Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:11](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)nc1
Reaction time: 18 h
Yield: 96.4 %

Procedure:
To a solution of 6-chloronicotinic acid (20.0 g, 0.127 mol) in CH2Cl2 (250 mL) was added oxalyl chloride (123.3 mL, 0.15 mol) with 1-5 drops of DMF. The solution was stirred 18 h and concentrated in vacuo. The residue was dissolved in CH2Cl2 (100 mL) and cooled in an ice bath. To this was added MeOH (20 mL) and the solution was stirred for 15 min while maintaining a temp below 40° C. The solvent was removed in vacuo, and the residue was dissolved in Et2O, washed with H2O and brine, dried with Na2SO4, and filtered through SiO2. The solvent was removed in vacuo to yield 6-chloronicotinic acid, methyl ester (21 g) as an off-white solid: 1H-NMR (300 MHz, CDCl3) δ 9.02 (d, J=13.8 Hz, 1H), 8.51-8.06 (m, 1H), 7.76-7.30 (m, 1H), 4.01 (s, 3H); EIMS m/z 171 ([M]+), which was used in Step 2 without further purification.
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])=[O:5].[CH3:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[Ca+2]>C(O)C>[CH3:21][CH:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=2[Cl:13])=[O:5])[CH2:24][CH2:23]1
Reactant: CC1CCNCC1
Reactant: O=C(c1ccc(Cl)cc1Cl)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: CC1CCN(c2ccc([N+](=O)[O-])cc2C(=O)c2ccc(Cl)cc2Cl)CC1
Yield: 74.4 %

Procedure:
Proceeding as indicated in example 2, with 0.053 mole (17.5 g) of 2,2',4'-trichloro-5-nitro-benzophenone, 0.088 mole (8.8 g) of 4-methylpiperidine and 0.0712 mole (9.8 g) of calcium carbonate in 50 cm3 of ethanol, 15.5 g (Yield: 75%) of the expected product are obtained after re-crystallization in a mixture of isopropyl ether and toluene (70 v./30 v.) M.P.: 103° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])=[CH:15][CH:14]=2)[N:3]=1.[C:26]([N:30]1[C:34]([CH3:35])=[CH:33][C:32]([NH2:36])=[N:31]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([N:30]1[C:34]([CH3:35])=[CH:33][C:32]([NH:36][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[N:4]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[CH:15][CH:14]=3)[N:3]=2)=[N:31]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1cc(N)nn1C(C)(C)C
Reactant: Cc1ccccc1-c1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Product: Cc1ccccc1-c1ccc(-n2nc(Nc3cc(C)n(C(C)(C)C)n3)c3ccccc3c2=O)cc1
Yield: 31 %

Procedure:
4-Bromo-2-(2′-methyl-biphenyl-4-yl)-2H-phtalazin-1-one (prepared from the appropriate starting materials in analogy to Method Q-1) was coupled with 1-tert-butyl-5-methyl-1H-pyrazol-3-ylamine in a Buchwald reaction as described in Method O to give the title compound (0.049 g, 31% yield). 1H-NMR: (400 MHz, D6-DMSO) 8.44 (1H, s), 8.40 (1H, d), 8.33 (1H, d), 8.05 (1H, t), 7.97 (1H, t), 7.62 (2H, d), 7.40 (2H, d), 7.30 (2H, d), 7.24 (2H, d), 6.00 (1H, s), 2.28 (3H, s), 2.12 (3H, s), 1.57 (9H, s); MS (ESI+)=464.36 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1>>[Cl:24][C:20]1[CH:19]=[C:18]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:29]4[CH:30]=[N:25][CH:26]=[N:27][CH:28]=4)[CH:3]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:23]=[CH:22][N:21]=1
Reactant: NC1=NC(c2cccc(Br)c2)(c2ccnc(Cl)c2)c2ccccc21
Reactant: OB(O)c1cncnc1
Product: NC1=NC(c2cccc(-c3cncnc3)c2)(c2ccnc(Cl)c2)c2ccccc21
Yield: 51 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-chloropyridin-4-yl)-1H-isoindol-3-amine (Example 120) as described in Example 67 Scheme #10, D in 51% yield using pyrimidine-5-boronic acid. 1H NMR (DMSO-d6) δ 9.18 (s, 1 H), 9.04 (s, 2 H), 8.31 (d, J=5.30 Hz, 1 H), 8.06-7.94 (m, 1 H), 7.89-7.81 (m, 1 H), 7.72-7.65 (m, 2 H), 7.57-7.45 (m, 4 H), 7.38 (dd, J=5.31, 1.52 Hz, 1 H), 7.36-7.33 (m, 1 H), 7.01 (br s, 2 H); MS (ESI) m/z 398 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][NH:5][C:6](=[O:16])[CH2:7][NH:8]C(OC(C)(C)C)=O.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:18]([OH:24])=[O:19].[CH3:1][O:2][C:3](=[O:17])[CH2:4][NH:5][C:6](=[O:16])[CH2:7][NH2:8]
Reactant: COC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CNC(=O)CN

Procedure:
N-tert-butoxycarbonyl glycyl glycine methyl ester 19 (9.20 g, 37.4 mmol) was dissolved in a 50% (v/v) solution of TFA in CH2Cl2 (120 mL) at room temperature. The reaction mixture was stirred for 1 h 30 min before the solvent and bulk of excess TFA were evaporated. The residue was washed with Et2O (3×50 mL) and CH2Cl2 (50 mL) and dried affording the title compound as a slightly reddish viscous liquid in quantitative yield and with spectral characteristics in accordance with literature data.9; δH (300 MHz; d6-DMSO) 8.91 (1H, t, J 6, NH), 8.20 (3H, br s, NH3+), 3.96 (2H, d, J 6, CαH2(Gly2)), 3.67-3.59 (5H, m, CαH2(Gly1)/OCH3); 13C-NMR (75 MHz, d6-DMSO): δC 169.9, 166.7, 158.7 (q, JCF 33), 116.4 (q, JCF 294), 54.9, 51.8, 40.6; m/z (ESI) 147.0769 (M+; C5H11N2O3 requires 147.0769)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C@@H:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=1)[OH:8])=[O:4].[H-].[Na+]>C1COCC1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C@@H:7]2[CH2:6][NH:5][C:3](=[O:4])[CH2:2][O:8]2)=[CH:10][C:11]=1[C:16]([F:19])([F:18])[F:17]
Reactant: O=C(CCl)NC[C@H](O)c1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CO[C@H](c2ccc(F)c(C(F)(F)F)c2)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
(R)-2-Chloro-N-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxyethyl)acetamide (2.45 g, 8.2 mmol) was dissolved in dry THF (30 mL). Under ice bath, sodium hydride (330 mg, 60% in mineral oil, 8.2 mmol) was added. The mixture was stirred at room temperature for 1 h and then warmed to room temperature and further stirred for 2 h. TLC indicated complete consumption of the starting material. The mixture was concentrated and extracted with ethyl acetate and water. The organic layer was dried and concentrated. The oily residue was dried in vacuum (2.25 g). This material was purified through ISCO flash column chromatography (80 g silica gel, methanol in dichloromethane, 0% to 5% gradient). The desired fraction was concentrated and crystallized from ether and hexanes to give (R)-6-(4-fluoro-3-trifluoromethyl-phenyl)-morpholin-3-one as a white solid (492 mg). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.41-3.64 (m, 2H) 4.24-4.59 (m, 2H) 4.81 (dd, J=9.06, 4.53 Hz, 1H) 6.51 (br. s., 1H) 7.17-7.27 (m, 1H) 7.51-7.62 (m, 1H) 7.66 (dd, J=6.61, 2.08 Hz, 1H). The mother liquor was concentrated to give a waxy material (230 mg), which TLC indicated it was mostly desired compound.
Reaction SMILES: [Si](C#N)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:13]1[C:18]([OH:19])=[C:17]([OH:20])[CH:16]=[C:15]([F:21])[C:14]=1[CH:22](O)[CH2:23][NH2:24].Cl>>[F:21][C:15]1[C:14]([CH2:22][CH2:23][NH2:24])=[CH:13][C:18]([OH:19])=[C:17]([OH:20])[CH:16]=1
Reactant: NCC(O)c1cc(O)c(O)cc1F
Agent: C[Si](C)(C)C#N
Agent: Cl
Agent: [Al+3]
Product: NCCc1cc(O)c(O)cc1F

Procedure:
FIG. 6 shows HPLC traces of a reaction mixture resulting from the incubation of dopamine with dopamine β-hydroxylase; (a) reaction at 1 min; (b) reaction at 1 h; and (c) coinjection of b with racemic NE. In less than 1 hour, a peak corresponding to (-)-NE (retention time 6.7 minutes) appeared when the enzyme mixture which contained dopamine as substrate was injected onto a chiral HPLC column; (+)-NE was not observed (FIG. 6). FIG. 7 shows HPLC traces of a reaction mixture resulting from the incubation of 6-fluorodopamine with dopamine β-hydroxylase: (a) reaction at 2 min; (b) reaction at 1 h; and (c) coinjection of b with racemic 6-FNE. An analogous result was obtained when 6-fluorodopamine was used as a substrate; a new HPLC peak at 18 minutes appeared (FIG. 7). Thus UV peak coeluted with the first radioactive peak collected from 6-[18F]FNE. Thus the levorotatory isomers of both NE and 6-FNE elute before their respective dextrorotatory enantiomers. This order of elution was also recently reported by Maeda et al., Appl. Radiat. Isot., 41, 463 (1990) the disclosure of which is incorporated by reference herein, for [11C]octopamine enantiomers when a Crownpak CR(+) HPLC column was used.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][O:26][CH3:27]>C(#N)C>[F:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:24][CH2:25][O:26][CH3:27])[CH2:12][CH2:13]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15]
Reactant: COCCBr
Reactant: CC(=O)c1cccc(C2CCNCC2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCC(c2cccc(C(C)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 1-(2-fluoro-3-piperidin-4-ylphenyl)ethanone (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-bromo-2-methoxyethane (0.01 g). MS m/z (rel. intensity, 70 eV) 279 (M+, 1), 235 (16), 234 (bp), 163 (3), 133 (4).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.Br[CH:17]([CH3:21])[C:18]([NH2:20])=[O:19].C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH:17]([CH3:21])[C:18]([NH2:20])=[O:19]
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Reactant: CC(Br)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C(N)=O)n1c(C(F)F)cc2c(Cl)c(C#N)ccc21
Temperature: 90 °C

Procedure:
Synthesized as described in Example 4 using 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile, 2-bromo-propionamide (2 eq) and Cs2CO3 (2 eq). After heating at 90° C. for 4 h, additional 2-bromo-propionamide (2 eq) and Cs2CO3 (2 eq) were added and the reaction mixture heated at 110° C. for 15 h: MS (ES) m/z 298 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])[CH3:11].C[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:11]/[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccccn1
Reactant: O=Cc1ccc(Br)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(/C=C/c1ccc(Br)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To an ethanol (500 mL) solution of 25.3 g (137 mmol) of 4-bromobenzaldehyde, 15.6 mL (139 mmol) of 2-acetylpyridine and 25.3 g of sodium methoxide (28% methanol solution, 131 mmol) were added under argon atmosphere, and the mixture was stirred at room temperature for 8 h. A formed solid was collected by filtration and washed with methanol to obtain 13.1 g (yield: 33%) of (E)-3-(4-bromophenyl)-1(2-pyridyl)-2-propen-1-one as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=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].N1CCCCC1.Cl>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:12][C:13]1=[O:21]
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1cccc2c1CCC2=O
Agent: Cl
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1cccc2c1CCC2=C1C(=O)Nc2ccccc21
Temperature: 130 °C
Yield: 44.8 %

Procedure:
A mixture of 0.5 g 4-methyl-1-indanone, 1.37 g oxindole and 3 ml piperidine in 5 ml dimethylforamide was heated in a sealed tube at 130° C. for 3 days to yield a reddish-black suspension. The mixture was added to 1N hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine dried over magnesium sulfate and concentrated. The resulting solid was precipitated from ethyl acetate/hexanes (2×) followed by methylene chloride/hexanes to afford 400 mg of 3-(4-methyl-indan-1-ylidene)-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][OH:10])=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:19]([C:21]([CH2:28][CH3:29])([C:25](Cl)=[O:26])[C:22](Cl)=[O:23])[CH3:20]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[C:22](=[O:23])[C:21]([CH2:28][CH3:29])([CH2:19][CH3:20])[C:25](=[O:26])[O:10]2)=[O:8])=[CH:11][CH:12]=1
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Reactant: COc1ccc(C(=O)NO)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1(CC)C(=O)ON(C(=O)c2ccc(OC)cc2)C1=O

Procedure:
A mixture consisting of 1.67 g (0.0107 mol) of 4-methoxybenzohydroxamic acid, mp 158-159° C (dec.)(lit. mp 156-157° C. (dec.), Beilstein Handbook of Organic Chemistry, series H, vol 10, p. 170), 5 ml of pyridine, and 100 ml of methylene chloride was prepared in a 250 ml round bottom flask. The mixture was cooled in an ice bath, and 2.107 g (0.0107 mol) of diethylmalonyl chloride was added dropwise over a 15 minute period with stirring. The reaction mixture was stirred for 2 hours at room temperature after which time all the hydroxamic acid had dissolved. The solution was extracted two times with 50 ml portions of water, three times with 50 ml portions of 5% hydrochloric acid, and two times with 50 ml portions of 5% sodium carbonate. The methylene chloride was dried (MgSO4) and evaporated to dryness under reduced pressure to give 2.19 g (70.4%) of crude 2-(4-methoxybenzoyl)-4,4-diethylisoxazolidine-3,5-dione as a solid residue Recrystallization of the solid from absolute ethanol gave pure 2-(4-methoxybenzoyl)-4,4-diethylisoxazolidine-3,5-dione as a white solid: mp 116-118° C.; IR (Nujol) 1810 (s,C=0), 1750 (s, C=0), 1690 cm-1 (s, C=0); 1H NMR (400 MHz, CDCl3) 7.83 (d, 2H), 6.98 (d, 2H), 3.89 (t, 3H), 1.95 (q, 4H), 1.01 (t, 6H); High resolution MS, calc'd for: C15H17NO5 : 291.1102. Found: 291.1106. Anal Calc'd for: C15H17NO5C, 61.84; H, 5.88; N, 4.81. Found: C, 61.83; H, 5.76; N, 4.76.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12].[H-].[Na+].F[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: CCOC(=O)c1cc2c(Cl)ccc(O)c2n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)ccc(Oc3cccc([N+](=O)[O-])c3)c2n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
After 0.50 g (1.97 mmol) of ethyl 4-chloro-7-hydroxy-1-methyl-2-indolecarboxylate was added to a suspension of 0.16 g (3.94 mmol) of 60% sodium hydride and 10 ml of dimethylformamide, the suspension was stirred at room temperature for 30 minutes. Then 0.28 g (1.9.7 mmol) of 1-fluoro-3-nitrobenzene was added to the solution at room temperature followed by stirring for 3 hours at 150° C. After cooling, the reaction mixture was poured onto ice water. The resulting mixture was then extracted three times with ethyl acetate. The combined extracts were washed with saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was isolated and purified by silica gel column chromatography to give 0.18 g (24.3%) of ethyl 4-chloro-1-methyl-7-(3-nitrophenoxy)-2-indolecarboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[CH2:17][C:18]1C=CC2C(=CC=CC=2)[CH:19]=1.[H-].[Na+].SCC(OCC)=O>O1CCCC1>[CH:14]1[C:15]2[C:2](=[CH:1][CH:17]=[CH:18][CH:19]=2)[CH:3]=[CH:4][C:5]=1[CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCOC(=O)CSCc1ccc(C)cc1
Agent: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CSCc1ccc2ccccc2c1

Procedure:
The procedure is as in Example 29 for the preparation of ethyl (4-methylbenzylthio)acetate, starting with 2-bromomethylnaphthalene (20 g), sodium hydride (5.1 g) in a 50% strength dispersion in liquid paraffin and ethyl 2-mercaptoacetate (10.9 g) in tetrahydrofuran (200 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (80:20 by volume) as eluent, ethyl (2-naphthylmethylthio)acetate (12 g) is obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:34][OH:35])=[C:19]([N:23]3[C:27]4[N:28]=[CH:29][N:30]=[CH:31][C:26]=4[C:25]([C:32]#[N:33])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:38])C.O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:34][OH:35])=[C:19]([N:23]3[C:27]4[N:28]=[CH:29][N:30]=[CH:31][C:26]=4[C:25]([C:32]([NH2:33])=[O:38])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5cncnc54)c3CO)ncc2c1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5cncnc54)c3CO)ncc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
In a 10 mL round-bottomed flask, 7-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (39 mg, 83.2 μmol, Eq: 1.00) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (1 mg, 2.33 μmol, Eq: 0.0280) were combined with Ethanol (2 ml) and Water (1 ml) to give a colorless solution. The reaction mixture was heated to 80° C. and stirred for 2 h. The reaction mixture was diluted with DCM. The reaction mixture was filtered through glass fiber paper. HPLC purification done to obtain 7-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid amide (33 mg, 66%, [M+H]+ 487).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][C:20]=1[Cl:33].N1C(C)=CC=CC=1C>CN1C(=O)CCC1>[Cl:33][C:20]1[CH:21]=[C:22]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:24][C:19]=1[CH2:18][N:9]1[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])=[N:8]1
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: Clc1cc(OCc2ccccc2)ccc1CBr
Solvent: CN1CCCC1=O
Solvent: Cc1cccc(C)n1
Product: O=C(Nc1ccn(Cc2ccc(OCc3ccccc3)cc2Cl)n1)c1c(F)cccc1F
Temperature: 160 °C

Procedure:
To a solution of 2,6-difluoro-N-(1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 9)(0.961 g, 4.31 mmol) and 1-(bromomethyl)-2-chloro-4-[(phenylmethyl)oxy]benzene (1.21 g, 3.88 mmol) in anhydrous NMP (15 ml) was added 2,6-lutidine (0.5 ml, 4.29 mmol, Aldrich). The reaction vessel (20 ml) was sealed and heated in Biotage Initiator microwave to 160° C. for 30 min. After cooling the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate (120 ml) and ethyl acetate (100 ml). The phases were separated and the aqueous phase extracted with ethyl acetate (50 ml). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (50 ml), dried (MgSO4), filtered and the solvent removed in vacuo to leave a red oil (2.84 g). The residue was loaded in dichloromethane and purified on silica (100 g×2) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (0.778 g); LCMS: (System 4) MH+=454, tRET=3.35 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8](/[C:10](=N/[S@@](C(C)(C)C)=O)/[CH2:11][CH2:12][CH3:13])[CH:9]=1)([O-:3])=[O:2].[C:21]([O:24][CH3:25])(=[O:23])[CH3:22]>>[CH3:25][O:24][C:21](=[O:23])[CH2:22][CH:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1)[CH2:11][CH2:12][CH3:13]
Reactant: COC(C)=O
Reactant: CCC/C(=N\[S@](=O)C(C)(C)C)c1cccc([N+](=O)[O-])c1
Product: CCCC(CC(=O)OC)c1cccc([N+](=O)[O-])c1

Procedure:
Starting from (R)-2-methyl-propane-2-sulfinic acid [1-(5-nitro-phenyl)-(E)-butylidene]-amide and methyl acetate, the product (S)-3-(R)-2-methyl-propane-2-sulfinylamino)-3-(3-nitro-phenyl)-hexanoic acid methyl ester was obtained as a white solid. MS (ESI): m/z=371.4 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([NH:13][C@H:14]([C:16]([N:18]1[CH2:32][CH2:31][CH2:30][C@H:19]1[C:20]([O:22]CC1C=CC=CC=1)=[O:21])=[O:17])[CH3:15])[CH2:3][CH2:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CO.C(O)C.[OH-].[Na+]>O>[O:1]=[C:2]([NH:13][C@H:14]([C:16]([N:18]1[CH2:32][CH2:31][CH2:30][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15])[CH2:3][CH2:4][C:5](=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C[C@H](NC(=O)CCC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CO
Product: C[C@H](NC(=O)CCC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 17 h

Procedure:
A mixture of the phenylmethyl ester product from part (a) (1.3 g., 3.0 mmole), methanol (3.5 ml.), ethanol (3.5 ml.), water (3.5 ml.), and 1N aqueous sodium hydroxide solution (3.5 ml., 3.5 mmole) is stirred at 25° for 17 hours, after which it is partially concentrated by rotary evaporation (to remove volatile alcohols). The solution is then diluted with water and washed with ethyl acetate (the ethyl acetate layer is discarded). The aqueous layer is acidified with hydrochloric acid and extracted twice with ethyl acetate. The extracts are combined, dried, and concentrated to give 1.0 g. of the desired product as a pale yellow oil. This oil is dissolved in water (150 ml.), filtered through charcoal, and lyophilized to give 500 mg. of 1-[N-(1,4-dioxo-4-phenylbutyl)-L-alanyl]-L-proline as a fluffy white powder. TLC (Rf 0.4 on silica gel, 1:1 methanol:ethyl acetate). [α]D =-80° (1% chloroform).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[H-].[Na+].[CH2:17]([O:19]C(OCC)CBr)[CH3:18].Cl.[OH-].[Na+]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][CH2:18][CH:17]=[O:19])=[CH:9][CH:8]=1
Reactant: OCc1ccc(-c2ncccn2)cc1
Reactant: CCOC(CBr)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=CCOCc1ccc(-c2ncccn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.7 %

Procedure:
A solution of the product from step A (559 mg, 3.00 mmol) in DMF (4 mL) was added dropwise to a suspension of sodium hydride (60% in mineral oil, 144 mg, 3.60 mmol) at 0° C. The solution was stirred for 30 min at 0° C., bromoacetaldehyde diethyl acetal (0.55 mL, 3.66 mmol) and tetrabutylammonium iodide (111 mg, 0.30 mmol) were added, and the resulting mixture was stirred at 70° C. for 12 h. Additional sodium hydride (60% in mineral oil, 70 mg, 1.75 mmol) and bromoacetaldehyde diethyl acetal (0.55 mL, 3.66 mmol) were added and heating at 70° C. was continued for 12 h. The reaction mixture was concentrated, the residue was diluted with water and extracted with ethyl acetate, the combined organic layers were dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 1:1 hexane/ethyl acetate) gave material which was taken up in ethanol (2 mL) and 10% aq. HCl (10 mL) and stirred for 12 h. The reaction mixture was made basic with aq. NaOH, extracted with ethyl acetate, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 1:1 hexane/ethyl acetate) provided 80 mg (12%) of the title compound. MS 229 (M+H)+.