Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28]O)=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:23]=[CH:24][C:25]([CH2:28][N:34]3[C:30](=[O:40])[C:31]4=[CH:39][CH:38]=[CH:37][CH:36]=[C:32]4[C:33]3=[O:35])=[CH:26][CH:27]=2)[CH:19]=[CH:20][CH:21]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(NCCCCc1cccc(-c2ccc(CO)cc2)c1)OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCCCCc1cccc(-c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.1 %

Procedure:
[3′-(4-Benzyloxycarbonylaminobutyl)biphenyl-4-yl]-methanol (0.40 g) was dissolved in tetrahydrofuran (4.1 mL). After addition of phthalimide (0.14 g) and triphenylphosphine (0.26 g) were added, diisopropyl azodicarboxylate (40% toluene solution, 0.5 g) was added dropwise, and the resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1) to give the title compound (0.4 g)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.BrC1C=CC(F)=C([N+]([O-])=O)C=1.F[C:25]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:26]=1[C:27]#[N:28].ClCCl>C(O)C.C(OCC)C>[C:27]([C:26]1[CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=[CH:32][C:25]=1[NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)#[N:28]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: NCCc1c[nH]c2ccccc12
Agent: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CCO
Solvent: CCOCC
Solvent: ClCCl
Product: N#Cc1cc([N+](=O)[O-])ccc1NCCc1c[nH]c2ccccc12
Yield: 40 %

Procedure:
2×500 mg (2×1 equiv) of tryptamine were dissolved under an argon atmosphere in 2×2 ml of absolute ethanol in three different flasks of a Carousel parallel synthesizer. 4-bromo-1-fluoro-2-nitrobenzene (690 mg, 1 equiv) and 2-fluoro-5-nitrobenzonitrile (520 mg, 1 equiv) were added, respectively, in one of the two parallel flasks (A and B) and the obtained mixtures were allowed to react at room temperature under magnetic stirring. The course of the reactions was followed by TLC (dichloromethane as the eluent). Reactions A and B were completed after 8 and 2 hours, respectively. The two mixtures were then diluted with ca. 15 ml of diethyl ether and the resulting precipitates were collected by filtration and washed with additional Et2O. TLC analyses showed in all precipitates residual traces of starting materials, thus each reaction mixture was purified by column chromatography on silica gel (approx. 20 grams). A mixture of petroleum ether/dichloromethane (8:2) was used until the starting nitroaromatic derivatives were eluted; subsequently, the target products were eluted by using dichloromethane. N-(2-nitro-4-bromophenyl)-tryptamine was collected as a red solid in 55% yield and finally N-(2-cyano-4-nitrophenyl)-tryptamine was obtained as a yellow solid in 40% yield.
Reaction SMILES: C(OC([C:6]1[C:7](=[O:26])[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=O)C.[OH-].[K+]>>[OH:16][C:15]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:7](=[O:26])[CH:6]=1
Reactant: CCOC(=O)c1c(O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Agent: [K+]
Agent: [OH-]
Product: O=c1cc(O)c2cccnc2n1-c1cccc([N+](=O)[O-])c1
Yield: 100.2 %

Procedure:
To 3-ethoxycarbonyl-4-hydroxy-1-(3-nitrophenyl)-1,8-naphthyridin-2 (1H)-one (4.42 g, 12.4 mmol) was added an aqueous solution (18 ml) of potassium hydroxide (2.44 g, 43.4 mmol), and the mixture was heated under reflux overnight, treated with activated carbon (150 mg), refluxed for 10 minutes, and filtered off. The resultant solution was acidified to pH1 with hydrochloric acid, filtered off to give precipitates which were washed with water and dried to afford 4-hydroxy-1-(3-nitrophenyl)-1,8-naphthyridin-2 (1H)-one (3.52 g, quantitative) as crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[O:10]1[CH2:22][CH:11]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18].[OH-].[Na+]>C(OCC)(=O)C>[C:17]([C:16]1[CH:15]=[C:14]([CH:21]=[CH:20][CH:19]=1)[O:13][CH2:12][CH:11]([OH:10])[CH2:22][NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:18]
Reactant: CCOC(=O)CCN
Reactant: N#Cc1cccc(OCC2CO2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNCC(O)COc1cccc(C#N)c1

Procedure:
This compound was prepared in accordance with Example 1 using 15.36 g of the hydrochloride of ethyl 3-aminopropanoate, 8.7 g of 3-(2,3-epoxypropoxy)benzonitrile, and 4.0 g of NaOH. The crude oil was dissolved in 200 ml of ethyl acetate, washed twice with water, and extracted with 2-n HCl. The pH of the water phase was adjusted to 9.5 and the solution extracted with ethyl acetate. The ethyl acetate phase was dried with MgSO4, filtered and evaporated. Ethyl N-[3-(3-cyanophenoxy)-2-hydroxypropyl]-3-aminopropanoate crystallized. Yield 2 g. Melting point 95° C. (base). The structure was determined using NMR.
Reaction SMILES: C(OC(=O)C(OCC)CC1C=CC(O)=C(F)C=1)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[C:30]([CH2:32]CO)[N:31]=2)=[CH:23][CH:22]=1.COC1C=CC(C(N)=S)=CC=1.[Cl:46]CC(CCl)=O>>[Cl:46][CH2:32][C:30]1[N:31]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[S:28][CH:29]=1
Reactant: O=C(CCl)CCl
Reactant: COc1ccc(-c2nc(CCO)cs2)cc1
Agent: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Agent: COc1ccc(C(N)=S)cc1
Product: COc1ccc(-c2nc(CCl)cs2)cc1

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-[2-(4-methoxy-phenyl)-thiazol-4-yl]-ethanol (prepared from 4-methoxy-thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a] to yield 4-chloromethyl-2-(4-methoxy-phenyl)-thiazole, followed by side chain elongation in analogy to the sequence described in examples 13 a] to 13 d]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[2-(4-methoxy-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[2-(4-methoxy-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid as a light yellow solid.
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1)=[O:2].[BH4-].[Na+]>C(O)C>[OH:2][CH2:1][C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1
Reactant: COC(=O)c1csc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1csc(CO)c1
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution of methyl 5-formylthiophene-3-carboxylate (500 mg) in ethanol (5.9 mL) was added sodium borohydride (55.6 mg) at room temperature in small portions, and the mixture was stirred for one hour. The reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue and this resulting mixture was extracted with ethyl acetate. The aqueous layer was extracted once again with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (403 mg).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8](C)[C@@H]2CCCC(=O)[C@H]2N2CCCC2)=[O:7])=[CH:4][CH:3]=1.COC(OC)OC.Cl>CO>[C:6]([NH2:8])(=[O:7])[C:5]1[CH:22]=[CH:23][CH:2]=[CH:3][CH:4]=1
Reactant: CN(C(=O)c1ccc(Br)cc1)[C@@H]1CCCC(=O)[C@H]1N1CCCC1
Agent: Cl
Solvent: COC(OC)OC
Solvent: CO
Product: NC(=O)c1ccccc1

Procedure:
To a solution of 1.0 g of trans-(±)-4-bromo-N-methyl-N-[3-oxo-2-(1-pyrrolidinyl)cyclohexyl]benzamide, prepared as described in Example 1C above, in fifty ml of dry methanol there is added 5 ml of trimethylorthoformate and 0.5 ml of 4M methanolic hydrogen chloride. The resulting mixture is refluxed for about 16 hours, cooled, and the solvent is removed in vacuo. The residual oil is crystallized from a hot methanol solution thereof diluted with diethyl ether until the mixture becomes cloudy to obtain the titled 4-bromo-N-methyl-N-[3,3-dimethoxy)-2-(1-pyrrolidinyl)cyclohexyl]benzamide, which is converted to a hydrochloride salt.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:7]=2[C:6]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:16].[Li][CH3:25]>C1(C)C=CC=CC=1>[CH3:23][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:7]=2[C:6]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)([OH:16])[CH3:25]
Reactant: Cc1ccc2c(C(=O)c3ccccn3)c(CCN(C)C)sc2c1
Reactant: [Li]C
Solvent: Cc1ccccc1
Product: Cc1ccc2c(C(C)(O)c3ccccn3)c(CCN(C)C)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (−78° C.) solution of [2-(2-dimethylamino-ethyl)-6-methyl-benzo[b]thiophen-3-yl]-pyridin-2-yl-methanone (0.444 g, 1.50 mmol) in anhydrous toluene (5 mL), MeLi (1 mL, 1.6 mmol, 1.6 M in ether) was added and the mixture was stirred while the temperature was kept <−60° C. After 2 hours, an additional aliquot of MeLi (0.2 mL, 0.32 mmol) was added and stirring was continued for another 2 hours. The reaction was quenched with a mixture of 1.3 mL 6N HCl and 2.6 mL MeOH while keeping the temperature <−45° C. The mixture was allowed to warm to room temperature and the organic phase was separated. The organic phase was extracted with 500 mL of 1N HCl. The combined aqueous phases were neutralized with 50% sodium hydroxide and extracted 3 times with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (dichloromethane/MeOH=97/3 up to 85/15) afforded 1-[2-(2-dimethylamino-ethyl)-6-methyl-benzo[b]thiophen-3-yl]-1-pyridin-2-yl-ethanol in quantitative yield.
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH2:12][OH:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[Cl-].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]#[N:25])=[CH:20][CH:19]=1)([O-:17])=[O:16]>>[CH2:1]([N:4]([CH2:11][CH2:12][OH:13])[C:5]1[CH:10]=[CH:9][C:8]([N:25]=[N:24][C:21]2[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: N#[N+]c1ccc([N+](=O)[O-])cc1
Reactant: C=CCN(CCO)c1ccccc1
Agent: [Cl-]
Product: C=CCN(CCO)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
N-allyl-N-(2-hydroxyethyl)benzenamine (7.1 g, 0.04 mol) is treated with a solution of p-nitrobenzenediazonium chloride, as discussed in Example 5, to provide N-allyl-N-(2-hydroxyethyl)-4-(4'-nitrophenylazo)benzenamine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(=NC(C)C)[O-])(C)C.C(NC(=NC(C)C)O[C:36]([CH3:39])([CH3:38])[CH3:37])(C)C>C(Cl)Cl>[N:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][CH2:13][CH:14]([C:17]([O:19][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:18])[CH2:15][CH2:16]1
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)N=C([O-])NC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 1-[(benzyloxy)carbonyl]piperidine-4-carboxylic acid in DCM (0.2 M), 3 eq of tert-butyl. N,N′-diisopropylimidocarbamate were added and the mixture was stirred at RT. After 30 min, a further 1.5 eq of tert-butyl N,N′-diisopropylimidocarbamate were added and the solution stirred for an additional hour. The solution was filtered through a pad of celite and then through a pad of silica gel to give the product (83%); MS (ES+) m/z 320 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].Br[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:16][CH2:15][CH:14]([O:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])[CH2:17][CH3:18]
Reactant: CCC(Br)CC
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCC(CC)Oc1ccc(C(=O)OC)c(O)c1

Procedure:
The methyl 4-[pent-3-oxy]salicylate used was prepared as follows. A mixture of methyl 4-hydroxysalicylate (74 g, 0.44 mole), 3-bromopentane (80 g, 0.53 mole), potassium iodide (20 g) and potassium carbonate (100 g) in methyl ethyl ketone (MEK, 500 mL) was heated at reflux for 65 hours. The cooled reaction mixture was then filtered and concentrated under reduced pressure. The resultant oily residue was stirred with dilute hydrochloric acid, then extracted into dichloromethane. The dichloromethane solution was washed with brine, dried over anhydrous sodium sulfate and concentrated to a clear liquid (67.0 g, 64% yield). The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[C:7]([CH:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH2:10]1)=[O:8].[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:23][C:24]2[CH:31]=[CH:30][CH:29]=[C:26]([CH3:27])[CH:25]=2)[CH:10]=1)=[O:8]
Reactant: Cc1cccc(C(=O)C2CNc3ccccc3C2=O)c1
Reactant: Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(C(=O)c3cccc(C)c3)c(=O)c3ccccc32)c1
Yield: 50.1 %

Procedure:
Compound 4y was prepared following the procedure outlined in Step 3 of Example 1 using 26 mg (0.65 mmol) of sodium hydride (60%), 132 mg (0.50 mmol) of 3-(3-methyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one, 3 mL of anhydrous dimethylformamide, and 120 mg (0.65 mmol) of 3-methylbenzylbromide. The crude product was purified by flash chromatography to yield 92 mg of a colorless solid 4y: LC-MSD, m/z for C25H21NO2, [M+H]+=368.5, [M+2H]+=369.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.586 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.37 (s, 3H), 2.42 (s, 3H), 5.39 (s, 2H), 7.01 (d, 2H), 7.15 (d, 1H), 7.22-7.44 (m, 5H), 7.55-7.58 (m, 3H), 8.29 (s, 1H), 8.47 (d, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:33])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[C@H:30]([OH:32])[CH3:31])[N:9]=3)[CH2:2]1.[OH:34][C:35]([CH3:40])([CH3:39])[C:36](O)=[O:37].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>C(Cl)Cl>[OH:34][C:35]([CH3:40])([CH3:39])[C:36]([N:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:33])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[C@H:30]([OH:32])[CH3:31])[N:9]=3)[CH2:2]1)=[O:37]
Reactant: CC(C)(O)C(=O)O
Reactant: C[C@@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C(C)(C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
To a solution of (R)-1-[1-(8-azetidin-3-ylmethyl-9-methyl-6-morpholin-4-yl-9H-purin-2-yl)-1H-benzoimidazol-2-yl]ethanol (57 mg, 0.13 mmol) in DCM (2 mL) was added 2-hydroxy-2-methyl-propionic acid (15 mg, 0.14 mmol), HOBt (19 mg, 0.14 mmol), NMM (31 μL, 0.28 mmol) and EDCI (27 mg, 0.14 mmol) and the resulting mixture stirred at r.t. for 1 h. The reaction mixture was partitioned between DCM and H2O, the organic phase dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording 861 (14 mg, 21%). LCMS (method I): RT 3.05 min, [M+H]+ 535.3. 1H NMR (DMSO, 400 MHz): δ 7.97-7.94 (1 H, m), 7.71-7.68 (1 H, m), 7.30-7.26 (2 H, m), 5.58-5.57 (1 H, m), 5.39 (1 H, d, J=6.33 Hz), 5.02 (1 H, s), 4.57-4.56 (1 H, m), 4.39-4.14 (4 H, brd s), 4.18 (1 H, dd, J=10.39, 5.70 Hz), 4.04-4.02 (1 H, m), 3.80-3.75 (4 H, m), 3.72 (3 H, s), 3.68 (1 H, dd, J=9.67, 5.21 Hz), 3.23-3.20 (2 H, m), 1.60 (3 H, d, J=6.48 Hz), 1.25 (6 H, s)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.[H-].[Na+].[CH2:16](I)[CH3:17]>C1COCC1>[CH2:16]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH3:17]
Reactant: COc1ccc2c(c1)CCNC2=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a mixture of 6-methoxy-3,4-dihydro-2H-isoquinolin-1-one (0.30 g, 1.69 mmol) in THF (10 mL) is added sodium hydride (60% mineral oil suspension, 100 mg). The suspension is heated at reflux for 1 h, and cooled to room temperature. Ethyl iodide (1.4 mL, 17 mmol) is added, and the mixture is stirred at room temperature overnight. The mixture is partitioned between EtOAc and water. After the aqueous phase is extracted with EtOAc (2×), the combined organic phase is washed with brine and dried (MgSO4). After removal of the solvent, the residue is purified by flash chromatography (Biotage 40M SiO2, elute 45% EtOAc:hexane−50% EtOAc:hexane, linear gradient) to yield 2-ethyl-6-methoxy-3,4-dihydro-2H-isoquinolin-1-one as a colorless oil (0.275 g, 78%). The material is dissolved in CH2Cl2 (10 mL) and cooled to −78° C. To the cooled mixture is added a solution of boron tribromide (1 M, 4.7 mL, 4.7 mmol) in CH2Cl2. After 0.5 h, the temperature is warmed to 0° C. and stirred for 3 h. After the reaction is carefully quenched with ice, EtOAc and water is added, and the mixture is vigorously stirred overnight. The phases are separated, and the organic phase is extracted with EtOAc (2×). The combined organic phase is washed with brine and dried (MgSO4). The solvent is removed in vacuo, and the residue is purified by chromatography (Varian 10 g SiO2 cartridge, elute 60% EtOAc:hexane) to provide 2-ethyl-6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (0.209 g, 82%). MS (ES+) 192.0
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[C:11]1([P:17](Cl)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][P:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:18]
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NP(=O)(c2ccccc2)c2ccccc2)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)diphenyl phosphinic amide was prepared by the method of Example 3 with 4-bromo-3-methyl-5-amino isoxazole (0.18 g, 1.0 mmol), THF (5 ml), NaH (60% oil dispersion, 88 mg, 2.2 mmol), and diphenyl phosphinic chloride (0.23 ml, 1.2 mmol). Recrystallization three times from chloroform and hexanes provided 0.17 g (45%) of faint pink crystals, m.p. 178.5-181° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH:9](=O)[CH3:10].COC(=O)COC1C=C(OC)C(SCCCN(CC)C2C=CC(C3C=CC=CC=3)=CN=2)=CC=1C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH3:10])=[N:6][CH:7]=1
Reactant: CC=O
Reactant: Nc1ccc(Br)cn1
Agent: CCN(CCCSc1cc(C)c(OCC(=O)OC)cc1OC)c1ccc(-c2ccccc2)cn1
Product: CCNc1ccc(Br)cn1

Procedure:
5-Bromo-pyridin-2-ylamine and acetaldehyde were treated under the conditions of Compound 64C to give the intermediate (5-bromo-pyridin-2-yl)-ethyl-amine. This was then reacted with Compound 64A to give the title product. MS m/z 481 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:18])[N:11]([CH3:17])[C:12](SC)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>Cl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:18])[N:11]([CH3:17])[C:12]([NH:24][C:23]3[CH:25]=[CH:26][C:20]([F:19])=[CH:21][CH:22]=3)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Nc1ccc(F)cc1
Reactant: CSc1ncc(-c2ccc(O)c(F)c2)c(=O)n1C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(O)c(F)c2)c1=O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
5-(3-Fluoro-4-hydroxyphenyl)-3-methyl-2-methylthio-3H-pyrimidin-4-one (Step 5, 0.39 g, 1.5 mmol) was suspended in 3.6 mL p-fluoroaniline and concentrated HCl (1 drop) was added. The reaction was heated in a microwave at 120° C. and 100 W for 10 min (using a Powermax feature on a CEM microwave). The reaction was cooled to RT and diluted with EtOAc (100 mL). The organic phase was extracted with 1 N NaOH (3×15 mL), and the aqueous extracts were neutralized with concentrated HCl. The aqueous layer was extracted with EtOAc (3×20 mL), and the organic extracts were combined, dried over Na2SO4, filtered, and concentrated to give desired compound. MS (ESI pos. ion) m/z: 330. Calc'd for C17H13F2N3O2: 329.10.
Reaction SMILES: N.[CH2:2]([O:4][C:5](=[O:24])[CH2:6][C:7]([C:22]#[N:23])([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:8][C:9](OCC)=[O:10])[CH3:3]>[Ni].C(O)C>[CH2:2]([O:4][C:5](=[O:24])[CH2:6][C:7]1([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:8][C:9](=[O:10])[NH:23][CH2:22]1)[CH3:3]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)c(Cl)c1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(=O)CC1(c2ccc(Cl)c(Cl)c2)CNC(=O)C1
Reaction time: 20 h

Procedure:
Combine Raney nickel (24 lb) and an aqueous concentrated ammonia solution (19 lb). Add a solution of 3-cyano-3-(3,4-dichlorophenyl)pentanedioic acid diethyl ester (15 lb) and ethanol (117 lb) in a pressure reactor. Hydrogenate at 200 psi and 35° C. After 20 hours, cool, vent the vessel, purge with nitrogen, and filter. Rinse the solids with ethanol. Evaporate the filtrate invacuo to give a residue. Crystallize the residue by dissolving in ethyl acetate and triturate the solution with heptane to give a solid. Collect the solid to give the title compound. Elemental Analysis calculated for C14H15Cl2NO3 : C 53.18; H 4.78; N 4.43; Found: C 53.113; H 4.72; N 4.46.