Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([C:15]([F:18])([F:17])[F:16])[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:19][C:20]1[C:25]([CH3:26])=[C:24](O)[CH:23]=[CH:22][C:21]=1/[CH:28]=[CH:29]/[C:30]([O:32]CC)=[O:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:24]3[CH:23]=[CH:22][C:21](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[C:20]([CH3:19])[C:25]=3[CH3:26])=[C:11]([C:15]([F:16])([F:18])[F:17])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1ccc(O)c(C)c1C
Reactant: OCc1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Product: Cc1c(/C=C/C(=O)O)ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 1 following Steps 5 and 6 by coupling of (3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methanol and (E)-ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)acrylate then hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=7.5 Hz, 2H), 7.55 (d, J=11.5 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 6.96 (d, J=5.5 Hz, 1H), 6.62 (d, J=12.0 Hz, 1H), 5.08 (s, 2H), 2.21 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH:13]1([CH2:16]Br)[CH2:15][CH2:14]1.BrC1C=C(C=C(OC(C)C)C=1)C(OC)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:16][CH:13]1[CH2:15][CH2:14]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: BrCC1CC1
Reactant: COC(=O)c1ccc(O)c(Br)c1
Agent: COC(=O)c1cc(Br)cc(OC(C)C)c1
Product: COC(=O)c1ccc(OCC2CC2)c(Br)c1

Procedure:
Prepared from methyl 3-bromo-4-hydroxybenzoate and cyclopropylmethylbromide according to the procedure for methyl 3-bromo-5-isopropoxybenzoate. LCMS-ESI (m/z) calculated for C12H13BrO3: 285.1; no m/z observed, tR=3.96 min. 1H NMR (400 MHz, CDCl3) δ 8.22 (t, J=2.8 Hz, 1H), 8.02-7.88 (m, 1H), 6.91-6.81 (m, 1H), 4.02-3.91 (m, 2H), 3.88 (d, J=5.5 Hz, 3H), 1.41-1.26 (m, 1H), 0.76-0.59 (m, 2H), 0.52-0.31 (m, 2H).
Reaction SMILES: C(C1C([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=NC(CC)=CN=1)C.Cl[C:23]1[C:24]([CH:32]2[CH2:34][CH2:33]2)=[N:25][CH:26]=[C:27]([CH:29]2[CH2:31][CH2:30]2)[N:28]=1>>[CH:32]1([C:24]2[C:23]([NH:11][C@@H:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][C@@H:13]3[OH:21])=[N:28][C:27]([CH:29]3[CH2:31][CH2:30]3)=[CH:26][N:25]=2)[CH2:34][CH2:33]1
Reactant: Clc1nc(C2CC2)cnc1C1CC1
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: O[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)cnc1C1CC1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3-chloro-2,5-dicyclopropylpyrazine and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.86-0.89, 2.00, 2.89, 3.11, 4.54, 5.17, 5.42, 6.22-6.24, 7.17-7.25, 7.64; MS (ESI+) for C19H21N3O m/z 308 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]([CH3:16])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH2:12][OH:13])[S:7][C:6]=2[C:14]=1[CH3:15].[H-].[Na+].[CH3:20][O:21][CH2:22]Cl.O>CN(C)C=O.C1C=CC=CC=1>[OH:1][C:2]1[C:3]([CH3:17])=[C:4]([CH3:16])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH2:12][O:13][CH2:20][O:21][CH3:22])[S:7][C:6]=2[C:14]=1[CH3:15]
Reactant: Cc1c(C)c2c(c(C)c1O)SC(CCCO)O2
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O
Product: COCOCCCC1Oc2c(C)c(C)c(O)c(C)c2S1
Temperature: 0 °C

Procedure:
5.0 g of 3-(5-hydroxy-4,6,7-trimethyl-1,3-benzoxathiole-2-yl)propanol (prepared as described in Example 71) were dissolved in 40 ml of dimethylformamide, and 260 mg of a 55% w/w oily suspension of sodium hydride was added at room temperature. The reaction mixture was then heated for 1 hour at 40°-45° C., after which it was cooled with ice-water, and then a solution of 1.6 g of chloromethyl methyl ether in 5 ml of benzene was added dropwise. After completion of the addition, the temperature of the mixture was gradually raised and then the mixture was heated for 1 hour at 50°-55° C. The reaction mixture was then poured into water and extracted with benzene. The extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel Lobar column chromatography, and the title compound was obtained from the fraction eluted with a 100:3 by volume mixture of benzene and ethyl acetate.
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][CH3:16])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([CH3:25])[CH:19]=1>C(O)COCCO.O>[CH3:25][C:20]1[CH:19]=[C:18]([F:17])[CH:24]=[CH:23][C:21]=1[N:22]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH3:16])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1cc(F)ccc1N
Reactant: COc1cccc2c1=NC(=O)C1CCOC=21
Solvent: O
Solvent: OCCOCCO
Product: COc1cccc2c3c(c(=O)[nH]c12)CCN3c1ccc(F)cc1C
Temperature: 250 °C
Yield: 78.9 %

Procedure:
4-Oxo-6-methoxy-2,3-dihydrofuro[3,2-c]quinoline (217 mg, 1.0 mmol) was dissolved in 10 ml of diethylene glycol in a pressure tube and (278 μl, 2.5 mmol) of 4-fluor-2-methylaniline (278 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 250° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent according to silica gel chromatography to obtain 256 mg of desired compound as solid in 79% of yield.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([SH:13])[CH2:10][C@H:9]1[CH2:14][N:15]([C:25](=[O:27])[CH3:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[F:24])=[O:7])[CH2:2][CH2:3][CH3:4].[C:28](Cl)(=[O:30])[CH3:29]>N1C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:28](=[O:30])[CH3:29])[CH2:10][C@H:9]1[CH2:14][N:15]([C:25](=[O:27])[CH3:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[F:24])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)Cl
Reactant: CCCCOC(=O)N1C[C@H](S)C[C@H]1CN(Cc1cc(F)ccc1F)C(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCOC(=O)N1C[C@H](SC(C)=O)C[C@H]1CN(Cc1cc(F)ccc1F)C(C)=O
Temperature: 25 °C
Yield: 82.2 %

Procedure:
130 mg (0.325 mmol) [2S,4R]-2-{[acetyl-(2,5-difluoro-benzyl)-amino]-methyl}-4-mercapto-pyrrolidine-1-carboxylic acid butyl ester in 3 ml pyridine were treated with 120 μl (1.68 mmol, 5.1 eq) acetyl chloride at 0° C. The resulting suspension was diluted with 8 ml CH2Cl2, and the mixture was stirred at RT over night, concentrated in vacuo and the oil was redissolved in EtOAc/1M HCl. The inorganic phase was extracted with CH2Cl2 and the organic phases were washed with 1M HCl and brine, dried over Na2SO4. The crude product was purified by flash column chromatography with EtOAc/hexane 1:1 as eluent yielding 118.2 mg (82%) [2S,4R]-2-{[acetyl-(2,5-difluoro-benzyl)-amino]-methyl}-4-acetylsulfanyl-pyrrolidine-1-carboxylic acid butyl ester as light yellow oil, MS: 443 (MH+).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N+:14]([O-])=O)(=[O:6])=[O:5])([CH3:3])[CH3:2]>[Fe].C(O)(=O)C>[CH:1]([S:4]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[NH2:14])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: Cc1ccc([N+](=O)[O-])c(S(=O)(=O)C(C)C)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1ccc(N)c(S(=O)(=O)C(C)C)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
To a mixture of 2-(isopropylsulfonyl)-4-methyl-1-nitrobenzene (Preparation Example 291) (7.41 g) and acetic acid (70 mL), iron powder (5.43 g) was added and stirred at 80° C. for 3 hours. Thereafter, insoluble materials in the reaction liquid were removed, and the solvent was distilled off under reduced pressure. After addition of ethyl acetate (150 mL) and removal of insoluble materials, the residue was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was washed with ethyl acetate-diisopropyl ether to give 2-(isopropylsulfonyl)-4-methylaniline (3.86 g) as a light yellow solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[C:5](Br)=[C:6](Br)[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+].[Br-:14].C([N+](CC)(CC)CCCCC)C>C(Cl)Cl>[Br:1][C:2]([Br:14])=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [Br-]
Reactant: BrCCc1cccc(Br)c1Br
Agent: CCCCC[N+](CC)(CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: BrC(Br)=Cc1ccccc1

Procedure:
A solution of 147.90 g. (0.431 mole) of 2-bromoethyl-dibromobenzene in 250 ml. of methylene chloride was stirred for 7 ks (2 hours) at 5 Hz (300 rpm) at 313 K. (40° C.) with 150 g (2.25 mole) of 60 percent sodium hydroxide solution and 3.12 g. (0.0124 mole) of triethylpentyl ammonium bromide. The product was washed with three 500-ml portions of water, dried over calcium sulfate (Drierite), and stripped of solvent in a rotary evaporator at a bath temperature of 323 K. (50° C.). The yield of product was 106.97 g. (77.2 percent of theory). GC analysis showed 27.1 percent of the desired ar-dibromostyrene, the remainder being largely unreacted starting material.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:21][C@H:22]([CH2:26][CH3:27])[C:23]([NH2:25])=[O:24])=[N:7][C:8]=1[NH:9][C:10]1[S:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[NH2:25][C:23](=[O:24])[C@H:22]([NH:21][C:6]1[N:7]=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[C:3]([C:1]([NH2:2])=[O:34])=[N:4][CH:5]=1)[CH2:26][CH3:27]
Reactant: CC(=O)O
Reactant: CC[C@@H](Nc1cnc(C#N)c(Nc2cc(-c3ccccc3)ns2)n1)C(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: CC[C@@H](Nc1cnc(C(N)=O)c(Nc2cc(-c3ccccc3)ns2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The compound (R)-2-(5-cyano-6-(3-phenylisothiazol-5-ylamino)pyrazin-2-ylamino)butanamide (8 mg, 0.021 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL) and aq. H2O2 (30%, 0.5 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (5 mg). MS found for C18H19N7O2S as (M+H)+ MS 398.2. UV: λ=UV 201.1, 267.7, 321.9 nm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:36].[CH3:37][N:38]([CH3:44])[CH2:39][CH2:40][CH2:41][NH:42][CH3:43]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:42]([CH2:41][CH2:40][CH2:39][N:38]([CH3:44])[CH3:37])[CH3:43])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:36]
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)(=O)=O)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Reactant: CNCCCN(C)C
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(N(C)CCCN(C)C)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C

Procedure:
3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (0.04 g, 0.078 mmol), N,N,N′-trimethyl-1,3-propanediamine (0.134 g, 0.115 mmol), and TEA (0.016 g, 0.156 mmol) were combined in CH2Cl2 (5 mL) and stirred under argon at room temperature. The solvents were pumped off in vacuo. The residue was flash chromatographed on silica gel (10 g) eluted with CH2Cl2 to 6:1:0.1, CH2Cl2: ethanol:NH4OH. The compound had an impurity which was removed by filtering through a silica gel plug with 3% MeOH/CH2Cl2 to give the title compound as an off-white amorphous solid. mp 104-109° C. LC-MS m/z 549 (M+H)+, 1.65 min (ret time).
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:13][C:14]([O:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C:8](=[O:36])[C:7]1=[O:37])=[N+]=[N-].Cl.CN(C)C=O.C(=O)([O-])O.[Na+]>[C].[Pd].C(Cl)Cl>[NH2:1][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:13][C:14]([O:16][CH:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C:8](=[O:36])[C:7]1=[O:37]
Reactant: [N-]=[N+]=NCCN1CCN(C(CC(=O)OC(c2ccccc2)c2ccccc2)c2cccnc2)C(=O)C1=O
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NCCN1CCN(C(CC(=O)OC(c2ccccc2)c2ccccc2)c2cccnc2)C(=O)C1=O
Reaction time: 2 h
Yield: 30.1 %

Procedure:
A mixture of 0.7 g of diphenylmethyl 3-[4-(2-azidoethyl)-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)-propionate, 0.13 g of 5% palladium-carbon, 2.8 ml of 1N hydrochloric acid and 7 ml of N,N-dimethylformamide was subjected to hydrogenation at ordinary temperature and atmospheric pressure for 2 hours. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. To the resulting residue were added 5 ml of diethyl ether and 1 ml of ethyl acetate and the resulting mixture was filtered to obtain a white solid. The solid obtained was added to a mixed solvent of 20 ml of methylene chloride and 10 ml of a saturated aqueous sodium hydrogencarbonate solution and stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted with two 10-ml portions of methylene chloride. The combined organic layer was washed with water and then a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 0.2 g of diphenylmethyl 3-[4-(2-aminoethyl)-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)-propionate as a brown oil.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[CH2:35][CH2:34][N:33]([C:2]3[C:3]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:4][C:5]4[C:10]([N:11]=3)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=4)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Reactant: COc1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccc(OC)cc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
A solution of methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (150 mg, 0.50 mmol, 1.00 equiv), 4-(4-methoxyphenyl)piperidine (191 mg, 1.00 mmol, 2.00 equiv), and DIEA (194.8 mg, 1.51 mmol, 5.00 equiv) in DMF (4 mL) was placed in an 8-mL sealed tube and stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water, and the resulting mixture was concentrated under vacuum. Purification via silica gel column (ethyl acetate/petroleum ether (1:50)) yielded 179.6 mg (63%) of methyl 3-(4-(4-methoxyphenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[CH:4][C:5]([C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)=O.N[C:14]1[C:18](C)=[CH:17][NH:16][N:15]=1>C(O)(=O)C>[CH3:17][C:18]1[CH:14]=[N:15][N:16]2[C:5]([C:7]3[CH:11]=[CH:10][O:9][CH:8]=3)=[CH:4][CH:3]=[N:2][C:12]=12
Reactant: CN(C)C=CC(=O)c1ccoc1
Reactant: Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: Cc1cnn2c(-c3ccoc3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(3-furyl)-2-propen-1-one and 3-amino-4-methylpyrazole in glacial acetic acid is heated at reflux temperature for 6 hours. The solvent is removed to give the product of the example.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1.Br[CH2:21][CH:22]=[CH:23][C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:27][C:26]([CH3:29])([CH3:28])[C:25]#[C:24]/[CH:23]=[CH:22]\[CH2:21][N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2]
Reactant: CC(C)(C)C#CC=CCBr
Reactant: CNCc1cccc(NC(=O)c2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C/C=C\C#CC(C)(C)C)Cc1cccc(NC(=O)c2ccccc2)c1

Procedure:
N-methyl-3-benzoylaminobenzylamine hydrochloride (277 mg) was dissolved in 3 ml of dimethylformamide, and 221 mg of 1-bromo-6,6-dimethyl-2-hepten-4-yne and 552 mg of potassium carbonate were stirred overnight at room temperature. The reaction mixture was diluted with water, and extracted with ethyl ether. The extract was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The desiccant was separated by filtration, and then the solvent was evaporated. The residue was purified by preparative thin-layer chromatography [thin-layer plate: Kieselgel 60F254, Art. 5744 (a product of E. Merck Co.); developing solvent: hexane/ethyl acetate=3/1] to give the following compounds as colorless oils.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:7]=1)=[O:5].[CH2:26]1[CH2:30][O:29][CH2:28][CH2:27]1>COC1C=CC([Mg]Br)=CC=1C>[CH3:28][O:29][C:30]1[CH:14]=[CH:15][C:6]([C:4]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=3)[CH:7]=2)=[O:5])=[CH:4][C:26]=1[CH3:27]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2ccccc2c1=O
Agent: COc1ccc([Mg]Br)cc1C
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 168 mg (0.50 mmol) of 1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 2.5 mL THF and 2.5 mL 0.5M 4-methoxy-3-methylphenylmagnesium bromide. Yield: 107 mg of a white solid. LC-MSD, m/z for C25H22N2O3 [M+H]+=399.1; HPLC retention time: 2.1 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=O)[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=[CH:18][CH:19]=2)[O:11][N:10]=1.B.O1CCCC1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH:17]=[CH:18][CH:19]=2)[O:11][N:10]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNc1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 0 °C

Procedure:
tert-Butyl 2-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenylamino)-2-oxoethylcarbamate (500 mg, 1.08 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and cooled to 0° C. Borane-tetrahydrofuran complex (1M soln in THF, 10.8 mL, 10.8 mmol) was added dropwise to the cool solution. The reaction mixture was allowed to stir while slowly warming to room temperature for 5 h. The reaction was quenched with 1N hydrochloric acid (25 mL) and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to yield tert-butyl 2-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenylamino)ethylcarbamate as a white solid. The product was carried forward without further purification. 1H NMR (CDCl3): 7.98 (s, 1H), 7.55-7.50 (m, 2H), 7.48-7.35 (m, 4H), 6.48 (s, 1H), 5.18 (br s, 1H), 4.00 (m, 2H), 3.58 (m, 2H), 1.48 ppm (s, 9H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:11]=[C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[CH:21]=2)=[N:14][CH:15]=1.O.C(Cl)Cl>CN(C=O)C>[NH2:9][C:10]1[N:11]=[C:12]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:13]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[CH:21]=2)=[N:14][C:15]=1[Br:1]
Reactant: CC(C)n1cc(-c2ncc(N)nc2-c2ccccc2)ccc1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reaction time: 2 h
Yield: 79.5 %

Procedure:
Under ice-bath cooling, N-bromosuccinimide (1.83 g) was added to a solution of 5-(5-amino-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (3.0 g) in DMF (90 ml). The mixture was stirred at the same temperature for 2 hours. Water and CH2Cl2 were poured into the mixture and the organic layer was separated, washed with sat. aq. sodium thiosulfate solution, sat. aq. NaHCO3 solution, water, and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica-gel, toluene-EtOAc), recrystallized from EtOH, and dried in vacuo to give 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (3.0 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][CH2:5][C:4]2[CH:3]=[C:2]([F:1])[CH:9]=[C:8]([F:10])[CH:7]=2)[CH2:13][CH2:12]1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: NC1CC1
Product: Fc1cc(F)cc(CNC2CC2)c1

Procedure:
Synthesized according to typical procedure J from 3,5difluorobenzaldehyde and cyclopropylamine.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]12[CH2:12][CH2:11][CH:8]([CH2:9][CH2:10]1)[CH2:7][N:6]1[C:13](=[O:31])[C:14]([O:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=[C:5]21.[F:32][C@@H:33]1[CH2:37][CH2:36][N:35]([C:38](=[O:42])[C:39]([OH:41])=O)[CH2:34]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CN(C)C1C=CN=CC=1>[F:32][C@@H:33]1[CH2:37][CH2:36][N:35]([C:38](=[O:42])[C:39]([N:3]([CH3:2])[C:4]23[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12]2)[CH2:7][N:6]2[C:13](=[O:31])[C:14]([O:22][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:24])=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=[C:5]32)=[O:41])[CH2:34]1
Reactant: O=C(O)C(=O)N1CC[C@@H](F)C1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(NC)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(N(C)C(=O)C(=O)N2CC[C@@H](F)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
To a stirred solution of ethyl 10-(methylamino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate hydrochloride (120 mg, 0.268 mmol) in DMF (4 mL) was added (R)-2-(3-fluoropyrrolidin-1-yl)-2-oxoacetic acid (130 mg, 0.804 mmol), diisopropylethylamine (0.281 mL, 1.607 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (306 mg, 0.804 mmol), 4-(dimethylamino)pyridine (DMAP) (9.82 mg, 0.080 mmol) and the resulting mixture stirred at room temperature for 16 h. The mixture was quenched with water and diluted with ethyl acetate, washed with 1N HCl, followed by sat.NaHCO3, dried (Na2SO4) filtered and concentrated. The crude product was purified on Biotage flash chromatography system using 30-100% ethyl acetate/hexane gradient to afford the title compound (80 mg, 0.144 mmol, 54% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ: 8.12-8.23 (2 H, m), 7.64 (1 H, t, J=7.48 Hz), 7.44-7.56 (2 H, m), 5.11-5.42 (1 H, m), 4.08-4.27 (2 H, m), 3.28-4.01 (9 H, m), 3.18 (3 H, d, J=3.05 Hz), 2.50 (1 H, brs), 1.72-2.37 (6 H, m), 0.99-1.11 (3 H, m). LCMS (M+H)=555.76.