-8.26 (bs, 1H), 7.73-7.96 (m, 3H), 7.29-7.51 (m, 4H), 6.45-6.47 (m, 1H), 4.74-4.77 (m, 2H), 3.80-3.82 (m, 2H), 1.21 (s, 9H); MS (ESI−) M/Z 425 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:20]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:21]([C:23]2([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[OH:36][CH:37]1[C:41]2([CH2:43][CH2:42]2)[CH2:40][N:39]([CH2:44][CH2:45][CH2:46]CS([O-])(=O)=O)[CH2:38]1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:36][CH:37]1[C:41]2([CH2:43][CH2:42]2)[CH2:40][N:39]([CH2:44][CH2:45][CH2:46][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([N:20]([C:29]5[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=5)[C:21]([C:23]5([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]5)=[O:22])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][CH:16]=2)[CH2:38]1
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)CC1
Reactant: O=S(=O)([O-])CCCCN1CC(O)C2(CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(OCCCN5CC(O)C6(CC6)C5)ccc34)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.4 %

Procedure:
To a solution of N-(3-fluoro-4-(7-hydroxy-quinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (266 mg, 0.56 mmol) in DMA (3 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propylmethanesulfonate (283 mg, 1.14 mmol) and Cs2CO3 (556 mg, 1.71 mmol). The reaction was then stirred at rt for 2 days. The solvent was then removed and the residue was partioned between saturated NaHCO3 aqueous solution (15 mL) and CHCl3 (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v) EtOAc/CH3OH/Et3N) to afford the title compound as a white solid (290 mg, 82%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:31][CH:30]([NH2:32])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl.C(O)C>[C:21]([O:25][C:26]([N:28]1[CH2:31][CH:30]([NH:32][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=3[F:19])=[CH:6][N:5]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(Cl)nc1N
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CN(C(=O)OC(C)(C)C)C2)nc1N
Temperature: 80 °C

Procedure:
To a stirred suspension of chloropyrimidine (700 mg, 2.34 mmol, Example 289) in methylene chloride (30 mL), amine (525 mg, 5.64 mmol, Example 318) in ethanol (30 mL) was added and the mixture heated at 80° C. for 4.5 hours. The solvent was removed and the residue was dissolved in ethyl acetate and the mixture was washed successively with 0.5N hydrochloric acid and water. The organic layer was dried with sodium sulfate and concentrated to give a white solid. 1.0 g, 98%. MS (ES) MH+=436.
Reaction SMILES: [OH-].[Na+].C([NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][C:13]([CH3:23])([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C:11]=2[C:24]=1[CH3:25])(=O)C>CO.O>[NH2:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][C:13]([CH3:23])([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C:11]=2[C:24]=1[CH3:25]
Reactant: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(CCc1ccccc1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CCc1ccccc1)O2
Temperature: 200 °C
Yield: 51.6 %

Procedure:
Aqueous 6N sodium hydroxide solution (3 ml) was added to a solution of 5-acetylamino-2,4,6,7-tetramethyl-2-(2-phenylethyl)-2,3-dihydrobenzofuran (0.7 g, 2.1 mmol) in methanol (3 ml) and the mixture was heated at 200° C. in an autoclave for 18 hours. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (isopropyl ether-ethyl acetate, 2:1). The crude crystals were recrystallized from hexane to obtain the desired compound (0.32 g, yield: 54.5%), m.p. 45°-46° C.(dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5](O)=[O:6].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.[CH3:35][NH:36][O:37][CH3:38].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([N:36]([O:37][CH3:38])[CH3:35])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 69.7 %

Procedure:
586 mg of 2,6-dichloroisonicotinic acid was dissolved in 10 ml of dimethylformamide, and 690 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 490 mg of 1-hydroxybenzotriazole, 440 mg of N,O-dimethylhydroxyamine hydrochloride and 1.67 ml of triethylamine were added, and the mixture was stirred at room temperature for 17 hours. To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, and the mixture was diluted with ethyl acetate. The mixture was washed with brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 500 mg of the objective compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:32][CH2:31][C:26]4(OCC[O:27]4)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O.[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:32][CH2:31][C:26](=[O:27])[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2ccc(N3CCC4(CC3)OCCO4)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCN(c2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cc2)CC1
Temperature: 90 °C
Reaction time: 7 h
Yield: 78.7 %

Procedure:
To a solution of 4-[4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl]piperazine-1-carboxylic acid benzyl ester (30 g) in 1,4-dioxane (450 ml) was added 1N-hydrochloric acid (240 ml) at ambient temperature, and the mixture was stirred for 7 hours at 90° C. The reaction mixture was poured into water. The mixture was adjusted to pH 10-12 with 1N-sodium hydroxide (480 ml), and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried, and evaporated under reduced pressure. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methyl alcohol (50:1) to give 4-[4-(4-oxopiperidin-1-yl)phenyl]piperazine-1-carboxylic acid benzyl ester (21.22 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9]([C:29]([F:32])([F:31])[F:30])=[N:10][N:11]([CH2:13][C:14]([NH:16][C:17]2[S:21][C:20]3[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[C:18]=2[C:26](=[O:28])[NH2:27])=[O:15])[CH:12]=1)(=O)=O.[CH3:33][NH2:34].C(O)=O>CN(C=O)C>[CH3:33][NH:34][CH2:6][CH2:7][C:8]1[C:9]([C:29]([F:30])([F:32])[F:31])=[N:10][N:11]([CH2:13][C:14]([NH:16][C:17]2[S:21][C:20]3[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[C:18]=2[C:26]([NH2:27])=[O:28])=[O:15])[CH:12]=1
Reactant: CN
Reactant: CS(=O)(=O)OCCc1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Solvent: O=CO
Solvent: CN(C)C=O
Product: CNCCc1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 120 °C
Yield: 13.1 %

Procedure:
The 2-(1-(2-(3-carbamoyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-2-oxoethyl)-3-(trifluoromethyl)1H-pyrazol-4-yl)ethyl methanesulfonate (30 mg, 0.061 mmol) was dissolved in DMF (1 mL) and methylamine (2 M in THF, 1 mL, 2 mmol) added. The reaction mixture was heated at 120° C. for 5 min in the microwave. The THF was removed in vacuo and the reaction mixture filtered and purified by preparative reverse phase HPLC to give the formic acid salt of the desired product (3.6 mg, 0.008 mmol, 12%).
Reaction SMILES: Br[C:2]1[CH:17]=[N:16][C:5]2=[C:6]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=[N:8][CH:9]=[C:4]2[CH:3]=1.[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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.CCO>[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([C:2]3[CH:17]=[N:16][C:5]4=[C:6]([N:10]5[CH2:15][CH2:14][O:13][CH2:12][CH2:11]5)[N:7]=[N:8][CH:9]=[C:4]4[CH:3]=3)[CH:24]=2)[CH2:19][CH2:20]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1cnc2c(N3CCOCC3)nncc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cnc2c(N3CCOCC3)nncc2c1
Temperature: 25 °C

Procedure:
This title compound by heating a mixture of 3-bromo-8-morpholinopyrido[2,3-d]pyridazine (0.033 g, 0.11 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.048 g, 0.16 mmol), sodium carbonate (0.049 g, 0.46 mmol) and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.011 g, 0.016 mmol) in DME (2.1 mL)/H2O (0.9 mL)/EtOH (0.6 mL) at 80° C. The mixture was cooled to RT, evaporated onto silica gel and purified flash chromatography eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→1:19) to give the title compound as a tan amorphous solid. MS m/z: 390.2 [M+1].
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1)=O.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21]>>[O:10]1[C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[C:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[NH:12][C:13]3=[O:21])=[CH:11][C:7]=2[CH2:8][CH2:9]1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: O=C1Cc2ccccc2N1
Product: O=C1Nc2ccccc2C1=Cc1ccc2c(c1)CCO2

Procedure:
2,3-Dihydro-5-formylbenzofuran (commercially available) was condensed with 2-oxindole to give 0.25 g of 3-(2,3-dihydrobenzofuran-5-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11].[I:12]N1C(=O)CCC1=O>CN(C)C=O>[I:12][C:5]1[S:1][C:2]([S:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1I
Reactant: N#CCCCSc1cccs1
Solvent: CN(C)C=O
Product: N#CCCCSc1ccc(I)s1
Yield: 95.9 %

Procedure:
2.3 g of thiophen-2-thiol, 3.0 g of 4-bromobutyronitrile and 5.5 g of potassium carbonate were stirred in N,N-dimethylformamide at room temperature to give 3.4 g of 4-(2-thienylsulfanyl)butane nitrile. 3.4 g of 4-(2-thienylsulfanyl)butane nitrile was reacted with 5.4 g of N-iodosuccinimide in N,N-dimethylformamide, whereby 5.5 g of the title compound was obtained as a pale yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]1[O:20][C:18](=[O:19])[CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16]1)[CH3:14].[Br:27][CH2:28]Br>CN(C)P(N(C)C)(N(C)C)=O.O1CCCC1>[Br:27][CH2:28][C:17]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH:15]([CH2:13][CH3:14])[O:20][C:18]1=[O:19]
Reactant: BrCBr
Reactant: CCC1CC(c2ccccc2)C(=O)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC1CC(CBr)(c2ccccc2)C(=O)O1
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
To a solution of 19.4 g. (0.19 m) diisopropylamine in 100 ml. of dry tetrahydrofuran is added dropwise 12.3 g. (0.19 m) n-butyl lithium at -75° C. under nitrogen. Stirring is continued for 1/2 hour when a solution of 30 g. (0.16 m) 4-ethyl-2-phenyl-gamma-butyrolactone in 50 ml. tetrahydrofuran is added dropwise in one hour. The resulting mixture is further stirred for 1/2 hour and a mixture of 33 g. (0.19 m) dibromomethane and 34 g. (0.19 m) hexamethylphosphoramide is added dropwise. The reaction temperature is maintained at -75° C. throughout the additions. The reaction mixture is stirred at room temperature overnite. It is then poured into 500 ml. of saturated ammonium chloride solution and extracted with ether. The combined ether extracts are dried over sodium sulfate and filtered. Solvent is removed under vacuum to give 39 g. of an oil which is further purified by bulb-to-bulb vacuum distillation to give 26 g. of pure product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=O)[CH2:5][C:6](=[O:16])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.C([O-])(=O)C.[NH4+:23]>CO>[CH3:1][O:2][C:3](=[O:18])/[C:4](/[NH2:23])=[CH:5]/[C:6](=[O:16])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1
Reactant: [NH4+]
Reactant: COC(=O)C(=O)CC(=O)/C=C/c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)/C(N)=C/C(=O)/C=C/c1ccc(Cl)cc1
Yield: 738.6 %

Procedure:
Using the procedure of Example 4, (E)-6-(4-chlorophenyl)-2,4-dioxo-hex-5-enoic acid methyl ester (6; 21.3 g, 0.008 mol) and ammonium acetate (12.33 g, 0.16 mol) were allowed to react in MeOH (150 mL) to afford (2Z,5E)-2-amino-6-(4-chlorophenyl)-4-oxo-hexa-2,5-dienoic acid methyl ester (9; 15.7 g, 74%) as a yellow solid: mp 112-113° C.; 1H NMR (400 MHz, CDCl3) δ 9.37 (br s, 1H), 7.64-7.42 (m, 3H), 7.38-7.32 (m, 2H), 6.75 (d, J=15.9 Hz, 1H), 6.14 (s, 1H), 5.99 (br s, 1H), 3.91 (s, 3H); HRMS-ESI (m/z): calcd for C13H12ClNO3, 265.050. found, 265.050.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH:11]([NH2:14])([CH3:13])[CH3:12].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:14][CH:11]([CH3:13])[CH3:12])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: O=C(O)c1cccc(Br)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CC(C)NC(=O)c1cccc(Br)n1

Procedure:
By the reaction in the same manner as in Example 55-(i) using 6-bromopicolinic acid (3.04 g), isopropylamine (5 ml), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.44 g) and 1-hydroxybenzotriazole (2.70 g), the title compound (3.10 g) was obtained as a colorless oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]([O:19][C:20](=[O:23])[NH:21][NH2:22])([CH3:18])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[C:15]([O:19][C:20]([NH:21]/[N:22]=[C:10]1/[CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12][CH2:11]/1)=[O:23])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N/N=C1\CCCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Yield: 38.1 %

Procedure:
1-Boc-3-piperidone (25 g; 125.47 mmol; 1.00 eq.) is dissolved in toluene (250 mL) to which tert-butyl-carbazate (16.58 g; 125.47 mmol; 1.00 eq.) is added and reaction mixture is heated to 60° C. for 4 hours. After this time reaction mixture is evaporated to dryness, taken up in ethyl acetate (100 mL) and heptane (100 mL), and the suspension is heated, then cooled down to rt and the suspension is filtered and dried to give 15 g (95%) of the title compound as a beige solid. MS (ESI−): 311.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([C:33]([F:44])([F:43])[F:32])[CH:39]=2)=[CH:8][CH:7]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)[C@H](Cc1ccc(-c2cccc(C(F)(F)F)c2)cc1)NC(=O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Temperature: 80 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To 0.05 g (0.1 mmol) of above resin-bound 3-(4-bromo-phenyl)-(2S)-[(3′-Chloro-4′-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester in 2.0 mL of DME were added 58.0 mg (0.3 mmol) of 3-(trifluoromethyl)phenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated at 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (100% DCM) to give 29 mg (50%) of the title compound. LC/MS (m/z): 572 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CN(C=O)C.O>[CH2:13]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2c(ccn2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 77.7 %

Procedure:
A solution of 5-bromoindole (5.02 g, 25.6 mmol) in DMF (50 mL) was cooled in an ice bath. Sodium hydride (2.30 g of 60% dispersion in oil, 57.5 mmol) was added. After stirring for 40 minutes under nitrogen at room temperature, the reaction mixture was again cooled in an ice bath and benzyl bromide (6.7 mL, 56 mmol) was added. The reaction mixture was stirred for 2 hours, poured into excess water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography (Biotage apparatus) using hexane as an eluant. Dyring at 60° C. for 35 minutes yielded the title compound as a white solid (5.69 g, 78%), mp 93–95° C. Mass spectrum (+ESI, [M+H]+) m/z 286; 1HNMR (500 MHz, DMSO-d6): δ7.7 (d,1H, J=1.8 Hz), 7.55 (d, 1H, J=3.1 Hz), 7.4 (d, 1H, J=8.7 Hz), 7.15–7.30 (m, 6H), 6.45 (dd, 1H, J=3.2 Hz and 0.6 Hz), and 5.45 ppm (s, 2H).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CC(C)=O>[CH3:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CCl
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccccc1C(=O)OC
Yield: 17 %

Procedure:
To a mixture of methyl salicylate (100 g, 657 mmol) and anhydrous K2CO3 (360 g, 2.605 mol) in anhydrous acetone (1000 ml) was added methyl chloroacetate (94 g, 866 mmol) and refluxed for 36 hours. The acetone was distilled off and water (1200 ml) was added. Crude 1 was extracted into chloroform, dried over Na2SO4 distilled and purified by column chromatography on silica gel using hexane as eluant to give pure 1 (25 grams, 17%) as a light yellow syrup.